Clinical trial NCT02969044
Conditions: Rheumatoid Arthritis
Sponsor: Pfizer
Start date: 2016-12-20; Completion date: 2017-12-12
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an 8 week study to assess the efficacy and safety profile of PF-06651600 in seropositive subjects with rheumatoid arthritis with an inadequate response to methotrexate (up to approximately 50% of subjects may also have had an inadequate response to 1 anti-TNF biologic).

Detailed description:

Arms: arm 1: Study Drug arm 2: Placebo
Interventions: intervention 1: Placebo intervention 2: PF-06651600
Intervention descriptions: intervention 1: None intervention 2: 200mg pill every day (QD) for 8 weeks

Protocol documents:
Prot_000.pdf: 
PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 1
A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP,
PLACEBO-CONTROLLED, MULTI-CENTER STUDY TO ASSESS THE 
EFFICACY AND SAFETY PROFILE OF PF-06651600 IN SUBJECTS WITH 
MODERATE TO SEVERE ACTIVE RHEUMATOID ARTHRITIS WITH AN 
INADEQUATE RESPONSE TO METHOTREXATE
Investigational Product Number:
PF-06651600
Investigational Product Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
131274
European Clinical Trials Database 
(EudraCT) Number:
2016-002862-30
Protocol Number:
B7981006
Phase:
2a
 
 
 


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Final Protocol Amendment 1, 26 October 2016
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
26 October 2016
In the Schedule of Activities, and 
Section 7.2.12, added audiogram testing

Rationale: To monitor for potential 
changes in hearing between baseline 
[between Visit 1 and Visit 2 
(inclusive)] and at the end of the study 
[between Visit 7 and Visit 9 
(inclusive)].
The following exclusion criteria has been 
added in Section 4.2:
Have current or recent history of clinically 
significant severe or progressive hearing loss 
or auditory disease. Subjects with hearing 
aids will be allowed to enter the study 
provided their hearing impairment is 
considered controlled/ clinically stable. 

Rationale:  This has been added to 
ensure that subject hearing for safety 
is fully evaluated prior to study entry.
Several additional minor changes were made 
to protocol language for the purposes of 
clarification.
Original protocol
31 August 2016 
Not applicable (N/A)
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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Final Protocol Amendment 1, 26 October 2016
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................8
APPENDICES ...........................................................................................................................8
PROTOCOL SUMMARY.........................................................................................................9
SCHEDULE OF ACTIVITIES................................................................................................13
1. INTRODUCTION ...............................................................................................................18
1.1. Mechanism of Action/Indication.............................................................................19
1.2. Background and Rationale ......................................................................................19
1.3. Non-Clinical Pharmacokinetics, Metabolism of PF-06651600 ..............................19
1.4. Non-Clinical Safety Studies with PF-06651600.....................................................20
1.5. Summary of Clinical Experience with PF-06651600 .............................................21
1.5.1. Summary of Clinical Safety of PF-06651600 ............................................22
1.5.2. Pharmacokinetics of PF-06651600.............................................................23
1.6. Summary .................................................................................................................25
1.6.1. Study Rationale...........................................................................................25
1.6.2. Dose Rationale............................................................................................25
1.6.3. Summary of Benefits and Risks .................................................................27
1.6.4. Additional Information ...............................................................................27
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................27
3. STUDY DESIGN.................................................................................................................29
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................30
4.1. Inclusion Criteria.....................................................................................................30
4.2. Exclusion Criteria....................................................................................................32
4.3. Lifestyle Requirements ...........................................................................................36
4.3.1. Contraception..............................................................................................36
4.4. Sponsor’s Qualified Medical Personnel..................................................................37
5. STUDY TREATMENTS.....................................................................................................38
5.1. Allocation to Treatment ..........................................................................................38
5.2. Breaking the Blind ..................................................................................................39
5.3. Subject Compliance.................................................................................................39
5.4. Investigational Product Supplies.............................................................................39


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5.4.1. Dosage Form(s) and Packaging..................................................................39
5.4.2. Preparation and Dispensing........................................................................40
5.5. Administration.........................................................................................................40
5.6. Investigational Product Storage ..............................................................................41
5.7. Investigational Product Accountability...................................................................41
5.7.1. Destruction of Investigational Product Supplies ........................................42
5.8. Background and Concomitant Treatment(s) ...........................................................42
5.8.1. Permitted Background Arthritis Therapy ...................................................42
5.8.2. Prohibited Background Arthritis Therapy ..................................................43
5.9. Rescue Medication ..................................................................................................46
6. STUDY PROCEDURES .....................................................................................................46
6.1. Screening.................................................................................................................47
6.2. Treatment Period.....................................................................................................47
6.3. Follow-up/End of Study..........................................................................................47
6.4. Subject Withdrawal/Early Withdrawal ...................................................................47
6.4.1. Withdrawal of Consent...............................................................................47
6.4.2. Lost to Follow-up .......................................................................................48
7. ASSESSMENTS..................................................................................................................48
7.1. Efficacy Assessments..............................................................................................48
7.1.1. American College of Rheumatology (ACR) Assessments.........................48
7.1.2. Tender/Painful Joint Count (68).................................................................49
7.1.3. Swollen Joint Count (66)............................................................................49
7.1.3.1. Tender and Swollen Joint Counts (28)......................................50
7.1.4. Patient’s Assessment of Arthritis Pain (PAAP)..........................................50
7.1.4.1. Patient’s Global Assessment (PtGA) of Arthritis .....................50
7.1.4.2. Physician’s Global Assessment (PhGA) of Arthritis ................50
7.1.4.3. High Sensitivity C-Reactive Protein (CRP)..............................50
7.1.4.4. Erythrocyte Sedimentation Rate (ESR).....................................51
7.1.4.5. Health Assessment Questionnaire – Disability Index 
(HAQ-DI) ..........................................................................................51
7.1.5. Composite Efficacy Assessments Derived from the ACR Core 
Dataset..............................................................................................................51
7.1.5.1. Simple Disease Activity Index (SDAI) Assessment.................51


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7.1.5.2. ACR Responder Analysis..........................................................51
7.1.6. Disease Activity Score (DAS) Assessments...............................................51
7.2. Safety and other Assessments .................................................................................52
7.2.1. Clinical Safety and Other Laboratory Tests ...............................................52
7.2.2. Physical Examination .................................................................................53
7.2.3. Medical History, Height and Weight..........................................................53
7.2.4. Pregnancy Testing ......................................................................................54
7.2.5. Vital Signs (Blood Pressure, Pulse Rate and Temperature) .......................54
7.2.6. Electrocardiogram.......................................................................................55
7.2.7. Interferon-Gamma Release Assay..............................................................55
7.2.8. Chest X-Ray................................................................................................55
7.2.9. Infection Monitoring...................................................................................56
7.2.10. Viral Surveillance.....................................................................................56
7.2.11. Dermatological Assessments....................................................................57
7.2.12. Audiogram ................................................................................................58
7.3. Pharmacokinetics ....................................................................................................59
7.3.1. Shipment of Pharmacokinetic Samples ......................................................59
7.4. Exploratory Biomarkers ..........................................................................................59
7.4.1. IFN-gamma-inducible protein 10 (IP-10)...................................................59
7.4.2. Anti-CCP and Rheumatoid Factor..............................................................59
7.4.3. Samples for Exploratory Fluorescence Activated Cell Sorting 
(FACS) analysis...............................................................................................59
7.5. Banked Biospecimens .............................................................................................60
7.5.1. Shipment of Biomarkers Samples ..............................................................61
7.5.2. Additional Research....................................................................................61
7.6. Rater Qualifications.................................................................................................61
8. ADVERSE EVENT REPORTING......................................................................................62
8.1. Requirements...........................................................................................................62
8.1.1. Additional Details on Recording Adverse Events on the CRF...................63
8.1.2. Eliciting Adverse Event Information..........................................................63
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal/Early Withdrawal section) ..............................................63
8.1.4. Time Period for Collecting AE/SAE Information......................................63


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8.1.4.1. Reporting SAEs to Pfizer Safety...............................................64
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................64
8.1.5. Causality Assessment .................................................................................64
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................64
8.2. Definitions...............................................................................................................65
8.2.1. Adverse Events...........................................................................................65
8.2.2. Abnormal Test Findings .............................................................................65
8.2.3. Serious Adverse Events ..............................................................................66
8.2.4. Hospitalization............................................................................................66
8.3. Severity Assessment................................................................................................68
8.4. Special Situations ....................................................................................................68
8.4.1. Protocol-Specified Serious Adverse Events...............................................68
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................68
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................70
8.4.3.1. Exposure During Pregnancy......................................................70
8.4.3.2. Exposure During Breastfeeding ................................................71
8.4.3.3. Occupational Exposure .............................................................71
8.4.4. Medication Errors .......................................................................................72
8.4.4.1. Medication Errors......................................................................72
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................72
9.1. Sample Size Determination.....................................................................................73
9.2. Efficacy Analysis ....................................................................................................73
9.2.1. Analysis of the Primary Endpoint...............................................................73
9.2.2. Analysis of Secondary Endpoints...............................................................74
9.3. Analysis of Other Endpoints ...................................................................................74
9.4. Randomization ........................................................................................................74
9.5. Safety Analysis........................................................................................................74
9.6. Data Monitoring Committee ...................................................................................74
9.7. PK/PD Unblinding Plan ..........................................................................................74
9.8. Unblinding for Biomarkers .....................................................................................75
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................75


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11. DATA HANDLING AND RECORD KEEPING .............................................................76
11.1. Case Report Forms/Electronic Data Record .........................................................76
11.2. Record Retention...................................................................................................76
12. ETHICS..............................................................................................................................77
12.1. Institutional Review Board/Ethics Committee......................................................77
12.2. Ethical Conduct of the Study ................................................................................77
12.3. Subject Information and Consent..........................................................................77
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................78
13. DEFINITION OF END OF TRIAL...................................................................................78
13.1. End of Trial in a Member State.............................................................................78
13.2. End of Trial in All Other Participating Countries.................................................79
14. SPONSOR DISCONTINUATION CRITERIA ................................................................79
15. PUBLICATION OF STUDY RESULTS..........................................................................79
15.1. Communication of Results by Pfizer ....................................................................79
15.2. Publications by Investigators ................................................................................80
16. REFERENCES ..................................................................................................................81
LIST OF TABLES
Table 1.
Skin and Subcutaneous Tissue Disorder Occurrence ...........................................22
Table 2.
Summary of Plasma PF-06651600 Pharmacokinetic Parameters Following 
Single Oral Doses, Study B7981001 ....................................................................23
Table 3.
Summary of Plasma and Urine PF-06651600 Pharmacokinetic Parameters 
Following Multiple Dose Administration for 14 days, Study B7981001.............24
Table 4.
Summary of Predicted Steady State Plasma Pharmacokinetic and 
Pharmacodynamic Parameters Following Multiple Dose Administration of 
PF-06651600.........................................................................................................26
Table 5.
Summary of the Predicted Average Percent In Vitro Signaling Inhibition 
Based on Steady State PK from 200 mg PF-06651600........................................26
Table 6.
Safety and other Laboratory Tests........................................................................52
Table 7.
Management of Dermatological Events ...............................................................57


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B7981006
Final Protocol Amendment 1, 26 October 2016
Page 8
LIST OF FIGURES
Figure 1.
Study Design Schematic.......................................................................................29
APPENDICES
Appendix 1. Abbreviations......................................................................................................84
Appendix 2. 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis24,25..........87
Appendix 3. Criteria for Classification of Functional Status in Rheumatoid Arthritis26.........89
Appendix 4. Prohibited Concomitant Medications..................................................................90
Appendix 5. Guidelines for Monitoring and Discontinuations................................................92
Appendix 6. Disease Activity Score (DAS) Assessments1......................................................94
Appendix 7. Patient’s Assessment of Arthritis Pain (PAAP)..................................................95
Appendix 8. Patient’s Global Assessment (PtGA) of Arthritis ...............................................96
Appendix 9. Physician’s Global Assessment (PhGA) of Arthritis..........................................97
Appendix 10. Oral Corticosteroid Equivalents28,29,30,31,32........................................................98
Appendix 11. Allowed Opioids and Approximate Equivalent Morphine Doses Of 
Opioid Analgesics33,34...........................................................................................99
Appendix 12. Common Terminology Criteria for Adverse Events v4.03 
(CTCAE)-Dermatology......................................................................................100
Appendix 13. HAQ-DI35........................................................................................................102
Appendix 14. Assessment of Itch (NRS)36 ............................................................................105


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Final Protocol Amendment 1, 26 October 2016
Page 9
PROTOCOL SUMMARY
Background and Rationale:
PF-06651600 is a potent, Janus kinase (JAK) 3 selective, covalent inhibitor.  It is an orally 
bioavailable small molecule that selectively inhibits JAK3 by irreversibly blocking the 
adenosine triphosphate (ATP) binding site without significantly inhibiting the other three 
JAK isoforms (JAK1, JAK2, and TYK2).  The molecule also has a high specificity against 
the broad human kinome. 
This JAK3-selective inhibition will lead to modulation of -common chain cytokine 
pathways, such as IL-7, IL-9, IL-15 and IL-21, some of which have been implicated in the 
pathophysiology of Rheumatoid Arthritis (RA).  PF-06651600 will spare inhibition of key
immuno-regulatory cytokines, such as IL-10, IL-35 which play a protective role in RA.  
Inhibition of JAK2 cytokine signaling, implicated to be associated with adverse effects such 
as neutropenia, thrombocytopenia and anemia14 will also be spared, thus making 
JAK3-selective inhibitors an attractive therapeutic modality. JAK3 is also expressed only in 
the hematopoietic cells and thus the rationale for improved therapeutic index of PF-06651600 
in RA over pan-JAK inhibition.  This multicenter, placebo controlled study will be the first 
determination of safety and efficacy of PF-06651600 in subjects with moderate to severe 
active RA who have had an inadequate response to methotrexate (up to approximately 50% 
of subjects may also have had an inadequate response to 1 anti-TNFbiologic DMARD). 
Objectives and Endpoints:
Primary Objectives:
Primary Endpoints:

To evaluate the efficacy of PF-06651600 
at 8 weeks in subjects with moderate to 
severe active RA.

Change from baseline in Simple Disease Activity
Index (SDAI) at Week 8.
Secondary Objectives:
Secondary Endpoints:

To evaluate the safety of PF-06651600.

Safety and tolerability of PF-06651600 versus 
placebo; vital signs, laboratory tests, adverse events 
(AEs) including infections and Serious Adverse 
Events (SAEs).

To assess other signs of clinical efficacy 
over 8 weeks.

Change from baseline in SDAI at Weeks 1, 2, 4 and 6.

Change from baseline in SDAI low disease activity 
scale (LDAS) and remission rates at Week 4, Week 6 
and Week 8.

Change from baseline in DAS28 LDAS and remission 
rates at Week 4, Week 6 and Week 8.
The following will also be calculated at Weeks 1, 2,4, 6 
and 8:

Change from baseline in DAS28-3 (ESR), DAS28-3 
(CRP), DAS28 -4 (ESR), and DAS28-4 (CRP).


PF-06651600 
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Final Protocol Amendment 1, 26 October 2016
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
Change from baseline in hsCRP.

Change from baseline in the Tender/Painful and 
Swollen Joint Count (28).

Change from baseline in the Physician Global 
Assessment of Arthritis.

To assess the effect of PF-06651600 on 
patient reported outcome measurements.

Change from baseline in the Patient’s Assessment of 
Arthritis Pain (VAS) and Patient Global Assessment 
of Arthritis (VAS) at Weeks 1, 2, 4, 6 and 8.

Change from baseline in the HAQ-DI at Weeks 1, 2, 
4, 6 and 8.
 
 
 
 
 
  
 
  
 
 
 
 
 
 


Change from baseline in ACR 20, ACR 50 and 
ACR 70 responder rates.

 

*Note: (Analysis of exploratory endpoints may be further detailed in the statistical analysis plan (SAP) or 
exploratory analysis plan (EAP).  Samples collected for exploratory endpoints may or may not be analyzed and, 
if analyzed, may or may not be reported in the CSR.)
CCI
CCI
CCI
CCI


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Final Protocol Amendment 1, 26 October 2016
Page 11
Study Design and Treatments:
Study Design Schematic
Note:  N indicates the total number of completers.
This is a Phase 2a, 8 week randomized double-blind, parallel group, placebo controlled, 
multi-center study to assess the efficacy and safety profile of PF-06651600 in seropositive 
subjects with moderate to severe active rheumatoid arthritis with an inadequate response to 
methotrexate (up to approximately 50% of subjects may also have had an inadequate 
response to 1 anti-TNFbiologic DMARD). 
Up to approximately 60 subjects may be randomized globally into the study to ensure at least 
approximately 50 subjects complete 8 weeks of active dosing (assuming a dropout rate of 
approximately 15%).  Subjects will participate in this study for approximately 17 weeks.  
This includes an up to 5-week screening period, an 8 week treatment period, and a 4 week 
follow-up period. 
After an up to 5 week screening period, eligible subjects will be randomized to receive 
200 mg QD of PF-06651600 or placebo (matching tablets for PF-06651600 QD) every day 
for 8 weeks in a blinded fashion. 
Statistical Methods:
Analysis of Primary Endpoint
The primary efficacy analysis will be conducted on Simple Disease Activity Index (SDAI)
change from baseline at 8 weeks. 
Analysis will include data on PF-06651600 and placebo arms. 
Analysis details will be outlined in statistical analysis plan (SAP).  The analysis will include: 
Analysis of Covariance (ANCOVA) models adjusting for SDAI baseline value; Bayesian 
PF-06651600, 200 mg QD, N= 30
8 Weeks
Dosing
5 Weeks 
Screening
4 Weeks 
Follow Up
Placebo QD, N= 20


PF-06651600 
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Final Protocol Amendment 1, 26 October 2016
Page 12
analysis of posterior distributions of the SDAI scores and placebo adjusted change from 
baseline; Advanced data visualization techniques for statistical result presentation. 
The primary analysis will be conducted on intention-to-treat (ITT) population (randomized 
subjects with at least one post baseline value).  Sensitivity analysis and handling of the 
missing values will be outlined in the SAP.
Analysis of Secondary Endpoints
Analyses of the secondary endpoints will be outlined in the SAP.  Continuous and discrete 
modeling techniques will be applied whenever applicable.  The statistical summaries will be 
presented by dose groups.  The correlations between the endpoints will be analyzed. 
Analysis of Other Endpoints
Analysis of other endpoints will be conducted as deemed appropriate.  Continuous and 
discrete modelling techniques will be applied whenever applicable.  Distribution summaries 
will be presented by means of summary tables data visualization methods.
Safety Analysis
All clinical Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Emergent 
Adverse Events (TEAEs), withdrawal due to AEs, electrocardiograms (ECGs), vital signs 
and safety laboratory data will be reviewed and summarized on an ongoing basis during the 
study to evaluate the safety of subjects. 
The safety analysis set will include all subjects who have received at least one dose of IP.  
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.  All safety endpoints will be listed and summarized in 
accordance with Pfizer Standards.  Categorical outcomes (eg, AEs) will be summarized by 
subject counts and percentage.  Continuous outcome (eg, blood pressure (BP), pulse rate, etc) 
will be summarized using N, mean, median, standard deviation, etc.  Change from baseline in 
laboratory data, ECGs and vital signs will also be summarized.  Subject listings will be 
produced for these safety endpoints accordingly. 


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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 table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Protocol Activity
Screening
Treatment Period
Follow Up/End of 
Study
Early
Withdrawalb
Visit Identifier
1
2
3
4
5
6
7
8s
9
Weeka
Week 0
Week 1
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
Study Day
Days -35 to Day 0
Day 1x
Day 8
Day 15
Day 29
Day 43
Day 57
Day 71
Day 85
Visit Window
2 Days based on Week 0/Day 1 visit
Informed consent
X
Inclusion/Exclusion Criteria
X
X
Demographics and RA history
X
Prior RA medications checkc
X
X
Smoking History
X
Medical history and Non RA medications
X
History of Alcohol and Drug Abuse
X
Heightv
X
Weightv
X
X
X
Contraception Checkr
X
X
X
X
X
X
X
Xs
X
X
Vital Signs (pulse rate, blood pressure), 
temperatured
X
X
X
X
X
X
X
X
X
Complete Physical Examinatione
X
X
X
X
Targeted Physical Examinatione
X
X
X
X
X
Rash assessment
X
X
X
X
X
X
X
Xs
X
X
ECG (12 lead)f
X
X
X
X
X
Chest X-rayg
X
Audiogramy
X
X
X
Laboratory Evaluations
Blood Chemistryh
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Rheumatoid Factor (RF)
X
X
X
X
X
X
C-Reactive Protein (hsCRP)
X
X
X
X
X
X
X
X
X


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Final Protocol Amendment 1, 26 October 2016
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Protocol Activity
Screening
Treatment Period
Follow Up/End of 
Study
Early
Withdrawalb
Visit Identifier
1
2
3
4
5
6
7
8s
9
Weeka
Week 0
Week 1
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
Study Day
Days -35 to Day 0
Day 1x
Day 8
Day 15
Day 29
Day 43
Day 57
Day 71
Day 85
Visit Window
2 Days based on Week 0/Day 1 visit
Anti CCP Antibodies (ACPA)
X
X
X
X
X
X
Erythrocyte Sedimentation Rate 
(ESR)
X
X
X
X
X
X
X
X
Serum Ig (IgA, IgM, IgG)
X
X
X
Serum IgE
X
X
X
Sample for IP-10
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
Pregnancy test i
X
X
X
X
X
X
X
X
X
FSH test (if applicable)t
X
HBsAg, HBcAb, HBsAb and 
HCVAb antibodyj
X
HIV testingk
X
HbA1c
X
Tuberculosis testl
X
Viral Surveillanceu
X
X
X
X
X
X
X
X
X
Sample for flow cytometry
X
X
X
Banked RNA biospecimen 
(Prep R1)m
X
X
X
X
Banked plasma biospecimens 
(Prep B1)m
X
X
X
X
Banked serum biospecimens 
(Prep B2)m
X
X
X
X
Genomic banked biospecimen 
(Prep D1)q,m
X
Study Treatment
Randomization (after all screening 
procedures are complete and 
reviewed) 
X
Administration and Dispensing of 
PF-06651600 or Placeboo
X
X
X
X
X
X
Investigational Product 
Accountability
X
X
X
X
X
X


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Final Protocol Amendment 1, 26 October 2016
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Protocol Activity
Screening
Treatment Period
Follow Up/End of 
Study
Early
Withdrawalb
Visit Identifier
1
2
3
4
5
6
7
8s
9
Weeka
Week 0
Week 1
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
Study Day
Days -35 to Day 0
Day 1x
Day 8
Day 15
Day 29
Day 43
Day 57
Day 71
Day 85
Visit Window
2 Days based on Week 0/Day 1 visit
Review of subject diary (review of 
subjects dosing record), IP
accountability and compliance 
check throughout the study p
X
X
X
X
X
X
X
Pharmacokinetic
Pre-dose (0hr) blood sample for PK 
analysis of PF-06651600 
X
X
X
X
X
X
Xw
Blood sample for PK analysis of 
PF-06651600  (0.5 hr) post dose
X
X
X
X
Blood sample for PK analysis of 
PF-06651600 at 1 hr post dose
X
X
X
Blood sample for PK analysis of 
PF-06651600 at 2 and 4 hr post 
dose
X
Efficacy assessments 
Tender/Painful Joint Count (68)
X
X
X
X
X
X
X
X
X
Swollen Joint Count (66)
X
X
X
X
X
X
X
X
X
Patient Assessment of Arthritis 
Pain (PAAP) VAS
X
X
X
X
X
X
X
X
X
Patient’s Global Assessment 
(PtGA) of Arthritis VAS
X
X
X
X
X
X
X
X
X
Physician’s Global Assessment 
(PhGA) of Arthritisn
X
X
X
X
X
X
X
X
X
Health Assessment Questionnaire –
Disability Index (HAQ-DI)
X
X
X
X
X
X
X
X
X
Serious and Non-Serious Adverse Event 
Assessment
X






X
X
X
Concomitant Medication & Treatments
X





X
X
X
Discharge from the study
X
X
Abbreviations: = ongoing/continuous event; CRP = C-Reactive Protein; DNA = deoxyribonucleic acid ; ECG = electrocardiogram; EOS = end of study; ESR 
= Erythrocyte Sedimentation Rate; FACS = fluorescence-activated cell sorting; FSH = follicle stimulating hormone; HAQ-DI = Health Assessment 
Questionnaire – Disability Index; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBsAb= hepatitis B surface antibody; 


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HCVAb = hepatitis C antibody; HIV = human immunodeficiency virus;  hsCRP = high-sensitivity C-reactive protein; IgA, IgG, IgM, IgE = Immunoglobulin of 
the A, G, M, E isotypes; IGRA = Interferon Gamma Release Assay; IP = investigational product; IP-10 = IFN-gamma-inducible protein 10; IRB = institutional 
review board; PK = pharmacokinetic; PAAP = Patient Assessment of Arthritis Pain; PtGA = patient’s global assessment; PhGA = Physician’s Global 
Assessment; PK=Pharmacokinetics; RNA = Ribonucleic Acid; VAS = Visual Analog Scale; WONCBP = women of non-childbearing potential.
a.
Visits should occur when scheduled, within the time window indicated in the column headings.  The screening visit is up to 5 weeks prior to Visit 2. On all 
clinic visit days, PtGA and PAAP VAS measures and HAQ-DI questionnaires, should be performed prior to any other assessments.  Vital signs, ECG and 
blood draws should be performed as specified in Section 7.  Assessments including joint counts, physician questionnaire, and pre-dose blood collections are 
to be performed prior to dosing unless otherwise stated.  Physician’s assessment should be performed without knowledge of patient reported VAS 
assessments Additional unscheduled assessments should be performed as clinically indicated.
b.
See Section 6.4 for guidelines on subject withdrawal/early withdrawal from the study.  Any subject who prematurely withdraws from the treatment period 
should undergo the procedures for an early withdrawal visit and return for follow up visits if medically needed in the opinion of the PI.  Document reasons 
for Early Withdrawal.
c.
Check and verify prior and current RA medications taken after informed consent is signed to ensure compliance with protocol eligibility criteria. Written 
informed consent must be obtained prior to performing any washout of prohibited medication.
d.
See Section 7.2.5 for guidelines on measurement of vital signs.  The same measurement method should be used consistently throughout the study. 
e.
All subjects will have a dermatological full body exam at Screening Visit. Additional Physical Exams (PEs) may be performed during the study at the 
investigator’s discretion.  See Section 7.2.2 for guidelines on collecting PEs.
f.
An ECG may be performed at other times, at the discretion of the investigator if there were findings during a previous examination or in the case of a 
new/open adverse event (AE).  See Section 7.2.6 for guidelines on ECGs. 
g.
See Section 7.2.8 for guidelines on Chest X-rays.
h.
A minimum of 8-hour fasting is required for lipid profile evaluation at Day 1, Week 4, Week 8, and EOS.  Laboratory tests may be repeated once during the
screening period; the last value will be used to determine eligibility.  See Section 7.2.1 for additional information on blood chemistry collection. 
i.
Required for women of childbearing potential who do not meet the definition of non-childbearing potential as per the inclusion/exclusion criteria.  Serum 
pregnancy test must be performed at screening. Pregnancy tests (serum/urine) may also be repeated more frequently as per request of IRBs/ECs or if 
required by local regulations. See Section 7.2.4.
j.
See Section 4 for subject eligibility criteria. 
k.
HIV testing per local regulations.  See Section 4 for subject eligibility criteria.
l.
IGRA official reading and method, or test as per country specific guidelines, must be located in source documentation.  See Section 4 for subject eligibility 
criteria.
m. These samples must be collected before administration of the investigational product.  See Section 7.5 for details.
n.
Physician’s assessment should be performed without knowledge of patient reported VAS assessments. 
o.
At the baseline visit, (Visit 2) the first dose of investigational product will be taken in the clinic.  Additionally, at Weeks 1, 2, 4, 6 and 8 subjects should be 
given their dose for that day in the clinic.  All other doses will be taken by the subject outside of the clinic.
p.
Subject diary dispensed and/or collected.  Subject diary, study compliance and investigational product administration entries are reviewed. See Section 5.3.


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q.
If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a subject 
visit.
r.
Except for women of non-child bearing potential. See Section 4.3.1 and Section 7.2.4.
s.
Telephone follow up.  Adverse Event and rash assessments (if needed) will be conducted verbally over the phone and if needed subject will be asked to 
come in for AE assessment.  Use of contraception will be confirmed and concomitant medication check will be done over the phone with the subject. 
t.
To confirm postmenopausal status (if applicable).
u.
In addition to time points specified, a plasma sample for viral surveillance sample may also be taken at the time of an adverse event. See Section 7.2.10 for 
details. 
v.
Height and Weight will be measured without shoes. 
w.
At the time of the visit, a blood sample will be collected for PK analysis.  As with all PK assessments, date and time of last dose and date and time of sample 
collection should be captured and reported. 
x.
Baseline Visit.
y.
Audiogram testing at screening must be completed and results available by the baseline visit (Visit 2) and audiogram testing at Week 8 (Visit 7) must be 
completed and results available by the Week 12 visit (Visit 9). For subjects that terminate early from the study, if possible, efforts must be made to complete 
the audiology testing and obtain the results. See Section 7.2.12 for details.


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1. INTRODUCTION
Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by joint 
inflammation and destruction, progressive disability and adverse psychological effects.  The 
prevalence of RA is approximately 0.5-1% of the population in developed regions with a 
4-fold higher frequency in women than in men.16  There is considerable evidence for both 
genetic and environmental contributions to RA.  A growing body of evidence has implicated
anti-citrullinated protein antibodies (ACPA) in more severe manifestations of RA.  ACPA 
positive (ACPA+) RA subjects tend to have more rapidly progressing disease and are less 
likely to respond to current therapy.20
There are multiple therapeutic options for managing the pain and slowing the progression of 
rheumatoid arthritis, but none completely cure the disease.  The current goal of treatment (as 
stipulated in the 2010 European League Against Rheumatism (EULAR) recommendations 
for the treatment of RA) aims toward achieving the lowest possible level of arthritis disease 
activity (ideally, remission), minimizing joint damage, and enhancing physical function and 
quality of life.17  Disease-modifying antirheumatic drugs (DMARDs) are the standard 
treatments for RA.  Conventional synthetic DMARDs (csDMARDs), such as methotrexate, 
are used either alone or in combination with newer biologic DMARDs.  They work to 
decrease pain and inflammation, to reduce or prevent joint damage, and to preserve the 
structure and function of the joints but rarely induce remission.  Use of biologic DMARDs, 
most commonly TNFinhibitors, is indicated when symptoms are not adequately controlled 
with csDMARDs.  Additional approved therapeutics include tocilizumab (interleukin (IL)-6 
receptor neutralizing antibody) and tofacitinib (a small molecule pan-Janus kinase (JAK) 
inhibitor).  Despite the considerable list of approved treatments for RA, there are significant 
numbers of subjects who do not achieve remission or achieve adequate reduction in disease 
activity.5
Tofacitinib, approved by the Food and Drug Administration (FDA) in 2012 is the first JAK 
inhibitor for the treatment of moderate-to-severe RA.  It is a pan-JAK inhibitor with 
inhibitory activity ranked in the order JAK3 > JAK1 > JAK2 > TYK2.  The broad inhibitory 
effect on JAK3, JAK1, JAK2 and TYK2 impacts a broad panel of cytokine signaling 
pathways including cytokines with anti-inflammatory roles such as IL-10.  Tofacitinib 
blockade of JAK2, also results in some of the treatment-associated adverse effects such as 
anemia and neutropenia.14 Thus, the rationale for selective JAK3 inhibition.  This rationale 
is additionally supported by the fact that JAK3 deficiency in mice and humans results in 
immunodeficiency due to lack of circulating NK and T cells.  Selectively expression of JAK3 
in hematopoietic cells and its essential role in lymphocyte development lends support for 
JAK3 as a target for immune suppression.9,3,12,18
The JAK family of kinases mediates signal transduction via interactions with type I and 
type II cytokine receptors.  Several JAK3 cytokines such as IL-15, IL-7, IL-9 and IL-21 have
been implicated in RA.21,6,19  Roles for IL-15 and IL-7 in the pathogenesis of RA have been 
demonstrated in mouse models.  Furthermore, levels of these cytokines are also reported to 
be elevated in blood/serum and synovial fluid in RA subjects and IL-7 and IL-21 cytokines 
also promote osteoclastogenesis.  Hence the rationale to target JAK3-mediated cytokine 
signaling pathways.  Additional support for the rationale for JAK3 inhibition in RA comes


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from several human clinical studies with HuMax-IL-15 (AMG714), a neutralizing antibody 
against IL-15 and decernotinib (VX-509, a JAK3-selective inhibitor).2,4,16,11,10,8  Therefore 
blocking signaling downstream of JAK3 may be beneficial in RA.
1.1. Mechanism of Action/Indication
PF-06651600 is a potent and selective covalent inhibitor of JAK3 that is currently under 
development for the treatment of RA and Ulcerative Colitis (UC).
1.2. Background and Rationale
PF-06651600 is a potent, Janus kinase (JAK)3 selective, covalent inhibitor. It is an orally 
bioavailable small molecule that selectively inhibits JAK3 by irreversibly blocking the 
adenosine triphosphate (ATP) binding site without significantly inhibiting the other three 
JAK isoforms (JAK1, JAK2, and TYK2).  The molecule also has a high specificity against 
the broad human kinome.
This JAK3-selective inhibition will lead to modulation of -common chain cytokine 
pathways, such as IL-7, IL-9, IL-15 and IL-21, some of which have been implicated in the 
pathophysiology of RA.  PF-06651600 will spare inhibition of key immuno-regulatory
cytokines, such as IL-10, IL-35 which play a protective role in RA.  Inhibition of JAK2 
cytokine signaling, implicated to be associated with adverse effects such as neutropenia, 
thrombocytopenia and anemia14 will also be spared, thus making JAK3-selective inhibitors 
an attractive therapeutic modality.  JAK3 is also expressed only in the hematopoietic cells 
and thus the rationale for improved therapeutic index of PF-06651600 in RA over pan-JAK 
inhibition. 
 
  
 
 
 
 
 
 
 
 
  
 
 
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1.5.1. Summary of Clinical Safety of PF-06651600
Eighty (80) subjects were enrolled into the FIH study.  Single doses up to 800 mg and 
multiple doses up to 400 mg daily, as both 400 mg QD and 200 mg BID were administered.  
PF-06651600 appears to be generally safe and well-tolerated.  No clinically-significant 
changes in vital signs, electrocardiogram or laboratory data were observed.  No dose-limiting 
adverse events were reported and no subjects met the protocol prescribed individual stopping 
rules.  There were no deaths in the study. 
The most commonly reported all causality treatment-emergent AEs across both Single 
Ascending Dose (SAD) and Multiple Ascending Dose (MAD) PF-06651600 cohorts were GI 
disorders, including diarrhea (9 subjects), abdominal pain (6 subjects), abdominal discomfort 
(2 subjects), and flatulence (3 subjects).  Change of bowel habit, constipation, fecal volume 
increased, discolored feces, nausea, paraesthesia oral, and vomiting have each also been 
reported (1 subject each event).  All cases were mild in severity with the exception of 
1 moderate TEAE each of abdominal pain, dysphagia, and vomiting.
Skin and subcutaneous tissue disorders including, but not limited to rash, maculopapular 
rash, dermatitis acneiform, and erythema of mild to severe intensity were reported in the 
PF-06651600 cohorts and are summarized in Table 1 below.  There were no skin and 
subcutaneous tissue disorders reported in the 5, 20, 50, 200, 400, and 800 single dose 
cohorts; nor were there any skin and subcutaneous tissue disorders reported in the 50 mg QD 
multiple dose cohort.
Table 1.
Skin and Subcutaneous Tissue Disorder Occurrence
N= # of subjects
Adverse Event
SAD
50 mg
N=8
SAD 
100 mg
N=8
MAD 
100 mg 
BID
N=8
MAD 
200 mg 
QD
N=8
SAD
400 mg
N=16
MAD 
400 mg 
QD
N=24
MAD 
200 mg 
BID
N=8
A
P
A
P
A
P
A
P
A
P
A
P
A
P
Acne
0
0
0
0
0
0
0
0
0
0
2*
1*
0
0
Dermatitis 
acneiform
0
0
0
0
2*
0
0
0
0
0
0
0
1*
0
Dry Skin
0
1**
0
0
0
0
0
0
0
0
2*
1*
0
0
Eczema
0
0
0
0
0
0
0
0
0
0
0
1*
0
0
Erythema
0
0
0
0
1*
0
2*
1*
0 
1*
1*
0
1**
0
Rash
0
0
1*
0
0
0
0
0
0
0
1*
0
0
0
Rash macular
0
0
1*
0
0
0
0
0
0
0
3*
0
0
0
Rash 
maculopapular
0
0
1**
0
1**
0
0
0
0
0
0
0
2
(1**/
1***)
0
Rash pruritic
0
0
0
0
0
0
0
0
0
0
0
0
1**
0
Seborrhoeic 
dermatitis
0
0
0
0
1*
0
0
0
0
0
0
0
0
0
Skin induration
0
0
0
0
0
0
0
0
0
0
0
0
0
1*
Abbreviations: A = active, P = placebo.
*- Mild **- Moderate ***- Severe


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Three (3) serious adverse events (SAEs) were reported in the FIH trial. 
The first event was a cutaneous abscess on the left buttock during the 200 mg single dose 
period in a subject who entered the study with a pre-existing boil on the left buttock. This 
was assessed 19 days after the single dose was administered and was considered related to 
the study drug. The subject was discontinued from treatment.  The SAE criterion was met as 
the incision and drainage procedure was performed in a hospital setting.
The second SAE was a sacrococcygeal cyst/pilonidal sinus abscess during the 400 mg single 
dose period.  This was assessed 19 days after the single dose was administered and was 
considered related to the study drug.  The SAE criterion was met as the incision and drainage 
procedure was performed in a hospital setting.
The third SAE was a varicella infection during the 400 mg QD MAD dose period.  The start 
date was 11 days after the last dose and was considered related to the study drug.  The source 
of the infection is unknown; however, a second subject, who had a reactivation of varicella 
zoster, may be the source as the subjects were confined during the same time.  The varicella 
infection resolved in 51 days. 
Please refer to the Investigator’s Brochure for more details on the clinical safety information 
with PF-06651600.
1.5.2. Pharmacokinetics of PF-06651600 
The pharmacokinetic (PK) parameters from the 5, 20, 50, 100, 200, 400 and 800 mg single 
dose levels are summarized below in Table 2.  In general, PF-06651600 AUCinf increased in 
a dose related manner over the 5 to 800 mg dose range with a slightly greater than 
proportional increase observed over the 200 mg to 400 mg dose range.  Cmax increased with 
dose in an apparent dose proportional manner.
Table 2.
Summary of Plasma PF-06651600 Pharmacokinetic Parameters Following 
Single Oral Doses, Study B7981001
PF-06651600 Parameter Summary Statisticsa by Treatment
Parameter, 
units
5 mg
20 mg
50 mg
100 mg
200 mg
400 mg
800 mg
N, n
6,6
6,6
6,6
6,6
6,6
12,12
6,6
AUCinf, 
ng.hr/mL
43.86 (26)
211.7 (39)
384.1 (47)
1085 (23)
2464 (42)
7824 (34)
16760 (18)
AUClast, 
ng.hr/mL
42.42 (26)
209.3 (40)
382.6 (47)
1081 (23 )
2461 (42)
7821 (34)
16760 (18)
Cmax, ng/mL 27.02 (29)
120.9 (54)
253. 3 (45)
647.7 (24)
1039 (40))
2691 (26)
4992 (11)
Tmax, hr
0.5 
(0.5-0.5
0.5 (0.5-1)
0.5 (0.5-1
0.5 (0.5-0.6)
0.75 (0.5-2)
1(0.5-2)
1.5 (1-2)
t½, hr
1.20 
(0.107)
1.2 (0.174)
1.13 (0.166)
1.48 (0.176)
1.75 (0.434) 2.18 (0.337)
2.48 
(0.460)
a
Geometric mean (geometric %CV) for all except:  median (range) for Tmax; arithmetic mean SD for t½.
N = Number of subjects in the treatment group and contributing to the mean; n= number of subjects where t½, 
AUCinf were determined.


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PF-06651600 was absorbed rapidly following single doses of 5 mg to 200 mg with median 
Tmax values 0.750 hours, and more slowly at the higher doses with a median Tmax of 1.0 and 
1.5 hours for the 400 mg and 800 mg doses, respectively.  Following attainment of Cmax, the 
disposition of PF-06651600 generally showed a monophasic decline at the lower doses of 
5 to 200 mg (mean t½ of 1.2 to 1.8 hours) while a biphasic decline observed at doses of 
400 to 800 mg (mean t½ of 2.2 to 2.5 hours).  An apparent trend toward longer t½ values at 
higher doses (400 and 800 mg) is probably due to concentrations remaining above the
quantifiable limit for a longer period of time at the higher doses and defining a later terminal 
phase. 
The PK parameters following administration of 50, 200 and 400 QD and 100 mg and 
200 mg BID for 14 days are summarized below in Table 3.
On Day 14 of multiple-dose administration, PF-06651600 was absorbed rapidly with median 
Tmax values of 1 hour or less across the entire range of doses, from a total daily dose of 50 mg 
(50 mg QD) up to 400 mg (200 mg BID or 400 mg QD).  Following attainment of Cmax, the 
disposition of PF-06651600 was consistent with that observed following single-dose 
administration, showing a monophasic decline for the lowest doses and a biphasic decline 
following the 200 mg BID and 400 mg QD dosing regimens and a mean terminal t½ of about 
approximately 1.3 to 2.3 hours.  In general, plasma PF-06651600 AUCand Cmax increased 
with dose across the 50 mg to 400 mg total daily dose range in a dose related manner based 
on visual comparison of individual and dose normalized geometric mean Cmax and AUC
values.  Steady-state generally appears to have been reached by Day 4 for the QD regimens 
and Day 6 for the BID regimens based on similar median trough (predose) concentrations on 
Days 6, 8, 10, 12 and 14.
Table 3.
Summary of Plasma and Urine PF-06651600 Pharmacokinetic Parameters 
Following Multiple Dose Administration for 14 days, Study B7981001
PF-06651600 Parameter Summary Statisticsa by Treatment
Parameter, units
50 mg (QD)
100 mg (BID)
200 mg (QD)
400 mg (QD)
200 mg (BID)
N, n
6, 6
4,4
5, 5
15, 14
5, 5
AUC, ng.hr/mL
540.1(38)
1984 (15)
4069 (22)
10040 (19)
5207 (24)
Cmax, ng/mL
315.2 (38)
663.0 (35)
1422 (28)
3136 (26)
1903 (27)
Tmax, hr
0.5 (0.5- 1)
0.75 (0.5- 2)
1 (0.5- 1)
1 (0.5- 2)
1 (0.5- 1)
CL/F, L/hr
92.56 (38)
50.43 (15)
49.14 (22)
39.85 (19)
30.41 (24)
t½, hr
1.3 (0.241)
2.11 (0.341)
1.84 (0.409)
2.16 (0.100)
2.27 (0.212)
Vz/F, L
170.6 (26)
151.4 (27)
128.0 (29)
126.1 (18)
125.3(18)
Ae%
4.09 (23)
6.46 (4)
5.47 (31)
6.46 (19)
7.04 (20)
CLr, mL/min
63.06 (28)
54.33 (12)
44.76 (38)
42.90 (18)
45.46 (17)
Geometric mean (geometric %CV) for all except:  median (range) for Tmax; arithmetic mean SD for t½;
N = Number of subjects in the treatment group and contributing to the mean; n= number of subjects where t½ 
was determined.
AUC, = Area under the concentration-time curve from zero to 24 hours (QD) or zero to 12 hours (BID) 
postdose at steady state; QD = Once daily; BID = Twice daily; Cmax = Peak plasma concentration; 
CL/F = apparent total body clearance; Vz/F = apparent volume of distribution; Ae% = Percent of dose 
recovered unchanged in urine over the dosing interval ; CLr = Renal clearance.


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Urinary recovery of PF-06651600 was low, with approximately <8% of the dose recovered 
unchanged in urine on Day 14 across all doses (geometric mean Ae% of 4.1% to 7.0%).  
Renal clearance ranged from 42.9 mL/min to 63.1 mL/min.
The relative bioavailability (B7981003) of 50 mg PF-06651600 tablets was compared to 
50 mg oral suspension.  The ratio (90% CI) of adjusted geometric mean was 93.49% 
(87.8, 100) for AUCinf and 90.4% (72.2, 113) for Cmax under fasted conditions.  When the 
50 mg tablets were administered under fed conditions, Tmax was slightly delayed with a 
median value of 1.0 hours, compared to a median Tmax 0.5 hours under fasted conditions.  For 
the 50 mg tablets fed vs. fasted, the ratio of adjusted geometric means for AUCinf and Cmax
was 102% (95.2, 109) and 61.5% (48.5, 77.8), respectively.
1.6. Summary 
1.6.1. Study Rationale
This multicenter, placebo controlled study will be the first determination of safety and 
efficacy of PF-06651600 in subjects with moderate to severe active RA who have had an 
inadequate response to methotrexate (up to approximately 50% of subjects may also have 
had an inadequate response to 1 anti-TNFbiologic DMARD).
The subject population in this study is methotrexate non-responders. These subjects could 
potentially also have failed one TNFinhibitor.  The inclusion of subjects who have failed 
one TNFinhibitor is driven by the fact that anti-TNFtherapy is widely used in the US 
(which is planned to be one of the countries participating in this study) in subjects who have 
failed methotrexate.  The decision to limit the number of TNFnon responders in B7981006 
(up to 50% of study subjects) is based on the American College of Rheumatology (ACR)
recommendations to reserve anti-TNFagents for RA subjects for whom prior methotrexate 
monotherapy led to an inadequate response, RA subjects with moderate disease activity and 
features of a poor prognosis, and for RA subjects with high disease activity, irrespective of 
prognostic features.15
In addition, although anti-TNFtherapy is very effective in controlling disease activity and 
slowing down radiological damage, prolonged response is only seen in approximately 
60-70% of the subjects,7 which indicates that there is an un-met need for RA subjects who 
fail anti-TNFtherapy.
An 8 week study was determined of an appropriate duration to assess disease activity and 
provide safety information for PF-06651600 in subjects with RA.  SDAI was selected as the 
primary endpoint since this assessment is the best predictor for transformational efficacy 
defined in terms of 6 month SDAI remission rate.
1.6.2. Dose Rationale
The dose selection strategy was designed to balance pharmacology and safety for an 8 week 
study) in this subject population. 


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The predicted PK parameters for PF-06651600 based on simulations using the global PK 
model are provided in Table 4.
Table 4.
Summary of Predicted Steady State Plasma Pharmacokinetic and 
Pharmacodynamic Parameters Following Multiple Dose Administration of 
PF-06651600
Dose
mg QD
Cmax
ng/mL
Predicted
Marginsa
AUCtau
ng.hr/mL
Predicted
Marginsa
IP-10 
%CFB
200
1254 (2.1)
11
3712 (14)
14
42 (19)
AUCtau = Area under the concentration-time curve from zero to 24 hours 
postdose at steady state; Cmax = Peak plasma concentration; QD = Once daily; 
%CFB= percent change from baseline; human unbound fraction (fu) = 0.86; 
1 ng/mL= 3.504 nM.
a.
NOAEL-highest dose in dogs, 45 mg/kg/day; Week 8 mean male and 
female Cmax (free) = 12,000 ng/mL; Cmax (total) = 14,634 ng/mL; AUCtau 
(free) = 44,100 ng•h/mL; AUCtau (total) = 53,780 ng•h/mL. dog (fu) = 0.82.
The predicted exposure during the treatment period at a dose of 200 mg QD for 8 weeks is 
projected to maintain 12- and 14-fold safety margins for Cmax and AUCtau, respectively.  The 
selective inhibition of JAK3 will lead to modulation of -common chain cytokine pathways, 
such as IL-7, IL-15 and IL-21 which have been implicated in the pathophysiology of RA.  In 
lymphocytes, PF-06651600 inhibited JAK1/JAK3 dependent STAT5 and STAT3 
phosphorylation by IL-15 and IL-21 respectively, with IC50s of 56.5 ng/mL and 103 ng/mL, 
respectively.  All other pathways were inhibited at IC50s >5708 ng/mL.  The predicted 
average percent IL-15 and IL-21 in-vitro signaling inhibition in human whole blood based on 
human PK are provided in Table 5.
Table 5.
Summary of the Predicted Average Percent In Vitro Signaling Inhibition 
Based on Steady State PK from 200 mg PF-06651600
Cytokine
Average Percent Signaling Inhibition
200 mg
IL-15
81
IL-21
71
Pharmacological modulation of the target can be inferred from the results. 
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1.6.3. Summary of Benefits and Risks
Overall, the safety profile observed during the Phase I program for PF-06651600 appears to 
be acceptable at dosages 
 administered orally. 
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure. 
1.6.4. Additional Information
Banked biospecimens will be collected for the purpose of conducting research; specific uses 
are described in the Banked Biospecimens section.  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/genomic/biomarker analyses and retaining them in the 
Biospecimen Banking System (BBS) make it possible to better understand the investigational 
product’s mechanism of action and to seek explanations for differences in, for example, 
exposure, tolerability, safety, and/or efficacy not anticipated prior to the beginning of the 
study. 
Banked biospecimens retained in the BBS also can be used in research on diseases of 
inflammation.
Providing these biospecimens is a required study activity for study sites and subjects, unless 
prohibited by local regulations or ethics committee (EC) decision. 
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objectives:
Primary Endpoints:

To evaluate the efficacy of PF-06651600 
at 8 weeks in subjects with moderate to 
severe active RA.

Change from baseline in simple disease activity index 
(SDAI) at Week 8.
Secondary Objectives:
Secondary Endpoints:

To evaluate the safety of PF-06651600.

Safety and tolerability of PF-06651600 versus placebo; 
vital signs, laboratory tests, adverse events (AEs) 
including infections, and Serious Adverse Events 
(SAEs).

To assess other signs of clinical efficacy 
over 8 weeks.

Change from baseline in SDAI at Weeks 1, 2, 4 and 6.

Change from baseline in SDAI low disease activity 
scale (LDAS) and remission rates at Week 4, Week 6 
and Week 8 

Change from baseline in DAS28 LDAS and remission 
rates at Week 4, Week 6  and Week 8.
The following will also be calculated at Weeks 1, 2,4, 6 
and 8:
CCI


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
Change from baseline in DAS28-3 (ESR), DAS28-3 
(CRP), DAS28 -4 (ESR), and DAS28-4 (CRP).

Change from baseline in hsCRP.

Change from baseline in the Tender/Painful and 
Swollen Joint Count (28).

Change from baseline in the Physician’s Global 
Assessment of Arthritis.

To assess the effect of PF-06651600 on 
patient reported outcome measurements.

Change from baseline in the Patient’s Assessment of 
Arthritis Pain (VAS) and Patient’s Global Assessment 
of Arthritis (VAS) at Weeks 1, 2, 4, 6 and 8.

Change from baseline in the HAQ-DI at Weeks 1, 2, 4, 
6 and 8.
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
CCI


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3. STUDY DESIGN
Figure 1.
Study Design Schematic
Note:  N indicates the total number of completers.
This is a Phase 2a, 8 week randomized double-blind, parallel group, placebo controlled,
multi-center study to assess the efficacy and safety profile of PF-06651600 in seropositive 
subjects with moderate to severe active rheumatoid arthritis with an inadequate response to 
methotrexate (up to approximately 50% of subjects may also have had an inadequate 
response to 1 anti-TNFbiologic DMARD). 
Up to approximately 60 subjects may be randomized globally into the study to ensure at least 
approximately 50 subjects complete 8 weeks of active dosing (assuming a dropout rate of 
approximately 15%).  Subjects will participate in this study for approximately 17 weeks.  
This includes an up to 5-week screening period, an 8 week treatment period, and a 4 week 
follow-up period. 
After an up to 5 week screening period, eligible subjects will be randomized to receive 
200 mg QD of PF-06651600 or placebo (matching tablets for PF-06651600 QD) every day 
for 8 weeks in a blinded fashion. 
Subjects will remain on stable background arthritis therapy, which must include methotrexate 
(supplemented with folic/folinic acid per local treatment guidelines).  Subjects additionally 
may continue stable doses of Nonsteroidal Anti-inflammatory Drugs (NSAIDs), COX-2 
inhibitors, allowed opioids (at doses the potency equivalent of 30 mg of 
orally-administered morphine), acetaminophen/paracetamol for pain control (2.6 grams per 
day), and/or low dose oral corticosteroids (10 mg prednisone or equivalent per day).  
Methotrexate must have been dosed orally for at least 3 months, the dose must have been 
stable for at least 4 weeks before first dose of study drug, and the dose must remain stable 
during the study.  Allowed methotrexate doses are 15 to 25 mg, inclusive, weekly, unless 
there is documented (in the source documentation) intolerance to or toxicity from these
doses, in which case a dose between 10 and <15 mg, inclusive, may be used. 
PF-06651600, 200 mg QD, N= 30
8 Weeks
Dosing
5 Weeks 
Screening
4 Weeks 
Follow Up
Placebo QD, N= 20


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Folic or folinic acid must be dosed per local standards of care stably for at least 4 weeks 
before first dose of study drug.  NSAIDs, COX-2 inhibitors, allowed opioids and/or low dose 
oral corticosteroids (10 mg prednisone or equivalent per day) must be dosed stably for at 
least 4 weeks prior to first dose of study drug (See Section 5.8).
4. SUBJECT ELIGIBILITY CRITERIA
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.
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study.
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject [or a legally acceptable representative] has been informed of all pertinent 
aspects of the study.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and 
other study procedures.
3. Male and female subjects (including Women of Childbearing Potential (WOCBP)) 
between the ages of 18 and 75 years, inclusive.  For subjects >70 years old, the site 
must discuss subject eligibility with the study team to ensure that these subjects are 
sufficiently healthy to participate.
4. Female subjects of childbearing potential must test negative for pregnancy at 
screening visit and baseline visit.
5. Female subjects of nonchildbearing potential must meet at least 1 of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause and have a serum follicle-stimulating hormone (FSH) level 
confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c.
Have medically confirmed ovarian failure. 


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All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential.
6. Diagnosis of rheumatoid arthritis (RA) and meeting the 2010 American College of 
Rheumatology (ACR)/European League Against Rheumatism (EULAR) 
classification criteria (see Appendix 2) for RA with a Total Score 6/10.  The 
duration of time since diagnosis of RA should minimally be sufficient to meet the 
definition of methotrexate inadequate response (see criteria 10 below).
7. Meets Class I, II or III of the ACR 1991 Revised Criteria for the classification of 
Global Functional Status in RA (see Appendix 2).
8. The subject has active disease at both Screening and Baseline, as defined by both:

6 joints tender or painful on motion; AND

6 joints swollen;
and 

High sensitivity C reactive protein (hsCRP) 7 mg/L at screening performed by 
the central laboratory.  Subjects who do not meet this entry criterion but satisfy all 
other study entry criteria may have serum hsCRP concentration re-tested and, if 
the repeat hsCRP concentration is 7 mg/L prior to the baseline visit, will be 
eligible to enroll into the study provided all other inclusion/exclusion criteria are 
met.
9. Subjects must be seropositive (rheumatoid factor positive and/or anti-citrullinated 
protein antibody positive) at the screening visit.
10. Subjects must have been taking oral MTX for at least 3 months at an adequate dose to 
determine that the subject had an inadequate response to MTX, defined, for the 
purpose of this study, by the investigator’s and subject’s opinions that the subject did 
not experience adequate benefit from methotrexate plus the presence of sufficient 
residual disease activity to meet the entry criteria.  Allowed methotrexate doses are 
15 to 25 mg, inclusive, weekly, unless there is documented (in the source 
documentation) intolerance to or toxicity from these doses, in which case a dose 
between 10 and <15 mg, inclusive, may be used (See Section 5.8). The dose must 
have been stable for at least 4 weeks before first dose of study drug, and the dose 
must remain stable during the study.  

Subjects should be on an adequate and stable dose of folic acid (not less than 
5 mg weekly, unless higher doses would violate the local label) for at least 
4 weeks prior to the first dose of investigational product or oral folinic acid 
(5 mg once per week) supplementation for at least 4 weeks prior to the first dose 
of study drug. Folic acid must be dosed per local standards of care stably for at 


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least 4 weeks before first study dose and the dose must remain stable during the 
study.  In countries which do not have approved folic acid 1 mg or folinic acid 
5 mg presentations, a regimen of folic acid of at least 5 mg weekly is acceptable.
11. Up to 50% of subjects may have received one approved TNF-inhibiting biologic 
agent administered in accordance with its labeling recommendations that was 
inadequately effective and/or not tolerated.  For the purpose of this study, inadequate 
efficacy is defined by the investigator’s and subject’s opinions that the subject did not 
experience adequate benefit from the anti-TNFinhibitor and the presence of 
sufficient residual disease activity to meet the entry criteria.  The anti-TNFinhibitor 
should have been discontinued for a minimum of the washout period defined as 
follows:

etanercept (Enbrel): 4 weeks.

infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), 
certolizumab (Cimzia): 10 weeks.
12. Subjects receiving non-prohibited medications (See Section 5.8) for any reason must 
be on a stable regimen, which is defined as not starting a new drug or changing 
dosage within 7 days or 5 half-lives (whichever is longer) prior to first study dose and  
the dose must remain stable during the study.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
2. Participation in other studies involving investigational drug(s) within 30 days or 
5 half-lives (whichever is longer) prior to study entry (screening visit) and/or during 
study participation.
3. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or 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.


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4. Any major illness/condition(s) or evidence of an unstable clinical condition (eg, renal, 
hepatic, hematologic, gastrointestinal, endocrine, pulmonary or local active 
infection/infectious illness) that, in the investigator’s judgment will substantially 
increase the risk to the subject if he or she participates in the study.
5. Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) and 
any history of cerebrovascular disease within 24 weeks before screening or in the 
period between the Screening Visit and the Baseline Visit.
6. Subjects with a known immunodeficiency disorder or a first degree relative with a 
hereditary immunodeficiency.
7. Subjects with acute or active chronic dermatological disorders within 4 weeks prior to 
study entry or in the period between the Screening Visit and the Baseline Visit.
8. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and 
female subjects of childbearing potential who wish to become pregnant or 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 28 days after the last dose of 
investigational product. 
9. History of alcohol or drug abuse with less than 6 months of abstinence prior to the 
Baseline Visit.
10. Subjects with any of the following acute or chronic infections or infections history:
a.
Any infection requiring treatment within 2 weeks prior to the Screening Visit or 
in the period between the Screening Visit and the Baseline Visit.
b. Any infection requiring hospitalization, parenteral antimicrobial therapy within 
60 days of the Baseline Visit, or as otherwise judged to be an opportunistic 
infection or clinically significant by the investigator, within the past 6 months of 
the Baseline Visit.
c.
Known active or history of recurrent bacterial, viral, fungal, mycobacterial or 
other infections.
d. Recurrent (more than one episode) herpes zoster or disseminated (a single 
episode) herpes zoster or disseminated (a single episode) herpes simplex. 
e.
Infected joint prosthesis at any time with the prosthesis still in situ.
f.
Subjects will be screened for Human Immunodeficiency Virus (HIV).  Subjects 
who test positive for HIV will be excluded from the study.


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g. Subjects will be screened for hepatitis B virus infection and will be excluded if 
positive for hepatitis B surface antigen (HBsAg).  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 positive, 
the subject will be excluded from the study. 
h. Subjects will be screened for hepatitis C virus (HCV Ab).  Subjects with positive 
HCV Ab tests will be reflex tested for HCV ribonucleic acid (HCV RNA).  Only 
subjects with negative HCV Ab or HCV RNA will be allowed to enroll in the 
study.
11. Subjects treated with prohibited medications will be excluded unless appropriate 
washout has been performed (See Section 5.8).
12. Any current evidence of untreated latent or active TB infection, evidence of currently 
active TB by chest x-ray, residing with or frequent close contact with individual(s) 
with active TB.  Subjects who have a positive Mantoux (PPD) tuberculin skin test or 
a positive Interferon Gamma Release Assay during screening or within 12 weeks 
prior to screening.  The following are acceptable assays: QuantiFERON- TB Gold 
test (QFT-G), QuantiFERON- TB Gold In-Tube test (QFT-GIT) and 
T-SPOT- TB test during screening or within 12 weeks prior to screening.

A positive Mantoux tuberculin skin test is defined as 5 mm of induration (or as 
defined by country specific or local standards) at 48-72 hours without 
consideration of prior Bacillus Calmette-Guerin (BCG) vaccination.  
Documentation of the dose and product used for the Mantoux tuberculin test as 
well as the official test reading must be obtained and available in the subject’s 
source documentation.

An Interferon-Gamma Release Assay (IGRA) is preferred for subjects with a 
prior BCG vaccination, but may be used for any subject.  Documentation of 
IGRA product used and the test result must be in the subject’s source 
documentation. 

If the results of the IGRA are indeterminate, the test may be repeated, and if a 
negative result is obtained, enrollment may proceed.  A positive test on repeat is 
exclusionary.
13. Current routine household contact with children or anyone else who have received 
varicella or oral polio or any other live (attenuated) vaccine within 6 weeks of first 
study dose, or during the course of the study (including the Follow Up period).
14. Any live (attenuated) vaccines from 30 days prior to the Baseline Visit and through 
the Follow Up Visit. 


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15. Subjects who have been in contact with people with acute infections within 2 weeks 
prior to the Screening Visit or in the period between the Screening Visit and the 
Baseline Visit.
16. History of any lymphoproliferative disorder (such as Epstein-Barr Virus 
(EBV)-related lymphoproliferative disorder, as reported in some subjects on 
immunosuppressive drugs), history of lymphoma, leukemia, myeloproliferative 
disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic 
disease. 
17. Have a history of a major organ transplant (eg, heart, lung, kidney and liver) or 
hematopoietic stem cell/marrow transplant.  Skin grafts are allowed.
18. History of severe allergic or anaphylactoid reaction to kinase inhibitors, or 
corticosteroid preparations.
19. Subjects with malignancy or history of malignancy (including but not limited to
lymphoma, leukemia, or lymphoproliferative disease), with the exception of subjects 
with adequately treated or excised non-metastatic basal cell or squamous cell cancer 
of the skin or cervical carcinoma in situ.
20. Pre-existing chronic autoimmune disease (eg, inflammatory bowel disease, Systemic 
Lupus Erthematosus (SLE), moderate to severe atopic dermatitis) other than RA.  
Secondary Sjogren’s -Syndrome associated with RA may be included.
21. Major surgery within 4 weeks of the Screening Visit or if scheduled to occur during 
the study, excluding diagnostic surgical procedures.
22. Previous treatment with total lymphoid irradiation. 
23. Subjects with any condition possibly affecting oral drug absorption (eg, gastrectomy, 
clinically-significant diabetic gastroenteropathy, or certain types of bariatric surgery 
such as gastric bypass).  Procedures such as gastric banding that simply divide the 
stomach into separate chambers are not exclusionary.
24. Screening 12-lead ECG that demonstrates clinically relevant abnormalities (eg, QTc 
>450 msec or a QRS interval >120 msec) which may affect subjects’ safety or 
interpretation of study results.  If QTc exceeds 450 msec, or QRS exceeds 120 msec, 
the ECG should be repeated two more times and the average of the three QTc or QRS 
values should be used to determine the subject’s eligibility.
25. Have current or recent history of clinically significant severe or progressive hearing 
loss or auditory disease. Subjects with hearing aids will be allowed to enter the study 
provided their hearing impairment is considered controlled/clinically stable. 
26. Subjects with an oral or tympanic temperature at the Baseline Visit of 38C or higher.


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27. Presence of any of the following laboratory abnormalities at the Screening Visit or 
within the 3 months prior to first study dose:

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 
1.5 times the upper limit of normal (ULN).

Total bilirubin level 1.5 times the ULN; subjects with a history of Gilbert’s 
syndrome may have a direct bilirubin measured and would be eligible for this 
study provided the direct bilirubin is ULN and other liver function assessments 
are normal.

Hemoglobin level 90 g/L (9.0 g/dL).

Platelet count 100 x 109/L (100,000 cells/mm3) or 1000 x 109/L 
(1,000,000 cells/mm3).

White blood cell (WBC) count 3.0 x 109/L (3000 cells/mm3) or absolute 
neutrophil count (ANC) <1500 cells/mm3 or absolute lymphocyte count of 
<0.5 x 109/L (<500 cells/mm3).

Serum creatinine level 177 mol/L (2 mg/dL).

Glycosylated hemoglobin (HbA1C) >10%.
28. In the opinion of the investigator or sponsor, have any uncontrolled clinically 
significant laboratory abnormality that would affect interpretation of study data or the 
subject’s participation in the study.
29. Grade 3 or greater laboratory abnormality based on the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 toxicity scale.
Screening laboratory tests with abnormal results may be repeated once to confirm abnormal 
results.  If results return to normal protocol acceptable limits within the 5-week screening 
period, the subject may enter the study. 
Subjects who fail screening can be rescreened once.
4.3. Lifestyle Requirements 
It is recommended that subjects avoid consumption of grapefruit juice exceeding 8 ounces 
(~240 ml) total in a day while in the study.
4.3.1. Contraception
In this study, fertile male subjects and female subjects who are of childbearing potential as 
applicable to the study will receive PF-06651600, which has been associated with suspected 
teratogenicity (based on the demonstrated nonclinical findings).  Subjects who are, in the 
opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) 


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must agree to use 2 methods of highly effective contraception throughout the study and for at 
least 28 days after the last dose of PF-06651600.  The investigator or his or her designee, in 
consultation with the subject, will confirm that the subject has selected 2 appropriate methods 
of contraception for the individual subject and his/her partner(s) from the list of permitted 
contraception methods (see below) and will confirm that the subject has been instructed in 
their consistent and correct use.  At time points indicated in the Schedule of Activities, the 
investigator or designee will inform the subject of the need to use 2 highly effective methods 
of contraception consistently and correctly and document the conversation, and the subject’s 
affirmation, in the subject’s chart.  In addition, the investigator or designee will instruct the 
subject to call immediately if 1 or both of the selected contraception methods is discontinued 
or if pregnancy is known or suspected in the subject or 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:

Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject or 
male subject’s female partner 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. 

Correctly placed copper-containing intrauterine device (IUD).

Male condom or female condom used WITH a separate spermicide product (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.

Male sterilization with absence of sperm in the postvasectomy ejaculate. 

Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose of investigational product.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study manual. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 


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contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
If the subject has a medical emergency and is unable to reach the investigator or the study 
staff, they need to visit the Emergency Room/Urgent Care or appropriate medical site for 
care by a qualified health professional per local guidelines. 
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator 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).
For this study, the investigational product is PF-06651600.  Investigational product will be
administered only to subjects who have provided informed consent.  Once a subject’s 
participation in the study has ended, investigational product will no longer be supplied to the 
subject by the investigative site and/or sponsor. 
5.1. Allocation to Treatment
Allocation of subjects to treatment groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR]).  The site 
personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the subject number. The site personnel will then be provided with a 
treatment assignment, randomization number, and dispensable unit (DU) or container number 
when investigational product is being supplied via the IRT system.  The IRT system will 
provide a confirmation report containing the subject number, randomization number, and DU 
or container number assigned. The confirmation report must be stored in the site’s files. 
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 


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5.2. Breaking the Blind 
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process.  Blinding codes should be 
broken only in exceptional circumstances when knowledge of the actual treatment code is 
absolutely essential for further management of the subject.  Investigators are encouraged to 
discuss with a member of the study team if they believe that unblinding is necessary.  When 
the blinding code is broken, the reason must be fully documented and entered in the case 
report form (CRF).
5.3. Subject Compliance
Subject compliance will be verified by the accounting of investigational product at each visit. 
For self-administration of PF-06651600 at home, compliance will be captured and completed 
by the subject within a Subject Dosing Diary.  When investigational product is administered 
at the research facility, it will be administered under the supervision of study personnel. 
Subjects will be directed to bring Subject Dosing Diary and blister cards with any remaining 
study drug to each visit for review.  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 (pill count) during any given time period.  Compliance 
will be documented in the source records. 
Non-compliance is defined as taking less than 80% or more than 120% of the allowed 
investigational product during the study treatment period.
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 interrupting investigational product for more than 5 days between 
study visits are to be discussed with the medical monitor for possible discontinuation from 
the study.
Upon completion of each visit, the Subject Dosing Diary should be collected from the subject 
at the site and stored in the site master file only.  The investigator has the discretion to 
withdraw any subject from the study for reasons of non-compliance with the dosing regimen.  
Inventory control of all investigational product must be rigorously maintained throughout the 
duration of the study until all medication has been accounted for and/or returned to the 
sponsor.  Any discrepancies noted between drug dispensing records and drug inventory must 
be reported to Pfizer.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Blinded PF-06651600 and its matching placebo will be provided as tablets in blister cards for 
oral administration.  The PF-06651600 50 mg tablets and their matching placebos will be 
supplied in separate blister cards and labeled according to local regulatory requirements. 


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5.4.2. Preparation and Dispensing
The investigational product will be dispensed using an IRT drug management system at each
visit from Week 0 through Week 8.  Each dispensing visit will provide sufficient 
investigational product to complete dosing until the next scheduled dispensing visit.  Visit 
dates are calculated such that visit windows are not cumulative and are anchored on Day 0. 
Investigational product should 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, Only qualified personnel 
who are familiar with procedures that minimize undue exposure to their person and to the 
environment should undertake the preparation, handling, and safe disposal of agents.
The subject should be instructed to maintain the product in the blister cards provided 
throughout the course of dosing and return the blister cards to the site at the next study visit. 
5.5. Administration
Subjects will receive PF-06651600 tablets and matching placebo for oral administration in 
blister packs.  Subjects will be dispensed blister cards and given clear dosing instructions. 
Investigational product tablets will be administered to the subject in the clinic on the morning 
of clinic visits and all other dosing will be performed by the subject outside of the clinic.  
Subjects will record their study drug dosing information within a Subject Dosing Diary 
which should be brought to each clinic visit.
Sites will be trained on how subjects should take tablets at home through the study or IP
manual and/or other vehicle(s).  Sites are responsible for communicating this information to 
the subject. 
If a dose is missed and the interval to the next dose is less than 6 hours, the missed dose 
should not be administered.  At the baseline visit, (Visit 2) the first dose of investigational 
product will be taken in the clinic.  Additionally, at Weeks 1, 2, 4, 6 and 8 subjects should 
take their dose for that day in the clinic.  All other doses will be taken by the subject outside 
of the clinic.
The investigational product may be administered with or without food. Subjects will 
swallow the investigational product whole, and will not manipulate or chew the 
investigational product prior to swallowing with a glass of water. 
Subjects who experience AEs that require treatment may have their study drug temporarily 
discontinued during treatment at the investigator’s discretion.  Subjects interrupting 
investigational product for more than 5 days are to be discussed with the medical monitor for 
possible discontinuation from the study.
Temporary discontinuation of study drug should be recorded in the CRF.


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5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
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 should 
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 evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products. 
5.7. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.


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All blister cards of study drug must be returned to the investigator by the subject at every 
visit and at the end of the trial.
5.7.1. Destruction of Investigational Product Supplies 
Returned investigational product can be destroyed only after the sponsor monitor has verified 
the accuracy of the dispensing and inventory record. 
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 investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Background and Concomitant Treatment(s)
All concomitant medication(s) and treatment(s) administered/taken during the study must be 
recorded with indication, daily dose, and start and stop dates of administration. 
All subjects will be questioned about concomitant medication at each site visit. 
Medications that are taken after informed consent is obtained, but before the first dose of 
investigational product, will be documented as prior medications.  Medications taken after 
the first dose of investigational product has been administered will be documented as 
concomitant medications. 
5.8.1. Permitted Background Arthritis Therapy
Methotrexate (MTX) (Required Background RA Treatment).
Subjects will continue on their pre-study dose of MTX (supplemented with folic/folinic 
acid). Subjects must have been taking oral MTX for at least 3 months at an adequate dose to 
determine that the subject had an inadequate response to MTX, defined, for the purpose of 
this study, by the investigator’s and subject’s opinions that the subject did not experience 
adequate benefit from MTX plus the presence of sufficient residual disease activity to meet 
the entry criteria.  The dose must have been stable for at least 4 weeks before first dose of 
study drug, and the dose must remain stable during the study.  Allowed MTX doses are 15 to 
25 mg, inclusive, weekly, unless there is documented (in the source documentation) 
intolerance to or toxicity from these doses, in which case a dose between 10 and <15 mg, 
inclusive, may be used.
Other background RA Treatments
The following concomitant medications may be continued during the study as background 
RA treatments, provided the dosage(s) do not change for the entire period from Screening 
through Discharge from the study (except for Rescue Medication. See Section 5.9) and have 
been stable for the stipulated interval before Randomization and dosing with the 
investigational product.


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
Anti-malarials (eg, chloroquine,hydroxychloroquine).

Nonsteroidal Anti-inflammatory Drugs (NSAIDs), selective Cyclooxygenase-2 
inhibitors ("COX-2 inhibitors") at a stable dose in accordance with local 
label/standard of care beginning at least 4 weeks prior to first study dose.

Opioids at doses the potency equivalent of 30 mg of orally-administered morphine 
at a stable dose beginning at least 4 weeks prior to first study dose (See 
Appendix 11).

Acetaminophen/paracetamol at doses 2.6 grams per day 

Low dose oral corticosteroids (10 mg prednisone or equivalent per day) at a stable 
dose beginning at least 4 weeks prior to first study dose (See Appendix 10).

Subjects should be on an adequate and stable dose of folic acid (not less than 5 mg 
weekly, unless higher doses would violate the local label) for at least 4 weeks prior to 
the first dose of investigational product or oral folinic acid (5 mg once per week) 
supplementation for at least 4 weeks prior to the first dose of study drug. Folic acid 
must be dosed per local standards of care stably for at least 4 weeks before first study 
dose and the dose must remain stable during the study.  In countries which do not 
have approved folic acid 1 mg or folinic acid 5 mg presentations, a regimen of folic 
acid of at least 5 mg weekly is acceptable.
Other Permitted Concomitant Medications
A subject who is receiving an allowed concomitant medication for any reason must be on a 
locally-approved medication and dose that is considered standard-of-care for the treated 
indication and be documented in the case report form with indication, daily dose, and start 
and stop dates of administration.
It is recommended that subjects receiving non-prohibited concomitant medications, vitamins, 
and dietary supplements must be on a stable regimen, which is defined as not starting a new 
drug or changing dosage within 7 days or 5 half-lives (whichever is longer) prior to first dose 
of investigational product and the dose must remain stable during the study.  
5.8.2. Prohibited Background Arthritis Therapy 
Disease Modifying Antirheumatic Drugs (DMARDs)

Subjects who have received the following treatment regimens are eligible to 
participate in the study, providing the following discontinuation periods are observed 
prior to the first dose of investigational product. (Biosimilars of the below agents 
should be considered the same as the originators).


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Biologics

TNF inhibitors

Up to 50% of subjects may have received one approved TNF-inhibiting biologic 
agent administered in accordance with its labeling recommendations that was 
inadequately effective and/or not tolerated. For the purpose of this study, 
inadequate efficacy is defined by the investigator’s and subject’s opinions that the 
subject did not experience adequate benefit from the anti-TNFand the presence 
of sufficient residual disease activity to meet the entry criteria.  The anti-TNF
should have been discontinued for a minimum of the washout period defined as 
follows: 27

etanercept (Enbrel): 4 weeks.

infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), 
certolizumab (Cimzia): 10 weeks.

Other Biologic Agents/DMARDs

Subjects who have previously been treated with other, non-TNFinhibiting 
biologic DMARDs (including, abatacept (Orencia), tocilizumab (Actemra), 
anakinra (Kineret), rituximab (Rituxan) or other selective B 
lymphocyte-depleting agents (both marketed and investigational)) or other 
lymphocyte-depleting agents/therapies (such as CamPath[alemtuzab], alkylating 
agents [eg, cyclophosphamide or chlorambucil], total lymphoid irradiation) are 
excluded from participation in the current study.

Subjects who have been previously treated with tofacitinib (Xeljanz) should 
have a washout treatment of 3 months prior to screening.

Intra-articular, intravenous or intramuscular corticosteroids, DMARDs including 
methotrexate and biologic response modifiers are not allowed during this study. 
Other RA Drugs
The following drugs are excluded during the study and for the prescribed washout period 
prior to the start of the study:

Auranofin (oral gold), aurothioglucose (injectable gold), aurothiomalate (injectable 
gold) must be discontinued for 8 weeks prior to the first dose of the investigational 
product.

Sulfasalazine, d-penicillamine, bucillamine, mizoribin, azathioprine, cyclosporine, 
tacrolimus, and staphylococcal protein A immuno-absorbant pheresis columns 


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(eg, PROSORBAdevice/column) must be discontinued for 4 weeks prior to the first 
dose of investigational product.

Subjects on Leflunomide (Arava) must undergo the following drug elimination 
procedure at least 4 weeks prior to the first dose of investigational product:

Cholestyramine at a dosage of 8 grams three times daily for at least 11 days, or 
activated charcoal at a dosage of 50 grams 4 times a day for at least 11 days to 
achieve non-detectable plasma levels (less than 0.02 mg/L or 0.02 g/mL) after 
stopping treatment with Arava22,23 Verify plasma levels less than 0.02 mg/L 
(0.02 g/mL) by two separate tests at least 14 days apart.  If plasma levels are 
higher than 0.02 mg/L, additional cholestyramine treatment should be considered. 

Tetracyclines and minocycline, unless prescribed for the treatment of acne or other 
dermatologic disorders, must be discontinued for 4 weeks prior to the first dose of 
investigational product.
Other Prohibited Concomitant Medications

Interferon therapy within 8 weeks prior to the Baseline Visit and through the 
Follow up Visit.

Lymphocyte-depleting agents/therapies.

Leukocyte apheresis including selective lymphocyte, monocyte, or granulocyte 
apheresis, or plasma exchange within 6 months of baseline and through the Follow up 
Visit. 

Other marketed immunosuppressants or biologics with immunomodulatory properties 
within 3 months prior to the Baseline Visit and through the Follow up Visit.

Use of immunosupressants used in transplantation (eg, mycophenolate mofetil, 
cyclosporine, rapamycin, or tacrolimus) within 30 days prior to the Baseline Visit and 
through the Follow up Visit.

Any live (attenuated) vaccines from 30 days prior to the Baseline Visit and through 
the Follow up Visit.

No investigational compounds, other than PF-06651600, may be taken during 
participation in this study.

Herbal medications with pharmaceutical properties must be discontinued at least 
4 weeks before the first dose of investigational product.

Subjects receiving prohibited concomitant medications, including moderate to potent 
CYP3A inducers or inhibitors (See Appendix 4) in the time periods described below:


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
For moderate to potent CYP3A inducers, within 28 days or 5 half-lives, 
whichever is longer, prior to the Baseline Visit.

For moderate to potent CYP3A inhibitors, within 7 days or 5 half-lives, 
whichever is longer, prior to the Baseline Visit.
Subjects who are treated with any prohibited medication during the course of the study will 
be discontinued. 
5.9. Rescue Medication
Rescue therapy for RA is not permitted except for transient (up to 10 consecutive days) 
addition or increased dose of acetaminophen/paracetamol (dosed no more than 2.6 grams per 
day) or an opioid (not exceeding the potency equivalent of 30 mg of orally-administered 
morphine) If a subject is already taking stable background doses of 
acetaminophen/paracetamol, s/he may increase the dose up to 2.6 grams per day for up to 
10 consecutive days for rescue purposes.  Subjects who require rescue for more than 
10 consecutive days should be discontinued from the trial.  Acetaminophen/paracetamol 
may be taken for up to 5 days/week for headache, fever, or other acute, non-arthritis pain, 
provided the total dose (including background dose) does not exceed 2.6 grams per day. 
Subjects should not be dosed with rescue treatments during the 24 hours prior to interval 
study visits and 7 days prior to the last day of the active dosing period (Week 8).  
(Note: baseline stable doses of acetaminophen/ paracetamol or opioids should NOT be 
discontinued in advance of study visits) (See Appendix 11).
6. STUDY PROCEDURES 
Visits should occur when scheduled, within the time window indicated in the Schedule of 
Activities.  Written informed consent must be obtained prior to performing any 
protocol-specific procedures, including washout of prohibited medications. On study drug 
dosing days, PtGA and PAAP VAS measures and HAQ-DI questionnaires, should be 
performed prior to any other assessments.  Assessments including joint counts, physician 
questionnaire, and pre-dose blood collections are to be performed prior to dosing unless 
otherwise stated.
Where possible the following order of activities should be followed during the clinic visits
1. Patient’s Assessment of Arthritis Pain (VAS) and Patient Global Assessment of Arthritis 
(VAS)
2. ECGs
3. Vital signs
4. Physician’s Global Assessment (PhGA) of Arthritis (Physician’s assessment should be 
performed without knowledge of patient reported VAS assessments)


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5. Blood and Urine Sample Collection 
6. Investigational Product Dosing
6.1. Screening
For screening procedures, see Schedule of Activities and ASSESSMENTS section.
6.2. Treatment Period
For treatment period procedures, see Schedule of Activities and ASSESSMENTS section.
6.3. Follow-up/End of Study
For follow-up and end of study procedures, see Schedule of Activities and ASSESSMENTS
section.
6.4. Subject Withdrawal/Early 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 (see also the 
Withdrawal From the Study Due to Adverse Events section) 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 (See Schedule of Activities for procedures to be followed at 
the Early Withdrawal Visit). Subjects who require rescue medication for more than 
10 consecutive days should be discontinued from the trial. (See Section 5.9)
Subjects who are discontinued from study treatment will enter into the Follow-up Period 
with the follow-up visit occurring 1 week after the last dose whenever possible and 
protocol specified follow-up procedures should be performed. 
See Appendix 4 for Guidelines for Monitoring and Discontinuations.  The Early Withdrawal
Visit applies to subjects who are randomized, received at least one dosing and then are 
prematurely withdrawn from the study treatment.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor. 
6.4.1. Withdrawal of Consent
If the subject 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.
Subjects should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or post-treatment 
study follow-up, and entered on the appropriate CRF page.  In the event that vital status 


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(whether the subject is alive or dead) is being assessed, publicly available information should 
be used to determine vital status only as appropriately directed in accordance with local law.
6.4.2. Lost to Follow-up 
Lost to follow-up is defined by the inability to reach the subject after a minimum of 2 phone 
calls (documented in the source documents), faxes, or e-mails as well as lack of response by 
the subject to 1 registered mail letter. 
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 it is determined that the subject has died, the site will use locally permissible methods to 
obtain the date and cause of death.  If, after all attempts, the subject remains lost to 
follow-up, then the last-known-alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Efficacy Assessments
7.1.1. American College of Rheumatology (ACR) Assessments 
The specific components of the ACR Assessments (ACR Core Dataset) that will be used in 
this study are:
1. Tender/Painful Joint count (TJC) (68).
2. Swollen Joint Count (SJC) (66).
3. Patient’s Assessment of Arthritis Pain.


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4. Patient’s Global Assessment of Arthritis.
5. Physician’s Global Assessment of Arthritis.
6. C-Reactive Protein (CRP), measured by high sensitivity methodology (hsCRP).
7. Erythrocyte Sedimentation Rate (ESR)
8. Health Assessment Questionnaire – Disability Index (HAQ-DI).
Components of the ACR Core Dataset will be collected at the visits indicated in the Schedule 
of Activities.
7.1.2. Tender/Painful Joint Count (68)
Sixty-eight (68) joints will be assessed by a joint assessor to determine the number of joints 
that are considered tender or painful.  The response to pressure/motion on each joint will be 
assessed using the following scale: Present/Absent/Not Done/Not Applicable (to be used for 
artificial or missing joints).  Artificial joints will not be assessed.
The 68 joints to be assessed are:

Upper Body: temporomandibular, sternoclavicular, acromioclavicular;

Upper Extremity: shoulder, elbow, wrist (includes radiocarpal, carpal and 
carpometacarpal considered as one unit), metacarpophalangeals (MCP I, II, III, IV, 
V), thumb interphalangeal (IP), proximal interphalangeals (PIP II, III, IV, V), distal 
interphalangeals (DIP II, III, IV, V);

Lower Extremity: hip, knee, ankle, tarsus (includes subtalar, transverse tarsal and 
tarsometatarsal considered as one unit), metatarsophalangeals (MTP I, II, III, IV, V), 
great toe interphalangeal (IP), proximal and distal interphalangeals combined (PIP II, 
III, IV, V).
7.1.3. Swollen Joint Count (66)
The joint assessor will also assess joints for swelling using the following scale:
Present/Absent/Not Done/Not Applicable (to be used for artificial or missing joints). 
Sixty-six (66) joints will be assessed for swelling, the same as those listed above for 
tenderness/pain, except that the right and left hip joints are not included in the swollen joint 
count.  Artificial joints will not be assessed.  Physician assessment should be performed 
without the knowledge of patient reported outcome measures.


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7.1.3.1. Tender and Swollen Joint Counts (28)
The twenty-eight tender/painful joint count includes the following joints: shoulders, elbows, 
wrists, metacarpophalangeal joints (MCP), proximal interphalangeal joints (PIP), and knees.  
Artificial joints will not be assessed.  This count will be calculated by Pfizer from the 
68 tender/painful joint count assessed by the joint assessor as described in Section 7.1.2.
The twenty-eight swollen joint count measurement will include the same joints as described 
above for 28 tender/painful joint count, and will be calculated by Pfizer from the 66 swollen 
joint count assessed for swelling by the joint assessor as described in Section 7.1.3.  Artificial 
joints will not be assessed.  Physician assessment should be performed without the 
knowledge of patient reported outcome measures.
7.1.4. Patient’s Assessment of Arthritis Pain (PAAP)
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 (See Appendix 7).  This assessment must be 
performed early in the clinic visit and before the subject has extensive contact with site 
personnel and/or investigator (and ideally should be performed before the TJC and SJC 
measurements) and prior to dosing.
7.1.4.1. Patient’s Global Assessment (PtGA) of Arthritis
Subjects will answer the following question, “Considering all the ways your arthritis affects 
you, how are you feeling today?”  The subject’s response will be recorded using a 100 mm 
visual analog scale (VAS) (See Appendix 8).  This assessment must be performed early in 
the clinic visit and before the subject has extensive contact with site personnel and/or 
investigator and prior to dosing.
7.1.4.2. Physician’s Global Assessment (PhGA) of Arthritis
The investigator will assess how the subject’s overall arthritis appears at the time of the visit.  
This is an evaluation based on the subject’s disease signs, functional capacity and physical 
examination, and should be independent of the Patient’s Global Assessment of Arthritis.  The 
investigator’s response will be recorded using a 100 mm visual analog scale (VAS) 
(See Appendix 9).  Physician assessment should be performed without the knowledge of 
patient reported outcome measures.
7.1.4.3. High Sensitivity C-Reactive Protein (CRP)
Samples for analysis of high sensitivity CRP (hsCRP) will be collected at the visits specified 
in the Schedule of Activities.  The samples will be shipped to and analyzed by a central 
laboratory.  After randomization, the investigator and Pfizer study personnel directly 
involved in the conduct of the trial will be kept blinded of the results of this test.


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7.1.4.4. Erythrocyte Sedimentation Rate (ESR)
Samples for analysis of ESR will be collected at the visits specified in the Schedule of 
Activities.  ESR will be analyzed by a local laboratory using the Westergren method.  The 
results from the local laboratory will be captured in a central database. 
7.1.4.5. Health Assessment Questionnaire – Disability Index (HAQ-DI) 
The HAQ-DI assesses the degree of difficulty a subject has experienced during the past week 
in 8 domains of daily living activities: dressing and grooming, arising, eating, walking, 
hygiene, reach, grip, and other activities.  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 “without any 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.  This questionnaire must be performed early in the clinic visit and before 
the subject has extensive contact with site personnel and/or investigator.  The form should 
then be checked by the site staff for completeness.  A copy of the questionnaire can be found 
in Appendix 13.  This must be performed early in the clinic visit and before the subject has
extensive contact with site personnel and/or investigator and prior to dosing.
7.1.5. Composite Efficacy Assessments Derived from the ACR Core Dataset
Composite endpoints in this study will be calculated by Pfizer using individual components.
7.1.5.1. Simple Disease Activity Index (SDAI) Assessment
The SDAI is a continuous composite measure derived components of the ACR Core Dataset.  
The SDAI will be calculated using the following formula:
SDAI = TJC (using 28 joints) + SJC (using 28 joints) + PtGA (0–10 cm scale) + PhGA 
(0-10 cm scale) + and hsCRP (mg/dL).1
7.1.5.2. ACR Responder Analysis
The American College of Rheumatology’s definition for calculating improvement in RA 
(ACR20) is calculated as a 20% improvement in tender and swollen joint counts and 
20% improvement in 3 of the 5 remaining ACR-core set measures: patient’s and physician’s
global assessments, pain, disability, and an acute-phase reactant.  Similarly, ACR50 and 
ACR70 are calculated with the respective percent improvement.  Components of the ACR 
Responder Index will be collected as indicated in the Schedule of Activities.
7.1.6. Disease Activity Score (DAS) Assessments
The Disease Activity Score (DAS) assessment is a continuous composite measure derived 
using differential weighting given to each component.  DAS28 is a measure based on 
28 tender and swollen joint counts.  DAS28 may be calculated with 3 components (not 
including assessment of an acute phase reactant) (DAS28-3) or 4 components 
(DAS28-4 = DAS28-3 + either ESR or CRP).  The formulae for calculation of DAS28-4 
(CRP) and DAS28-4 (ESR) are presented in Appendix 6.  Components of DAS28-3 (CRP), 


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DAS28-3 (ESR), DAS28-4 (CRP), and DAS28-4 (ESR) will be collected as indicated in the 
Schedule of Activities.
The components of the DAS 28 arthritis assessment include:

Tender/Painful Joint Count (28).

Swollen Joint Count (28).

CRP or ESR.

Patient’s Global Assessment of Arthritis.
7.2. Safety and other Assessments
Safety will be assessed by the spontaneous reporting of AEs, physical examinations, ECGs, 
and clinical laboratory results in all subjects who received at least 1 dose of investigational 
product.  Investigators and Pfizer clinician/medical monitor will review individual subject 
data throughout the conduct of the trial to ensure subjects’ well-being.
7.2.1. Clinical Safety and Other Laboratory Tests
The following laboratory tests will be performed at times defined in the Schedule of 
Activities.  Laboratory tests may be repeated once during the screening period; the last value 
will be used to determine eligibility.  Unscheduled clinical labs may be obtained at any time 
during the study to assess any perceived safety concerns.
Table 6.
Safety and other Laboratory Tests
Hematology
Blood Chemistry 
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils (Abs and %)
Eosinophils (Abs and %)
Basophils (Abs and %)
Lymphocytes (Abs and %)
Monocytes (Abs and %)
Reticulocyte count (Abs and %)
PT/INR/PTT
BUN/Urea & Creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (Bicarbonate)
AST, ALT
Total bilirubin
Direct bilirubing
Alkaline phosphatase
Uric acid
Albumin
Total protein
Lipid profiles c
Creatine kinase (CK)
CK fractionationh
pH
Glucose 
Protein 
Blood 
Ketones
Nitrites
Leukocyte 
esterase
Urobilinogen
Urine bilirubin
Microscopyd
FSHa
Pregnancy Testsb
HbA1c
HIVi, HBsAg, HBc Ab, HBsAb 
and HCVAb, HCV RNA
IGRAk
Viral surveillancee
Ig subtypes
Herpitiform rash evaluation 
(HSV and HZV swab)
Skin biopsies/swabsf
IP-10j
Anti CCP antibodiesj
Rheumatoid Factorj
C-Reactive Protein (hsCRP) j
T cell, B cell and NK cell
subsets
ESR
Exploratory samples (serum, 
plasma, RNA, DNA)
a.
In females who are amenorrheic for at least 12 consecutive months to confirm post-menopausal status. 
b.
Pregnancy tests (serum/urine) for women of childbearing potential. Serum pregnancy test must be 
performed at screening.


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c.
Lipid profile panel will include total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein 
(HDL), and triglycerides.  A minimum of 8-hour fasting is required for lipid profile evaluation at Day 1, 
Week 4, Week 8, and EOS. 
d.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
e.
Blood sample will be collected for potential exploratory viral load analyses including but not limited to 
CMV, EBV, HSV1, HSV2, and VZV, if applicable.
f.
When required in cases of skin rash adverse events. Skin swabs for herpetiform rash and skin swab for 
potential drug-related rash 
g.
Only if total bilirubin is elevated.
h.
Only if CK is elevated.
i.
HIV testing per local regulations.
j.
After randomization, the investigator and Pfizer study personnel directly involved in the conduct of the trial 
will be kept blinded of the results of this test.
k.
Complete at screening.
7.2.2. Physical Examination
Complete Physical Examination:
Complete physical examinations must be performed by the investigator, sub-investigator or a 
qualified health professional per local guidelines and will be performed at the visits identified 
in Schedule of Activities.  Complete physical examinations consist of assessments of general 
appearance which includes but is not limited to:general appearance, head, eyes, ears, nose 
and throat (HEENT), mouth, heart; lungs; breast (optional); abdomen; external genitalia 
(optional); extremities; neurologic function, back, lymph nodes and skin (including presence 
of rash). In addition, a dermatological full body exam must be performed at the Screening 
Visit by the investigator, sub-investigator or a qualified health professional per local 
guidelines.
Targeted Examination
At all other visits, as defined in the Schedule of Activities, a targeted physical examination 
will be performed by the investigator, sub-investigator or a qualified health professional per 
local guidelines and should include skin (including presence of rash), lungs, heart, abdomen 
and lymph nodes and examination of body systems where there are symptom complaints by 
the subject.  Any clinically significant changes from the baseline examination should be 
recorded as AEs.  
Additional physical examinations may be performed at the investigator’s discretion.
7.2.3. Medical History, Height and Weight
Medical history in addition to RA history including history of drug, alcohol, tobacco use, 
skin rash, skin infection, and any dermal abnormalities that may predispose to infection will 
be collected at Screening.  
Complete RA disease history includes RA diagnosis and collection of details of RA at 
Screening. This includes but is not limited to background, RA history including disease 
duration and extent of disease. 


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Height and weight will be measured without the subject wearing shoes.  Height (inches or 
centimeters) and weight (lbs or kg) will be measured and recorded in the source document as 
indicated in the Schedule of Activities.
7.2.4. Pregnancy Testing
Pregnancy tests are required to be done (if applicable) as specified in the Schedule of 
Activities. 
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.  For female subjects of 
childbearing potential, 2 negative pregnancy tests are required before receiving 
investigational product (1 negative pregnancy test at screening and 1 at the baseline visit 
immediately before investigational product administration).  Following a negative pregnancy 
test result at screening, appropriate contraception must be commenced and the second 
negative pregnancy test result will then be required at the baseline visit and within 5 days 
after the first day of the menstrual period (counting the first day of the menstrual period as 
Day 1) before the subject may receive the 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 repeated at 
every visit and at the end of the study to confirm that the subject has not become pregnant 
during the study.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed 
during the active treatment period and when potential pregnancy is otherwise suspected, and 
may be repeated if requested by institutional review boards (IRBs)/ethics committees (ECs)
or if required by local regulations.  In the case of a positive confirmed pregnancy, the subject 
will be withdrawn from administration of investigational product but will remain in the study 
for further follow-up..
7.2.5. Vital Signs (Blood Pressure, Pulse Rate and Temperature)
Sitting BP, pulse rate, and temperature will be measured after approximately 5 minutes of 
rest at times specified in the Schedule of Activities.  It is preferred that the same 
measurement method be used consistently throughout the study.  Additional collection times 
or changes to collection times will be permitted, as necessary to ensure appropriate collection 
of safety data.  When the timing of these measurements coincides with a blood collection, it 
is preferred that vital signs be obtained prior to the nominal time of blood collection. 
Sitting blood pressure will be measured with the subject’s arm supported at the level of the 
heart, and recorded to the nearest mmHg.  It is preferred that the same arm (preferably the 
dominant arm) be used throughout the study. 
A properly sized and calibrated Blood Pressure (BP) cuff, will be used to measure BP each 
time.  The use of automated devices for measuring BP and pulse rate is acceptable, although, 
when done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. 
It is preferred that body temperature be collected (either oral or tympanic) and that the same 
method be used consistently throughout the study.


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7.2.6. Electrocardiogram
Single twelve (12) lead ECGs will be obtained on all subjects.  All scheduled ECGs should 
be performed after the subject has rested quietly for at least 10 minutes. 
When the timing of these measurements coincides with a blood collection, the ECG should 
be obtained prior to the nominal time of the blood collection, BP, and pulse rate. 
If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more 
times and the average of the three QTc or QRS values should be used to determine the 
subject’s eligibility.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, repeat measurements may not be necessary if a qualified physician’s 
interpretation determines that the QTc values are in the acceptable range.
An ECG may also be performed at other times, at the discretion of the investigator if there 
were findings during a previous examination or in the case of a new/open adverse event 
(AE).
7.2.7. Interferon-Gamma Release Assay
IGRA will be tested during screening or within 12 weeks prior to screening.  The following 
are acceptable assays: QuantiFERON-TB Gold test (QFT-G), QuantiFERON-TB Gold 
In-Tube test (QFT-GIT) and T-SPOTTB test.  Blood sampling may include 3 mL up to 
10 mL of blood.  Site personnel should follow the processing and analyses steps based on the 
assay chosen.  Ensure incubation steps are followed as appropriate.
A documented IGRA test performed within 12 weeks prior to screening is acceptable.  IGRA 
product used, official reading and method, or test as per country specific guidelines, must be 
located in the subjects source documentation. 
7.2.8. Chest X-Ray
Chest radiograph (posterior-anterior and lateral views are recommended, however local 
guidelines should be followed) or other appropriate diagnostic image (ie, Computerised 
Tomography (CT) or Magnetic Resonance Imaging (MRI)) with no evidence of current, 
active TB or previous inactive TB, general infections, heart failure or malignancy taken at 
Screening or within 12 weeks prior to Screening and read by a qualified radiologist.  
Documentation of the official reading must be located and available in the source 
documentation.


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7.2.9. Infection Monitoring
Subjects will be monitored for development of any infection (viral, bacterial, and fungal).  
Infections will be classified as either treated or non-treated infections.  All treated infections 
occurring during the study should be cultured if feasible and the results (eg, any identified 
organisms or absence of growth) recorded in the CRF.
Treated infections are infections that:

Require antimicrobial therapy by any route of administration or; 

Require any surgical intervention (eg, incision and drainage).
Treated infections will be further classified as serious or non-serious.  Serious infections are 
treated infections that:

Require parenteral antimicrobial therapy or; 

Required hospitalization for treatment or; 

Meet other criteria that require the infection to be classified as a SAE.
A subject who experiences a serious infection should be discontinued from the study.  A 
serious infection should be reported as a SAE and should be listed as the reason for 
discontinuation in the CRF.  All serious infections occurring during the study should undergo 
appropriate laboratory investigations, including culture, and the results (eg, any identified 
organisms or absence of growth) be recorded in the CRF.
Subjects who experience non-serious infections that require treatment may have their study 
drug temporarily discontinued during treatment at the investigator’s discretion.  Consultation 
with the Pfizer medical monitor is available.  Temporary discontinuation of study drug 
should be recorded in the CRF. 
7.2.10. Viral Surveillance
Blood samples will be collected according to the times outlined in the Schedule of Activities 
and may be used to test viral load that may include Cytomegalovirus (CMV), Epstein-Barr 
Virus (EBV), Varicella Zoster Virus (VZV) and Herpes Simplex Virus Type 1 (HSV1) and 
Herpes Simplex Virus Type 2 (HSV2).
Due to delayed reporting times for these assays, the results might not be available along with 
the other study tests. 
In addition to time points specified, a plasma sample for viral surveillance sample may also 
be taken at the time of an adverse event. 


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7.2.11. Dermatological Assessments
All subjects will have a dermatological full body exam at Screening Visit. Skin lesions will 
be evaluated as defined in the National Cancer Institute Common Toxicity Criteria for 
Adverse Events v4.03 (See Appendix 12, for Dermatology/Skin Category) and managed as 
shown below. 
Table 7.
Management of Dermatological Events
Dermatologic Event (CTCAE v 4.03)*
Course of Management
Acne/Acneiform Rash/Maculopapular Rash
Grade 1/2
1. Investigator’s discretion for withdrawing 
investigational product.
2. Execute reasonable monitoring.
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Grade 3
1. Discontinue investigational product.
2. Monitor to resolution (defined as a Return to Baseline 
status).
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Pruritus
Grade 1 Mild or localized
1. Investigator’s discretion for withdrawing 
investigational product.
2. Execute reasonable monitoring.
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Grade 2 Intense or widespread
1. Discontinuation of the investigational product may 
not be required unless condition is sustained >4 days 
or at the investigator’s discretion.
2. Execute reasonable monitoring.
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Grade 3 Intense or widespread and interfering 
with activities of daily living
1. Permanently discontinue investigational product.
2. Monitor to resolution (Return to Baseline).
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
* Refer to Appendix 12 for clarification.
Herpetiform Rash 
For any occurrence of a suspected herpetiform rash (eg, herpes zoster and herpes simplex), 
specimens for viral DNA analysis will be obtained: A swab of the affected area will be 
collected for confirmation; a blood sample for viral surveillance will be collected for the 
analysis of viral load. Details for these collections will be provided in the laboratory manual.
Drug-Related Rash
All potential drug related reports of rash will be followed up until resolution or clinically 
stable or in agreement with Pfizer.   


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All events of rash should be treated according to international and local guidelines for the 
treatment of rash, eg, where appropriate, topical corticosteroids and/or agents such as 
antibiotics or antivirals could be prescribed. 
All subjects reporting an unexplained skin rash should be referred to a local dermatologist or 
appropriately qualified physician according to local guidelines for formal comprehensive 
dermatologic evaluation.  A 4 mm punch biopsy will be taken unless there is a clear, 
non-drug related etiology (eg, infection, pre-existing condition) or other clinical rationale 
(eg, if the rash is present on the face it may not be appropriate to take a biopsy) or if a subject 
refuses to have biopsy performed.  The biopsy will be sent to the local laboratory for 
histological investigation of the rash in order to gain insight into potential etiology of the 
rash. Note: For herpetiform rash, no biopsy is required.
In addition to a biopsy of suspected drug-related rash, a swab (for microbiological 
assessment) of the affected area will also be taken for culture and sensitivity to assess for any 
bacterial, viral or fungal pathogens, if applicable.  A blood sample for viral surveillance will 
be collected for the analysis of viral load, if applicable. 
Subjects reporting rash should assess itch on a 10-point numeric rating scale (NRS) provided 
by Pfizer (Appendix 14). The investigator (and/or designee) will enter this assessment into 
the data collection tool. 
Investigators (and /or designee) will complete required documentation and take appropriate 
photographs of the rash.
All de-identified biopsy results, culture results, photographs, and any additional relevant test 
results will be forwarded to Pfizer (and/or designee) for review within 30 days of receipt by 
the investigator.
An independent dermatologist contracted by Pfizer will review all relevant data and 
summarize the data at the end of the study
7.2.12. Audiogram
All subjects will have an audiogram at times specified in the Schedule of Activities.
Audiogram testing at screening must be completed and results available by the baseline visit 
(Visit 2) and audiogram testing at Week 8 (Visit 7) must be completed and results available 
by the Week 12 visit (Visit 9). For subjects that terminate early from the study, if possible, 
efforts must be made to complete the audiology testing and obtain the results.
When possible the subject should have the audiogram performed at the same evaluation 
center during the study. 
If there is a clinically meaningful, treatment related decline in hearing from baseline, the 
subject will be followed off treatment with appropriate testing at regular intervals, until 
hearing returns to baseline or is determined to be clinically stable.


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The information from the audiogram will be entered into the data collection tool.  
Any de-identified audiogram results/reports and any additional relevant test results (if 
applicable) may be requested to be forwarded to Pfizer (and/or designee) at any time during 
the study. 
7.3. Pharmacokinetics
During all study periods, blood samples to provide plasma for pharmacokinetic analysis of
PF-06651600 and for potential exploratory analysis of its metabolite(s) will be collected into 
appropriately labeled tubes containing K2EDTA at times specified in the Schedule of 
Activities.  The date and time of last dose and date and time of sample collection should be 
recorded in the source documents and data collection tool (eg, CRF/DCT).
7.3.1. Shipment of Pharmacokinetic Samples
The shipment address and contact information will be provided to the investigator site prior 
to the initiation of the study.
7.4. Exploratory Biomarkers
All blood, serum, plasma and urine samples for assessment of biomarkers must be collected 
prior to investigational product administration.  Any or all samples may not be analyzed, and 
data may or may not be included in the clinical study report.  Any exploratory biomarkers 
assessed would be to further understand RA or the effects PF-06651600 only.
Analysis of exploratory endpoints may be further detailed in the statistical analysis plan 
(SAP) or exploratory analysis plan (EAP).  Pooled or exploratory analyses, if conducted, 
utilizing the retained exploratory genomic and biomarker samples across PF-06651600 
studies or across multiple programs will be documented in a separate analysis plan.
7.4.1. IFN-gamma-inducible protein 10 (IP-10)
Samples for analysis of IP-10 will be collected at the visits specified in the Schedule of 
Activities.  The samples will be shipped to and analyzed by a contract lab.  After
randomization, the investigator and Pfizer study personnel directly involved in the conduct of 
the trial will be kept blinded of the results of this test.
7.4.2. Anti-CCP and Rheumatoid Factor
A blood sample for assaying Anti-CCP and Rheumatoid Factor will be collected according to 
the Schedule of Activities.  After randomization, the investigator and Pfizer study personnel 
directly involved in the conduct of the trial will be kept blinded of the results of this test.
7.4.3. Samples for Exploratory Fluorescence Activated Cell Sorting (FACS) analysis 
Whole blood samples will be collected according to the times specified in the Schedule of 
Activities.  This blood sample will be used to run a standard T cell, B cell and NK cell
subsets (TBNK) panel, and may be used to analyze additional FACS analyses.


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7.5. Banked Biospecimens
Banked biospecimens will be collected from subjects for exploratory research relating to the 
drug response in diseases of inflammation.  These collections are not typically associated 
with a planned assessment described in the protocol.  They will be handled in a manner that 
protects each subject’s privacy and confidentiality.  Banked biospecimens will be assigned 
the subject’s study identification code (ID) at the site.  The data generated from these banked 
biospecimens will also be indexed by this ID.  Biospecimens will be kept until destruction in 
facilities with access limited to authorized personnel, and biospecimen-derived data will be 
stored on password-protected computer systems.  The key between the subject’s ID and the 
subject’s direct personally identifying information (eg, name, address) will be held at the 
study site.  Biospecimens will be used only for the purposes described in the protocol and 
informed consent document; any other uses require additional ethical approval.  Unless a 
time limitation is required by local regulations or ethical requirements, biospecimens will be 
stored for many years (no time limit) to allow for research in the future, including research 
conducted during the lengthy drug-development process and also postmarketing research.  
Subjects may withdraw their consent for the use of their banked biospecimens at any time by 
making a request to the investigator; in this case, any remaining biospecimens will be 
destroyed, but data already generated from the biospecimens will continue to be available to 
protect the integrity of existing analyses. 
Unless prohibited by local regulations or ethics committee decision, a 4-mL blood genomic 
banked biospecimen Prep D1 (dipotassium edetic acid [ethylenediaminetetraacetic acid] 
[K2EDTA] whole-blood collection optimized for DNA analysis) will be collected at the 
time specified in the Schedule of Activities section of the protocol to be retained for potential 
pharmacogenomic/genomic/biomarker analyses related to drug response in diseases of 
inflammation.  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.  The primary purpose is to examine DNA; however, the biospecimen may 
also be used to study other molecules (eg, RNA, proteins, and metabolites).
If not collected on the designated collection day, collect at the next available time point when 
biospecimens are being collected in conjunction with a subject visit.  These samples must be 
collected before administration of the investigational product.
Additional banked biospecimens to be retained for such exploratory analyses in this study 
include the following: 

Prep B1 (K2EDTA plasma collection optimized for biomarker/proteomic/
metabonomic analysis): A 10-mL blood biospecimen will be collected at times 
specified in the Schedule of Activities section of the protocol. 

Prep B2 (serum collection optimized for biomarker/proteomic/metabonomic 
analysis): a 10-mL blood biospecimen will be collected at times specified in the 
Schedule of Activities section of the protocol. 


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
Prep R1 (PAXGene whole-blood collection optimized for RNA analysis): A 
2.5-mL blood biospecimen will be collected at times specified in the Schedule of 
Activities section of the protocol.
The banked biospecimens will be collected from all subjects unless prohibited by local 
regulations or IRB/EC.
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document that they will not be compensated 
in this event.
7.5.1. Shipment of Biomarkers Samples
The shipment address and contact information for the lab will be provided to the investigator 
site. 
7.5.2. Additional Research
Unless prohibited by local regulations or IRB/EC decision, subjects will be asked to indicate 
on the consent form whether they will allow banked biospecimens to also be used to design 
and conduct research in order to gain a further understanding of other diseases and to 
advance science, including development of other medicines for patients.
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Banked Biospecimens section will be used.  Subjects may still 
participate in the study if they elect not to allow their banked biospecimens to be used for the 
additional purposes described in this section.
7.6. Rater Qualifications 
Tender and swollen joint counts will be evaluated by a designated study staff member at the 
clinic. 
For consistency, the same assessor should perform all joint-count evaluations across the 
study for an individual subject when possible.  It is especially important that the same 
assessor evaluate the subject at Screening, Baseline, and Week 8 to ensure integrity of the 
eligibility criteria and the clinical response up to the Week 8 primary endpoint.  Only if the 
assigned joint count assessor cannot be present, the joint counts should be performed by a 
different study staff member. 
The joint count assessor must have a background in performing RA or other clinical trials 
involving swollen and tender joint assessment and to have personal prior experience 
performing joint assessments. 


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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 


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subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
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.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject/legally acceptable representative.  In addition, each study 
subject/legally acceptable representative will be questioned about the occurrence of AEs in a 
non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal/Early Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.


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8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
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.
8.1.5. 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 on the CRF, 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.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. 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.


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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study 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 signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or


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
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; 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 
recording as an AE.
8.2.3. 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.
Or that is considered to be:

An important medical event.
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.
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.
8.2.4. 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 


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tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is 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 outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

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 SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.


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8.3. Severity Assessment
If required on the AE page of the CRF, 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.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.


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The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 


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All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the Liver Function Test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).


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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
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.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the 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.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.


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An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

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.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 


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appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
The information from the placebo arm will be combined with the historic database using 
Bayesian statistical methodology.  The historic study data base will include the data obtained 
from Phase III tofacitinib trials available to the Sponsor.  The integration details and 
historical data specifications will be detailed in SAP.  The integration with historical data 
will involve application of statistical procedures attempting maximization of the 
commensurability between the current trial and the subgroup of the historical data used for 
synthesizing the prior distribution. 
9.1. Sample Size Determination
The primary endpoint of the study will be the change from baseline in SDAI at 8 weeks.  The 
study will enroll approximately 50 completers allocated as follows: 
PF-06651600 (200 mg) (N)
Placebo (N)
30
20
Assuming a 15% dropout rate* the study will enroll approximately 60 subjects.
The study will have over 90% power to detect separation from placebo, assuming a 13 point 
difference in response between the placebo and 200 mg arm (standard deviation is assumed 
to be 14 points for both arms*) and controlling Type-I error rate at 5% level.  More detailed 
sample size considerations will be discussed in the SAP.
*Based on information from Phase 3 tofacitinib studies. 
9.2. Efficacy Analysis
9.2.1. Analysis of the Primary Endpoint 
The primary efficacy analysis will be conducted on SDAI change from baseline at 8 weeks. 
Analysis will include data on PF-06651600 and placebo arms. 
Analysis details will be outlined in statistical analysis plan.  The analysis will include: 
ANCOVA models adjusting for SDAI baseline value; Bayesian analysis of posterior 
distributions of the SDAI scores and placebo adjusted change from baseline; Advanced data 
visualization techniques for statistical result presentation. 
The primary analysis will be conducted on intention-to-treat (ITT) population (randomized 
subjects with at least one post baseline value).  Sensitivity analysis and handling of the 
missing values will be outlined in the SAP.


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9.2.2. Analysis of Secondary Endpoints
Analyses of the secondary endpoints will be outlined in the SAP.  Continuous and discrete 
modeling techniques will be applied whenever applicable.  The statistical summaries will be 
presented by dose groups.  The correlations between the endpoints will be analyzed. 
9.3. Analysis of Other Endpoints
Analysis of other endpoints will be conducted as deemed appropriate.  Continuous and 
discrete modelling techniques will be applied whenever applicable.  Distribution summaries 
will be presented by means of summary tables and data visualization methods.
9.4. Randomization
The indicator of prior exposure and inadequate response to anti-TNFtreatment will be used 
as a stratification variable for randomization.  Randomization will be stratified to achieve 
equal proportion of anti-TNFinadequate responders in all arms.
9.5. Safety Analysis
All clinical AEs, SAEs, TEAEs, withdrawal due to AEs, ECGs, vital signs and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of subjects. 
The safety analysis set will include all subjects who have received at least one dose of IP.  
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.  All safety endpoints will be listed and summarized in 
accordance with Pfizer Standards.  Categorical outcomes (eg, AEs) will be summarized by 
subject counts and percentage.  Continuous outcome (eg, BP, pulse rate, etc) will be 
summarized using N, mean, median, standard deviation, etc.  Change from baseline in 
laboratory data, ECGs and vital signs will also be summarized.  Subject listings will be 
produced for these safety endpoints accordingly.
9.6. Data Monitoring Committee 
This study will not use a data monitoring committee.
9.7. PK/PD Unblinding Plan
A PK/PD unblinding plan approved by the clinical lead, clinical pharmacology lead and 
statistical lead will be in place to describe the procedures to be employed in safeguarding the 
study blind for members of this study team.  These procedures will be in accordance with 
applicable Pfizer SOPs for releasing randomization codes and breaking the study blind. 
Under this plan a group of Statisticians, PK/PD data provider, PK/PD analyst and PK/PD 
support would be unblinded in order to initiate the building of statistical models of the PK, 
dose/response as well as exposure/response analysis models and conduct associated 
simulations.  The aim of this work would be to facilitate a fuller interpretation of the study 
upon completion (at appropriate interim milestone). 


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This group will not serve on the study team during the period of early unblinding.  The 
unblinding may occur after the last subject has been randomized.  The details of the 
procedures will be described in the PK/PD Unblinding Plan for Modelling and Simulation for 
study B7981006 which will be finalized prior to the start of the PK/PD unblinding. 
9.8. Unblinding for Biomarkers
In order to expedite the analyses of the biomarkers, an unblinded team may review the 
biomarker data (including exploratory biomarkers) and exposure data on an ongoing basis.  
This group will minimally be comprised of a bioanalyst and a statistician, but may also 
include clinicians/precision medicine personnel, clinical pharmacologist and PK/PD 
analyst/support staff as appropriate.  This group will be unblinded when needed in order to 
conduct the analyses of the biomarkers in accordance with a biomarker data analysis plan, 
and will be independent of the study team.  This unblinding process will be in accordance 
with Pfizer SOPs related to Releasing Randomization Codes and Breaking the Blind and will 
not have any impact on the conduct of the study. 
The biomarker plan, approved by the clinical lead, clinical pharmacology lead and statistical 
lead, will be in place to describe the procedures to be employed in safeguarding the study 
blind for members of the study team.  The biomarker plan will outline the range of possible 
analyses and provide details of the decision-making process regarding unblinding.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent 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.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/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 investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  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.


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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 or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/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. 


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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 the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
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 numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The investigator
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 and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.


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The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection. 
The investigator must ensure that each study subject, or his or her legally acceptable 
representative is fully informed about the nature and objectives of the study and possible 
risks associated with participation. 
Whenever consent is obtained from a subject’s legally acceptable representative, the 
subject’s assent (affirmative agreement) must subsequently be obtained when the subject has 
the capacity to provide assent, as determined by the IRB/EC.  If the investigator determines 
that a subject’s decisional capacity is so limited he/she cannot reasonably be consulted, then, 
as permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
subject’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study subject does not provide his or her own consent, the source documents
must record why the subject did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the subject’s legally 
acceptable representative, the consent signer’s relationship to the study subject (eg, parent, 
spouse), and that the subject’s assent was obtained or waived.  If assent is obtained verbally,
it must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative, before any 
study-specific activity is performed.  The investigator will retain the original of each subject's 
signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. 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.


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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 
PF-06651600 at any time.If a study is prematurely terminated, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 1 month.  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 (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final 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 prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.


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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 the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, 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 it is 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 investigator sites, and that any subsequent publications 
by the PI 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.
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.
Anderson J et al., Rheumatoid Arthritis Disease Activity Measures: American College 
of Rheumatology Recommendations for Use in Clinical Practice, Arthritis Care & 
Research Vol. 64, No. 5, May 2012, pp 640–647.
2.
Decernotinib drug information available online at
http://adisinsight.springer.com/drugs/800028324.
3.
Baird, A. M., et al. (1998). "T cell development and activation in Jak3-deficient mice." 
J Leukoc Biol 63(6): 669-677.
4.
Baslund, B., et al. (2005). "Targeting interleukin-15 in patients with rheumatoid 
arthritis: a proof-of-concept study." Arthritis Rheum 52(9): 2686-2692.
5.
Feist E, Burmester G (2013). Small molecules targeting JAKs—a new approach in the 
treatment of rheumatoid arthritis. Rheumatology 52 (8): 1352-1357.
6.
Churchman, S. M. and F. Ponchel (2008). "Interleukin-7 in rheumatoid arthritis." 
Rheumatology (Oxford) 47(6): 753-759.
7.
Coenen JH M., (2007) Pharmacogenetics of anti-TNF treatment in patients with 
rheumatoid arthritis. July 2007 ,Vol. 8, No. 7, Pages 761-773.
8.
Fleischmann, R. M., et al. (2015). "A randomized, double-blind, placebo-controlled, 
twelve-week, dose-ranging study of decernotinib, an oral selective JAK-3 inhibitor, as 
monotherapy in patients with active rheumatoid arthritis." Arthritis Rheumatol 67(2): 
334-343.
9.
Frucht, D. M., et al. (2001). "Unexpected and variable phenotypes in a family with 
JAK3 deficiency." Genes Immun 2(8): 422-432.
10.
Genovese, M. C., et al. (2016). "Efficacy of VX-509 (decernotinib) in combination with 
a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical 
and MRI findings." Ann Rheum Dis.
11.
Genovese, M. C., et al. (2016). "VX-509 (Decernotinib), an Oral Selective JAK-3 
Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis." 
Arthritis Rheumatol 68(1): 46-55.
12.
Nosaka, T., et al. (1995). "Defective lymphoid development in mice lacking Jak3." 
Science 270(5237): 800-802.
13.
Olaharski, A.J., et al. (2009) “Identification of a kinase profile that predicts 
chromosome damage induced by small molecule kinase inhibitors.” PLoS 
computational biology 5:e1000446.


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14.
O'Shea, J. J., et al. (2013). "Janus kinase inhibitors in autoimmune diseases." Ann 
Rheum Dis 72 Suppl 2: ii111-115.
15.
Saag, K. G., et.al., (2008), American College of Rheumatology 2008 recommendations 
for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in 
rheumatoid arthritis. Arthritis & Rheumatism, June 2008 59 (6): 762–784.
16.
Silman, A. J. and J. E. Pearson (2002). "Epidemiology and genetics of rheumatoid 
arthritis." Arthritis Res 4 Suppl 3: S265-272.
17.
Smolen, J. S., et al. (2010). "EULAR recommendations for the management of 
rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic 
drugs." Ann Rheum Dis 69(6): 964-975.
18.
Tanaka, Y. (2015). "Recent progress and perspective in JAK inhibitors for rheumatoid 
arthritis: from bench to bedside." J Biochem 158(3): 173-179.
19.
Rojas-Zuleta, W. G. and G. Vasquez (2016). "Th9 lymphocytes: A recent history from 
IL-9 to its potential role in rheumatic diseases." Autoimmun Rev 15(7): 649-655.
20.
Willemze, A., et al. (2012). "The influence of ACPA status and characteristics on the 
course of RA." Nat Rev Rheumatol 8(3): 144-152.
21.
Yang, X. K., et al. (2015). "Therapeutic potential of IL-15 in rheumatoid arthritis." Hum 
Immunol 76(11): 812-818.
22.
Arava(Leflunomide) Prescribing label. Revised July 2011. Available online at 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020905s022lbl.pdf.
23.
van Riel, P. L., et al. (2004). "Leflunomide: a manageable safety profile." J Rheumatol 
Suppl 71: 21-24.
24.
Aletaha, D., et al. (2010). "2010 Rheumatoid arthritis classification criteria: an 
American College of Rheumatology/European League Against Rheumatism 
collaborative initiative." Arthritis Rheum 62(9): 2569-2581.
25.
Aletaha, D., et al. (2010). "2010 rheumatoid arthritis classification criteria: an American 
College of Rheumatology/European League Against Rheumatism collaborative 
initiative." Ann Rheum Dis 69(9): 1580-1588.
26.
Hochberg, M. C., et al. (1992). "The American College of Rheumatology 1991 revised 
criteria for the classification of global functional status in rheumatoid arthritis." Arthritis 
Rheum 35(5): 498-502.
27.
RA drug information wash out is available online at http://dudleygroup.nhs.uk/wp-
content/uploads/2014/07/Guidelines-for-rheumatology-patients-on-biologic-therapy-
V1.pdf.


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28.
Mager, D. E., et al. (2003). "Dose equivalency evaluation of major corticosteroids: 
pharmacokinetics and cell trafficking and cortisol dynamics." J Clin Pharmacol 43(11): 
1216-1227.
29.
Sebb R, and M. Singer (2005). Oxford Handbook of Critical Care. Oxford University 
Press.
30.
Deflazacort drug information available online at 
www.cw.bc.ca/library/pdf/pamphlets/bcch388deflazacort.pdf.
31.
Shapiro, G. G., et al. (1979). "Cloprednol therapy in steroid-dependent asthma." 
Pediatrics 63(5): 747-753.
32.
Brune K. Chapter 3. Drug therapy today. In: Laufer S, Gay S, Brune K, editors. 
Inflammation and rheumatic diseases: the molecular basis of novel therapies. Stuttgart, 
Germany: Georg Thieme Verlag; 2003: p. 69-92.
33.
Adapted from Twycross, R., et al. (1998). Palliative Care Formulary. Abingdon: 
Radcliffe Medical Press.
34.
Adapted from Twycross, R. (1994). Pain relief in advanced cancer. Edinburgh: 
Churchill Livingstone.
35.
Fries JF. (1983) “The assessment of disability: from first to future principles.” Br J 
Rheumatol 22(supple):48-58.
36.
Phan, N. Q., Blome C., et al. (2012). "Assessment of pruritus intensity: prospective 
study on validity and reliability of the visual analogue scale, numerical rating scale and 
verbal rating scale in 471 patients with chronic pruritus." Acta Derm Venereol 92(5): 
502-507.)


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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
AE
adverse event
ACR
american college of rheumatology
ACPA
anti-citrullinated protein antibodies 
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve
ATP
adenosine triphosphate
BA
bioavailability
BID
twice a day
BBS
biospecimen banking system
BP
blood pressure
Cmax
peak or maximum observed concentration
CK
creatine kinase
CMV
cytomegalovirus
CRF
case report form
CSA
clinical study agreement
CSR
clinical study report
CT
computerised tomography
CTA
clinical trial application
CTCAE
common terminology criteria for adverse events
CYP
cytochrome p
DCT
data collection tool
DILI
drug-induced liver injury
DMARD
disease-modifying antirheumatic drugs 
DNA
deoxyribonucleic acid
DU
dispensable unit
EBV
epstein-barr virus
EC
ethics committee
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
EDP
exposure during pregnancy
EOS
end of study
EU
european union
EudraCT
european clinical trials database
EULAR
european league against rheumatism 
FACS
fluorescence-activated cell sorting
FDA
food and drug administration 
FIH
first in human


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Abbreviation
Term
FSH
follicle-stimulating hormone
FU
follow up
fu
fraction unbound
GCP
good clinical practice
GGT
gamma-glutamyl transferase
GST
glutathione-S-transferase
HAQ-DI
health assessment questionnaire – disability index
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBcAb 
hepatitis B core antibody
HIV
human immunodeficiency virus
hsCRP
high-sensitivity C-reactive protein
HSV
herpes simplex virus
IC50
50% inhibitive concentration
ICH
international conference on harmonisation
ID
identification
IgA, G, M, E
immunoglobulin of the A, G, M , E isotypes
IGRA
interferon-gamma release assay
IL 
interleukin  
IND
investigational new drug application
IFN
interferons 
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
ITT
intent to treat
IUD
intrauterine device
IV
intravenous
IWR
interactive web response
JAK
janus kinase 
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LFT
liver function test
LOAEL
lowest observed adverse effect level
LSLV
last subject last visit 
MAD
multiple ascending dose
MCP
metacarpophalangeals
MRI
magnetic resonance imaging
N/A
not applicable
NOAEL
no observed adverse effect level
NRS
numeric rating scale
NSAID
nonsteroidal anti-inflammatory drugs
PAAP
patient assessment of arthritis pain


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Abbreviation
Term
PCD
primary completion date
PD
pharmacodynamics(s)
PGx
pharmacogenomics(s)
PhGA
physician’s global assessment
PI
principal investigator
PK
pharmacokinetic
PO
per os (oral)
PT
prothrombin time
PtGA
patient’s global assessment
RA
rheumatoid arthritis
RNA
ribonucleic acid
SAE
serious adverse event
SAD
single ascending dose
SAP
statistical analysis plan
SC
subcutaneous
SDAI
simple disease activity index
SJC
swollen joint count
SLE
systemic lupus erthematosus 
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TEAE
treatment emergent adverse event
TJC
tender joint count
TNF
tumor necrosis factor
TNF
tumor necrosis factor alpha
TNFi
TNF inhibitors 
UC
ulcerative colitis
UGT
uridine 5’-diphospho-glucuronosyltransferase
ULN
upper limit of normal
US
United States
VAS
visual analog scale
VZV
varicella zoster virus 
WBC
white blood cells
WONCBP
women of non-childbearing potential


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Appendix 2. 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis24,25
Presented below are the 2010 American College of Rheumatology (ACR)/European League 
Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis. 
Target population (Who should be tested?) must have:
1)  have at least 1 joint with definite clinical synovitis (swelling)*
2)  with the synovitis not better explained by another disease†
Classification criteria for RA (score-based algorithm: add score of categories A–D;
a score of _6/10 is needed for classification of a patient as having definite RA)‡
A. Joint involvement§
SCORE (A) ______
1 large joint¶ 
0
2-10 large joints 
1
1-3 small joints (with or without involvement of large joints)# 
2
4-10 small joints (with or without involvement of large joints) 
3
>10 joints (at least 1 small joint)** 
5
B. Serology (at least 1 test result is needed for classification)††
SCORE (B) ______
Negative RF and negative ACPA 
0
Low-positive RF or low-positive ACPA 
2
High-positive RF or high-positive ACPA 
3
C. Acute-phase reactants (at least 1 test result is needed for classification)‡‡
SCORE (C) ______
Normal CRP and normal ESR 
0
Abnormal CRP or abnormal ESR 
1
D. Duration of symptoms§§
SCORE (D) ______
<6 weeks 
0
6 weeks 
1
TOTAL SCORE (A+B+C+D) ___________
A TOTAL Score of 6/10 is needed for classification of a patient as having definite RA)‡
* The criteria are aimed at classification of newly presenting patients.  In addition, patients with 
erosive disease typical of rheumatoid arthritis (RA) with a history compatible with prior fulfillment 
of the 2010 criteria should be classified as having RA.  Patients with longstanding disease, 
including those whose disease is inactive (with or without treatment) who, based on retrospectively 
available data, have previously fulfilled the 2010 criteria should be classified as having RA.


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† Differential diagnoses vary among patients with different presentations, but may include conditions 
such as systemic lupus erythematosus, psoriatic arthritis, and gout.  If it is unclear about the 
relevant differential diagnoses to consider, an expert rheumatologist should be consulted.
‡ Although patients with a score of <6/10 are not classifiable as having RA, their status can be 
reassessed and the criteria might be fulfilled cumulatively over time.
§ Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by
imaging evidence of synovitis.  Distal interphalangeal joints, first carpometacarpal joints, and first
metatarsophalangeal joints are excluded from assessment.  Categories of joint distribution are 
classified according to the location and number of involved joints, with placement into the highest 
category possible based on the pattern of joint involvement.
¶ “Large joints” refers to shoulders, elbows, hips, knees, and ankles.
# “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second 
through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.
** In this category, at least 1 of the involved joints must be a small joint; the other joints can include 
any combination of large and additional small joints, as well as other joints not specifically listed 
elsewhere (eg, temporomandibular, acromioclavicular, sternoclavicular, etc.).
†† Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the
laboratory and assay; low-positive refers to IU values that are higher than the ULN but 3 times the 
ULN for the laboratory and assay; high-positive refers to IU values that are >3 times the ULN for 
the laboratory and assay.  Where rheumatoid factor (RF) information is only available as positive or 
negative, a positive result should be scored as low-positive for RF.  ACPA= anti-citrullinated 
protein antibody.
‡‡ Normal/abnormal is determined by local laboratory standards.  CRP = C-reactive protein; 
ESR = erythrocyte sedimentation rate.
§§ Duration of symptoms refers to patient self-report of the duration of signs or symptoms of 
synovitis (eg, pain, swelling, tenderness) of joints that are clinically involved at the time of 
assessment, regardless of treatment status.


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Appendix 3. Criteria for Classification of Functional Status in Rheumatoid Arthritis26
Class I: Completely able to perform usual activities of daily living (self-care, vocational, and 
avocational).
Class II: Able to perform usual self-care and vocational activities, but limited in avocational 
activities.
Class III: Able to perform usual self-care activities, but limited in vocational and avocational 
activities.
Class IV: Limited in ability to perform usual self-care, vocational, and avocational activities.
Usual self-care activities including dressing, feeding, bathing, grooming, and toileting.  
Avocational (recreational and/or leisure) and vocational (work, school, homemaking) 
activities are patient-desired and age- and sex-specific.


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Appendix 4. Prohibited Concomitant Medications
This is not an all-inclusive list.  Study personnel should stay current and consult with their 
pharmacy to exclude all concomitant medications that are either moderate to potent CYP3A 
inhibitors or inducers.
Moderate to Potent CYP3A Inhibitors*
Moderate to Potent CYP3A 
Inducers**
Amprenavir
Avasimibe#
Amiodarone 
Bosentan
Aprepitant
Barbiturates
Atazanavir
Carbamazepine#
Boceprevir
Efavirenz 
Casopitant
Etravirine
Cimetidine
Mitotane#
Ciprofloxacin
Modafinil
Clarithromycin#
Nafcillin
Cobicistat#
Phenobarbital#
Conivaptan#
Phenytoin#
Darunavir
Rifabutin#
Diethyldithiocarbamate
Rifampin #
Diltiazem
St. John’s Wort#
Dronedarone
Talviraline
Elvitegravir#
Erythromycin
Fluconazole
Fluvoxamine
Imatinib
Indinavir#
Itraconazole#
Ketoconazole#
Lopinavir#
Mibefradil#
Mifepristone (RU486)
Nefazodone#
Nelfinavir#
Norfloxacin
Posaconazole#
Ritonavir #
Saquinavir#
Schisandra sphenanthera
Telaprevir
Telithromycin#
Tipranavir#
Tofisopam
Troleandomycin#
Verapamil
Voriconazole#
* 
All prohibited drugs that are CYP3A inhibitors require at least a 7 day or 
5 half-lives (whichever is longer) washout prior to the first dose of study drug.  
Note: Amiodarone requires discontinuation at least 290 days (~5 half-lives, 
half-life averages ~58 days) prior to the first dose of study drug.


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** All prohibited drugs that are CYP3A inducers require at least a 28 day or 
5 half-lives (whichever is longer) washout prior to the first dose of study drug.
# 
Notated as potent inhibitors or inducers. 
It is recommended that subjects avoid consumption of grapefruit juice exceeding 
8 ounces (~240 ml) total in a day while in the study.
In a situation where appropriate medical care of a subject requires the use of a 
prohibited CYP3A inhibitor or inducer:
Moderate to potent inhibitors and inducers of CYP3A are not permitted in the study 
EXCEPT in emergency situations requiring no more than one day of administration.  
Note: Amiodarone and mitotane are not permitted for any duration due to their long 
half-lives.  Topical (including skin or mucous membranes) application of 
antimicrobial and antifungal medications is permitted.


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Appendix 5. Guidelines for Monitoring and Discontinuations
These guidelines for subject safety monitoring and discontinuation are to be applied to all 
subjects in this study.  Additional individual subject monitoring is at the discretion of the 
investigator and dependent on any perceived safety concerns.  Unscheduled clinical labs may 
be obtained at any time during the study to assess such concerns, and a subject may be 
withdrawn at any time at the discretion of the investigator.
Monitoring
The following laboratory abnormalities require re-testing within 1 week:

Absolute neutrophil count <2000/mm3; (< 2 x 109/L)

Hemoglobin <9.0 g/dL;

Platelet count below <100,000/mm3; (<100 x 109/L)

Lymphocyte counts <500 lymphocytes/mm3; (<0.5x109/L)

Any single AST and/or ALT elevation 3 times the upper limit of normal (repeat 
laboratory testing should include albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, PT [prothrombin time] with INR [international 
normalized ratio], and alkaline phosphatase), regardless of the total bilirubin.  
(Please note that 3 times the upper limit of normal increases in ALT, AST need 
confirmation on separate blood draw before undertaking thorough evaluation for 
liver injury);

All potential treatment-related reports of rash will be followed up until resolution or in
agreement with Pfizer.  

Positive urine -hCG test, the subject will have study drug interrupted and a serum 
sample collected on the same day (or as soon as possible) and submitted to the central 
laboratory for -hCG testing.
Discontinuation
The sponsor’s Clinical team should be notified as soon as possible and subject treatment will 
be discontinued and the subject withdrawn from this study for:

Two sequential hemoglobin value <8.0 g/dL or one that drops 2 g/dL below baseline

Two sequential absolute neutrophil counts <750/mm3 ; (<0.75 x 109/L)

Two sequential platelet counts <75,000/mm3 ;(<75 x 109/L)

Two sequential lymphocyte counts <500 lymphocytes/mm3; (<0.5x109/L)


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
Two sequential AST or ALT elevation 3 times the upper limit of normal with at 
least one total bilirubin value 2 times the upper limit of normala

Two sequential AST or ALT elevation 3 times the upper limit of normal 
accompanied by signs or symptoms consistent with hepatic injurya

Two sequential AST or ALT elevation 5 times the upper limit of normal, regardless 
of total bilirubin or accompanying signs or symptomsa

Serious infections, defined as any infection (viral, bacterial, and fungal) requiring 
parenteral antimicrobial therapy, hospitalization for treatment, or meeting other 
criteria that require the infection to be classified as serious adverse event

Other serious or severe AEs, at the discretion of the investigator or sponsor

Female subjects found to be pregnant during the study; For women of child-bearing 
potential with any positive urine -hCG test, the subject will have study drug 
interrupted and a serum sample submitted to the central laboratory for -hCG testing

Subjects who are treated with any prohibited medication during the course of the 
study

Serious or severe drug-related rash at the discretion of the investigator or sponsor. 
(See Section 7.2.11)

Subjects who require rescue doses of acetaminophen/paracetamol or opioid for more 
than 10 consecutive days or within the last 7 days before the last dose should be 
discontinued from the trial;
a 
In each case, there is a need for additional investigations, such as review of ethanol, recreational 
drug and dietary supplement consumption; testing for acute hepatitis A, B or C infection and 
biliary tract imaging should be promptly discussed with the Pfizer medical monitor or designee.
If a patient has any clinically significant, treatment emergent abnormalities at the conclusion 
of the study, the medical monitor (or designated representative) should be notified and every 
effort should be made to arrange follow-up evaluations at appropriate intervals to document 
the course of the abnormality. All abnormal laboratory events of clinical significance should 
be followed until the laboratory values have returned to the normal or baseline levels or is 
otherwise considered stable by the investigator.


PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 94
Appendix 6. Disease Activity Score (DAS) Assessments1
DAS-28-4 (CRP) Assessment
The formula for calculation of DAS28-4 (CRP) using 4 components:

Swollen Joints (0–28);

Tender Joints (0–28);

CRP

Patient’s Global Assessment of Arthritis (PtGA) (0 – 100 mm VAS).
DAS28-4 (CRP)= 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint 
count) + 0.36 ln(CRP [mg/L] +1) + 0.014 (PtGA [mm]) + 0.96
DAS-28-4 (ESR) Assessment
The formula for calculation of DAS28-4 (ESR) using 4 components:

Swollen Joints (0–28);

Tender Joints (0–28);

Erythrocyte Sedimentation Rate (ESR);

Patient’s Global Assessment of Arthritis (PtGA) (0 – 100 mm VAS).
DAS28-4 (ESR)= 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint 
count) + 0.70 ln (ESR [mg/L] + 0.014 (PtGA [mm]) 


PF-06651600 
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Final Protocol Amendment 1, 26 October 2016
Page 95
Appendix 7. Patient’s Assessment of Arthritis Pain (PAAP)
MY PAIN AT THIS TIME IS:
(PLEASE MAKE AN X MARK ON THE LINE BELOW.)
No   ________________________________________________________Most Severe
Pain
Pain
[Note: Scale will be 100 mm in length]


PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 96
Appendix 8. Patient’s Global Assessment (PtGA) of Arthritis
CONSIDERING ALL THE WAYS YOUR ARTHRITIS AFFECTS YOU, HOW ARE 
YOU FEELING TODAY?
(PLEASE MAKE AN X MARK ON THE LINE BELOW.)
Very   ______________________________________________________ Very 
Well
Poorly
[Note: Scale will be 100 mm in length]


PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 97
Appendix 9. Physician’s Global Assessment (PhGA) of Arthritis
THE PATIENT’S ARTHRITIS AT THIS TIME IS:
(PLEASE MAKE AN X MARK ON THE LINE BELOW.)
Very   ______________________________________________________ Very
Good
Poor
[Note: Scale will be 100 mm in length]


PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 98
Appendix 10. Oral Corticosteroid Equivalents28,29,30,31,32
The following is a summary of corticosteroid equivalents.
Oral corticosteroids – subjects already taking oral corticosteroids must be on a stable dose of 
10 mg/day of prednisone or equivalent for at least 4 weeks prior to first dose of study drug. 
Compound
Equivalent Dose (mg)
Prednisone
10
Prednisolone
10
6-methylprednisolone
8
Triamcinolone
8
Betamethasone
1.2
Dexamethasone
1.5
Hydrocortisone
40
Cortisone
50
Deflazacort
12
Cloprednol
5
Prednylidene
12
Note: these dose relationships apply to oral administration.


PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 99
Appendix 11. Allowed Opioids and Approximate Equivalent Morphine Doses Of 
Opioid Analgesics33,34
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
Propoxyphene HCl 
(Darvon, Darvocet, 
Doloxene) Propoxyphene 
napsylate (Darvon-N, 
Darvocet-N 100)
300 mg 
propoxyphene HCl
400 mg 
propoxyphene 
napsylate
~0.1
6-12 hrs; 30-36 hrs. 
for active metabolite 
(norpropoxyphene)
Sites should contact project team for acceptable alternative preparations and related data.


PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 100
Appendix 12. Common Terminology Criteria for Adverse Events v4.03
(CTCAE)-Dermatology
The NCI Common Terminology Criteria for Adverse Events v4.03 is a descriptive 
terminology that can be utilized for Adverse Event (AE) reporting.  A grading (severity) 
scale is provided for each AE term.  One page of the Dermatology/Skin Category is 
presented, which contains listings for Pruritus, Rash/Desquamation, and Rash: 
Acne/acneiform.
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Pruritus
Mild or localized; 
topical intervention 
indicated
Intense or 
widespread; 
intermittent; skin 
changes from 
scratching (eg,
edema, papulation, 
excoriations, 
lichenification, 
oozing/crusts); oral 
intervention 
indicated; limiting 
instrumental ADL
Intense or 
widespread; constant; 
limiting self care 
ADL or sleep; oral 
corticosteroid or 
immunosuppressive 
therapy indicated
-
-
Definition: A disorder characterized by an intense itching sensation.
Purpura
Combined area of 
lesions covering 
<10% BSA
Combined area of 
lesions covering 10 -
30% BSA; bleeding 
with trauma
Combined area of 
lesions covering 
>30% BSA; 
spontaneous bleeding
-
-
Definition: A disorder characterized by hemorrhagic areas of the skin and mucous membrane. Newer lesions appear 
reddish in color.  Older lesions are usually a darker purple color and eventually become a brownish-yellow color.
Rash acneiform
Papules and/or 
pustules covering 
<10% BSA, which 
may or may not be 
associated with 
symptoms of pruritus 
or tenderness
Papules and/or 
pustules covering 
10 - 30% BSA, which 
may or may not be 
associated with 
symptoms of pruritus 
or tenderness; 
associated with 
psychosocial impact; 
limiting instrumental 
ADL
Papules and/or 
pustules covering 
>30% BSA, which 
may or may not be 
associated with 
symptoms of pruritus 
or tenderness; 
limiting self care 
ADL; associated with 
local superinfection 
with oral antibiotics 
indicated
Papules and/or 
pustules covering any 
% BSA, which may 
or may not be 
associated with 
symptoms of pruritus 
or tenderness and are 
associated with 
extensive 
superinfection with 
IV antibiotics 
indicated; life-
threatening 
consequences
Death
Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest 
and back.
Rash maculo-papular Macules/papules 
covering
<10% BSA with or 
without symptoms 
(eg, pruritus, burning, 
tightness)
Macules/papules 
covering 10
- 30% BSA with or 
without symptoms 
(eg, pruritus, burning, 
tightness); limiting 
instrumental ADL
Macules/papules 
covering
>30% BSA with or 
without associated 
symptoms; limiting 
self care ADL
-
-
Definition: A disorder characterized by the presence of macules (flat) and papules (elevated).  Also known as morbillform 
rash, it is one of the most common cutaneous adverse events, frequently affecting the upper trunk, spreading centripetally 
and associated with pruritus.


PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 101
Rash/desquamation and erythema multiforme progressing to Grade 2, acne/acneiform rash or 
pruritus progressing to Grade 3 are the severity levels for permanently discontinuing a 
subject from investigational product.
Pruritus progressing to Grade 2 sustained (>4 days) is cause to permanently discontinue 
investigational product.


PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 102
Appendix 13. HAQ-DI35
Health Assessment Questionnaire - Disability Index (HAQ-DI)Stanford University 
1983 version:
In this section we are interested in learning how your illness affects your ability to function in 
daily life. 
Please check the response which best describes your usual abilities OVER THE PAST 
WEEK:
Without ANY 
difficulty
With SOME 
difficulty
With MUCH 
difficulty
UNABLE 
to do
DRESSING & GROOMING
Are you able to:
-Dress yourself, including tying 
shoelaces and doing buttons?
-Shampoo your hair?
ARISING
Are you able to:
-Stand up from a straight chair?
-Get in and out of bed?
EATING
Are you able to:
-Cut your meat?
-Lift a full cup or glass to your 
mouth?
-Open a new milk carton?
WALKING
Are you able to:
-Walk outdoors on flat ground?
-Climb up five steps?


PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 103
Please check any AIDS OR DEVICES that you usually use for any of these activities:
Cane
Devices used for dressing (button hook, zipper pull, 
long-handled shoe horn, etc.)
Walker
Crutches
Built up or special utensils 
Wheelchair
Special or built up chair
Other (Specify:_______________)
Please check any categories for which you usually need HELP FROM ANOTHER 
PERSON:
Dressing and Grooming
Eating
Arising 
Walking
Please check the response which best describes your usual abilities OVER THE PAST 
WEEK:
Without ANY 
difficulty
With SOME 
difficulty
With 
MUCH 
difficulty
UNABLE 
to do
HYGIENE
Are you able to:
-Wash and dry your body?
-Take a tub bath?
-Get on and off the toilet?
REACH
Are you able to:
-Reach and get down a 5-pound object 
(such as a bag of sugar) from just above 
your head?
-Bend down to pick up clothing from the 
floor?


PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 104
Without ANY 
difficulty
With SOME 
difficulty
With 
MUCH 
difficulty
UNABLE 
to do
GRIP
Are you able to:
-Open car doors?
-Open jars, which have been previously 
opened?
-Turn faucets on and off?
ACTIVITIES
Are you able to:
-Run errands and shop?
-Get in and out of a car?
-Do chores such as vacuuming or yard 
work?
Please check any AIDS OR DEVICES that you usually use for any of these activities:
Raised toilet seat
Bathtub bar
Bathtub seat 
Long-handled appliances for reach
Jar opener (for jars previously 
opened)
Long-handled appliances in bathroom
Other (Specify:_______________)
Please check any categories for which you usually need HELP FROM ANOTHER 
PERSON:
Hygiene
Gripping and opening things
Reach
Errands and chores


PF-06651600 
B7981006
Final Protocol Amendment 1, 26 October 2016
Page 105
Appendix 14. Assessment of Itch (NRS)36
Severity of Pruritus
Select the number that best describes your itching over the past 24 hours (check one number 
only).
10
9
8
7
6
5
4
3
2
1
0
10
9
8
7
6
5
4
3
2
1
0
No 
itching
Worst 
possible 
itching

SAP_001.pdf: 
Protocol B7981006 (PF-06651600) Statistical Analysis Plan
Page 1
Protocol B7981006
A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP, 
PLACEBO-CONTROLLED, MULTI-CENTER STUDY TO ASSESS THE EFFICACY 
AND SAFETY PROFILE OF PF-06651600 IN SUBJECTS WITH MODERATE TO 
SEVERE ACTIVE RHEUMATOID ARTHRITIS WITH AN INADEQUATE RESPONSE 
TO METHOTREXATE
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
18-JAN-2018


Protocol B7981006 (PF-06651600) Statistical Analysis Plan
Page 2
TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives .......................................................................................................5
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................8
3.1. Primary Endpoint(s) ..................................................................................................8
3.2. Secondary Endpoint(s) ..............................................................................................8
3.3. Patient Outcomes Research (PRO) Endpoints ..........................................................8
...............................................................................................8
3.5. Baseline Variables.....................................................................................................9
3.6. Safety Endpoints .......................................................................................................9
3.6.1. Adverse Events .............................................................................................9
3.6.2. Laboratory Data............................................................................................9
3.6.3. Vital Signs ..................................................................................................10
3.6.4. Electrocardiogram (ECG)...........................................................................10
4. ANALYSIS SETS ...............................................................................................................10
4.1. Intent-to-Treat Analysis Set ....................................................................................10
4.2. Safety Analysis Set..................................................................................................10
4.3. Other Analysis Sets .................................................................................................10
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................10
5.1. Hypotheses and Decision Rules ..............................................................................10
5.2. General Methods .....................................................................................................10
5.2.1. Analyses for Binary Data............................................................................10
5.2.2. Analyses for Continuous Data....................................................................11
5.2.3. Analyses for Categorical Data....................................................................11
5.2.4. Analyses for Time to Event Data................................................................12
5.3. Methods to Manage Missing Data ..........................................................................12
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Protocol B7981006 (PF-06651600) Statistical Analysis Plan
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5.3.1. Binary Endpoint..........................................................................................12
5.3.2. Continuous Endpoints.................................................................................12
6. ANALYSES AND SUMMARIES ......................................................................................12
6.1. Primary Endpoint(s) ................................................................................................12
6.1.1. Primary Analysis ........................................................................................13
6.1.2. Sensitivity/Robustness Analyses ................................................................13
6.2. Secondary Endpoint(s) ............................................................................................13
6.2.1. SDAI...........................................................................................................13
6.2.2. DAS ............................................................................................................14
6.2.3. hsCRP .........................................................................................................14
6.2.4. Tender/Painful and Swollen Joint Count....................................................15
6.2.5. PhGA of Arthritis .......................................................................................15
6.3. PRO Endpoints........................................................................................................15
15
6.5. Subset Analyses.......................................................................................................16
6.6. Baseline and Other Summaries and Analyses.........................................................16
6.6.1. Baseline Summaries....................................................................................16
6.6.2. Study Conduct and Subject Disposition .....................................................16
6.6.3. Study Treatment Exposure .........................................................................16
6.6.4. Concomitant Medications and Non-Drug Treatments................................16
6.7. Safety Summaries and Analyses .............................................................................16
6.7.1. Adverse Events...........................................................................................17
6.7.2. Laboratory Data..........................................................................................17
6.7.3. Vital Signs ..................................................................................................17
6.7.4. Electrocardiogram.......................................................................................17
6.7.5. Physical Examination .................................................................................17
7. INTERIM ANALYSES.......................................................................................................17
8. REFERENCES ....................................................................................................................17
9. APPENDICES .....................................................................................................................18
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments................................................5
Table 2.
Study Objectives and Endpoints.............................................................................5
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Protocol B7981006 (PF-06651600) Statistical Analysis Plan
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LIST OF FIGURES
Figure 1.
Study Design Schematic.........................................................................................7
APPENDICES
Appendix 1. SUMMARY OF EFFICACY ANALYSES........................................................18
Appendix 2. DETAILS OF VISIT WINDOWS......................................................................20
Appendix 3. DATA DERIVATION DETAILS ......................................................................21
Appendix 4. ADDITIONAL METHODOLOGY DETAILS ..................................................23


Protocol B7981006 (PF-06651600) Statistical Analysis Plan
Page 5
1. VERSION HISTORY
This SAP for study B7981006 is based on the protocol dated 22AUG2016.
Table 1.
Summary of Major Changes in SAP Amendments
SAP 
Version
Change
Rationale
1
Not Applicable
Not Applicable
2
Derivation/update of the 
prior distribution for placebo 
response based on the review 
of baseline data.  Changes 
made to Appendix 4
Availability and review of study baseline SDAI 
data.  The prior placebo distribution depends on 
current study baseline data.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B7981006.  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
Table 2.
Study Objectives and Endpoints
Primary Objectives:
Primary Endpoints:

To evaluate the efficacy of 
PF-06651600 at 8 weeks in 
subjects with moderate to severe 
active rheumatoid arthritis.

Change from baseline in simple disease 
activity index (SDAI) at Week 8.
Secondary Objectives:
Secondary Endpoints:

To evaluate the safety of 
PF-06651600.

Safety and tolerability of PF-06651600 versus 
placebo; vital signs, laboratory tests, adverse 
events (AEs) including infections, and 
Serious Adverse Events (SAEs).

To assess other signs of clinical 
efficacy over 8 weeks.

Change from baseline in SDAI at Weeks 1, 2, 
4, and 6.

SDAI low disease activity scale and remission 
rates at Weeks 4, 6, and 8.

Disease activity score (DAS) low disease 
activity scale and remission rates at Weeks 4, 
6, and 8: DAS28-3 (erythrocyte sedimentation 


Protocol B7981006 (PF-06651600) Statistical Analysis Plan
Page 6
rate (ESR)), DAS28-3 (C-reactive protein 
(CRP)), DAS28 -4 (ESR), and DAS28-4 
(CRP).
The following will also be calculated at Weeks 1, 
2,4, 6, and 8:

Change from baseline in DAS28-3 (ESR), 
DAS28-3 (CRP), DAS28 -4 (ESR), and 
DAS28-4 (CRP).

Change from baseline in high sensitivity
C-reactive protein (hsCRP).

Change from baseline in the Tender/Painful 
and Swollen Joint Count (28).

Change from baseline in the Physician’s 
Global Assessment (PhGA) of Arthritis.

To assess the effect of 
PF-06651600 on patient reported 
outcome measurements.

Change from baseline in the Patient’s 
Assessment of Arthritis Pain (PAAP) Visual 
Analogue Scale (VAS) and Patient’s Global 
Assessment (PtGA) of Arthritis VAS at 
Weeks 1, 2, 4, 6, and 8.

Change from baseline in the Health 
Assessment Questionnaire – Disability Index 
(HAQ-DI) at Weeks 1, 2, 4, 6, and 8.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol B7981006 (PF-06651600) Statistical Analysis Plan
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

 

Change from baseline in American College of 
Rheumatology 20 (ACR20), ACR50, and 
ACR70 responder rates.

 
.

*Note: Analysis of exploratory endpoints may be further detailed in SAP or exploratory analysis plan.  Samples 
collected for exploratory endpoints may or may not be analyzed and, if analyzed, may or may not be reported in 
the CSR.
2.2. Study Design
Figure 1.
Study Design Schematic
Note: N indicates the total number of completers.
This is a Phase 2a, 8 week randomized double-blind, parallel group, placebo controlled, 
multi-center study to assess the efficacy and safety profile of PF-06651600 in seropositive 
subjects with moderate to severe active rheumatoid arthritis with an inadequate response to 
methotrexate (up to approximately 50% of subjects may also have had an inadequate 
response to 1 anti- tumor necrosis factor (TNF) biologic disease-modifying antirheumatic 
drug).
Up to approximately 60 subjects may be randomized globally into the study to ensure at least 
approximately 50 subjects complete 8 weeks of active dosing (assuming a dropout rate of 
approximately 15%).  Subjects will participate in this study for approximately 16 weeks.  
This includes an up to 5-week screening period, an 8 week treatment period, and a 4 week 
follow-up period.
After an up to 5 week screening period, eligible subjects will be randomized to receive 
200 mg twice a day (QD) of PF-06651600 or placebo (matching tablets for PF-06651600 
QD) every day for 8 weeks in a blinded fashion.
PF-06651600, 200 mg QD, N= 30
8 Weeks
Dosing
5 Weeks 
Screening
4 Weeks 
Follow Up
Placebo QD, N= 20
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Protocol B7981006 (PF-06651600) Statistical Analysis Plan
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
The primary endpoint for this study is change from baseline in SDAI at Week 8.  The SDAI 
is a continuous composite measure derived from components of the ACR Core Dataset at 
baseline (Day 1), Weeks 1, 2, 4, 6, and 8.
3.2. Secondary Endpoint(s)

Change from baseline in SDAI at Weeks 1, 2, 4, and 6.

SDAI low disease activity scale and remission rates at Weeks 4, 6, and 8.

DAS28-3 (ESR), DAS28-3 (CRP), DAS28 -4 (ESR), and DAS28-4 (CRP) low 
disease activity scale and remission rates at Weeks 4, 6, and 8.
The following will also be calculated at Weeks 1, 2, 4, 6, and 8:

Change from baseline in DAS28-3 (ESR), DAS28-3 (CRP), DAS28 -4 (ESR), and 
DAS28-4 (CRP).

Change from baseline in hsCRP.

Change from baseline in the Tender/Painful and Swollen Joint Count (28).

Change from baseline in the PhGA of Arthritis.
3.3. Patient Outcomes Research (PRO) Endpoints

Change from baseline in the PAAP VAS and PtGA of Arthritis VAS at Weeks 1, 2, 4, 
6, and 8.

Change from baseline in the HAQ-DI at Weeks 1, 2, 4, 6, and 8.
 
 
 
 
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Protocol B7981006 (PF-06651600) Statistical Analysis Plan
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
ACR20, ACR50, and ACR70 responder rates.

3.5. Baseline Variables
Below are baseline variables:

Screening: Demographics and RA history, smoking history, medical history and non 
RA medications, history of alcohol and drug abuse, height, and weight.

Day 1: Vital signs (pulse rate, blood pressure), temperature, and complete physical 
examination.
3.6. Safety Endpoints
Safety will be assessed by the spontaneous reporting of AEs, physical examinations and 
clinical laboratory results in all subjects who receive at least one dose of the investigational 
product.  Unscheduled safety assessments may be performed at any time during the study to 
assess any perceived safety concerns.
3.6.1. Adverse Events
An adverse event 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 (for example, during the baseline or run-in 
period), or

the event was seen prior to the start of treatment but increased in severity during 
treatment.
A 3-tier approach will be used to summarize AEs.  Under this approach, AEs are classified 
into 1 of 3 tiers.  Different analyses will be performed for different tiers (see Section 6.7.1).
Tier-1 events: These are pre-specified events of clinical importance and are maintained in a 
list in the product’s Safety Review Plan.
Tier-2 events: These are events that are not tier-1 but are “common”.  A Medical Dictionary 
for Regulatory Activities (MedDRA) Preferred Term (PT) is defined as a tier-2 event if there 
are at least 4 in any treatment group.
Tier-3 events: These are events that are neither tier-1 nor tier-2 events.
3.6.2. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the Pfizer
reporting standards.
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Protocol B7981006 (PF-06651600) Statistical Analysis Plan
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3.6.3. Vital Signs
Absolute values and changes from baseline in systolic and diastolic blood pressure, 
respiratory rate, pulse rate and temperature will be summarized by treatment and visit, 
according to Pfizer reporting standards.
3.6.4. Electrocardiogram (ECG)
Categorical summary tables will be summarized by treatment and visit using Pfizer reporting 
standards.  A listing of ECG comments on findings and normal/abnormal results will be 
provided.
4. ANALYSIS SETS
4.1. Intent-to-Treat Analysis Set
An intent-to-treat (ITT) analysis set will include all subjects who were randomized to the 
study and received at least one dose of the randomized investigational drug (PF-06651600 or 
placebo).
4.2. Safety Analysis Set
The safety (SAF) analysis set is defined as those subjects who received at least one dose of 
the investigational drug.
4.3. Other Analysis Sets
None.
5. GENERAL METHODOLOGY AND CONVENTIONS
Final analyses will occur after database lock after Last Subject Last Visit (LSLV).
5.1. Hypotheses and Decision Rules
The null hypothesis that the distribution of SDAI change from baseline at Week 8 is the same 
between the active and placebo arms will be tested using Bayesian framework outlined in 
Appendix 4.  Statistical separation from the placebo will be observed if the probability of 
treatment effect * being greater than zero is over 90%.
5.2. General Methods
In general, number and percent will be presented for binary variables.  Number, mean, 
standard deviation (or standard error of the mean), median, minimum, and maximum will be 
presented for continuous variables.  In addition, graphics may be used to present the data.
5.2.1. Analyses for Binary Data
The normal approximation for the difference in binomial proportions will be used to assess
the difference between active and placebo.
The normal-approximation to the test statistic for the difference in binomial random variables 
is calculated as


Protocol B7981006 (PF-06651600) Statistical Analysis Plan
Page 11
c
c
c
i
i
i
c
i
i
n
p
p
n
p
p
p
p
Z
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
ˆ
ˆ





where pˆ refers to the relative frequency, n to sample size, the subscript c refers to the control 
group (eg, placebo) and the subscript i refers to the active group.
Two-sided 95% confidence intervals are formed by:
c
c
c
i
i
i
c
i
n
p
p
n
p
p
Z
p
p
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
)
ˆ
ˆ
(
975
.0





5.2.2. Analyses for Continuous Data
Mixed Effect Model Repeat Measurement (MMRM) for Longitudinal Continuous Data:
The fixed effects of treatment, visit, and treatment-by-visit interaction will be included, along 
with patient as a random effect.  Unstructured covariance matrix will be assumed.
When modeling the change from baseline values, the variable of visit will start with the first 
post-baseline visit, and the actual baseline value will be included as a covariate.  At each 
visit, estimates of mean values and the mean differences between the active treated group and 
the placebo group will be derived from the model.  The corresponding p-values, standard 
errors and 95% confidence intervals will also be derived from the model.
Below is an example of potential statistical analysis system (SAS) code:
PROC MIXED DATA=XXX;
   CLASS SUBJID TREATMENT VISIT;
   MODEL CHGBASE=TREATMENT VISIT TREATMENT*VISIT BASE/ALPHA=0.05 DDFM=KR;
   REPEATED VISIT/SUBJECT=SUBJID TYPE=UN;
   LSMEANS TREATMENT*VISIT/ALPHA=0.05 CL DIFF;
RUN;
Analysis of Covariance (ANCOVA) for Non-longitudinal Continuous Data:
The non-longitudinal continuous data will be analyzed by ANCOVA with treatment as the 
factor.  When modelling change from baseline values, the actual baseline value will be 
included as a covariate.  Active dose group will be contrasted versus placebo.
Below is an example of potential SAS code:
PROC MIXED DATA=XXX;
   CLASS TREATMENT;
   MODEL CHGBASE=TREATMENT BASE/ALPHA=0.05;
   LSMEANS TREATMENT/ALPHA=0.05 CL PDIFF;
RUN;
5.2.3. Analyses for Categorical Data
The frequency and percentage for each category will be presented.


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5.2.4. Analyses for Time to Event Data
None.
5.3. Methods to Manage Missing Data
In general, for descriptive statistics missing values will not be imputed.  In addition, for 
safety endpoints missing values will not be imputed.  Unless there is an explicit instruction, 
missing values will be used for lower limits of detection and quantitation.
5.3.1. Binary Endpoint
For the binary response endpoints (eg, SDAI remission rates), subjects with missing values 
will be handled by:

non-responder imputation (NRI) method, ie, setting any missing values to be 
non-responsive (0)

will be used as observed (ie, excluding any missing values from analysis)
5.3.2. Continuous Endpoints
For non-patient reported outcome variables, the missing values will be handled as following:

For continuous endpoints measured longitudinally, the missing values post-baseline 
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.

For the continuous endpoint not measured longitudinally, the post-baseline missing 
values will be:

as observed (ie, excluding any missing values from analysis);

imputed using last observation carried forward (LOCF).
For PRO endpoints, rules suggested by the developers of these PROs will be followed in 
calculating the values of a given component at a scheduled assessment.  If these rules are not 
enough for imputing a value, then the missing values will be handled in the same way as 
non-patient reported outcome variables.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
The primary efficacy analysis will be conducted on simple disease activity index (SDAI) 
change from baseline at Week 8.  Analysis will include data on PF-06651600 and placebo 
arms.
Analyses of the primary endpoint will be based on ITT population.


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6.1.1. Primary Analysis
The primary analysis will be based on the Bayesian analysis outlined in Appendix 4.
6.1.2. Sensitivity/Robustness Analyses
There are 3 sets of analyses.
Set 1:
The sensitivity analysis will be based sensitivity prior models on the Bayesian analysis 
outlined in Appendix 4.
Set 2:

Missing data imputation

Observed

LOCF

ANCOVA (see Section 5.2.2)

Baseline SDAI as a covariate

Baseline SDAI and previous anti-TNF use as covariates
Set 3:

Missing data imputation – none (Observed).

MMRM (see Section 5.2.2) for analysis of change from baseline in SDAI at Weeks 1, 
2, 4, 6, and 8.

Baseline SDAI as a covariate

Baseline SDAI and previous anti-TNF use as covariates
6.2. Secondary Endpoint(s)
6.2.1. SDAI
Analysis of number of subjects with SDAI remission (SDAI3.3) and SDAI low disease 
activity (SDAI11) at Weeks 4, 6, and 8:

ITT population set

Missing data imputation

Observed


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
NRI

Normal approximation
Analysis of change from baseline in SDAI at Weeks 1, 2, 4, 6, and 8:

ITT population set

Missing data imputation – none (Observed)

MMRM
6.2.2. DAS
For DAS28-3 (ESR), DAS28-3 (CRP), DAS28 -4 (ESR), and DAS28-4 (CRP), analysis of 
number of subjects with DAS28 remission (DAS<2.6) and DAS28 low disease activity 
(DAS28<3.2) at Weeks 4, 6, and 8:

ITT population set

Missing data imputation

Observed

NRI

Normal approximation
Analysis of change from baseline in DAS28-3 (ESR), DAS28-3 (CRP), DAS28 -4 (ESR), 
and DAS28-4 (CRP)SDAI at Weeks 1, 2, 4, 6, and 8:

ITT population set

Missing data imputation – none (Observed)

MMRM
6.2.3. hsCRP
Analysis of change from baseline in hsCRP at Weeks 1, 2, 4, 6, and 8:

ITT population set

Missing data imputation – none (Observed)

MMRM


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6.2.4. Tender/Painful and Swollen Joint Count
Analysis of change from baseline in the Tender/Painful and Swollen Joint Count (28) at 
Weeks 1, 2, 4, 6, and 8:

ITT population set

Missing data imputation – none (Observed)

MMRM
6.2.5. PhGA of Arthritis
Analysis of change from baseline in PhGA of arthritis at Weeks 1, 2, 4, 6, and 8:

ITT population set

Missing data imputation – none (Observed)

MMRM
6.3. PRO Endpoints
Analysis of change from baseline in for outcomes research endpoints at Weeks 1, 2, 4, 6, and 
8:

Endpoints are PAAP VAS, PtGA VAS, and HAQ-DI

ITT population set

Missing data imputation – none (Observed)

MMRM
6.4.
, only ACR20, ACR50, and 
ACR70 rate will be summarized:

CCI
CCI


Protocol B7981006 (PF-06651600) Statistical Analysis Plan
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Additional statistical analyses of other exploratory endpoints (including PK analysis) will be 
provided in a separate document.
6.5. Subset Analyses
Summary statistics for the SDAI endpoints will be presented by baseline smoking status and 
by previous anti-TNF use.
6.6. Baseline and Other Summaries and Analyses
6.6.1. Baseline Summaries
Demographics and medical history variables as defined in Section 3.5 will be summarized by
treatment group.
6.6.2. Study Conduct and Subject Disposition
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed in the ITT analysis set, and as well as for safety.  Frequency counts 
will be supplied for subject discontinuations by treatment.
Data will be reported in accordance with Pfizer reporting standards.
6.6.3. Study Treatment Exposure
A summary of compliance and the number of doses received as well as the median total dose 
by visit and treatment group will be provided.
6.6.4. Concomitant Medications and Non-Drug Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
6.7. Safety Summaries and Analyses
Safety analysis will be based on the SAF analysis set.
All clinical AEs, SAEs, treatment-emergent signs and symptoms (TEAEs), withdrawal due to 
AEs, ECGs, vital signs and safety laboratory data will be reviewed and summarized on an 
ongoing basis during the study to evaluate the safety of subjects.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.  All safety endpoints will be listed and summarized in 
accordance with Pfizer Data Standards.  Categorical outcomes (eg, AEs) will be summarized 
by subject counts and percentage.  Continuous outcome (eg, blood pressure, pulse rate, etc) 
will be summarized using N, mean, median, standard deviation, etc.  Change from baseline in 
laboratory data, ECGs and vital signs will also be summarized.  Subject listings will be 
produced for these safety endpoints accordingly.


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6.7.1. Adverse Events
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of
adverse events.  Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification.  As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation.  The 3-tier approach facilitates this exploratory analysis.
The analyses of adverse events under the 3-tier approach are considered exploratory.  There 
will be no adjustment for multiple comparisons or stratification factors in the analyses unless 
specified.
Nominal p-values (Tier-1 events only) and 95% confidence intervals (Tier-1 and Tier-2 
events) will be provided for between treatment differences in the percentage of patients with 
events.  Reporting p-values and confidence intervals will follow Pfizer standards.
6.7.2. Laboratory Data
Laboratory data will be listed and summarized by treatment and visit in accordance with the 
Pfizer reporting standards.
6.7.3. Vital Signs
Absolute values and changes from baseline in systolic and diastolic blood pressure, 
respiratory rate, pulse rate and temperature will be listed summarized by treatment and visit
in accordance with the Pfizer reporting standards.
6.7.4. Electrocardiogram
Categorical summary tables will be summarized by treatment and visit using Pfizer reporting 
standards.  A listing of ECG comments on findings and normal/abnormal results will be 
provided.
6.7.5. Physical Examination
All physical exam data will be provided in the listings.
7. INTERIM ANALYSES
No interim analysis is planned.  Final analyses will follow the official database release.
8. REFERENCES
None.


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9. APPENDICES
Appendix 1. SUMMARY OF EFFICACY ANALYSES
All efficacy analyses will be based on ITT set.  Treatment groups will be PF-06651600 and 
placebo.
Primary Efficacy Endpoint
Statistical Method
Missing Data
Change from baseline in SDAI at 
Week 8
ANCOVA with baseline SDAI as a 
covariate
Observed
Change from baseline in SDAI at 
Week 8
ANCOVA with baseline SDAI as a 
covariate
LOCF
Change from baseline in SDAI at 
Week 8
ANCOVA with baseline SDAI and 
anti-TNF use as covariates
Observed
Change from baseline in SDAI at 
Week 8
ANCOVA with baseline SDAI and 
anti-TNF use as covariates
LOCF
Change from baseline in SDAI at 
Week 8
Bayesian analysis of posterior 
distributions of the SDAI scores and 
placebo adjusted change from 
baseline
-
Secondary Efficacy Endpoints
Statistical Method
Missing Data
SDAI remission and low disease 
activity at Weeks 4, 6, and 8
Normal approximation
Observed
SDAI remission and low disease 
activity at Weeks 4, 6, and 8
Normal approximation
NRI
DAS28-3 (ESR), DAS28-3 (CRP), 
DAS28 -4 (ESR), and DAS28-4 
(CRP) remission and disease activity 
at Weeks 4, 6, and 8
Normal approximation
Observed
DAS28-3 (ESR), DAS28-3 (CRP), 
DAS28 -4 (ESR), and DAS28-4 
(CRP) remission and disease activity 
at Weeks 4, 6, and 8
Normal approximation
NRI


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Change from baseline in SDAI at 
Weeks 1, 2, 4, 6, and 8
MMRM
Observed
Change from baseline in DAS28 
(eg, DAS28-3 (ESR), DAS28-3 
(CRP), DAS28 -4 (ESR), and 
DAS28-4 (CRP)) at Weeks 1, 2, 4, 6, 
and 8
MMRM
Observed
Change from baseline in hsCRP at 
Weeks 1, 2, 4, 6, and 8
MMRM
Observed
Change from baseline in in the 
Tender/Painful and Swollen Joint 
Count (28) at Weeks 1, 2, 4, 6, and 8
MMRM
Observed
Change from baseline in PhGA of 
Arthritis at Weeks 1, 2, 4, 6, and 8
MMRM
Observed
Outcomes Research Endpoints
Statistical Method
Missing Data
Change from baseline in in PAAP
VAS and PtGA of Arthritis VAS at 
Weeks 1, 2, 4, 6, and 8
MMRM
Observed
Change from baseline in in the 
HAQ-DI at Weeks 1, 2, 4, 6, and 8
MMRM
Observed
ACR20, ACR50, and ACR70 at 
Weeks 4, 6, and 8
ACR20, ACR50, and ACR70 at 
Weeks 4, 6, and 8
CCI
CCI
CCI
CCI


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Appendix 2. DETAILS OF VISIT WINDOWS
Visit windows will be used for efficacy variables, and for any safety data that 
display/summarize by study visit.  For other endpoints (eg, ECG, vital signs), visit windows 
will be applied for summary statistics by study visits if required.
Visit Label
Target Day
Definition [Day window]
Screening
Days -35 to Day 0
Baseline
Day 1, 
Randomization
Day 1
Week 1
8
Days 2 to 11
Week 2
15
Days 12 to 22
Week 4
29
Days 23 to 36
Week 6
43
Days 37 to 50
Week 8
57
Days 51 to 64
Follow Up/End of Study
Week 10
71
Days 65 to 78
Week 12
85
Days 79 to -
For the lab values, if the calculated study day for the labelled baseline visit is not study 
Day 1, but falls within 40 days before the start of the study dosing, then that data should be 
used for the baseline instead of leaving baseline missing.
For the other values, if the calculated study day for the labelled baseline visit is not study 
Day 1, but falls before the start of the study dosing, then that data should be used for the 
baseline instead of leaving baseline missing.
If two or more visits fall into the same window, keep the one closest to the Target Day.  If 
two visits are equaled distant from the Target Day in absolute value, the later visit should be 
used.
Safety analysis may follow Pfizer standard.


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Appendix 3. DATA DERIVATION DETAILS
A patient is said to have achieved the ACR20 criteria+ when all of the following bulleted 
points are true:

A 20% improvement from baseline in the tender/painful joint count (TCJ28).

A 20% improvement from baseline in the swollen joint count (SJC28).

A 20% improvement from baseline in at least 3 of the following 5 variables:
1. PhGA of Arthritis;
2. PAAP VAS;
3. PtGA of Arthritis VAS;
4. HAQ disability index;
5. Results of ESR or CRP blood test (both of which test for inflammation).
ACR50 and ACR70 are defined analogously.
There are many forms of the DAS.  The DAS used in this study is the DAS using the 
28-count subsets of tender/painful joints and swollen joints, together with either CRP or 
ESR, to derive the DAS28-3 (CRP), DAS28-4 (CRP), or DAS28-3 (ESR) and DAS28-4 
(ESR), which are calculated using the following formulae, respectively:
DAS28-4(ESR) = (0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*ln(ESR) + 0.014*GH
DAS28-3(ESR) = [0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*ln(ESR)]*1.08 + 0.16
DAS28-4(CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96
DAS28-3(CRP) = [0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1)] * 1.10 + 1.15
where TJC28 is number of painful joints out of 28 joints, SJC28 is number of swollen joints 
out of 28 joints, GH is the general health or patients’ global assessment of disease activity on 
a 100 mm VAS, ln is the natural logarithm, ESR is in mm/first hour, and CRP is in mg/L.
Handling Missing Joint Counts:

A missing painful/tender assessment or one NOT DONE at baseline is set to “not 
painful/tender”;

A missing swollen assessment or one NOT DONE at baseline is set to “not swollen”;
                                                
+ Felson DT, Anderson JJ, Boers M, et al.  American College of Rheumatology Preliminary Definition of 
Improvement in Rheumatoid Arthritis. Arthritis Rheum 1995; 38:727-35.


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
A missing painful/tender assessment or one NOT DONE post baseline is set to 
“painful/tender”;

A missing swollen assessment or one NOT DONE at post baseline is set to 
“swollen”.
Note that joints marked NOT APPLICABLE are not to be counted in the summation of 
swollen and painful/tender joints at baseline and post baseline.
Any new NOT APPLICABLE for a joint POST BASELINE is set to “painful/tender” and 
“swollen”.
Any intra-articular injection (baseline and post baseline) sets the joint status to 
“painful/tender” and “swollen” - on or after the date of the injection.


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Appendix 4. ADDITIONAL METHODOLOGY DETAILS
Details of Bayesian analysis of posterior distributions of the SDAI scores
Notation/Definitions
Primary Model – Bayesian Analysis of Covariance
Prior Models:
Note:
is calculated based on commensurability between the historic and current study 
baseline patient profiles including both arms.  The baseline profiles were based on
baseline SDAI score prior ant-TNF exposure status.  Geographic data was not used in 
the assessment of the prior distribution.
At least two alternative sensitivity prior models will be considered for 
with one 
being a noninformative prior 
Also sensitivity models will be considered 
with 
modeled using t distribution with three degrees of freedom.
Data visualization techniques
Table shells of figures displaying the primary endpoint results (see below) will be provided 
in programming document.

Distribution of treatment effect 
.

Display of change from baseline by treatment group based on Bayesian Analysis of 
Covariance.

Display of change from baseline by treatment group based on Bayesian Analysis of 
Covariance vs baseline SDAI.