Clinical trial NCT02831855
Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis Tofacitinib CP-690,550 Xeljanz methotrexate withdrawal withdrawal study
Sponsor: Pfizer
Start date: 2016-09-01; Completion date: 2018-12-17
Enrollment: 694 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to evaluate the efficacy and safety of tofacitinib modified release formulation (11mg QD) versus tofacitinib modified release formulation plus continued methotrexate treatment in subjects with moderate to severe rheumatoid arthritis who are insufficiently responding to their stable dose of methotrexate treatment.

Detailed description:

Arms: arm 1: Open-label tofacitinib tablet and blinded methotrexate capsule arm 2: open-label tofacitinib tablet and blinded matching placebo for methotrexate capsule
Interventions: intervention 1: CP-690,550 intervention 2: Methotrexate intervention 3: Placebo
Intervention descriptions: intervention 1: During the open-label run-in phase (Day 1 to Week 24), all subjects will receive one tablet open-label tofacitinib MR 11mg orally QD and open-label methotrexate capsule(s) orally every week at prior stabilized dose.

During the double-blind phase, subjects who are randomized to the treatment arm will receive the same dosage of tofacitinib and methotrexate as describe above. intervention 2: During the open-label run-in phase (Day 1 to Week 24), all subjects will receive one tablet open-label tofacitinib MR 11mg orally QD and open-label methotrexate capsule(s) orally every week at prior stabilized dose.

During the double-blind phase, subjects who are randomized to the treatment arm will receive the same dosage of tofacitinib and methotrexate as describe above. intervention 3: During the double-blind phase, subjects who are randomized to the comparison arm will receive 11mg QD tofacitinib and the placebo capsules matching for methotrexate.

Protocol documents:
Prot_000.pdf: 
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A PHASE 3B/4 RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED 
STUDY OF METHOTREXATE (MTX) WITHDRAWAL IN SUBJECTS WITH 
RHEUMATOID ARTHRITIS (RA) TREATED WITH TOFACITINIB 11MG 
MODIFIED RELEASE (MR) FORMULATION 
Compound:
CP 690,550
Compound Name:
Tofacitinib citrate
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2016-001825-15
Protocol Number:
A3921192
Phase:
Phase 3B/4
CCI


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Document History
Document
Version Date
Summary of Changes 
Original protocol
09 May 2016
Not applicable (N/A)
Amendment 1
09 Feb 2017
Belgium, Czech Republic, Germany, Hungary, 
Italy, Poland, Spain, United Kingdom country 
specific amendment.  The following changes were 
made:
1. Exclusion of subjects screened in Belgium, 
Czech Republic, Germany, Hungary, Italy, 
Poland, Spain, and the United Kingdom who
have resided in or traveled in areas of endemic 
tuberculosis or endemic mycoses.
2. Addition of Quantiferon testing at week 24 for 
all patients.
3. Addition of text to Section 1.2.1 that 
tofacitinib is under review in the EU and not 
yet approved.
4. Clarification to the Schedule of Activities and 
Section 7.2 that careful assessment of the skin 
for melanoma and nonmelanoma skin cancer 
is part of the Assessment of New Physical 
Findings.
5. Addition of a statement regarding the risk of 
administration of NSAIDs and methotrexate 
and the prohibition of the use of folate 
antagonists during the study.
6. Clarification of discontinuation criteria.
7. Change to Section 7.16 and 7.17 indicating 
that CRP and ESR are blinded to the 
investigator and site staff after randomization 
instead of screening.
8. Changes to Section 4.4.5 Contraception and 
Reproductive Status section added in 
Appendix 7. 


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Amendment 2
04 Dec 2017
The following changes were made:
1. Addition of text to Section 1.2.1 that 
tofacitinib has been approved in the EU. 
2. Addition of the ECG at End of Study visit in 
the Schedule of Activities and in Section 
6.2.7.
3. The number of subjects enrolled was 
increased from 580 to 680.
4. The LDA assessment was changed from 
DAS28-4(ESR) <3.2 and DAS28-4(CRP) 
<3.2 to DAS28-4(ESR) 3.2 and 
DAS28-4(CRP) 3.2.
5. Stool examination for parasites in Peru (Table 
4; Clinical Laboratory Tests) will be deleted 
since Peru is not involved this study.
6. Changes from baseline in tender/painful joint 
counts, swollen joint counts, subject 
assessment of arthritis pain, subject global 
assessment of arthritis, and physician global 
assessment of arthritis were added as other 
efficacy endpoints.
The following changes previously described in 
the protocol administrative change letters (PACL) 
dated 17Jun2016, 14Jul2016, 05Jul2017 and 
07Sep2017 were made:
1. In Section 7.4, Electrocardiogram, the 
electrocardiogram (ECG) at the End of Study 
visit was deleted and comparison of the End 
of Study ECG was not to be completed per the 
PACL dated 17Jun2016.  However, the 
decision has been made to keep the ECG at 
the End of Study visit so this change will not 
be made.
2. In Sections 6.1 (screening), 6.2.4 (Visit 3) and 
6.2.6 (Visit 5): the sentence “Subjects are 
required to fast for at least 6 hours prior to the 
visit” is deleted.
3. In Section 6.2.2 (Visit 1): “Smoking history 
and alcohol consumption” will be added as 
one of the information collected.
4. In Sections 7.16, C-Reactive Protein (CRP)
and 7.17, Erythrocyte Sedimentation Rate 


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(ESR) will be changed so that the Investigator 
and other site personnel participating in the 
study and Pfizer study personnel will be kept 
blinded of the results of this test after the 
randomization visit.
5. In Section 4.2, Exclusion Criteria, Criterion 
8b, has been revised to also exclude any prior 
JAK inhibitor usage. 
6. Section 9.6 has been retitled and includes 
information regarding potential safety and 
efficacy analyses of data obtained in the Open 
Label Phase of the study.
7. In Appendix 3, Prohibited Concomitant 
Medications: The medication "baricitinib 
(Olumiant)" has been added to the Prohibited 
Concomitant Medications table, listed under 
Nonbiologic DMARDs.
8. In Section 3.0, Study Design:
a.
“The enrollment will be monitored by 
Sponsor to ensure approximately 50% of 
enrolled subjects will have moderate 
disease activity (defined as DAS28 (ESR) 
>3.2 and <5.1) and approximately 50% 
will have severe disease activity (defined 
as DAS28 (ESR) >5.1).” is removed 
from the protocol.
b. “In addition, the proportion of subjects 
who have been exposed to one or more 
biologics prior to enrollment” is changed 
to “In addition, the proportion of subjects 
who have had an insufficient response to 
one or more biologics prior to enrollment”
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
LIST OF FIGURES .................................................................................................................10
APPENDICES .........................................................................................................................10
PROTOCOL SUMMARY.......................................................................................................11
STUDY DESIGN.....................................................................................................................15
SCHEDULE OF ACTIVITIES................................................................................................17
1. INTRODUCTION ...............................................................................................................20
1.1. Mechanism of Action/Indication.............................................................................20
1.2. Background and Rationale ......................................................................................20
1.2.1. Tofacitinib Immediate Release (IR) Formulation.......................................20
1.2.2. Tofacitinib Modified Release (MR) Formulation.......................................21
1.2.3. Rationale.....................................................................................................22
1.2.4. Single Reference Safety Document (SRSD) ..............................................22
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................22
2.1. Objectives................................................................................................................22
2.1.1. Primary Objectives .....................................................................................22
2.1.2. Secondary Objectives .................................................................................22
2.1.3. Other Objectives.........................................................................................23
2.1.4. Exploratory Objectives ...............................................................................23
2.2. Endpoints.................................................................................................................23
2.2.1. Efficacy Endpoints......................................................................................23
2.2.1.1. Primary Efficacy Endpoint........................................................23
2.2.1.2. Secondary Efficacy Endpoints ..................................................23
2.2.1.3. Other Efficacy Endpoints..........................................................24
2.2.1.4. Safety Endpoints .......................................................................24
2.2.1.5. Exploratory Endpoints...............................................................24
3. STUDY DESIGN.................................................................................................................25
4. SUBJECT SELECTION......................................................................................................26
4.1. Inclusion Criteria.....................................................................................................26
4.2. Exclusion Criteria....................................................................................................29


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4.3. Randomization Criteria ...........................................................................................32
4.4. Lifestyle Guidelines ................................................................................................32
4.4.1. Non-Pharmacologic Interventions..............................................................32
4.4.2. Vaccine and Exposure to Infections Guidelines.........................................32
4.4.3. Dietary Supplements...................................................................................33
4.4.4. Surgery........................................................................................................33
4.4.5. Contraception and Reproductive Status......................................................34
4.5. Sponsor’s Qualified Medical Personnel..................................................................35
4.6. Rater Qualifications.................................................................................................35
5. STUDY TREATMENTS.....................................................................................................35
5.1. Allocation to Treatment ..........................................................................................36
5.2. Breaking the Blind ..................................................................................................36
5.3. Subject Compliance.................................................................................................37
5.4. Investigational Product Supplies.............................................................................37
5.4.1. Dosage Form(s) and Packaging..................................................................37
5.4.2. Preparation and Dispensing........................................................................38
5.5. Administration.........................................................................................................38
5.6. Investigational Product Storage ..............................................................................39
5.7. Investigational Product Accountability...................................................................40
5.7.1. Destruction of Investigational Product Supplies ........................................40
5.8. Concomitant Treatment(s).......................................................................................40
5.8.1. Allowed Concomitant Medications............................................................41
5.8.1.1. Treatment for Latent Tuberculosis............................................41
5.8.1.2. Stable Background Arthritis Therapy .......................................41
5.8.2. Disallowed Concomitant Medications........................................................42
5.8.2.1. Disease Modifying Antirheumatic Drugs (DMARDs) .............42
5.8.2.2. Immune-Modulating Biologic Products....................................42
5.8.2.3. CYP3A4 and CYP2C19 Inhibitors and CYP3A4 Inducers ......42
5.8.2.4. Immunizations...........................................................................43
5.8.2.5. Investigational medication ........................................................43
5.9. Rescue Medication ..................................................................................................43


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6. STUDY PROCEDURES .....................................................................................................43
6.1. Screening.................................................................................................................43
6.2. Study Period ............................................................................................................45
6.2.1. Visit Windows ............................................................................................46
6.2.2. Visit 1 (Baseline Visit; Day 1)....................................................................46
6.2.3. Visit 2 (Week 6; Day 42)............................................................................48
6.2.4. Visit 3 (Week 12; Day 84)..........................................................................48
6.2.5. Visit 4 (Randomization; Week 24; Day 168) .............................................49
6.2.6. Visit 5 (Week 36; Day 252)........................................................................51
6.2.7. Visit 6 (End of Study Visit; Week 48; Day 336/Early Withdrawal 
Visit) ................................................................................................................51
6.2.8. Telephone Follow-up (At least 28 days following last dose of study 
drugs) ...............................................................................................................52
6.3. Subject Withdrawal.................................................................................................53
7. ASSESSMENTS..................................................................................................................53
7.1. Physical Examination..............................................................................................53
7.2. Assessment of New Physical Findings....................................................................54
7.3. Chest Radiograph ....................................................................................................54
7.4. Electrocardiogram ...................................................................................................54
7.5. Assessments of Disease Activity.............................................................................54
7.6. Joint Counts.............................................................................................................55
7.6.1. Tender/Painful Joint Count (28 Joint Count)..............................................55
7.6.2. Swollen Joint Count (28 Joint Count) ........................................................55
7.7. Subject Assessment of Arthritis Pain......................................................................56
7.8. Subject Global Assessment of Arthritis ..................................................................56
7.9. Physician Global Assessment of Arthritis...............................................................56
7.10. Health Assessment Questionnaire – Disability Index (HAQ-DI) .........................56
7.11. SF-36 Health Survey (Version 2, Acute) ..............................................................56
7.12. EuroQol EQ-5D Health State Profile....................................................................56
7.13. Work Productivity and Activity Impairment (WPAI) Questionnaire ...................57
7.14. Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale......57
7.15. Routine Assessment of Patient Index Data 3 (RAPID3).......................................57


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7.16. C-reactive Protein (CRP) ......................................................................................57
7.17. Erythrocyte Sedimentation Rate (ESR).................................................................57
7.18. Clinical Laboratory Tests......................................................................................57
7.19. Pregnancy Testing.................................................................................................59
7.20. Adjudicated Events ...............................................................................................60
7.21. Banked Biospecimens ...........................................................................................60
7.21.1. Markers of Drug Response.......................................................................60
7.21.2. Additional Research..................................................................................61
7.22. Assessment of Suicidal Ideation and Behavior (SIB) ...........................................62
7.23. Triggered Requirements for Monitoring and Discontinuation Criteria.................62
8. ADVERSE EVENT REPORTING......................................................................................64
8.1. Adverse Events........................................................................................................64
8.2. Reporting Period .....................................................................................................65
8.3. Definition of an Adverse Event...............................................................................65
8.4. Medication Errors....................................................................................................66
8.4.1. Tofacitinib Overdose ..................................................................................67
8.4.2. Methotrexate Overdose...............................................................................67
8.5. Serious Infections....................................................................................................67
8.6. Abnormal Test Findings..........................................................................................68
8.7. Serious Adverse Events...........................................................................................68
8.7.1. Protocol-Specified Serious Adverse Events...............................................69
8.7.2. Potential Cases of Drug-Induced Liver Injury............................................69
8.8. Hospitalization ........................................................................................................70
8.9. Severity Assessment................................................................................................71
8.10. Causality Assessment............................................................................................71
8.11. Exposure During Pregnancy..................................................................................72
8.12. Occupational Exposure .........................................................................................73
8.13. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal)...............................................................................................................73
8.14. Eliciting Adverse Event Information ....................................................................73
8.15. Reporting Requirements........................................................................................73
8.15.1. Serious Adverse Event Reporting Requirements .....................................74


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8.15.2. Non-serious Adverse Event Reporting Requirements..............................74
8.15.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................74
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................74
9.1. Sample Size Determination.....................................................................................75
9.2. Descriptive Analysis ...............................................................................................75
9.3. Efficacy Analysis ....................................................................................................75
9.3.1. Analysis of the Primary Endpoint...............................................................75
9.3.2. Analysis of Secondary Endpoints...............................................................76
9.4. Analysis of Other Efficacy and Exploratory Endpoints..........................................76
9.5. Safety Analysis........................................................................................................76
76
9.7. Data Monitoring Committee ...................................................................................77
9.8. Safety Event Adjudication/Review Committees.....................................................77
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................77
11. DATA HANDLING AND RECORD KEEPING .............................................................78
11.1. Case Report Forms/Electronic Data Record .........................................................78
11.2. Record Retention...................................................................................................79
12. ETHICS..............................................................................................................................79
12.1. Institutional Review Board/Ethics Committee......................................................79
12.2. Ethical Conduct of the Study ................................................................................79
12.3. Subject Information and Consent..........................................................................80
12.4. Subject Recruitment ..............................................................................................80
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................80
13. DEFINITION OF END OF TRIAL...................................................................................81
13.1. End of Trial in a Member State.............................................................................81
13.2. End of Trial in All Other Participating Countries.................................................81
14. SPONSOR DISCONTINUATION CRITERIA ................................................................81
15. PUBLICATION OF STUDY RESULTS..........................................................................81
15.1. Communication of Results by Pfizer ....................................................................81
15.2. Publications by Investigators ................................................................................82
16. REFERENCES ..................................................................................................................84
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LIST OF TABLES
Table 1.
Treatment arms.....................................................................................................36
Table 2.
DMARDs – Required Washout Period.................................................................42
Table 3.
Disease Activity Indicators...................................................................................55
Table 4.
Clinical Laboratory Tests .....................................................................................58
LIST OF FIGURES
Figure 1.
Study Design.........................................................................................................26
APPENDICES
Appendix 1. Abbreviations......................................................................................................86
Appendix 2. The 2010 American College of Rheumatology/European League Against 
Rheumatism Classification Criteria for Rheumatoid Arthritis.............................89
Appendix 3. Prohibited Concomitant Medications..................................................................91
Appendix 4. Cockcroft-Gault Formula for Estimating GFR ...................................................92
Appendix 5. Approximate Equivalent Morphine Doses Of Opioid Analgesics......................93
Appendix 6. Rescue Therapy...................................................................................................94
Appendix 7. Belgium, Czech Republic, Germany, Hungary, Italy, Poland, Spain, and 
United Kingdom Specific Protocol Requirements ...............................................96


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PROTOCOL SUMMARY
Background and Rationale
Tofacitinib (CP-690,550) is a potent, selective inhibitor of the Janus kinase (JAK) family of 
kinases with a high degree of selectivity against other kinases in the human genome.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 heterodimeric receptors associated with JAK3 and/or JAK1 with 
functional selectivity over receptors that signal via pairs of JAK2.2 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 signaling. 
The Phase 2 and 3 studies in the RA development program have demonstrated that tofacitinib 
Immediate Release (IR) 5 mg twice daily (BID) consistently reduces signs and symptoms of 
rheumatoid arthritis (RA), improves physical function and other subject-reported outcomes 
such as fatigue, pain and health-related aspects of quality of life in subjects with moderate to 
severe RA. Combined with its inhibition of the progression of structural damage, the 
development program has demonstrated tofacitinib as an effective targeted synthetic 
disease-modifying antirheumatic drug (DMARD) in treating RA.5-10 Ongoing long-term 
extension and Phase 3b/4 post authorization safety studies are aimed to demonstrate 
sustained efficacy and a consistent safety profile as seen in the Phase 2 and 3 controlled 
clinical trials. Data from completed and ongoing clinical trials demonstrate tofacitinib’s 
manageable safety profile. The overall benefit-risk profile of the tofacitinib IR formulation 
remains favorable (refers to Investigator Brochure (IB) for further details). Tofacitinib IR 
5 mg BID is currently approved in the United States (US), European Union (EU), and 
40 other countries for the treatment of adult patients with RA.
To enable once daily (QD) dosing, Pfizer has developed a modified release (MR) osmotic 
tablet formulation of tofacitinib at a dose strength of 11 mg. Seven Phase 1 healthy volunteer 
studies have been completed to characterize the biopharmaceutical aspects of the tofacitinib 
MR 11mg QD formulation and establish similarity in key pharmacokinetic (PK) exposure 
parameters and relative bioavailability (BA) as compared to the currently approved 
tofacitinib IR 5 mg BID formulation.  The tofacitinib MR clinical pharmacology 
development program has demonstrated that the MR 11 mg QD dose has equivalent Area 
Under Concentration (AUC) and Cmax compared to the currently approved IR 5 mg BID 
dose.  Exposure-response (E-R) relationships from the IR development program show that 
Cav is the relevant parameter for efficacy and that the slightly lower (29%) Cmin of the MR 
formulation is not clinically important to the efficacy of tofacitinib.  These data support the 
consistent efficacy between MR 11 mg QD and IR 5 mg BID.  Likewise, the overall


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similarity in PK parameters and duration of JAK1/3 inhibition over the dosing interval, along 
with exposure-safety relationships from the IR program, indicate that the safety of MR 11 mg 
QD will be consistent with that of the IR 5 mg BID.  The MR formulation of tofacitinib was 
also shown to be generally safe and well tolerated in 7 healthy volunteer studies. 
Collectively, these data support a favorable benefit-risk profile for the MR 11 mg QD 
formulation for the treatment of adult patients with moderately to severely active RA, and the 
efficacy and safety of tofacitinib MR 11 mg QD are expected to be consistent with that 
demonstrated for tofacitinib IR 5 mg BID. A New Drug Application (NDA) for the MR 
osmotic tablet formulation of tofacitinib (dosed at 11 mg QD) for the treatment of RA is 
under review by the Food and Drug Administration (FDA).
The tofacitinib IR 5mg BID formulation has demonstrated efficacy both as a monotherapy 
and in combination with methotrexate (MTX) in previous trials. However, it remains 
unknown whether the tofacitinib efficacy will be sustained after the withdrawal of MTX 
among RA patients who achieve low disease activity following treatment with tofacitinib
plus MTX. Results of the current study will inform the value of the continued MTX 
treatment among subjects who have responded to combined therapy of tofacitinib and MTX. 
A MR 11mg QD regimen has the potential to offer an additional dosing option to subjects, 
and based on the equivalence of key pharmacokinetic parameters, efficacy and safety are 
expected to be consistent with that demonstrated for tofacitinib IR 5 mg BID. Therefore, the 
current study will evaluate the sustained efficacy and safety of the tofacitinib MR 11 mg QD 
regimen among RA patients undergoing blinded withdrawal of MTX. 
Complete information for tofacitinib may be found in the single reference safety document 
(SRSD), which for this study is the tofacitinib IB.  The SRSD for MTX is the Summary of 
Product Characteristics (SPC). 
STUDY OBJECTIVES AND ENDPOINTS
OBJECTIVES
Primary Objectives
To compare the efficacy of tofacitinib MR 11mg monotherapy to tofacitinib MR 11mg with
continued MTX, as measured by the change in the Disease Activity Score utilizing 
4 components including erythrocyte sedimentation rate (DAS28-4 (ESR)) from 
randomization (at Week 24) to the end of the double-blind MTX withdrawal phase (at 
Week 48).
Secondary Objectives

To compare the efficacy of tofacitinib MR 11mg monotherapy to tofacitinib MR 
11mg with continued MTX in the double-blind MTX withdrawal phase (at Week 36), 
as measured by DAS28-4 (ESR).


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
To compare the efficacy of tofacitinib MR 11mg monotherapy to tofacitinib MR 
11mg with continued MTX in the double-blind MTX withdrawal phase (at Weeks
48 and 36), as measured by Disease Activity Score 28-4 (C-reactive protein)
(DAS28-4 (CRP)), Clinical Disease Activity Index (CDAI), Simplified Disease 
Activity Index (SDAI), Low Disease Activity (LDA), remission, ACR20, ACR 50, 
and ACR 70.

To compare effects of tofacitinib MR 11mg monotherapy to tofacitinib MR 11mg 
with continued MTX on health outcome measures in the double-blind MTX 
withdrawal phase (at Weeks 48 and 36), as measured by Health Assessment 
Disability Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Survey 
Short Form -36 (SF-36), Work Productivity and Activity Impairment (WPAI), 
European Quality of Life - 5 dimensions questionnaire (EuroQol EQ-5D), and 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale.

To evaluate the safety and tolerability of tofacitinib MR 11mg monotherapy versus
tofacitinib MR 11mg with continued MTX.
Other Objectives

To describe efficacy of treatment with tofacitinib 11mg with MTX in the open-label 
run-in phase (at Weeks 12 and 24), as measured by DAS28-4 (ESR), 
DAS28-4 (CRP), CDAI, SDAI, LDA, remission, ACR20, ACR 50, ACR70.

To describe effects of treatment with tofacitinib MR 11mg with MTX on health 
outcome measures in the open-label run-in phase (at Weeks 12 and 24), as measured 
by HAQ-DI, SF-36, WPAI, EuroQol EQ-5D, and FACIT-Fatigue scale.
Exploratory Objectives

To collect exploratory biomarker/genomics samples for bio-banking. 

US and Canada ONLY: To explore effects of treatment with tofacitinib MR 11mg 
with/without MTX on health outcome measure in the open-label run-in phase (at 
Weeks 12 and 24) and the double-blind MTX withdrawal phase (at Weeks 48 and 
36), as measured by Routine Assessment of Patient Index Data 3 (RAPID3).
Endpoints 
Efficacy Endpoints
Primary Efficacy Endpoint
Change in DAS28-4 (ESR) score from randomization (at Week 24) to the end of 
double-blind MTX withdrawal phase (at Week 48). 


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Secondary Efficacy Endpoints

Change in the DAS28-4 (ESR) from Week 24 to Week 36;

Changes in the DAS28-4 (CRP), CDAI and SDAI, respectively, from Week 24 to 
Week 48 and from Week 24 to Week 36; 

LDA as assessed by DAS28-4(ESR) 3.2, DAS28-4(CRP) 3.2, CDAI10 and 
SDAI11, respectively, at Weeks 48 and 36;

Remission as assessed by ACR-EULAR Boolean remission 
criteria,11 DAS28-4 (ESR)<2.6, DAS28-4 (CRP)<2.6, CDAI≤2.8 and SDAI≤3.3, 
respectively, at Weeks 48 and 36;

ACR20, ACR 50, and ACR70 responses, respectively, at Weeks 48 and 36;

Change in the HAQ-DI, the SF-36 (8 domain scores and 2 component scores), WPAI, 
EuroQol EQ-5D and the FACIT-Fatigue scale score, respectively, from Week 24 to 
Week 48 and from week 24 to Week 36;

HAQ-DI response (ie, decrease of at least 0.22) at Weeks 48 and 36.
Other Efficacy Endpoints

Changes in DAS28-4 (ESR), DAS28-4 (CRP), CDAI, SDAI, HAQ-DI, 
SF-36 (8 domain scores and 2 component scores), WPAI, EuroQol EQ-5D score and 
FACIT-Fatigue scale score, respectively, from day 1 to Week 12 and from day 1 to 
Week 24;

LDA as assessed by DAS28-4(ESR) <3.2, DAS28-4(CRP) <3.2, CDAI10 and 
SDAI11, respectively, at Weeks 12 and 24;

Remission as assessed by ACR-EULAR Boolean remission criteria, 
DAS28-4 (ESR)<2.6, DAS28-4 (CRP)<2.6, CDAI2.8 and SDAI3.3, respectively, 
at Weeks 12 and 24;

ACR20, ACR 50, and ACR70 responses, respectively, at Weeks 12 and 24;

HAQ-DI response (ie, decrease of at least 0.22) at Weeks 12 and 24.

Changes in tender/painful joint counts, swollen joint counts, subject assessment of 
arthritis pain, subject global assessment of arthritis, physician global assessment of 
arthritis, and CRP, respectively, from day 1 to Week 12 and from day 1 to Week 24, 
from Week 24 to Week 48 and from week 24 to Week 36.


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Safety Endpoints

All adverse events (AEs), including serious adverse events (SAEs).

Clinically significant abnormal laboratory parameters.
Exploratory Endpoints

Exploratory biomarker/genomics endpoints will be specified in a separate protocol 
and/or statistical analysis plan if exploratory analyses utilizing the bio-banked 
exploratory genomic and biomarker samples across tofacitinib studies or across 
multiple programs are conducted.

US and Canada ONLY: RAPID3 summary score at Weeks 12, 24, 36 and 48.
STUDY DESIGN
Study A3921192 is a 12-month randomized, double-blind, placebo-controlled withdrawal 
study in a total of approximately 580 subjects with moderate to severe RA (defined as CDAI
>10 and DAS28 (ESR) 3.2) who are insufficiently responding to their stable dose of MTX
treatment.  The enrollment will be monitored by Sponsor to ensure approximately 50% of 
enrolled subjects will have moderate disease activity (defined as DAS28 (ESR) 3.2 and 
5.1) and approximately 50% will have severe disease activity (defined as DAS28 (ESR) 
> 5.1).  In addition, the proportion of subjects who have had an insufficient response to one 
or more biologics prior to the enrollment should be 25% (ie, 145 subjects).
After reviewing the rate of achievement of LDA and monitoring the discontinuation rate in 
the open-label period, the decision was made to increase in enrollment numbers from 
approximately 580 to 680 factoring in a discontinuation rate of approximately 15% during 
the open label run-in phase.  As of 02 Aug 2017, study was 50% enrolled with 81% having 
severe disease activity.  The LDA rate (~79% based upon a small sample size) was higher 
than protocol assumptions and historic data.  It is expected that enrolling >50% of subjects 
with severe disease activity will result in a sufficient number of subjects with LDA at 
Week 24.  Therefore, the enrollment requirement of 50% of subjects with severe disease 
activity and 50% with moderate disease activity was removed from the protocol.
Following enrollment, all subjects will receive open-label tofacitinib MR 11mg QD added to
MTX at their previously stabilized dose for 24 weeks (run-in phase).  At the end of the run-in 
phase (Week 24), only subjects who achieve low disease activity (LDA) as assessed by 
CDAI (ie, CDAI ≤10) (approximately 232 subjects) will be randomized into the 24-week 
double-blind, placebo-controlled MTX withdrawal phase.  Subjects who do not achieve LDA 
(defined by CDAI >10) at this time point will be discontinued from the study.  Subjects 
entering the double-blind phase will be randomized in a 1:1 ratio to either continue the run-in 
phase treatment regimen (tofacitinib MR 11mg QD with blinded MTX) or to receive 
tofacitinib monotherapy (tofacitinib MR 11mg QD with blinded matching placebo for MTX).  
Randomization will be stratified by subject’s prior exposure to a biologic DMARD.  
Randomized subjects will be followed up to the end of Week 48.  The primary efficacy 


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endpoint is the change in DAS28-4 (ESR) from randomization (at Week 24) to the end of 
double-blind MTX withdrawal phase (at Week 48).
STATISTICAL METHODS
Based on estimated CDAI-defined low disease activity rate of 40% derived from prior Phase 
3 studies and factoring in a discontinuation rate of approximately 15% during the open label 
run-in phase, approximately 680 subjects will be enrolled to the run-in phase with the aim of 
at least 232 subjects being randomized into the blinded MTX withdrawal phase at Week 24.  
With a two-sided Type-I error of 5% and an assumed standard deviation (SD) of 1.4 for the 
difference in change from randomization in DAS28-4 (ESR) between the two arms, a sample 
size of 232 subjects randomized at Week 24 would provide 90% power to declare 
non-inferiority of tofacitinib monotherapy relative to tofacitinib plus methotrexate with a 
non-inferiority margin of 0.6.
The primary endpoint of change from randomization in DAS28-4 (ESR) at Week 48 will be 
analyzed as a continuous variable using a linear mixed-effect model of repeated measures 
(MMRM) that includes the fixed effects of treatment, visit, treatment-by-visit interaction, 
prior use of a biological DMARD, and baseline DAS28-4 (ESR) value as a covariate.  
Within-subject variability will be accounted for using a random effect with an unstructured 
covariance matrix.  Change from randomization at any visit post-randomization will be 
defined as the DAS28-4 (ESR) value at that visit minus the value at randomization.
The analysis will be based on the Full Analysis Set (FAS), which is defined as those subjects 
who received at least one dose of tofacitinib MR 11mg plus MTX during the open label
run-in period, and were randomized and received at least one dose of the randomized 
investigational drug regimen (tofacitinib MR 11mg with MTX or tofacitinib MR 11mg with 
placebo for MTX) during the blinded MTX withdrawal period.
A robustness analysis based on a per-protocol analysis set will be performed.  Sensitivity
analyses using different methods of handling missing data will also be conducted; further 
details will be outlined in the SAP.
STATISTICAL DECISION RULES
The primary analysis will be a non-inferiority test to show that tofacitinib MR 11mg 
monotherapy is not less effective (non-inferior) than tofacitinib MR 11mg with continued 
MTX within the margin of non-inferiority set at 0.6 (ie, the difference in mean change from 
randomization in DAS 28-4 (ESR) between the two arms).  In other words, the change from 
randomization in DAS28-4(ESR) for the tofacitinib MR 11mg with placebo for MTX arm 
may be less favorable than that for the tofacitinib MR 11mg with continued MTX arm by no
more than 0.6.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the 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 visits (unplanned visits) in addition to those listed on the schedule of activities (SOA), in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Protocol Activities
Screening 
Visit
Visit 
1 (Baseline)
Visit 2
Visit 3
Visit 
4 (Randomization)
Visit 5
Visit 6 (End of 
Study/Early 
Withdrawal)k
Telephone 
Follow-upo
Day -30
(+10 days; 
ie, -
40 days)
Day 1
Week 6
(Day 42)
(±5 days)
Week 12
(Day 84)
(±10 days)
Week 24
(Day 168)
(±10 days)
Week 36
(Day 252)
(±10 days)
Week 48
(Day 
336)(±10 days)/early 
withdrawal
At least 28 days
following last 
dose of study 
drugs (+14 days)
Informed Consent
X
Medical History, Prior 
Medication 
X
RA diagnosis
X
Complete Physical Examination
X
Xn
X
Assessment of New Physical 
Findingsq
X
X
X
X
Inclusion/Exclusion criteria
X
X
Laboratory Testing
   Blood Chemistry
X
X
X
X
X
X
X
   CRPa
X
X
X
X
X
X
   ESR
X
X
X
X
X
X
   Hematology
X
X
X
X
X
X
X
   Banked biospecimens
X
X
X
X
   HIV Serology
X
   HBsAg, HBcAb, HBsAbb
X
  HCV Ab, HCV RNAb
X
   Lipid Profile (fasting) 
X
X
X
X
   Pregnancy test,c
   Contraceptive Check and
   Documentation
X
X
X
X
X
X
X
   QuantiFERON-Gold®™
X
Xl
   Rheumatoid Factor
X


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Protocol Activities
Screening 
Visit
Visit 
1 (Baseline)
Visit 2
Visit 3
Visit 
4 (Randomization)
Visit 5
Visit 6 (End of 
Study/Early 
Withdrawal)k
Telephone 
Follow-upo
Day -30
(+10 days; 
ie, -
40 days)
Day 1
Week 6
(Day 42)
(±5 days)
Week 12
(Day 84)
(±10 days)
Week 24
(Day 168)
(±10 days)
Week 36
(Day 252)
(±10 days)
Week 48
(Day 
336)(±10 days)/early 
withdrawal
At least 28 days
following last 
dose of study 
drugs (+14 days)
   Anti-cyclic citrullinated 
   peptide (Anti-CCP) antibody
X
   FSH (if applicable)d  
X
Urinalysis
X
Chest X-ray or CTe
X
ECG
X
X
Randomization
X
Investigational Product 
Dispensing
X
X
X
X
Joint Count (28)f
X
X
X
X
X
X
Subject Assessment of Arthritis 
Pain
X
X
X
X
X
Subject Global Assessment of 
Arthritis
X
X
X
X
X
Physician Global Assessment of 
Arthritis
X
X
X
X
X
HAQ-DIg
X
X
X
X
X
SF-36 (Version 2, Acute)
X
X
X
X
X
EuroQol EQ-5Dh
X
X
X
X
X
Work Productivity and Activity 
Impairment (WPAI) 
X
X
X
X
X
FACIT-Fatiguei
X
X
X
X
X
Routine Assessment of Patient 
Index Data 3 (RAPID3) (US 
and Canada ONLY)
X
X
X
X
X
Safety Assessment/AE 
Reporting/Assessment for AEs 
Requiring Adjudicationj
Xm
X
X
X
X
X
X
Xp
Concomitant Medication 
Review
X
X
X
X
X
X
Provide/review dosing diary 
X
X
X
X
X
X
Return unused investigational 
products 
X
X
X
X


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Page 19
a.
After screening, the investigator and other site personnel participating in the study and Pfizer study personnel will be kept blinded of the results of CRP.
b.
See Exclusion Criteria 3 and Table 4 in Section 7.17 for details.
c.
Pregnancy tests (serum/urine) may also be repeated more frequently as per request of IRBs/ECs or if required by local regulations. 
d.
To confirm post-menopausal status, if applicable.
e.
Chest radiograph or Chest CT scan unless previously performed and documented within 3 months prior to screening.
f.
Joint counts done by a blinded joint assessor. 
g.
Health Assessment Questionnaire – Disability Index.
h.
European Quality of Life 5 Dimension Questionnaire.
i.
Functional assessment of chronic illness therapy-fatigue scale.
j.
Specific safety events will be submitted to the appropriate Safety Event Adjudication/Review Committee for adjudication. 
k.
Subjects who do not achieve LDA at Week 24 and are therefore not randomized do not require a separate EOS visit except for QuantiFERON Gold®TM
In-Tube Test. 
l.
QuantiFERON Gold®TM in-Tube Test will be performed for ALL subjects (those who meet LDA and those who do not meet LDA at week 24) in Belgium, 
Czech Republic, Germany, Hungary, Italy, Poland, Spain, and the United Kingdom.  For all other countries the test will ONLY be performed for subjects 
who do not achieve LDA at Week 24 and are therefore not randomized.
m. Report and assess AEs within appropriate reporting period. See Section 6.1 for details.
n.
Height will not be collected in the Case Report Form (CRF).
o.
Can be combined with the End of Study visit as long as the Telephone Follow-up occurs at least 28 days after last administration of study drugs.
p.
Includes a query of pregnancy status in addition to AEs. 
q.
Assessment of new physical findings consists of an abbreviated physical examination assessing the following:  weight, vital signs, skin examination 
including a careful examination for melanoma and nonmelanoma skin cancer, lungs, heart, lower extremities for peripheral edema, abdomen, and lymph 
nodes.


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Tofacitinib (CP-690,550) is a potent, selective inhibitor of the Janus kinase (JAK) family of 
kinases with a high degree of selectivity against other kinases in the human genome.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 heterodimeric receptors associated with JAK3 and/or JAK1 with 
functional selectivity over receptors that signal via pairs of JAK2.2 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).3,4 At higher 
exposures, inhibition of erythropoietin, prolactin, and other hormones can occur via 
inhibition of JAK2 signaling.
1.2. Background and Rationale
1.2.1. Tofacitinib Immediate Release (IR) Formulation
The Phase 2 and 3 studies in RA development program demonstrated that tofacitinib IR 5 mg 
twice daily (BID) consistently reduces signs and symptoms of RA, improves physical 
function and other subject-reported outcomes such as fatigue, pain and health-related aspects 
of quality of life in subjects with moderate to severe RA. Combined with its inhibition of the 
progression of structural damage, the development program has demonstrated tofacitinib as 
an effective targeted synthetic DMARD in treating RA.5-10 Ongoing long-term extension and 
Phase 3b/4 post authorization safety studies are aimed to demonstrate sustained efficacy and 
a consistent safety profile as seen in the Phase 2 and 3 controlled clinical trials. 
Data from completed and ongoing clinical studies demonstrate tofacitinib’s manageable 
safety profile. As of April 2014, Over 10,000 subjects have received at least 1 study dose of 
oral tofacitinib in either a randomized clinical study or a long-term extension (LTE) study in 
multiple indications. Approximately 6100 adult RA subjects have been exposed to 
tofacitinib with greater than 16,800 subject years of exposure in Phase 2, 3, 
3B/4 post-authorization and LTE studies. Potentially important safety risks that have been 
observed with the oral use of tofacitinib in the Phase 2 and Phase 3 studies include serious 
and other important infections, including tuberculosis (TB) and herpes zoster; the potential 
for malignancies including lymphoma; and the potential for gastrointestinal (GI) 
perforations. Subjects receiving tofacitinib may also be at increased risk of nonmelanoma 
skin cancers (NMSC).  Cardiovascular disease and interstitial lung disease (ILD) are findings 
seen in RA subjects receiving tofacitinib, and are recognized comorbidities for RA as well as 
being associated with other RA therapies.  Changes in laboratory values have also been 
observed including a dose-dependent increase in low density lipoprotein (LDL) cholesterol 
and dose-dependent decreases in neutrophils and hemoglobin.  Other laboratory changes 


Tofacitinib citrate
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Page 21
observed with tofacitinib treatment include decreases in lymphocytes and increases in 
transaminases, serum creatinine, and creatine kinase (CK).  Laboratory changes observed 
with tofacitinib treatment are manageable; recovery of laboratory changes upon 
discontinuation of tofacitinib treatment is characteristically observed.  Based on nonclinical 
data, there is the potential for tofacitinib to have effects on pregnancy and the fetus.  More 
details of identified risks with tofacitinib in RA are presented in the XELJANZ(tofacitinib 
citrate) Investigator Brochure (IB).
Based on the most recent data from clinical trials and post-marketing experience, the overall 
benefit-risk profile of the tofacitinib IR formulation remains favorable (refer to tofacitinib IB 
for further details). Tofacitinib IR 5 mg BID is currently approved in the United States (US), 
European Union (EU), and 40 other countries.
1.2.2. Tofacitinib Modified Release (MR) Formulation
To enable once daily (QD) dosing, Pfizer has developed a modified release (MR) osmotic 
tablet formulation of tofacitinib at a dose strength of 11 mg. Seven Phase 1 healthy volunteer 
studies have been completed to characterize the biopharmaceutical aspects of the tofacitinib 
MR 11mg QD formulation and establish similarity in key pharmacokinetic (PK) exposure 
parameters and relative bioavailability (BA) as compared to the currently approved 
tofacitinib IR 5 mg BID formulation. The clinical pharmacology development program has 
demonstrated that the MR 11 mg QD dose has equivalent Area Under Concentration (AUC)
and Cmax compared to the currently approved IR 5 mg BID. Exposure-response (E-R) 
relationships from the IR development program show that Cav is the relevant parameter for 
efficacy and that the slightly lower (29%) Cmin of the MR formulation is not clinically 
important to the efficacy of tofacitinib.  These data support the consistent efficacy between
MR 11 mg QD and IR 5 mg BID.
Likewise, the overall similarity in PK parameters and duration of JAK1/3 inhibition over the 
dosing interval, along with exposure-safety relationships from the IR program, indicate that 
the safety of MR 11 mg QD will be consistent with that of the IR 5 mg BID. Of the 172 total 
subjects in the 7 healthy volunteer studies, 67 reported adverse events (AEs).  AEs were 
generally similar between the MR formulations and the IR tablets.  There were no deaths, 
serious adverse events (SAEs), severe AEs, or dose reductions/temporary discontinuations 
due to AEs.  The majority of AEs were considered to be mild and related to treatment, and 
none of the reported AEs were considered clinically important. 
Collectively, these data support a favorable benefit-risk profile for the MR 11 mg QD 
formulation for the treatment of adult patients with moderately to severely active RA, and
showed the efficacy and safety of tofacitinib MR 11 mg QD are expected to be consistent 
with that demonstrated for tofacitinib IR 5 mg BID. A New Drug Application (NDA) for the
MR osmotic tablet formulation of tofacitinib (dosed at 11 mg QD) for the treatment of RA is 
under review by the Food and Drug Administration (FDA).


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1.2.3. Rationale
The tofacitinib IR 5mg BID formulation has demonstrated efficacy both as a monotherapy 
and in combination with methotrexate (MTX) in previous trials. However, it remains 
unknown whether the tofacitinib efficacy will be sustained after the withdrawal of MTX 
among RA patients who achieve low disease activity following treatment with MTX plus 
tofacitinib. Results of the current study will inform the value of the continued MTX 
treatment among subjects who have responded to combined therapy of tofacitinib and MTX. 
A MR 11mg QD regimen has the potential to offer an additional dosing option to subjects, 
and based on the equivalence of key pharmacokinetic parameters, efficacy and safety are 
expected to be consistent with that demonstrated for tofacitinib IR 5 mg BID. Therefore, the 
current study will evaluate the sustained efficacy and safety of the tofacitinib MR 11 mg QD 
regimen among RA patients undergoing blinded withdrawal of MTX. 
1.2.4. Single Reference Safety Document (SRSD)
Complete information for tofacitinib may be found in the single reference safety document 
(SRSD), which for this study is the tofacitinib IB. The SRSD for MTX is the Summary of 
Product Characteristics (SPC). 
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Objectives
To compare the efficacy of tofacitinib MR 11mg monotherapy to tofacitinib MR 11mg with 
continued MTX, as measured by the change in the Disease Activity Score utilizing 
4 components including erythrocyte sedimentation rate (DAS28-4 (ESR)) from 
randomization (at Week 24) to the end of the double-blind MTX withdrawal phase (at 
Week 48).
2.1.2. Secondary Objectives

To compare the efficacy of tofacitinib MR 11mg monotherapy to tofacitinib MR 
11mg with continued MTX in the double-blind MTX withdrawal phase (at Week 36), 
as measured by DAS28-4 (ESR).

To compare the efficacy of tofacitinib MR 11mg monotherapy to tofacitinib MR 
11mg with continued MTX in the double-blind MTX withdrawal phase (at Weeks 
48 and 36), as measured by Disease Activity Score 28-4 (C reactive protein) 
(DAS28-4 (CRP)), Clinical Disease Activity Index (CDAI), Simplified Disease 
Activity Index (SDAI), Low Disease Activity (LDA), remission, ACR20, ACR 50, 
and ACR 70. 


Tofacitinib citrate
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Page 23

To compare effects of tofacitinib MR 11mg monotherapy to tofacitinib MR 11mg 
with continued MTX on health outcome measures in the double-blind MTX 
withdrawal phase (at Weeks 48 and 36), as measured by Health Assessment 
Disability Questionnaire-Disability Index (HAQ DI), Medical Outcomes Survey 
Short Form -36 (SF-36), Work Productivity and Activity Impairment (WPAI), 
European Quality of Life 5 dimensions questionnaire (EuroQol EQ 5D), and 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale.

To evaluate the safety and tolerability of tofacitinib MR 11mg monotherapy versus 
tofacitinib MR 11mg with continued MTX.
2.1.3. Other Objectives

To describe efficacy of treatment with tofacitinib 11mg with MTX in the open-label 
run-in phase (at Weeks 12 and 24), as measured by DAS28-4 (ESR), 
DAS28-4 (CRP), CDAI, SDAI, LDA, remission, ACR20, ACR 50 and ACR70.

To describe effects of treatment with tofacitinib MR 11mg with MTX on health 
outcome measures in the open-label run-in phase (at Weeks 12 and 24), as measured 
by HAQ-DI, SF-36, WPAI, EuroQol EQ-5D, and FACIT-Fatigue scale.
2.1.4. Exploratory Objectives

To collect exploratory biomarker/genomics samples for bio-banking.

US and Canada ONLY: To explore effects of treatment with tofacitinib MR 11mg 
with/without MTX on health outcome measure in the open-label run-in phase (at 
Weeks 12 and 24) and the double-blind MTX withdrawal phase (at Weeks 48 and 
36), as measured by Routine Assessment of Patient Index Data 3 (RAPID3).
2.2. Endpoints
2.2.1. Efficacy Endpoints
2.2.1.1. Primary Efficacy Endpoint
Change in DAS28-4 (ESR) score from randomization (at Week 24) to the end of 
double-blind MTX withdrawal phase (at Week 48).
2.2.1.2. Secondary Efficacy Endpoints

Change in the DAS28-4(ESR) from Week 24 to Week 36;

Changes in the DAS28-4 (CRP), CDAI and SDAI, respectively, from Week 24 to 
Week 48 and from Week 24 to Week 36;

LDA as assessed by DAS28-4(ESR) 3.2, DAS28-4(CRP) 3.2, CDAI10 and 
SDAI11, respectively, at Weeks 48 and 36;


Tofacitinib citrate
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Final Protocol Amendment 2, 04 Dec 2017
Page 24

Remission as assessed by ACR-EULAR Boolean remission 
criteria,11 DAS28-4 (ESR)<2.6, DAS28-4 (CRP)<2.6, CDAI2.8 and SDAI3.3, 
respectively, at Weeks 48 and 36;

ACR20, ACR 50, and ACR70 responses, respectively, at Weeks 48 and 36;

Change in the HAQ-DI, the SF-36 (8 domain scores and 2 component scores), WPAI, 
EuroQol EQ-5D and the FACIT-Fatigue scale score, respectively, from Week 24 to 
Week 48 and from Week 24 to Week 36;

HAQ-DI response (ie, decrease of at least 0.22) at Weeks 48 and 36.
2.2.1.3. Other Efficacy Endpoints

Changes in DAS28-4 (ESR), DAS28-4 (CRP), CDAI, SDAI, HAQ-DI, 
SF-36 (8 domain scores and 2 component scores), WPAI, EuroQol EQ-5D score and 
FACIT-Fatigue scale score, respectively, from day 1 to Week 12 and from Day 1 to 
Week 24;

LDA as assessed by DAS28-4(ESR)3.2, DAS28-4(CRP)3.2, CDAI10 and 
SDAI11, respectively, at Weeks 12 and 24;

Remission as assessed by ACR-EULAR Boolean remission criteria, 
DAS28-4 (ESR)<2.6, DAS28-4 (CRP)<2.6, CDAI2.8 and SDAI3.3, respectively,
at Weeks 12 and 24;

ACR20, ACR 50, and ACR70 responses, respectively, at Weeks 12 and 24;

HAQ-DI response (ie, decrease of at least 0.22) at Weeks 12 and 24;

Changes in tender/painful joint counts, swollen joint counts, subject assessment of 
arthritis pain, subject global assessment of arthritis, physician global assessment of 
arthritis, and CRP, respectively, from day 1 to Week 12 and from day 1 to Week 24, 
from Week 24 to Week 48 and from week 24 to Week 36.
2.2.1.4. Safety Endpoints

All adverse events (AEs), including serious adverse events (SAEs);

Clinically significant abnormal laboratory parameters.
2.2.1.5. Exploratory Endpoints

Exploratory biomarker/genomics endpoints will be specified in a separate protocol 
and/or statistical analysis plan if exploratory analyses utilizing the bio-banked 
exploratory genomic and biomarker samples across tofacitinib studies or across 
multiple programs are conducted;


Tofacitinib citrate
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Page 25

US and Canada ONLY: RAPID3 summary scores at Weeks 12, 24, 36 and 48.
3. STUDY DESIGN
Study A3921192 is a 12-month randomized, double-blind, placebo-controlled withdrawal 
study in a total of approximately 580 subjects with moderate to severe RA (defined as CDAI 
>10 and DAS28 (ESR) 3.2) who are insufficiently responding to their stable dose of MTX 
treatment.  The enrollment will be monitored by Sponsor to ensure approximately 50% of 
enrolled subjects will have moderate disease activity (defined as DAS28 (ESR) 3.2 and 
5.1) and approximately 50% will have severe disease activity (defined as DAS28 (ESR). In 
addition, the proportion of subjects who have had an insufficient response to one or more 
biologics prior to the enrollment should be 25% (ie, 145 subjects).
After reviewing the rate of achievement of LDA and monitoring the discontinuation rate in 
the open-label period, the decision was made to increase in enrollment numbers from 
approximately 580 to 680 factoring in a discontinuation rate of approximately 15% during 
the open label run-in phase.  As of 02 Aug 2017, study was 50% enrolled with 81% having 
severe disease activity.  The LDA rate (~79% based upon a small sample size) was higher 
than protocol assumptions and historic data.  It is expected that enrolling >50% of subjects 
with severe disease activity will result in a sufficient number of subjects with LDA at Week 
24.  Therefore, the enrollment requirement of 50% of subjects with severe disease activity 
and 50% with moderate disease activity was removed from the protocol.
Following enrollment, all subjects will receive open-label tofacitinib MR 11mg QD added to 
MTX at their previously stabilized dose for 24 weeks (run-in phase). At the end of the run-in 
phase (Week 24), only subjects who achieve low disease activity (LDA) as assessed by 
CDAI (ie, CDAI ≤10) (approximately 232 subjects) will be randomized into the 24-week 
double-blind, placebo-controlled MTX withdrawal phase. Subjects who do not achieve LDA 
(defined by CDAI >10) at this time point will be discontinued from the study.  Subjects 
entering the double-blind phase will be randomized in a 1:1 ratio to either continue the run-in 
phase treatment regimen (tofacitinib MR 11mg QD with blinded MTX) or to receive 
tofacitinib monotherapy (tofacitinib MR 11mg QD with blinded matching placebo for MTX).  
Randomization will be stratified by subject’s prior exposure to a biologic DMARD.  
Randomized subjects will be followed up to the end of Week 48.  The primary efficacy 
endpoint is the change in DAS28-4 (ESR) from randomization (at Week 24) to the end of 
double-blind MTX withdrawal phase (at Week 48).


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Figure 1.
Study Design
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 participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate 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 has been informed of all pertinent aspects of the study.
2. Subjects are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
3. Must be 18 years of age or older.
Week 24 
  (Day 168)
Randomization (1:1) 
Baseline
(Day 1)
Week 6
(Day 42)
Tofacitinib MR 11mg QD + MTX
Tofacitinib MR 11mg QD + MTX
Week 48 (24 weeks post-
randomization) (Day 336)
  Open-label 
(Run-in phase)
       MTX withdrawal
(Double-blind phase)
Week 36
(Day 252)
Primary Endpoint: 
ΔDAS28-4(ESR) 
(Week 48 – Week 24)
Randomization Criteria:
CDAI-defined LDA
(CDAI ≤10)
Screening
(Day -30)
Screening
     Tofacitinib MR 11mg QD + placebo for 
MTX
Week 12 
(Day 84)


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4. Have a score of 6 or greater on the 2010 American College of 
Rheumatology/European League Against Rheumatism Classification Criteria for 
Rheumatoid Arthritis at and/or prior to Screening Visit. 
5. Have 4 tender/painful joints on motion and 4 swollen joints (28 joint counts) at 
both Screening Visit and Baseline Visit (Visit 1).
6. Have moderate to severe disease activity as defined by CDAI>10 and DAS28-4(ESR)
3.2 at Baseline Visit. 
7. Have taken an oral MTX treatment regimen (15-25mg/week) continuously for at least 
4 months prior to the screening visit and has taken a stable weekly dose of oral MTX 
with supplemental folic acid or folinic acid for at least 4 weeks prior to the baseline 
visit (conversion from parenteral MTX to oral MTX will require stabilization of the 
treatment regimen for at least 1 month):

MTX doses between 10mg/week and <15mg/week are allowed only if there is 
documented intolerance or toxicity from higher doses in the source 
documentation.

MTX doses less than 10mg/week or more than 25mg/week are not permitted 
under any circumstances.
a.
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. 

Subjects must have an inadequate clinical response to MTX, defined as the 
presence of sufficient residual disease activity to meet the entry criteria.
8. Male subjects able to father children and female subjects of childbearing potential and 
at risk for pregnancy must agree to use 2 highly effective methods of contraception 
throughout the study and for at least 3 months after the last dose of assigned 
treatment.  For contraception details to be applied in Belgium, Czech Republic, 
Germany, Hungary, Italy, Poland, Spain, and the United Kingdom see Appendix 7.
9. Female subjects of childbearing potential must test negative for pregnancy at 
screening visit and baseline visit. 
10. Female subjects who are not of childbearing potential (ie, meet at least 1 of the 
following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 


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
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) level 
confirming the post-menopausal state.
All other female subjects (including females with tubal ligations) will be 
considered to be of childbearing potential.
11. Subjects must screen negative for active tuberculosis or inadequately treated 
tuberculosis infection (active or latent) as evidenced by all of the following:
a.
Negative QuantiFERON Gold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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
can be substituted for the QuantiFERON Gold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 (or chest Computed Tomography (CT) scan, if available) 
taken at screening without changes suggestive of active tuberculosis (TB) 
infection, unless previously performed and documented within 3 months prior 
to screening.
c.
No history of tuberculosis infection unless one of the following is 
documented:

Subjects with prior or current latent tuberculosis have no evidence of 
active tuberculosis and must be taking or have completed an adequate 
course of therapy for latent tuberculosis in a locale where rates of primary 
multi-drug resistant TB infection are <5%, and chest radiographs (or chest 
CT scan) are negative for active disease; the chest radiograph must be 
obtained at screening or, if previously performed and documented, within 
3 months prior to screening. 

Subjects with prior active tuberculosis has no current evidence of active 
disease and have completed an adequate course of therapy for active 
tuberculosis (a multi-drug regimen recognized by the World Health 
Organization) and chest radiographs (or chest CT scan) are negative for 


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active disease; the chest radiograph must be obtained at screening or, if 
previously performed and documented, within 3 months prior to 
screening.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Subjects who are investigational site staff members directly involved in the conduct 
of the study 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 study.
2. Pregnant female subjects; breastfeeding female subjects; male subjects with partners 
currently pregnant; male subjects able to father children and female subjects of 
childbearing potential who are unwilling or unable to use 2 highly effective methods 
of contraception as outlined in this protocol for the duration of the study and for at 
least 3 months after the last dose of investigational product.  For contraception details 
to be applied in Belgium, Czech Republic, Germany, Hungary, Italy, Poland, Spain, 
and the United Kingdom see Appendix 7.
3. Subjects with any of the following infection or infection history: 
a.
Any infection requiring treatment within 2 weeks prior to the Baseline Visit
(Visit 1).
b. Any infection requiring hospitalization, parenteral antimicrobial therapy, or as 
otherwise judged to be an opportunistic infection or 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.
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.


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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 where adequate treatment 
cannot be documented.
i.
Subjects screened in Belgium, Czech Republic, Germany, Hungary, Italy, Poland, 
Spain, and the United Kingdom who have resided or traveled in areas with 
endemic tuberculosis or endemic mycoses will be excluded.
4. 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.
5. Subjects with any uncontrolled clinically significant laboratory abnormality or any of 
the following laboratory abnormalities:
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 <0.5x 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) <40 mL/min using the Cockcroft-Gault 
formula.
6. Subjects with a history of insufficient response to ≥2 biologics, regardless of the 
class.
7. Participation in other studies involving investigational drug(s) within 4 weeks or 
5 half-lives (whichever is longer) after discontinuation of the investigational 
compound prior to the current study entry and/or during study participation, unless 
further restrictions to class of compound are specified in Section 4.2 (exclusion 
criteria) and Section 5.8 (concomitant treatment).
8. Subjects requiring or have received any prohibited concomitant medication as 
outlined in Appendix 3: Prohibited Concomitant Medication, including:


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a.
Subjects who have received live or live attenuated vaccines within 4 weeks prior 
to the first dose of study drug or are planning to receive live or live attenuated 
vaccines at any time during treatment or within 6 weeks following discontinuation 
of study drug.
b. .Subjects who have previously been treated with tofacitinib, baricitinib, or any 
other investigational JAK inhibitors.
c.
Subjects who are being treated with biologic or non-biologic DMARDs (including 
antimalarials) other than MTX within their specified washout window at study 
entry (defined in Appendix 3: Prohibited Concomitant Medications, and 
Section 5.8.2: Disallowed Concomitant Medications).
d. Subjects who are being treated with corticosteroids, other than stable low dose 
oral corticosteroids in doses equivalent to 10 mg prednisone per day, within 
4 weeks prior to the first dose of the study drug.
e.
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 CYP3A4 inducers (defined
in Appendix 3: Prohibited Concomitant Medications).
9. 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).
10. Subjects who had significant trauma or surgical procedure within 1 month prior to the 
Baseline Visit (Visit 1).
11. Subjects with any rheumatic autoimmune disease, other than RA and Sjogren’s 
syndrome.
12. 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).
13. 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.
14. Subjects with history of, or current evidence for, severe gastrointestinal narrowing
(pathologic or iatrogenic); eg, esophageal motility disorders, “short gut” syndrome 
due to adhesions or decreased transit time, past history of peritonitis, chronic 
intestinal pseudoobstruction, or Meckel’s diverticulum.


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15. Subjects with history of documented diverticulitis in the source documentation.
16. Alcohol or substance abuse unless in full remission for more than 6 months prior to 
first dose of investigational drugs.
17. 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 
All eligible subjects enrolled in the study will initially receive open-label tofacitinib 
combined with MTX for 24 weeks (run-in phase).  At the end of the 24-week open-label
run-in phase, only subjects who achieve Low Disease Activity (LDA) (as assessed by CDAI 
≤10) will be randomized to the 24-week double-blind, placebo-controlled, MTX withdrawal 
phase.  Subjects who do not achieve the LDA (as assessed by CDAI>10) at this time point 
will be discontinued from the study.
Subjects who enter the 24-week double-blind phase will be randomized in a 1:1 ratio to 
either continue the run-in phase treatment (tofacitinib MR 11mg QD with blinded MTX) or 
to receive tofacitinib monotherapy (tofacitinib MR 11mg QD with blinded placebo for MTX. 
Randomization will be stratified by whether or not the subject was ever exposed to a biologic 
DMARD previously.
4.4. Lifestyle Guidelines 
4.4.1. Non-Pharmacologic Interventions
The subject may continue all non-pharmacologic therapies, such as physical therapy, as 
indicated and deemed appropriate for his/her physical condition.
4.4.2. Vaccine and Exposure to Infections Guidelines
It is recommended that subjects be up to date on all recommended vaccination (including 
pneumococcal vaccine and flu vaccine) per local practice guideline prior to enrollment.
Vaccination with live components is prohibited within the 4 weeks prior to first dose of 
investigational product to 6 weeks after last dose of investigational product.  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, measles, mumps, rubella, varicella (“chickenpox”) vaccine or varicella-zoster 
vaccine, oral polio vaccine, rotavirus, Yellow Fever and the intranasal (inhaled) flu vaccine. 


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Following vaccination with live component vaccines, the virus may be shed in bodily fluids, 
including stool, and there is a potential risk that the virus may be transmitted.  General 
guidelines for immunosuppressed subjects suggest that household contact with children and 
others who have been vaccinated with live vaccine components should be avoided following 
their vaccination with the following vaccines for the stated time period:

Attenuated typhoid fever vaccination for 4 weeks following vaccination;

Oral polio vaccination for 6 weeks following vaccination;

Attenuated rotavirus vaccine for 10 days following vaccination;

FluMist(intranasal flu vaccine) for 1 week following vaccination.
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 
potent CYP3A4 inhibition or induction, or both moderate CYP3A4 and potent CYP2C19
inhibition.  Otherwise, herbals with pharmaceutical properties must be discontinued for at 
least 4 weeks prior to first dose of investigational product, unless there is sufficient data 
available regarding the duration of an herbal medication’s pharmacokinetic and 
pharmacodynamic effects to allow a shorter washout to be specified (eg, 5 half-lives). 
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. 
4.4.4. Surgery
During the course of this study, no elective surgery should be scheduled without first 
consulting with the Pfizer study clinician.  Preferably, elective surgery should be scheduled 
before the study entry or delayed until participation in the study is completed.
It is recommended that subjects who require major surgery temporarily discontinue 
tofacitinib approximately 1 week prior to the surgical procedure and remain off tofacitinib
after the surgical procedure until sutures/staples are removed. Investigational products can 
be resumed when the sutures/staples are removed.  If absorbing sutures or chemical closure 
methods are utilized, investigational product can be resumed when the operative site is 
sufficiently healed and risk of infection is minimal.


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4.4.5. Contraception and Reproductive Status
In this study, male subjects who are able to father children and female subjects who are of 
childbearing potential will receive MTX, which has been associated with teratogenic risk, 
and tofacitinib, which has been associated with teratogenic risk in animals (further 
information can be found in the single safety reference document).  Those who, in the 
opinion of the investigator, are sexually active and at risk for pregnancy with their partner(s) 
must agree to use with their partner(s) two (2) methods of highly effective contraception 
throughout the study and continue for at least 3 months after the last dose.  The investigator
or his or her designee, in consultation with the subject, will select 2 appropriate methods of 
contraception for the individual subject and his/her partner(s) from the list of permitted 
contraception methods (see below) and instruct the subject in their consistent and correct use.  
The investigator or his or her designee will discuss with the subject the need to use 2 highly 
effective methods of contraception consistently and correctly according to the schedule of 
activities and document such conversation, and the subject’s affirmation, in the subject’s 
chart.  In addition, the investigator or his or her designee will instruct the subject to call 
immediately if a selected contraception method is discontinued or if pregnancy is known or 
suspected in the subject or the subject’s partner. 
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 the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (ie, oral, inserted, injected, implanted, transdermal)provided the subject (or 
the subject’s partner(s)) plans to remain 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) or intrauterine system.
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository). For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
Pregnancy testing will be performed and documented at every visit unless the 
non-childbearing potential is confirmed and documented.  The specific contraceptive 
methods will be documented and at every visit, their consistent and correct use will be 
ascertained and documented in the subject’s case report form.


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For contraception and reproductive status details to be applied in Belgium, Czech Republic, 
Germany, Hungary, Italy, Poland, Spain, and the United Kingdom see Appendix 7.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list 
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 numbers, 
contact information for the investigational site, and contact details for a contact center 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 contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the 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 the study team 
for advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigational site.
4.6. Rater Qualifications 
A Joint Count Assessor blinded to subject data (including adverse events, subject reported 
outcomes and physician assessments of disease activity and/or severity) will assess the 
number of swollen and tender/painful joints, as part of the assessment of RA activity.  The 
Joint Count Assessor at each site is required to be a health care professional who has been 
trained in rheumatology and specializes in the treatment of subjects 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
For the purposes of this study, and per International Conference on Harmonization (ICH)
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).  Tofacitinib and MTX are 
investigational products in this study. 
All subjects enrolled in the study will initially receive open-label tofacitinib and MTX for 
24 weeks (run-in phase).  Subjects who achieve LDA (as assessed by CDAI ≤10) at the end 
of the run-in phase will be randomly allocated (in a 1:1 ratio) to either tofacitinib with 
continued MTX arm or tofacitinib with placebo arm as presented in Table 1.


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Table 1.
Treatment Arms
Open-label phase (all subjects)
One tablet open-label tofacitinib MR 11mg orally QD + open-label MTX capsule(s) orally every week at 
prior stabilized dose
Double-blind phase (subjects will be randomized to one of the two arms below) 
Arm 1 (tofacitinib MR 11mg QD with blinded MTX): One tablet open-label tofacitinib 11 mg orally QD 
+ blinded MTX capsule(s) orally every week at prior stabilized dose
OR
Arm 2 (tofacitinib MR 11mg QD with blinded placebo for MTX, ie, tofacitinib MR 11mg QD 
monotherapy): One tablet open-label tofacitinib 11 mg orally QD + blinded matching placebo capsule(s) for 
MTX orally every week at prior stabilized dose 
5.1. Allocation to Treatment
Allocation of subjects to treatment arms will proceed through the use of an automatic 
Interactive Web-based Response (IWR) system provided by the Sponsor.  There is a 
24-hour-a-day, 365-days-a-year IWR helpdesk available for any questions or issues. The 
study specific IWR reference manual will provide the contact information and further details 
on the use of the IWR system. 
At the screening visit, the site personnel (study coordinator or specified designee) will enter 
the subject into the IWR by indicating minimal information sufficient to distinguish one 
subject from another (eg, the date of birth and initials of the subject) and receive the unique 
subject identification (ID) number generated by the IWR for each subject.  The subject who 
is failed to pass the screening will not be enrolled into the study.  The subject who passes the 
screening will be enrolled into the study and assigned with the open-label treatments.
Following the confirmation of LDA status at the end of the run-in phase, the site personnel
will be required to enter or select information including but not limited to the protocol 
number, the subject ID number, the date of birth and/or initials of the subject, the LDA status 
and the prior use of biologic DMARDs in the IWR. The site personnel will then be provided 
with a treatment assignment code which corresponds to the number on the dispensable unit 
(DU) or container in the site’s inventory.  The corresponding DU or container will be 
dispensed to the subject.  The IWR system will provide a confirmation report containing the 
subject number and DU or container number assigned. The confirmation report must be 
stored in the site’s files.
5.2. Breaking the Blind 
This study will be subject-, investigator-, and sponsor-blinded.  At the initiation of the study, 
the study site will be instructed on using IWR for breaking the blind.  The blind should only 
be broken in emergency situations for reasons of subject safety.  Whenever possible, the 


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investigator should attempt to contact the Pfizer study team before breaking the blind.  When 
the blind for a subject is broken, the reason must be fully documented and entered on the case 
report form (CRF).  At all other times, treatment and randomization information will be kept 
confidential and will not be released to the investigator/study staff until the conclusion of the 
study.
5.3. Subject Compliance
Compliance with expected consumption of dispensed investigational product will be assessed 
by comparing the expected number of doses to be taken to the number of doses returned
during any given time period, keeping in mind that subjects may have their investigational 
product temporarily withheld due to abnormal laboratory tests, adverse events, or the need to 
take a short course of a prohibited concomitant medication.  Doses of investigational 
products 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 on the CRF with the 
reason for reduced drug consumption. 
Compliance of less than 80% of the expected number of doses for any one of the 
investigational products in the interval should be documented in the dosing log of the 
subject’s CRF with the reason for non-compliance (less than expected consumption), 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.  Subjects 
who are less than 80% compliant with the dosage regimen for any two consecutive visit 
periods during the study should be withdrawn from the study.
Compliance of more than 120% of the expected number of doses for any one of the
investigational products in the interval should be documented in the dosing log of the 
subject’s CRF with the reason for non-compliance (more than expected consumption), and 
should be reported as a protocol deviation and recorded as a dosing error. 
Subjects who are non-compliant will be counseled and the site will implement appropriate 
measures to secure subject compliance, as appropriate to the site and reason for 
non-compliance.
Subjects will record all Tofacitinib and MTX dosing in a dosing diary.  It will be reviewed 
with the subject at every study visit for compliance.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
During the run-in phase, tofacitinib citrate MR 11 mg tablets and MTX 2.5 mg capsules will 
be provided in open-label bottles for oral administration by Sponsor.  During the 
double-blind phase, open-label bottles of tofacitinib MR 11mg tablets and blinded bottles of 
MTX 2.5 mg capsules or matching placebo capsules for MTX will be provided for oral 
administration by Sponsor. 


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5.4.2. Preparation and Dispensing
At each dispensing visit (Baseline Visit/Visit 1, and Visits 3, 4 and 5), subjects will receive a 
sufficient quantity of investigational products to last until their next scheduled dispensing
visit plus an additional amount to accommodate the allowable visit windows. Investigational 
products, along with written dosing instructions (dosing cards), will be dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, practitioner, or pharmacist) as allowed by local, state, and institutional 
guidance.  The amount of investigational products dispensed at each visit must be recorded.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.
5.5. Administration
All investigational products will be self-administered by the subject as specified in the dosing 
card with written instructions. 
Investigational products may be taken with or without food, other than on study visit days 
where fasting is required.  Subjects will swallow the investigational product whole and intact, 
and will not manipulate (eg, crush or split) or chew the medication prior to swallowing.
Subjects will take their tablets (tofacitinib) once daily in the morning, and take their capsules 
(MTX or matching placebo for MTX) once a week (the same day of the week and 
approximately the same time each week) unless dose division is required to manage 
intolerance. 
At the beginning of the enrollment (ie, baseline visit/visit 1), subjects must discontinue the 
use of their personal (commercial) supply of MTX.  All tofacitinib and MTX drug supplies 
will be provided by the Sponsor during study participation after the screening period. 
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 4 weeks 
prior to the baseline visit (visit 1).  Dosages of MTX (oral administration of up to 
25 mg/week) are as approved in the respective Single Reference Safety Document (SRSD), 
as identified in Section 1.2.4 of this protocol. MTX doses between 10mg/week and
15 mg/week are allowed only in the presence of documented intolerance to or toxicity from 
higher doses in the source documentation.  Doses less than 10 mg/week or more than 
25 mg/week are not permitted under any circumstances.  The pre-study stable dose of MTX 
will be continued in the study period. The dose of MTX or matching placebo for MTX will 
be maintained throughout study participation unless dose reductions are further required due 
to drug toxicity. Dose reductions will be documented in the CRF.
Subjects who are randomized to placebo for MTX arm will receive full withdrawal of MTX 
(ie, no tapering) at the time of randomization.


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The typical local standard of care practices for the administration of MTX include: laboratory 
testing, follow up care, contraindications, and folate supplementation.  MTX laboratory 
testing is typically every 3 months once a subject is stabilized on MTX. However, in some 
regions, more frequent MTX testing and procedures are required; therefore MTX tests and 
procedures should be performed according to local standards of care throughout the study, 
regardless of study assignment.  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. 
5.6. Investigational Product Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any marketed products, are stored in a secured area with 
controlled access under required storage conditions and in accordance with applicable 
regulatory requirements.
The investigational drug product should be stored in its original container and in accordance 
with the label.  See the dosing card for storage conditions of the product. Storage conditions 
stated in the single reference safety document (SRSD) (tofacitinib IB and MTX SPC revised
December 2012) will be superseded by the storage conditions stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as
applicable, including frozen, refrigerated and/or room temperature products).  This is to be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product label storage conditions are to be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor. 


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Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion. Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products. 
Please refer to dosing card for additional details on the investigational drug storage dispensed 
to subjects. 
5.7. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  At each study visit (except baseline
/visit1 and Week 6/Visit 2), the subject must return the containers of investigational products 
to the investigator and the amount of any unused medications will be recorded.  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 investigational products returned
by the subjects.
5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Concomitant Treatment(s)
All concomitant medication taken during the study must be recorded with the 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. 
Medications taken after informed consent but before the first dose of investigational products 
will be documented as prior medications.  Medications taken after the first dose of 
investigational products will be documented as concomitant medications.


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5.8.1. Allowed Concomitant Medications
All concomitant DMARDs including antimalarials are excluded at Baseline Visit/Visit 1, 
except MTX. 
5.8.1.1. Treatment for Latent Tuberculosis
Subjects who are diagnosed as having latent tuberculosis (ie, positive tuberculosis test, chest 
x-ray or CT negative for active tuberculosis, and no evidence of active disease) at screening 
must have either been previously treated with an adequate course of treatment or be currently 
taking isoniazid.  Subjects that the investigator considers 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.  A subject may enroll into the study after at least one 
month of isoniazid therapy or per local guideline.
PLEASE NOTE: although commonly used in the treatment of tuberculosis, rifampin, 
rifampicin, rifabutin and rifapentene are prohibited concomitant medications in this study.
5.8.1.2. Stable Background Arthritis Therapy
Subjects will continue on their stable background arthritis therapy, which can include
nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 inhibitors 
(COX-2 inhibitors), opioids, acetaminophen, and/or low dose oral corticosteroids (10 mg 
prednisone or equivalent per day) throughout the trial.  Dosages of
NSAIDs/COX-2 inhibitors, opioids, acetaminophen, and corticosteroids must have been 
stable for at least 4 weeks prior to first study dose and should remain so during the study 
treatment period, except if adjustment is needed to protect a subject’s safety.  However, the 
total daily dose of acetaminophen may not exceed the locally approved recommended daily 
dose, and the total daily dose of opioid must not exceed the potency equivalent of 30 mg of 
orally-administered morphine (Appendix 5: Approximate Equivalent Morphine Doses of 
Opioid Analgesics).  Please note that administration of NSAIDs with MTX (usually at high 
doses) can lead to serious adverse reactions including gastrointestinal and hematological 
toxicity.
Low dose oral corticosteroids in doses equivalent to ≤10 mg prednisone per day is allowed 
during the study period.  However, the prednisone dose increase should not exceed the initial 
dose during the study period.
Intra-articular corticosteroids may be given during the first 3 months of the run-in phase in 
no more than two joints, in a cumulative dose of no more than 80 mg methylprednisolone or 
its equivalent during any 6 month study period.  Injections are not allowed after 3 months.  
Injected joints will also be considered as having their pre-injection status (tender/painful or 
swollen) for the remainder of the trial.


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Intravenous or intramuscular corticosteroids are not allowed during this study.
Biologic DMARDs and non-biologic DMARDs (other than MTX) are not allowed during 
this study.
5.8.2. Disallowed Concomitant Medications 
5.8.2.1. Disease Modifying Antirheumatic Drugs (DMARDs)
All DMARDs (except MTX) are disallowed during the study period.  All prohibited 
concomitant DMARDs should be discontinued at least 4 weeks or 5 half-lives (whichever is 
longer) prior to the first dose of investigational products (Baseline Visit/Visit 1).  Specific 
medications and required discontinuation (washout) times are listed in Table 2.
Table 2.
DMARDs – Required Washout Period
Required Washout Period Prior to Baseline/Visit 1
52 weeks
Rituximab or other selective B lymphocyte depleting agents (both marketed and
investigational): discontinued for 1 year prior to the first dose of investigational 
products and if CD19/20+ counts are normal by fluorescence-activated cell 
sorting (FACS) analysis
20 weeks
Gold compounds, including auranofin (Ridaura),and injectable gold 
(aurothioglucose or aurothiomalate)
18 weeks
Canakinumab 
12 weeks
Abatacept, certolizumab pegol, tocilizumab
10 weeks
Golimumab 
8 weeks
Infliximab, leflunomide*
6 weeks
Adalimumab 
4 weeks
Anakinra, azathioprine, cyclosporine, etanercept,  tacrolimus, mizoribin, 
tetracycline, minocycline, penicillamine, sulfasalazine, bucillamine, chloroquine, 
hydroxychloroquine
* Leflunomide (Arava®) must be discontinued 8 weeks prior to the first dose of study drug if no elimination 
procedure is followed. Alternately, it should be discontinued with the following elimination procedure at least 
4 weeks prior to the first dose of study drug: Cholestyramine at a dosage of 8 grams three times daily for at least 
24 hours, or activated charcoal at a dosage of 50 grams 4 times a day for at least 24 hours (US PI, Elimination 
Procedure to significantly lower leflunomide drug levels).
5.8.2.2. Immune-Modulating Biologic Products
While receiving study drug, no immune-modulating biologic products are allowed to be 
administered, including biologic DMARDs (except MTX).
5.8.2.3. 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). 


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Tofacitinib exposure is decreased when co-administered with potent CYP3A4 inducers (eg,
rifampin). 
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 4 weeks or 5 half-lives (whichever is longer) prior to the Baseline 
Visit (Visit 1).  Only systemically administered drugs listed in Appendix 3 (Prohibited 
Concomitant Medication) require discontinuation; other routes of administration (eg, topical, 
vaginal, ophthalmic) are not prohibited. 
If a medication that is a potent CYP3A4 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, tofacitinib should be interrupted during 
treatment. 
If a medication that is a potent CYP3A4 inducer is administered during the study for any 
reason, including the treatment of an adverse event, tofacitinib may be continued, but the 
concomitant administration of the medication should be noted as a protocol deviation.
5.8.2.4. Immunizations
Live or live-attenuated vaccines should not be given concurrently with investigational 
products (refer to Section 4.4.2 for more details).
5.8.2.5. Investigational medication
Any investigational medications must be discontinued prior to baseline visit (visit 1) for 
4 weeks or 5 half-lives, whichever is longer.  No investigational compounds (other than 
tofacitinib and MTX) may be taken during the study period.
5.9. Rescue Medication
Please refer to Appendix 5 (Approximate Equivalent Morphine Doses of Opioid Analgesics) 
and Appendix 6 (Rescue Therapy) for details. 
6. STUDY PROCEDURES 
Please refer to Section 7 (Assessment) for details of exams and tests listed in this section. 
6.1. Screening
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 will be screened 30 days (+10 day window, ie, 40 days) prior to administration of
investigational products to confirm that they meet the entrance criteria for the study.  
Subjects must complete all screening procedures and assessments and have test results 
available prior to the baseline visit (visit 1).  If a subject is not enrolled within 30 days 
(+10 days window) after the screening visit, all screening procedures and assessment must be 


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repeated unless otherwise noted (below).  Sponsor approval must be obtained prior to 
re-screening a subject. 
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 5.8: Concomitant Medication and Appendix 3: Prohibited 
Concomitant Medication).  For these subjects, written informed consent and the study subject 
identification (SSID) number must be obtained prior to initiation of the washout period.  The
screening assessments should be scheduled towards the end of the washout period to meet the
30-day (+10 days) screening duration.  Additionally, screening procedures may need to be 
repeated to provide valid data (eg, laboratory testing) and turnaround time may extend 
beyond the screening duration. In this case, sponsor approval must be obtained.  In no 
instance should the extended screening duration exceed 3 months.
Subjects who do not have all tests completed within screening period or who temporarily do 
not meet study entry criteria (eg, treatment with antibiotics during the screening period or for 
administrative reasons) may be re-screened one time; the subject’s prior ID number and 
reason for re-screening must be documented. 
Screening laboratory tests can be repeated once if deemed clinically appropriate (judged by 
the principal investigator) except for the following tests: 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.
Subjects will continue their usual stable dose of MTX during the screening period.
Procedures to be performed during the screening period include:

Informed Consent.

Review of inclusion/exclusion criteria.

Prior 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. 

Medical History: include previous vaccination. 

Complete Physical Examination: height, weight, vital signs, general appearance, skin 
(presence of rash, skin lesions with malignant features), HEENT (head, eyes, ears, 
nose and throat), lungs (auscultation), heart (auscultation for presence of murmurs, 
gallops, rubs), lower extremities (peripheral edema), abdominal (palpation and 


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auscultation), neurologic (mental status, station, gait, reflexes, motor and sensory 
function, coordination) and lymph nodes.

Laboratory testing (Blood Chemistry, Hematology, CRP, ESR, HIV Serology, 
HBsAg, HBcAb, HBsAb, HCV Ab, HCV RNA,  FSH (required to confirm 
postmenopausal status, if applicable), Rheumatoid Factor, anti-cyclic citrullinated 
peptide antibodies (anti-CCP), Urinalysis.  All required laboratory testing must be 
complete and reported; any invalid specimens must be retested and reported prior to 
the Baseline Visit (Visit 1). 

Pregnancy testing must be completed for all women of childbearing potential: all 
subjects must test negative; confirmation and documentation of the use of two highly 
effective methods of contraception by subjects of childbearing potential or their 
partners must be done. Non childbearing potential must be documented.  For 
contraception and reproductive status details to be applied in Belgium, Czech 
Republic, Germany, Hungary, Italy, Poland, Spain, and the United Kingdom see 
Appendix 7.

QuantiFERON Gold®TM In-Tube Test: unless the subject has previously received an 
adequate course of therapy for either latent or active TB infection (see 
Section 5.8.1.1: 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 Radiography).

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.

Serious Adverse Event (SAE) Reporting (after the subject provides informed 
consent).

Assess safety events (ie, reportable safety events within the appropriate reporting 
period) for adjudication by the appropriate adjudication or review committee and 
collect biopsies of potential malignancy events for central laboratory pathologist over 
read and report to Pfizer Study Team or designee.
6.2. Study Period
As part of adverse event monitoring, site personnel will assess safety events for adjudication 
and potential malignancy events for biopsy submission and central laboratory pathologist 
over read.  Specific safety events will be submitted to the appropriate Safety Event 
Adjudication/Review Committee for adjudication as described in Section 9.8. 
Site personnel will report safety events and potential malignancy events to the Pfizer Study 
Team or designee based on the following reference time points:


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
Events that are serious adverse events (SAEs) occurring after the time of informed 
consent will be submitted for adjudication/review or central histopathology review, as 
appropriate.

Events that are non-serious AEs occurring after the time of first dose of study drug 
will be submitted for adjudication/review or central histopathology review, as 
appropriate.
6.2.1. Visit Windows
The screening period is expected to be no longer than 30 days (+ 10 day window) prior to the 
Baseline Visit (Visit 1), unless exceptions noted in Section 6.1 are documented.  All visits 
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.  Visit 1 is the baseline visit; the visit window for Visit 
2 will be 5 days; the visit windows for Visit 3 to Visit 6 will be 10 days; and the visit 
window for telephone follow-up will be +14 days to ensure capture of all data.
Partial and unplanned 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.
6.2.2. Visit 1 (Baseline Visit; Day 1) 
At Visit 1 (Baseline Visit), subjects will convert their personal (commercial) supply of MTX 
to the MTX supplied by the Sponsor with the stable dose established before the screening 
period.
Subjects are required to fast for at least 6 hours prior to the visit. 
Procedures to be performed at Baseline Visit/Visit 1 include:

Complete Physical Examination (excluding height): weight, vital signs, general 
appearance, skin (skin lesions with malignant features), 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.  In addition, smoking history and alcohol 
consumption will be documented.

Review of inclusion/exclusion criteria. 

Laboratory testing including blood chemistry, hematology, CRP, lipid profile 
(fasting), ESR.

Biospecimen collection for banking.


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
Pregnancy testing must be completed for all women of childbearing potential: all 
subjects must test negative; confirmation and documentation of the use of two highly 
effective methods of contraception by subjects of childbearing potential or their 
partners must be done. Non childbearing potential must be documented.  For 
contraception and reproductive status details to be applied in Belgium, Czech 
Republic, Germany, Hungary, Italy, Poland, Spain, and the United Kingdom see 
Appendix 7.

28 tender /painful and swollen joint count.

Completion of the following assessments:

Subject assessment of arthritis pain.

Subject global assessment of arthritis.

Physician global assessment of arthritis.

Health Assessment Questionnaire – Disability Index (HAQ DI).

SF 36 (Version 2, Acute).

European Quality of Life 5 Dimension Questionnaire (EuroQol EQ 5D).

Work Productivity and Activity Impairment (WPAI) Questionnaire.

Functional assessment of chronic illness therapy fatigue (FACIT Fatigue Scale).

US and Canada ONLY: RAPID3.

Safety assessment and AE reporting.

Assess safety events for adjudication by the appropriate adjudication or review 
committee and collect biopsies of potential malignancy events for central laboratory 
pathologist over read and report to Pfizer Study Team or designee.

Concomitant Medication Review.

Dispense investigational products as identified by the drug dispensing system.  
Dispense dosing diary to subject and instruct subject on proper use of the diary.

Schedule the subject to return for Visit 2. 


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6.2.3. Visit 2 (Week 6; Day 42) 
There is a ±5 day window for this visit.  Subjects are required to fast for at least 6 hours prior 
to the visit.  Procedures to be performed at Visit 2 include:

Assessment of new physical findings (weight, vital signs, skin examination including 
careful examination for melanoma and nonmelanoma skin cancer, lungs, heart, lower 
extremities for peripheral edema, abdomen and lymph nodes).Laboratory testing 
including blood chemistry, hematology, lipid profile (fasting).

Biospecimen collection for banking.

Pregnancy testing must be completed for all women of childbearing potential: all 
subjects must test negative; confirmation and documentation of the use of two highly 
effective methods of contraception by subjects of childbearing potential or their 
partners must be done. For contraception and reproductive status details to be applied 
in Belgium, Czech Republic, Germany, Hungary, Italy, Poland, Spain, and the United 
Kingdom see Appendix 7.

Safety Assessment and AE Reporting. 

Assess safety events for adjudication by the appropriate adjudication/ review 
committee and collect biopsies of potential malignancy events for central laboratory 
pathologist over read and report to Pfizer Study Team or designee.

Concomitant Medication Review.

Review dosing diary with the subject.

Schedule the subject to return for Visit 3. 
6.2.4. Visit 3 (Week 12; Day 84)
There is a ±10 day window for this visit.  Procedures to be performed at Visit 3 include:

Assessment of new physical findings (weight, vital signs, skin examination including 
careful examination for melanoma and nonmelanoma skin cancer, lungs, heart, lower 
extremities for peripheral edema, abdomen and lymph nodes).

Laboratory testing including blood chemistry, hematology, CRP, ESR.

Pregnancy testing must be completed for all women of childbearing potential: all 
subjects must test negative; confirmation and documentation of the use of two highly 
effective methods of contraception by subjects of childbearing potential or their 
partners must be done. For contraception and reproductive status details to be applied 
in Belgium, Czech Republic, Germany, Hungary, Italy, Poland, Spain, and the United 
Kingdom see Appendix 7.


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
28 tender /painful and swollen joint counts.

Completion of the following assessments:

Subject assessment of arthritis pain.

Subject global assessment of arthritis.

Physician global assessment of arthritis.

HAQ DI.

SF 36 (Version 2, Acute).

EuroQol EQ 5D.

WPAI Questionnaire.

FACIT-Fatigue Scale.

US and Canada ONLY: RAPID3.

Safety Assessment and AE Reporting.

Assess safety events for adjudication by the appropriate adjudication/ review 
committee and collect biopsies of potential malignancy events for central laboratory 
pathologist over read and report to Pfizer Study Team or designee.

Concomitant Medication Review.

Return unused investigational products.

Review dosing diary with the subject.

Dispense investigational products as identified by the drug dispensing system. 

Schedule the subject to return for Visit 4 (Randomization).
6.2.5. Visit 4 (Randomization; Week 24; Day 168)
There is a ±10 day window for this visit.  Subjects are required to fast for at least 6 hours 
prior to the visit.  Procedures to be performed at Visit 4 include:

Assessment of new physical findings (weight, vital signs, skin examination including 
careful examination for melanoma and nonmelanoma skin cancer, lungs, heart, lower 
extremities for peripheral edema, abdomen and lymph nodes).


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
Laboratory testing including blood chemistry, hematology, CRP, ESR, lipid profile 
(fasting).

Biospecimen collection for banking.

Pregnancy testing must be completed for all women of childbearing potential: all 
subjects must test negative; confirmation and documentation of the use of two highly 
effective methods of contraception by subjects of childbearing potential or their 
partners must be done. For contraception and reproductive status details to be applied 
in Belgium, Czech Republic, Germany, Hungary, Italy, Poland, Spain, and the United 
Kingdom see Appendix 7.

28 tender /painful and swollen joint counts.

Completion of the following assessments:

Subject assessment of arthritis pain.

Subject global assessment of arthritis.

Physician global assessment of arthritis.

HAQ DI.

SF 36 (Version 2, Acute).

EuroQol EQ 5D.

WPAI Questionnaire.

FACIT -Fatigue Scale.

US and Canada ONLY: RAPID3.

Review dosing diary with the subject.

Safety Assessment and AE Reporting.

Assess safety events for adjudication by the appropriate adjudication or review 
committee and collect biopsies of potential malignancy events for central laboratory 
pathologist over read and report to Pfizer Study Team or designee.

Concomitant Medication Review.

Return unused investigational products.


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
Confirm the subject is eligible for randomization (achieve LDA as assessed by 
CDAI).

Randomize eligible subjects and dispense investigational products as identified by the 
randomization/drug dispensing system. 

Schedule the subject to return for Visit 5.

QuantiFERON GoldIn-Tube Test will be performed for all subjects (those who 
meet LDA and those who do not meet LDA at week 24) in Belgium, Czech Republic, 
Germany, Hungary, Italy, Poland, Spain, and the United Kingdom.  For all other 
countries the test will ONLY be performed for subjects who do not achieve LDA at 
Week 24 and are therefore not randomized. 
6.2.6. Visit 5 (Week 36; Day 252)
There is a ±10 day window for this visit.  Procedures to be performed at Visit 5 include:

All Visit 3 assessments (refer to Section 6.2.4).

Schedule the subject to return for Visit 6 (End of Study Visit).
6.2.7. Visit 6 (End of Study Visit; Week 48; Day 336/Early Withdrawal Visit)
Subjects who did not achieve LDA at Week 24 and were therefore not randomized do not 
require a separate EOS visit except for QuantiFERON GoldIn-Tube Test.
There is a ±10 day window for this visit.  Subjects are required to fast for 6 hours prior to the 
visit.  Procedures to be performed at Visit 6 include:

Complete Physical Examination: height, weight, vital signs, general appearance, skin 
(presence of rash or suspicious lesions), 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.

Laboratory testing including blood chemistry, hematology, CRP, lipid profile 
(fasting), ESR. 

12-lead electrocardiogram.

Biospecimen collection for banking.

Pregnancy testing must be completed for all women of childbearing potential: all 
subjects must test negative; confirmation and documentation of the use of 2 highly 
effective methods of contraception by subjects of childbearing potential or their 


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partners must be done. For contraception and reproductive status details to be applied 
in Belgium, Czech Republic, Germany, Hungary, Italy, Poland, Spain, and the United 
Kingdom see Appendix 7.

28 tender /painful and swollen joint counts.

Completion of the following assessments:

Subject assessment of arthritis pain.

Subject global assessment of arthritis.

Physician global assessment of arthritis.

HAQ DI.

SF 36 (Version 2, Acute).

EuroQol EQ 5D.

WPAI Questionnaire.

FACIT Fatigue Scale.

US and Canada ONLY: RAPID3.

Safety Assessment and AE reporting. 

Assess safety events for adjudication by the appropriate adjudication or review 
committee and collect biopsies of potential malignancy events for central laboratory 
pathologist over read and report to Pfizer Study Team or designee.

Concomitant Medication Review.

Review of dosing diary with the subject (the diary will be returned at this visit).

Return unused investigational products.
6.2.8. Telephone Follow-up (At least 28 days following last dose of study drugs)
This visit should occur at least 28 days following the last dose of study drugs.  This visit can 
be combined with the End of Study visit as long as it occurs at least 28 days following the 
last dose of study drugs.  If it is not combined with the End of Study visit, this visit can be 
performed over the phone.  There is a +14 day window for the telephone follow-up.

AE assessment.

Pregnancy status.


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6.3. Subject Withdrawal
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. A complete list of specific discontinuation criteria 
for this study is listed in Section 7.23.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  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 that the subject return all unused investigational 
product(s), request that the subject return for a final visit, if applicable, and follow up with 
the subject regarding any unresolved adverse events (AEs).
If a subject completely withdraws from the study, and also withdraws consent for disclosure 
of future information, no further evaluations should be performed, and no additional data 
should be collected.  The sponsor may retain and continue to use any data collected before 
such withdrawal of consent.
If a subject has discontinued investigational product for greater than 14 consecutive days, the 
subject will be discontinued from the study.
Subjects who experience a single episode of disease flare at any time during the study 
(including the open-label run-in and double-blind phase) that could not be controlled by 
rescue medications will be discontinued from the study.
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 is to take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator is to document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team is to be informed of these incidents in a timely fashion.
7.1. Physical Examination
A complete physical examination will be performed at the Screening Visit, Baseline 
Visit (Visit 1) and End of Study Visit (Visit 6).  The following parameters and body systems 
will be examined and any abnormalities described: height (not required for Baseline 
Visit/Visit1), weight, vital signs, general appearance, skin (presence of rash, skin lesions with 
malignant features), 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. 


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7.2. Assessment of New Physical Findings 
At all other visits (Visits 2-5), an abbreviated physical examination will be performed 
assessing the following: weight, vital signs, skin examination including careful examination 
for melanoma and non-melanoma skin cancer, 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 AEs; ongoing AEs should be updated, as 
appropriate. 
7.3. Chest Radiograph
A chest radiograph or chest CT scan 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 chest radiograph must be negative for active 
tuberculosis infection.
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 (see Section 5.8.1.1).
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 need a new 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, 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 3 below.


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Table 3.
Disease Activity Indicators
Indicator
Definition/Calculation
DAS28-4 (CRP)
0.56*√(TJC28) + 0.28*√(SJC28) + 0.36*ln(CRP in mg/l +1) + 
0.014*PtGA in mm+ 0.96
DAS28-4 (ESR)
0.56*√(TJC28) + 0.28*√(SJC28) + 0.70*In(ESR in mm/ hour) + 
0.014*PtGA in mm
Simplified Disease 
Activity Index (SDAI)
(28TJC) + (28SJC) + [PhyGA in cm] + [PtGA in cm] + [CRP in 
mg/dL]
Clinical Disease Activity 
Index (CDAI)
(28TJC) + (28SJC) + [PhyGA in cm] + [PtGA in cm]
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: subject and physician global 
assessments, pain, disability, and an acute-phase reactant (eg, 
CRP).  Similarly, ACR50 and 70 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, 
subject’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; ESR = 
erythrocyte sedimentation rate in mm/first hour, PtGA = subject’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 blinded 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 (MCP) 
joints, proximal interphalangeal (PIP) joints, and knees.  Artificial joints will not be assessed.
7.6.2. Swollen Joint Count (28 Joint Count)
The blinded 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.


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7.7. Subject Assessment of Arthritis Pain
Subjects will assess the severity of their arthritis pain using a 100 mm visual analog scale 
(VAS) by placing a mark on the scale between 0 (no pain) and 100 (most severe pain), which 
corresponds to the magnitude of their pain.
7.8. Subject 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 
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 Subject’s Global Assessment of Arthritis.  
The Investigator’s response will be recorded using a 100 mm VAS.
7.10. Health Assessment Questionnaire – Disability Index (HAQ-DI)
The HAQ-DI12 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.  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.
7.11. SF-36 Health Survey (Version 2, Acute)
The SF-36 (v.2, Acute)13 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. 
7.12. EuroQol EQ-5D Health State Profile 
The EuroQol EQ-5D Health State Profile14 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. The form should then be checked by site staff 
for completeness. 


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7.13. 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.15 WPAI outcomes are expressed as impairment 
percentages with higher numbers indicating greater impairment and less productivity.
7.14. Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale 
The FACIT – Fatigue Scale is a subject completed questionnaire16 consisting of 13 items that 
assess fatigue.  Instrument scoring yields a range from 0 to 52, with higher scores 
representing better subject status (less fatigue).  This questionnaire should be completed by 
the subject prior to any procedures being performed at the visit, if possible.  The form should 
then be checked by site staff for completeness. 
7.15. Routine Assessment of Patient Index Data 3 (RAPID3)
RAPID3 is a pooled index of the 3 patient-reported American College of Rheumatology 
rheumatoid arthritis (RA) Core Data Set measures: function, pain, and patient global estimate 
of status.  Each of the 3 individual measures is scored 0 to 10, for a total of 30.  Disease 
severity may be classified on the basis of RAPID3 scores: >12 = high; 6.1-12 = moderate; 
3.1-6 = low; < or =3 = remission.17
7.16. C-reactive Protein (CRP)
The CRP will be collected at the time points identified in the Schedule of Activity and 
analyzed by a central laboratory.  It will be used in the calculation of several efficacy 
parameters.  After randomization, the Investigator and other site personnel participating in 
the study and Pfizer study personnel will be kept blinded of the results of this test.
7.17. Erythrocyte Sedimentation Rate (ESR) 
The ESR will be analyzed by a local laboratory using the Westergren method.  The local 
laboratory will report results to the central laboratory.  After randomization, the investigator 
and other site personnel participating in the study and Pfizer study personnel will be kept 
blinded of the results of this test.
7.18. Clinical Laboratory Tests
Blood and urine samples will be collected at the time points identified in the Schedule Of 
Activities.  Unscheduled clinical laboratory tests may be obtained at any time during the 
study to assess any perceived safety concerns.


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Table 4.
Clinical Laboratory Tests
Tests
Comments
Chemistry:
Urea nitrogen, creatinine, glucose, calcium, 
sodium, potassium, bicarbonate, chloride, total 
protein, total bilirubin, direct bilirubin, indirect 
bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline 
phosphatase, gamma-glutamyl transferase (GGT), 
albumin, creatine kinase (CK)
Creatinine clearance is calculated by the 
central laboratory according to the 
Cockcroft-Gault Formula at Screening Visit
(Appendix 4)
See Section 7.23 for retesting requirements for 
ALT and AST elevated 3 X ULN
Hematology:
Hemoglobin, Hematocrit, RBC, RBC morphology, 
WBC, Neutrophils (%, abs), Lymphocytes (%, 
abs), Monocytes (%, abs), Eosinophils (%, abs), 
Basophils (%, abs), Platelets
See Section 7.22 for monitoring requirements 
related to hemoglobin, neutrophil and 
lymphocyte counts
CRP
Refer to Section 7.16
ESR
Refer to Section 7.17
Banked Biospecimens
Refer to Section 7.21
Rheumatoid factor
Anti-cyclic citrullinated peptide
FSH
To confirm post-menopausal status, if 
applicable
HIV Serology
Hepatitis B Surface antigen (HBsAg)
Hepatitis B Core Antibody (HBcAb)
Hepatitis B Surface Antibody (HBsAb)
Subjects with a positive hepatitis B surface 
antigen (HBsAg) test will be excluded from 
the study.
Subjects with 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.
Hepatitis C virus antibody (HCV Ab)
Hepatitis C RNA (HCV RNA)
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)
Subjects should be fasting for at least 6 hours 
prior to obtaining specimen.


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Table 4.
Clinical Laboratory Tests
Tests
Comments
Serum or Urine Pregnancy Testing
All female subjects of childbearing potential, 
regardless of whether or not they are sexually 
active.  Two negative pregnancy tests are 
required before receiving investigational 
product. 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 7.19)
May be repeated if pregnancy is suspected or 
at the request of the IRB/EC or local 
regulations.
QuantiFERON TB Gold®™ in Tube Test
See Sections 5.8.1.1 and 7.3 for further details 
on management of positive tests.
Urinalysis:
Specific Gravity, pH, Protein, Glucose
Ketones, Blood, Leukocyte Esterase
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
See Section 8.7.2 for further details on 
management of elevations. 
ALT = alanine aminotransferase (SGPT); AST = aspartate aminostransferase (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; 
It is recommended that for potential herpes zoster adverse events a laboratory diagnosis of varicella 
zoster virus infection be confirmed and that the virus be characterized.  (Specimens should be 
obtained from vesicular fluid, maculopapular lesions, or crusts from lesions).  Details of the test, 
method and laboratory details will be provided in a separate manual.
7.19. Pregnancy Testing
For female subjects of childbearing potential, 2 negative pregnancy tests are required before 
receiving investigational products.  The second negative test should be obtained at least 
19 days after the first and should be done during the first 5 days of the menstrual period 
immediately preceding the first dose of investigational product.  In the absence of regular 
menstrual bleeding, the study candidate should have used 2 forms of contraception for at 
least 1 month before the second pregnancy test.  Pregnancy tests will also be done whenever 
1 menstrual cycle is missed during the active treatment period (or when potential pregnancy 
is otherwise suspected), and repeated at all study visits (from screening visit to the end of 


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study visit) to confirm that the subject has not become pregnant during the study.  All 
pregnancy tests used in this study, either urine or serum, must have a sensitivity of at least 
25 mIU/mL and must be performed by a certified laboratory.  In the case of a positive 
confirmed pregnancy, the subject will be withdrawn from administration of investigational 
product and from the study.  Pregnancy tests may also be repeated as per request of 
institutional review boards (IRBs)/ethics committees (ECs) or if required by local 
regulations. 
7.20. Adjudicated Events 
The Pfizer Study Team or designee will provide a listing of specific documents needed to 
support event adjudication by the Adjudication Committees (see Section 9.6).  Obtaining and 
submitting the documentation will be the responsibility of the study site.  Event 
documentation will vary with the event requiring adjudication and may include (but not be 
limited to): hospital discharge summaries, operative reports, clinic notes, ECGs, diagnostic 
tests, pathology reports, autopsy reports and death certificate information, as applicable.
7.21. Banked Biospecimens
7.21.1. Markers of Drug Response
Studying the 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), 
ribonucleic acid (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 subjects 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. 
To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s study identification (ID) number.  Samples will be kept in a 
facility accessible only by swiping a badge.  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 be used only for the purposes described here and in the informed consent 
document/subject 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 
postmarketing 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 


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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/subject 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 study.
A 4-mL blood biospecimen Prep D1 (K2 edetic acid [ethylenediaminetetraacetic acid] 
[EDTA] whole blood collection optimized for DNA analysis) will be collected at visits 
1 (baseline visit) to be retained for potential pharmacogenomic/biomarker analyses related to 
drug response.  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. 
Prep R1 (PAXGene whole blood collection optimized for RNA analysis): Two 2.5-mL 
blood biospecimens (2 paxgene tubes, 2.5 ml/tube) will be collected at visits 1, 2, 4 and 6, 
respectively, for potential pharmacogenomics/biomarker analyses related to drug response.
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 visits 1, 2, 4, and 6;

Prep B2 (serum collection optimized for biomarker/ proteomics/metabonomic 
analysis): a 10 mL blood biospecimen will be collected at visits 1, 2, 4, and 6. 
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/subject information sheet that 
they will not be compensated in this event.
7.21.2. Additional Research
Unless prohibited by local regulations or ethics committee decision, 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 study, and related conditions;


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
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 among 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 the Markers of Drug Response section will be used.  Subjects may 
still participate in the clinical study if they elect not to allow their banked biospecimens to be 
used for the additional purposes described in this section.
7.22. Assessment of Suicidal Ideation and Behavior (SIB)
There are no current medically significant suicidality concerns for tofacitinib or methotrexate 
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.
7.23. Triggered Requirements for Monitoring and Discontinuation Criteria
Conditions in which Prompt Retesting is Required
Condition
Action
Neutrophil counts <1000 cells/mm3
The subject should return to the study site for 
prompt retesting, ideally within 3-5 days.
Platelet counts <100,000 platelets/mm3
The subject should return to the study site for 
prompt retesting, ideally within 3-5 days.
Lymphocyte counts <500 lymphocytes/mm3
The subject should return to the study site for 
prompt retesting, ideally within 3-5 days.
Any single AST and/or ALT elevation >3 times 
the upper limit of normal (ULN)*
The subject should return to the study site for 
prompt retesting, ideally within 3-5 days*.
Any single hemoglobin value <8.0 g/dL or one 
that drops 2 g/dL below baseline. 
The subject should return to the study site for 
prompt retesting, ideally within 3-5 days.
Any serum creatinine increase >50% over the 
average of screening (most recent value prior to 
baseline) and baseline values OR an absolute 
increase in serum creatinine >0.5 mg/dL 
(>44.2 mol/L) over the average of screening 
(most recent value prior to baseline) and 
baseline values
The subject should return to the study site for 
prompt retesting, ideally within 3-5 days.
* 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.  A subject with a total bilirubin 
value 2 × ULN concurrently may need to return to the investigational site and be evaluated as soon as 
possible, preferably within 48 hours from awareness of the abnormal results (refer to Section 8.7.2).


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Discontinuation Criteria
Condition
Action
2 sequential AST or ALT elevations ≥3 x 
ULN with a total bilirubin value ≥2 x ULN
Treatment with all study drugs will be 
discontinued and the subject withdrawn from 
this study. 
2 sequential AST or ALT elevations ≥3 x 
ULN with an elevated INR
Treatment with all study drugs will be 
discontinued and the subject withdrawn from 
this study.
2 sequential AST or ALT elevations ≥3 x 
ULN accompanied by symptoms consistent 
with hepatic injury
Treatment with all study drugs will be 
discontinued and the subject withdrawn from 
this study. 
2 sequential AST or ALT elevations ≥5 x 
ULN, regardless of Total Bilirubin or 
accompanying symptoms
Treatment with all study drugs will be 
discontinued and the subject withdrawn from 
this study. 
Two sequential hemoglobin values 
<8.0 g/dL or a decrease of more than 30% 
from baseline value;
Treatment with all study drugs will be 
discontinued and the subject withdrawn from 
this study.  Follow up to resolution
Two sequential platelet counts 
<75,000 platelets/mm3;
Treatment with all study drugs will be 
discontinued and the subject withdrawn from 
this study.  Follow up to resolution
2 sequential neutrophil counts 
<1000 cells/mm3
Treatment with all study drugs will be 
discontinued and the subject withdrawn from 
this study.  Follow up to resolution
Confirmed lymphocyte counts 
<500 lymphocytes/mm3 by repeat testing
Treatment with all study drugs will be 
discontinued and the subject withdrawn from 
this study.  Follow up to resolution
Confirmed increases in serum creatinine 
>50% over the average of screening and 
baseline values and the absolute value of 
serum creatinine is above upper limit of 
normal range.  
Treatment with all study drugs will be 
discontinued and the subject withdrawn from 
this study.  Retesting should occur until the 
serum creatinine is within 10% of the 
pretreatment value.
Serious infections defined as any infection 
(viral, bacterial, or fungal) requiring 
parenteral antimicrobial therapy or 
hospitalization for treatment, or meeting 
other criteria that require the infection to be 
classified as a serious adverse event. 
Treatment with all study drugs will be 
discontinued and the subject withdrawn from 
this study
Opportunistic infection, including 
tuberculosis, judged significant by 
investigator
Treatment with all study drugs will be 
discontinued and the subject withdrawn from 
this study
Malignancies excluding adequately treated non 
melanoma skin cancer (NMSC) and cervical 
carcinoma in situ
Treatment with all study drugs will be 
discontinued and the subject withdrawn from this 
study


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Pregnancy or refusal to use appropriate 
contraception
Permanently withdraw the subject from the study 
and follow any pregnancy to resolution.
Use of rescue medications for more than 
10 consecutive days
Treatment with all study drugs will be 
discontinued and the subject withdrawn from this 
study (see Appendix 6 for details).
Anaphylactic or other serious allergic reaction
Immediately discontinue study drug and institute 
appropriate therapy.  
Symptoms suggestive of a lupus-like syndrome
Discontinue study drug and institute appropriate 
therapy
Other Triggered Requirements for Monitoring
Condition
Action
Increase lipid parameters (total cholesterol, 
LDL cholesterol, HDL cholesterol, 
triglycerides)
Monitor and treat according to local guidance (eg, 
diet and behavior modification, statin therapy)
Surgery
Interrupt study drug 1 week prior to a scheduled 
surgical procedure and may resume when 
operative site is sufficiently healed and risk of 
infection is minimal.
(Study drug administration can be resumed only if 
the off-drug period is 14 consecutive days.) 
Use of potent CYP3A4 and 
CYP2C19 Inhibitors and CYP3A4 Inducers
Treatment with potent CYP3A4 inhibitors or with 
medications that are both a moderate 
CYP3A4 inhibitor and potent inhibitor of 
CYP2C19 require that tofacitinib is interrupted 
during treatment.  Treatment with a potent 
CYP3A4 does not require tofacitinib 
discontinuation but should be noted as a protocol 
deviation.  See Appendix 3 for a list of 
CYP3A4 and CYP2C19 Inhibitors and 
CYP3A4 Inducers.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; g/dL = grams per deciliter; GGT = 
gamma-glutamyl transpeptidase, HDL== high density lipoprotein; LDL= low density lipoprotein; 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. 


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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 a 
serious adverse event (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 AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
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.  SAEs 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 SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the subject has taken at least 1 dose of investigational product through the subject’s last 
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;


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
Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, 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 medication 
error CRF, which is a specific version of the AE page, 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 is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
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. 
Examples of overdose for each investigational product are listed in Sections 8.4.1 and 8.4.2.


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8.4.1. Tofacitinib Overdose
All overdoses are medication errors.  There is no experience with tofacitinib overdose.  
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 rheumatoid arthritis 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 CYP3A4 inhibitor 
(Appendix 3) is assumed to result in a doubling of exposure.  For further details, please refer 
to the tofacitinib Investigator Brochure.
8.4.2. Methotrexate Overdose
Leucovorin is indicated to diminish the toxicity and counteract the effect of methotrexate 
overdose.  Leucovorin administration should begin as promptly as possible.  As the time 
interval between MTX administration and leucovorin initiation increases, the effectiveness of 
leucovorin in counteracting toxicity decreases.  Monitoring of the serum MTX concentration
is essential in determining the optimal dose and duration of treatment with leucovorin.
In cases of massive overdose, hydration and urinary alkalinization may be necessary to 
prevent the precipitation of MTX and/or its metabolites in the renal tubules.  For further 
details, please refer to the product label for MTX. 
8.5. Serious Infections 
A serious infection is any infection (viral, bacterial, and fungal) 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 be discontinued from the study and the serious adverse event should be listed as the 
reason for discontinuation in the CRF.  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 8.1 on Adverse Event Reporting.


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8.6. 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 (outside of protocol-stipulated dose 
adjustments) 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.
Clinically significant laboratory findings at the final assessment should be followed to 
resolution or until determined by the investigator to be stabilized.  Repeat tests may be 
indicated to establish this. 
8.7. Serious Adverse Events
A serious adverse event 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 may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.


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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.
8.7.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.7.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level 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. 
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 values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 × ULN, or 
8 × ULN (whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN or
if the value reaches ≥3 × ULN (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. 


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In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (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 person, 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 liver function test (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.
8.8. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  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, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outsubject/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 
workup of persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);


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
Administrative admission (eg, for yearly physical examination);

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;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive 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.
8.9. Severity Assessment
If required on the AE 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 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.10. 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 SAE 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 the 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. 


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In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.11. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a 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 an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
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 general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer 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 baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.


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
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 SAEs when the investigator assesses the infant death as related or 
possibly related to exposure to the investigational product.
Additional information regarding the EDP may be requested by the 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 in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.12. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.13. Withdrawal Due to Adverse Events (See Also the Section on Subject Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  A complete list of specific discontinuation criteria for this study is listed in 
Section 7.23.
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.14. 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.
8.15. 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.


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8.15.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  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 time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outsubject 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 or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames 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, vaccines, and/or 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. 
8.15.2. 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.
8.15.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Methodologies for summary and statistical analyses of data collected in this study are 
summarized here and further detailed in a Statistical Analysis Plan (SAP), 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
Based on estimated CDAI-based low disease activity rate of 40% derived from prior phase 
3 studies and factoring in a discontinuation rate of approximately 15% during the open label 
run-in phase, approximately 680 subjects will be enrolled to the run-in phase with the aim of 
at least 232 subjects being randomized into the blinded MTX withdrawal phase at Week 24.  
With a two-sided Type-I error of 5% and an assumed standard deviation of 1.4 for the 
difference in change from randomization in DAS28-4 (ESR) between the two arms, a sample 
size of approximately 232 subjects randomized at Week 24 would provide 90% power to 
declare non-inferiority of tofacitinib monotherapy relative to tofacitinib plus methotrexate 
with a non-inferiority margin of 0.6.
9.2. Descriptive Analysis
Patient and clinical characteristics at baseline and randomization (ie, the end of open-label
phase) will be summarized with the use of descriptive statistics.  Frequencies and percentages 
will be used to describe categorical variables and mean and standard deviations (or median 
with interquartile range [IQR] and range, where appropriate) will be calculated for 
continuous variables.
Descriptive statistics will also be provided for all efficacy and safety endpoints at each visit 
in open-label phase or double-blind withdrawal phase as appropriate.  Further details will be 
outlined in the SAP. 
9.3. Efficacy Analysis
9.3.1. Analysis of the Primary Endpoint 
The primary endpoint of change from randomization in DAS28-4(ESR) at Week 48 will be 
analyzed as a continuous variable using a linear mixed-effect model of repeated measures 
(MMRM) that includes the fixed effects of treatment, visit, treatment-by-visit interaction, 
prior use of a biological DMARD, and baseline DAS28-4 (ESR) value as a covariate.  
Within-subject variability will be accounted for using a random effect with an unstructured 
covariance matrix.  Change from randomization at any visit post-randomization will be 
defined as the DAS28-4 (ESR) value at that visit minus the value at randomization.
The primary analysis will be a non-inferiority test to show that tofacitinib MR 11mg QD 
monotherapy is not less effective (non-inferior) than tofacitinib MR 11mg QD with MTX 
within the margin of non-inferiority set at 0.6 (ie, the difference in mean change from 
randomization in DAS28-4 (ESR) between the two arms). In other words, the change from 
randomization in DAS28-4(ESR) for the tofacitinib MR 11mg QD monotherapy arm may be 
less favorable than that for the tofacitinib MR 11mg QD with continued MTX arm by no 
more than 0.6. The estimated treatment difference and the associated 95% confidence 
interval (CI) will be presented.  If the upper bound of the 95% two-sided CI for the difference 
(tofacitinib monotherapy arm minus tofacitinib with MTX arm) in change from 
randomization in DAS 28-4 (ESR) between the two arms is lower than 0.6, then tofacitinib 
monotherapy will be declared to be non-inferior to the tofacitinib with continued MTX 
treatment.


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The analysis will be based on the Full Analysis Set (FAS), which is defined as those subjects 
who received at least one dose of tofacitinib plus MTX during the open label period and were 
randomized and received at least one dose of the randomized investigational drug (tofacitinib 
MR 11mg QD with placebo for MTX or tofacitinib MR 11mg QD with MTX) during the 
blinded MTX withdrawal period.
A robustness analysis based on a per-protocol analysis set will be performed.  Sensitivity 
analyses using different methods of handling missing data will also be conducted; further 
details will be outlined in the SAP.
9.3.2. Analysis of Secondary Endpoints
Binary secondary endpoints will be analyzed using the normal approximation for the 
difference in binomial proportions.
Continuous secondary endpoints will be analyzed using similar methods as the primary 
endpoint, ie, a linear mixed-effect model of repeated measures (MMRM) that includes the 
fixed effects of treatment, visit, treatment-by-visit interaction, and baseline value as a 
covariate.  Within-subject variability will be accounted for using a random effect with an 
unstructured covariance matrix.
The estimated treatment difference and the associated 95% confidence interval (CI) will be 
presented. 
9.4. Analysis of Other Efficacy and Exploratory Endpoints
Analyses for other efficacy endpoints and exploratory endpoints will be discussed and 
detailed in the SAP.
9.5. Safety Analysis
The safety analysis set is defined as those subjects who received at least one dose of 
tofacitinib MR 11mg QD with MTX at entry into the study.  All displays of safety data will 
be separated by the open-label phase and the double-blind phase.
 
 
 
 
CCI


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9.7. Data Monitoring Committee
This study will use an External Data Monitoring Committee (EDMC).
The EDMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the charter.  The recommendations made by the EDMC to alter the conduct of 
the study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
that are not endpoints, to regulatory authorities, as appropriate. 
9.8. Safety Event Adjudication/Review Committees 
To help assess specific safety events in this study, external adjudication committees have 
been established to harmonize and standardize selected safety event assessment.  Members of 
these safety event adjudication committees will be blinded to treatment assignment in order 
to allow for unbiased assessments. These committees include a Cardiovascular Endpoint 
Adjudication Committee (CV EAC), Malignancy Adjudication Committee (MAC), 
Opportunistic Infection Review Committee (OIRC), Hepatic Event Review Committee 
(HERC) and Gastrointestinal Perforation Review Committee (GIPRC). Further information 
about these committees can be found in the respective charters, including specific 
descriptions of the scope of their responsibilities and the processes and definitions used to 
review and assess specific safety events. 
In addition to these external committees, an internal committee of medically qualified Pfizer 
personnel with expertise in the assessment and diagnosis of respiratory disease will review 
and categorize potential events of interstitial lung disease (Interstitial Lung Disease Review 
Committee, ILDRC).
Additional safety event adjudication or review committees may be established to harmonize 
and standardize selected safety event assessments.  As described above, individual committee 
charters will provide specific descriptions of the scope of responsibilities and the processes 
and definitions used to review and assess specific safety events.
In addition to the event adjudication or review committees described above, all biopsies of 
potentially malignant tumors, suspicious lymphadenopathy, or possible extranodal 
lymphoproliferative disorder are to be submitted to the central laboratory for review by 
central laboratory pathologists.  In some instances, additional expert pathology review of 
submitted samples may be performed.  Description of the scope of review and the processes 
used to obtain and assess biopsies is described in the Histopathology Review for Potential 
Malignancy charter.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its designee will conduct periodic monitoring visits during study conduct 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 are 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.  This 
verification may also occur after study completion.


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During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), 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.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
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 are true. Any corrections to entries made in the CRFs or 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 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 investigative 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 
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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, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to 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 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/Ethics Committee
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/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC 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 & 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 ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The study site 
will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study subject 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, 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 IRBs/ECs and investigator databases may be used as 
recruitment procedures.  Pfizer will have an opportunity to review and approve the content of 
any study recruitment materials directed to potential study subjects before such materials are 
used. 
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 that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.


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13. DEFINITION OF END OF TRIAL
13.1. 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 a sufficient number of 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.
13.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as last subject last visit (LSLV). 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of
tofacitinib for use in subjects 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 7 days.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. 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), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in subjects that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date for 
studies in adult populations or within 6 months of the primary completion date for studies in 
pediatric populations.


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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 study concluded according to the pre-specified protocol or was 
terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual subjects has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication 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, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.. 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, the investigator is free to publish separately, subject to the 
other requirements of this section.


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For all publications relating to the study, the 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 CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor 
selectivity. Nat Biotechnol 2008; 26:127-32.
2.
Meyer DM, Jesson MI. Anti-inflammatory activity and neutrophil reductions mediated 
by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm 
(Lond) 2010;7:41.
3.
Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol 
2007;178(5):2623-9.
4.
O’Sullivan LA, Liongue C, Lewis RS, et al. Cytokine receptor signaling through the 
JAK STAT-Socs pathway in disease. Mol Immunol 2007;44(10):2497-506.
5.
Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, et al. Phase IIb 
dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab 
monotherapy versus placebo in patients with active rheumatoid arthritis with an 
inadequate response to disease-modifying antirheumatic drugs. Arthritis and 
rheumatism. 2012;64(3):617-29. Epub 2011/09/29.
6.
Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. 
Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. The New 
England journal of medicine. 2012; 367(6):495-507. Epub 2012/08/10.
7.
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 
placebo in combination with background methotrexate in patients with active 
rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis and 
rheumatism. 2012;64(4):970-81. Epub 2011/10/19.
8.
Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, et al. 
Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in 
patients with active rheumatoid arthritis: a randomized trial. Annals of internal 
medicine. 2013;159(4):253-61. Epub 2013/09/13.
9.
Burmester GR, Benda B, Gruben D, Bradley J, Mebus C. Tofacitinib for rheumatoid 
arthritis - Authors' reply. Lancet. 2013; 381(9880):1812-3. Epub 2013/05/28.
10.
van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garcia Meijide JA, Wagner S, 
et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. The New 
England journal of medicine. 2012;367(6):508-19. Epub 2012/08/10.
11.
Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American 
College of Rheumatology/European League Against Rheumatism provisional definition 
of remission in rheumatoid arthritis for clinical trials. Arthritis and rheumatism. 
2011;63(3):573-86. Epub 2011/02/05.


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12.
Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the health 
assessment questionnaire, disability and pain scales. The Journal of rheumatology. 
1982;9(5):789-93. Epub 1982/09/01.
13.
Ware JE KM, 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.
14.
Hurst NP, Kind P, Ruta D, Hunter M, Stubbings A. Measuring health-related quality of 
life in rheumatoid arthritis: validity, responsiveness and reliability of EuroQol (EQ-5D). 
British journal of rheumatology. 1997;36(5):551-9. Epub 1997/05/01.
15.
Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work 
productivity and activity impairment measure.  PharmacoEconomics 1993; 4(5):353-
365.
16.
Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in cancer patients compared 
with fatigue in the general United States population. Cancer. 2002;94(2):528-38. Epub 
2002/03/20.
17.
Pincus T, Yazici Y, Bergman MJ. RAPID3, an index to assess and monitor patients 
with rheumatoid arthritis, without formal joint counts: similar results to DAS28 and 
CDAI in clinical trials and clinical care. Rheum Dis Clin North Am. 2009 
Nov;35(4):773-8.


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Appendix 1. Abbreviations
This is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ACIP
advisory Committee on Immunization Practices
ACPA
anti-cyclic citrullinated peptide 
ACR
american college of rheumatology
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUCinf
area under the concentration-time curve from time 0 to 
infinity
BCG 
Bacille Calmette Guérin 
BID
twice daily
CD
cluster of differentiation
CDAI
clinical disease activity index
CHD
coronary heart disease
Cav
average observed concentration
Cmax
peak or maximum observed concentration
Cmin
minimum observed concentration
COX
cyclooxygenase
CRF
case report form
CRP
c-reactive protein
CSA
clinical study agreement
CT
computed tomography
CTA
clinical trial application
DAS
disease activity score
DAI
dosage and administration instructions
DMARD
disease-modifying antirheumatic drug
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
EDMC
external data monitoring committee 
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
ESR
erythrocyte sedimentation rate
EQ-5D
European Quality of Life - 5 dimensions questionnaire 
EU
European Union
EudraCT
European Clinical Trials Database
EuroQol
European Quality of Life 
FACIT
Functional Assessment of Chronic Illness Therapy


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FACS
fluorescence-activated cell sorting
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United 
States)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
HAQ-DI
Health Assessment Questionnaire-Disability Index 
HBcAb
hepatitis B core antibody 
HbsAb
hepatitis B surface antibody 
HbsAg
hepatitis B surface antigen 
HDL
high density lipoprotein
HEENT
head, eyes, ears, nose and throat
HIV
human immunodeficiency virus
HRQL
health-related quality of life
HZ
herpes zoster
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ID
identification
IFNγ
Interferon gamma
IL
interleukin
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IRC
internal review committee
IUD
intrauterine device
IVRS
interactive voice response system
JAK
janus kinase
IWR
interactive web response
LDA
low disease activity
LDL
low density lipoprotein
LFT
liver function test
LSLV
last subject last visit 
LTE
long-term extension
MCP
metacarpophalangeal
MTX
methotrexate
N/A
not applicable
NK
Natural killer
NSAID
nonsteroidal anti-inflammatory drug
NYHA
New York heart association
PCD
primary completion date
PhyGA
physician’s global assessment of health


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PIP
proximal interphalangeal 
PT
prothrombin time
PtGA 
subject’s global assessment of health
QD
once daily
RA
rheumatoid arthritis
RAPID3
Routine Assessment of Patient Index Data 3
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SDAI
simplified disease activity index
SF-36
short form (36) health survey 
SIB
suicidal ideation and behavior
SJC
swollen joint count
SOA
schedule of activities
SOP
standard operating procedure
SPC
summary of product characteristics
SRSD
single reference safety document
SSID
study subject identification
TB
tuberculosis
TJC
tender joint count
TNF
tumor necrosis factor
TNFi
tumor necrosis factor inhibitor
TST
tuberculin skin test
TYK
tyrosine kinase
ULN
upper limit of normal
US
United States
USPI
United States package insert
UTN
Universal Trial Number
VAS
visual analogue scale
VZV
varicella zoster virus
WPAI
Work Productivity and Activity Impairment 


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Appendix 2. The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for 
Rheumatoid Arthritis
Score
Target population (Who should be tested?): Patients who
Have at least 1 joint with definite clinical synovitis (swelling)*
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.


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§Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis.  Distal 
interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment.  Categories of joint 
distribution are classified according to the location and number of involved joints, with placement into the highest category possible based on the 
pattern of joint involvement.
¶“Large joints” refers to shoulders, elbows, hips, knees, and ankles.
#“Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb 
interphalangeal joints, and wrists.
**In this category, at least 1 of the involved joints must be a small joint; the other joints can include any combination of large and additional 
small joints, as well as other joints not specifically listed elsewhere (eg, temporomandibular, acromioclavicular, sternoclavicular, etc.).
†† Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay; low-positive refers to 
IU values that are higher than the ULN but ≤3 times the ULN for the laboratory and assay; high-positive refers to IU values that are >3 times the 
ULN for the laboratory and assay.  Where rheumatoid factor (RF) information is only available as positive or negative, a positive result should be 
scored as low-positive for RF.  ACPA = anti-citrullinated protein antibody.
‡‡Normal/abnormal is determined by local laboratory standards.  CRP = C-reactive protein; ESR = erythrocyte sedimentation rate.
§§ Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (eg, pain, swelling, tenderness) of joints 
that are clinically involved at the time of assessment, regardless of treatment status.


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Appendix 3. Prohibited Concomitant Medications
All prohibited investigational compounds require discontinuation for at least 4 weeks or 
5 half-lives (whichever is longer) prior the Baseline Visit. 
All investigational compounds, other than study drugs (tofacitinib and MTX), are prohibited 
during the study. 
Please refer to Appendix 6 for prohibited corticosteroids.
Only systemically administered drugs listed below are prohibited; topical, ophthalmic, or 
intravaginal administration is allowed. 
The use of folate antagonists such as trimethoprim is prohibited during the study.
Prohibited Concomitant Medications
CYP3A4 and/or CYP2C19 Inhibitors 
CYP3A4 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
Rituximab, anakinra (Kineret), etanercept 
(Enbrel), infliximab (Remicade), abatacept 
(Orencia), tocilizumab (Actemra),
certolizumab pegol (Cimzia®),  Golimumab 
(Simponi TM), adalimumab (Humira), 
Oral gold (auranofin), injectable gold 
(aurothioglucose, aurothiomalate), sulfasalazine, 
d-penicillamine, bucillamine, mizoribin, 
azathioprine, leflunomide (Arava), 
cyclosporine, tacrolimus, tetracyclines (unless 
prescribed for acne),  antimalarials 
(chloroquine, hydroxychloroquine), baricitinib
*Discontinue for at least 30 days
** See Section 5.8 for specific washout requirements.


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Final Protocol Amendment 2, 04 Dec 2017
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Appendix 4. 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.


Tofacitinib citrate
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Final Protocol Amendment 2, 04 Dec 2017
Page 93
Appendix 5. Approximate Equivalent Morphine Doses Of Opioid Analgesics
Common opioid analgesics
Drug
Maximum Allowed 
Total Daily Dose
Relative potency to oral 
morphine
Half-Life
Morphine 
30 mg
1
1.5 – 4 hrs
Hydrocodone (Vicodin, Lortab)
30 mg
1
3.8 – 4.5 hrs
Hydromorphone (Dilaudid)
7.5 mg
4
2.5 hrs
Meperidine (Demerol, Pethidine)
300 mg
0.1
3.2 – 3.7 hrs
Methadone (Dolophine, 
Methadose, Physeptone)
10 mg
3.0
23 hrs
Codeine (Paveral, Tylenol 
#2 and #3)
200 mg
0.15
2.5 – 3.5 hrs
Oxycodone [Roxicodone; 
Percocet, Tylox]
15 mg  
~2
3.2 hrs
Tramadol [Ultram, Zydol; 
Zamadol, Ultracet, Tramal]
300 mg
~0.1
4.7 – 5.1 hrs
Sites should contact project team for acceptable alternative preparations and related data.
References:
1. Twycross R, Wilcock A, Thorp S. Palliative Care Formulary.  Abingdon: Radcliffe Medical Press, 1998.
2. Twycross R.  Pain relief in advanced cancer. Edinburgh: Churchill Livingstone, 1994.


Tofacitinib citrate
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Final Protocol Amendment 2, 04 Dec 2017
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Appendix 6. Rescue Therapy
Acetaminophen/ paracetamol is allowable as rescue medication if dosed no more than the 
locally approved recommended daily dose for no more than 10 consecutive days.  If a subject 
is already taking stable background doses of acetaminophen/ paracetamol, s/he may increase 
the dose up to the locally approved recommended daily dose for up to 10 consecutive days 
for rescue purposes.
Acetaminophen/paracetamol is not permitted as a part of combination products such as 
over-the-counter “cold remedies” or in combination with opioids if the 
acetaminophen/paracetamol dose will exceed the locally approved recommended daily dose.  
Subjects who require rescue for more than 10 consecutive days should be discontinued from 
the trial.  In addition, subjects should not be dosed with rescue acetaminophen/paracetamol 
or opioids within 24 hours prior to a study visit.  However, baseline stable 
acetaminophen/paracetamol or opioids should NOT be discontinued in advance of study 
visits. 
Low dose oral corticosteroids in doses equivalent to ≤10 mg prednisone per day is allowed 
during the study period.  However, the prednisone dose increase should not exceed the initial 
dose during the study period.
Intra-articular corticosteroids may be given during the first 3 months of the run-in phase in 
no more than two joints, in a cumulative dose of no more than 80 mg methylprednisolone or 
its equivalent during any 6 month study period.  Injections are not allowed after 3 months.  
Injected joints will also be considered as having their pre-injection status (tender/painful or 
swollen) for the remainder of the trial.
Intravenous or intramuscular corticosteroids are not allowed during this study. 
Biologic response modifiers are not allowed during this study.
Subjects should not be dosed with any rescue intervention within 24 hours prior to a 
study visit.
The following paradigm should be used to determine appropriate opioid rescue 
therapy:
For subjects who are NOT on stable, background opioid therapy: any of the following 
single opioid agents may be given as rescue medication (with or without acetaminophen/ 
paracetamol) for no more than 10 consecutive days in the following total daily doses:
1. Hydrocodone, not to exceed 30 mg total daily dose.
2. Oxycodone, not to exceed 15 mg total daily dose.
3. Tramadol, not to exceed 300 mg total daily dose.


Tofacitinib citrate
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For subjects who ARE on stable, background opioid therapy:
1. They may NOT add a second opioid agent for rescue.
2. If their background medication is 1 of the 3 listed above, they may, within the above 
maximum total dosage limits, increase the dosage for up to 10 consecutive days for 
rescue purposes.
3. If their background medication is a short-acting (half-life <5 hours, Appendix 5) 
opioid that is not one of those listed above, they may increase the dosage for up to 
10 consecutive days (up to a total daily dose which must not exceed the potency 
equivalent of 30 mg of orally-administered morphine (Appendix 5) for rescue 
purposes.
4. Sustained release opioid formulations (eg, OxyContin®, MS Contin®) and opioids 
with half-lives greater than 5 hours (eg, methadone) may NOT be USED for rescue 
medication.
5. Sustained release opioid formulations (eg, OxyContin®, MS Contin®) and opioids 
with half-lives greater than 5 hours (eg, methadone; see also Appendix 4) may NOT 
be INCREASED for rescue purposes.


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Appendix 7. Belgium, Czech Republic, Germany, Hungary, Italy, Poland, Spain, and 
United Kingdom Specific Protocol Requirements
In Belgium, Czech Republic, Germany, Hungary, Italy, Poland, Spain, and the United 
Kingdom, the following changes are made to the protocol:
4.4.5 Contraception and Reproductive Status
In this study, male subjects who are able to father children and female subjects who are of 
childbearing potential will receive MTX, which has been associated with teratogenic risk in 
humans, and tofacitinib which has been associated with teratogenic risk in animals (further 
information can be found in the single safety reference document).  Those who, in the 
opinion of the investigator, are sexually active and at risk for pregnancy with their partner(s) 
must agree to use with their partner(s) highly effective contraception throughout the study 
and continue for at least 6 months after the last dose.  The investigator or his or her designee, 
in consultation with the subject, will select the appropriate method of contraception for the 
individual subject and his/her partner(s) from the list of permitted contraception methods 
below and instruct the subject in their consistent and correct use.  The investigator or his or 
her designee will discuss with the subject the need to use a highly effective method of 
contraception consistently and correctly according to the schedule of activities and document 
such conversation, and the subject’s affirmation, in the subject’s chart.  In addition, the 
investigator or his or her designee will instruct the subject to call immediately if a selected 
contraception method is discontinued or if pregnancy is known or suspected in the subject or 
the subject’s partner. 
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).
One of the below options must be used to satisfy the requirement for highly effective 
contraception:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (ie, oral, inserted, injected, implanted, transdermal) with either:
a.
male condom or female condom used WITH a spermicide (ie, foam, gel, film, 
cream, or suppository).  For countries where spermicide is not available, this 
option is not appropriate;
b. male sterilization.
2. Correctly placed copper-containing intrauterine device (IUD) or intrauterine system 
combined with either:
a.
male condom or female condom used WITH a spermicide (ie, foam, gel, film, 
cream, or suppository).  For countries where spermicide is not available, this 
option is not appropriate;


Tofacitinib citrate
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Final Protocol Amendment 2, 04 Dec 2017
Page 97
b. male sterilization. 
3. Male sterilization with absence of sperm in the postvasectomy ejaculate combined 
with:
a.
male condom or female condom used WITH a spermicide (ie, foam, gel, film, 
cream, or suppository.  For countries where spermicide is not available, this 
option is not appropriate;
b. bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive 
procedure. 
4. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label)
combined with:
a.
IUD or intrauterine system;
b. male condom or female condom used WITH a spermicide (ie, foam, gel, film, 
cream, or suppository).  For countries where spermicide is not available, this 
option is not appropriate;
c.
male sterilization.
Pregnancy testing will be performed and documented at every visit unless the 
non-childbearing potential is confirmed and documented.  The specific contraceptive 
methods will be documented and at every visit, their consistent and correct use will be 
ascertained and documented in the subject’s case report form.

SAP_001.pdf: 
Protocol A3921192 (CP-690,550) Statistical Analysis Plan
Page 1
Protocol A3921192
A PHASE 3B/4 RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED STUDY 
OF METHOTREXATE (MTX) WITHDRAWAL IN SUBJECTS WITH RHEUMATOID 
ARTHRITIS (RA) TREATED WITH TOFACITINIB 11MG MODIFIED RELEASE (MR) 
FORMULATION
Statistical Analysis Plan 
(SAP)
Version:
4.0
Date:
09-Nov-2018


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
Page 2
TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................7
2.1. Study Objectives .......................................................................................................7
2.1.1. Primary Objectives .......................................................................................7
2.1.2. Secondary Objectives ...................................................................................7
2.1.3. Other Objectives...........................................................................................8
2.1.4. Exploratory Objectives .................................................................................8
2.2. Study Design .............................................................................................................8
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9
3.1. Primary Efficacy Endpoint(s)....................................................................................9
3.2. Secondary Efficacy Endpoint(s)................................................................................9
3.3. Other Efficacy Endpoints........................................................................................10
3.4. Exploratory Endpoints.............................................................................................10
3.5. Baseline Variables...................................................................................................10
3.6. Safety Endpoints .....................................................................................................12
3.6.1. Adverse Events...........................................................................................12
3.6.2. Laboratory Data..........................................................................................12
4. ANALYSIS SETS ...............................................................................................................12
4.1. Full Analysis Set .....................................................................................................12
4.2. Per Protocol Analysis Set........................................................................................13
4.3. Safety Analysis Set..................................................................................................13
4.4. Other Analysis Sets .................................................................................................13
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................13
5.1. Hypotheses and Decision Rules ..............................................................................13
5.2. General Methods .....................................................................................................14
5.2.1. Analyses for Binary Data............................................................................14
5.2.2. Analyses for Continuous Data....................................................................14
5.2.3. Analyses for Categorical Data....................................................................14
5.3. Methods to Manage Missing Data ..........................................................................15


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
Page 3
5.3.1. Joint Counts ................................................................................................15
5.3.2. DAS28-4(ESR), DAS28-4(CRP), CDAI, SDAI ........................................15
5.3.3. LDA and Remission ...................................................................................16
5.3.4. ACR20, ACR50, ACR70............................................................................16
5.3.5. Patient Reported Outcomes ........................................................................17
6. ANALYSES AND SUMMARIES ......................................................................................17
6.1. Primary Endpoint(s) ................................................................................................17
6.1.1. Change in DAS28-4 (ESR) Score from Randomization (at Week 24) 
to the End of Double-Blind MTX Withdrawal Phase (at Week 48)................17
6.1.1.1. Primary Analysis.......................................................................17
6.1.1.2. Sensitivity/Robustness Analyses...............................................18
6.2. Secondary Endpoint(s) and Other Endpoints in the Double-Blind Phase...............19
6.2.1. Change in the DAS28-4(ESR) from Week 24 to Week 36 ........................19
6.2.2. Changes in the DAS28-4 (CRP) from Week 24 to Week 48 and from 
Week 24 to Week 36........................................................................................19
6.2.3. Other Continuous Endpoints in the Double-Blind Phase ...........................20
6.2.4. LDA as assessed by DAS28-4(ESR) ≤ 3.2 at Weeks 48 and 36................21
6.2.5. Other Binary Endpoints in the Double-Blind Phase...................................21
6.2.6. ACR 20, 50, 70 at Weeks 48 and 36...........................................................21
6.3. Other Endpoint(s)....................................................................................................22
6.3.1. Changes in DAS28-4 (ESR) from Day 1 to Week 12 and from Day 1 
to Week 24.......................................................................................................22
6.3.2. Other Continuous Endpoints in Open-Label Run-in Phase........................22
6.3.3. LDA as assessed by DAS28-4(ESR) ≤ 3.2 at Weeks 12 and 24................23
6.3.4. Other Binary Endpoint in Open-Label Run-in Phase.................................23
6.3.5. ACR 20, 50, and 70 at Weeks 12 and 24....................................................23
6.4. Exploratory Endpoints.............................................................................................24
6.5. Subset Analyses.......................................................................................................24
6.6. Baseline and Other Summaries and Analyses.........................................................24
6.6.1. Baseline Summaries....................................................................................24
6.6.2. Study Conduct and Subject Disposition .....................................................24
6.6.3. Study Treatment Exposure .........................................................................24
6.6.4. Concomitant Medications and Non-Drug Treatments................................24


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
Page 4
6.7. Safety Summaries and Analyses .............................................................................25
6.7.1. Adverse Events...........................................................................................25
6.7.2. Laboratory Data..........................................................................................25
6.7.3. Vital Signs ..................................................................................................25
6.7.4. Physical Examination .................................................................................25
6.7.5. ECG ............................................................................................................25
25
8. REFERENCES ....................................................................................................................26
9. APPENDICES .....................................................................................................................27
LIST OF TABLES
Table 1. Summary of Major Changes in SAP Amendments .....................................................5
LIST OF FIGURES
Figure 1.
Study Design...........................................................................................................9
APPENDICES
Appendix 1. DATA DERIVATION DETAILS ......................................................................27
Appendix 1.1. Endpoints Definition and Derivation ...............................................................27
Appendix 1.2. Definition and Use of Visit Windows in Reporting.........................................28
CCI


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
Page 5
1. VERSION HISTORY
This  Statistical Analysis Plan (SAP) for study A3921192 is based on Protocol Amendment 2 
dated 04-Dec-2017.  
Table 1. Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1
Not Applicable
Not Applicable
2
a.
Section 7 was changed for analysis 
of openlabel phase
b. Window of open-label Week 24 
was changed as “Days 127 –
Discontinuation Day
/randomization (early one)”
Based on Protocol 
Adminstrative Change 
Letter 05-Jul-2017
3
a.
In Section 2.2, based on recent 
calculations, the number of subjects 
was increased from 580 to 680 for 
the open-label phase in order to 
achieve at least 232 subjects in the 
double-blind phase.
b. The LDA assessment was changed 
from DAS28-4(ESR) < 3.2 and 
DAS28-4(CRP) < 3.2 to 
DAS28-4(ESR) ≤3.2 and 
DAS28-4(CRP) ≤3.2, in Sections 
3.2, 3.3, 5.3.3, 6.2.4, 6.2.5, 6.3.3, 
6.3.4 and Appendix 1.1.
c.
Change in tender/painful joint 
counts, swollen joint counts, subject 
assessment of arthritis pain, subject 
global assessment of arthritis, 
physician global assessment of 
arthritis, and CRP were added as 
other efficacy endpoints in Sections 
3.3, 6.2.3 and 6.3.2.
d. Analysis for exploratory endpoint 
RAPID3 was added in Section 6.4.
e.
Baseline Disease Characteristics of 
Based on Protocol 
Amendment 2 04-Dec-
2017


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
Page 6
prior use of tsDMARD, baseline 
MTX dose, baseline steriod dose, 
ESR, CRP, tender joint counts, 
swollen joint counts, pain VAS, 
subject global assessment, 
physician global assessment, 
DAS28-4(ESR), DAS28-4(CRP), 
HAQ-DI, CDAI, and SDAI were 
added in Section 3.5.
f.
“Line plots of the LS means and 
95% CI ……” was changed to
“Line plots of the LS means (+/-
SE) ……” in Section 6.
g. “Line plots of the percentage and 
95% CI …..” was changed to “Line 
plots of the percentage (+/-
SE) ……” in Section 6.
h. Observed cases were added for 
analyses in Section 6.
i.
Summary of ECG was added in 
Section 6.7.5.
j.
Analysis window for Week 6 was 
added in Appendix 1.2.
k. Updated analysis window for 
Baseline in Appendix 1.2.
4
a.
Added details for MMRM when the 
model with unstructured covariance 
structure doesn’t converge in 
Section 5.2.2.
b. Added details for NRI in Section 
5.3.3 and Section 5.3.5.
c.
Removed “Canada” in the region 
definition in Section 6.5.
d. Added details for subgroup MMRM 
model in Section 6.5.
e.
Added details for windowing in 
To add analysis details 
based on BDR1 
discussions


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
Page 7
Appendix 1.2.
f.
Updated the window for 
Randomization in Appendix 1.2
g. Corrected typos in the document.
2. INTRODUCTION
The tofacitinib Immediate Release (IR) 5mg twice daily (BID) formulation has demonstrated 
efficacy both as a monotherapy and in combination with methotrexate (MTX) in previous 
trials.  However, it remains unknown whether the tofacitinib efficacy will be sustained after 
the withdrawal of MTX among RA patients who achieve low disease activity following 
treatment with MTX plus tofacitinib.  Results of the current study will inform the value of the 
continued MTX treatment among subjects who have responded to combined therapy of 
tofacitinib and MTX.  A modified release (MR) 11mg once daily (QD) regimen has the 
potential to offer an additional dosing option to subjects, and based on the equivalence of key 
pharmacokinetic parameters, efficacy and safety are expected to be consistent with that 
demonstrated for tofacitinib IR 5 mg BID.  Therefore, the current study will evaluate the 
sustained efficacy and safety of the tofacitinib MR 11 mg QD regimen among rheumatoid 
arthritis (RA) patients undergoing blinded withdrawal of MTX.
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study A3921192.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
2.1.1. Primary Objectives
To compare the efficacy of tofacitinib MR 11mg monotherapy to tofacitinib MR 11mg with
continued MTX, as measured by the change in the Disease Activity Score utilizing 4
components including erythrocyte sedimentation rate (DAS28-4 (ESR)) from randomization
(at Week 24) to the end of the double-blind MTX withdrawal phase (at Week 48).
2.1.2. Secondary Objectives

To compare the efficacy of tofacitinib MR 11mg monotherapy to tofacitinib MR 11mg 
with continued MTX in the double-blind MTX withdrawal phase (at Week 36), as 
measured by DAS28-4 (ESR).

To compare the efficacy of tofacitinib MR 11mg monotherapy to tofacitinib MR 11mg 
with continued MTX in the double-blind MTX withdrawal phase (at Weeks 48 and 
36), as measured by Disease Activity Score 28-4 (C reactive protein) (DAS28-4 
(CRP)), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index 
(SDAI), Low Disease Activity (LDA), remission, ACR20, ACR 50, and ACR 70.


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
Page 8

To compare effects of tofacitinib MR 11mg monotherapy to tofacitinib MR 11mg with 
continued MTX on health outcome measures in the double-blind MTX withdrawal 
phase (at Weeks 48 and 36), as measured by Health Assessment Disability 
Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Survey Short Form -36 
(SF-36), Work Productivity and Activity Impairment (WPAI), European Quality of 
Life 5 dimensions questionnaire (EuroQol EQ 5D), and Functional Assessment of 
Chronic Illness Therapy (FACIT)-Fatigue scale.

To evaluate the safety and tolerability of tofacitinib MR 11mg monotherapy versus 
tofacitinib MR 11mg with continued MTX.
2.1.3. Other Objectives

To describe efficacy of treatment with tofacitinib 11mg with MTX in the open-label 
run-in phase (at Weeks 12 and 24), as measured by DAS28-4 (ESR), DAS28-4 (CRP), 
CDAI, SDAI, LDA, remission, ACR20, ACR 50 and ACR70.

To describe effects of treatment with tofacitinib MR 11mg with MTX on health
outcome measures in the open-label run-in phase (at Weeks 12 and 24), as measured
by HAQ-DI, SF-36, WPAI, EuroQol EQ-5D, and FACIT-Fatigue scale.
2.1.4. Exploratory Objectives

To collect exploratory biomarker/genomics samples for bio-banking.

US and Canada ONLY: To explore effects of treatment with tofacitinib MR 11mg 
with/without MTX on health outcome measure in the open-label run-in phase (at 
Weeks 12 and 24) and the double-blind MTX withdrawal phase (at Weeks 48 and 36), 
as measured by Routine Assessment of Patient Index Data 3 (RAPID3).
2.2. Study Design
Study A3921192 is a 12-month randomized, double-blind, placebo-controlled withdrawal
study in a total of approximately 680 subjects with moderate to severe RA (defined as CDAI
>10 and DAS28 (ESR) ≥3.2) who are insufficiently responding to their stable dose of MTX
treatment. In addition, the proportion of subjects who have had an insufficient response to 
one or more biologics prior to the enrollment should be ≤ 25% (ie, ≤145 subjects). Following 
enrollment, all subjects will receive open-label tofacitinib MR 11mg QD added to MTX at 
their previously stabilized dose for 24 weeks (run-in phase). At the end of the run-in phase 
(Week 24), only subjects who achieve low disease activity (LDA) as assessed by CDAI (ie, 
CDAI ≤10) (approximately 232 subjects) will be randomized into the 24-week double-blind,
placebo-controlled MTX withdrawal phase. Subjects who do not achieve LDA (defined by
CDAI >10) at this time point will be discontinued from the study. Subjects entering the
double-blind phase will be randomized in a 1:1 ratio to either continue the run-in phase
treatment regimen (tofacitinib MR 11mg QD with blinded MTX) or to receive tofacitinib
monotherapy (tofacitinib MR 11mg QD with blinded matching placebo for MTX).
Randomization will be stratified by subject’s prior exposure to a biologic DMARD
(bDMARD). Randomized subjects will be followed up to the end of Week 48. The primary 


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
Page 9
efficacy endpoint is the change in DAS28-4 (ESR) from randomization (at Week 24) to the 
end of double-blind MTX withdrawal phase (at Week 48).
Figure 1.
Study Design
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Efficacy Endpoint(s)
Change in DAS28-4 (ESR) score from randomization (at Week 24) to the end of double-blind 
MTX withdrawal phase (at Week 48).
3.2. Secondary Efficacy Endpoint(s)

Change in the DAS28-4(ESR) from Week 24 to Week 36;

Changes in the DAS28-4 (CRP), CDAI and SDAI, respectively, from Week 24 to 
Week 48 and from Week 24 to Week 36; 

LDA as assessed by DAS28-4(ESR) 3.2, DAS28-4(CRP) 3.2, CDAI10 and 
SDAI11, respectively, at Weeks 48 and 36;

Remission as assessed by ACR-EULAR Boolean remission criteria,
DAS28-4 (ESR)<2.6, DAS28-4 (CRP)<2.6, CDAI≤2.8 and SDAI≤3.3, respectively, 
at Weeks 48 and 36;

ACR20, ACR 50, and ACR70 responses, respectively, at Weeks 48 and 36;


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
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
Change in the HAQ-DI, the SF-36 (8 domain scores and 2 component scores), WPAI, 
EuroQol EQ-5D and the FACIT-Fatigue scale score, respectively, from Week 24 to 
Week 48 and from Week 24 to Week 36;

HAQ-DI response (ie, decrease of at least 0.22) at Weeks 48 and 36.

Note: 

For subjects entering the double-blind phase, the value at randomization (Week 24) 
for each endpoint  is the last nonmissing observation before the first dose of study 
drug in double-blind phase.

The baseline (Day 1) value for each endpoint is the last nonmissing observation 
before the first dose of study drug in open-label run-in phase.

ACR20, ACR 50, ACR70, and HAQ-DI responses are relative to baseline (Day 1).
3.3. Other Efficacy Endpoints

Changes in DAS28-4 (ESR), DAS28-4 (CRP), CDAI, SDAI, HAQ-DI, SF-36 
(8 domain scores and 2 component scores), WPAI, EuroQol EQ-5D score and 
FACIT-Fatigue scale score, respectively, from day 1 to Week 12 and from Day 1 to 
Week 24;

LDA as assessed by DAS28-4(ESR) 3.2, DAS28-4(CRP) 3.2, CDAI10 and 
SDAI11, respectively, at Weeks 12 and 24;

Remission as assessed by ACR-EULAR Boolean remission criteria, 
DAS28-4 (ESR)<2.6, DAS28-4 (CRP)<2.6, CDAI≤2.8 and SDAI≤3.3, respectively, 
at Weeks 12 and 24;

ACR20, ACR 50, and ACR70 responses, respectively, at Weeks 12 and 24;

HAQ-DI response (ie, decrease of at least 0.22) at Weeks 12 and 24. 

Change in tender/painful joint counts, swollen joint counts, subject assessment of 
arthritis pain, subject global assessment of arthritis, physician global assessment of 
arthritis, and CRP, respectively, from Day 1 to Week 12 and from Day 1 to Week 24,
from Week 24 to Week 48 and from Week 24 to Week 36.
3.4. Exploratory Endpoints

US and Canada ONLY: RAPID3 summary scores at Weeks 12, 24, 36 and 48.
3.5. Baseline Variables
Demographic and baseline characteristics include: 

Age (in years);


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
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
Sex;

Race;

Region;

Height (in cms);

Weight (in kg);

Body Mass Index;

Duration of disease (in years);

Rheumatoid Factor (positive/negative);

Anti-cyclic citrullinated peptide (Anti-CCP) antibody (positive/negative);

Prior use of bDMARD (yes/no);

Prior use of TNFi (yes/no);

Prior use of MTX (yes/no);

Prior use of csDMARD (yes/no);

Prior use of tsDMARD (yes/no);

Prior use of corticosteroid (yes/no);

Baseline MTX dose;

Baseline Steroid Dose;

Disease activity (moderate or severe based on DAS28-4(ESR) at baseline);

DAS28-4(ESR);

DAS28-4(CRP);

ESR;

CRP;

Tender Joint Counts;

Swollen joint Counts;

Subject global assessment;

Physician global assessment;

Pain VAS;

HAQ-DI;

CDAI;

SDAI.


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Note: Prior use of bDMARD will be used in the mixed-effect model of repeated measures 
(MMRM) model as a covariate. It will be based on the CRF data.  
3.6. Safety Endpoints
3.6.1. Adverse Events

All adverse events (AEs), including serious adverse events (SAEs).

Adjudicated safety events
An AE is considered treatment emergent relative to a given treatment if:

the event occurs for the first time during the effective duration of treatment and was 
not seen prior to the start of treatment, or

the event was seen prior to the start of treatment but increased in severity during 
treatment.
The effective duration of treatment is determined by the lag time.  Any event occurring 
within 28 days, whether this occurs during a break in treatment or at the end of treatment, is
attributed to the corresponding treatment period.  
3.6.2. Laboratory Data

Clinically significant abnormal laboratory parameters.

Clinical laboratory values and change from baseline at Weeks 12 and 24.

Clinical laboratory values and change from baseline and randomization at Weeks 36 
and 48.
4. ANALYSIS SETS
4.1. Full Analysis Set
There are two full analysis sets, one is for open-label run-in phase and one is for double-blind
MTX withdrawal phase.

Open-Label Period Full Analysis Set (FAS-OL)
FAS-OL includes all subjects who received at least one dose of tofacitinib MR 11mg plus 
MTX during open-label phase.

Double-Blind Period Full Analysis Set (FAS-DB)
FAS-DB includes all subjects who received at least one dose of tofacitinib MR 11mg plus 
MTX during the open-label run-in phase, and were randomized and received at least one 
dose of the randomized investigational drug regimen (tofacitinib MR 11mg with MTX or
tofacitinib MR 11mg with placebo for MTX) during the blinded MTX withdrawal phase. 


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A randomized but not treated subject, or treated but not randomized subject during MTX 
withdrawal phase will be excluded from FAS-DB.    
A subjects who was randomized but took incorrect treatment during MTX withdrawal phase 
will be reported under the randomized treatment group for all efficacy analyses.
4.2. Per Protocol Analysis Set 
The Per Protocol Analysis Set (PPAS) will be a subset of subjects from FAS-DB. Subjects 
who had a protocol deviation during the blinded MTX withdrawal period thought to affect
the efficacy analysis will be excluded from the Per Protocol efficacy analysis. The PPAS will 
be defined for double-blind period only. Note that the protocol deviation may have occurred 
during open-label period. Protocol deviations will be assessed by the study team prior to 
unblinding the study. This list of subjects along with exclusions from per protocol analyses 
will be put into the trial master file.
4.3. Safety Analysis Set
There are three safety analysis sets, two for two study phases (open-label run-in phase and 
double-blind MTX withdrawal phase) and one for overall study period.

Open-Label Run-in Phase Safety Analysis Set (Safety-OL)
Safety-OL will include all subjects who received at least one dose of tofacitinib MR 11mg 
QD plus MTX during open-label run-in period. It is same as FAS-OL.

Double-Blind MTX Withdrawal Phase Safety Analysis Set (Safety-DB)
Safety-DB will include all subjects who received at least one dose of study drug (tofacitinib 
MR 11mg QD with blinded MTX or tofacitinib MR 11mg QD with blinded matching 
placebo for MTX) during double-blind MTX withdrawal phase.

Overall Study Safety Analysis Set (Safety-All)
Safety-All consists of all subjects who received at least one dose of study drug during the 
study.
4.4. Other Analysis Sets
N/A.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
The primary analysis will be a non-inferiority test to show that tofacitinib MR 11mg QD
monotherapy is not less effective (non-inferior) than tofacitinib MR 11mg QD with MTX 
within the margin of non-inferiority set at 0.6 (ie, the difference in mean change from 
randomization in DAS28-4 (ESR) between the two arms). If the upper bound of the 95% two-
sided confidence interval (CI) for the difference (tofacitinib monotherapy arm minus 
tofacitinib with MTX arm) in change from randomization to Week 48 in DAS 28-4 (ESR) 


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
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between the two arms is lower than 0.6, then tofacitinib monotherapy will be declared to be 
non-inferior to the tofacitinib with continued MTX treatment.
5.2. General Methods 
In general, number and percent will be presented for categorical 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 will be used to 
present the data. 
The data will be described and analyzed by study phase.
Note that the primary statistical hypotheses are based on data solely from blinded MTX 
withdrawal phase.  Analyses of endpoints during open-label run-in phase are intended to be 
descriptive in nature.
5.2.1. Analyses for Binary Data
Binary endpoints in the blinded MTX withdrawal phase will be analyzed using the normal 
approximation for the difference in binomial proportions. The estimated treatment difference, 
the associated 95% CI and p-value will be presented. 
Binary endpoints in the open-label run-in phase will be summarized using number,
percentage and 95% CI of percentage.
5.2.2. Analyses for Continuous Data
The primary endpoint of change from randomization in DAS28-4(ESR) at Week 48 will be 
analyzed using a linear mixed-effect model of repeated measures (MMRM) that includes the 
fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological 
DMARD, and baseline DAS28-4 (ESR) value as a covariate. Within-subject variability will 
be accounted for using a random effect with an unstructured covariance matrix. The least 
square (LS) mean of treatment, and LS mean difference and the associated 95% confidence 
interval (CI) will be presented.
If the model with an unstructured covariance matrix doesn’t converge or is unstable, 1st 
order autoregressive will be fitted instead. If the convergence problem persists, compound 
symmetry will be used.
Continuous secondary endpoints in the blinded MTX withdrawal phase will be analyzed 
using similar methods as the primary endpoint.
Continuous endpoints in the open-label run-in phase will be descriptively summarized using 
number, mean, standard deviation (standard error of the mean), minimum, 1st, 2nd and 3rd 
quartiles and maximum. 
5.2.3. Analyses for Categorical Data
Categorical endpoints will be summarized using number and percentage. 


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5.3. Methods to Manage Missing Data
For continuous endpoints, missing values will not be imputed for descriptive statistics.  For 
continuous endpoints in the blinded MTX withdrawal phase, the missing values post-
randomization will be handled in a linear mixed-effect model with repeated measures for this 
continuous variable, where the values are assumed to be missing at random.  
Multiple Imputation will be used for sensitivity analysis for DAS28-4(ESR) change from 
randomization (Week 24) in the double-blind phase. Imputed values will be sampled (or 
randomly drawn) from the normal distribution based on the observed mean and SD of non-
missing data by treatment and time point and the full analysis will be conducted on the 
‘filled-in’ (observed and imputed together) data multiple times (500 times). The final results 
will be presented as a summary of these multiple analyses.
In addition, missing values for safety endpoints will not be imputed.
5.3.1. Joint Counts

Tender joint count (TJC)
TJC is defined as the number of tender joints with abnormality. In case of missing 
joint assessment, the TJC will be prorated as follows:
28*(number of joints with tender score as “Present”)/(number of non-missing tender 
joints).  
Joints with a response of "Not Done” or “Not Applicable" will be handled as missing. 
If less than 20 joints have non-missing tender scores, then TJC will be defined as 
missing. 

Swollen joint count (SJC)
SJC is defined as the number of swollen joints with abnormality. In case of missing 
joint assessment, the SJC will be prorated as follows:
28*(number of joints with swollen score as “Present”)/(number of non-missing 
swollen joints).  
Joints with a response of "Not Done” or “Not Applicable" will be handled as missing. 
If less than 20 joints have non-missing swollen scores, then SJC will be defined as 
missing.
5.3.2. DAS28-4(ESR), DAS28-4(CRP), CDAI, SDAI
DAS28-4(ESR) is a derived variable from 4 components. If any component is missing, 
DAS28-4(ESR) will be missing.  
Above approach will also be used for DAS28-4(CRP), CDAI, SDAI.   


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5.3.3. LDA and Remission
The binary variables derived from the continuous endpoints (such as DAS28-4 (ESR)) will 
be imputed using Non-Responder Imputation (NRI)  method. Missing values due to a patient 
dropping from the study for any reason (eg, lack of efficacy or adverse event) will be handled 
by setting the the response value to nonresponsive from that visit onward. This also means 
that if a patient withdraws at a visit but had responsive values at that visit, the binary variable 
is still set to nonresponsive.   
NRI approach will be used to impute the missing data of LDA as assessed by:

DAS28-4(ESR) ≤3.2;

DAS28-4(CRP) ≤3.2;

CDAI10;

SDAI11.
and Remission as assessed by:

ACR-EULAR Boolean remission criteria;

DAS28-4 (ESR)<2.6;

DAS28-4 (CRP)<2.6;

CDAI≤2.8; and 

SDAI≤3.3.
For subjects who don’t enter the blinded MTX withdrawal phase, the imputation is only 
applied up to Week 24.
5.3.4. ACR20, ACR50, ACR70
Because the ACR20, ACR50, ACR70 variables are based on several component variables, it 
is possible that the values may still be calculated even if the component variables have some 
missing values. In this case, no imputation method is needed. If the ACR value is still 
missing, an imputation method will be applied.
If the ACR value is missing due to missing values in any of the components, while the 
patient 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 values of ACR20, ACR50 and ACR70 will be determined.
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.


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After the LOCF imputation has been applied, missing values due to a patient dropping from 
the study for any reason (eg, lack of efficacy or adverse event) will be handled by setting the 
ACR value (ACR20, ACR50 and ACR70) to nonresponsive from that visit onward. This also 
means that if a patient withdraws at a visit but had responsive ACR values at that visit, the 
ACR value is still set to nonresponsive. This method also goes by the name Non-Responder 
Imputation, NRI. 
It is also the case that LOCF method does not carry forward any baseline values, as a 
convention. That is, a value carried forward must be a post-baseline value. If there are no 
post-baseline values that are non missing, the component remains missing.
Regardless of any imputation or none, if for some reason the ACR value still can’t be 
determined, including the case where baseline data is missing, then its value will be set to 
non-responder.
For subjects who don’t enter the blinded MTX withdrawal phase, the imputation is only 
applied up to Week 24. 
5.3.5. Patient Reported Outcomes
For the HAQ-DI, SF-36, WPAI, EuroQol EQ-5D and the FACIT-Fatigue, rules suggested by 
the producers of these will be followed in calculating the values. If these rules are not enough 
for imputing a value, then the value is missing.
NRI approach (see Section 5.3.3) will be used to impute the missing data of HAQ-DI 
response (ie, decrease of at least 0.22). 
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Change in DAS28-4 (ESR) Score from Randomization (at Week 24) to the End of 
Double-Blind MTX Withdrawal Phase (at Week 48)
6.1.1.1. Primary Analysis

Analysis time points: Week 48

Analysis population: FAS-DB

Analysis methodology: Change from randomization (at Week 24) will be analyzed 
using the MMRM (specified in Section 5.2.2).  

Covariate: Baseline of DAS28-4(ESR) and prior use of a bDMARD.

Imputation for missing values: Observed data will be included in the MMRM model, 
the missing values will be handled in the model, where the values are assumed to be 
missing at random.

Supporting objective and Decision rule: Primary Objective, upper bound of 95% CI 
of treatment difference < 0.6.


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Reporting results:

Raw data:  The sample size, mean, standard deviation, median, minimum and 
maximum at randomization (Week 24) and post-randomization visits will be 
presented for each treatment arm.

Change from randomization: The sample size, mean, standard deviation, median, 
minimum and maximum will be presented for each treatment arm. The LS means, 
95% confidence interval for the LS means, difference between the LS means between
treatment groups and the corresponding 95% CI, p-value will be presented.  
Figures

Line plots of the LS means (+/-SE) at Weeks 48 and 36 for two treatment groups.

Plot of 95% CI of the LS mean difference between treatment groups at Weeks 48 and 
36.
6.1.1.2. Sensitivity/Robustness Analyses
To support the interpretation of the primary analysis the following analyses will be 
performed:  
6.1.1.2.1. Analysis for PPAS

Dependent Variable: Change in the DAS28-4(ESR) from Week 24 to Week 48

Analysis time points: Week 48 

Analysis population: PPAS 

Analysis methodology: Change from Week 24 will be analyzed using the MMRM 
(specified in Section 5.2.2).  

Covariate: Baseline of DAS28-4(ESR) and prior use of a bDMARD.

Imputation for missing values: Observed data will be included in the MMRM model, 
the missing values will be handled in the model, where the values are assumed to be 
missing at random. 

Supporting objective and Decision rule: Primary Objective, upper bound of 95% CI 
of treatment difference <0.6.
Reporting results:

Raw data: The sample size, mean, standard deviation, median, minimum and 
maximum at randomization (Week 24) and post-randomization visits will be 
presented for each treatment arm.


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
Change from randomization: The sample size, mean, standard deviation, median, 
minimum and maximum will be presented for each treatment arm. The LS means, 
95% confidence interval for the LS means, difference between the LS means between 
treatment groups, the corresponding 95% CI and p-value will be presented.  
Figures

Line plots of the LS means (+/-SE) at Weeks 48 and 36 for two treatment groups.

Plot of 95% CI of the LS mean difference between treatment groups at Weeks 48 and 
36.
6.1.1.2.2. Multiple Imputations  

Dependence Variable: Change in the DAS28-4(ESR) from Week 24 to Week 48

Analysis population: FAS-DB

Analysis time point: Week 48

Analysis methodology: Change from Week 24 will be analyzed using the MMRM 
(specified in Section 5.2.2).  

Covariate: Baseline of DAS28-4(ESR) and prior use of a biological DMARD

Imputation for missing values: multiple imputation (see Section 5.3).
Reporting results:

Change from Week 24: The LS means, 95% confidence interval for the LS means, 
difference between the LS means between treatment groups and the corresponding 
95% CI will be presented.

Plot of 95% CI of the LS mean difference between treatment groups at Weeks 48 and 
36.
6.2. Secondary Endpoint(s) and Other Endpoints in the Double-Blind Phase
6.2.1. Change in the DAS28-4(ESR) from Week 24 to Week 36
All analyses performed for Week 48 will be performed for Week 36. See Section 6.1.1.
6.2.2. Changes in the DAS28-4 (CRP) from Week 24 to Week 48 and from Week 24 to 
Week 36

Analysis time points: Week 48 and Week 36 

Analysis population: FAS-DB 

Analysis methodology: Change from Week 24 will be analyzed using the MMRM 
(specified in Section 5.2.2).  

Covariate: Baseline of DAS28-4(CRP) and prior use of a bDMARD


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
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
Imputation for missing values: observed data will be included in the MMRM model, 
the missing values will be handled in the model, where the values are assumed to be 
missing at random. 
Reporting results:

Raw data: The sample size, mean, standard deviation, median, minimum and 
maximum at randomization (Week 24) and post-randomization visits will be 
presented for each treatment arm.

Change from Week 24: The sample size, mean, standard deviation, median, minimum 
and maximum will be presented for each treatment arm. The LS means, 95% 
confidence interval for the LS means, difference between the LS means between 
treatment groups, the corresponding 95% CI and p-value will be presented.
Figures

Line plots of the LS means (+/-SE) at Weeks 48 and 36 for two treatment groups.

Plot of 95% CI of the LS mean difference between treatment groups at Weeks 48 and 
36.
6.2.3. Other Continuous Endpoints in the Double-Blind Phase
The same analysis in Section 6.2.2 will be performed for changes from Week 24 to Week 48 
and from Week 24 to Week 36 in the:

CDAI;

SDAI;

Tender/painful joint counts;

Swollen joint counts;

Subject assessment of arthritis pain VAS;

Subject global assessment of arthritis;

Physician global assessment of arthritis;

CRP;

HAQ-DI;

SF-36 (8 domain scores and 2 component scores);

WPAI;

EuroQol EQ-5D;

FACIT-Fatigue scale score;


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
RAPID3 (US and Canada ONLY).
6.2.4. LDA as assessed by DAS28-4(ESR) ≤3.2 at Weeks 48 and 36

Analysis time points: Week 48 and Week 36;

Analysis population: FAS-DB;

Analysis methodology: normal approximation (specified in Section 5.2.1);  

Imputation for missing values: NRI (Section 5.3.3), observed cases.
Reporting results:

The sample size, frequency and percentage of responders at post-randomization visits 
will be presented for each treatment arm difference between treatment groups and the 
corresponding 95% CI and p-value will be presented.
Figures

Line plots of the percentage (+/-SE) at Weeks 48 and 36 for two treatment groups.
6.2.5. Other Binary Endpoints in the Double-Blind Phase
The same analysis in Section 6.2.4 will be performed at Weeks 48 and 36 for 

LDA as assessed by DAS28-4(CRP) ≤3.2;

LDA as assessed CDAI10;

LDA as assessed SDAI11;

Remission as assessed by ACR-EULAR Boolean remission criteria;

Remission as assessed by DAS28-4 (ESR)<2.6;

Remission as assessed by DAS28-4 (CRP)<2.6;

Remission as assessed by CDAI≤2.8;

Remission as assessed by SDAI≤3.3;

HAQ-DI response (ie, decrease of at least 0.22).
6.2.6. ACR 20, 50, 70 at Weeks 48 and 36

Analysis time points: Week 48 and Week 36;

Analysis population: FAS-DB;

Analysis methodology: normal approximation (specified in Section 5.2.1);  

Imputation for missing values: NRI (Section 5.3.4), observed cases


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Reporting results:

The sample size, frequency and percentage of responders at post-randomization visits 
will be presented for each treatment arm difference between treatment groups and the
corresponding 95% CI and p-value will be presented.
Figures

Line plots of the percentage (+/-SE) at Weeks 48 and 36 for two treatment groups.
6.3. Other Endpoint(s)
6.3.1. Changes in DAS28-4 (ESR) from Day 1 to Week 12 and from Day 1 to Week 24

Analysis time points: Week 12 and Week 24 

Analysis population: FAS-OL 

Analysis methodology: descriptive summary.  

Imputation for missing values: no imputation.
Reporting results:

Raw data: The sample size, mean, standard deviation, median, minimum and 
maximum at baseline will be presented.

Change from Day 1: The sample size, mean, standard deviation, median, minimum 
and maximum will be presented.
6.3.2. Other Continuous Endpoints in Open-Label Run-in Phase
The same analysis in Section 6.3.1 will be performed for changes from Day 1 to Week 12 
and from Day 1 to Week 24 in the

DAS28-4 (CRP);

CDAI;

SDAI;

Tender/painful joint counts;

Swollen joint counts;

Subject assessment of arthritis pain VAS;

Subject global assessment of arthritis;

Physician global assessment of arthritis;

CRP;

HAQ-DI;


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
SF-36 (8 domain scores and 2 component scores);

WPAI;

EuroQol EQ-5D;

FACIT-Fatigue scale score;

RAPID3 (US ONLY).
6.3.3. LDA as assessed by DAS28-4(ESR) ≤3.2 at Weeks 12 and 24

Analysis time points: Week 12 and Week 24;

Analysis population: FAS-OL;

Analysis methodology: descriptive summary;  

Imputation for missing values: NRI (Section 5.3.3), observed cases. 
Reporting results:

The sample size, frequency, percentage of responders, and 95% CI of percentage will 
be presented.
6.3.4. Other Binary Endpoint in Open-Label Run-in Phase
The same analysis in Section 6.3.3 will be performed at Weeks 12 and 24 for 

LDA as assessed by DAS28-4(CRP) ≤3.2 

LDA as assessed CDAI10 

LDA as assessed SDAI11 

Remission as assessed by ACR-EULAR Boolean remission criteria 

Remission as assessed by DAS28-4 (ESR)<2.6 

Remission as assessed by DAS28-4 (CRP)<2.6 

Remission as assessed by CDAI≤2.8 

Remission as assessed by SDAI≤3.3

HAQ-DI response (ie, decrease of at least 0.22)
6.3.5. ACR 20, 50, and 70 at Weeks 12 and 24

Analysis time points:  Week 12 and Week 24 

Analysis population:  FAS-OL 

Analysis methodology:  descriptive summary.  


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
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
Imputation for missing values: NRI (Section 5.3.4). 
Reporting results:

The sample size, frequency, percentage of responders and 95% CI of percentage will 
be presented.
6.4. Exploratory Endpoints
See Section 6.2.3 and Section 6.3.2 for the analysis of exploratory endpoint RAPID3.
6.5. Subset Analyses 
To check the consistency of the primary endpoint across subgroups, change from 
randomization at Week 48 and Week 36 will be analyzedfor below subgroups:

Age group: 18-45, 46-64, ≥65;

Geographic region: US, Europe, Latin America, Rest of the World;

Race: White, Black, Asian, Other;

Prior bDMARD: Yes, No;

Disease severity: Moderate (DAS28-4 (ESR) ≥ 3.2 and ≤5.1), Severe (DAS28-4 
(ESR) >5.1).
Each subgroup factor along with its 2-way and 3-way interactions with treatment group and 
visit will be added to the MMRM model without imputation for missing data described in 
Section 5.2.2, and outputs from this augmented model will be used for comparisons within 
each subgroup.
6.6. Baseline and Other Summaries and Analyses
6.6.1. Baseline Summaries
Demographic and baseline characteristics will be summarized for FAS-OL and FAS-DB 
according to Pfizer data standards.
6.6.2. Study Conduct and Subject Disposition
Subjects evaluation, disposition, discontinuation will be summarized for FAS-OL and FAS-
DB according to Pfizer data standards.
6.6.3. Study Treatment Exposure
Treatment duration and number of subjects by treatment duration category will be 
summarized for FAS-OL and FAS-DB according Pfizer data standards.
6.6.4. Concomitant Medications and Non-Drug Treatments
Prior drug and non-drug treatment for RA, concomitant drug and non-drug treatment for RA 
for FAS-OL and FAS-DB according to Pfizer data standards.


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6.7. Safety Summaries and Analyses
6.7.1. Adverse Events
Adverse events will be summarized according to Pfizer data standards for each phase. 

TEAEs;

Serious AEs;

Serious infections;

Adjudicated events.
AEs will not be double counted across phases.  Counting of AEs will be based on start date 
of AE.  If the start date of an AE is in the open-label phase, the end date of the AE in the 
double-blind phase and severity of AE remained the same or became lower in both phases, 
then the AE will be counted in open-label phase, not in the double-blind phase. However, if 
the same AE started in the open-label phase, and get worse in severity in the double-blind 
phase, then the AE will be counted in both phases. 
In all these analyses attention will be restricted to assessments that occurred no more than 28 
calendar days after the last dose of study drug.
6.7.2. Laboratory Data
Safety laboratory data will be summarized according to Pfizer standards for each phase.
6.7.3. Vital Signs
Descriptive summary tables will be provided in accordance with Pfizer reporting standards
for each phase.
6.7.4. Physical Examination
Descriptive summary tables will be provided in accordance with Pfizer reporting standards
for each phase.
6.7.5. ECG
ECG data at screening and Week 48/end of study, change from screening to Week 48/end of 
study, number (%) of subjects with any clinically significant changes will will be 
descriptively summarized by treatment group in double-blind phase and for FAS-DB.
 
 
 
 
  
CCI


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
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8. REFERENCES 
1.
Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American
College of Rheumatology/European League Against Rheumatism provisional definition 
of remission in rheumatoid arthritis for clinical trials. Arthritis and rheumatism. 
2011;63(3):573-86. Epub 2011/02/05.
2.
Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the health 
assessment questionnaire, disability and pain scales. The Journal of rheumatology. 
1982;9(5):789-93. Epub 1982/09/01.
3.
Ware JE KM, 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.
4.
Hurst NP, Kind P, Ruta D, Hunter M, Stubbings A. Measuring health-related quality of 
life in rheumatoid arthritis: validity, responsiveness and reliability of EuroQol (EQ-5D). 
British journal of rheumatology. 1997;36(5):551-9. Epub 1997/05/01.
5.
Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work 
productivity and activity impairment measure. PharmacoEconomics 1993; 4(5):353-
365.
6.
Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in cancer patients compared 
with fatigue in the general United States population. Cancer. 2002;94(2):528-38. Epub 
2002/03/20.
7.
Pincus T, Yazici Y, Bergman MJ. RAPID3, an index to assess and monitor patients 
with rheumatoid arthritis, without formal joint counts: similar results to DAS28 and 
CDAI in clinical trials and clinical care. Rheum Dis Clin North Am. 2009 
Nov;35(4):773-8.


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
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9. APPENDICES 
Appendix 1. DATA DERIVATION DETAILS
Appendix 1.1. Endpoints Definition and Derivation
Endpoint
Defination/Calculation
DAS28-4 (CRP)
0.56*√(TJC28) + 0.28*√(SJC28) + 0.36*ln(CRP in mg/l +1) + 
0.014*PtGA in mm+ 0.96
DAS28-4 (ESR)
0.56*√(TJC28) + 0.28*√(SJC28) + 0.70*In(ESR in mm/ hour) + 
0.014*PtGA in mm
SDAI
(28TJC) + (28SJC) + [PhyGA in cm] + [PtGA in cm] + [CRP in 
mg/dL]
CDAI
(28TJC) + (28SJC) + [PhyGA in cm] + [PtGA in cm]
ACR20/50/70 responder
ACR20: at least 20% improvement in tender and swollen joint 
counts and at least 20% improvement in at least 3 of the 5 
remaining ACR-core set measures: subject and physician global 
assessments, pain, HAQ-DI, and CRP. Similarly, ACR50 and 70 
are calculated with the respective percent improvements.
ACR/EULAR Boolean-based 
definition of remission
all of the following satisfied: TJC ≤ 1, SJC ≤ 1, CRP ≤ 1 mg/dL, 
PtGA ≤ 1 on a 0-10 scale
LDA of DAS28-4 (CRP)
DAS28-4 (CRP) ≤3.2
LDA of DAS28-4 (ESR)
DAS28-4 (ESR) ≤3.2
LDA of SDAI
SDAI ≤ 11
LDA of CDAI
CDAI ≤ 10
Remission of DAS28-4 (CRP)
DAS28-4 (CRP) < 2.6
Remission of DAS28-4 (ESR)
DAS28-4 (ESR) < 2.6
Remission of SDAI
SDAI ≤ 3.3
Remission of CDAI
CDAI ≤ 2.8
HAQ-DI responder
Decrease ≥ 0.22
RAPID3
(HAQ * 3.33 + pain VAS in mm/10 + PtGA in mm/10)/3.
TJC = tender joint count; SJC = swollen joint count; CRP = C-reactive protein in mg/L; ESR = erythrocyte 
sedimentation rate in mm/first hour, PtGA = subject’s global assessment of health; PhyGA = physician’s global 
assessment of health, HAQ-DI = Health Assessment Disability Questionnaire-Disability Index; LDA = Low 
Disease Activity. RAPID3 = Routine Assessment of Patient Index Data 3.


Protocol A3921192 (CP-690,550) Statistical Analysis Plan
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Appendix 1.2. Definition and Use of Visit Windows in Reporting
Visit windows will be used for efficacy variables, and for any safety displays that display by 
week. 
If more than one observation from the same subject falls into the same visit window, the 
value closest to the targeted day will be used as the observation for that week. If two visits 
are equal distant from the Targeted Day in absolute value, the later visit should be used. All 
observations will, however, be included in the listings.
For endpoints derived from multiple components, eg, DAS28-4(ESR), each component will 
be windowed to select the value for analysis at a specific visit, and the value of the endpoint 
will then be derived. This means the component values may be from different visit dates that 
fall within the analysis window.
Subjects’ observations will be excluded from visit windows if the data was collected more 
than 7 days off study drug. (Safety analysis may follow Pfizer standard.)
Visit Label
Targeted Day
Analysis window for data sets
Open-Label Run-In Phase
Baseline
Day 1
Last Observation up to and 
including First Dosing Date
(no earlier than Day -90)    
Week 6
Day 42
Days 2 – 63
Week 12
Day 84
If there is Week 6 visit such as 
lab tests: Days 64 – 126; 
If no Week 6 visit: Days 2 –
126
Week 24
Day 168
Day 127 – Discontinuation Day
/Randomization Day (the 
earlier one)
Double-Blind Phase
Randomization (Week 24) Randomization Day
Last Observation up to 
and including First 
Dosing Date in 
Double-Blind Phase
(no earlier than Day 
127)
Week 36
Randomization Day + 84
Randomization Day + 1 –
Randomization Day + 126
Week 48
Randomization Day + 168 Randomization Day + 127 –