Conditions: Arthritis, Rheumatoid
Keywords: Post-marketing Phase 4 Open-label Safety Surveillance CP690550 Xeljanz oral treatment
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4372
Healthy volunteers: no

Brief summary:
This post-marketing study is designed to compare the safety of tofacitinib versus TNF inhibitor with respect to major cardiovascular adverse events and malignancies, excluding non-melanoma skin cancers when given to subjects with rheumatoid arthritis. Other safety events, including non-melanoma skin cancers, hepatic events, infections, and efficacy parameters will be collected and evaluated in the study.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: TNF inhibitor Arm - adalimumab will be used in US, Canada and Puerto Rico; etanercept will be used in all other countries.

Interventions: intervention 1: tofacitinib intervention 2: tofacitinib intervention 3: adalimumab intervention 4: etanercept
Intervention descriptions: intervention 1: Oral tablet, 5 mg BID intervention 2: Oral tablet, 10 mg BID intervention 3: Pre-filled syringe, 40 mg subcutaneous injection, every other week intervention 4: Pre-filled syringe, 50 mg subcutaneous injection, every week

Protocol document:
Prot_000.pdf: 
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PHASE 3B/4 RANDOMIZED SAFETY ENDPOINT STUDY OF 2 DOSES OF 
TOFACITINIB IN COMPARISON TO A TUMOR NECROSIS FACTOR (TNF)
INHIBITOR IN SUBJECTS WITH RHEUMATOID ARTHRITIS
Compound:
CP-690,550-10
Compound Name:
Tofacitinib citrate
US IND Number:
European Clinical Trial Database 
(EudraCT) Number:
2013-003177-99
Protocol Number:
A3921133
Phase:
Phase 3b/4
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, 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.
CCI


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Document History
Document
Version Date
Summary of Changes
Original protocol
25-Apr-2013
N/A
Amendment 1
10-Jul-2013
Prior to initiation of the study and in response to 
US FDA comments and recommendations, the 
following changes were made to the study
protocol:
1.
Reduced the study from 8 years to 5 years.
2.
Increased N from 3900 to approximately 
4000.
3.
Enriched the study population to include 
only patients ≥50 yrs with 6 painful/tender 
joints and 6 swollen joints and who have at 
least one risk factor for cardiovascular 
disease.
4.
Eliminated the double-blind substudy (all 
drug supplies are open-label).
5.
Changed the comparator from all 
adalimumab to adalimumab in US, Puerto 
Rico and Canada with etanercept in the rest 
of world.
6.
Removed the need for blinded joint 
assessors.
7.
Have all patients on background 
methotrexate.
8.
Allow prior use of biologic DMARDs with 
appropriate washout, unless intolerant or 
unresponsive to previous use.
9.
Added Section ‘Immunizations’ live or live-
attenuated vaccines should not be given 
concurrently with study medication.
10. Eliminated the 2-week visit.
11. Reduced joint counts from 66/68 to 28 at 
every visit.
12. Aligned the contraceptive requirements with 
the removal of methotrexate as a 
comparator.
13. Removed the following PROs: MOS Sleep 
Scale, FACIT-Fatigue, and RA Healthcare 
Resource Utilization Questionnaires and 
reduced the frequency of SF-36, EuroQol 
EQ-5D, and Work Productivity and Activity 
Impairment (WPAI) Questionnaires.


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Document
Version Date
Summary of Changes
14. Eliminated routine urinalysis testing, except 
at Screening Visit.
15. Eliminated routine ECGs, except at 
Screening Visit and End of Study Visit.
16. Removed laboratory testing not used in 
safety evaluation of either tofacitinib or 
TNFi’s; CRP will not be blinded.
17. Monitoring and discontinuation criteria is 
aligned with the US approved labeling.
18. There will be no interim analyses of the 
data, only end of study analysis.
19. The study will be stopped on 
recommendation of the Steering Committee 
and only after consultation with the US 
FDA.
20. The Steering Committee will maintain 
Performance Standards, review metrics and 
implement corrective actions.
Amendment 2
16-Aug-2013
1.
Typographical corrections and clarifications
2.
Added Japan-specific screening and 
monitoring requirements.
3.
Added reference for endpoint definitions 
and clarification regarding endpoint 
composite for MACE.
4.
Added cholestyramine or activated charcoal 
elimination procedure to reduce leflunomide 
washout to 4 weeks.
Amendment 3
20-Nov-2013
1.
Typographical corrections and 
clarifications.
2.
Changes to reporting processes for the 
primary safety endpoints to limit their 
inclusion in AE tables reviewed outside the 
blinded Steering Committee.
3.
Addition of a washout period for rituximab 
as a prohibited concomitant DMARD.
4.
Removed Japan-specific screening and 
monitoring requirements as Japan will not 
be participating in this study.
Amendment 4
30-Jan-2014
1.
Typographical corrections.
2.
Addition of voriconazole as a prohibited 
concomitant medication.
3.
Clarification of the role of the OTIS registry 
in the US only and follow-up of 
pregnancies.


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Document
Version Date
Summary of Changes
4.
Remove the requirement for 
adalimumab/etanercept dispensing at Visit 
2, as drug supply to sites will be sufficient 
to supply drug at Visit 1 and then at Visit 3.
5.
Clarification of the respective roles of the 
Steering Committee and the DMC and 
provision to allow the DMC to review 
adjudicated and non-adjudicated primary 
endpoint data in an unblinded manner at the 
explicit request of the DMC.
Amendment 5 
30-Mar-2014
1.
In Section 1.2 added reference to 
Section 7.8 of the XELJANZ Investigator 
Brochure as the section that contains 
reference safety information. 
2.
Added Appendix 4 with Sweden-specific 
text for exclusion criteria, triggered event 
criteria, and the addition of the Overall 
Risk-Benefit Assessment (ORBA) with 
references to the appendix in the body of the 
protocol at the request of the Swedish 
competent authority.
Amendment 6
30-May-2014
1.
Added Appendix 5 with and Czech 
Republic, Spain and United Kingdom-
specific text for exclusion criteria, triggered 
event criteria, and additional laboratory 
testing (lymphocyte subset testing) at the 
request of the respective competent 
authorities for each country.
Amendment 7
12-Jan-2015
1.
Added Appendix 6 with Canada specific 
text regarding the use of 2 methods of 
contraception, one highly effective and one 
effective method as per the request of the 
competent authority.
Amendment 8
1.
Reduced treatment in the tofacitinib 10 mg 
BID arm to 5 mg BID in response to a 
recommendation from the Data Safety 
Monitoring Board for a safety signal.
2.
Added requirement for all subjects to be 
provided a consent addendum, which they 
will be required to sign agreeing to continue 
in the study.
3.
Deep vein thrombosis, pulmonary emboli, 
arterial thrombosis and arterial emboli were 
added to the CV adjudication charter and 
are noted as additional events to be 
adjudicated.


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Document
Version Date
Summary of Changes
4.
Added mandatory revised privacy text.
5.
Removed Appendix 4 as no subjects were 
screened or randomized in Sweden and 
enrollment is closed.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.


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PROTOCOL SUMMARY
As a commitment to the United States Food and Drug Administration (US FDA), this Post 
Authorization Safety Study (PASS) will evaluate the safety of tofacitinib 5 mg twice daily 
(BID) and tofacitinib 10 mg BID compared to a tumor necrosis factor inhibitor (TNFi). 
The primary objective of this endpoint study is to evaluate the safety of tofacitinib at two 
doses versus a TNFi; the co-primary endpoints are adjudicated major adverse cardiovascular 
events (MACE) and adjudicated malignancies excluding non-melanoma skin cancers during 
study participation.
The study will be declared complete when all of the following conditions are met:

At least 1500 subjects have been followed for 3 years.

The targeted number of MACE is observed.

The targeted number of malignancies, excluding non-melanoma skin cancers, is
observed.
To achieve all of these conditions, it is expected that the study will include approximately 
4000 subjects, recruited over 3 years and the total duration of the study will be approximately 
5 years after the first subject is randomized.  
The Steering Committee will consider the ongoing accumulation of the adjudicated primary 
endpoint events and performance standard metrics and may determine that sufficient events 
have occurred to assess the primary objectives of the study or that it is not feasible to 
continue the trial in pursuit of these objectives.  These determinations by the Steering 
Committee will be made in accordance with pre-specified rules documented in the Steering 
Committee Charter and in the Statistical Analysis Plan and following consultations with the 
US FDA, and could result in recommendations for changes to the study design, including 
changes in number of subjects studied or duration of study.  
Subject population
Adult subjects who are 50 years of age or older, with moderately or severely active 
rheumatoid arthritis who have had an inadequate response to methotrexate alone and who 
have certain risk factors for cardiovascular disease will be enrolled in this study. A minimum 
of approximately 4000 subjects will be enrolled in the study.
Assessments
The following assessments will be used to evaluate safety:

Changes in physical assessments, including weight and vital signs.

AE reporting, incidence and severity.


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
Incidence and severity of safety laboratory abnormalities.

Adherence to contraceptive use.

Adherence to protocol requirements.

Concomitant medication review.

Review of eligibility to continue study drug.
The following assessments will be used to evaluate efficacy:

28 joint counts.

Patient Global Assessment.

Patient Assessment of Pain.

Physician Global Assessment.

C-reactive Protein (CRP).

A number of patient reported outcomes, including the Health Assessment 
Questionnaire – Disability Index (HAQ-DI).
Treatments
All subjects will be enrolled on their previously prescribed dose of methotrexate and will be 
randomly assigned to one of three active treatment arms in the study:

Tofacitinib 5 mg BID.

Tofacitinib 10 mg BID.*

TNFi: adalimumab 40 mg subcutaneous (SC) injection every other week in the 
United States, Puerto Rico and Canada; etanercept 50 mg SC injection weekly in all 
other countries.
* In response to new safety information about tofacitinib that was provided to Study 
A3921133 investigators on 19 February 2019, investigators were notified to verbally inform 
subjects randomized to tofacitinib 10 mg BID to reduce the dose of tofacitinib to 5 mg BID 
within 7 calendar days of this notification, secure their verbal agreement to continue in the 
study, and if they agreed, reduce their dose of tofacitinib to 5 mg BID for the remainder of 
the study. Tofacitinib is supplied as 5 mg tablets, which allowed subjects to decrease from 
their previous dose of 2 tablets twice daily to 1 tablet twice daily. 


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Adjustments to methotrexate and other background medications will be allowed during the 
study with provisions to allow subjects who are not adequately treated with study drug to 
switch to standard of care while remaining in the study. 
The study will be open-label and the randomization scheme for the study population 
(approximately 4000 subjects) will be in a ratio of 1:1:1 with approximately 1300 subjects 
randomized to tofacitinib 5 mg BID; approximately 1300 subjects randomized to tofacitinib 
10 mg BID (subjects are switched to 5 mg BID per Amendment 8); and approximately 1300 
subjects randomized to a TNFi.
Safety Analysis
The safety analysis will include all subjects in the study. 
The primary statistical safety objective is the estimation of the hazard ratios relative to the 
TNF inhibitor control for the two tofacitinib doses combined and for each dose of tofacitinib 
separately for the co-primary events of major adverse cardiovascular events (MACE) and 
malignancies excluding non-melanoma skin cancers.  Analyses of primary safety endpoints 
will be based upon adjudicated events.
Both total time (ITT) and on treatment analyses of the main safety endpoints will be 
conducted. The on treatment analysis for MACE will censor subjects who cross over from 
tofacitinib or adalimumab to standard of care at 60 days after standard of care is initiated. 
The principal analysis for malignancies will not censor for subjects crossing to standard of 
care (ie, will be the total time analysis).  
Secondary safety endpoints will be summarized according to treatment received at the time 
of the event. 
For the purposes of statistical analyses, subjects who were randomized to tofacitinib 10 mg 
BID will be maintained in the tofacitinib 10 mg BID treatment arm after reducing the dose of 
tofacitinib to 5 mg BID.


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SCHEDULE OF ACTIVITIES BY VISIT (SCREENING – MONTH 6)
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to Study Procedures and Assessments sections of the protocol for detailed information 
on each procedure and assessment required for compliance with the protocol.
The investigator may schedule unplanned visits in addition to those listed on the schedule of 
activities, in order to conduct assessments required to protect the well-being of the subject.
Protocol Activities –
Screening to Month 6
Screen
Visit 1 
Day 1
Visit 2 
Monthf 2
Visit 3 
Monthf
3
Visit 4 
Monthf 6
Visit Windows (see Section 6.2.1 for further 
detail)
NA
See 
6.2.1
2 
weeks
1.5 
months
1.5 
months
Informed Consent
X
Medical History and Confirm Diagnosis
X
Physical Examination, including height
X
Assessment of New Physical Findings
X
X
X
X
Weight, Vital Signs
X
X
X
X
X
Inclusion/Exclusion criteria
X
X
Blood Chemistrya, Hematologya
X
X
X
X
X
C-reactive Protein (CRP)
X
X
X
X
X
Banked Biospecimens
X
HIV Serology, HBsAg, HBcAb, HBsAbb
X
HCV Ab, HCV RNAc
X
Lipid Profile (fasting)
X
X
X
Pregnancy testd
X
X
X
X
X
QuantiFERON Gold®™In-Tube Test
X
Rheumatoid Factor
X
Anti-cyclic citrullinated peptide (anti-CCP)
X
Urinalysis
X
Chest X-ray
X
ECG
X
Randomization  
X
Study Medication Dispensing
X
X
X
Contraceptive Use Documentation
X
X
X
X
X
Joint Count (28)
X
X
X
X
X
Patient Assessment of Arthritis Pain
X
X
X
X
Patient Global Assessment of Arthritis
X
X
X
X
Physician Global Assessment of Arthritis
X
X
X
X
HAQ-DI
X
X
X
X
SF-36 (Version 2, Acute)
X
X
X
EuroQol EQ-5D 
X
X
X
Work Productivity and Activity Impairment 
(WPAI) 
X
X
X
Safety Assessment/ AE Reporting
X
X
X
X
Concomitant Medication Review
X
X
X
X
X
End of Study Assessment
a.
Re-testing of abnormal laboratories may be required (see Section 7.15).
b.
See Exclusion Criteria 4e and 4f for details. 
c.
See Exclusion Criteria 4g for details.
d.
Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations.
e.
History of concomitant medications at Screening includes a history of prior DMARD treatment. 
f.
Calendar months.


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SCHEDULE OF ACTIVITIES BY VISIT (MONTH 9 – END OF STUDY)
Visits are outlined through Month 60, but will continue sequentially until the end of study is 
declared, at which time all subjects will be required to return for an End of Study Visit.
Protocol Activities –
Months 9 to 60 and End of Study 
Follow-up Visit
Visits 5, 
9, 13, 17,
21 
[Monthsf
9, 21, 
33,45, 
57]
Visit 6, 
10, 14, 
18, 22 
[Monthsf
12, 24, 
36, 48, 
60]
Visits 7, 
11, 15, 
19 
[Monthsf
15, 27, 
39, 51]
Visits 8, 
12, 16, 
20 
[Monthsf
18, 30, 
42, 54]
End of 
Study 
Visit 
End of 
Study 
Follow 
Upg
Visit Windows (see Section 6.2.1)
1.5 
months
1.5 
months
1.5 
months
1.5 
months
1.0
months
+0.5 
months
Assessment of New Physical Findings
X
X
X
X
X
X
Weight, Vital Signs
X
X
X
X
X
X
Blood Chemistrya, Hematologya
X
X
X
X
X
C-reactive Protein (CRP)
X
X
X
X
X
Banked Biospecimens
Xb
X
Lipid Profile (fasting)
X
X
Pregnancy testc
X
X
X
X
X
X
QuantiFERON Gold®™ In-Tube Test
Xd
Chest X-ray
Xe
Xe
ECG
X
Study Medication Dispensing
X
X
X
X
Contraceptive Use Documentation
X
X
X
X
X
X
Joint Count (28)
X
X
X
X
X
Patient Assessment of Arthritis Pain
X
X
X
X
X
Patient Global Assessment of Arthritis
X
X
X
X
X
Physician Global Assessment of Arthritis
X
X
X
X
X
HAQ-DI
X
X
X
X
X
SF-36 (Version 2, Acute)
X
X
EuroQol EQ-5D
X
X
Work Productivity and Activity 
Impairment (WPAI) Questionnaire
X
X
Safety Assessment/ AE Reporting
X
X
X
X
X
X
Concomitant Medication Review
X
X
X
X
X
X
End of Study Assessment
X
a.
Re-testing of abnormal laboratories may be required (see Section 7.15).
b.
Month 12 visit only.
c.
Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations. 
d.
QFT is not performed in subjects who had a positive test previously and were adequately treated for latent TB, subjects 
newly testing positive for latent TB with negative CXR and no evidence of active disease are required to start a 
9 month treatment course of isoniazid to continue in the study.
e.
Only for subjects testing positive to QFT at annual visit.
f.
Calendar Months.
g.
Occurs 28 days after End of Study visit. 


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................16
LIST OF FIGURES .................................................................................................................16
APPENDICES .........................................................................................................................16
1. INTRODUCTION ...............................................................................................................17
1.1. Indication.................................................................................................................17
1.2. Background and Rationale ......................................................................................17
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................19
2.1. Objectives................................................................................................................19
2.1.1. Safety..........................................................................................................19
2.1.2. Efficacy.......................................................................................................20
2.2. Endpoints.................................................................................................................20
2.2.1. Safety Endpoints.........................................................................................21
2.2.1.1. Co-Primary Safety Endpoints....................................................21
2.2.1.2. Secondary Safety Endpoints......................................................21
2.2.2. Efficacy Endpoints......................................................................................22
3. STUDY DESIGN.................................................................................................................22
4. SUBJECT SELECTION......................................................................................................24
4.1. Inclusion Criteria.....................................................................................................24
4.2. Exclusion Criteria....................................................................................................27
4.3. Randomization Criteria ...........................................................................................30
4.4. Life Style Guidelines...............................................................................................30
4.4.1. Non-Pharmacologic Interventions..............................................................30
4.4.2. Vaccine Guidelines.....................................................................................30
4.4.3. Dietary Supplements...................................................................................30
4.4.4. Surgery........................................................................................................31
4.4.5. Reproductive Status of Women Subjects and Partners of Male 
Subjects............................................................................................................31
4.5. Sponsor Qualified Medical Personnel.....................................................................32
4.6. Rater Qualifications.................................................................................................32
5. STUDY TREATMENTS.....................................................................................................32
5.1. Allocation to Treatment ..........................................................................................32


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5.2. Breaking the Blind ..................................................................................................33
5.3. Drug Supplies..........................................................................................................33
5.3.1. Formulation and Packaging........................................................................33
5.3.1.1. Open-Label Study Medication ..................................................33
5.3.2. Preparation and Dispensing........................................................................34
5.3.3. Administration............................................................................................34
5.3.4. Medication Errors .......................................................................................34
5.3.4.1. Tofacitinib Overdosage.............................................................35
5.3.4.2. Adalimumab Overdosage..........................................................35
5.3.4.3. Etanercept Overdosage..............................................................35
5.3.5. Compliance.................................................................................................36
5.4. Drug Storage and Drug Accountability...................................................................36
5.5. Concomitant Medication(s).....................................................................................38
5.5.1. Allowed Concomitant Medications............................................................38
5.5.1.1. Methotrexate..............................................................................38
5.5.1.2. Folate Supplementation.............................................................38
5.5.1.3. Treatment for Latent Tuberculosis............................................38
5.5.1.4. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and 
Other Analgesics ...............................................................................39
5.5.1.5. Corticosteroid Use.....................................................................39
5.5.2. Disallowed Concomitant Medications........................................................39
5.5.2.1. Disease Modifying Antirheumatic Drugs (DMARDs) .............39
5.5.2.2. Immune-Modulating Biologic Products....................................40
5.5.2.3. CYP3A4 and CYP2C19 Inhibitors and CYP3A4 Inducers ......40
5.5.2.4. Immunizations...........................................................................41
5.6. Rescue Therapy.......................................................................................................41
5.6.1. Changes in Assigned Drug .........................................................................41
6. STUDY PROCEDURES .....................................................................................................42
6.1. Screening Visit ........................................................................................................42
6.2. Study Period ............................................................................................................43
6.2.1. Visit Windows ............................................................................................44
6.3. Visit 1, Baseline Visit (Day 1) ................................................................................44


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6.4. Follow-up Visits......................................................................................................45
6.4.1. Visit 2 (Month 2) ........................................................................................45
6.4.2. Visit 3 (Month 3) ........................................................................................46
6.4.3. Visit 4 (Month 6) ........................................................................................47
6.4.4. Visits 5, 7, 9, 11, 13, 15, 17, 19, 21, etc, as Required Through the 
End of the Study (Calendar Months 9, 15, 21, 27, 33, 39, 45, 51, 57, etc)......48
6.4.5. Visits 6, 10, 14, 18, 22, etc, as Required Through the End of the 
Study (Months 12, 24, 36, 48, 60, etc.) – Annual Study Visits .......................48
6.4.6. Visits 8, 12, 16, 20, etc, as Required Through the End of the Study 
(Months 18, 30, 42, 54, etc).............................................................................49
6.5. End of Study Visit...................................................................................................50
6.6. End of Study Follow-up Visit .................................................................................51
6.7. Subject Withdrawal.................................................................................................51
7. ASSESSMENTS..................................................................................................................52
7.1. Physical Examination..............................................................................................52
7.2. Assessment of New Physical Findings and Safety Assessments ............................52
7.3. Chest Radiograph ....................................................................................................53
7.4. Electrocardiogram ...................................................................................................53
7.5. Assessments of Disease Activity.............................................................................53
7.6. Joint Counts.............................................................................................................54
7.6.1. Tender/Painful Joint Count (28 Joint Count)..............................................54
7.6.2. Swollen Joint Count (28 Joint Count) ........................................................54
7.7. Patient Assessment of Arthritis Pain.......................................................................54
7.8. Patient Global Assessment of Arthritis ...................................................................55
7.9. Physician Global Assessment of Arthritis...............................................................55
7.9.1. Health Assessment Questionnaire – Disability Index (HAQ-DI)...............55
7.9.2. SF-36 Health Survey (Version 2, Acute)....................................................55
7.9.3. EuroQol EQ-5D Health State Profile (Health-related Quality of Life)......55
7.9.4. Work Productivity and Activity Impairment (WPAI) Questionnaire.........55
7.9.5. C-reactive Protein (CRP)............................................................................56
7.10. Clinical Laboratory Tests......................................................................................56
7.11. Pregnancy Testing.................................................................................................58
7.12. Pregnancies Occurring During Study....................................................................58


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7.13. Banked Biospecimens ...........................................................................................58
7.13.1. Markers of Drug Response.......................................................................58
7.13.2. Additional Research..................................................................................60
7.14. Suicidality Assessment..........................................................................................60
7.15. Triggered Requirements for Monitoring...............................................................60
8. ADVERSE EVENT REPORTING......................................................................................63
8.1. Adverse Events........................................................................................................63
8.2. Reporting Period .....................................................................................................63
8.3. Definition of an Adverse Event...............................................................................64
8.4. Infections.................................................................................................................64
8.4.1. Treated Infections.......................................................................................65
8.4.2. Serious Infections .......................................................................................65
8.5. Abnormal Test Findings..........................................................................................65
8.6. Serious Adverse Events...........................................................................................66
8.6.1. Protocol-Specified Serious Adverse Events...............................................66
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................67
8.7. Hospitalization ........................................................................................................69
8.8. Severity Assessment................................................................................................70
8.9. Causality Assessment..............................................................................................70
8.10. Exposure During Pregnancy..................................................................................71
8.11. Withdrawal Due to Adverse Events (See Also Section on Subject 
Withdrawal)...............................................................................................................72
8.12. Eliciting Adverse Event Information ....................................................................72
8.13. Reporting Requirements........................................................................................72
8.13.1. Serious Adverse Event Reporting Requirements .....................................72
8.13.2. Non-Serious Adverse Event Reporting Requirements .............................73
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities ...................73
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................73
9.1. Sample Size Determination.....................................................................................74
9.2. Safety Analysis........................................................................................................74
9.2.1. Analysis of Primary Safety Endpoint .........................................................74
9.2.2. Analysis of Secondary Safety Endpoints....................................................75


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9.3. Efficacy Analysis ....................................................................................................76
9.4. Interim Analysis ......................................................................................................76
9.5. Data Monitoring Committee ...................................................................................76
9.6. Steering Committee.................................................................................................77
9.7. External Adjudication/Review Committees............................................................78
9.7.1. Hepatic Event Review Committee..............................................................78
9.7.2. Opportunistic Infection Review Committee...............................................78
9.7.3. Cardiovascular Safety Endpoint Adjudication Committee.........................79
9.7.4. Malignancy Adjudication Committee and Histopathology Over-read.......80
9.8. Additional Safety Event Review Committees.........................................................80
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................81
11. DATA HANDLING AND RECORD KEEPING .............................................................81
11.1. Case Report Forms/Electronic Data Record .........................................................81
11.2. Record Retention...................................................................................................82
12. ETHICS..............................................................................................................................82
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............82
12.2. Ethical Conduct of the Study ................................................................................82
12.3. Subject Information and Consent..........................................................................83
12.4. Subject Recruitment ..............................................................................................83
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................83
13. PERFORMANCE STANDARDS.....................................................................................84
13.1. Enrollment Rate Performance Standard................................................................84
13.2. Target Population Performance Standard..............................................................85
13.3. Primary Endpoint Safety Event Rate Performance Standard................................85
13.4. Subject Ineligibility Performance Standard ..........................................................86
13.5. Adherence to Assigned Treatment Performance Standard....................................87
13.6. Cross-Ins Performance Standard...........................................................................88
13.7. Subject Retention Performance Standard..............................................................88
13.8. Timeliness of Data Performance Standard............................................................89
14. DEFINITION OF END OF TRIAL...................................................................................89
14.1. End of Trial in a Member State.............................................................................89


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14.2. End of Trial in all Other Participating...................................................................89
15. SPONSOR DISCONTINUATION CRITERIA ................................................................89
16. PUBLICATION OF STUDY RESULTS..........................................................................90
16.1. Communication of Results by Pfizer ....................................................................90
16.2. Publications by Investigators ................................................................................90
17. REFERENCES ..................................................................................................................92
LIST OF TABLES
Table 1.
DMARDs - Required Washout Period Prior to Randomization Visit..................40
Table 2.
Disease Activity Indicators...................................................................................54
Table 3.
Clinical Laboratory Tests .....................................................................................56
Table 4.
Lymphocyte Subsets and Markers........................................................................98
LIST OF FIGURES
Figure 1.
Study Design (Minimum 1300 Per Arm, Total N=4000).....................................24
APPENDICES
Appendix 1. The 2010 American College of Rheumatology/European League Against 
Rheumatism Classification Criteria for Rheumatoid Arthritis16 ..........................94
Appendix 2. Prohibited Concomitant Medications..................................................................96
Appendix 3. Cockcroft-Gault Formula for Estimating GFR ...................................................97
Appendix 4. Sweden-Specific Protocol Requirements............................................................98
Appendix 5. Czech Republic, Spain and United Kingdom Specific Protocol 
Requirements........................................................................................................98
Appendix 6. Canada Specific Requirements for the Use of Two Methods of Effective 
Contraception........................................................................................................99


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1. INTRODUCTION
1.1. Indication
Tofacitinib (CP-690,550) is a novel, oral Janus kinase (JAK) inhibitor being investigated as a 
targeted immunomodulator and disease-modifying therapy in Rheumatoid Arthritis (RA).1,7
1.2. Background and Rationale
Tofacitinib 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.1  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 heterodimers containing JAK1 or JAK3 (JAK1/3) with functional selectivity 
over JAK2 homodimer signaling.2 Inhibition of JAK1 and JAK3 by tofacitinib blocks 
signaling through the common gamma chain containing receptors for several cytokines, 
including interleukin (IL)-2, -4, -7, -9, -15, and -21. These cytokines are integral to 
lymphocyte activation, development, homeostasis, proliferation, and function; therefore, 
inhibition of their signaling may result in modulation of multiple aspects of the immune 
response. In addition, inhibition of JAK1 will result in attenuation of signaling by additional 
pro-inflammatory cytokines, such as IL-6 and interferon (IFN)γ.3,4 At higher exposures, 
inhibition of erythropoietin, prolactin, and other hormones can occur via inhibition of JAK2 
homodimer signaling. Tofacitinib is efficacious in rodent models of arthritis as assessed by 
clinical and histological measures of disease progression in the mouse collagen-induced 
arthritis (CIA) and rat adjuvant-induced arthritis (AIA) models. Tofacitinib is also 
efficacious in delayed type hypersensitivity models5 and rodent and primate transplant 
models.5, 6 Thus, tofacitinib shows promise in multiple models of autoimmunity and immune 
dysregulation. The broad immunosuppressive, immunomodulatory mechanisms of JAK3 
inhibition is expected to block cytokine signaling which plays a key role in the pathogenesis 
of psoriasis, and dampen innate and adaptive immune responses which plays a role in 
ulcerative colitis. The anti-inflammatory properties of JAK are expected to inhibit the effect 
of the infiltrating lymphocytes in the ocular surface and lacrimal gland.
RA is a chronic and debilitating autoimmune disease characterized by inflammation and 
destruction of the joints, substantial disability, and a significant impact on health status and 
quality of life; this results in a substantial economic burden to patients and society.8 In 
kinase assays, tofacitinib inhibits JAK1, JAK2, and JAK3, and to a lesser extent tyrosine 
kinase 2; in cellular settings, tofacitinib preferentially inhibits signaling by heterodimeric 
receptors associated with JAK3 and/or JAK1 with functional selectivity over JAK2-paired 
receptors.  Inhibition of JAK1 and JAK3 by tofacitinib blocks signaling through the common 
gamma chain-containing receptors for several cytokines, including interleukin (IL)-2, -4, -7, 
-9, -15, and -21,7,9 which are integral to lymphocyte function, and inhibition of their signaling 
may thus result in modulation of multiple aspects of the immune response.
In Phase 2b dose-ranging studies that evaluated a dose range of 1-15 mg twice daily (BID), 
tofacitinib demonstrated sustained efficacy and manageable safety over 24 weeks in patients 
with active RA when used as monotherapy10 or in combination with background 
methotrexate (MTX).11 Tofacitinib 5 and 10 mg BID were selected as optimal doses for 


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evaluation in Phase 3, which included a broad range of therapeutic scenarios investigating 
tofacitinib as monotherapy12 or in combination with MTX13,14 and non-MTX nonbiologic 
disease modifying antirheumatic drugs (DMARDs).15
Phase 3 studies were initiated with two doses of tofacitinib, 5 mg BID and 10 mg BID, 
administered as monotherapy or concurrently on a background of non-biologic DMARDs. 
These studies demonstrated sustained efficacy and manageable safety up to 2 years in 
patients with active RA. Long-term extension studies have been ongoing since Phase 2 and 
have enrolled patients who participated in a Phase 2 or Phase 3 study; these open-label 
studies have demonstrated continued efficacy and a similar safety profile as seen in the 
controlled clinical trials. The preponderance of long-term data collected in these trials was 
obtained in patients on 5 mg BID of tofacitinib. 
This Post-Authorization Safety Study (PASS) was developed in response to the requirements 
of the US Food and Drug Administration to further define the safety profile of tofacitinib 
5 mg BID and 10 mg BID, especially with respect to major adverse cardiovascular events 
(MACE) and malignancies, and to provide comparative safety analyses to a TNF inhibitor in 
an open-label manner.  
The subcutaneously self-administered TNFi’s, adalimumab and etanercept, will be included 
in this study.  Subjects randomized to receive TNFi in the United States (US), Puerto Rico 
and Canada will receive adalimumab; in all other countries, subjects randomized to receive 
TNFi will receive etanercept.
Based on the totality of the non-clinical and clinical data generated thus far, identified risks 
associated with tofacitinib include infection, lipid elevations, anemia, neutropenia and 
malignancies. The identified risks for the completed studies with tofacitinib in RA are 
presented in the XELJANZ(tofacitinib citrate) Investigator Brochure. 
New safety information about tofacitinib was provided to Study A3921133 investigators on 
19 February 2019. That information stated that Pfizer received communication from the 
Tofacitinib Rheumatology Data Safety Monitoring Board (DSMB) stating that on the basis of 
the data reviewed thus far in Study A3921133, there is a statistically and clinically important 
difference in the occurrence of pulmonary embolism within the tofacitinib 10 mg BID 
treatment arm compared to the TNFi control arm, and the overall incidence per person year 
in the tofacitinib 10 mg BID arm is substantially higher than the TNFi control arm and 
substantially higher than observed in other studies across the tofacitinib program.  
Additionally, the DSMB noted an increase in all-cause mortality in the 10 mg BID arm 
compared to the tofacitinib 5 mg BID and TNFi treatment arms. 
Based on the totality of evidence including a review of selected efficacy parameters and a 
finding of only minor increments in efficacy with tofacitinib 10 mg BID beyond the efficacy 
seen in the 5 mg BID group, the DSMB further stated that continued treatment with 
tofacitinib 10 mg BID in Study A3921133 entails a risk that is not sufficiently balanced.


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The DSMB stated they also believe that the risk-benefit profile of tofacitinib 5 mg BID in 
comparison to TNFi control remains appropriately balanced, and that the scientific question 
of evaluating the safety of tofacitinib 5 mg BID versus TNFi with respect to the co-primary 
and secondary safety endpoints in Study A3921133 is worthwhile and important. 
For this reason, the DSMB has recommended modifying Study A3921133 to discontinue 
treatment with tofacitinib 10 mg BID.  They further recommended that patients in the 
tofacitinib 5 mg BID and TNFi control treatment arms should continue to receive their 
assigned treatments.  
Pfizer has accepted this recommendation and with Amendment 8 is modifying the tofacitinib 
10 mg BID treatment arm accordingly. Investigators were instructed to contact all subjects 
taking tofacitinib 10 mg BID within 7 calendar days and verbally inform them of this 
information, secure their verbal agreement to continue in the study and if they agreed, reduce 
their dose of tofacitinib to 5 mg BID. This amendment documents these changes and requires 
all subjects to sign the Addendum to the Informed Consent Document at their next study 
visit, explaining the safety information and secure their agreement to continue in the study.
The comparator TNFi, adalimumab, is reported to be associated with risks of infection, 
malignancy, anaphylaxis or serious allergic reactions, demyelinating disease, cytopenias, 
pancytopenia, heart failure, and Lupus-like syndrome. The identified risks for adalimumab 
in RA are presented in the Humira(adalimumab) United States Package Insert (USPI), 
content revised January 2019.
The comparator TNFi, etanercept, is reported to be associated with risks of infection, 
malignancy, demyelinating disease, lymphoma, congestive heart failure, pancytopenia or 
aplastic anemia, anaphylaxis or serious allergic reactions, Lupus-like syndrome or 
autoimmune hepatitis.  The identified risks for etanercept in RA are presented in the Enbrel
(etanercept) EU SmPC, revised October 2017.
Complete information for tofacitinib may be found in the Single Reference Safety Document
(SRSD), which for this study is the XELJANZ(tofacitinib citrate) Investigator Brochure, 
Section 7.8 Undesirable Effects (All indications); the Single Reference Safety Document for 
the comparator agent, adalimumab, is the USPI, revised January 2019; the Single Reference 
Safety Document for etanercept is the EU SmPC, revised October 2017.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Safety
The primary objective of this endpoint study is to evaluate the safety of tofacitinib at two 
doses versus TNFi; the co-primary endpoints are adjudicated major adverse cardiovascular 
events (MACE) and adjudicated malignancies excluding non-melanoma skin cancers during 
study participation.
The following assessments will be used to evaluate safety in the entire study population:


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
Changes in physical assessments, including weight and vital signs.

AE reporting, incidence and severity.

Incidence and severity of safety laboratory abnormalities.

Adherence to contraceptive use.

Adherence to protocol requirements.

Concomitant medication review.

Review of eligibility to continue study drug
2.1.2. Efficacy
The following assessments will be used to evaluate efficacy in the study population:

28 joint counts.

Patient Global Assessment.

Patient Assessment of Pain.

Physician Global Assessment.

C-reactive Protein (CRP).

A number of patient reported outcomes, including the Health Assessment 
Questionnaire – Disability Index (HAQ-DI).
2.2. Endpoints
This study will use independent endpoint adjudication committees for the adjudication of 
events of interest (EoI), including the co-primary endpoints.  For those events meeting the 
co-primary endpoint pre-defined criteria, the Steering Committee will be responsible for 
reviewing the aggregate accumulation of these events and for informing the Sponsor of 
recommendations made (eg, to continue the study or to stop the study).  All other adjudicated 
events (eg, opportunistic infections, hepatic events, non-primary CV or malignancy events) 
will be reported in the usual fashion (See Section 8 Adverse Event Reporting).
The investigator for the site of incidence will be notified of any malignancy or cardiovascular 
event reported as an EoI that is adjudicated by the Endpoint Adjudication Committee as NOT 
meeting endpoint criteria; the investigator at the study site must re-evaluate the EoI and 
report the event to Pfizer. SAEs must be reported in accordance with the timeframes 
described in the Serious Adverse Event Reporting Requirements section of this protocol (See 
8.13).  The investigator’s SAE awareness date in this instance is identified as the date that the 
investigator site of incidence receives the notification that an EoI does not meet endpoint 


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criteria.  Handling SAEs in this manner will allow Pfizer to meet its Sponsor reporting 
obligations to regulatory authorities upon receipt of such SAEs.  Any EoI that are pending 
adjudication at the annual safety report cutoff date will not be included in the safety tables of 
the annual report.
2.2.1. Safety Endpoints
The safety endpoints will be collected and analyzed for all subjects in the study, through the 
end of the study. 
2.2.1.1. Co-Primary Safety Endpoints
The following co-primary safety endpoints will be analyzed to provide comparative rates for 
tofacitinib vs. the combined TNFi:

Malignancies, excluding non-melanoma skin cancers (adjudicated).

Major adverse cardiovascular events (MACE) (adjudicated).  
The definitions of MACE used in this study are consistent with those outlined in the 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials22
with the exclusion of cardiovascular death due to pulmonary embolism.  The following 
events are included, as defined:

Cardiovascular death.

Death due to acute myocardial infarction (MI).

Sudden cardiac death.

Death due to heart failure.

Death due to stroke.

Death due to cardiovascular procedures.

Death due to cardiovascular hemorrhage.

Death due to other cardiovascular causes: peripheral artery disease.

Non-fatal myocardial infarction (MI).

Non-fatal stroke of any classification, including reversible focal neurologic 
defects with imaging evidence of a new cerebral lesion consistent with ischemia 
or hemorrhage.
2.2.1.2. Secondary Safety Endpoints
The secondary safety endpoints will include an evaluation of the following events:


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
Opportunistic infection events including tuberculosis (adjudicated).

Hepatic events (adjudicated).

Cardiovascular events other than MACE (adjudicated).

All adverse events (AEs), including serious adverse events (SAEs).

Clinically significant abnormal laboratory parameters.

All cause mortality (adjudicated).

Reasons for permanent or temporary discontinuation of study medication.
2.2.2. Efficacy Endpoints
Efficacy endpoints will include:

Change from baseline to each post-baseline scheduled visit in DAS28-4 (CRP). 
Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI). 

Rate of remission at each post-baseline scheduled visit including: 

ACR-EULAR Boolean remission (defined as the subject satisfying all of the 
following: tender joint count ≤1, swollen joint count ≤1, C-reactive protein ≤1 mg/dL, 
patient global assessment ≤1 on a 0-10 scale).

SDAI ≤3.3.

CDAI ≤2.8.

Rate of low disease activity (LDA) at each post-baseline scheduled visit including:

SDAI ≤11.

CDAI ≤10.

DAS28-4(CRP) ≤3.2.

ACR20, ACR50, and ACR70 response rate of at each post-baseline scheduled visit.

Change from baseline to each post-baseline scheduled visit in the HAQ-DI.
3. STUDY DESIGN
This is a Phase 3b/4 randomized, parallel arm, open-label safety endpoint study. All subjects 
will be randomized in a 1:1:1 ratio to one of the three treatment arms with approximately 
1300 subjects in each treatment arm:


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1. Tofacitinib 5 mg BID (oral).
2. Tofacitinib 10 mg BID (oral).*
3. TNFi: In the US, Puerto Rico and Canada, subjects randomized to TNFi will receive 
adalimumab 40 mg every other week (QOW) by subcutaneous injection (SC); in all 
other countries, subjects randomized to TNFi will receive etanercept 50 mg once 
weekly by SC injection.
* In response to new safety information about tofacitinib that was provided to Study 
A3921133 investigators on 19 February 2019, investigators were notified to verbally inform 
subjects randomized to tofacitinib 10 mg BID to reduce the dose of tofacitinib to 5 mg BID 
within 7 calendar days of this notification, secure their verbal agreement to continue in the 
study, and if they agreed, reduce their dose of tofacitinib to 5 mg BID for the remainder of 
the study. Tofacitinib is supplied as 5 mg tablets, which allowed subjects to decrease from 
their previous dose of 2 tablets twice daily to 1 tablet twice daily.
During the study, subjects may require alternate therapies in addition to, or instead of, their 
randomized drug assignment. All subjects, regardless of their treatment regimen will 
participate in the study until study completion. (See Sections 5.6.1 and 6.5).
Study completion will be declared when all 3 of the following conditions are met:
1. At least 1500 subjects have been followed for at least 3 years.
2. The targeted number of MACE are observed (See Section 9.2.1).
3. The targeted number of malignancies excluding non-melanoma skin cancers are observed 
(See Section 9.2.1).
It is expected that approximately 4000 subjects will participate in the study and the expected 
duration of the study is approximately 5 years following randomization of the first subject.
The exact number of subjects and duration of the study will be determined by the pre-
specified rules outlined in the charter of the blinded Steering Committee. (See Section 9.6)
The study design schematic for the study is represented in Figure 1.


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Figure 1.
Study Design (Minimum 1300 Per Arm, Total N=4000)
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.
All subjects are required to meet the inclusion and exclusion criteria defined below. 
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating that the 
subject (or a legal representative) has been informed of all pertinent aspects of the study.
2. Must be at least 50 years of age or older.
3. Has moderate to severe rheumatoid arthritis inadequately controlled with methotrexate 
alone with a score of 6 or greater on the 2010 American College of 
Rheumatology/European League Against Rheumatism Classification Criteria for 
Rheumatoid Arthritis (Appendix 1).
4. Has ≥6 tender/painful joints on motion and ≥6 swollen joints (28 joint count).
5. Has a C-reactive protein measured by a high sensitivity assay (hs-CRP) ≥0.3 mg/dL in 
the central laboratory.
Reduced to 5 mg BID
per Amendment 8


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6. Meets Class I, II or III of the American College of Rheumatology (ACR) 1991 Revised 
Criteria for Global Functional Status in RA where usual self-care activities including 
dressing, feeding, bathing, grooming, and toileting; avocational (recreational and/or 
leisure) and vocational (work, school, homemaking) activities are subject-desired and 
age- and sex-specific.

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.
7. Has taken methotrexate continuously for at least 4 months prior to the Screening visit and 
has taken a stable weekly dose of methotrexate with supplemental folic or folinic acid for 
at least 6 weeks prior to the Baseline visit.

Methotrexate doses less than 15 mg/week are allowed only in the presence of 
documented intolerance or toxicity from higher doses.

Doses higher than 25 mg/week are not permitted under any circumstances.

Folic acid doses should be at least 5 mg per week; folinic acid doses should be at least 
2.5 mg per week.
8. Have at least one of the following cardiovascular risk factors at screening:

Current cigarette smoker.

Diagnosis of hypertension.

High density lipoprotein (HDL) <40 mg/dL.

Diabetes mellitus.

Family history of premature coronary heart disease (CHD); the family history should 
be considered positive for premature CHD if clinical CHD or sudden death can be 
documented in a first degree male relative younger than 55 years of age or in a first 
degree female relative younger than 65 years of age.

Presence of extra-articular disease associated with rheumatoid arthritis, which may 
include nodules, Sjögren’s syndrome, anemia of chronic disease and pulmonary
manifestations.


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
History of coronary artery disease including a history of revascularization procedure, 
coronary artery bypass grafting, myocardial infarction, cardiac arrest, unstable 
angina, acute coronary syndrome.
9. Subjects must be willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
10. Male and female subjects of childbearing potential must agree to use a highly effective 
method of contraception throughout the study and for at least 28 days after the last dose 
of assigned treatment.  A subject is of childbearing potential if, in the opinion of the 
investigator, he/she is biologically capable of having children and is sexually active. (For 
Canada, please refer to Appendix 6 for specific contraception requirements).
11. Female subjects of childbearing potential must test negative for pregnancy.
12. Female subjects who are not of childbearing potential must meet at least one of the 
following criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure or;

Achieved postmenopausal status, defined as: cessation of regular menses for at least 
12 consecutive months with no alternative pathological or physiological cause; and 
have a serum follicle-stimulation hormone (FSH) level within the laboratory’s 
reference range for postmenopausal females.
13. Subjects must screen negative for active tuberculosis or inadequately treated tuberculosis 
infection (active or latent) as evidenced by the following:
a.
Negative QuantiFERON Gold®TM In-Tube test performed at screening:

This is required unless the subject has been adequately treated for active or latent 
tuberculosis or a negative QuantiFERON Gold®TM In-Tube test was previously 
performed and documented within the 3 months prior to screening. 

A negative tuberculin skin test (TST) is one that is <5 mm induration and it can 
be substituted for the QuantiFERON Gold ® TM In-Tube test only if the central 
laboratory is unable to perform the test or the test is reported as indeterminate 
after at least 2 successive attempts. 

It is strongly recommended that subjects with a history of Bacille Calmette Guérin 
(BCG) vaccination be tested with the QuantiFERON Gold®™ In-Tube test. 
b. Chest radiograph taken at screening without changes suggestive of active tuberculosis 
(TB) infection, unless previously performed and documented within 3 months prior to 
screening (see Section 7.3).


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c.
No history of tuberculosis infection unless one of the following is documented:

Subject with prior or current latent tuberculosis has no evidence of active 
tuberculosis and must be taking or have completed an adequate course of therapy 
for latent tuberculosis (9 months of isoniazid in a locale where rates of primary 
multi-drug resistant TB infection are <5% or an alternative regimen recognized by 
the World Health Organization) and a chest radiograph is negative for active 
disease; the chest radiograph must be obtained at screening or, if previously 
performed and documented, within 3 months prior to screening (see Section 7.3).

Subject with prior active tuberculosis has 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) and a chest 
radiograph is negative for active disease; the chest radiograph must be obtained at 
screening or, if previously performed and documented, within 3 months prior to 
screening (see Section 7.3).
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study and the reason 
for exclusion from the study will be documented:
1. Subjects who are investigational site staff members directly involved in the conduct of 
the trial and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are Pfizer employees directly involved in the conduct of the 
trial.
2. Subjects who are classified Class IV of the ACR 1991 Revised Criteria for Global 
Functional Status in RA (ie, are limited in their ability to perform usual self-care, 
vocational, and avocational activities).
3. Pregnant females; breastfeeding females; sexually active males and females of 
childbearing potential who are unwilling or unable to use a highly effective method of 
contraception as outlined in this protocol for the duration of the study and for at least 
28 days after last dose of investigational product (for Canada, please refer to Appendix 6
for specific contraception requirements).
4. Subjects with infections or history of infections: 
a.
Any infection requiring treatment within 2 weeks prior to the Baseline visit.
b. Any infection requiring hospitalization, parenteral antimicrobial therapy, or as 
otherwise judged clinically significant by the investigator, within the past 6 months.
c.
Infected joint prosthesis at any time with the prosthesis still in situ.
d. Recurrent (more than one episode) herpes zoster or disseminated (a single episode) 
herpes zoster or disseminated (a single episode) herpes simplex.


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e.
Subjects will be screened for human immunodeficiency virus (HIV). Subjects who 
test positive for HIV will be excluded from the study.
f.
Subjects will be screened for hepatitis B virus infection. Subjects with hepatitis B 
surface antigen (HBsAg) negative testing but who test positive for hepatitis B core 
antibody (HBcAb) must have further testing for hepatitis B surface antibody 
(HBsAb). If HBsAb is negative, the subject will be excluded from the study.
g. Subjects will be screened for hepatitis C virus antibodies (HCV Ab). Subjects with 
positive HCV Ab tests will be reflex tested for hepatitis C virus ribonucleic acid 
(HCV RNA). Only subjects with negative HCV Ab or HCV RNA will be allowed to 
enroll in the study.
h. Subjects are excluded for current active tuberculosis infection or prior active or latent 
tuberculosis that was inadequately treated or cannot be documented (See Section 4.1
Inclusion Criteria #13). 
5. Subjects with any current malignancy or a history of malignancy, with the exception of 
adequately treated or excised non-metastatic basal cell or squamous cell cancer of the 
skin or cervical carcinoma in situ.
6. Subjects with any uncontrolled clinically significant laboratory abnormality or any of the 
following laboratory abnormalities (For additional Sweden-specific laboratory criteria, 
see Appendix 4 and Czech Republic, Spain and United Kingdom-specific laboratory 
criteria, see Appendix 5):
a.
Evidence of hematopoietic disorder or hemoglobin <9 g/dL.
b. White blood cell count <3.0 x 109/L (<3000/mm3).
c.
Absolute lymphocyte count <0.5 x 109/L (<500/mm3).
d. Absolute neutrophil count <1.0 x 109/L (<1000/mm3).
e.
Platelet count <100 x 109/L (<100,000/mm3).
f.
Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) >1.5 times the 
upper limit of normal (x ULN).
g. Estimated glomerular filtration rate (GFR) <60 mL/min using the Cockcroft-Gault 
formula (Appendix 3).
7. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
4 weeks or 5 half-lives (whichever is longer) after discontinuation of the investigational 
compound before the current study begins and/or during study participation, unless 
further restrictions to class of compound are specified in Section 4.2 Exclusion Criteria
and Section 5.5 Concomitant Medication(s).


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8. Subjects requiring or have received any prohibited concomitant medication as outlined in 
Appendix 2, including:
a.
Subjects who have received live or live attenuated vaccines within 6 weeks prior to 
the first dose of study drug or at any time during treatment or within 6 weeks 
following discontinuation of study drug (See Section 4.4.2).
b. Subjects who have been previously treated with tofacitinib.
c.
Subjects who are being treated with biologic or non-biologic DMARDs other than 
MTX or antimalarials within their specified washout window at study entry (see 
Table 1).
d. Subjects who previously experienced inadequate response, intolerance, allergy or 
hypersensitivity to adalimumab (US, Puerto Rico and Canada) or to etanercept (all 
other countries) or for whom adalimumab (US, Puerto Rico and Canada) or 
etanercept (all other countries) are contraindicated.
e.
Subjects who are being treated with corticosteroids, other than low dose oral 
corticosteroids in doses equivalent to 10 mg prednisone per day at study entry.
f.
Subjects who require concomitant treatment with medications that are potent 
inhibitors of cytochrome P450 3A4 (CYP3A4), both moderate inhibitors of CYP3A4 
and potent inhibitors of CYP2C19, or potent CYP inducers.
9. Subjects who have Class III or Class IV heart failure according to the New York Heart 
Association (NYHA) functional classification system.
10. Subjects with a screening 12-lead electrocardiogram that demonstrates clinically 
significant abnormalities requiring urgent treatment (eg, acute myocardial infarction, 
serious tachy- or bradyarrhythmias) or that is indicative of serious underlying heart 
disease (eg, cardiomyopathy, major congenital heart disease, low voltage in all leads).
11. Subjects who had significant trauma or surgical procedure within 1 month prior to the 
Baseline visit.
12. Subjects with any rheumatic autoimmune disease, other than RA and Sjogren’s 
syndrome.
13. Subjects with a first degree relative with a hereditary immunodeficiency.
14. Subjects with lymphoproliferative disorders (eg, Epstein Barr Virus (EBV) related 
lymphoproliferative disorder), a history of lymphoma, leukemia, or signs and symptoms 
suggestive of current lymphatic disease.
15. Alcohol or substance abuse unless in full remission for greater than 6 months prior to first 
dose of study drug.


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16. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.  
4.3. Randomization Criteria 
Subjects must complete all screening tests and procedures without evidence of exclusionary 
conditions and the investigator must attest to the suitability of the subject for inclusion in the
study prior to randomizing the subject. Study treatments include orally administered 
tofacitinib and subcutaneously injected adalimumab in the US, Puerto Rico and Canada or 
subcutaneously injected etanercept in all other countries. 
4.4. Life Style Guidelines
4.4.1. Non-Pharmacologic Interventions
The subject may continue or initiate all non-pharmacologic therapies, such as physical 
therapy, as indicated and deemed appropriate for his/her physical condition.
4.4.2. Vaccine Guidelines
It is recommended that subjects be up to date on all recommended vaccinations prior to 
enrollment in the study, including pneumococcal vaccine, herpes zoster vaccine, and flu 
vaccine. 
Vaccination with live components should not be given concurrently with study medication.  
In addition, current routine household contact with children and others who have been 
vaccinated with live vaccine components may pose a risk during treatment and for 6 weeks 
following completion of the study.  Some of these vaccines include adenovirus Type 4 & 
Type 7, BCG, Dengue Fever, herpes zoster (“shingles”), measles, mumps, rubella, varicella, 
oral polio vaccine, rotavirus, Yellow Fever, and the intranasal flu vaccine.  
Subjects should avoid household contact with individuals receiving live or attenuated 
vaccinations; some examples include: varicella, attenuated typhoid fever, oral polio, 
attenuated rotavirus, FluMist® (inhaled flu vaccine).
4.4.3. Dietary Supplements
For the purposes of this protocol, dietary supplements are defined as vitamins, minerals, 
purified food substances, and herbals with pharmaceutical properties.
Vitamins, minerals and purified food substances are allowed in amounts not known to be 
associated with adverse effects (such as hypervitaminosis).  Herbals with pharmaceutical 
properties are allowed only if there is acceptable evidence of no moderate or potent CYP3A 
inhibition or induction.  Otherwise, herbals with pharmaceutical properties should not be 
given concurrently with study drug.


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4.4.4. Surgery
It is recommended that subjects who require major surgery temporarily discontinue study 
medication approximately 2 weeks prior to the surgical procedure, unless there are other 
safety concerns that require earlier discontinuation; if discontinued, study medication can be 
resumed following the surgical procedure when the sutures/staples are removed.  If absorbing 
sutures or chemical closure methods are utilized, study medication can be resumed when the 
operative site is sufficiently healed and risk of infection is minimal.
If a biopsy is performed during the course of the study, histopathology slides should be sent 
to the central laboratory for processing and over-read by the central pathology laboratory. 
Subjects should be treated based on the local pathology results.
4.4.5. Reproductive Status of Women Subjects and Partners of Male Subjects
All male and female subjects who, in the opinion of the investigator, are biologically capable 
of having children and are sexually active, must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for at least 28 days after the last dose of investigational product.  The investigator, in 
consultation with the subject, will select the most appropriate method of contraception for the 
individual subject from the permitted list of contraception methods, and instruct the subject 
in its consistent and correct use.  The investigator, at each study visit, will confirm and 
document consistent and correct use.  In addition, the investigator will instruct the subject to 
call immediately if the selected birth control method is discontinued or if pregnancy is known 
or suspected (for Canada, please refer to Appendix 6 for specific contraception 
requirements).
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, inserted, injected or implanted hormonal methods of 
contraception are allowed provided the subject remains on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, 
cream, suppository).
4. Male sterilization with appropriately confirmed absence of sperm in the post-
vasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy.


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4.5. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the coordinator’s manual.
To facilitate access to appropriately-qualified medical personnel on study related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study number, 
contact information for the investigational site and contact details for a help desk in the event 
that the investigational site staff cannot be reached to provide advice on a medical question 
or problem originating from another healthcare professional not involved in the subject’s 
participation in the study. The help desk number can also be used by investigational staff if 
they are seeking advice on medical questions or problems, however it should only be used in 
the event that the established communication pathways between the investigational site and 
the study team are not available. It is therefore intended to augment, but not replace the 
established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study. The help desk 
number is not intended for use by the subject directly and if a subject calls that number they 
will be directed back to the investigational site.
4.6. Rater Qualifications
This study will use a Joint Count Assessor to assess the number of swollen and tender/painful 
joints, as part of the assessment of RA activity. The Joint Count Assessor should be a health 
care provider who has been trained in rheumatology and specializes in the treatment of 
patients with rheumatoid arthritis or has experience in conducting at least 20 joint count 
assessments in clinical trials or has been trained by a health care professional and conducted 
over 20 supervised joint count assessments.
5. STUDY TREATMENTS
Study treatments include tofacitinib 5 mg BID or 10 mg BID (10 mg BID reduced to 5 mg 
BID with Amendment 8), administered orally, as the citrate salt tablet formulation or TNFi 
(adalimumab 40 mg administered every other week in solution for subcutaneous injection in 
the US, Puerto Rico and Canada or etanercept 50 mg administered weekly in solution for 
subcutaneous injection in all other countries). Subjects will be randomized to one of the 
three treatment arms. 
5.1. Allocation to Treatment
Subjects will be allocated to receive open-label drug supplies in accordance with the 
randomization schedule.
Randomization will be accomplished using IVRS (an automated web/telephone 
randomization system provided by the sponsor).  The IVRS contains the randomization 
schedule.  At the Screening Visit, the investigative site will contact the IVRS (online or by 
telephone call).  The site will enroll the subject into the IVRS by indicating minimal 
information sufficient to distinguish one subject from another (eg, date of birth and initials) 
and receive the Subject Identification (ID) number.  At the Baseline Visit, the system will 


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associate that subject with the next available treatment on the randomization schedule and 
provide the randomization number.
The system will then give the investigative site a code which corresponds to study 
medication that is to be dispensed.  This code corresponds to study medication of that 
treatment group to which the subject has just been randomized.
The site will call the system on visits when study medication is to be dispensed.  The 
randomization schedule allows for overage; enrollment will be controlled by the IVRS and 
when a sufficient number of subjects have enrolled, the randomization part of the system will 
be stopped.  The part of the system that supplies codes will continue until the last subject
randomized has been dispensed the last supply of study medication.
All subjects will be provided open-label study medication through the end of the study.
All study medication will be dispensed as appropriate for self-administration by study 
subjects.
With Amendment 8, those subjects previously randomized to tofacitinib 10 mg BID will only 
receive 1 bottle of 5 mg tablets instead of 2 bottles at each visit. 
5.2. Breaking the Blind
All drug supplies will be open-label supplies and labeled appropriately to include drug 
substance, dose, and dosing instructions. There will be no need to “break the blind” as drug 
will not be blinded.
5.3. Drug Supplies
5.3.1. Formulation and Packaging
Each bottle of tofacitinib and prefilled syringe of either adalimumab or etanercept will be 
labeled appropriately as per the regulatory label requirement.  Refer to investigational 
product manual for details on clinical packaging.
5.3.1.1. Open-Label Study Medication
5.3.1.1.1. Tofacitinib Supplies
Tofacitinib will be provided as 5 mg tablets for oral administration by the Sponsor.  Tablets 
will be supplied in bottles as appropriate for the dosing regimen. 
5.3.1.1.2. Comparator Study Medication: Adalimumab Supplies
The comparator adalimumab will be provided as 40 mg prefilled syringes for injection in
cartons by Sponsor or sourced locally by the study sites. 
5.3.1.1.3. Comparator Study Medication: Etanercept Supplies
The comparator etanercept will be provided as 50 mg prefilled syringes for injection in 
cartons by the Sponsor.


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5.3.2. Preparation and Dispensing
All study/comparator medication will be dispensed in bottles and as prefilled syringes. At
each dispensing visit, subjects will receive a sufficient quantity of study medication to last 
until their next scheduled drug dispensing visit plus an additional amount to accommodate 
visits scheduled within the allowed visit range.  Subjects will also receive written dosing
instructions. 
5.3.3. Administration
All subjects must continue using their personal supply of methotrexate. The pre-study stable 
dose of methotrexate will be continued in all subjects throughout the study, unless 
modification is clinically indicated.
Subjects will be trained prior to receiving their study medication supplies in the proper 
techniques for study medication administration, including proper self-injection, if required. 
Subjects will be provided with medication instructions relevant to their study treatment arm. 
Study medication will be taken according to the instructions provided to the subject. The 
amount of trial medication dispensed at each visit must be recorded. At each drug dispensing 
study visit the subject must return the trial medication containers and any unused medication 
and unused syringes for accountability and the amount of drug returned will be recorded to 
account for all dispensed trial medication.
Dosage of adalimumab used in this study (subcutaneous injections of 40 mg every other 
week) is as approved in the Single Reference Safety Document (SRSD) for adalimumab in 
patients with RA, as identified in Section 1 of this protocol.
Dosage of etanercept used in this study (subcutaneous injections of 50 mg every week) is as 
approved in the Single Reference Safety Document (SRSD) for etanercept in patients with 
RA, as identified in Section 1 of this protocol.
5.3.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong subject, at the wrong time, or at the wrong dosage strength.  Such 
medication errors occurring to a study participant are to be captured on the adverse event 
(AE) page of the case report forms (CRFs) and on the SAE form when appropriate.  In the 
event of medication dosing error, the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated adverse event(s) is 


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captured on an adverse event (AE) CRF page (refer to Adverse Event Reporting section for 
further details).
All overdoses are medication errors.  For the purpose of this study, medication errors will be 
reported as protocol deviations if the subject reported taking 2-fold or more of their 
prescribed dose for one or more days or were identified as consuming more than 120% of 
their prescribed dose over the visit interval. 
The following sections provide examples of overdosage for each study medication.
5.3.4.1. Tofacitinib Overdosage  
There is no experience with overdose of tofacitinib. Pharmacokinetic data up to and 
including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the 
administered dose is expected to be eliminated within 24 hours. There is no specific antidote 
for overdose with tofacitinib. In case of an overdose, it is recommended that the subject be 
monitored for signs and symptoms of adverse reactions. Subjects who develop adverse 
reactions should receive appropriate treatment.
Overdoses of tofacitinib are defined by doses and duration of dosing not administered in the 
tofacitinib development program. The following doses and duration of dosing have been 
administered in tofacitinib clinical trials without evidence of dose-limiting symptoms and are 
not considered overdoses: 

≤100 mg tofacitinib daily for up to 2 weeks.

≤60 mg tofacitinib daily for up to 6 weeks.

≤30 mg tofacitinib daily for up to 6 months.
Please note, that concomitant treatment with a prohibited potent CYP3A inhibitor 
(Appendix 2) is assumed to result in a doubling of exposure. Thus, the doses noted above 
should be reduced by one half for each of the time intervals if the subject is taking a 
prohibited potent CYP3A inhibitor. For further details, please refer to the XELJANZ
(tofacitinib) Investigator Brochure.
5.3.4.2. Adalimumab Overdosage
Doses up to 10 mg/kg have been administered to subjects in clinical trials without evidence 
of dose-limiting toxicities. In case of overdosage, it is recommended that the subject be 
monitored for any signs or symptoms of adverse reactions or effects and appropriate 
symptomatic treatment instituted immediately as described in the locally approved labeling 
for adalimumab.
5.3.4.3. Etanercept Overdosage
Toxicology studies have been performed in monkeys at doses up to 30 times the human dose 
with no evidence of dose-limiting toxicities. No dose-limiting toxicities have been observed 


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during clinical trials of etanercept. Single intravenous doses up to 60 mg/m2(approximately 
twice the recommended dose) have been administered to healthy volunteers in an 
endotoxemia study without evidence of dose-limiting toxicities.
5.3.5. Compliance
Compliance with expected consumption of dispensed medication will be assessed by 
determining the expected number of doses to be taken during any given time period and 
comparing that to the number of doses returned, keeping in mind that subjects may have their 
study drug temporarily withheld due to abnormal laboratory tests, adverse events, or the need 
to take a short course of a prohibited concomitant medication. Doses not taken during these 
events do not constitute protocol deviations and should not be considered dosing errors, but 
should be noted in the dosing log with the reason for reduced drug consumption. 
Subjects, who are less than 80% compliant with the orally administered dosage regimen or 
have not used 2 or more injectable syringes expected to be used in the interval, will be 
counseled and the site will implement appropriate measures to secure subject compliance, 
including instituting interim visits to evaluate and encourage compliance, as appropriate to 
the site and reason for non-compliance. 
When compliance of less than 70% of the expected number of doses for any one of the orally 
administered study medications or the subject has not used 3 or more injectable syringes that 
were expected to be used in the interval is suspected, the reason for non-compliance (more 
than or less than expected consumption) with the dosing regimen should be documented in 
the dosing log of the subject’s case report form, and should be reported as a protocol 
deviation and unless there is a protocol stipulated reason for non-compliance with the dosing 
regimen, this should be recorded as a dosing error. 
When compliance of more than 120% of the expected number of doses for the orally 
administered dosage regimen or have used 2 or more injectable syringes than was expected to 
be used in the interval, the reason for non-compliance (more than expected consumption) 
with the dosing regimen should be documented in the dosing log of the subject’s case report 
form with the reason for non-compliance, reported as a protocol deviation, and recorded as a 
dosing error. 
5.4. Drug Storage and Drug Accountability 
The investigational drug product should be stored in accordance with the drug label. Storage 
conditions stated in the SRSD (ie, Investigator Brochure (IB) for tofacitinib, United States 
Package Insert (USPI) for adalimumab, EU SmPC for etanercept, or Local Product 
Document (LPD)) will be superseded by the drug label storage requirements.
Deviations from the storage requirements, including any actions taken, must be documented 
and reported to the sponsor. Once a deviation is identified, the investigational product must 
be quarantined and not used until the sponsor provides documentation of permission to use 
the investigational product.


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Investigators and site staff are reminded to check temperatures daily (ie, manually or by 
using alarm systems to alert of any excursions) and ensure that thermometers are working 
correctly as required for proper storage of investigational products.  These include 
thermometers for both the room storage and refrigerator storage.  Any temperature 
excursions should be reported to the sponsor in accordance with Drug Administration 
Information (DAI) sheets provided to the site.


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To ensure adequate records, all drug supplies will be accounted for in the drug accountability 
inventory forms and will be monitored by the accounting of unused study medication 
returned by the patients.  At the end of the clinical trial, all drug supplies unallocated or 
unused by the patients must be returned to Pfizer or its appointed agent, or destroyed in an 
approved manner unless otherwise authorized by Pfizer.  In either case, the forms must 
identify the investigational product, including batch or code numbers, and account for its 
disposition on a subject by subject basis, including specific dates and quantities.  The forms 
must be signed by the individual who dispensed the drug.
5.5. Concomitant Medication(s)
All concomitant medication taken during the study must be recorded with generic name of 
the medication, reason for administration, dose and frequency, route of administration and 
start and stop dates in the subject’s case report form.  A subject who is receiving an allowed 
concomitant medication for any reason should be on a locally approved medication and a 
dose that is considered standard of care for the treated indication. 
5.5.1. Allowed Concomitant Medications
Please note that all concomitant DMARDs are excluded at entry into the study, except 
methotrexate and antimalarial DMARDs (ie, chloroquine, hydroxychloroquine). During the 
study, if a subject is not adequately treated with their assigned study treatment, non-biologic 
DMARDs (ie, chloroquine, hydroxychloroquine, sulfasalazine, leflunomide) may be added to 
their treatment regimen; methotrexate dosage may be modified if clinically indicated (see 
Section 5.6).
5.5.1.1. Methotrexate
All subjects entering the study must have taken MTX continuously for at least 4 months prior 
to the Screening visit and have been taking a stable, weekly dose of MTX for at least 6 weeks 
prior to the Baseline visit and continue taking that dose throughout the study, unless 
modification is clinically indicated.
MTX doses less than 15 mg/week are allowed only in the presence of documented 
intolerance to or toxicity from higher doses. Doses higher than 25 mg/week are not 
permitted under any circumstances.
5.5.1.2. Folate Supplementation
Subjects must receive either folic acid (at least 5 mg weekly) or folinic acid (at least 2.5 mg 
weekly) as folate supplementation according to local MTX label guidelines and standard of 
care. 
5.5.1.3. Treatment for Latent Tuberculosis
Subjects who are diagnosed as having latent tuberculosis (ie, positive tuberculosis test, chest 
x-ray negative for active tuberculosis, and no evidence of active disease) at Screening or 
during the course of the study must have either been previously treated with an adequate 
course of treatment or be currently taking isoniazid. Subjects that the investigator considers 


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to be at high-risk to develop tuberculosis (eg, residing in high-risk areas or travel to high-risk 
areas) may be started on isoniazid treatment at the discretion of the investigator.  When 
indicated, isoniazid treatment is required to be administered orally at 300 mg/day for a total 
of 9 months of treatment and the treatment must be recorded in the subject’s case report 
form. If an alternate treatment regimen is implemented, the reason for this must be 
documented and a copy of the local standard of care guideline identifying such treatment 
must be provided to the study team. Within approximately one month of initiating treatment 
with isoniazid, the subject should have transaminase levels checked.
PLEASE NOTE: although commonly used in the treatment of tuberculosis, rifampin, 
rifampicin, rifabutin and rifapentene are prohibited concomitant medications in this study.
5.5.1.4. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Other Analgesics
Subjects may continue taking stable daily doses of NSAIDs. Subjects, who require 
intermittent therapy for symptom relief, may use short-acting analgesics including NSAIDs, 
acetaminophen/paracetamol, and opioids.  Topical NSAIDs are allowed at any time during 
the study.
5.5.1.5. Corticosteroid Use
Daily dosages of oral corticosteroids should remain at doses 10 mg prednisone or 
equivalent per day. Reductions in oral corticosteroid dose are allowed as needed to protect a 
subject’s safety.  
Intra-articular corticosteroids, intramuscular corticosteroids (eg, DepoMedrol) and short-
term oral corticosteroid use (eg, Medrol Pak) will be allowed during the study.  
5.5.2. Disallowed Concomitant Medications
All prohibited concomitant medications should be discontinued at least 4 weeks or 5 half 
lives (whichever is longer) prior to the Baseline visit; specific medications and required 
discontinuation times are listed below.  A list of prohibited concomitant medications is 
provided in Appendix 2.
Any investigational treatment must be discontinued prior to the Baseline visit for 4 weeks or 
5 half lives, whichever is longer.  
5.5.2.1. Disease Modifying Antirheumatic Drugs (DMARDs)
5.5.2.1.1. Methotrexate
All subjects should be maintained on their stable dose of MTX, unless modification of dose 
is clinically indicated.
5.5.2.1.2. Other DMARDs
Subjects who have received biologic or non-biologic DMARDs are eligible to participate in 
the study, providing the following discontinuation periods are observed prior to the first dose 
of study drug (Table 1).


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Table 1.
DMARDs - Required Washout Period Prior to Randomization Visit 
52 weeks
Rituximab (subject must have normal CD 19/20+ counts by FACS analysis)
20 weeks
Gold compounds, including auranofin (Ridaura),and injectable gold (aurothioglucose or 
aurothiomalate)
12 weeks
Abatacept, certolizumab pegol, leflunomide*, tocilizumab
10 weeks
Golimumab 
8 weeks
Infliximab 
6 weeks
Adalimumab 
4 weeks
Anakinra, azathioprine, cyclosporine, etanercept, minocycline, penicillamine, 
sulfasalazine, tacrolimus
* Alternately, leflunomide may be discontinued 4 weeks prior to Randomization Visit when discontinued using 
an elimination procedure (ie, 8 grams cholestyramine 3 times daily for at least 24 hours or 50 grams activated 
charcoal 4 times daily for at least 24 hours), as described in the leflunomide package labeling to significantly 
lower leflunomide drug levels.
5.5.2.2. Immune-Modulating Biologic Products
While receiving study drug, no immune-modulating biologic products are allowed to be 
administered concomitantly, including other biologic DMARDs (Appendix 2).
5.5.2.3. CYP3A4 and CYP2C19 Inhibitors and CYP3A4 Inducers
Tofacitinib exposure is increased when co-administered with medications that are potent 
inhibitors of cytochrome P450 (CYP) 3A4 (eg, ketoconazole) and medications that result in 
both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (eg, fluconazole). 
Tofacitinib exposure is decreased when co-administered with potent CYP3A4 inducers (eg, 
rifampin). 
During treatment with adalimumab, the formation of CYP450 enzymes may be suppressed 
by increased levels of cytokines (eg, TNFα, IL-6) during chronic inflammation. It is possible 
for a molecule that antagonizes cytokine activity, such as adalimumab, to influence the 
formation of CYP450 enzymes. Upon initiation or discontinuation of adalimumab in patients 
being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the 
effect (eg, warfarin) or drug concentration (eg, cyclosporine or theophylline) is 
recommended and the individual dose of the drug product may be adjusted as needed.
To ensure sufficient washout of these effects on safety and efficacy endpoints, drugs that are 
potent CYP3A4 and CYP2C19 inhibitors and drugs that are potent CYP3A4 inducers must 
be discontinued for at least 7 days or 5 half lives (whichever is longer) prior to the Baseline 
visit. Only systemically administered drugs listed in Appendix 2 require discontinuation; 
other routes of administration (eg, topical, vaginal, ophthalmic) are not prohibited. 
If a medication that is a potent CYP3A inhibitor or is both a moderate inhibitor of CYP3A4 
and potent inhibitor of CYP2C19 is administered during the study for any reason, including 
the treatment of an adverse event, all study medication should be interrupted during 
treatment. 


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If a medication that is a potent CYP3A inducer is administered during the study for any 
reason, including the treatment of an adverse event, study medication may be continued, but 
the concomitant administration of the medication should be noted as a protocol deviation.
5.5.2.4. Immunizations
Live or live-attenuated vaccines should not be given concurrently with study medication.  If 
immunization with a live or live-attenuated vaccine is required during the study, study drug 
should be temporarily discontinued prior to vaccination.
5.6. Rescue Therapy
All subjects enrolled in this study should remain on their randomized, assigned treatment for 
the length of the study. However, it is understood that some subjects may need adjustments 
to their therapy during the study.  If adjustment in RA therapy is being considered, it is 
recommended that the first modification to a subject’s therapy be the addition or optimization 
of treatment with short-acting analgesics, corticosteroids and methotrexate. 
5.6.1. Changes in Assigned Drug
The investigator should consider the need for adjustment in treatment for the individual 
subject based on 1) disease duration, 2) disease activity, and 3) current medication regimen. 
It is recommended that subjects who have Clinical Disease Activity Index (CDAI) >10 and 
have not had at least a 10 point decrease in CDAI compared to Baseline at Month 3 may be 
considered for modification of treatment.  Subjects who in the investigator’s opinion require 
treatment should be treated appropriately.  
Changes in the randomized dose of study drug (ie, tofacitinib 5 mg BID, tofacitinib 10 mg 
BID, adalimumab 40 mg every other week, etanercept 50 mg weekly) are not allowed prior 
to Amendment 8, at which time subjects in the tofacitinib 10 mg BID treatment arm had their 
dose of tofacitinib decreased to 5 mg BID.  If modification of analgesic, corticosteroid or 
methotrexate is not sufficient, consider adding a nonbiologic DMARD (eg, chloroquine, 
hydroxychloroquine, sulfasalazine, leflunomide) in addition to the study treatment.  It is 
recommended that if modifications are made to the subject’s treatment regimen, the 
investigator should wait 3-6 months before further modifications are made.  If such 
modifications do not provide adequate treatment, and it is in the subject’s best interest to 
discontinue study assigned treatment (tofacitinib or adalimumab or etanercept), standard of 
care therapy should be initiated. It should be noted that standard of care treatment will not be 
provided by the study. 
It is important to note that investigators will be required to document all treatments, time on 
treatment regimens and the rationale for decisions in escalating or changing therapies. 
Subjects on alternate therapies will remain in the study and continue to be followed, 
performing all study procedures according to the protocol until the end of the study.


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6. STUDY PROCEDURES 
6.1. Screening Visit
The study investigator or a sub-investigator will discuss, with each subject, the nature of the 
study, its requirements, and its restrictions.  Written informed consent must be obtained prior 
to performance of any protocol specific procedures.
Subjects must complete the screening procedures and have test results available prior to the 
Baseline visit to confirm that they meet the entrance criteria for the study.   All screening 
procedures must be completed within a 1 month window, unless otherwise noted.
Subjects, who are on prohibited medications and are deriving a beneficial response from 
them, should not be entered into this study. However, there may be subjects taking a 
prohibited medication who have experienced an ineffectual/suboptimal response or side 
effects and wish to enter the study.  These subjects may require a washout period that extends 
beyond the screening duration (See Section 5.5 Concomitant Medication(s)).  Additionally, 
screening procedures may need to be repeated to provide valid data (eg, laboratory testing) 
and turnaround time may extend beyond the screening duration. For these subjects, written 
informed consent and a Study Subject Identification (SSID) number must be obtained prior 
to initiation of the washout period.  In no instance should the screening window exceed 
3 months.
Subjects who do not have all tests completed within the 1 month screening period or who 
temporarily do not meet study entry criteria (eg, treatment with antibiotics during the 
screening period or for administrative reasons) may re-screen one time; the subject’s prior 
SSID number and reason for re-screening must be documented.
Subjects should be fasting for at least 6 hours prior to laboratory testing. No subject who is 
disqualified by laboratory testing will be permitted to re-screen (ie, positive hepatitis or HIV 
screen, positive QuantiFERON Gold®TM In-Tube Test without adequate treatment, confirmed 
hemoglobin<9 g/dL, confirmed transaminases >1.5 x ULN). 
Subjects who do not meet screening criteria and/or do not re-screen, must be discontinued 
and the reason for screen-failure must be documented in the CRF.
Procedures to be performed during the screening period include:

Informed Consent.

Confirmation of RA diagnosis and Classification of RA: subject must have a score of 6 or 
greater on the 2010 American College of Rheumatology/European League Against 
Rheumatism classification criteria for rheumatoid arthritis (Appendix 1).

Medical History: include previous vaccination history, smoking status, average weekly 
alcohol consumption, family history of premature coronary heart disease (CHD), and 
history of any prior episodes of herpes zoster. 


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
Complete Physical Examination: height, weight, vital signs, general appearance, skin 
(presence of rash), HEENT (head, eyes, ears, nose and throat), lungs (auscultation), heart 
(auscultation for presence of murmurs, gallops, rubs), lower extremities (peripheral 
edema), abdominal (palpation and auscultation), neurologic (mental status, station, gait, 
reflexes, motor and sensory function, coordination) and lymph nodes.

Fasting laboratory testing (Blood Chemistry, Hematology, CRP, HIV Serology, HBsAg, 
HBcAb, HBsAb, HCV Ab, HCV RNA, Rheumatoid Factor, anti-cyclic citrullinated 
peptide antibodies (anti-CCP), Urinalysis, Lipid Profile): All required laboratory testing 
must be complete and reported; any invalid specimens must be retested and reported prior 
to the Baseline visit.

Pregnancy testing must be completed for all women of child-bearing potential: all 
subjects must test negative; confirmation and documentation of the use of a highly 
effective method of contraception by sexually active subjects of child-bearing potential
must be done (for Canada, please refer to Appendix 6 for specific contraception 
requirements).

QuantiFERON Gold®TM In-Tube Test: unless the subject has previously received an 
adequate course of therapy for either latent or active TB infection (Section 5.5.1.3
Treatment for Latent Tuberculosis).

Chest x-ray must show no evidence of active tuberculosis or other finding that would 
exclude the subject from the study (see Section 7.3 Chest Radiograph).

12-lead electrocardiogram.

RA Activity: 28 tender/painful and swollen joint counts performed and the number of 
swollen joints and the number of tender/painful joints meet the criteria for inclusion.

History of Prior and Concomitant Medications: this includes start dates and stop dates 
with reason for discontinuation (if appropriate), dosage and frequency of administration, 
and indication treated (make sure all indications are listed in the medical history) for all 
current medications, any medications taken within the 4 weeks prior to screening 
procedures, and a complete history of all DMARDs ever taken including the dates of 
administration and the reasons for discontinuation. 
6.2. Study Period
It is expected that a minimum of approximately 4000 subjects will be enrolled in the study 
and the study will continue until at least 1500 subjects complete 3 years in the study and the 
estimated number of malignancy events and MACE are observed.  Screening to enroll a total 
of approximately 4000 subjects is expected to be completed in approximately 3 years and the 
endpoints achieved in approximately 5 years from first subject randomized. Thus, each 
subject’s individual participation will vary, depending on when the subject is randomized 
into the study.  


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Subjects who discontinue assigned study drug are required to continue in the study and 
perform all study tests and procedures until the study is complete.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject and document their current status.  All attempts to contact the subject and information 
received during contact attempts must be documented in the subject’s medical record.  In any 
circumstance, every effort should be made to document subject outcome, if possible.  The 
investigator should inquire about the reason for withdrawal, request the subject to return all 
unused investigational product(s), request the subject to return for a final visit, if applicable, 
and follow up with the subject regarding any unresolved adverse events (AEs).
6.2.1. Visit Windows
The screening period is expected to be no longer than 4 weeks in duration, unless exceptions 
noted in Section 6.1 are documented, with the Baseline visit (Day 1) occurring within the 
28 days following the day that the subject signs the informed consent. 
All other visits (Visits 2-22) should be conducted as close to the scheduled visit day as 
possible.  Exceptions may be made to accommodate holidays and unexpected events, such as 
weather-related site closures or illnesses requiring hospitalization. In these cases, the visit 
should be scheduled or re-scheduled as close to the original visit schedule as possible. 
All visits will contribute to the dataset. The visit window for Visit 2 (Month 2) is 2 weeks; 
all other visit windows are 1.5 months to ensure capture of all data.
Partial visits (ie, those that do not include all required procedures) must be noted clearly and 
the reason documented in the subject’s case report form.
6.3. Visit 1, Baseline Visit (Day 1)
Subjects are required to fast for at least 6 hours prior to the visit. Subjects who have met all 
the inclusion criteria and have no exclusion criteria present may participate in the study.  
Procedures that will be performed prior to the first dose of study drug include:

Physical assessment including assessment of new physical findings, weight and vital 
signs.

Review of inclusion/exclusion criteria.

Fasting laboratory testing including blood chemistry, hematology, CRP, lipid profile.

Pregnancy testing must be completed for all women of child-bearing potential: all 
subjects must test negative; confirmation and documentation of the use of a highly 
effective method of contraception by sexually active subjects of child-bearing potential 
must be done (for Canada, please refer to Appendix 6 for specific contraception 
requirements).


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
Banked biospecimen sample.

28 tender /painful and swollen joint counts.

Completion of the following assessments:

Patient assessment of arthritis pain.

Patient global assessment of arthritis.

Physician global assessment of arthritis.

HAQ-DI.

SF-36 (Version 2, Acute).

EuroQol EQ-5D.

Work Productivity and Activity Impairment (WPAI) Questionnaire.

Safety Assessment and AE Reporting.

Concomitant Medication Review.

Confirm that all screening procedures have been completed and the subject is eligible for 
randomization.

Randomize and dispense study medication as identified by the randomization/drug 
dispensing system.

Schedule the subject to return for Visit 2 (Month 2).
6.4. Follow-up Visits
6.4.1. Visit 2 (Month 2)
Subjects are required to fast for at least 6 hours prior to the visit. Procedures that will be 
performed on Visit 2, Month 2 include:

Assessment of new physical findings, weight and vital signs.

Fasting laboratory testing including blood chemistry, hematology, CRP, lipid profile.

Pregnancy testing must be completed for all women of child-bearing potential: all 
subjects must test negative; confirmation and documentation of the use of a highly 
effective method of contraception by sexually active subjects of child-bearing potential 
must be done (for Canada, please refer to Appendix 6 for specific contraception 
requirements).


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
28 tender /painful and swollen joint counts.

Completion of the following assessments:

Patient assessment of arthritis pain.

Patient global assessment of arthritis.

Physician global assessment of arthritis.

HAQ-DI.

Safety Assessment and AE Reporting.

Concomitant Medication Review.

Schedule the subject to return for Visit 3 (Month 3).
6.4.2. Visit 3 (Month 3)
Subjects are not required to fast for this visit.  Procedures that will be performed on Visit 3, 
Month 3 include:

Assessment of new physical findings, weight and vital signs.

Non-fasting laboratory testing including blood chemistry, hematology, CRP.

Pregnancy testing must be completed for all women of child-bearing potential: all 
subjects must test negative; confirmation and documentation of the use of a highly 
effective method of contraception by sexually active subjects of child-bearing potential 
must be done (for Canada, please refer to Appendix 6 for specific contraception 
requirements).

28 tender /painful and swollen joint counts.

Completion of the following assessments:

Patient assessment of arthritis pain.

Patient global assessment of arthritis.

Physician global assessment of arthritis.

HAQ-DI.

SF-36 (Version 2, Acute).

EuroQol EQ-5D.


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
Work Productivity and Activity Impairment (WPAI) Questionnaire.

Safety Assessment and AE Reporting.

Concomitant Medication Review.

Dispense study medication.

Schedule the subject to return for Visit 4 (Month 6).
6.4.3. Visit 4 (Month 6)
Subjects are not required to fast for this visit.  Procedures that will be performed on Visit 4, 
Month 6 include:

Assessment of new physical findings, weight and vital signs.

Non-fasting laboratory testing including blood chemistry, hematology, CRP.

Pregnancy testing must be completed for all women of child-bearing potential: all 
subjects must test negative; confirmation and documentation of the use of a highly 
effective method of contraception by sexually active subjects of child-bearing potential 
must be done (for Canada, please refer to Appendix 6 for specific contraception 
requirements).

28 tender /painful and swollen joint counts.

Completion of the following assessments:

Patient assessment of arthritis pain.

Patient global assessment of arthritis.

Physician global assessment of arthritis.

HAQ-DI.

SF-36 (Version 2, Acute).

EuroQol EQ-5D.

Work Productivity and Activity Impairment (WPAI) Questionnaire.

Safety Assessment and AE Reporting.

Concomitant Medication Review.

Dispense study medication.

Schedule the subject to return for Visit 5 (Month 9).


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6.4.4. Visits 5, 7, 9, 11, 13, 15, 17, 19, 21, etc, as Required Through the End of the Study
(Calendar Months 9, 15, 21, 27, 33, 39, 45, 51, 57, etc)
Subjects are not required to fast for this visit. Procedures that will be performed at Visits 5, 7, 
9, 11, 13, 15, 17, 19 and 21 (Months 9, 15, 21, 27, 33, 39, 45, 51 and 57, respectively) 
include:

Assessment of new physical findings, weight and vital signs.

Non-fasting laboratory testing including blood chemistry, hematology, CRP.

Pregnancy testing must be completed for all women of child-bearing potential: all 
subjects must test negative; confirmation and documentation of the use of a highly 
effective method of contraception by sexually active subjects of child-bearing potential 
must be done (for Canada, please refer to Appendix 6 for specific contraception 
requirements).

28 tender /painful and swollen joint counts.

Completion of the following assessments:

Patient assessment of arthritis pain.

Patient global assessment of arthritis.

Physician global assessment of arthritis.

HAQ-DI.

Safety Assessment and AE Reporting.

Concomitant Medication Review

Dispense study medication.

Schedule the subject to return for next visit.
6.4.5. Visits 6, 10, 14, 18, 22, etc, as Required Through the End of the Study (Months 12, 
24, 36, 48, 60, etc.) – Annual Study Visits
Subjects are required to fast for 6 hours prior to the visit and withhold their study medication 
on the day of the visit. Procedures that will be performed at Visits 6, 10, 14, 18 and 22
(Months 12, 24, 36, 48 and 60, etc.) include:

Assessment of new physical findings, weight and vital signs.

Fasting laboratory testing including blood chemistry, hematology, CRP, lipid profile.


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
Banked biospecimen sample (Visit 6 only).

QuantiFERON Gold®™ In-Tube Test (QFT) only for subjects who tested negative at 
their last QFT; subjects newly testing positive must have chest x-ray performed. Please 
note: subjects with a new positive QFT, a chest x-ray that does not show active disease
and no other evidence of active disease are required to be treated for latent tuberculosis 
infection, as described in Section 5.5.1.3 Treatment for Latent Tuberculosis. QFT is not 
performed in subjects who had prior positive testing (screening visit or prior annual 
visits) and/or previously received adequate treatment for tuberculosis.

Pregnancy testing must be completed for all women of child-bearing potential: all 
subjects must test negative; confirmation and documentation of the use of a highly 
effective method of contraception by sexually active subjects of child-bearing potential 
must be done (for Canada, please refer to Appendix 6 for specific contraception 
requirements).

28 tender /painful and swollen joint counts.

Completion of the following assessments:

Patient assessment of arthritis pain.

Patient global assessment of arthritis.

Physician global assessment of arthritis.

HAQ-DI.

SF-36 (Version 2, Acute).

EuroQol EQ-5D.

Work Productivity and Activity Impairment (WPAI) Questionnaire.

Safety Assessment and AE Reporting.

Concomitant Medication Review.

Dispense study medication.

Schedule the subject to return for next visit.
6.4.6. Visits 8, 12, 16, 20, etc, as Required Through the End of the Study (Months 18, 30, 
42, 54, etc)
Subjects are not required to fast for this visit. Procedures that will be performed at Visits 8, 
12, 16 and 20 (Months 18, 30, 42 and 54, etc.) include:

Assessment of new physical findings, weight and vital signs.


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
Non-fasting laboratory testing including blood chemistry, hematology, CRP.

Pregnancy testing must be completed for all women of child-bearing potential: all 
subjects must test negative; confirmation and documentation of the use of a highly 
effective method of contraception by sexually active subjects of child-bearing potential 
must be done (for Canada, please refer to Appendix 6 for specific contraception 
requirements).

28 tender /painful and swollen joint counts.

Completion of the following assessments:

Patient assessment of arthritis pain.

Patient global assessment of arthritis.

Physician global assessment of arthritis.

HAQ-DI.

Safety Assessment and AE Reporting.

Concomitant Medication Review.

Dispense study medication.

Schedule the subject to return for next visit.
6.5. End of Study Visit
Within one month following the official end of study, subjects are to return for an End of 
Study Visit. Subjects are required to fast for 6 hours prior to the visit. Procedures that will 
be performed at the end of the study include:

Complete physical examination, including height.

Assessment of new physical findings, weight and vital signs.

Fasting laboratory testing including blood chemistry, hematology, CRP, lipid profile.

12-lead electrocardiogram.

Banked biospecimen sample.

Pregnancy testing must be completed for all women of child-bearing potential: all 
subjects must test negative; confirmation and documentation of the use of a highly 
effective method of contraception by sexually active subjects of child-bearing potential 
must be done (for Canada, please refer to Appendix 6 for specific contraception 
requirements).


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
28 tender /painful and swollen joint counts.

Completion of the following assessments:

Patient assessment of arthritis pain.

Patient global assessment of arthritis.

Physician global assessment of arthritis.

HAQ-DI.

SF-36 (Version 2, Acute).

EuroQol EQ-5D.

Work Productivity and Activity Impairment (WPAI) Questionnaire.

Safety Assessment and AE Reporting.

Concomitant Medication Review.

End of study assessment, including a discussion and plans for future care.

Schedule the subject to return after 28 days for End of Study Follow-up visit.
6.6. End of Study Follow-up Visit
One month (28 days) after the last dose of study medication is taken, the subject will attend 
an end of study follow-up visit. The following procedures will be performed: 

Assessment of new physical findings, weight and vital signs.

Pregnancy testing must be completed for all women of child-bearing potential; 
confirmation and documentation of the use of a highly effective method of contraception 
by sexually active subjects of child-bearing potential must be done (for Canada, please 
refer to Appendix 6 for specific contraception requirements).

Safety Assessment and AE Reporting, including follow-up of any ongoing AEs.

Concomitant Medication Review.
6.7. Subject Withdrawal
It is important to continue all subjects in the study and perform all tests and procedures until 
the study is completed to enable collection of safety data, even if a subject withdraws from 
the study assigned treatment, unless the subject withdraws their consent to continue 
participation. 


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Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject and document their current status.  All attempts to contact the subject and information 
received during contact attempts must be documented in the subject’s medical record.  In any 
circumstance, every effort should be made to document subject outcome, if possible.  The 
investigator should inquire about the reason for withdrawal, request the subject to return all 
unused investigational product(s), request the subject to return for a final visit, if applicable, 
and follow up with the subject regarding any unresolved adverse events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, this should be documented and no further evaluations should be performed, and 
no additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well being of the subject. When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.
The study team will be informed of these incidents in a timely fashion.
7.1. Physical Examination
A standard physical examination will be performed at the Screening visit.  The following 
parameters and body systems will be examined and any abnormalities described: height, 
weight, general appearance, skin (presence of rash), HEENT (head, eyes, ears, nose and 
throat), lungs (auscultation), heart (auscultation for presence of murmurs, gallops, rubs), 
lower extremities (peripheral edema), abdominal (palpation and auscultation), neurologic 
(mental status, station, gait, reflexes, motor and sensory function, coordination) and lymph 
nodes.  
7.2. Assessment of New Physical Findings and Safety Assessments
At all visits after the Screening visit, an abbreviated physical examination will be performed 
assessing the following: weight, vital signs, lungs, heart, lower extremities for peripheral 
edema, abdomen and lymph nodes.  Any clinically significant changes from the last complete 
physical examination should be recorded as adverse events (AEs); ongoing AEs should be 
updated, as appropriate.  


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7.3. Chest Radiograph
A chest radiograph will be obtained at the Screening Visit in all subjects, unless it has been 
taken and documented within the 3 months prior to the Screening visit.  To be considered 
eligible for the study, the radiograph must be negative for active tuberculosis infection.
During the course of this study, annual screening for latent and/or active TB will be 
conducted using the QuantiFERON-TB Gold In-Tube test. All subjects with positive 
results must have a chest radiograph performed and the radiograph must be negative for 
active tuberculosis infection. Subjects identified as having latent TB should be treated 
appropriately (Section 5.5.1.3 Treatment for Latent Tuberculosis).
Chest computed tomography (CT) scans will not be performed as part of the study 
procedures. However, if a chest CT scan has been performed for other reasons within the 
3 months prior to a scheduled chest radiograph; subjects do not have to perform a chest 
radiograph, but rather, the results of the chest CT scan may be used to confirm the absence of 
active tuberculosis infection. 
7.4. Electrocardiogram
A 12-lead electrocardiogram (ECG) will be obtained on all subjects at the Screening visit and 
at the End of Study visit.  All ECGs should be performed after the subject has rested quietly 
for at least 10 minutes.  ECGs will be read locally. All ECG results will be documented in 
the CRF and copies of the tracings maintained in the subject’s source documentation.  
Subjects with a screening 12-lead electrocardiogram that demonstrates clinically significant 
abnormalities requiring urgent treatment (eg, acute myocardial infarction, serious tachy- or 
bradyarrhythmias) or that is indicative of serious underlying heart disease (eg, 
cardiomyopathy, major congenital heart disease, low voltage in all leads) should not be 
enrolled in the study.
End of Study ECGs will be compared to the Screening ECG and any clinically significant 
changes will be recorded as adverse events, submitted for adjudication and evaluated further, 
as clinically warranted.
7.5. Assessments of Disease Activity
Individual components for the following indicators of disease activity will be collected 
throughout the study as described in Table 2.


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Table 2.
Disease Activity Indicators
Indicator
Definition/Calculation
DAS28-4 (CRP)
DAS28-CRP(4) = 0.56*√(TJC28) + 0.28*√(SJC28) + 
0.36*ln(CRP+1) + 0.014*PtGA + 0.96
Simplified Disease Activity Index (SDAI)
(28TJC) + (28SJC) + PhyGA + PtGA + CRP
Clinical Disease Activity Index (CDAI)
(28TJC) + (28SJC) + MDGA + PtGA
American College of Rheumatology (ACR) 
Response Rates
The ACR’s definition for calculating a 20% improvement in 
RA (ACR20) is as follows: 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 (eg, CRP). Similarly, ACR50, 70 and 90 are 
calculated with the respective percent improvements.
ACR/EULAR Boolean-based definition of 
remission
At any time point, a subject must satisfy all of the following: 
tender joint count 1, swollen joint count 1, CRP 1 
mg/dL, patient’s global assessment of health 1 on a 0-10 
scale
TJC = tender joint count; SJC = swollen joint count; CRP = C-reactive protein in mg/L; PtGA = patient’s global 
assessment of health; PhyGA = physician’s global assessment of health
7.6. Joint Counts
7.6.1. Tender/Painful Joint Count (28 Joint Count)
Twenty-eight (28) joints will be assessed by a joint assessor 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 joints).
The 28 joints to be assessed are the shoulders, elbows, wrists, metacarpophalangeal joints 
(MCP), proximal interphalangeal joints (PIP), and knees.  Artificial joints will not be 
assessed.
7.6.2. Swollen Joint Count (28 Joint Count)
The joint assessor will also assess these joints for swelling using the following scale: 

Present/Absent/Not Done/Not Applicable (to be used for artificial joints).
The 28 swollen joint count includes the following joints: shoulders, elbows, wrists, 
metacarpophalangeal joints (MCP), proximal interphalangeal joints (PIP), and knees.  
Artificial joints will not be assessed.
7.7. Patient Assessment of Arthritis Pain
Subjects will assess the severity of their arthritis pain using a 100 mm visual analog scale 
(VAS) placing a mark on the scale between 0 (no pain) and 100 (most severe pain), which 
corresponds to the magnitude of their pain.


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7.8. Patient Global Assessment of Arthritis
Subjects will answer the following question, “Considering all the ways your arthritis affects 
you, how are you feeling today?”  The subject’s response will be recorded using a 100 mm 
visual analog scale (VAS).
7.9. Physician Global Assessment of Arthritis
The investigator will assess how the subject’s overall arthritis appears at the time of the visit.  
This is an evaluation based on the subject’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).
7.9.1. Health Assessment Questionnaire – Disability Index (HAQ-DI)
The HAQ-DI assesses the degree of difficulty a subject has experienced during the past week 
in 8 domains of daily living activities: dressing and grooming, arising, eating, walking, 
hygiene, reach, grip, and other activities.17 Each activity category consists of 2-3 items.  For 
each question in the questionnaire, the level of difficulty is scored from 0 to 3 with 
0 representing “no difficulty,” 1 as “some difficulty,” 2 as “much difficulty,” and 3 as 
“unable to do”.  Any activity that requires assistance from another individual or requires the 
use of an assistive device adjusts to a minimum score of 2 to represent a more limited 
functional status.  The form should then be checked by the site staff for completeness.
7.9.2. SF-36 Health Survey (Version 2, Acute)
The SF-36 v.2 (Acute)18 is a 36-item generic health status measure.  It measures 8 general 
health domains: physical functioning, role physical, bodily pain, general health, vitality, 
social functioning, role emotional and mental health.  These domains can also be summarized 
as physical and mental component scores.  The form should be checked for completeness by 
the site staff.  
7.9.3. EuroQol EQ-5D Health State Profile (Health-related Quality of Life)
The EuroQol EQ-5D Health State Profile is a copyrighted, subject completed instrument 
designed to assess impact on health-related quality of life in five domains: mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression.  Additionally, scores from the 
five domains may be used to calculate a single index value, also known as a utility score.  
The validity and reliability of the EuroQol EQ-5D has been established in a number of 
disease states, including rheumatoid arthritis.19  The form should then be checked by site staff 
for completeness.  
7.9.4. Work Productivity and Activity Impairment (WPAI) Questionnaire
The Work Productivity & Activity Impairment Questionnaire (WPAI): Rheumatoid Arthritis 
is a 6-item questionnaire that is specific for rheumatoid arthritis and yields four types of 
scores: absenteeism, presenteesism (impairment at work/reduced job effectiveness), work 
productivity loss and activity impairment. WPAI outcomes are expressed as impairment 
percentages with higher numbers indicating greater impairment and less productivity.


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7.9.5. C-reactive Protein (CRP)
The CRP will be collected at each visit and analyzed by a central laboratory.  It will be used 
in the calculation of several efficacy parameters.  CRP test results will not be blinded and 
will be provided to the investigator for all visits.
7.10. Clinical Laboratory Tests
Blood and urine samples will be collected at the time points identified in Table 3. 
Unscheduled clinical laboratory tests may be obtained at any time during the study to assess 
any perceived safety concerns. For Czech Republic, Spain and United Kingdom, see 
Appendix 5 for additional testing required.
Table 3.
Clinical Laboratory Tests
Tests
Visits
Comments
Chemistry
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin
ALT (SGPT)
AST (SGOT)
Creatinine
Screening Visit and every visit 
thereafter including the End of 
Study Visit
Creatinine clearance is calculated by the 
central laboratory according to the Cockcroft-
Gault Formula at Screening Visit 
(Appendix 3)
See Section 7.15 for retesting requirements 
for ALT and AST elevated 3 X ULN
Hematology
Hemoglobin
Hematocrit
RBC with morphology
WBC
Neutrophils (%, abs)
Lymphocytes (%, abs)
Monocytes (%, abs)
Eosinophils (%, abs)
Basophils (%, abs)
Platelets
Screening Visit and every visit 
thereafter including the End of 
Study Visit
See Section 7.15 for monitoring requirements 
related to hemoglobin, neutrophil and 
lymphocyte counts
C-reactive Protein
Screening visit and every study 
visit including the End of Study 
Visit
Refer to Section 7.9.5
Banked Biospecimens
Visit 1, Visit 6 and End of Study 
Visit
Refer to Section 7.13
Rheumatoid Factor
Screening visit
Anticyclic citrullinated 
peptide antibodies 
(ACPA)
HIV Serology
Screening visit
Hepatitis B Surface 
antigen (HBsAg)
Hepatitis B Core 
Antibody (HBcAb)
Hepatitis B Surface 
Antibody (HBsAb)
Screening Visit
Subjects with hepatitis B surface antigen 
(HBsAg) negative testing but who test 
positive for hepatitis B core antibody 
(HBcAb) must have further testing for 
hepatitis B surface antibody (HBsAb). If 
HBsAb is negative, the subject will be 
excluded from the study (see Section 4.2)


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Table 3.
Clinical Laboratory Tests
Tests
Visits
Comments
Hepatitis C virus antibody 
(HCV Ab)
Hepatitis C RNA (HCV 
RNA)
Screening Visit
Subjects with positive HCV Ab tests will be 
reflex tested for hepatitis C virus ribonucleic 
acid (HCV RNA). Only subjects with 
negative HCV Ab or HCV RNA will be 
allowed to enroll in the study.
Lipids
Triglycerides
Total Cholesterol
HDL (direct)
LDL (Friedwald)
Screening Visit, Visit 1, Visit 2, 
Visit 6 and annually thereafter, 
End of Study Visit
Subjects should be fasting for at least 6 hours 
prior to obtaining specimen.
Serum Pregnancy Testing
Screening Visit and every study 
visit thereafter, including End of 
Study Follow-up Visit
May be repeated if pregnancy is 
suspected or at the request of the 
IRB/IEC or local regulations.
All female subjects of childbearing potential, 
regardless of whether or not they are sexually 
active. All pregnancy tests used in this study 
must have sensitivity of at least 25 mIU/mL 
and must be performed by a certified 
laboratory.  
(See Section 7.11)
Quantiferon TB Gold
Screening Visit, Visit 6 and 
annually thereafter.
Subjects should withhold study medication 
on the day of the visit. See Section 5.5.1.3
and 7.3 for further details on management of 
positive tests.
Urinalysis
Specific Gravity
pH
Protein
Glucose
Ketones
Blood
Leukocyte Esterase
Screening Visit
Tests to include when
repeat AST and/or ALT 
are required:
Albumin
Creatine kinase (CK)
Total bilirubin
Direct bilirubin
Indirect bilirubin, GGT
PT/INR
Alkaline phosphatase
At same time as AST and/or ALT 
are repeated for elevations as 
noted in Section 7.15
See Section 8.6.2 for further details on 
management of elevations. 
ALT = alanine aminotransferase (SGPT); AST = aspartate transaminase (SGOT); HDL = high density 
lipoprotein; HIV = human immunodeficiency virus; LDL = low density lipoprotein; SGOT = serum glutamic-
oxaloacetic transaminase (AST); SGPT = serum glutamic pyruvate transaminase (ALT); TB = tuberculosis; X 
ULN = times the upper limit of normal; 


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7.11. Pregnancy Testing
Pregnancy testing must be conducted on all female subjects of childbearing potential, 
regardless of whether or not they are sexually active at least at every scheduled visit of the 
study. Serum pregnancy testing will be performed by the central laboratory for all visits.
For female subjects of childbearing potential, a serum pregnancy test, with sensitivity of
25 mIU/mL, will be performed at screening, before investigational product administration 
at the baseline visit, and at the end of treatment visit.  A negative pregnancy result is required 
before the subject may receive the investigational product.  Pregnancy tests will also be done 
whenever one menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected), repeated at every study visits and at the end of the study 
to confirm the subject has not become pregnant during the study.  In the case of a positive 
human chorionic gonadotropin (hCG) test, the subject will be withdrawn from study 
medication but may remain in the study.  Pregnancy tests may also be repeated as per request 
of an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) or if required 
by local regulations.
7.12. Pregnancies Occurring During Study
If an unplanned pregnancy occurs in a female subject or the partner of a male subject while 
the man or woman is enrolled in this study, regardless of therapy at the time of pregnancy, 
the pregnancy will be followed to termination and outcome will be documented.  
In addition, for those pregnancies occurring in the United States, the pregnancy will be 
followed through an existing Pfizer-sponsored pregnancy registry (ie, Tofacitinib Pregnancy 
Exposure Registry OTIS Autoimmune Diseases in Pregnancy Project, A3921203).  The 
registry will collect exposure and outcome information for those pregnancies and all live 
born infants followed in this registry will be examined by one of a team of study-dedicated 
dysmorphologists within the first year of life.
7.13. Banked Biospecimens
7.13.1. Markers of Drug Response
Variation in genetic markers and other biomarkers may help to explain some of the 
variability in response seen with some drugs among different individuals.  This is referred to 
as pharmacogenomic/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
RNA, protein, and metabolite variation patterns of subjects who respond well and those who 
respond poorly to treatment may help to better define the most appropriate group of patients 
in which to target a given treatment. Collecting biospecimens for exploratory 
pharmacogenomic/biomarker analyses and retaining them in the Pfizer BioBank makes it 
possible to better understand the drug’s mechanism of action and to seek explanations for 
differences in, for example, exposure, efficacy, tolerability, or safety not anticipated prior to 
the beginning of the study. Providing these biospecimens is a required study activity for 
study sites and subjects, unless prohibited as such by local regulations or ethics committee 
decision. 


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To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s study ID number. Samples will be kept in a facility 
accessible only by badge-swipe. Data will be stored on password-protected computer 
systems. The key between the code and the subject’s personal identifiers will be held at the 
study site; the researchers using the biospecimens and data generated from them will not 
have access to the key nor any personally identifying information. Biospecimens will only 
be used for the purposes described here and in the informed consent document/patient 
information sheet; any other uses require additional ethical approval. Unless a time 
limitation is required by local regulations or ethical requirements, biospecimens will be 
stored indefinitely to allow for future research on the topics described here, including 
research conducted during the lengthy drug development process and also post-marketing
research. Subjects can withdraw their consent for the use of their biospecimens at any time 
by making a request to the investigator, in which event any remaining biospecimen will be 
destroyed; data already generated from the biospecimens will continue to be stored to protect 
the integrity of existing analyses. It is very unlikely that results generated from the 
biospecimens will have any clinical, diagnostic, or therapeutic implications for the individual 
study participants. Subjects are notified in the informed consent document/patient 
information sheet that their results will not be given to them, unless required by local laws or 
regulations, in which case results will be returned via the investigator. Results will not be 
provided to family members or other physicians; nor will they be recorded in the subject’s 
medical record.  There is no intention to contact subjects after completion of the clinical trial.
A 4 mL blood biospecimen, Prep D1 (K2 EDTA whole blood collection optimized for 
DNA analysis), will be collected at the Visit 1, Visit 6, and the End of Study Visit to be 
retained for potential pharmacogenomic/biomarker analyses related to drug response, unless 
prohibited by local regulations or ethics committee decision.  For example, putative safety 
biomarkers, drug metabolizing enzyme genes, drug transport protein genes, or genes thought 
to be related to the mechanism of drug action may be examined.  Additional biospecimens to 
be retained for exploratory analyses in this study include:

Prep B1 (K2 EDTA plasma collection optimized for 
biomarker/proteomic/metabonomic analysis): a 10 mL blood biospecimen will be 
collected at the Visit 1, Visit 6 and the End of Study Visit.

Prep B2 (serum collection optimized for biomarker/ proteomics/metabonomic 
analysis): a 10 mL blood biospecimen will be collected at the Visit 1, Visit 6 and the End 
of Study Visit.
The Banked Biospecimens will be collected from all subjects unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage and 
shipment instructions are provided in the central laboratory manual.  
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document/patient information sheet that 
they will not be compensated in this event.


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7.13.2. Additional Research
Unless prohibited by local regulations, subjects will be asked to indicate on the consent form 
whether they will allow the Banked Biospecimens to also be used for the following research:

Investigations of the disease under study in the clinical trial, and related conditions;

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to Pharmacogenomics/biomarkers.  
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimen specified in Markers of Drug Response Section will be used.  Subjects may still 
participate in the clinical trial if they elect not to allow their Banked Biospecimens to be used 
for the additional purposes described in this section.
7.14. Suicidality Assessment
There are no current medically significant suicidality concerns for any of the study drugs (ie, 
tofacitinib, adalimumab or etanercept) in this study or their respective mechanisms of action. 
Ongoing and aggregate cumulative safety reviews and pharmacovigilance activities will be 
conducted; if any concerns are identified that would warrant changes to these assessments, 
surveillance tools will be implemented, as appropriate.
7.15. Triggered Requirements for Monitoring 
For additional Czech Republic, Spain and United Kingdom-specific laboratory criteria, see 
Appendix 5.


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Condition
Action
Neutrophil counts <1000 cells/mm3
The subject should return to the study site for 
prompt retesting.
Persistent neutrophil counts of 500-1000 cells/mm3
Interrupt study drug until neutrophil count is 
greater than or equal to 1000 cells/mm3
Confirmed neutrophil counts <500 cells/mm3 by repeat 
testing
Discontinue study drug and follow to resolution.
Lymphocyte counts <1000 cells/mm3
The subject should return to the study site for 
prompt retesting.
Confirmed lymphocyte counts <500 lymphocytes/mm3 by 
repeat testing
Discontinue study drug and follow to resolution.
Any single AST and/or ALT elevation ≥3 x ULN
The subject 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.
2 sequential AST or ALT elevations ≥3 x ULN with a total 
bilirubin value ≥2 x ULN
If drug-induced liver injury is suspected, 
interrupt study drug until the diagnosis is 
excluded.
The subject 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 subject, 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.
Conduct study visits until end of study.
2 sequential AST or ALT elevations ≥3 x ULN with an 
abnormal INR
Permanently withdraw the subject from the 
study drug and follow to resolution. 
The subject 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 subject, 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. 
Conduct study visits until end of study.


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Condition
Action
2 sequential AST or ALT elevations ≥3 x ULN 
accompanied by symptoms consistent with hepatic injury
Permanently withdraw the subject from the 
study drug and follow to resolution. 
The subject 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 subject, 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. 
Conduct study visits until end of study.
2 sequential AST or ALT elevations ≥5 x ULN, regardless 
of Total Bilirubin or accompanying symptoms
Permanently withdraw the subject from the 
study drug and follow to resolution. 
The subject 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 subject, 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. 
Conduct study visits until end of 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).
Hemoglobin <8.0 g/dL or a decrease of 2 g/dL compared 
to baseline, confirmed by repeat testing
Interrupt the administration of study drug until 
hemoglobin values have normalized.
Serious infections (those requiring hospitalization and/or 
those requiring parenteral antimicrobials)
Interrupt study drug until the infection is 
controlled.
Surgery
Interrupt study drug 2 weeks prior to a scheduled 
surgical procedure and may resume when 
operative site is sufficiently healed and risk of 
infection is minimal.
Subjects who cannot be adequately treated for RA within 
study guidelines
Provide alternate treatment and continue the 
subject in the study. 
Pregnancy or refusal to use appropriate contraception
Permanently withdraw the subject from the study 
drug and follow any pregnancy to resolution
conducting study visits until end of study.
Use of prohibited concomitant medications
See Section 5.5 Concomitant Medication(s) of the 
protocol for specific actions.


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Condition
Action
Anaphylactic or other serious allergic reaction
Immediately discontinue study drug and institute 
appropriate therapy. Continue subject in study on 
standard of care treatment and conduct study visits 
until the end of the study
Symptoms suggestive of a lupus-like syndrome
Discontinue study drug and institute appropriate 
therapy. Continue subject in study on standard of 
care treatment and conduct study visits until the 
end of the study
Vomiting, diarrhea, or if stomatitis occurs, all of which 
may result in dehydration
Interrupt study drug until recovery occurs.
Interruption of study assigned drug for 2 months 
Must be switched to standard of care treatment
ALT = alanine aminotransferase; AST = aspartate aminotransferase; g/dL = grams per deciliter; GGT = gamma-
glutamyl transpeptidase, PT/INR = Prothrombin Time International Normalized Ratio; mm = millimeter; x ULN 
= times the upper limit of normal
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
trial.  
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  Serious adverse events occurring to a subject 
after the active reporting period has ended should be reported to the Sponsor if the 
investigator becomes aware of them; at a minimum, all serious adverse events that the 
investigator believes have at least a reasonable possibility of being related to study drug are 
to be reported to the Sponsor.


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AEs (serious and non-serious) should be recorded on the CRF from the time the subject has 
taken at least one dose of study treatment through last subject visit.  
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy;

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Infections
All treated infections occurring during the study, including, but not limited to, respiratory 
infections, cutaneous infections, urinary tract infections and episodes of suspicious or febrile 
diarrhea, should be cultured and any identified organisms noted in the CRF.


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All potential opportunistic infections will be adjudicated by an external review committee
(see Section 9.7.2 Opportunistic Infection Review Committee).
Infections should be classified as either serious infections or treated infections, as defined 
below.
8.4.1. Treated Infections
A treated infection is any infection that requires antimicrobial therapy by any route of 
administration or any surgical intervention (eg, incision and drainage).  Subjects who 
experience infections that require treatment can have their study drug temporarily 
discontinued during antimicrobial therapy.  This information should be noted in the CRF.
8.4.2. Serious Infections
A serious infection is any treated infection that requires hospitalization for treatment or 
requires parenteral antimicrobial therapy or meets other criteria that require it to be classified 
as a serious adverse event.  A subject who experiences a serious infection should have study 
drug interrupted until the subject recovers.  Appropriate laboratory investigations, including 
but not limited to cultures should be performed to establish the etiology of any serious 
infection.  All adverse events, including serious adverse events, should be reported as 
described in Section 8 on Adverse Event Reporting. All serious infections will be reviewed 
by the Opportunistic Infection Review Committee to determine whether they are potential 
opportunistic infections (Section 9.7.2).
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing (eg, temporary discontinuation of study 
drug) or discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.


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8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Lack of efficacy should be reported as an AE when it is associated with an SAE.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject, or if the event may require intervention to prevent one of the other AE outcomes, 
the important medical event should be reported as serious.
Examples of such events are 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.
8.6.1. Protocol-Specified Serious Adverse Events 
All lymphomas and lymphoproliferative disorders, regardless of causality must be reported 
as SAEs and as potential safety endpoints. 
For all other potential safety endpoint events, unless the investigator believes that there is a 
causal relationship between study drug and an event specified below, these events should not
be reported by the investigator as SAEs as described in Section 8.13.1.  These events are 
anticipated to occur in a population with rheumatoid arthritis.  However, these events should 
still be captured as adverse events in the potential safety endpoint case report form.
Protocol-specified events that will not be reported in an expedited manner:
1. Malignancies, excluding non-melanoma skin cancers.
2. Major adverse cardiovascular events (MACE).  
The definitions of MACE used in this study include the following events:

Cardiovascular death.

Death due to acute myocardial infarction (MI).


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
Sudden cardiac death.

Death due to heart failure.

Death due to stroke.

Death due to cardiovascular procedures.

Death due to cardiovascular hemorrhage.

Death due to other cardiovascular causes: peripheral artery disease.

Non-fatal myocardial infarction (MI).

Non-fatal stroke of any classification, including reversible focal neurologic 
defects with imaging evidence of a new cerebral lesion consistent with ischemia 
or hemorrhage.
Should the Data Monitoring Committee (DMC) determine that these pre-specified events 
occur more frequently in a drug treatment group, these events will be submitted and reported 
in accordance with Pfizer’s safety reporting requirements as described in Section 2.2. 
Except for the co-primary endpoints identified above, all EoIs, including EoIs that require 
adjudication (eg, hepatic events, NMSC, non-cardiovascular deaths, opportunistic infections)
will be reported as described in Section 8.13. EoIs that are adjudicated as not meeting the 
pre-specified endpoint criteria will be returned to the investigator for re-evaluation and 
submission as an AE or SAE, as appropriate.  For all EoIs returned to the investigator, the 
awareness date of the event becomes the date the EoI is received back from adjudication.
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced 
liver injury (potential Hy’s Law cases) and should always be considered important medical 
events.  
Reported transaminase elevations from both AEs and laboratory reports will be reviewed by 
the study team to identify any potential cases of drug-induced liver injury that occur during 
the course of the study; all potential cases of drug-induced liver injury will be adjudicated by 
an external review committee, which may request additional data surrounding the event to 
assist in the classification of such events (see Section 9.7.1 Hepatic Event Review 
Committee). The investigator should refer to the following guidance when evaluating 
subjects with transaminase elevations.


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The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT 3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin 2 X ULN with no evidence of hemolysis 
and an alkaline phosphatase 2 X ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
upper limit of normal, the following threshold values should be used in the definition 
mentioned above:

For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 X ULN, or 8 X ULN 
(whichever is smaller).
Concurrent with

For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased by one time the upper limit of normal or ≥3 times the 
upper limit of normal (whichever is smaller).
The subject should return to the investigational 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 
AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/INR, and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced subject, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted. All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for LFT abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
Law cases should be reported as SAEs and study drug should be interrupted at least until the 
event is resolved.
All potential cases of drug-induced liver injury will be reviewed by the Hepatic Event 
Review Committee (Section 9.7.1). 


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8.7. Hospitalization
AEs reported from studies associated with hospitalization or prolongations of hospitalization 
are considered serious.  Any initial admission (even if less than 24 hours) to a healthcare 
facility meets these criteria.  Admission also includes transfer within the hospital to an 
acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical floor to a 
coronary care unit, neurological floor to a tuberculosis unit).
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Routine emergency room admissions;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment lab abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical exam);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.


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Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
If required on the AE case report forms (CRFs), the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the AE.  For 
purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the serious adverse reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  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 (see Section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product", 
this should be clearly documented on study records.  
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.


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8.10. Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy (also 
referred to as exposure in-utero (EIU) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or being
exposed (eg, due to treatment or environmental exposure) or after discontinuing or 
having been directly exposed to the investigational product;
2. A male has been exposed (eg, due to treatment or environmental exposure) to the 
investigational product prior to or around the time of conception or is exposed during 
his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on a Serious Adverse Event (SAE) Report and 
Exposure During Pregnancy (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 subject reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) 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 pregnancy outcome information for all EDP reports with an 
unknown outcome.  The investigator will follow the pregnancy until completion or until 
pregnancy termination) and notify Pfizer of the outcome as a follow up to the initial EDP 
Supplemental Form.  In the case of a live birth, the structural integrity of the neonate can be 
assessed at the time of birth.  In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless pre-procedure test findings are 
conclusive for a congenital anomaly and the findings are reported).
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, 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 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 
serious adverse events when the investigator assesses the infant death as related or 
possibly related to exposure to investigational product.


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Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  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 study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner. The Investigator must document on the EDP 
Supplemental Form that the subject was given the Pregnant Partner Release of Information 
Form to provide to his partner.
8.11. Withdrawal Due to Adverse Events (See Also Section on Subject Withdrawal)
Please note: Subjects should not be withdrawn from the study due to adverse events. 
However, the assigned study drug may be withdrawn and is considered a withdrawal from 
the assigned treatment group. Withdrawal as described in this section refers to withdrawal 
from the assigned treatment group, as subjects should continue in the study until the study is 
completed.
Withdrawal due to AE should be distinguished from withdrawal due to insufficient response, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. Insufficient response to study medication should only be reported as an AE only when 
associated with an SAE (See Section 8.6 Serious Adverse Events). 
When a subject withdraws due to an SAE, the SAE must be reported in accordance with the 
reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject.  In addition, each study subject will be questioned about AEs.
8.13. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.13.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event. If an SAE occurs, Pfizer is to be notified within 24 hours of the site’s notification that 
an SAE has been deemed a non-endpoint and has been sent back to the site.  The 
investigator’s SAE awareness date in this instance is identified as the date that the 
investigator receives the non-endpoint SAE back from the endpoint adjudication committee.  
As noted in the Endpoints section, when the investigator has judged the SAE to have a causal 
relationship with the investigational product, the investigator must report the event to the 
sponsor within 24 hours of investigator awareness, even if that event is a component of the 
endpoint.


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In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy and exposure via 
breastfeeding cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications and illnesses must be provided.  In the case of a subject death, a summary of 
available autopsy findings must be submitted as soon as possible to Pfizer or its designated 
representative. 
8.13.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan, which will be maintained by the Sponsor.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.


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9.1. Sample Size Determination
The statistical objectives with respect to the primary safety endpoints, that is, malignancy 
(excluding non-melanoma skin cancer), and MACE, include drawing inferences with 95% 
(two-sided) confidence that the hazard ratios of the combined tofacitinib regimens versus the 
TNFi control regimen are less than 1.8.  Assuming that the true hazard ratio is 1.0 the 
required number of events is 138 for malignancies to achieve 90% power and 103 for MACE 
to achieve 80% power. 
The planned enrollment is approximately 4000 patients within 3 years (1000 in the first year 
and 1500 per year in the second and third years of recruitment). The assumed ‘dropout or 
Loss to Follow-up’ (LTFU) rate for MACE is 10% in the first year, 7% in the second and 5% 
per year, thereafter. For malignancies, because they will be followed after discontinuation 
the LTFU rate is assumed to be 5% in the first year, 3.5% in the second year and 2.5% per 
year thereafter.  The assumed event rate for MACE is 1.0 event per hundred patient-years 
and the assumed rate for malignancy is 1.1 events per hundred patient-years; assumptions are 
based on results from the CORRONA database,20 and also based on a meta-analysis of TNF-
inhibitors.21 Based on those assumptions it is expected that the trial will accrue the desired 
number of events in approximately 5 years.
Additionally, the statistical objectives with respect to the primary safety endpoints include 
drawing inferences with 95% (two-sided) confidence that the hazard ratios of the tofacitinib 
10 mg regimen to the tofacitinib 5 mg regimen are less than 2.0. Assuming that the true 
hazard ratio is 1.0 the required number of events is 87 for malignancies to achieve 90% 
power and 65 for MACE to achieve 80% power.  Based on the same assumptions of patient 
enrollment, LTFU and event rates, the trial is expected to accrue the desired number of 
events in approximately 5 years.
The trial will conclude when the required number of events (138 malignancies and 
103 MACE) has been observed.  It is likely that more than the required events may be 
observed in one endpoint in order to get the required event in another, therefore the power 
may be higher for a given endpoint (eg, more than 103 MACE events may need to be 
observed in order to observe 138 malignancy events).  The final analysis will utilize all 
observed events.  
Software for sample size and power calculation was East 5®, Cytel Inc, Boston, MA, USA.
9.2. Safety Analysis
9.2.1. Analysis of Primary Safety Endpoint
The co-primary safety endpoints of malignancies and MACE will be analyzed to provide 
comparative rates for tofacitinib vs. the combined TNFi.
The primary statistical safety objective is the estimation of the hazard ratios relative to the 
TNFi control for the two tofacitinib doses combined and for each dose of tofacitinib 
separately for the adjudicated events of MACE and malignancy excluding non-melanoma 
skin cancer.  Analysis of the primary safety endpoints will be based upon adjudicated events.


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Hazard ratios for the safety events of main interest will be calculated separately for each 
primary endpoint. The ratios for both tofacitinib doses combined versus the control, for each 
tofacitinib dose versus the control, and for the two tofacitinib doses versus each other will be 
reported along with their 95% confidence intervals. Adjustments for multiplicity will not be 
applied.
The primary statistical method for deriving estimators for hazard ratios will be the fitting of 
proportional hazards (Cox) regression models. A model containing only the single 
independent variable for treatment group will be calculated and reported. The effects of 
adding other predictors to the model, such as geographic region, age, gender, and so forth 
will be fully explored and reported.  An analysis by TNFi subset strata (ie, the sites/regions 
where either adalimumab or etanercept was used) will be conducted to assure consistency of 
results.
A Surveillance, Epidemiology, and End Results (SEER) analysis of the malignancy endpoint 
will be conducted.
Both total time (or ITT) and on treatment analyses of the main safety endpoints will be 
conducted.  The total time analysis will not censor times to event and will ascribe events to 
randomized treatment.  
The on-treatment analysis for MACE will censor subjects who crossover from tofacitinib, 
adalimumab or etanercept to standard of care at 60 days after standard of care is initiated. 
The principal analysis for malignancies will not censor for subjects crossing to standard of 
care (ie, will be the total time analysis).  
9.2.2. Analysis of Secondary Safety Endpoints
The secondary safety endpoints will include an evaluation of the following events:

Opportunistic infection events including tuberculosis (adjudicated).

Hepatic events (adjudicated).

Cardiovascular events other than MACE (adjudicated).

All AEs, including SAEs.

Clinically significant abnormal laboratory parameters.

All cause mortality (adjudicated).

Reasons for permanent or temporary discontinuation of study medication.
Adverse events and clinical laboratory abnormalities (Section 2.2.1.2) will be summarized 
according to treatment received at the time of the event.  Both ITT and on treatment analyses 
will be conducted for the other secondary endpoints listed in Section 2.2.1.2.


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9.3. Efficacy Analysis
Efficacy endpoints will include:

Change from baseline to each post-baseline scheduled visit in DAS28-4 (CRP). 
Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI). 

Rate of remission at each post-baseline scheduled visit including: 

ACR-EULAR Boolean remission (defined as the subject satisfying all of the 
following: tender joint count ≤1, swollen joint count ≤1, CRP ≤1 mg/dL, patient 
global assessment ≤1 on a 0-10 scale).

SDAI ≤3.3.

CDAI ≤2.8.

Rate of low disease activity (LDA) at each post-baseline scheduled visit including:

SDAI ≤11.

CDAI ≤10.

DAS28-4(CRP) ≤3.2.

ACR20, ACR50, and ACR70 response rate of at each post-baseline scheduled visit.

Change from baseline to each post-baseline scheduled visit in the HAQ-DI.
Descriptive statistics of efficacy endpoints for all subjects in the study will be provided from 
baseline to the declared end of the study.  Differences between each tofacitinib regimen and 
the TNFi regimen, as well as between tofacitinib regimens, will be estimated.
Details may be found in the statistical analysis plan.
9.4. Interim Analysis
No interim analysis of the study data will be performed for use outside the DMC and the 
Steering Committee. 
9.5. Data Monitoring Committee 
This study will use an external Data Monitoring Committee (DMC). 
The DMC will be responsible for ongoing monitoring of safety of subjects in the study in an 
unblinded manner according to the Charter.  All safety data, including potential primary 
endpoint data will be forwarded to, and reviewed by, the DMC on a regular basis. Based on 
these reviews, the DMC will have the capacity to make recommendations to Pfizer that might 
impact the future conduct of the trial.  The recommendations made by the DMC to alter the 


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conduct of the study will be forwarded to Pfizer and the Steering Committee for final 
decision.  Pfizer will forward such decisions, which may include summaries of aggregate 
analyses of endpoint events and of safety data which are not endpoints, to regulatory 
authorities, as appropriate.  
9.6. Steering Committee
The Steering Committee is a committee established by Pfizer to oversee the conduct of the 
trial, assess at intervals the progress of a clinical trial (ie, Performance Standards), the 
aggregate accumulation of primary endpoint events (ie, MACE and malignancies) meeting 
pre-specified criteria, and the attainment of 1500 subjects completing 3 years in the study. 
The Steering Committee will recommend to the study team whether to continue, modify or 
stop a trial, independently from the study team.  The Steering Committee will include only 
non-Pfizer trial experts who are not members of the study team.
The Steering Committee will consider the ongoing accumulation of the adjudicated primary 
endpoint events and study performance standard metrics and may determine that sufficient 
events have occurred to assess the primary objectives of the study or that it is not feasible to 
continue the trial in pursuit of the stated objectives.  These determinations by the Steering 
Committee will be made in accordance with pre-specified rules documented in the Steering 
Committee Charter and in the Statistical Analysis Plan and following consultations with the 
US FDA could result in recommendations for changes in study design, including changes in 
number of subjects studied or duration of study.  
The Steering Committee Charter will pre-specify all reviews of the data that will be 
performed during the conduct of the study and how the data will be evaluated to determine 
that study completion can be declared.
The Steering Committee will be responsible for blinded review of adjudicated, aggregate
primary endpoint data according to its charter. 
Any recommendations made by the Steering Committee to alter the conduct of the study will 
be forwarded to the study team who will confer with the US FDA prior to implementation of 
any changes in the study design. Pfizer will forward such decisions, which may include 
summaries of aggregate analyses of endpoint events and of safety data which are not 
endpoints to regulatory authorities, as appropriate.
The numbers of events necessary to achieve the targeted statistical power for the 
comparisons of the hazards for the primary endpoints with respect to the various 
combinations of treatment groups and boundaries were given in a previous section of this 
protocol.  
Additionally, the Steering Committee will maintain detailed Performance Standards (refer to
Section 13), periodically review metrics and implement corrective actions, as needed.


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9.7. External Adjudication/Review Committees
The external, independent adjudication (or review) committees that are planned for use in 
this study are described below.  All review committees will make a detailed assessment and 
follow-up of events to determine if the event meets pre-defined criteria.  To assist in this 
process, sites may be asked to submit additional data to facilitate that assessment.  The 
review and classification processes for each are defined in detail in the respective charters.
9.7.1. Hepatic Event Review Committee
The Hepatic Event Review Committee (HERC) will review, assess and categorize potential 
events of hepatic injury reported in this study.  Case review and assessment by the HERC 
will be independent of Pfizer. 
Events will be identified for adjudication by study investigators, Pfizer personnel (or 
designee) and/or by search of the clinical, safety and laboratory databases. Each reviewed 
event will be assessed as to whether the event represents drug-associated drug-induced liver 
injury (DILI).  Each case reviewed will be classified for the following categories:

Drug Induced Liver Injury (DILI).

Pattern of Injury.

Hy’s Law Case.

Severity of injury.

Recovery.

Liver Failure.

Likely, competing or alternative cause(s).
The product of the HERC will be narrative in format.  The process of adjudication will be 
defined in the Hepatic Event Review Committee’s charter.
9.7.2. Opportunistic Infection Review Committee
The Opportunistic Infection Review Committee (OIRC) will review, assess and categorize 
potential opportunistic infections (OI) reported in this study.  Case review and assessment by 
the OIRC will be independent of Pfizer.
Events will be identified for adjudication by study investigators, Pfizer personnel (or 
designee) and/or by search of the clinical and safety databases. Each potential OI will be 
assessed as to whether it meets specific criteria:  

Opportunistic Infection (type specified).

Special Interest Infection (type specified).


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
Does not meet criteria.

Unevaluable or Undetermined.
The process of adjudication will be defined in the Opportunistic Infection Review 
Committee’s charter.
Both the reported and adjudicated event terms will be reported in the study database; 
analyses will be based on adjudicated events.
9.7.3. Cardiovascular Safety Endpoint Adjudication Committee
The Cardiovascular Endpoint Adjudication Committee (CV-EAC) will evaluate and 
adjudicate selected CV safety events by a consistent set of criteria.  Case review and 
assessment by the CV-EAC will be independent of Pfizer.
Events will be identified for adjudication by study investigators, Pfizer personnel (or 
designee) and/or by search of the clinical and safety databases. Cardiovascular events to be 
adjudicated include:

Death (coronary and non-coronary).

Myocardial Infarction.

All Coronary Revascularization.

Unstable Angina.

New Ischemic Heart Disease.

Stroke (fatal and non-fatal).

Transient Ischemic Attack (TIA).

Congestive Heart Failure (CHF).

Peripheral Arterial Vascular Disease (PAVD) – first diagnosis or procedure.

Deep Vein Thrombosis

Pulmonary Embolism

Arterial Embolism

Arterial Thrombosis
The process of adjudication will be defined in the Cardiovascular Endpoint Adjudication 
Committee’s charter.


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Both the reported and adjudicated event terms will be reported in the study database; 
analyses will be based on adjudicated events.
9.7.4. Malignancy Adjudication Committee and Histopathology Over-read
The Malignancy Adjudication Committee (MAC) will review, assess and categorize potential 
malignancies reported in this study. Case review and assessment by the MAC will be 
independent of Pfizer.
Events will be identified for adjudication by study investigators, Pfizer personnel (or 
designee) and/or by search of the clinical and safety databases. Each potential event will be 
assessed as to whether 1) it meets criteria for classification as a malignancy and 2) the type of 
malignancy.
Additionally, any biopsy that is performed to evaluate the potential presence of a malignant 
process will be reviewed independently by blinded, board-certified pathologists at a central 
laboratory.
This includes any biopsy performed to evaluate a potential malignancy in which the local 
pathology evaluation is consistent with either a benign process, a “pre-malignant process” or 
dysplasia, and includes cases of basal cell carcinoma and squamous cell carcinoma of the 
skin, and carcinoma in situ of the cervix. Pathology review will also include procedures 
performed for other reasons (ie, cosmetic surgery or removal of ischemic tissue) in which a 
malignancy is identified by the local pathology evaluation. Histopathology review will not 
encompass routine screening procedures for dysplasia such as a Papanicolaou (Pap) smear 
but will encompass cervical biopsy procedures as follow-up for abnormal Pap smear 
findings.
The MAC will review case information including patient history, diagnostic tests such as 
imaging, local biopsy results, central pathologist’s diagnosis, surgical outcomes and other 
medical records as appropriate and available.
The local pathologist’s diagnosis and the central pathologist’s diagnosis, as well as both the 
reported and adjudicated event terms will be reported in the study database.
9.8. Additional Safety Event Review Committees
Additional safety event review committees may be established for review of specific events, 
such as interstitial lung disease and gastrointestinal (GI) perforations, to enhance the 
specificity and accuracy of reporting for these events.  
These safety event review committees may be internal or external and will be independent of 
the study teams.
The review process will be defined in the respective committee charters. As for external 
review committees, sites may be asked to submit additional data to facilitate that assessment.


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10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities.
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.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's records or the physician's subject chart.  
In these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.


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11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 and 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.


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12.3. Subject Information and Consent
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.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC before use, and available for inspection.
The investigator must ensure that each study subject, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legal representative before any study-specific 
activity is performed. The investigator will retain the original of each subject's signed 
consent document.
12.4. Subject Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.  
12.5. 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 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which 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 subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. PERFORMANCE STANDARDS
During the study, the following performance standards will be monitored and evaluated. 
Metrics will be reported to the Steering Committee and additional measures may be taken by 
the Steering Committee to ensure the study integrity and timely completion of the study.  The 
Steering Committee will maintain a Performance Standard Document with a complete 
description of the performance standards applied to this study, acceptable targets and 
remedial steps to be taken if not satisfactorily met.  An overview of the performance 
standards is presented here.
13.1. Enrollment Rate Performance Standard
The purpose of this performance standard is to identify an acceptable rate of enrollment that 
allows subjects to be enrolled in the study at a rate sufficient to provide acceptable data to 
allow interpretation of the study endpoints within the requirements of this protocol.  An 
acceptable target rate of enrollment provides guidance to the operational study team in 
determining the country footprint of the study and ultimately the selection of sites. 
During the first 12 months of the study, sites will be in various stages of start-up; the 
recruitment rate is expected to gradually increase relative to the number of sites actively 
recruiting and then remain stable through the recruitment period. The sample size and 
recruitment period may vary dependent upon the Steering Committee’s recommendations to 
the study team. A minimum of approximately 4000 subjects randomized over approximately 
a 3-year recruitment period with at least 1500 subjects completing approximately 3 years in 
the study is expected and the target number of events for MACE and malignancies has been 
achieved.
The target rate of enrollment for this study is to randomize all subjects by the end of the 
recruitment period. Recruitment rates are followed monthly by study, region and investigator 
site.  
This study is being managed by an Alliance Partner. The Alliance Partner will have 
risk/mitigation plans in place to identify specific remedial actions to be taken, depending on 
the reason for variance from the expected recruitment rate; these actions will be implemented 
as appropriate (Clinical Trial Process Quality Standard (CTPQS)-106 Plan and Manage 
Study Execution, Version 3, Effective Date: 15-Feb-2013).
If recruitment falls below 100 subjects per month for 3 consecutive months and all sites 
planned have been initiated, the study team will identify the issues impacting recruitment and 
implement appropriate strategies if feasible, which may include increasing the number of 
sites participating in the study, providing recruitment tools to sites, which may include the 
development of site-specific advertisements and brochures, and/or retraining of sites to 
increase enrollment.


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13.2. Target Population Performance Standard
The purpose of this performance standard is to identify the acceptable target population to be 
recruited into this study. 
The acceptable population is defined as subjects 50 years of age or older with active 
rheumatoid arthritis and cardiovascular risk factors that meet all inclusion criteria for the 
study as defined in Section 4.1 Inclusion Criteria and that do not have evidence of any 
exclusion criteria as defined in Section 4.2 Exclusion Criteria.
The performance standard for this study is that all subjects enrolled in the study meet the 
definition for inclusion.
Inclusion and exclusion criteria are monitored as subjects are enrolled in the study. Subjects 
are noted as protocol deviations if they do not meet the criteria for inclusion in the study (see 
Section 13.4 Subject Ineligibility Performance Standard). If a subject who is identified as not 
meeting the criteria is randomized to study drug, appropriate steps will be taken by the study 
team, including immediate withdrawal of the subject, if warranted to protect the safety of the 
subject.
Subjects who were not completely eligible for inclusion in the study for reasons that impact 
the analysis of the study endpoints will be excluded from the Per Protocol Analysis Set, but 
included in the Full Analysis Set.
This study is being managed by an Alliance Partner. The Alliance Partner will have 
risk/mitigation plans in place to identify specific remedial actions to be taken, depending on 
the reason for deviation for including subjects that do not meet the inclusion/exclusion 
criteria; these actions will be implemented as appropriate (CTPQS-106 Plan and Manage 
Study Execution, Version 3, Effective Date: 15-Feb-2013).
13.3. Primary Endpoint Safety Event Rate Performance Standard
The purpose of this performance standard is to prospectively identify the presumed rate at 
which the primary endpoint safety events occur during the study to inform decisions 
regarding enrollment or length of the study.
There are two co-primary endpoints in this study; major adverse cardiovascular events 
(MACE) and malignancies.
The performance standard for this study is the rate of MACE, which is 1.0 event per hundred 
patient-years, and the assumed rate for malignancy, which is 1.1 events per hundred patient-
years.
Rates of events will be calculated for the blinded treatment groups for use by the Steering 
Committee periodically and will guide the Steering Committee in making recommendations 
regarding the sample size or length of study needed to evaluate the comparative endpoints.  
Rates significantly higher than expected may result in recommendation for a smaller study, 
while rates significantly lower than expected may result in a recommendation for a larger, 


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longer study or discontinuation of the study for infeasibility.  All modifications to the study 
design will be made only following consultations with the US FDA.
13.4. Subject Ineligibility Performance Standard
The purpose of this performance standard is to identify the standard by which deviations 
from the protocol are identified that may render subjects ineligible for continued inclusion in 
the study or in statistical analyses of the study.
Protocol deviation identification and documentation will be accomplished for this study 
according to the Sponsor’s standard operating procedures (SOPs) that require periodic review 
of individual protocol deviations and periodic review of aggregated cumulative protocol 
deviations.  Prior to initiation of the study, a list of potentially important protocol deviations 
(pIPDs) is developed in alignment with the requirements of the protocol. This list is updated, 
as necessary, to include other deviations identified during the course of the study.  Monitors 
identify and log all protocol deviations during the course of the study at each participating 
site. Additionally, pIPDs are prospectively identified; pIPDs are used by the statistician and 
clinician in determining eligibility for inclusion in the statistical analysis of the study and are 
considered for inclusion in the body of the clinical study report.  An initial assessment of the 
individual protocol deviations is made by the study clinician.  Review of individual and 
aggregate cumulative protocol deviations, which include all aspects of subject participation 
in the study, are used by the study team to understand study issues and evaluate the protocol, 
including operational procedures, to identify areas where retraining may be required or 
modification to procedures are necessary for compliance to the protocol. 
Periodic and aggregate cumulative adverse events, serious adverse events and abnormal 
laboratory findings are reviewed by the study clinician to identify expected and unexpected 
safety signals and to identify subjects who potentially should be discontinued from the study.  
If an event is identified that would require subject discontinuation, the site is informed of this 
finding by the study team and if the subject is found to require discontinuation, 
discontinuation is required.
The performance standard for this study is at least monthly review of individual protocol 
deviations, adverse events and laboratory abnormalities with aggregate cumulative review of 
these events at least quarterly during the conduct of the study and once after database lock.
If the clinician determines that a protocol deviation affected the safe use of study drug in a 
manner that directly resulted in a serious adverse event (SAE), exposure during pregnancy, 
or was likely to recur and could affect the safe use of the drug in a manner that would likely 
result in an SAE or exposure during pregnancy, the event is forwarded to a cross-functional 
team that assesses the documentation and determines if the event meets the criteria, a 
protocol deviation alert letter, explaining the deviation is sent to participating investigators. 
If unexpected signals are identified in the safety database, the event(s) will be brought to the 
Safety Risk Management Committee for review and evaluation across all studies in the 
tofacitinib program and reported internally and externally, as required for the event.


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Subjects with pIPDs that could impact endpoint analysis will be excluded from the Per 
Protocol Analysis Set, but included in the Full Analysis Set.
This study is being managed by an Alliance Partner. The Alliance Partner will have 
risk/mitigation plans in place to identify specific remedial actions to be taken, depending on 
the reason for ineligibility of the subject; these actions will be implemented with specific 
steps taken dependent upon the reason for the deviation (CTPQS-106 Plan and Manage 
Study Execution, Version 3, Effective Date: 15-Feb-2013).
13.5. Adherence to Assigned Treatment Performance Standard
The purpose of this performance standard is to identify the standard by which subjects are 
determined to be compliant with their assigned treatment during the study and how they will 
be handled in the analysis of study data.
Adherence to the assigned treatment is necessary to the integrity of the study analysis, which 
is dependent upon exposure to the assigned treatments.  Compliance is determined by pill 
and syringe counts as described in Section 5.3.5 and study treatment and concomitant 
medication dosing logs. 
There are several performance standards for compliance for this study:

< 80% compliant with the dosage regimen for any one of the orally administered 
study medications or have not used 2 or more injectable syringes expected to be used 
over the time between scheduled visits.

These subjects will be counseled and the site will implement appropriate 
measures to secure subject compliance, including instituting interim visits to 
evaluate and encourage compliance, as appropriate to the site and reason for non-
compliance. 

< 70% compliant with the dosage regimen for any one of the orally administered 
study medications or have not used 2 or more injectable syringes expected to be used 
over the time between scheduled visits.

The reason for non-compliance with the dosing regimen should be documented in 
the dosing log of the subject’s case report form, and should be reported as a 
protocol deviation and unless there is a protocol stipulated reason for non-
compliance with the dosing regimen, this should be recorded as a dosing error. 

> 120% compliance with the dosing regimen for any one of the orally administered 
study medications or have not used 2 or more injectable syringes expected to be used
over the time between scheduled visits.

The reason for non-compliance (more than expected consumption) with the 
dosing regimen should be documented in the dosing log of the subject’s case 


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report form with the reason for non-compliance, reported as a protocol deviation, 
and recorded as a dosing error. 
Subjects who are found to be <70% or >120% compliant with the dosage regimen for any 
one of the study medications at any time during the study will be censored from efficacy 
analyses utilizing the Per Protocol Analysis Set, but will be included in analyses utilizing the 
Full Analysis Set.
This study is being managed by an Alliance Partner. The Alliance Partner will have 
risk/mitigation plans in place to identify specific remedial actions to be taken, depending on 
the reason non-compliance with the dosing regimen; these actions will be implemented if the 
event exceeds the respective performance standard (CTPQS-106 Plan and Manage Study 
Execution, Version 3, Effective Date: 15-Feb-2013).
13.6. Cross-Ins Performance Standard
Subjects will either remain in their respective assigned treatment (tofacitinib 5 mg BID, 
tofacitinib 10 mg BID, adalimumab 40 mg QOW or etanercept 50 mg weekly) or be 
identified as being switched to standard of care, which may include tofacitinib, adalimumab 
or etanercept if those compounds are standard of care in their locality. Therefore, a 
performance standard for Cross-Ins is not relevant to this study.
13.7. Subject Retention Performance Standard
The purpose of this performance standard is to identify subject retention performance 
standards and to define the actions to be taken if the performance standard is not met.
The performance standard for subject retention within their assigned treatment group is an 
assigned treatment discontinuation rate of approximately 15% annually during the conduct of 
the study with higher discontinuation rates seen during the first year of the study.
The expected assigned treatment discontinuation rates were developed from overall 
discontinuation rates seen in tofacitinib RA Phase 2/3 studies and the Long-Term Extension 
Studies and have been applied to this study as the projected performance standard for subject 
retention within their assigned treatment group.  
Discontinuation rates, including reason for discontinuation, are collected and reviewed by the 
study clinician periodically during the study. Discontinuation rates will be evaluated at least 
monthly for trends in total rates and components of these rates (eg, adverse events, 
insufficient clinical response, no longer willing to participate). 
This study is being managed by an Alliance Partner. The Alliance Partner will have 
risk/mitigation plans in place to identify specific remedial actions to be taken, depending on 
the reason for the increased rate in discontinuation; these actions will be implemented if the 
rate of discontinuation exceeds the performance standard. However, intermediate 
interventions may be applied if component rates are trending upwards and reasons can be 
identified and addressed by the study team (eg, inappropriate subject selection, retraining of 


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sites, etc) (CTPQS-106 Plan and Manage Study Execution, Version 3, Effective Date: 
15-Feb-2013).
13.8. Timeliness of Data Performance Standard
The purpose of this performance standard is to evaluate timeliness of data entry and define 
actions to be taken if the performance standard is not met.
The performance standard for timeliness of data entry is compliance to the requirement that 
investigators complete data entry into the case report form (CRF) within four (4) calendar 
days of that data becoming available. 
This study is being managed by an Alliance Partner. The Alliance Partner will have a process 
in place to monitor timely CRF data entry that includes monthly monitor review of 
investigator performance to data entry timelines and a structured action plan and 
escalation/communication process triggered by site performance with data entry timelines 
(CTPQS-113 Study Site Initiation, Monitoring and Closure, Version 5, Effective Date: 
15-Feb-2013). 
14. DEFINITION OF END OF TRIAL
14.1. End of Trial in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
14.2. End of Trial in all Other Participating
End of Trial in all other participating countries is defined as that time when sufficient 
subjects have been recruited and completed the study (or the study is prematurely terminated 
by the Sponsor) and the database has been locked for the final study analysis.
15. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, a recommendation by the DMC, a 
recommendation by the Steering Committee, or at the discretion of Pfizer.  In addition, Pfizer 
retains the right to discontinue development of tofacitinib for use in patients with rheumatoid 
arthritis at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within one week.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.


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16. PUBLICATION OF STUDY RESULTS
16.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov). Pfizer registers study 
protocols and posts Basic Results on ClincialTrials.gov for Pfizer-sponsored interventional 
studies in human subjects that evaluate the safety and/or efficacy of a Pfizer product.
The results are posted in a tabular format called Basic Results. 
For studies involving a Pfizer product, the timing of the posting depends on whether the 
Pfizer product is approved for marketing in any country at the time the study is completed:

For studies involving products applicable under the US Food and Drug 
Administration Amendments Act of 2007 (FDAAA), ie, FDA-approved products, 
Pfizer posts results within one year of the primary completion date (PCD). For studies 
involving products approved in any country, but not FDA approved, Pfizer posts 
results one year from last subject, last visit (LSLV);

For studies involving products that are not yet approved in any country, Pfizer posts 
the results of already-completed studies within 30 days of  US regulatory approval, 
or one year after the first ex-US regulatory approval of the product (if only submitted 
for approval ex-US);

For studies involving products whose drug development is discontinued before 
approval, Pfizer posts the results within one year of discontinuation of the program (if 
there are no plans for outlicensing or within two years if outlicensing plans have not 
completed).
Primary Completion Date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical trial concluded according to the pre-specified protocol or was 
terminated.
16.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug. However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed. If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.


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Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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17. REFERENCES
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O’Sullivan LA, Liongue C, Lewis RS, et al. Cytokine receptor signaling through the 
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Strand V, Singh JA. Improved health-related quality of life with effective disease-
modifying antirheumatic drugs: evidence from randomized controlled trials. Am J 
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inhibitor of JAK kinases, CP-690,550, and inhibition of specific JAK/STAT pathways 
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International Inflammation Research Association Conference, Chantilly, Virginia, 21-
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Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, et al. Phase IIb 
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Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, et al. A 
phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus 
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rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum 
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12.
Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. 
Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J 
Med 2012;367:495-507.
13.
Burmester G, Blanco R, Charles-Schoemann C, Wollenhaupt J, Zerbini C, Benda B, et 
al. Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in combination with 
methotrexate, in patients with active rheumatoid arthritis with an inadequate response to 
tumor necrosis factor-inhibitors: a 6-month Phase 3 study [Abstract]. Arthritis Rheum 
2011;63:S279.
14.
van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garcia Meijide JA, Wagner S, 
et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 
2012;367:508-19.
15.
Kremer JM, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, et al. 
Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in combination with traditional 
DMARDS: a Phase 3 efficacy and safety study in patients with active rheumatoid 
arthritis with an inadequate response to DMARDs [Abstract]. Ann Rheum Dis 
2011;70:170.
16.
Aletaha D, Neogi T, Silman AJ et al. (September 2010). "2010 rheumatoid arthritis 
classification criteria: an American College of Rheumatology/European League Against 
Rheumatism collaborative initiative". Ann. Rheum. Dis. 69 (9): 1580–8. 
doi:10.1136/ard.2010.138461. PMID 20699241.
17.
Fries JF, Spitz PW, Young DY.  The dimensions of health outcomes: the health 
assessment questionnaire, disability and pain scales.  J Rheumatol 1985; 9 (5):789-93.
18.
Ware JE, Kosinski M, Dewey JE.  How to score Version 2 of the SF-36 Health Survey 
(Standard & Acute forms).  In: How to score Version 2 of the SF-36 Health Survey 
(Standard & Acute forms).  Lincoln, Rhode Island: QualityMetric, Incorporated; 2000: 
235 pages.
19.
Hurst NP, Kind P, Ruta D, et al.  Measuring health-related quality of life in rheumatoid 
arthritis: validity, responsiveness and reliability of EuroQol (EQ-5D).  Br J Rheumatol 
1997; 36 (5):551-9.
20.
CORRONA data analysis.  Data on File, Pfizer Inc.
21.
Meta-analysis of TNF inhibitors. Data on File, Pfizer Inc.
22.
Hicks KA, Hung J, Mahaffey KW, et al. Standardized Definitions for Cardiovascular 
and Stroke End Point Events in Clinical Trials. Draft Definitions for Testing, 2012. 
Available at the website: www.cardiac-safety.org/think-tanks/ecrf-forms-
forposting/Draft%20Definitions%20for%20Testing%20November%209-
%202012%20with%20MI%20Preamble%20CLEAN.pdf 


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Appendix 1. The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for 
Rheumatoid Arthritis16
Score
Target population (Who should be tested?): Patients who
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)‡
Joint involvement§
1 large joint¶
2-10 large joints
1-3 small joints (with or without involvement of large joints)#
4-10 small joints (with or without involvement of large joints)
>10 joints (at least 1 small joint)**
0
1
2
3
5
Serology (at least 1 test result is needed for classification)††
Negative RF and negative ACPA
Low-positive RF or low-positive ACPA
High-positive RF or high-positive ACPA
0
2
3
Acute-phase reactants (at least 1 test result is needed for classification)‡‡
Normal CRP and  normal ESR
Abnormal CRP or abnormal ESR
0
1
Duration of symptoms§§
<6 weeks
≥6 weeks
0
1
*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.


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#“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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Appendix 2. Prohibited Concomitant Medications
Prohibited drugs, including investigational compounds, require discontinuation for at least 
7 days or 5 half lives (whichever is longer) prior the Baseline visit.  All investigational 
compounds, other than study drug, are prohibited during the study. Only systemically 
administered drugs listed below are prohibited; topical, ophthalmic, or intravaginal
administration is allowed.
Prohibited Concomitant Medications
Potent CYP3A/CYP2C19 Inhibitors 
Moderate or Potent CYP3A Inducers
Protease inhibitors:
Protease inhibitors:
indinavir (Crixivan)
efavirenz (Sustiva)*
nelfinavir (Viracept)
nevirapine (Viramune)*
ritonavir (Kaletra, Norvir)
Anticonvulsants:
Saquinavir (Invirase)
barbiturates*
Macrolide antibiotics:
phenobarbital*
clarithromycin  (Biaxin, Prevpac)
phenytoin (Dilantin, Phenytek)
telithromycin (Ketek)
carbamazepine (Carbatrol, Tegretol)*
Other antibiotics:
Antibiotics:
chloramphenicol 
rifampicin/rifampin (Rifadin, Rifamate)
Antifungals:
rifabutin (Mycobutin)*
fluconazole (Diflucan)
rifapentene (Priftin)*
ketoconazole (Nizoral)
Antidepressants:
itraconazole (Sporanox)
voriconazole (Vfend)
St.  John's Wort*
Antidepressants:
Other compounds:
fluvoxamine (Luvox)
modafinil (Provigil)
nefazodone (Serzone)
troglitazone (Rezulin)
Prohibited Concomitant DMARDs**
Biologic DMARDs 
Nonbiologic DMARDs
anakinra (Kineret), etanercept (Enbrel), 
adalimumab (Humira), infliximab 
(Remicade), abatacept (Orencia), 
tocilizumab (Actemra), rituximab 
(Rituxan, Mabthera)
Oral gold (auranofin), injectable gold 
(aurothioglucose, aurothiomalate), 
sulfasalazine, d-penicillamine, 
bucillamine, mizoribin, azathioprine, 
leflunomide (Arava), cyclosporine, 
tacrolimus
* Discontinue for at least 30 days
**See Section 5.5.2 for specific washout requirements and Section 5.6.1 for using standard of care treatment in 
subjects who are not controlled with their respective study drug.


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Appendix 3. Cockcroft-Gault Formula for Estimating GFR
Creatinine Clearance (estimated) / Conventional mL/min =
((140 - Age (years)) X Weight (kg) X Factora) / (72 X Serum Creatinine (mg/dL))
a Factor is equal to 0.85 in females and 1.00 in males.


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Appendix 4. Sweden-Specific Protocol Requirements
The content of this Appendix is deleted as no subject was screened or enrolled in Sweden.
Appendix 5. Czech Republic, Spain and United Kingdom Specific Protocol 
Requirements
In the Czech Republic, Spain and the United Kingdom, the following changes have been 
made to the protocol sections listed:
4.2. Exclusion Criteria
Additional exclusion criteria apply:
6. c.  Absolute lymphocyte count <0.75 x 109/L (<750/mm3)
6. d.  Absolute neutrophil count <1.2 x 109/L (<1200/mm3)
7.10 Clinical Laboratory Tests 
Subjects in the listed countries who are randomized to and are receiving tofacitinib will have 
additional laboratory testing performed.  Lymphocyte subset assessments will be conducted 
at each study visit (Baseline, Month 2, Month 3 and every 3 months thereafter). The 
lymphocyte subsets and markers to be tested are identified in Table 4.
Table 4.
Lymphocyte Subsets and Markers
Subsets
Markers
Total T cells
CD3+
CD4+ T cells
CD3+CD4+
CD8+ T cells
CD3+CD8+
NK cells
CD3-CD16+CD56+
B cells
CD3-CD19+
7.15 Triggered Requirements for Monitoring 
Additional requirements for discontinuation of study drug include:

Opportunistic infection judged significant by the investigator.

Two sequential neutrophil counts <1000 neutrophils/mm3.


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Appendix 6. Canada Specific Requirements for the Use of Two Methods of Effective 
Contraception.
Subjects in Canada who are woman of childbearing potential and sexually active must use 
two contraceptive methods at the same time, one highly effective contraceptive method and 
one additional effective contraceptive method. 
Highly effective contraceptive methods may include hormonal contraceptives (eg, combined 
oral contraceptives, patch, vaginal ring, injectables, and implants), intrauterine device (IUD) 
or intrauterine system (IUS), vasectomy or tubal ligation.
Effective methods may include barrier methods of contraception (eg, male condom, female 
condom, cervical cap, diaphragm or contraceptive sponge).  The proper use of diaphragm or 
cervical cap includes use of spermicide and is considered one barrier method. The cervical 
cap and contraceptive sponge are less effective in parous women. The use of spermicide 
alone is not considered a suitable barrier method for contraception.


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SAP_001.pdf: 
Protocol A3921133 Statistical Analysis Plan Version 5 (Amendment 4) Final
PFIZER CONFIDENTIAL
Page 1
Protocol A3921133
PHASE 3B/4 RANDOMIZED SAFETY ENDPOINT STUDY OF 2 DOSES OF 
TOFACITINIB IN COMPARISON TO A TUMOR NECROSIS FACTOR (TNF) 
INHIBITOR IN SUBJECTS WITH RHEUMATOID ARTHRITIS 
Statistical Analysis Plan 
(SAP)
Version:
5 (Amendment 4)
Date:
08-Jul-2020


Protocol A3921133 Statistical Analysis Plan Version 5 (Amendment 4) Final
PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS 
TABLE OF CONTENTS...........................................................................................................2
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..............................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................6
2. INTRODUCTION .................................................................................................................9
2.1. Study Design ...........................................................................................................10
SCHEDULE OF ACTIVITIES BY VISIT (SCREENING – MONTH 6)..............................12
SCHEDULE OF ACTIVITIES BY VISIT (MONTH 9- END OF STUDY) .........................13
2.2. Study Objectives .....................................................................................................14
2.2.1. Safety Objective..........................................................................................14
2.2.2. Efficacy Objective ......................................................................................14
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING................................14
4. HYPOTHESES AND DECISION RULES.........................................................................15
4.1. Statistical Hypotheses .............................................................................................15
4.2. Statistical Decision Rules........................................................................................15
5. ANALYSIS SETS ...............................................................................................................15
5.1. Full Analysis Set .....................................................................................................15
5.2. ‘Per Protocol’ Analysis Set .....................................................................................15
5.3. Safety Analysis Set..................................................................................................15
5.4. Treatment Misallocations........................................................................................16
5.5. Protocol Deviations.................................................................................................16
5.5.1. Deviations Assessed Prior to Randomization.............................................16
5.5.2. Deviations Assessed Post-Randomization..................................................16
6. ENDPOINTS AND COVARIATES ...................................................................................17
6.1. Efficacy Endpoints ..................................................................................................17
6.2. Safety Endpoints .....................................................................................................17
6.3. Other Endpoints.......................................................................................................22
6.3.1. Pharmacokinetics Endpoints.......................................................................22
6.3.2. Pharmacodynamics Endpoints....................................................................22
6.3.3. Outcomes Research Endpoints ...................................................................22
6.4. Covariates................................................................................................................23
7. HANDLING OF MISSING VALUES ................................................................................23


Protocol A3921133 Statistical Analysis Plan Version 5 (Amendment 4) Final
PFIZER CONFIDENTIAL
Page 3
7.1. Safety Data ..............................................................................................................23
7.1.1. Censoring Time for Time-to-event.............................................................24
7.2. Efficacy Data...........................................................................................................25
7.2.1. Outcomes Research Endpoints ...................................................................25
7.3. Missing Data due to COVID-19 Pandemic.............................................................26
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................26
8.1. Statistical Methods ..................................................................................................26
8.1.1. Analyses of Time-to-Event Data ................................................................26
8.1.2. Analyses of Incidence Rates.......................................................................26
8.1.3. Analyses of Continuous Efficacy Data.......................................................28
8.1.4. Analyses of Binary Efficacy Data ..............................................................28
8.2. Statistical Analyses .................................................................................................28
8.2.1. Primary Analysis ........................................................................................29
8.2.2. Analyses of Other Safety Endpoints...........................................................30
8.2.3. Analyses of Efficacy Endpoints..................................................................31
8.2.4. Analyses of Outcome Research Endpoints.................................................31
8.2.5. Subgroup Analyses by Age ........................................................................32
9. REFERENCES ....................................................................................................................33
10. APPENDICES ...................................................................................................................34
LIST OF FIGURES
Figure 1.
Study Design (minimum 1300 per arm, total N=4000)............................11
APPENDICES
Appendix 1. DATA DERIVATION DETAILS ......................................................................34
Appendix 1.1. Definition and Use of Visit Windows in Reporting.........................................34
Appendix 1.2. Definition of Protocol Deviations that Relate to Statistical 
Analyses/Populations................................................................................36
Appendix 1.3. Definition of Analysis Populations/Sets ..........................................................36
Appendix 1.4. Further Definition of Endpoints.......................................................................36
Appendix 2. STATISTICAL METHODOLOGY DETAILS..................................................37
Appendix 2.1. Further Details of Interim Analyses.................................................................37
Appendix 2.2. Further Details of the Statistical Methods........................................................37


Protocol A3921133 Statistical Analysis Plan Version 5 (Amendment 4) Final
PFIZER CONFIDENTIAL
Page 4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
ACR
American College of Rheumatology
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Transaminase
ATE
Arterial Thromboembolism
BID
Twice Daily
BMI
Body Mass Index
CaPS
CDISC and Pfizer Standard
CDAI
Clinical Disease Activity Index
CI
Confidence Interval
CRF
Case Report Form
CRP
C-reactive Protein
CSR
Clinical Study Report
CXR
Chest X-Ray
DAS
Disease Activity Score
DILI
Drug-induced Liver Injury
DMARD
Disease Modifying Antirheumatic Drug
DMC
Data Monitoring Committee
DVT
Deep Vein Thrombosis
ECG
Electrocardiogram
EQ-5D/EuroQol - 5D
European Quality of Life - 5 Dimensions
EQ-VAS
EuroQol Visual Analog Scale
EULAR
European League against Rheumatism 
FAS
Full Analysis Set
GI
Gastrointestinal
HAQ-DI
Health Assessment Questionnaire-Disability Index
HDL-c
High Density Lipoprotein Cholesterol
IEC
Independent Ethics Committee
INH
Isoniazid
IRB
Institutional Review Board
JTS
Joints
LDA
Low Disease Activity
LDL-c
Low Density Lipoprotein Cholesterol
LLA
Lipid Lowering Agent
LOCF
Last Observation Carried Forward
LSM
Least Squares Mean
MACE
Major Adverse Cardiovascular Event
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial Infraction
MMRM
Mixed Model for Repeated Measures
NMSC
Non-melanoma Skin Cancer


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Page 5
Abbreviation
Definition
NSAID
Nonsteroidal Anti-inflammatory Drug
OI
Opportunistic Infection
PASS
Post Authorization Safety Study
PD
Protocol Deviation
PE
Pulmonary Embolism
pIPD
Potentially Important Protocol Deviation
QFT
QuantiFERON-TB Gold
QOW
Every Other Week
RA
Rheumatoid Arthritis
SDAI
Simplified Disease Activity Index
SAE
Serious Adverse Event
SAS
Safety Analysis Set
SC
Subcutaneous Injection
SEER
Surveillance, Epidemiology, and End Results
SF-36
Short Form Health Survey - 36 Items
SIR
Standardized Incidence Ratio
SMQ
Standardized MedDRA Query
SOP
Standard Operation Procedure
TB
Tuberculosis
TEAE
Treatment Emergent Adverse Event
TNFi
Tumor Necrosis Factor Inhibitor
TST
Tuberculin Skin Test
ULN
Upper Limit of Normal
US FDA
United States Food and Dru Administration
VAS
Visual Analog Score
WPAI
Work Productivity Impairment


Protocol A3921133 Statistical Analysis Plan Version 5 (Amendment 4) Final
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Page 6
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Document
Version Date
Summary of Changes
Original SAP (Version 1)
1-May-2013
N/A
Amendment 1 (Version 2)
26-Jan-2014
1.
The study has not started to enroll patients. This 
amendment incorporates changes made to the 
original SAP, which are also aligned with the 
changes made in Amendments 1-3 to the protocol.
Major changes are:
2.
Eliminated the double-blind efficacy sub-study and 
related contents.
3.
Removed MOS Sleep scale, FACIT-Fatigue, and 
RA Healthcare Resource Utililization
Questionnaires from the endpoints.
4.
Changed comparator from all adalimumab to TNFi 
(adalimumab in US, Puerto Rico and Canada, with 
etanercept in the rest of world).
5.
Increased N from 3900 to approximately 4000.
6.
Have all patients on background methotrexate.
7.
Eliminated interim analysis.
8.
Clearly stated statistical hypotheses for the primary 
objectives.
9.
Updated statistical decision rules corresponding to 
the statistical hypotheses.
10. Changed Safety Analysis Set to be the set 
containing subjects randomized and had at least one 
dose of drug (the same as Full Analysis Set). It had
all treated subjects with at least one dose of drug 
regardless of randomized or not.
11. Clarified the application for the analysis data sets:
12. Safety Analysis Set will be used for all safety 
endpoints;
13. Full Analysis Set will be used for all efficacy and 
outcome research endpoints;
14. Per Protocol Analysis Set will be used for
robustness analysis of the primary safety endpoints.


Protocol A3921133 Statistical Analysis Plan Version 5 (Amendment 4) Final
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Page 7
Document
Version Date
Summary of Changes
15. Added reference for endpoint definitions and 
clarification regarding endpoint composite for 
MACE in section 6.2.
16. Added gender as one of the covariates.
17. Changed the cutoff visit for missing data 
imputation from Month 6 (which corresponded to 
the deleted sub-efficacy study) to Month 36.
18. Clarified missing data handling for continuous 
endpoints: LOCF for component scores before 
subjects withdraw, and BOCF for component 
scores after subjects withdraw, to align with the 
approach for binary composite endpoints.
19. For continuous endpoints, changed MMRM model 
approach to t distribution based estimation for
two-sample comparison.
20. For binary safety data, dropped logistic model 
approach from section 8.1.
21. Changed 3-month attribution window for AEs and 
malignancies to 60 days in the estimation of crude 
incidence rates in section 8.1.1 to align with the
attribution window defined in time-to-event 
analyses.
22. Added definition of Tier-3 events in the 3-tier 
method.
23. Eliminated the day 14 visit, and modified cutoff 
days for the window definition for month 2, 3, 6, 9 
visits in the appendices.
24. Typographical corrections and clarifications.
Amendment 2 (SAP 
version 3)
13-May-2019
1.
Section 2.1: provided safety information based on 
protocol amendment 8 regarding subjects who 
randomized to tofacitinib 10 mg BID.
2.
The definition of Per-Protocol Analysis Set was 
modified to be more clear.
3.
Section 6.1: removed the reference statement about 
Pfizer rulebook.
4.
Section 6.2: added following endpoints: DVT, PE, 
ATE, DVT or PE. Updated definition of 
thromboembolic events.


Protocol A3921133 Statistical Analysis Plan Version 5 (Amendment 4) Final
PFIZER CONFIDENTIAL
Page 8
Document
Version Date
Summary of Changes
5.
Added Section 7.1.1 specified the rules of counting 
the time to event, the text was removed from 
Section 5.3 (Safety Analysis Set) to Section 7.1.1.
6.
Section 7: specified that no imputation will be done 
for safety endpoints, and no imputation will be 
done for efficacy endpoints after the declared study 
completion day.
7.
Section 8: specified that data collected after 
subject’s discontinuation from the study will be 
summarized separately from the analyses described 
in this SAP.
8.
Section 8.2: clarified that all analyses identified for 
the tofacitinib 10 mg BID treatment arm will be 
conducted as stated prior to protocol amendment 8.
9.
Section 8.2.2: clarified how data collected under 
standard of care will be summarized for TEAE. 
10. Section 8.2.2: removed 3-tier analysis of AEs.
11. Section 8.2.2: added TEAE definition.
12. Section 8.2.2: added endpoint of DVT, PE, ATE, 
DVT or PE to analysis.
13. Section 8.2.5: added for additional non-standard 
safety table details.
14. Appendix 1.1: added rules of visit windowing 
specific to SF-36, EQ-5D, and WPAI due to their 
different schedule of evaluations, as well as those 
specific to lipids (fasting) due to the same reason.
Amendment 3 (SAP 
version 4)
30-Jun-2020
1.
Section 5: clarified FAS and SAS.
2.
Section 6.2: added the word “adjudicated” for the 
adjudicated safety endpoints for clarity and internal 
consistency within the document. Clarified 
terminology for deaths (updated terms to: all-cause
deaths and all-cause deaths associated with 
adjudicated primary endpoint criteria) for clarity 
and internal consistency within the document.
3.
Section 7.2: for continuous endpoints, updated 
missing data handling by use of a MMRM for 
consistency with Sponsor’s convention established 
across tofacitinib development programs.
4.
Section 7.3: added a new section to describe
missing data handling due to COVID-19 pandemic 
and associated summaries and data listings. 
5.
Section 8.1.2: exact 95% CI will be used instead of 
approximate 95% CI for the crude incidence rate 
for consistency with Sponsor’s convention 
established across tofacitinib development 


Protocol A3921133 Statistical Analysis Plan Version 5 (Amendment 4) Final
PFIZER CONFIDENTIAL
Page 9
Document
Version Date
Summary of Changes
programs. Clarified the calculation for SIR for 
malignancies.
6.
Section 8.1.3: for analyzing continuous endpoints, 
t-test will be replaced by a MMRM for consistency 
with Sponsor’s convention established across 
tofacitinib development programs. 
7.
“On-Treatment Time” will be renamed as “60-Day 
On-Treatment Time” for internal consistency 
throughout the document.
8.
“28-day rule” will be renamed as “28-Day 
On-Treatment Time” for internal consistency 
throughout the document.
9.
Section 8.2.5: subgroup analysis by age 
(<65 vs ≥65 years) for all-cause deaths will be 
added.
10. Appendix 1.1: clarified the baseline for ECG data.
11. Appendix 2.2: added algorithm of SIR and 
associated confidence interval.
12. Made minor updates for clarity and consistency 
throughout.
Amendment 4 (SAP 
version 5)
08JUL2020
Section 7.2.: Updated missing data handling for efficacy 
data to accommodate the trial design as a time-to-event
safety study.
2. INTRODUCTION
Note: in this document any text taken directly from the protocol is italicized. 
As a commitment to the United States Food and Drug Administration (US FDA), this Post 
Authorization Safety Study (PASS) will evaluate the safety of tofacitinib 5 mg twice daily 
(BID) and tofacitinib 10 mg BID compared to a tumor necrosis factor inhibitor (TNFi).
The primary objective of this endpoint study is to evaluate the safety of tofacitinib at two 
doses versus a TNFi; the co-primary endpoints are adjudicated major adverse 
cardiovascular events (MACE) and adjudicated malignancies excluding non-melanoma skin 
cancers during study participation. 
This document contains the plans for analyses in support of above objective.  


Protocol A3921133 Statistical Analysis Plan Version 5 (Amendment 4) Final
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Page 10
2.1. Study Design
This is a Phase 3b/4 randomized, parallel arm, open-label safety endpoint study.  All subjects 
will be randomized in a 1:1:1 ratio to one of the three treatment arms with approximately 
1300 subjects in each treatment arm:
1. Tofacitinib 5 mg BID (oral).
2. Tofacitinib 10 mg BID (oral).*
3. TNFi: In the US, Puerto Rico and Canada, subjects randomized to TNFi will receive 
adalimumab 40 mg every other week (QOW) by subcutaneous injection (SC); in all 
other countries, subjects randomized to TNFi will receive etanercept 50 mg once 
weekly by SC injection.
* In response to new safety information about tofacitinib that was provided to Study 
A3921133 investigators on 19 February 2019, investigators were notified to verbally inform 
subjects randomized to tofacitinib 10 mg BID to reduce the dose of tofacitinib to 5 mg BID 
within 7 calendar days of this notification, secure their verbal agreement to continue in the 
study, and if they agreed, reduce their dose of tofacitinib to 5 mg BID for the remainder of 
the study. Tofacitinib is supplied as 5 mg tablets, which allowed subjects to decrease from 
their previous dose of 2 tablets twice daily to 1 tablet twice daily. 
During the study, subjects may require alternate therapies in addition to, or instead of, their 
randomized drug assignment. All subjects, regardless of their treatment regimen will 
participate in the study until study completion.
Study completion will be declared when all 3 of the following conditions are met:
1. At least 1500 subjects have been followed for at least 3 years.
2. The targeted number of MACE are observed.
3. The targeted number of malignancies excluding non-melanoma skin cancers are 
observed.
It is expected that approximately 4000 subjects will participate in the study and the expected 
duration of the study is approximately 5 years following randomization of the first subject. 
The exact number of subjects and duration of the study will be determined by the 
pre-specified rules outlined in the charter of the blinded Steering Committee.
The study design schematic for the study is represented in Figure 1.


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Figure 1.
Study Design (minimum 1300 per arm, total N=4000)
Reduced to 5 mg BID 
per Amendment 8


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SCHEDULE OF ACTIVITIES BY VISIT (SCREENING – MONTH 6)
Protocol Activities –
Screening to Month 6
Screen
Visit 1 
Day 1
Visit 2 
Monthf
2
Visit 3 
Monthf
3
Visit 4 
Monthf
6
Visit Windows
NA
See 
Protocol
6.2.1
2 
weeks
1.5 
months
1.5 
months
Informed Consent
X
Medical History and Confirm Diagnosis
X
Physical Examination, including height
X
Assessment of New Physical Findings
X
X
X
X
Weight, Vital Signs
X
X
X
X
X
Inclusion/Exclusion criteria
X
X
Blood Chemistry,a Hematologya
X
X
X
X
X
C-reactive Protein (CRP)
X
X
X
X
X
Banked Biospecimens
X
HIV Serology, HBsAg, HBcAb, HBsAbb
X
HCV Ab, HCV RNAc
X
Lipid Profile (fasting)
X
X
X
Pregnancy testd
X
X
X
X
X
QuantiFERON Gold®™In-Tube Test
X
Rheumatoid Factor
X
Anti-cyclic citrullinated peptide (anti-CCP)
X
Urinalysis
X
Chest X-ray
X
ECG
X
Randomization  
X
Study Medication Dispensing 
X
Xg
X
X
Contraceptive Use Documentation
X
X
X
X
X
Joint Count (28) 
X
X
X
X
X
Patient Assessment of Arthritis Pain
X
X
X
X
Patient Global Assessment of Arthritis
X
X
X
X
Physician Global Assessment of Arthritis
X
X
X
X
HAQ-DI
X
X
X
X
SF-36 (Version 2, Acute)
X
X
X
EuroQol EQ-5D 
X
X
X
Work Productivity and Activity Impairment 
(WPAI) 
X
X
X
Safety Assessment/AE Reporting
X
X
X
X
Concomitant Medication Reviewe
X
X
X
X
X
End of Study Assessment
a.
Re-testing of abnormal laboratories may be required (see Protocol section 7.15).
b.
See Exclusion Criteria 4e and 4f for details (Protocol section 4.2). 
c.
See Exclusion Criteria 4g for details (Protocol section 4.2). 
d.
Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations.
e.
History of concomitant medications at Screening includes a history of prior Disease Modifying Antirheumatic Drug
(DMARD) treatment. 
f.
Calendar months.
g.
Adalimumab or etanercept only.


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SCHEDULE OF ACTIVITIES BY VISIT (MONTH 9- END OF STUDY)
Visits are outlined through Month 60, but will continue sequentially until the end of study is 
declared, at which time all subjects will be required to return for an End of Study Visit.
Protocol Activities –
Months 9 to 60 and End of Study 
Follow-up Visit
Visits 5, 
9, 13, 
17, 21 
[Monthsf
9, 21, 
33,45, 
57]
Visit 6, 
10, 14, 
18, 22 
[Monthsf
12, 24, 
36, 48, 
60]
Visits 7, 
11, 15,
19 
[Monthsf
15, 27, 
39, 51]
Visits 8, 
12, 16, 
20 
[Monthsf
18, 30, 
42, 54]
End 
of 
Study 
Visit 
End of 
Study 
Follow 
Upg
Visit Windows
1.5 
months
1.5 
months
1.5 
months
1.5 
months
1.0 
months
+0.5 
months
Assessment of New Physical Findings
X
X
X
X
X
X
Weight, Vital Signs
X
X
X
X
X
X
Blood Chemistry,a Hematologya
X
X
X
X
X
C-reactive Protein (CRP)
X
X
X
X
X
Banked Biospecimens
Xb
X
Lipid Profile (fasting)
X
X
Pregnancy testc
X
X
X
X
X
X
QuantiFERON Gold®™In-Tube Test
Xd
Chest X-ray
Xe
Xe
ECG
X
Study Medication Dispensing
X
X
X
X
Contraceptive Use Documentation
X
X
X
X
X
X
Joint Count (28)
X
X
X
X
X
Patient Assessment of Arthritis Pain
X
X
X
X
X
Patient Global Assessment of Arthritis
X
X
X
X
X
Physician Global Assessment of 
Arthritis
X
X
X
X
X
HAQ-DI
X
X
X
X
X
SF-36 (Version 2, Acute)
X
X
EuroQol EQ-5D
X
X
Work Productivity and Activity 
Impairment (WPAI) Questionnaire
X
X
Safety Assessment/ AE Reporting
X
X
X
X
X
X
Concomitant Medication Review
X
X
X
X
X
X
End of Study Assessment
X
a.
Re-testing of abnormal laboratories may be required (see Protocol section 7.15).
b.
Month 12 visit only.
c.
Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations. 
d.
QFT is not performed in subjects who had a positive test previously and were adequately treated for latent TB, subjects 
newly testing positive for latent TB with negative CXR and no evidence of active disease are required to start a 9 month 
treatment course of isoniazid to continue in the study.
e.
Only for subjects testing positive to QFT at annual visit.
f.
Calendar Months.
g.
Occurs 28 days after End of Study visit. 


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2.2. Study Objectives
2.2.1. Safety Objective
The primary objective of this endpoint study is to evaluate the safety of tofacitinib at two 
doses versus TNFi; the co-primary endpoints are adjudicated major adverse cardiovascular 
events (MACE) and adjudicated malignancies excluding non-melanoma skin cancers during 
study participation.
The following assessments will be used to evaluate safety in the entire study population:

Changes in physical assessments, including weight and vital signs.

AE reporting, incidence and severity.

Incidence and severity of safety laboratory abnormalities.

Adherence to contraceptive use.

Adherence to protocol requirements.

Concomitant medication review.

Review of eligibility to continue study drug.
2.2.2. Efficacy Objective
The efficacy analysis is secondary objective for this study. The efficacy analysis is to 
estimate differences between each tofacitinib regimen and TNFi regimen, as well as between 
the two tofacitinib regimens. The following assessments related to the signs and symptoms
of patient health and functional status will be captured directly in Case Report Form (CRF)
and be used to evaluate efficacy in the study population:

28 joint counts;

Patient Global Assessment;

Patient Assessment of Pain;

Physician Global Assessment;

C-reactive Protein (CRP);

A number of patient reported outcomes, including the Health Assessment 
Questionnaire – Disability Index (HAQ-DI).
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No interim analyses of the study data is planned for use outside the Data Monitoring 
Committee (DMC) and the Steering Committee. Any interim analyses planned for the DMC 
and the Steering Committee will be specified in their respective charters.
The final analysis will be performed using the complete, final, quality-controlled database 
generated from all visits and information generated as of the time of the end of active 
follow-up in the study. 


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Unblinding will not be needed as this is an open-label study.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
The hypothesis to be tested is, for the primary safety endpoints of malignancy and MACE, 
whether the two tofacitinib doses is non-inferior to the TNFi control and whether tofacitinib 
10 mg BID is non-inferior to tofacitinib 5 mg BID.
4.2. Statistical Decision Rules 
The hazard ratios relative to the TNFi control regimen for the tofacitinib regimens will be 
estimated together with 95% two-sided confidence intervals (CI). Non-inferiority of
tofacitinib regimens to TNFi control regimen will be concluded if the upper confidence limits
for both malignancy (Total Time Analysis) and MACE (60-Day On-Treatment Time 
Analysis), are less than 1.8.
Additionally, hazard ratios of tofacitinib 10 mg BID vs. tofacitinib 5 mg BID along with
95% two-sided CIs will be estimated. Non-inferiority of tofacitinib 10 mg BID to tofacitinib 
5 mg BID will be concluded if the upper confidence limits for both malignancy (Total Time 
Analysis) and MACE (60-Day On-Treatment Time Analysis) are less than 2.0.
Adjustments for multiplicity will not be applied.
5. ANALYSIS SETS
The following analysis sets are defined.
5.1. Full Analysis Set
The term 'Full Analysis Set' (FAS) is used to describe the analysis set which is as complete as 
possible. It will include all subjects who were randomized in the study and received at least 
one dose of the randomized investigational drug (tofacitinib or TNFi). Subjects will be 
analyzed in the treatment groups as they are randomized. 
5.2. ‘Per Protocol’ Analysis Set 
The ‘Per Protocol’ analysis set will include all randomized subjects from FAS with no 
important protocol deviations that could impact the analysis, as determined by the potentially 
important protocol deviation (pIPD) process. The list of patients that will be excluded from 
the per-protocol analysis set will be finalized prior to the database release.
5.3. Safety Analysis Set
The Safety Analysis Set (SAS) will include all subjects who were randomized in the study 
and received at least one dose of the randomized investigational drug (tofacitinib or TNFi). 
Subjects will be analyzed in the treatment groups as they received.


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5.4. Treatment Misallocations
For subjects with errors in treatment allocation, described below is the convention under 
which treatment groups they will be reported for efficacy and safety analyses: 
If a subject was:

Randomized but not treated, then the subject will be excluded from all analyses
according to the definitions of FAS, Per Protocol, and Safety Analysis Sets given just 
above. 

Randomized but took incorrect treatment, then the subject will be reported under 
his/her randomized treatment group for all analyses based on FAS (or Safety Analysis 
Set), but will be omitted from analyses based on Per Protocol Analysis Set.
5.5. Protocol Deviations 
Protocol deviation identification and documentation will be accomplished for this study 
according to the Sponsor’s standard operating procedures (SOPs) that require periodic 
review of individual protocol deviations and periodic review of aggregated cumulative 
protocol deviations.  Prior to initiation of the study, a list of potentially important protocol 
deviations (pIPDs) is developed in alignment with the requirements of the protocol. This list 
is updated, as necessary, to include other deviations identified during the course of the study.  
Additionally, pIPDs are prospectively identified; pIPDs are used by the statistician and 
clinician in determining eligibility for inclusion in the statistical analysis of the study and are 
considered for inclusion in the body of the clinical study report.  
Subjects with pIPDs that could impact endpoint analysis will be excluded from the Per 
Protocol Analysis Set, but included in the Full Analysis Set.
Protocol deviations classified as pIPDs are included in a Protocol Deviation Listing in the 
clinical study report.
5.5.1. Deviations Assessed Prior to Randomization
Granted exceptions or waivers to the inclusion or exclusion criteria are prohibited by the 
Sponsor’s standard operating procedures and thus, are not expected to occur.  Entry into the 
study by any subject who does not meet the study inclusion or exclusion criteria will be 
identified as protocol deviation. 
5.5.2. Deviations Assessed Post-Randomization
The deviation resulting in exclusion from the safety analysis set and the full analysis set is 
failure to take any study medication. 


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6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoints
Efficacy endpoints will be secondary endpoints in this safety study. The efficacy endpoints
are:

Change from baseline to each post-baseline scheduled visit in DAS28-4 (CRP),
Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI). 

Rate of remission at each post-baseline scheduled visit including: 

ACR-EULAR Boolean remission (defined as the subject satisfying all of the 
following: tender joint count ≤1, swollen joint count ≤1, C-reactive protein 
≤1 mg/dl, patient global assessment ≤1 on a 0-10 scale);

SDAI ≤3.3;

CDAI ≤2.8.

Rate of low disease activity (LDA) at each post-baseline scheduled visit including:

SDAI ≤11;

CDAI ≤10;

Disease Activity Score (DAS)28-4(CRP) ≤3.2.

ACR20, ACR50, and ACR70 response rate of at each post-baseline scheduled visit.

Change from baseline to each post-baseline scheduled visit in the HAQ-DI.
6.2. Safety Endpoints
Co-Primary 

Malignancies, excluding non-melanoma skin cancers (adjudicated).

Major adverse cardiovascular events (MACE) (adjudicated).
The definitions of MACE used in this study are consistent with those outlined in the 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical 
Trials1 with the exclusion of cardiovascular death due to pulmonary embolism.  The 
following events are included, as defined:

Cardiovascular death:

Death due to acute myocardial infarction (MI);

Sudden cardiac death;


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
Death due to heart failure;

Death due to stroke;

Death due to cardiovascular procedures;

Death due to cardiovascular hemorrhage;

Death due to other cardiovascular causes: peripheral artery disease.

Non-fatal myocardial infarction (MI).

Non-fatal stroke of any classification, including reversible focal neurologic 
defects with imaging evidence of a new cerebral lesion consistent with ischemia 
or hemorrhage.
Secondary

Opportunistic infection events including tuberculosis (adjudicated):

The opportunistic infection (OI) events by all OIs, tuberculosis adjudicated as OI,
herpes zoster adjudicated as OI and all other OI;

Tuberculosis events separately from the evaluation of opportunistic infections:

Proportion of subjects with QuantiFERON-TB Gold (QFT) or Tuberculin 
Skin Test (TST) positive subjects with a history of TB by region;

QFT and TST newly positive by time in the study, newly positive treated with 
Isoniazid (INH) or other Tuberculosis (TB) prophylaxis, newly positive with 
positive Chest X-Ray (CXR), newly positive with negative CXR by region;

Patient Years exposure by treatment arm, with or without TB;

Proportion and Incidence Rate of Tuberculosis by time in the study;

Tuberculosis Severity and Seriousness by treatment arm.

Hepatic events (adjudicated) including:

Drug-induced Liver Injury (DILI) - Probable, Highly Likely and Definite;

DILI – Listed separately;

DILI – Cases meeting classification and severity;

Subjects with elevations of Transaminase levels >1x Upper Limit of Normal
(ULN), ≥3xULN, ≥5xULN (based on laboratory values).


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
Cardiovascular events other than MACE (adjudicated).

All Adverse Events (AEs), including Serious Adverse Events (SAEs):

Herpes zoster:

Baseline Characteristics with and without herpes zoster;

Patient Years of exposure with and without herpes zoster;

Proportion and Incidence Rate by Age Category, Time in study for all Herpes 
Zoster;

Proportion and Incidence Rate by Age Category and Time in Study for Herpes 
zoster by number of dermatomes;

List of subjects with Herpes Zoster Ophthalmic and Visceral cases;

List of subjects with serious Herpes Zoster with and without history of 
chicken pox (varicella); with and without history of chicken pox (varicella) 
vaccine; with and without history of herpes zoster vaccine (varicella); with 
and without history of history of shingles (herpes zoster);

List of subjects with non-serious Herpes Zoster with and without history of 
chicken pox (varicella); with and without history of chicken pox vaccine 
(varicella); with and without history of herpes zoster vaccine (varicella); with 
and without history of shingles (herpes zoster);

Risk factors associated with herpes zoster (cox regression analysis) including 
region, baseline corticosteroid use, age group, smoking status, treatment arm;

Time to resolution of all Herpes Zoster Cases, single dermatomes, 2 adjacent 
dermatomes, disseminated herpes zoster by treatment arm;

Severity and seriousness of Herpes Zoster by treatment arm;

Post Herpetic neuralgia after Herpes Zoster by treatment arm;

Permanent and temporary discontinuations due to Herpes Zoster by treatment 
arm;

Herpes Zoster considered OI by treatment arm.

Serious infections.

Gastrointestinal (GI) perforations (adjudicated):


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
Incidence rate for all GI events adjudicated as meeting criteria by treatment
arm;

Listing of all GI events adjudicated, including location, risk factors and 
outcome, by treatment arm. 

Nonmelanoma skin cancers (adjudicated).

Interstitial lung disease (adjudicated by a sponsor review committee, independent 
of the study team).

Deep vein thrombosis (DVT) (adjudicated): subjects who experienced any DVT.

Pulmonary embolism (PE) (adjudicated): subjects who experienced any PE.

Arterial thromboembolism (ATE) (Standardized MedDRA Query (SMQ)): 
subjects who experienced any ATE.

DVT or PE (adjudicated): subjects who experienced any DVT or PE.

Thromboembolic events (TE) subjects who experienced any DVT (adjudicated), 
PE (adjudicated) or ATE (SMQ).

SMQ of Hypertension.

Clinically significant abnormal laboratory parameters:

Hematology, including hemoglobin, neutrophils and lymphocytes;

Lipids;

Liver tests including Alanine Aminotransferase (ALT), Aspartate Transaminase
(AST) and total bilirubin.

All-cause mortality (adjudicated) (also known as all-cause deaths associated with the 
adjudicated primary endpoint criteria under Bullet Deaths below).

Reasons for permanent or temporary discontinuation of study medication.

Concomitant drugs by treatment group, in the following categories:

Lipid Lowering Agents (LLA) including Statins;

DMARDS;

Steroids;

Analgesics and Nonsteroidal Anti-inflammatory Drug (NSAIDS);


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
INH and Rifampacin.

Laboratory Data Descriptive Statistics for the following tests:

Hemoglobin;

Platelets;

Creatine Kinase;

Serum Creatinine;

Total Cholesterol;

Low Density Lipoprotein Cholesterol (LDL-c);

High Density Lipoprotein Cholesterol (HDL-c);

Total Cholesterol/HDL-c Ratio;

Total Cholesterol/LDL-c Ratio;

Triglycerides.

Vital Sign Descriptive Statistics Summaries, including BMI.

Baseline Characteristics including:

Duration of Rheumatoid Arthritis (RA);

Cardiovascular Risk;

Subjects with Nodules, Sjoegren’s Syndrome, Anemia of Chronic Disease, 
Pulmonary manifestations;

Joints (JTS), CDAI, SDAI, Smoking History, Alcohol use.

Deaths:

List of all-cause deaths associated with the adjudicated primary endpoint criteria;

List of all-cause deaths;

Incidence rate (95% CI) for all-cause deaths associated with the adjudicated 
primary endpoint criteria;

Incidence rate (95% CI) for all-cause deaths.


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
Patient Years exposure by treatment arm, including standard of care and by time 
point.
6.3. Other Endpoints
6.3.1. Pharmacokinetics Endpoints 
None.
6.3.2. Pharmacodynamics Endpoints 
None.
6.3.3. Outcomes Research Endpoints
Outcomes Research Endpoints, also known as Patient-Reported Outcomes, are:
Patient Global Assessment of Arthritis, a value on the scale of 0 to 100 (a visual-
analog score, VAS).
Patient Global Assessment of Pain, a VAS, scale of 0 to 100.
Health Assessment Questionnaire-Disability Index (HAQ-DI) is a total score based on 
items that query the patient on how well the patient can dress and groom self, arise 
from bed, eat during the day, walk, perform hygiene, reach, grip, and perform 
common daily activities.  The HAQ-DI alone is analyzed, and is on the scale of
0 to 3.
SF-36 Health Survey (Version 2, Acute) has 36 items that are summarized into eight 
domain scores measuring Physical Functioning, Role Physical (physical life), Social 
Functioning, Bodily Pain, Mental Health, Role Emotional (emotional life), Vitality, 
and General Health: these in turn are summarized into two component scores: Mental, 
and Physical.  These 8 domains and 2 scores are individually analyzed.  They are 
scaled to be centered at 50, with a standard deviation of 10.  Each domain score can 
also be expressed on the scale of 0 to 100. 
Work Productivity and Activity Impairment (WPAI) has 6 items that measure four 
concepts: Absenteeism (percentage of time missed from work); Presenteeism 
(percentage of impairment experienced while at work); Work productivity loss 
(overall work impairment - the combination of absenteeism and presenteeism); and 
Activity impairment (the percentage of impairment in daily activities).  The four 
scores are individually analyzed.
EuroQoL EQ-5D has five items for each of the domains Unusual Activities; 
Anxiety/Depression; Pain/Discomfort; Mobility; and, Self Care. These five are in 
turn summarized into a single utility score. There is also a EuroQol visual-analog 
score (EQ-VAS, 0 -100) anchored with 0 as the worst health you can imagine and 
100 as the best health you can imagine.  The scores are individually analyzed, and the 
utility score is analyzed as well.


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The endpoints of interest are the actual values and the change from baseline values at each 
post-baseline scheduled visit including:

Patient Assessment of Arthritis;

Patient Global Assessment of Pain;

HAQ-DI;

SF-36 (each of the 8 domain scores (norm-based) and 2 component summary scores);

WPAI (each of the four scores);

EQ-5D (five domain scores and Utility Score) and EQ-VAS.
6.4. Covariates 
The following demographic variables will be included as covariates in the multivariate Cox 
proportional hazard model:
Geographic regions:  
4 levels: USA/Canada, Europe, Latin America, and rest of world.
Age:
In years (to the nearest year) at entry to the study (categorized as 50 to <65, 65 to 
<75, ≥75).
Smoking:
Current or ex-smoker, lifetime nonsmoker.
Gender:
Male and Female.
7. HANDLING OF MISSING VALUES
7.1. Safety Data
Missing values for safety endpoints will not be imputed.   


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7.1.1. Censoring Time for Time-to-event
There are three ways in defining the time to an event:

The “60-Day On-Treatment Time” is the time from first study dose to an event 
observed while a subject is exposed to the study treatment plus the applicable 
attribution window. The 60-Day On-Treatment Time analysis will censor subjects 
who cross over from tofacitinib or TNFi to standard of care at 60 days after the last 
dose of randomized study drug.

The “Total Time” is the time from first study dose to an event regardless whether the 
event occurs during on-treatment period or after the subject discontinues the study 
treatment and is still being followed. The Total Time analysis will not censor 
subjects who cross over from tofacitinib or TNFi to standard of care and will ascribe 
events to randomized treatments. 

The “28-Day On-Treatment Time” is the time from first study dose to an event 
observed while a subject is exposed to the study treatment plus the applicable 
attribution window. The 28-Day On-Treatment Time analysis will censor subjects 
who cross over from tofacitinib or TNFi to standard of care at 28 days after the last 
dose of randomized study drug.
More specifically, in time-to-event analyses for a given event, a subject’s time to event will 
be considered censored if any of the following conditions occurs prior to the subject 
experiencing the event in question:

The subject is lost to follow-up (censoring time = study day of last on-study contact, 
eg, last visit, last lab test, and the like).

The subject withdraws consent (censoring time = study day of last on-study contact).

The subject is in the study under the protocol at the declared end of the study 
(censoring time = study day of last on-study contact).

The subject dies without having experienced the event of interest 
(censoring time = study day of death).
For the 60-Day On-Treatment Time Analyses of time-to-event, in addition to the 
foregoing, when a subject changes from the randomized study treatment to standard of care, 
the subject’s time to event will be considered censored (censoring time = last dose day of 
randomized study regimen + the attribution window, or the study day of last on-study 
contact, whichever is earlier). It will be used for the primary safety endpoint MACE but 
excluding malignancy (excluding Non-melanoma Skin Cancer (NMSC)), and the attribution 
window will be 60 days. In other words, the censoring time will be the earliest of study day 
of last on-study contact, study day of death, and last dose day of randomized study regimen 
plus 60 days.


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For the Total Time Analyses of time-to-event, the censoring time will follow the four 
foregoing listed cases, ie, the censoring time will not change when a subject changes from 
the randomized study treatment to standard of care. In other words, the censoring time will 
be the earlier of study day of last on-study contact and study day of death.
For the 28-Day On-Treatment Time Analyses of time-to-event, in addition to the 
foregoing, when a subject changes from the randomized study treatment to standard of care, 
the subject’s time to event will be considered censored (censoring time = last dose day of 
randomized study regimen + the attribution window, or the study day of last on-study 
contact, whichever is earlier). It will be used for all the secondary safety endpoints, and the 
attribution window will be 28 days. In other words, the censoring time will be the earliest of 
study day of last on-study contact, study day of death, and last dose day of randomized study 
regimen plus 28 days.
7.2. Efficacy Data
For binary variables, such as ACR20, remission with respect to SDAI≤3.3, if the value is 
missing due to missing values in any of the components, while the subject is still enrolled, 
the method of last observation carried forward (LOCF) will be used to carry forward any of 
the missing components, and from that mix of actual and carried forward values, the value of 
the binary composite variable will be determined. Note that, this approach should result in 
the same value for ACR20, ACR50 and ACR70 if their components are partially available 
but can be used to determine the ACR values without imputation (see definition for ACR 
response rate in Appendix 1.4).
This type of LOCF method will be known as “LOCF mixed components”, since it is 
based on calculating the composite value based on a mixture of values at a visit and 
values carried forward from previous visits. It can be justified as an attempt to carry 
forward as little information as possible.
After LOCF imputation has been applied, the composite binary variable can be calculated
from the imputed components. 
If baseline data is missing, then the post-baseline value will be set to non-responder.
DAS28-4(CRP), CDAI and SDAI are derived variables based on multiple components. If any 
component is missing, the endpoint will be considered as missing. A Mixed Model for 
Repeated Measures (MMRM) will be used to analyze continuous endpoints with repeated 
measures without explicit imputation for missing values. 
7.2.1. Outcomes Research Endpoints
For the outcome research endpoints, rules for scoring and handling of missing data suggested 
by the developers will be followed.  


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7.3. Missing Data due to COVID-19 Pandemic
Because of the COVID-19 pandemic, some scheduled on-site visits may be substituted by 
remote visits such as telephone contacts. The data collected via the remote visits will be 
treated the same as the data collected by the on-site visits. 
Missing data due to COVID-19 pandemic will be handled the same as that for other missing 
data. 
In addition, the following summaries will be provided.

Discontinuation due to COVID-19 impact will be reported in the disposition table.

Missed visits due to COVID-19 impact are recorded as PD and will be in the specific 
PD tables in the Clinical Study Report (CSR).

A set of summary/listing tables based on a subset of protocol deviations associated 
with COVID-19 will be provided.  Study drug discontinuation, subject 
discontinuation due to COVID-19 and adverse events related to COVID-19 will be 
summarized as well.  The source information will be captured in the protocol 
deviation.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
In general, number and percent will be presented for binary variables, number, mean, 
standard deviation (standard error of the mean), minimum, 1st, 2nd and 3rd quartiles and 
maximum will be presented for continuous variables. In addition, graphics may be used to 
present the data.
8.1. Statistical Methods 
8.1.1. Analyses of Time-to-Event Data 
Comparisons of hazard functions in time-to-event analyses will be carried out via (linear) 
Cox proportional hazard models. Censoring conventions are given in Section 7. A 
univariate analysis model containing only the single independent variable for treatment group 
will be calculated and reported. 
In addition, the effects of adding other predictors to the Cox model, such as geographic 
region, age group, gender, and smoking status will be fully explored and reported. 
8.1.2. Analyses of Incidence Rates 
Crude incidence rates will be reported as the total number of subjects with admissible events 
divided by the total (for all qualifying subjects) time at risk for the cohort/treatment group of 
interest. For subjects with events, the time at risk will be the time to the first event, for 
subjects without events, it will be the censoring time defined in Section 7.1.1.
When subjects change regimens from study medication to standard of care then the following 
counting rules will be used to account for group changes in the estimation of crude incidence 
rates (where applicable):


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
For MACE: there will be a 60-day risk window during which events will be attributed 
to both treatment groups, after which they will be assigned to the current treatment 
group.

Malignancies (excluding NMSC): there will be a 60-day risk window during which 
events will only be attributed to the prior treatment group, after which they will be 
assigned to both treatment groups.
The 95% CIs for the crude incidence rate will be calculated for incidence rates based on the 
assumption that the actual count of cases arises from a Poisson distribution.  The approach 
used in Daly et al.2,3 describing the calculation of exact confidence limits will be used.  If 
x denotes the actual number of subjects with events, (1 – ) denotes the confidence level, 
xL denotes the lower confidence limit and xU denotes the upper confidence limit, then the 
following formula yields values for xL and xU,
When x >0,
xL = 0.5 * 2(2x; /2) and xU = 0.5 * 2(2x+2; 1-/2),
When x = 0,
xL = 0 and xU = 0.5 * 2(2x+2; 1-/2).
In the above notation, 2(n; p) represents the pth quantile of the chi-square distribution with 
n degrees of freedom.
Once xL and xU are obtained, they are to be adjusted for the at-risk population per 
100 subject-years by multiplying by (100/total subject-years of event exposure).
Indirect standardization will also be used in a second analysis of malignancy data.  With 
indirect standardization, age and sex-specific cancer rates in a standard population 
(ie, general US population via the Surveillance Epidemiology and End Results [SEER] 
registry) are used as weights for person-time of the age and sex-specific subgroups in the 
tofacitinib trial population. The resulting standardized incidence ratio (SIR) represents the 
ratio of the incident number of cases of cancer in the tofacitinib population to the incident 
number that would be expected if the study population had the same incidence rate as the US 
population. The SIR along with the 95% CI will be calculated for the adjudicated 
malignancies excluding NMSC and each cancer type (corresponding to the ones where the 
SEER incidence rates are available) for each randomized tofacitinib group (not for the TNFi 
group). For each cancer type and each treatment group, the expected number of cancer cases
will be calculated as the SEER incidence rate (cancer type specific incidence rates) 
multiplied by the person-time (cancer type specific person-time) of each age (age categories 
according to SEER) and sex combination summed over all the age and sex combinations.
The detailed calculation is provided in Appendix 2.2.


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8.1.3. Analyses of Continuous Efficacy Data 
Continuous data (ie, change from baseline) will be summarized. 
Repeated measures data for continuous endpoints will be analyzed as change from baseline 
with a mixed model for repeated measures (MMRM) that includes fixed effects of treatment
group, visit, treatment-group by visit interaction, baseline value, and baseline-value by visit
interaction, without imputation for missing values. A common unstructured
variance-covariance matrix will be used, provided the model converges, otherwise an 
alternative covariance structure, eg, heterogeneous compound symmetry (CSH), will be 
attempted.  The Kenward-Roger degrees of freedom approximation will be used.  Least 
squares means [LSM] of the treatments, LSM of the treatment difference, 2-sided p-value 
and 95% CI at each time point will be generated using this MMRM. If the Baseline is 
missing or if there are no post-baseline measurements, the subject will be excluded from this 
analysis.
8.1.4. Analyses of Binary Efficacy Data
Binary data will be summarized and compared between two treatment groups using the 
normal approximation of binomial proportions and 95% CI of treatment difference will be 
constructed. The normal-approximation to the test statistic for the difference in binomial 
random variables is calculated as:
c
c
c
i
i
i
c
i
i
n
p
p
n
p
p
p
p
Z
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
ˆ
ˆ





where pˆ refers to the relative frequency, n to sample size, the subscripts i and c refer to two 
treatment group.
Two-sided 95% CIs are formed by:
c
c
c
i
i
i
c
i
n
p
p
n
p
p
p
p
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
96
.1
)
ˆ
ˆ
(





8.2. Statistical Analyses 
As of 19 February 2019, the tofacitinib 10 mg BID treatment arm reduced dosing to 
tofacitinib 5 mg BID; all analyses identified for the tofacitinib 10 mg BID treatment arm will 
be conducted as stated even though subjects in that treatment arm reduced their prescribed 
dose. Specifically, all references to the Tofacitinib 10 mg BID arm will include subjects 
randomized to tofacitinib 10 mg BID and discontinued study drug prior to Amendment 8 and 
those subjects who were randomized to tofacitinib 10 mg BID and had their dose of 
tofacitinib reduced to 5 mg BID with Protocol Amendment 8.


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8.2.1. Primary Analysis
Safety endpoint analyses will be carried out using the data collected on the Safety Analysis 
Set. 
Two methods in defining time to an event will be used for the co-primary time-to-event 
safety endpoints: 60-Day On-Treatment Time and Total Time (see Section 7.1.1 for 
definitions). The 60-Day On-Treatment Time definition will be used for primary MACE
analysis. The Total Time definition will be used for primary malignancies (excluding 
NMSC).
This primary objective will be addressed via the analysis of the times to these events by 
proportional hazard (Cox) models via univariate model analysis. See details in Section 8.1.1.  
In the time-to-event analyses using a Cox model, the treatment groups will be tofacitinib 
5 mg BID, tofacitinib 10 mg BID, and TNFi regimen (adalimumab 40 mg QOW SC and
etanercept 50 mg QW SC combined).
Ninety-five percent CIs for the hazard ratios for the combined tofacitinib regimens compared 
to the TNFi regimen as well as for the 3 pair-wise treatment comparisons, tofacitinib 
10 mg BID vs. tofacitinib 5 mg BID, tofacitinib 5 mg BID vs. TNFi, tofacitinib 10 mg BID 
vs. TNFi, will be presented. For this analysis, only treatment group will be used as an
independent variable in the model.  For the Total Time analyses changes from original 
randomized treatment will be ignored.  For the 60-Day On-Treatment Time analyses, rules 
for censoring times to event due to switching from randomized treatment to standard of care 
are given in Section 7.  
Further, multivariate analysis and analysis by TNFi subset strata (ie, the sites/regions where 
either adalimumab or etanercept was used, in other words, USA/Puerto Rico/Canada as one 
stratum, the rest as the other stratum) will be conducted to assure consistency of results. No 
additional analyses comparing adalimumab vs. etanercept will be conducted for the purpose 
of reporting the primary endpoints of the study; when reporting the primary endpoint 
analyses, any difference in hazard ratio between the two TNFi controls will be attributed to 
geographic difference.
These analyses will be used to check the robustness and to assure consistency of the results 
for primary safety endpoints:

Models containing independent variable of treatment group adjusted with geographic
region, age group, gender, and smoking status (see covariates in Section 6.4) will be 
fitted using Safety Analysis Set. 

An analysis by TNFi subset strata (ie, the sites/regions where either adalimumab or 
etanercept was used) will be performed using Safety Analysis Set.

The same analyses conducted based on Safety Analysis Set will be conducted using 
Per Protocol Analysis Set.


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Unadjusted, or “crude” incidence rates by Total Time, 60-Day On-Treatment Time and 
28-Day On-Treatment Time analysis will be calculated as well. 
8.2.2. Analyses of Other Safety Endpoints
The analyses will be based on the Safety Analysis Set. The 28-Day On-Treatment Time will 
be applied to all the events of interest, see Section 7.1.1.
The times to the secondary endpoints of opportunistic infection events excluding 
tuberculosis, tuberculosis, hepatic events, cardiovascular events (MACE and others), serious 
infections, GI perforations, non-melanoma skin cancers, interstitial lung disease, DVT, PE, 
ATE, DVT or PE, thromboembolic events (TE) and all-cause mortality will be analyzed by 
Cox models via univariate model analysis. See Section 8.1.1.  The 28-Day On-Treatment 
Time analysis will be conducted.
The times to herpes zoster events will be analyzed by a multivariate Cox model with region, 
baseline corticosteroid use, age group, smoking status, treatment as predictors. The 28-Day 
On-Treatment Time analysis will be conducted.
Unadjusted, or “crude” incidence rates will be calculated as well. Note that the ratios of 
these rates approximate, but are not exactly equal to, the hazard ratios.
A Surveillance, Epidemiology, and End Results (SEER) analysis of the malignancy endpoint 
will be conducted. In this analysis, standardized incidence ratio (SIR) for malignancies 
represents the ratio of the incident number of cases of cancer in the tofacitinib population to 
the incident number that would be expected if the study population had the same incidence 
rate as the US population. By way of interpretation, a SIR of more than 1.0 indicates that 
proportionally more cases of cancer have occurred in the tofacitinib population than the 
comparator, whereas a SIR of less than 1.0 indicates that proportionally fewer cancer cases 
have occurred.
The Sponsor has standard (ie, used for all its clinical trials) summary displays and listings for 
MedDRA-coded adverse events, demography, medical history, length of time in study and 
discontinuation, concomitant and concurrent medications, physical examination, ECG, 
laboratory tests, weight, pulse rate, and blood pressure.  These standards, called CaPS 
(CDISC and Pfizer Standards), will be utilized in the reporting of these routine safety 
variables. For laboratory tests total cholesterol, LDL-c, HDL-c, total cholesterol/HDL-c 
ratio, LDL-c/HDL-c ratio, Triglyceride, the summary will be produced by subjects on statins, 
subjects not on statins and subjects on any lower lipid agents including statins.
Only treatment emergent adverse events (TEAE) will be summarized. An event is 
considered TEAE if the event occurs for the first time during the effective duration of 
treatment and is not seen prior to the start of treatment or the event is seen prior to the start of 
treatment but increase in severity during treatment.
No inferential analysis is pre-planned for this set of variables. 


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These standard summaries of routine safety and subject characteristic data will be organized 
according to initially randomized group, ie, tofacitinib 5 mg BID, tofacitinib 10 mg BID, 
tofacitinib combined, and TNFi combined.
For the summaries of TEAE, the treatment emergence for the standard of care will be derived 
comparing events that happen after switching to the standard of care with events that happen
before switching including those after the first dose of randomized treatment.
For subjects who switch from the randomized treatment to standard of care, a separate TEAE 
table will be presented for these subjects according to their initially randomized group.
8.2.3. Analyses of Efficacy Endpoints
All efficacy analyses will be based on the Full Analysis Set.
Descriptive statistics of efficacy endpoints for all subjects in the study will be provided from 
baseline to the declared end of the study. Differences between each tofacitinib regimen 
(5 mg BID, 10 mg BID, or combined) and the TNFi regimen as well as between tofacitinib 
regimens will be estimated. The difference estimates will be derived based on the following 
models:

Analysis of continuous data, ie, change from baseline in DAS28-4(CRP), SDAI,
CDAI, HAQ-DI will be analyzed using 95% CI of treatment difference based on 
MMRM analysis. (See discussions in Section 8.1.3).

Dichotomized data will be summarized and compared between treatment groups 
using the normal approximation of binomial proportions and 95% CI of treatment 
difference (see discussions in Section 8.1.4). This approach will be used for the 
following efficacy variables:

Rate of remission: ACR-EULAR Boolean remission, SDAI ≤3.3, CDAI ≤2.8.

Rate of low disease activity (LDA): SDAI ≤ 11, CDAI ≤10, DAS28-4 (CRP) 
≤3.2.

ACR20, ACR50, and ACR70 response rate.
For efficacy analyses, the treatment groups will be tofacitinib 5 mg BID, tofacitinib 
10 mg BID, and TNFi regimen.
8.2.4. Analyses of Outcome Research Endpoints
All the outcome analyses are based on the Full Analysis Set.
Descriptive statistics at baseline and each scheduled post-baseline measure from the 
patient-reported outcome instruments will be calculated and reported. These outcome 
research endpoints are described in Section 6.3.3. 


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In general, the approach for the outcomes research endpoints will follow that of the other 
continuous endpoints.  For the outcome analyses, the treatment groups will be tofacitinib 
5 mg BID, tofacitinib 10 mg BID, and TNFi regimen.
8.2.5. Subgroup Analyses by Age
The following endpoints will be also analyzed using subjects with age ≥65 (vs <65) years 
based on the Safety Analysis Set.

All infections;

Serious infections;

Herpes zoster;

Opportunistic infections;

Tuberculosis;

All non-serious adverse events;

All serious adverse events;

All deaths;

All other adjudicated events including endpoints.


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9. REFERENCES
1.
Hicks KA, Hung J, Mahaffey KW, et al. Standardized Definitions for Cardiovascular 
and Stroke End Point Events in Clinical Trials. Draft Definitions for Testing, 2014. 
Available at the website:
https://pdfs.semanticscholar.org/5f9d/51b979ce9bd4da94dc4ce3a6689bfc9890dd.pdf.
2.
Daly LB, Bourke GJ, Mcgilvray J. Interpretation and use of medical statistics, 4th Ed. 
Oxford: Blackwell Scientific Publications, 1991.
3.
Daly LB. Simple SAS macros for the calculation of exact binomial and Poisson 
confidence limits. Comp. Biol. Med. 1992; 22:351-361.
4.
Breslow NE, Day NE (1987). Statistical Methods in Cancer Research. Vol. II, The 
Design and Analysis of Cohort Studies (IARC Scientific Publication No. 82). Lyon, 
France: International Agency for Research on Cancer.
5.
Sahai H, Khurshid A (1996). Statistics in Epidemiology: Methods, Techniques, and 
Applications. Boca Raton, FL: CRC Press, Inc.
6.
Sahai H, Khurshid A (1993). Confidence Intervals for the Mean of a Poisson 
Distribution: A Review. Biometrical J, 35: 857-67.


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10. APPENDICES 
Appendix 1. DATA DERIVATION DETAILS
Appendix 1.1. Definition and Use of Visit Windows in Reporting
Visit Label
Month Label
Target Day
Definition [Day window]
Screening
0
30 days prior to Day 1
Visit 1
Month 0
Day 1, 
Randomization
Day 1
Visit 2
Month 2
60
Days 42 to 74
Visit 3
Month 3
90
Days 75 to 135
Visit 4
Month 6
180
Days 136 to 225
Visit 5
Month 9
270
Days 226 to 315
Visit 6
Month 12
360
Days 316 to 405
Visit 7
Month 15
450
Days 406 to 495
Visit 8
Month 18
540
Days 496 to 585
Visit 9
Month 21
630
Days 586 to 675
Visit 10
Month 24
720
Days 676 to 765
Visit 11
Month 27
810
Days 766 to 855
Visit 12
Month 30
900
Days 856 to 945
Visit 13
Month 33
990
Days 946 to 1035
Visit 14
Month 36
1080
Days 1036 to 1125
Visit 15
Month 39
1170
Days 1126 to 1215
Visit 16
Month 42
1260
Days 1216 to 1305
Visit 17
Month 45
1350
Days 1306 to 1395
Visit 18
Month 48
1440
Days 1396 to 1485
Visit 19
Month 51
1530
Days 1486 to 1575
Visit 20
Month 54
1620
Days 1576 to 1665
Visit 21
Month 57
1710
Days 1666 to 1755
Visit 22
Month 60
1800
Days 1756 to 1845
Visit 23
Month 63
1890
Days 1846 to 1935
Visit 24
Month 66
1980
Days 1936 to 2025
Visit 25
Month 69
2070
Days 2026 -
Additional visits will follow the same algorithm ie, Visit Month Label increases by 3 months; 
Target Day increases by 90 days and the window for each visit is 90 days from the previous 
visit window.
For the purposes of reporting, the convention is to refer to Day 1 as the day of randomization.
For the lab values, if the calculated study day for the labeled baseline visit is not study Day 1,
but falls within 40 days before the start of the study dosing, then that data should be used for 
the baseline instead of leaving baseline missing. 
For ECG, if there are multiple visits prior to Day 1, the value collected at the latest visit will 
be used as baseline.


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For the other values, if the calculated study day for the labeled baseline visit is not study 
Day 1, but falls within 30 days 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 equal distant from the Target Day in absolute value, the later visit should be 
used. 
Safety analysis to follow CaPS (CDISC and Pfizer Standards).
For outcome research endpoints collected on a different schedule, such as SF-36, EQ-5D, and 
WPAI, the following visit windows will be used: 
Visit Label
Month Label
Target Day
Definition [Day window]
Visit 1
Month 0
Day 1, 
Randomization
Day 1
Visit 3
Month 3
90
Days 42 to 135
Visit 4
Month 6
180
Days 136 to 270
Visit 6
Month 12
360
Days 271 to 540
Visit 10
Month 24
720
Days 541 to 900
Visit 14
Month 36
1080
Days 901 to 1260
Visit 18
Month 48
1440
Days 1261 to 1620
Visit 22
Month 60
1800
Days 1621 -
Additional visits will follow the same algorithm ie, Visit Month Label increases by 
12 months; Target Day increases by 360 days and the window for each visit is 360 days from 
the previous visit window.
For lipid profile (fasting), the following visit windows will be used:
Visit Label
Month Label
Target Day
Definition [Day window]
Visit 1
Month 0
Day 1, 
Randomization
Day 1
Visit 2
Month 2
60
Days 42 to 210
Visit 6
Month 12
360
Days 211 to 540
Visit 10
Month 24
720
Days 541 to 900
Visit 14
Month 36
1080
Days 901 to 1260
Visit 18
Month 48
1440
Days 1261 to 1620
Visit 22
Month 60
1800
Days 1621 -


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Additional visits will follow the same algorithm ie, Visit Month Label increases by 
12 months; Target Day increases by 360 days and the window for each visit is 360 days from 
the previous visit window.
Appendix 1.2. Definition of Protocol Deviations that Relate to Statistical 
Analyses/Populations
None.
Appendix 1.3. Definition of Analysis Populations/Sets 
None.
Appendix 1.4. Further Definition of Endpoints
Indicator
Definition/Calculation
DAS28-4 (CRP)
DAS28-4(CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) 
+ 0.36*ln(CRP+1) + 0.014* PtGA + 0.96
Simplified Disease Activity Index (SDAI)
(TJC28) + (SJC28) + PhyGA/10 + PtGA/10 + CRP/10
Clinical Disease Activity Index (CDAI)
(TJC28) + (SJC28) + PhyGA/10 + PtGA/10
American College of Rheumatology (ACR) 
Response Rates
The ACR’s definition for calculating a 20% improvement in 
RA (ACR20) is as follows: 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 (eg, CRP).  Similarly, ACR50, 70 and 90 are 
calculated with the respective percent improvements.
ACR/EULAR Boolean-based definition of 
remission
subject must satisfy all of the following: TJC28 ≤1, SJC28
≤1, CRP ≤10, PtGA ≤10
where TJC28 is number of painful joints out of 28 joints; SJC28 is number of swollen joints out of 28 joints; 
PtGA is the patient’s global assessment of disease activity on a 100 mm VAS;
PhyGA is the physician’s global assessment of disease activity on a 100 mm VAS; 
CRP = C-reactive protein in mg/L;
ln is the natural logarithm;
sqrt is square root
Patient’s Global Assessment of Health: Subjects will answer the following question, 
“Considering all the ways your arthritis affects you, how are you feeling today?”  The 
subject’s response will be recorded using a 100 mm visual analog scale (VAS).
Physician’s Global Assessment of Health: The investigator will assess how the subject’s 
overall arthritis appears at the time of the visit.  This is an evaluation based on the subject’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).


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Appendix 2. STATISTICAL METHODOLOGY DETAILS 
None.
Appendix 2.1. Further Details of Interim Analyses
None.
Appendix 2.2. Further Details of the Statistical Methods
Definition of the SIR
Suppose the person-time from a treatment group is allocated among M subgroups defined by 
the cross-classification of sex and age group. Let tk represent the person-time for that 
subgroup and Dk represent the observed number of subjects with events in the kth subgroup, 
and let 
represent the SEER incidence rate for the kth subgroup, where k = 1, 2, ..., M. 
Given this notation, the SIR is defined as:
where the total number of subjects with events observed in the treatment group is 
, and the expected total number of subjects with events is 
(Breslow and Day, 1987;4 Sahai and Khurshid, 1996).5
Exact Confidence Limits for the True SIR
Sahai and Khurshid (1993,6 1996)5 discuss the following method for obtaining the exact 
confidence limits, SIRL and SIRU, for the true SIR, . Assuming D is Poisson distributed 
with mean µ = E(D), confidence limits for µ are obtained using the relationship between the 
Poisson distribution and the chi-square distribution. Then these limits are divided by the 
expected total number of subjects with events, E*, to obtain the limits.
and 
where 
is the 100*percentile of the chi-square distribution with v degrees of freedom.