Conditions: Rheumatoid Arthritis
Keywords: Tofacitinib, CP-690,550, Janis kinase, JAK inhibitor, modified release, Xeljanz
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 209
Healthy volunteers: no

Brief summary:
This is a 12 week study that will evaluate the efficacy and safety of the 11 mg tofacitinib modified release tablet taken once a day in patients with rheumatoid arthritis who continue taking methotrexate. Results for the modified release tablets will be compared to the efficacy and safety of the 5 mg tofacitinib immediate release tablets taken twice a day in patients with rheumatoid arthritis who continue taking methotrexate.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Tofacitinib intervention 2: Tofacitinib
Intervention descriptions: intervention 1: tofacitinib modified release 11 mg tablet administered once time a day for 12 weeks intervention 2: tofacitinib immediate release 5 mg tablet administered twice a day for 12 weeks

Protocol document:
Prot_001.pdf: 
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A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, 
PHASE 3 STUDY TO DEMONSTRATE NON-INFERIORITY FOR THE 
EFFICACY OF A ONCE DAILY DOSE OF TOFACITINIB MODIFIED 
RELEASE TABLET TO A TWICE DAILY DOSE OF THE IMMEDIATE 
RELEASE TABLET IN ADULT PATIENTS WITH RHEUMATOID ARTHRITIS 
ON BACKGROUND METHOTREXATE
Compound:
CP-690,550
Compound Name:
Tofacitinib citrate
United States (US) Investigational New 
Drug (IND) Number:
N/A
European Clinical Trials Database 
(EudraCT) Number:
N/A
Universal Trial Number:
N/A
Protocol Number:
A3921215
Phase:
Phase 3
 
 
 


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Document History
Document
Version Date
Summary of Changes
Amendment 3
13-Aug-2015
Added “X” at visit 3 and 4 in Dispense Dosing Diary
of the schedule of activities table and added Dispense 
Dosing Diary to Visits 3 and 4 in Procedures section
Updated and corrected the description for mode of 
action of tofacitinib in section 1.1.
Updated the descriptions for background information 
of Tofacitinib in section 1.2
Added “a history of, or current evidence for, severe 
gastrointestinal narrowing (pathologic or iatrogenic )”
as a new exclusion criterion (#12)
Added “or other methods that yield results 
comparable to the Westergren method” for ESR 
measurement in inclusion criteria #6-b 
Added description for washout period of other 
investigational drugs in exclusion criterion #23 and 
section 5.8.3
Corrected description of footnote in table 3 in 
accordance to Japan package insert of leflunomide
Corrected definition of the difference between arms 
in primary endpoint to in section 9.2.1 and 9.2.2
Added the Gastrointestinal Perforation Review 
Committee (GIPRC) in list of abbreviations and 
section 9.6
Updated descriptions in section 8 and 15 to align with 
latest protocol template
Corrected some typos and inadequate descriptions
Amendment 2
30-Oct-2014
Added the chest CT scan as screening procedure in 
schedule of activities.
Added the chest CT scan as screening procedure in 
inclusion criterion 13.
Added the chest CT scan as screening procedure in 


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exclusion criterion 2.
Added the subjects who have previously received 
other JAK3 inhibitors treatment in exclusion criterion
21.
Added the chest CT scan as screening procedure in 
Section 6.1.
Added the chest CT scan as screening procedure in 
Section 7.2.5.
Modified the current guideline in Appendix 10.  
Amendment 1
16-Sep-2014
Modified the abbreviations. 
Added the IWRS in Section 5.1 and 5.2.
Modified the information recorded in Table 1.
Modified the criteria of fasting and deleted the rule of 
re-screening in Section 6.1.
Deleted additional biospecimens for exploratory 
analyses in Section 7.3.1.
Modified the criteria of retesting in Section 7.5.
Added the biopsy criteria in Appendix 11.
Original 
protocol
12-Aug-2014
Not Applicable (N/A)


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ABBREVIATIONS
This is a list of abbreviations that may or may not be used in the protocol.
Abbreviation
Term
ACR
American College of Rheumatology
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AS
ankylosing spondylitis
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time profile
AUCinf
area under the plasma concentration- time profile 
from time zero extrapolated to infinite time
BCG
Bacille Calmette Guérin
BE
bioequivalence
BID
twice daily
Cav
average concentration
CD
Crohn’s disease
CFP
culture filtrate protein
CHD
coronary heart disease
CIs
confidence intervals
CK
creatine kinase
Cmax
peak plasma concentration
Cmax,adj
dose adjusted maximum concentration
Cmin
trough concentration
CRF
case report form
CRP
C-reactive protein
CSA
clinical study agreement
CT
computed tomography
CV
cardiovascular
CV EAC
Cardiovascular Endpoint Adjudication Committee
CYP
cytochrome
DAS
Disease Activity Score
DMARD
Disease Modifying Antirheumatic Drug
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EBV
Epstein Barr Virus
EC
ethics committee
ECG
electrocardiogram
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
ELISA
Enzyme-Linked Immunosorbent Assay
EQ-5D
European Quality of Life - 5 dimensions
questionnaire
EOS
end of study
ESAT
early secretory antigenic target


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ESR
erythrocyte sedimentation rate
ET
early termination
EudraCT
European Clinical Trials Database
EULAR
European League Against Rheumatism
FACIT
Functional Assessment of Chronic Illness Therapy
FAS
full analysis set 
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act 
(United States)
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GIPRC
Gastrointestinal Perforation Review Committee 
HAQ-DI
Health Assessment Questionnaire-Disability Index
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL
high density lipoprotein
HEENT
head, eyes, ears, nose and throat
HERC
Hepatic Event Review Committee
HIV
human immunodeficiency virus
IB
investigator’s brochure
IC50
concentration required to produce 50% of the 
maximum effect
ICF
informed consent form
ICH
International Conference on Harmonisation
ID
identification
IFN
interferon
IL
interleukin
ILD
Interstitial Lung Disease
ILDRC
Interstitial Lung Disease Review Committee
INR
international normalized ratio
IP
interphalangeal
IR
immediate release
IRB
institutional review board
IU
international unit
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
IWRS
interactive web response system
JAK
Janus Kinase
JAS
Japan Atherosclerosis Society
LCAP
leukocytapheresis


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LDA
low disease activity
LDL
low density lipoprotein
LFT
liver function test
LOCF
last observation carried forward
LPD
lymphoproliferative disorder
LSLV
last subject last visit 
MAC
Malignancy Adjudication Committee
MCP
metacarpophalangeal
MMRM
mixed effect model with repeated measures 
MR
modified release
MTP
metatarsophalangeal
MTX
methotrexate
N/A
not applicable
NIL
spot count in the negative 
NMSC
non-melanoma skin cancer
NRI
non-responder imputation
NSAID
non-steroidal anti-inflammatory drug
OI
opportunistic infection
OIRC
Opportunistic Infection Review Committee
PA
posteroanterior
PCD
primary completion date
PCP
pneumocystis pneumonia
PCR
polymerase chain reaction
PGx
pharmacogenomics
PIP
proximal interphalangeal
pIPD
potentially important protocol deviation
PK
pharmacokinetics
PPD
purified protein derivative
PRO
patient reported outcome
PsA
psoriatic arthritis
PsO
psoriasis
PT
prothrombin time
PtGA
patient’s global assessment of health
QD
once daily
QFT
Quantiferon 3G/QuantiFERON®-TB
RA
rheumatoid arthritis
RANKL
receptor activator of nuclear factor kappa-β ligand
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SF-36
Short Form 36 Health Survey
SGOT
serum glutamic-oxaloacetic transferase
SGPT
serum glutamic-pyruvic transferase
SIB
suicidal ideation and behavior
SJC
swollen joint count
SOA
schedule of activities


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SRSD
single reference safety document
SSID
study subject identification
TB
tuberculosis
TJC
tender joint count
TNF
tumor necrosis factor
TNFi
tumor necrosis factor inhibitor
TyK2
tyrosine kinase 2
UC
ulcerative colitis
ULN
upper limit of normal
US
United States
VAS
visual analog scale
VZV
varicella-zoster virus
WBC
white blood cell


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PROTOCOL SUMMARY
BACKGROUND AND RATIONALE
Tofacitinib is a potent, selective inhibitor of the Janus Kinase (JAK) family of kinases 
with a high degree of selectivity against other kinases in the human genome. The 
immediate release (IR) formulation of tofacitinib has been approved for the treatment of 
rheumatoid arthritis (RA) as a twice daily (BID) regimen. Tofacitinib is being developed 
for the treatment of psoriasis (PsO, oral and topical), spondylarthropathies (ankylosing 
spondylitis [AS] and psoriatic arthritis [PsA]) and inflammatory bowel disease (Crohn’s 
disease [CD] and ulcerative colitis [UC]).
The modified release (MR) formulation of tofacitinib is being studied as a disease-
modifying antirheumatic drug (DMARD) for the once daily (QD) treatment of RA. The 
MR QD regimen has the potential to improve drug compliance of patients, patient
convenience, and to offer additional dosing options for patients.
This study will seek to compare the efficacy and safety of the MR 11 mg QD regimen to
the IR 5 mg BID regimen for the treatment of RA.
OBJECTIVES AND ENDPOINTS 
Objectives
Primary Objective
1. To demonstrate the non-inferiority for efficacy of tofacitinib MR 11 mg QD to IR 5 
mg BID for the treatment of signs and symptoms in patients with active RA on a 
stable background of methotrexate (MTX), as measured by Disease Activity Score 
28-4 (C-reactive protein) [DAS28-4(CRP)] change from Baseline at Week 12.
Secondary Objectives
1. To evaluate the similarity in efficacy of tofacitinib MR 11 mg QD and IR 5 mg BID
for the treatment of signs and symptoms of RA, as measured by DAS28-4 erythrocyte 
sedimentation rate (ESR) change from Baseline, American College of Rheumatology 
20% improvement (ACR20), ACR50, ACR70 responses, remission, and Low Disease 
Activity (LDA), at Week 12.
2. To evaluate the similarity in efficacy of tofacitinib MR 11 mg QD and IR 5 mg BID
for physical function status as measured by health assessment questionnaire-disability
index (HAQ-DI) change from Baseline at Week 12.
3. To evaluate the similarity in effects on patient’s health outcome measures (change 
from Baseline in short form 36 health survey (SF-36), functional assessment of 
chronic illness therapy (FACIT) fatigue and euro quality of life-5 dimensions
questionnaire [EQ-5D]) of tofacitinib MR 11 mg QD and IR 5 mg BID at Week 12.
4. To evaluate the safety and tolerability of tofacitinib MR 11 mg QD in comparison 
with IR 5 mg BID in patients.


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Other Objectives
The efficacy and health outcome objectives will also be evaluated at other post-Baseline
visits.
Endpoints
Efficacy Endpoints
Primary Efficacy Endpoint

Change from Baseline in DAS28-4(CRP) at Week 12.
Secondary Efficacy Endpoints

Change from Baseline in DAS28-4(ESR) at Week 12.

ACR20, ACR50 and ACR70 response at Week 12.

Remission at Week 12, as assessed by: DAS28-4(CRP) < 2.6 and DAS28-4(ESR) 
< 2.6.

LDA at Week 12, as assessed by: DAS28-4(CRP) ≤3.2 and DAS28-4(ESR) ≤3.2.

Change from Baseline in HAQ-DI at Week 12.

HAQ-DI response (decrease of at least 0.22) at Week 12.

Change from Baseline in the SF-36 8 domain scores and 2 component scores at 
Week 12.

Change from Baseline in the FACIT-Fatigue scale at Week 12.

Change from Baseline in the EQ-5D at Week 12.
Other Efficacy Endpoints
Primary and secondary efficacy endpoints at other selected post-baseline scheduled visits.
Safety Endpoints
All the safety data will be summarized descriptively through appropriate data tabulations, 
descriptive statistics, and graphical presentations, including:

All adverse events (AEs), including serious adverse events (SAEs).

Clinically significant abnormal laboratory parameters.
STUDY DESIGN
This is a multicenter, randomized, double blind, parallel group, phase 3 study to evaluate
efficacy and safety of tofacitinib MR 11 mg QD tablet compared to IR 5 mg BID tablet


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following 12 weeks treatment in patients with moderate to severe active RA on a stable 
background of MTX.
Subjects will be randomized in a 1:1 ratio for the 2 treatment arms with a total sample 
size of approximately 200 subjects; there will be approximately 100 subjects randomized 
into the 11 mg MR QD group and approximately 100 patients into the 5 mg IR BID group.
STUDY TREATMENTS
All subjects will be randomly assigned to one of two active treatment arms in the study:

Tofacitinib 11 mg MR QD

Tofacitinib 5 mg IR BID 
STATISTICAL METHOD
The primary efficacy endpoint, DAS28-4(CRP), will be expressed as a change from 
Baseline. The analysis will be conducted using a linear mixed effect model with repeated 
measures (MMRM), which will include baseline as a covariate, treatment, visit (week 4 
and 12), and treatment by visit interaction as fixed effects. Subjects will be a random 
effect and unstructured covariance will be assumed. The estimate of treatment difference 
and the associated 2-sided 95% confidence interval (type-I error [alpha] of 0.025 in each 
tail) at the primary time point of week 12 will be made from this model. Non-inferiority 
of tofacitinib MR 11 mg QD to IR 5 mg BID will be concluded if the lower bound of the
2-sided 95% confidence interval is greater than the pre-specified non-inferiority margin
of −0.6.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and 
procedures.  Refer to the Study Procedures and Assessments sections of the protocol for 
detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect 
the well-being of the subject.
Visit Identifier
Visits
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Screening
Baseline
Day 1
Week 4
Week 8 
Week 12 
(EOS/ET) 1
Study Day
−27
1
29
57
85
Visit Window (Days)
+7 (i.e. −34
to 0)
0
±3
±3
±3
Informed Consent 
X
Medical History 2
X
Prior treatments/medications
X
Concomitant treatments/ medications
X



X
Inclusion/Exclusion criteria
X
X
Complete Physical Examination 3
X
Targeted Physical Examination 3
X
X
X
Vital Signs, Temperature 4
X
X
X
X
Whole blood interferon (IFN)-γ release assay 
(Quantiferon-3G/QuantiFERON®-TB Gold In-
Tube or T-SPOT) 5
X
12-lead Electrocardiogram
X
Chest X-ray(posteroanterior (PA) and lateral) or
chest computed tomography (CT) scan 6
X
Blood/Urine
Rheumatoid Factor
X
Hematology 7, Chemistry Panel 8
X
X
X
X
Lipid Profile (fasting) 9
X
X
X
X
Serum Pregnancy Test (β -HCG) 10
X
Urine Pregnancy Test (β-HCG) 11
X
X
X
Urinalysis 11
X
X
X
X
Serum β-D-glucan and KL-6
X
HIV Serology
X
HBsAg, HBcAb, HBsAb,
HBV DNA testing (if necessary)12
X
HCV Ab, HCV RNA PCR (if HCV Ab 
positive)
X
Varicella-Zoster Virus (VZV)
X
Lymphocyte subset markers 13
X
X
X
Banked biospecimens (PGx sampling)
X
ACR/ DAS
C-Reactive Protein (CRP)
X
X
X
X
Erythrocyte Sedimentation Rate (ESR)
X
X
X
X
Joint assessment:Tender/Painful Joint 
Count: (68 joints), Swollen Joint Count (66 
joints)
X
X
X
X
Patient Assessment of Arthritis Pain (VAS)
X
X
X
Patient Global Assessment (VAS)
X
X
X
Physician Global Assessment (VAS)
X
X
X
Health Assessment Questionnaire -
Disability Index (HAQ-DI)
X
X
X
SF-36 (Version 2, Acute)
X
X
X


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Visit Identifier
Visits
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Screening
Baseline
Day 1
Week 4
Week 8 
Week 12 
(EOS/ET) 1
Study Day
−27
1
29
57
85
Visit Window (Days)
+7 (i.e. −34
to 0)
0
±3
±3
±3
FACIT- Fatigue Scale
X
X
Euro Quality of Life Questionnaire (EQ-5D)
X
X
Randomization
X
Study Drug Dispensing-New bottles supplied
X
X
X
Dispense Dosing Diary
X
X
X
Drug Accountability
X
X
X
Review of subject Dosing Diary
X
X
X
Adverse Events
X


X
1.
Study procedures to be performed at the End of Study (EOS) or Early Termination (ET) Visit.
2.
Medical history includes previous vaccination history, smoking status, average weekly alcohol consumption, 
family history of premature coronary heart disease (CHD), history of any prior episodes of herpes zoster and
confirmation of RA diagnosis.
3.
Complete physical exam includes height, weight, general appearance, skin (presence of rash), HEENT (head, eyes, 
ears, nose and throat), lungs (auscultation), heart (auscultation for presence of murmurs, gallops, rubs), lower 
extremities (peripheral edema), abdominal (palpation and auscultation), neurologic (mental status, station, gait, 
reflexes, motor and sensory function, coordination) and lymph nodes.
Targeted physical exam includes weight, examination of heart, lungs, lower extremities for peripheral edema, 
abdomen and lymph nodes.
4.
Temperature will be collected as axillary temperature. The same method should be used throughout the study.
5.
Mantoux Purified Protein Derivative (PPD) tuberculin skin test will be allowed, if there are two consecutive 
indeterminate results of QFT-G or T-SPOT test in subjects who have not received Bacille Calmette Guérin (BCG) 
vaccination during screening period.
6.
Chest X-ray (PA and lateral) or chest CT scan (with or without IV contrast) must be obtained at screening or 
within 12 weeks prior to screening and read by a qualified radiologist or respiratologist. If necessary, a chest CT 
scan (with or without IV contrast) may be performed during screening following initial performance of chest 
radiographs (PA and lateral) at the clinical discretion of the investigator. If pulmonary signs and symptoms are 
observed at and after baseline visit, unscheduled imaging test (e.g. chest X-ray or chest CT scan) may be 
performed based on the judgment by investigator as appropriate. 
7.
Hematology includes hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differential and platelet count.
8.
Chemistry Panel includes blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, bicarbonate, 
chloride, total protein, total bilirubin, direct bilirubin, indirect bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), albumin, creatine 
kinase (CK).
9.
Lipid Profile includes total cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL) 
cholesterol, and triglycerides under fasting condition.
10. Serum pregnancy test for women of childbearing potential only.
11. Dipstick in all cases; urinalysis includes specific gravity, pH, protein, glucose, ketones, blood, nitrite, leukocyte 
esterase and urine sediment (microscopy). Urine culture is performed if clinically indicated.  Urine pregnancy test 
(β-HCG) is required only for women who are of childbearing potential; may be repeated more frequently if a 
menstrual cycle is missed, or if potential pregnancy is otherwise suspected.
12. HBV DNA assay may be required for a subset of subjects with specified serological test results (refer to
Appendix 5)
13. Lymphocyte subset markers include CD3+, CD3−CD19+, CD3+CD4+CD8−, CD3+CD4−CD8+, 
CD3+CD16+CD56+, CD3−CD16+CD56+, CD3−CD16+CD56−, CD3−CD16−CD56+, CD3−CD16−CD56−, 
CD4/CD8


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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................2
ABBREVIATIONS ...................................................................................................................4
PROTOCOL SUMMARY.........................................................................................................8
SCHEDULE OF ACTIVITIES................................................................................................11
LIST OF TABLES...................................................................................................................16
LIST OF FIGURES .................................................................................................................17
APPENDICES .........................................................................................................................17
1. INTRODUCTION ...............................................................................................................18
1.1. Mechanism of Action/Indication ......................................................................................18
1.2. Background and Rationale................................................................................................18
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................20
2.1. Objectives .........................................................................................................................20
2.1.1. Primary objective........................................................................................20
2.1.2. Secondary objectives ..................................................................................20
2.1.3. Other Objectives.........................................................................................21
2.2. Endpoints ..........................................................................................................................21
2.2.1. Efficacy Endpoints......................................................................................21
2.2.2. Safety Endpoints.........................................................................................21
3. STUDY DESIGN.................................................................................................................21
4. SUBJECT SELECTION......................................................................................................22
4.1. Inclusion Criteria ..............................................................................................................22
4.2. Exclusion Criteria .............................................................................................................25
4.3. Randomization Criteria.....................................................................................................27
4.4. Lifestyle Guidelines..........................................................................................................27
4.4.1. Non-Pharmacologic Interventions..............................................................28
4.4.2. Vaccination.................................................................................................28
4.4.3. Diet and Dietary Supplements....................................................................28
4.4.4. Reproductive Status of Women Subjects and Partners of Male 
Subjects............................................................................................................28
4.5. Surgery..............................................................................................................................29
4.6. Sponsor’s Qualified Medical Personnel............................................................................29
5. STUDY TREATMENTS.....................................................................................................30


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5.1. Allocation to Treatment....................................................................................................30
5.2. Breaking the Blind............................................................................................................30
5.3. Subject Compliance ..........................................................................................................31
5.4. Drug Supplies....................................................................................................................31
5.4.1. Dosage Form(s) and Packaging..................................................................31
5.4.2. Preparation and Dispensing........................................................................32
5.5. Administration ..................................................................................................................32
5.6. Drug Storage.....................................................................................................................32
5.7. Drug Accountability..........................................................................................................33
5.8. Prior and Concomitant Treatment(s) ................................................................................33
5.8.1. Prior treatment(s)........................................................................................33
5.8.2. Permitted Concomitant treatment(s)...........................................................34
5.8.3. Prohibited Concomitant Treatment(s) ........................................................35
6. STUDY PROCEDURES .....................................................................................................37
6.1. Screening (Week −4: Day −34 to Day 0) .........................................................................37
6.2. Study Period......................................................................................................................39
6.2.1. Visit 2, Baseline Visit (Day 1)....................................................................39
6.2.2. Visit 3 (Week 4: Day 29 3 days) ..............................................................40
6.2.3. Visit 4 (Week 8: Day 57 3 days) ..............................................................41
6.2.4. Visit 5 (Week 12: Day 85 3 days) End of Study or Early 
Termination......................................................................................................41
6.3. Follow-up Visit.................................................................................................................42
6.4. Subject Withdrawal...........................................................................................................42
7. ASSESSMENTS..................................................................................................................42
7.1. Efficacy.............................................................................................................................43
7.1.1. Assessments of Disease Activity................................................................43
7.1.2. DAS Assessments.......................................................................................43
7.1.3. ACR Assessments.......................................................................................44
7.1.4. Patient Reported Outcomes ........................................................................45
7.2. Safety ................................................................................................................................46
7.2.1. Complete Physical Examination.................................................................46
7.2.2. Targeted Physical Examinations.................................................................47
7.2.3. Vital signs and body temperature ...............................................................47
7.2.4. 12-lead electrocardiogram ..........................................................................47


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7.2.5. Chest Radiograph or chest CT scan............................................................47
7.2.6. Clinical Laboratory Tests ...........................................................................47
7.2.7. Adjudicated Adverse Events.......................................................................51
7.3. Banked Biospecimens.......................................................................................................51
7.3.1. Markers of Drug Response.........................................................................51
7.3.2. Additional Research....................................................................................52
7.4. Assessment of Suicidal Ideation and Behavior (SIB).......................................................53
7.5. Triggered Requirements....................................................................................................53
8. ADVERSE EVENT REPORTING......................................................................................55
8.1. Adverse Events .................................................................................................................55
8.2. Reporting Period...............................................................................................................56
8.3. Definition of an Adverse Event ........................................................................................56
8.4. Medication Errors .............................................................................................................57
8.4.1. Tofacitinib Overdose ..................................................................................58
8.5. Infections...........................................................................................................................58
8.5.1. Treated Infections.......................................................................................58
8.5.2. Serious Infections .......................................................................................58
8.6. Abnormal Test Findings ...................................................................................................58
8.7. Serious Adverse Events ....................................................................................................59
8.7.1. Protocol-Specified Serious Adverse Events...............................................59
8.7.2. Potential Cases of Drug-Induced Liver Injury............................................59
8.8. Hospitalization..................................................................................................................61
8.9. Severity Assessment .........................................................................................................62
8.10. Causality Assessment......................................................................................................62
8.11. Exposure During Pregnancy ...........................................................................................62
8.12. Occupational Exposure...................................................................................................64
8.13. Withdrawal Due to Adverse Events (Refer to Also the Section on Subject 
Withdrawal)...............................................................................................................64
8.14. Eliciting Adverse Event Information..............................................................................64
8.15. Reporting Requirements .................................................................................................64
8.15.1. Serious Adverse Event Reporting Requirements .....................................64
8.15.2. Non-serious Adverse Event Reporting Requirements..............................65
8.15.3. Sponsor Reporting Requirements to Regulatory Authorities ...................65
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................65


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9.1. Sample Size Determination...............................................................................................65
9.2. Efficacy Analysis..............................................................................................................66
9.2.1. Statistical Hypothesis..................................................................................66
9.2.2. Statistical Decision Rule.............................................................................66
9.2.3. Analysis of Primary Efficacy Endpoint......................................................66
9.2.4. Robustness Analysis...................................................................................66
9.2.5. Analysis of Secondary and Other Efficacy Endpoints ...............................66
9.3. Safety Analysis .................................................................................................................67
9.4. Interim Analysis................................................................................................................67
9.5. Data Monitoring Committee.............................................................................................67
9.6. Safety Event Adjudication/Review Committees ..............................................................68
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................68
11. DATA HANDLING AND RECORD KEEPING .............................................................69
11.1. Case Report Forms/Electronic Data Record...................................................................69
11.2. Record Retention ............................................................................................................69
12. ETHICS..............................................................................................................................70
12.1. Institutional Review Board (IRB)/Ethics Committee (EC) ............................................70
12.2. Ethical Conduct of the Study..........................................................................................70
12.3. Subject Information and Consent....................................................................................70
12.4. Subject Recruitment........................................................................................................71
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP.............71
13. DEFINITION OF END OF TRIAL...................................................................................71
13.1. End of Trial in All Participating Countries.....................................................................71
14. SPONSOR DISCONTINUATION CRITERIA ................................................................71
15. PUBLICATION OF STUDY RESULTS..........................................................................72
15.1. Communication of Results by Pfizer..............................................................................72
15.2. Publications by Investigators..........................................................................................72
16. REFERENCES ..................................................................................................................74
LIST OF TABLES
Table 1.
Prior Treatment(s).................................................................................................34
Table 2.
Concomitant Treatment(s)....................................................................................34
Table 3.
DMARDs - Required Washout Period Prior to Baseline Visit.............................36
Table 4.
Disease Activity Indicators...................................................................................43


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Table 5.
Clinical Laboratory Tests .....................................................................................48
LIST OF FIGURES
Figure 1.
Study Design.........................................................................................................22
APPENDICES
Appendix 1. American College of Rheumatology (ACR) 1987 Revised 
Classification ........................................................................................................76
Appendix 2. Criteria for Classification of Functional Status in Rheumatoid Arthritis ...........77
Appendix 3. Prohibited Concomitant Medications..................................................................78
Appendix 4. Cockcroft-Gault Formula for Estimating GFR ...................................................80
Appendix 5. Screening Procedure of Hepatitis B virus Infection............................................81
Appendix 6. Health Assessment Questionnaire-Disability Index (HAQ-DI)..........................82
Appendix 7. Short Form -36, version 2, acute (SF-36) ...........................................................84
Appendix 8. FACIT-Fatigue....................................................................................................90
Appendix 9. EQ-5D .................................................................................................................91
Appendix 10. Recommended Clinical Management of Cholesterol .......................................92
Appendix 11. Evaluation of Potentially Malignant Tumors, Suspicious 
Lymphadenopathy or Possible Extra-nodal Lymphoproliferative 
Disorder (LPD) .....................................................................................................93


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Tofacitinib, also referred to elsewhere in this protocol as tofacitinib citrate and/or CP-
690,550, is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a
high degree of selectivity against other kinases in the human genome1. In kinase assays, 
tofacitinib, inhibits JAK1, JAK2, JAK3, and to a lesser extent tyrosine kinase 2 (TyK2). 
In cellular settings where JAK kinases signal in pairs, tofacitinib preferentially inhibits 
signaling by heterodimeric receptors associated with JAK3 and/or JAK1 with functional 
selectivity over receptors that signal via pairs of JAK2 2. Inhibition of JAK1 and JAK3 
by tofacitinib blocks signaling through the common gamma chain containing receptors 
for several cytokines, including interleukin (IL)-2, -4, -7, -9, -15, and -21. These 
cytokines are integral to lymphocyte activation, development, homeostasis, proliferation, 
and function; therefore, inhibition of their signaling may result in modulation of multiple 
aspects of the immune response. In addition, inhibition of JAK1 will result in attenuation 
of signaling by additional pro-inflammatory cytokines, such as IL-6 and interferon (IFN)-
γ3,4.  At higher exposures, inhibition of erythropoietin, prolactin, and other hormones can 
occur via inhibition of JAK2 homodimer signaling.
The immediate release (IR) oral formulation of tofacitinib is approved in the United 
States (US), Japan and other countries for the treatment of rheumatoid arthritis (RA). In 
addition, tofacitinib is being developed for the treatment of psoriasis (PsO, oral and
topical), spondylarthropathies (ankylosing spondylitis [AS] and psoriatic arthritis [PsA]) 
and inflammatory bowel disease (Crohn’s disease [CD] and ulcerative colitis [UC]).
1.2. Background and Rationale
RA is a chronic, autoimmune disease characterized by joint inflammation and destruction, 
progressive disability and adverse psychological effects.  RA represents significant health 
and socioeconomic burdens for the individual patient and society5 and there is currently 
no cure for RA. The purpose of treatment is to control disease activity, alleviate signs 
and symptoms, maintain physical function, optimize quality of life, reduce the rate of 
joint damage, and, if possible, induce complete remission.
Disease-modifying antirheumatic drugs (DMARDs) partially fulfill these goals; but often 
fall short of adequate minimization or prevention of progressive joint damage and 
optimization of quality of life.  In addition, these DMARDs are frequently associated with 
clinical tolerability and safety issues.  Biologic agents, such as tumor necrosis factor 
(TNF) inhibitors (TNFi), are more rapidly efficacious and successfully halt or slow joint 
damage, especially in combination with methotrexate (MTX).  However, use of these 
agents remains limited due to the inconvenience of the required parenteral routes of 
administration and apparent loss of initial efficacy with continued use in a significant 
proportion of patients.  Thus, the need exists for additional DMARD options.
Tofacitinib (CP-690,550) is a novel, oral JAK inhibitor for the treatment of RA.
In Phase 2b dose-ranging studies that evaluated a dose range of 1-15 mg twice daily 
(BID), tofacitinib demonstrated sustained efficacy and manageable safety over 24 weeks 
in patients with active RA when used as monotherapy 6 or in combination with 
background MTX 7.  Tofacitinib IR 5 and 10 mg BID were selected as optimal doses for 


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evaluation in Phase 3, which includes a broad range of therapeutic scenarios investigating 
tofacitinib as monotherapy8 or in combination with MTX 9,10 and non-MTX, nonbiologic 
DMARDs 11.
The Phase 3 studies demonstrated sustained efficacy and manageable safety up to 2 years 
in patients with active RA.  Long-term extension studies have been ongoing since Phase 
2 and have enrolled patients who participated in a Phase 2 or Phase 3 study; these 
open-label studies have demonstrated continued efficacy and a consistent safety profile as 
seen in the controlled clinical trials.  Long-term data collected in these trials was obtained
in patients on both 10 and 5 mg BID of tofacitinib.
Tofacitinib is an immunomodulator with important safety risks that include serious and 
other infections including tuberculosis and herpes zoster infections, and potential for 
malignancies including lymphoma, and potential for gastrointestinal (GI) perforations. 
Patients receiving tofacitinib may be at increased risk of nonmelanoma skin cancer 
(NMSC). Cardiovascular disease and interstitial lung disease (ILD) are findings seen in 
RA patients receiving tofacitinib, and are recognized comorbidities for RA as well as 
being associated with other RA therapies.
Changes in laboratory values have also been observed with oral tofacitinib including a 
dose-dependent increase in low density lipoprotein (LDL) cholesterol and dose–
dependent decreases in neutrophils and hemoglobin. Other laboratory changes observed 
with oral tofacitinib treatment include decreases in lymphocytes and increases in 
transaminases, serum creatinine, and creatine kinase (CK). Laboratory changes observed 
with oral tofacitinib treatment are monitorable and manageable and recovery of 
laboratory changes upon discontinuation of oral tofacitinib treatment is characteristically 
observed.
Currently tofacitinib is administered as an immediate release (IR) tablet formulation twice 
daily (BID). A once daily (QD) formulation will enhance ease of clinical use and patient 
convenience. The modified release (MR) formulation administered QD has been designed 
to offer equivalent area under the plasma concentration-time curve (AUC), and similar 
maximum plasma concentration (Cmax) and minimum plasma concentration (Cmin) as the 
IR formulation administered BID; therefore, it is expected that the MR formulation will
maintain comparable efficacy and consistent safety as that observed for the IR 
formulation.
The data from the pharmacokinetics (PK) studies conducted to date have indicated that
the MR formulation of tofacitinib is similar to the IR formulation based on key exposure 
parameters such as area under the plasma concentration-time profile (AUC), average 
concentration (Cav), peak plasma concentration (Cmax) and Time above JAK1/3 
concentration required to produce 50% of the maximum effect (IC50) in both Asian and 
Western healthy subjects.
Study A3921163, a randomized, 2-period crossover, single dose, fasted study (N=26, 
healthy Westerners), evaluated the single dose bioequivalence (BE) of the MR 11 mg 
tablet and the IR 10 mg (5 mg tablet ×2). Results from A3921163 demonstrated that ratio 
of the geometric means (MR 11 mg/IR 10 mg [5 mg tablet ×2]) for AUCinf was 103.89% 
and the 90% confidence intervals (CIs) for AUCinf were (100.46%, 107.44%); the 90% 
CIs were completely contained within the 80-125% BE acceptance limits indicating that 


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the MR 11 mg tablet and the IR 10 mg (5 mg tablet ×2) are equivalent. The ratio of 
geometric means (MR 11 mg/IR 10 mg [5 mg tablet ×2]) for dose adjusted maximam 
concentration (Cmax, adj), comparing the observed peak exposure for MR 11 mg to the 
expected peak exposure for a single IR 5 mg dose (half of the observed Cmax for IR 10 
mg), was 92.44% and the 90% CIs were (85.03%, 100.50%); the 90% CIs for Cmax, adj
were also contained within the 80% to 125% interval. A single dose of the MR tablet was 
found to be safe and well tolerated in this study.
A consistent daily coverage for inhibition of JAK1/3 may be required to preserve the 
effectiveness of tofacitinib. As a result of simulation utilizing the single dose PK data 
from Study A3921163, Time above JAK1/3 IC50 for the MR 11 mg tablet administered
QD was predicted to be similar compared to the IR 5 mg tablet administered BID, 
suggesting the possibility of similar efficacy and safety between the MR tablet QD and IR 
tablet BID. Additionally, AUC, Cav, Cmax and trough concentration (Cmin) were predicted 
to be similar to the IR tablet BID.
Study A3921215  is a Phase 3, three month, randomized, double blind, parallel group, 
multicenter study that seeks to demonstrate non inferiority for the efficacy of tofacitinib 
MR 11 mg QD compared to IR 5 mg BID in adult Japanese patients with RA on stable 
background methotrexate.
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the investigators brochure.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary objective
1. To demonstrate the non-inferiority for efficacy of tofacitinib MR 11 mg QD to IR 5 
mg BID for the treatment of signs and symptoms in patients with active RA on a 
stable background of MTX, as measured by DAS28-4(CRP) change from Baseline at 
Week 12.
2.1.2. Secondary objectives
1. To evaluate the similarity in efficacy of tofacitinib MR 11 mg QD and IR 5 mg BID
for the treatment of signs and symptoms of RA, as measured by DAS28-4(ESR)
change from Baseline, ACR20, ACR50, ACR70 responses, remission, and LDA, at 
Week 12.
2. To evaluate the similarity in efficacy of tofacitinib MR 11 mg QD and IR 5 mg BID
for physical function status as measured by HAQ-DI change from Baseline at Week
12.
3. To evaluate the similarity in effects on patient’s health outcome measures (change 
from Baseline in SF-36, FACIT Fatigue and EQ-5D) of tofacitinib MR 11 mg QD and
IR 5 mg BID at Week 12.
4. To evaluate the safety and tolerability of tofacitinib MR 11 mg QD in comparison 
with IR 5 mg BID in patients.


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2.1.3. Other Objectives
The efficacy and health outcome objectives will also be evaluated at other post-Baseline
visits.
2.2. Endpoints
2.2.1. Efficacy Endpoints
2.2.1.1. Primary Efficacy Endpoint

Change from Baseline in DAS28-4(CRP) at Week 12.
2.2.1.2. Secondary Efficacy Endpoints

Change from Baseline in DAS28-4(ESR) at Week 12.

ACR20, ACR50 and ACR70 response at Week 12.

Remission at Week 12, as assessed by: DAS28-4(CRP) < 2.6 and DAS28-4(ESR) 
< 2.6.

LDA at Week 12, as assessed by: DAS28-4(CRP) ≤3.2 and DAS28-4(ESR) ≤3.2.

Change from Baseline in HAQ-DI at Week 12.

HAQ-DI response (decrease of at least 0.22) at Week 12.

Change from Baseline in the SF-36 8 domain scores and 2 component scores at 
Week 12.

Change from Baseline in the FACIT-Fatigue scale at Week 12.

Change from Baseline in the EQ-5D at Week 12.
2.2.1.3. Other Efficacy Endpoints
Primary and secondary efficacy endpoints at other selected post-baseline scheduled visits.
2.2.2. Safety Endpoints
All the safety data will be summarized descriptively through appropriate data tabulations, 
descriptive statistics, and graphical presentations, including:

All adverse events (AEs), including serious adverse events (SAEs).

Clinically significant abnormal laboratory parameters.
3. STUDY DESIGN
This is a multicenter, randomized, double blind, parallel group, phase 3 study to evaluate
efficacy and safety of tofacitinib MR 11 mg QD tablet compared to IR 5 mg BID tablet at 
12 weeks treatment in patients with active RA on a stable background MTX.


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Subjects will be randomized in a 1:1 ratio for the 2 treatment arms with a total sample 
size of approximately 200 subjects; there will be approximately 100 subjects randomized 
into the 11 mg MR QD group and approximately 100 patients into the 5 mg IR BID group.
The study design schematic for the study is represented in Figure 1.
Figure 1.
Study Design
Approximately 100 per arm, N=200
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The 
following eligibility criteria are designed to select subjects for whom protocol treatment is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular subject.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into 
the study:
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
3. Subjects must be 20 years of age or older at time of informed consent.
4. Subjects must meet the American Rheumatism Association 1987 revised criteria for 
classification of RA at least 6 months prior to screening (refer to Appendix 1). This 
information must be documented in the subject’s source documents.
Randomization  1:1
Tofacitinib MR 11mg Tablet, Once Daily 
Tofacitinib IR 5 mg Tablet, Twice Daily
Screening
−4                           0                          4                           8                           12 (Weeks)


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5. Subjects must have active disease at both screening and baseline, as defined by 
having both:
a.
6 tender/painful joints on motion (from 68 joints assessed); and;
b. 6 swollen joints (from 66 joints assessed).
6. Subjects must also have active disease, as defined by one of the following criteria at 
screening:
a.
CRP >0.7 mg/dL in the central laboratory; or;
b. ESR (Westergren method or other methods that yield results comparable to 
the Westergren method) >28 mm/hr.
7. Subjects must meet Class I, II or III of the ACR 1991 Revised Criteria for Global 
Functional Status in RA at screening (refer to Appendix 2).
8. Subjects must be receiving ongoing treatment with MTX and folic acid as described 
below.

Subjects must have taken oral MTX continuously for at least 4 months prior 
to the first dose of study medication (baseline visit) and be on a stable dose of 
6.0 mg to 16 mg weekly, for at least 6 weeks prior to baseline visit.

Subjects should be on an adequate and stable dose of folic acid or folinic acid
for at least 4 weeks prior to baseline visit. The doses of folic acid or folinic 
acid are according to local standard of care. 
9. Subjects must have discontinued all prohibited concomitant medications for the 
required time prior to baseline visit (refer to section 5.8.3 and Appendix 3).
10. Subjects receiving non-prohibited concomitant medications for any reason must be on 
a stable regimen, which is defined as not starting a new drug or changing dosage 
within 7 days or 5 half-lives (whichever is longer) prior to baseline visit, or as defined 
in Concomitant Medications (refer to section 5.8.1 and 5.8.2).
11. Female subjects of childbearing potential must have negative pregnancy test results at 
screening and baseline visit.
12. Female subjects who are not of childbearing potential (ie, meet at least 1 of the 
following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 


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physiological cause; a serum follicle stimulating hormone (FSH) level within the 
laboratory’s reference range for postmenopausal women. 
13. No evidence of active or latent or inadequately treated infection with mycobacterium 
tuberculosis (TB) as defined by meeting both criteria “a” and “b” below:
a.
Chest radiographs (PA and lateral) or chest CT scan (with or without IV 
contrast), taken at or within 12 weeks prior to screening visit, without changes 
suggestive of active TB infection as determined by a qualified radiologist or a 
respirologist. If necessary, a chest CT scan (with or without IV contrast) may 
be performed during screening following initial performance of chest 
radiographs (PA and lateral) at the clinical discretion of the investigator.
b.
Subjects who correspond to any of the following
1)
A negative test for blood IFN-γrelease assay, i.e. Quantiferon-
3G/QuantiFERON® TB Gold In-tube (QFT-G) or T-SPOT test, 
performed at or within 12 weeks prior to screening visit.
Note 1)
Subjects with a history of Bacille Calmette Guérin (BCG) vaccination 
MUST be tested with the blood IFN-γ release assay.
Note 2)
In subjects who didn’t receive BCG vaccination, if there are two 
consecutive  indeterminate results of QFT-G or T-SPOT test, a 
Mantoux/ Purified Protein Derivative (PPD) tuberculin skin test will be 
allowed during screening period.  A negative Mantoux/PPD tuberculin 
skin test result is required to meet the inclusion criterion.
Note 3)
In subjects who have previously received an adequate course of therapy 
for either latent (6-9 months of isoniazid or an acceptable alternative 
regimen) or active (acceptable multi drug regimen) TB infection, neither 
a QFT-G or T-SPOT test nor a PPD test need be obtained.  
Documentation of adequate treatment for active and/or latent TB will be 
obtained prior to baseline visit.
2)
Subjects who are currently being treated for latent TB infection can only 
be enrolled with documentation of an adequate treatment regimen and 
with prior approval by the sponsor.
Note 1)
In this study, latent TB is defined to meet all following conditions:

A positive result of blood IFN-γ release assay or PPD skin test 
performed at or within 12 weeks prior to screening visit, AND


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
Without any changes suggestive of active TB or old TB infection 
on the chest radiograph or chest CT scan evaluated by a qualified 
radiologist or a respirologist, AND

Without clinical signs or symptoms suggestive of active TB, AND

Without history of previously treated active or latent TB
Note 2)
Adequate treatment regimens for latent TB is defined to meet following 
conditions.

At least 4 weeks of treatment with isoniazid or an acceptable 
alternative regimen must be completed prior to randomization, and
the treatment with isoniazid or an acceptable alternative regimen
for latent TB must continue for 9 months or appropriate period.
If at least 4 weeks of treatment with isoniazid or an acceptable 
alternative regimen for latent TB is not completed prior to 
randomization, the subject is to be a screening failure. If the subject is 
still willing to participate to this study, the screening procedures must be 
repeated (and meet the eligibility criteria) after taking separate informed 
consent.
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
1. Subjects with any of the following laboratory abnormalities:
a.
Hemoglobin < 9 g/dL;
b.
Absolute white blood cell (WBC) count of < 3.0 × 109/L (< 3000/mm3);
c.
Absolute neutrophil count of < 1.2 × 109/L (< 1200/mm3);
d.
Absolute lymphocyte count of < 0.75 × 109/L (< 750/mm3);
e.
Platelet count < 100 × 109/L (< 100,000/mm3);
f.
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >
1.5 times the upper limit of normal (× ULN);
g.
Estimated glomerular filtration rate (GFR) <40 mL/min using the Cockcroft-
Gault formula (refer to Appendix 4).
2.
Current or recent history of uncontrolled clinically significant renal, hepatic, 
hematological, gastrointestinal, endocrine, metabolic (including uncontrolled 
clinically significant hypercholesterolemia), pulmonary, cardiac, or neurological 
disease. Investigators should carefully evaluate patients who exhibit symptoms, 
especially fever or cough.  If clinical laboratory findings (serum -D glucan, KL-6) 


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or findings on the chest radiograph or chest CT scan (taken within 12 weeks prior to 
screening) are suggestive of serious lung disease, such as interstitial pneumonia, the 
patient will be excluded from enrollment in this study.
3.
History of any other autoimmune rheumatic disease, other than rheumatoid arthritis 
and Sjogren’s syndrome.
4.
History of an infected joint prosthesis at any time, with the prosthesis still in situ.
5.
History of any lymphoproliferative disorder (LPD), such as Epstein Barr Virus 
(EBV) related lymphoproliferative disorder, history of lymphoma, leukemia, or signs 
and symptoms suggestive of current lymphatic disease.
6.
History of recurrent (more than one episode) herpes zoster or disseminated (a single 
episode) herpes zoster or disseminated (a single episode) herpes simplex.
7.
History of infection requiring hospitalization, history of infection requiring 
parenteral antimicrobial therapy, or infection otherwise judged clinically significant 
by the investigator, within the 6 months prior to baseline visit.
8.
History of infection requiring antimicrobial therapy within 2 weeks prior to baseline 
visit.
9.
Any prior treatment with non B cell-specific lymphocyte depleting agents/therapies 
[e.g., rituximab, alkylating agents (e.g., cyclophosphamide or chlorambucil), total 
lymphoid irradiation, etc] and leukocytapheresis (LCAP).
10. Subjects who have been vaccinated with live or attenuated vaccines within the 
6 weeks prior to baseline visit or are to be vaccinated with these vaccines at any time 
during treatment and within 6 weeks after the last dose of investigational product.
11. Subjects with any condition possibly affecting oral drug absorption, e.g., 
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.
12. Subjects with a history of, or current evidence for, severe gastrointestinal narrowing 
(pathologic or iatrogenic ).
13. Pregnant female subjects; breastfeeding female subjects; male subjects with partners 
currently pregnant; male and female subjects of childbearing potential who are 
unwilling or unable to use a highly effective method of contraception as outlined in 
this protocol for the duration of the study and for at least 28 days after the last dose 
of investigational product.
14. History of alcohol or drug abuse, unless in full remission for greater than 6 months of 
abstinence prior to baseline visit.
15. Screening 12-lead electrocardiogram (ECG) that demonstrates clinically relevant 
abnormalities which may affect subject safety or interpretation of study results.


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16. Subjects with a first degree relative with a hereditary immunodeficiency.
17. Subjects with a malignancy or with a history of malignancy, with the exception of 
adequately treated or excised non-metastatic basal cell or squamous cell cancer of the 
skin, cervical carcinoma in situ.
18. Significant trauma or major surgery procedure within 4 weeks prior to baseline visit. 
19. Subjects requiring prohibited concomitant medications including prohibited dietary 
supplements (Refer to Appendix 3).
20. Subjects infected with human immunodeficiency virus (HIV) or hepatitis B virus 
(HBV) (Please refer the detail of HBV screening in Appendix 5).
21. Subjects infected with hepatitis C virus (HCV). Subjects with positive HCV 
antibodies (HCV Ab) must have further testing for HCV RNA by polymerase chain 
reaction (PCR). Subjects with detectable HCV RNA will be excluded from the study.
22. Subjects who have previously received tofacitinib or other JAK3 inhibitors treatment 
including clinical study.
23. Subjects who are investigational site staff members directly involved in the conduct 
of the study and their family members, site staff members otherwise supervised by 
the investigator, or subjects who are Pfizer employees directly involved in the 
conduct of the study.
24. Participation in other clinical studies involving investigational drug(s) (Phases 1-4) 
within 12 weeks or 5 half-life (whichever is longer), or device(s) within 12 weeks,
prior to baseline visit and/or during study participation.
25. Subjects who have an allergy/hypersensitivity to MTX, or previous serious toxicity 
when administered methotrexate.
26. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the subject
inappropriate for entry into this study.
4.3. Randomization Criteria 
Subjects must complete all screening tests and procedures without evidence of 
exclusionary conditions and the investigator must attest to the suitability of the subject for 
inclusion in the study prior to randomizing the subject.
4.4. Lifestyle Guidelines
In order to participate in the study, subjects must be made aware of the following life 
style guidelines and restrictions that apply during and after the study period.  Details of 
these life style guidelines are provided in sections as noted.


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
On study visit days, comply with fasting requirement for at least 9 hours prior to 
the visit.

On study visit days, do not smoke or ingest caffeine (e.g., tea, coffee, some soft 
drinks/ colas and energy drinks) during the 30 minutes prior to blood pressure, 
pulse rate and ECG measurements.
4.4.1. Non-Pharmacologic Interventions
The subject may continue non-pharmacologic therapies, such as physical therapy, as 
indicated and deemed appropriate for physical condition.  The subject should not initiate 
new non-pharmacologic therapies or change the currently on-going non-pharmacologic 
therapies throughout the study period.
4.4.2. Vaccination
4.4.2.1. Household Contact with Others Vaccinated
During the study and for 6 weeks following the last dose of study drug, subjects should 
avoid routine household contact with children or adults who have been vaccinated with 
live or attenuated live vaccines in the previous 6 weeks.  
Due to these vaccine guidelines, it is recommended that study investigators advise 
potential subjects to be current with vaccinations before being randomized into the study 
(note time window per exclusion criteria #10).  Subjects may still be vaccinated with 
killed or inactivated vaccines at any time during the study; however, the adequacy of the 
immune response to vaccination for subjects taking tofacitinib has not been studied and is 
not known.The data on the adequacy of the immune response to vaccination for subjects 
taking tofacitinib are limited.
4.4.3. Diet and Dietary Supplements
It is recommended that subjects avoid consumption of grapefruit or grapefruit juice  while 
in the study.
For the purposes of this protocol, dietary supplements are defined as vitamins, minerals, 
purified food substances, and herbals with pharmaceutical properties.
Vitamins, minerals and purified food substances are allowed in amounts not known to be 
associated with adverse effects (such as hypervitaminosis).  Herbals with pharmaceutical 
properties are allowed only if there is acceptable evidence of no potent CYP3A inhibition 
or induction.  Otherwise, herbals with pharmaceutical properties should not be given 
concurrently with investigational product.
4.4.4. Reproductive Status of Women Subjects and Partners of Male Subjects
All male and female subjects who, in the opinion of the investigator, are biologically 
capable of having children and are sexually active must agree to use a highly effective 
method  of contraception consistently and correctly for the duration of the active 
treatment period and for at least 28 days after the last dose of investigational product.  
The investigator or his/her designee, in consultation with the subject, will confirm the 
subject has selected the most appropriate method of contraception for the individual 
subject from the permitted list of contraception methods (refer to below) and instruct the 


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subject in its consistent and correct use.  Subjects need to affirm that they meet at least 
one of the selected methods of contraception.  The investigator or his/her designee will 
discuss with the subject the need to use highly effective contraception consistently and 
correctly according to the schedule of activities (SOA) and document such conversation 
in the subject’s chart.  In addition, the investigator or his/her designee will instruct the 
subject to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected.  
Highly effective methods of contraception are those that, alone or in combination, result 
in a failure rate of less than 1% per year when used consistently and correctly (ie, perfect 
use) and include the following:
1. Established use of oral, inserted, injected, or implanted hormonal methods of 
contraception is allowed provided the subject plans to remain on the same 
treatment throughout the entire study and has been using that hormonal 
contraceptive for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, 
cream, or suppository.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).
4.5. Surgery
During the course of this study, no elective surgery should be scheduled without first
consulting with sponsor. Investigators should contact sponsor regarding subjects who 
undergo non-elective surgery to discuss their suitability to remain in the study.
4.6. 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 coordinator’s manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card 
contains, at a minimum, protocol and investigational compound identifiers, patient study 
numbers, contact information for the investigational site, and contact details for a help 
desk in the event that the investigational site staff cannot be reached to provide advice on 
a medical question or problem originating from another healthcare professional not 
involved in the subject’s participation in the study. The help desk number can also be 
used by investigational staff if they are seeking advice on medical questions or problems;
however, it should only be used in the event that the established communication pathways 
between the investigational site and the study team are not available. It is therefore 
intended to augment, but not replace, the established communication pathways between 
the investigational site and the study team for advice on medical questions or problems 


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that may arise during the study. The help desk number is not intended for use by the 
subject directly, and if a subject calls that number, he or she will be directed back to the 
investigational site.
5. STUDY TREATMENTS
Study treatments include tofacitinib MR 11 mg QD and IR 5 mg BID, administered orally.
All subjects will be randomized to one of the two treatment arms.
5.1. Allocation to Treatment
Subjects will be allocated in accordance with the randomization schedule.
Randomization will be accomplished using interactive web response system (IWRS) 
/interactive voice response system (IVRS) (an automated web/telephone randomization 
system provided by the sponsor).  The IWRS/IVRS contains the randomization schedule.  
At the Screening Visit, the investigative site will contact the IWRS/IVRS (online or by 
telephone call).  The site will enroll the subject into the IWRS/IVRS by indicating 
minimal information sufficient to distinguish one subject from another (e.g., date of birth) 
and receive the subject identification (ID) number.  At the baseline visit, the system will 
associate that subject with the next available treatment on the randomization schedule and 
provide the randomization number.
The system will then give the investigative site a code which corresponds to study 
medication that has been previously shipped to the site and is in the site’s inventory ready 
to be dispensed.  This code corresponds to study medication of that treatment group to 
which the subject has just been randomized.
The site will call the system on visits when study medication is to be dispensed.  The 
randomization schedule allows for overage as such enrollment will be controlled by the 
IWRS/IVRS and when a sufficient number of subjects have enrolled, the randomization 
part of the system will be stopped.  The part of the system that supplies codes will 
continue until the last subject randomized has been dispensed the last supply of study 
medication.
All study medication will be dispensed as appropriate for self-administration by study 
subjects.
5.2. Breaking the Blind
The study will be subject, investigator, and sponsor-blinded and the process for breaking 
the blind is outlined below.  At the initiation of the study at sites participating in this 
study, the study site will be instructed on using IWRS/IVRS for breaking the blind.  
Blinding should only be broken in emergency situations for reasons of subject safety.  
The investigator should contact the Pfizer study team before breaking the blind.  When 
the blind for a subject has been broken, the reason must be fully documented and entered 
on the case report form (CRF). At all other times, treatment and randomization 
information will be kept confidential and will not be released to the investigator/study 
staff until the conclusion of the study.


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5.3. Subject Compliance
Study medication accountability and compliance will be assessed by the site at each clinic
visit starting at the visit after the baseline visit (Visit 2) up to Week 12 (Visit 5). Non-
compliance is defined as taking less than 80% or more than 120% of study drug products 
during the double-blind study treatment period and as directed by the dosing instructions. 
Subjects will record their study drug dosing information in a Subject Dosing Diary.
Subjects are to bring the Subject Dosing Diary and the two bottles of investigational
product with any remaining study drug to each visit for review. Upon completion of each 
visit, the Subject Dosing Diary shall 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. Investigators should indicate on the appropriate 
CRF page noncompliance with study treatment and provide an explanation.
Inventory control of all study medications 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 the drug 
inventory must be reported to Pfizer.
5.4. Drug Supplies
Tofacitinib tablets and matching placebo tablets will be provided by the sponsor and 
dispensed for oral administration. Sufficient study medication will be dispensed at 
baseline visit (Visit 2), week 4 visit (Visit 3) and week 8 visit (Visit 4) to complete dosing 
for the entire study treatment period.
5.4.1. Dosage Form(s) and Packaging
Subjects will be randomized to receive either tofacitinib MR 11 mg QD or tofacitinib IR
5 mg BID.  The following medication will be provided by the sponsor and dispensed for 
oral administration:

Tofacitinib MR 11 mg tablets

Placebo tablets to match tofacitinib MR 11 mg tablets

Tofacitinib IR 5 mg tablets

Placebo tablets to match tofacitinib IR 5 mg tablets
The IR 5 mg and the matching placebo tablets are identical in appearance.  The MR 11
mg and the matching placebo tablets are identical in appearance.
Study medication will be packaged in two bottles.  Each bottle will be labeled 
appropriately.  Refer to investigational product manual for details on clinical packaging.


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5.4.2. Preparation and Dispensing
All study medication will be dispensed in bottles. At each dispensing visit, subjects will 
receive a sufficient quantity of study medication to last until their next scheduled visit 
plus an additional amount to accommodate visits scheduled within the allowed visit 
range.  Subjects will also receive written dosing instructions and a dosing diary.
The investigational product should be dispensed using a drug management system at each 
visit from baseline visit (Visit 2) to week 8 visit (Visit 4).  Dispensing will be performed
by a qualified staff member according to unique container numbers on the bottles 
provided, in quantities appropriate for the study visit schedule.  The subject/caregiver 
should be instructed to maintain the product in the bottle provided throughout the course 
of dosing and return the bottle to the site at the next study visit.
Investigational product should be prepared and dispensed by an appropriately qualified 
and experienced member of the study staff (e.g., physician, nurse, physician’s assistant, 
practitioner, or pharmacist) as allowed by local, state, and institutional guidance.
5.5. Administration
Subjects will be provided with medication instructions relevant to their study treatment 
arm. Study medication will be taken according to the instructions provided to the subject.
Subjects should be instructed to take one tablet from each bottle in the morning and one
tablet from bottle of IR in the evening, approximately 12 hours apart. Subjects will 
therefore be taking three tablets per day. Subjects must record drug compliance on the
subject dosing diary.
If a tofacitinib dose is missed and the interval to the next scheduled dose is less than 6 
hours, the missed dose of tofacitinib IR should not be administered. Subjects will 
swallow the study medication whole, and will not manipulate or chew the medication 
prior to swallowing.
5.6. Drug Storage
The investigator, or an approved representative, e.g., pharmacist, will ensure that all 
investigational products, including any comparative agents and/or marketed products are 
stored in a secured area with controlled access under recommended storage conditions 
and in accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with 
the drug label. Storage conditions stated in the single reference safety document (SRSD)
(ie, investigator’s brochure [IB] or Japan package insert) will be superseded by the 
storage conditions stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should 
be captured from the time of investigational product receipt throughout study.  Even for 
continuous monitoring systems, a log or site procedure which ensures active daily 
evaluation for excursions should be available.  The operation of the temperature 


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monitoring device and storage unit (for example, refrigerator), as applicable, should be 
regularly inspected to ensure it is maintained in working order.  
Any excursions from the product label storage conditions should be reported upon 
discovery. The site should actively pursue options for returning the product to labeled 
storage conditions, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  
Once an excursion is identified, the investigational product must be quarantined and not 
used until the sponsor provides documentation of permission to use the investigational 
product.  Specific details regarding information the site should report for each excursion 
will be provided to the site. 
Site staff will instruct subjects on the storage requirements for take home medications 
including how to report temperature excursions. 
5.7. Drug Accountability
The investigator’s site must maintain adequate records documenting the receipt, use, loss, 
or other disposition of the drug supplies by using patient dosing diary.  To ensure 
adequate records, all drug supplies will be accounted for in the drug accountability 
inventory forms as instructed by sponsor and will be monitored by counting of unused 
medications from individual bottles returned by the subject at each visit from week 4 
(Visit 3) to week 12 (Visit 5).
All bottles must be returned to the investigator or designee by the subject and the 
investigator or designee will return the bottles to sponsor unless sponsor authorizes 
destruction at the study site. In the event of destruction at the site, the investigator or 
designee must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
sponsor. Destruction must be adequately documented.  The sponsor or designee will 
provide guidance on the destruction of unused investigational product (e.g., at the site).
5.8. Prior and Concomitant Treatment(s)
All prior and concomitant treatments will be recorded with generic name of the 
medication (or treatment name), reason for usage, dose and frequency, route of 
administration and start and stop dates in the subject’s case report form (CRF) from the 
first day of the screening period until the end of the study.  A subject who is receiving a 
permitted concomitant medication for any reason should be on a locally approved 
medication and a dose that is considered standard of care for the treated indication.  
5.8.1. Prior treatment(s)
The information for prior treatment therapies and medications received within the 
specified time periods prior to signing the informed consent form (ICF) are to be recorded 
as identified in Table 1. 


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Table 1.
Prior Treatment(s)
Treatment type
Information Recorded
Recording Period
For RA biologics, non-
biologic DMARDs including 
MTX, folic acid or folinic 
acid, corticosteroids, 
NSAIDs and others
Dose, unit, frequency, route,
start and stop dates and
reason for discontinuation
(biologics and non-biologic 
DMARDs excluding MTX 
only)
From 4 months prior to 
signing ICF to the first day of 
screening visit
Lipid lowering agents
Dose, unit, frequency, route,
start and stop dates
From 4 weeks prior to 
signing ICF to the first day of 
screening visit
All other treatments
Indication, start and stop 
dates
From 4 weeks prior to 
signing ICF to the first day of 
screening visit
Abbreviations:
RA= Rheumatoid Arthritis; DMARDs= Disease Modifying Antirheumatic Drugs; ICF= Infromed Consent
form; MTX=Methotrexate; NSAIDs=Non-Steroidal Anti-Inflammatory Drugs
All prior biologics and DMARDs are excluded at entry into the study, except MTX.
5.8.2. Permitted Concomitant treatment(s)
All concomitant treatments taken during the study will be recorded from the first day of 
the screening period until the end of the study as identified in Table 2.
Table 2.
Concomitant Treatment(s)
Treatment type
Information Recorded
Recording Period
For RA* background MTX, 
folic acid or folinic acid,
corticosteroids, NSAIDs and 
others
Dose, unit, frequency, route,
start and stop dates
From the first day of 
screening visit to last visit 
date
Lipid lowering agents
Dose, unit, frequency, route,
start and stop dates
From the first day of 
screening visit to last visit 
date
All other treatments**
Indication, start and stop 
dates
From the first day of 
screening visit to last visit 
date


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Table 2.
Concomitant Treatment(s)
Treatment type
Information Recorded
Recording Period
*:
Concomitant treatment for RA must remain at a stable dose (no increase or decrease) during the study
treatment period. Concomitant treatment should not be started during the study treatment period.
**: Includes nonprescription drugs, vitamins, and dietary supplements.
Abbreviations:
RA= Rheumatoid Arthritis; MTX = Methotrexate; NSAIDs = Non-Steroidal Anti-Inflammatory Drugs
Please note that all concomitant DMARDs are excluded at entry into the study, except 
MTX. The following treatments of RA are allowed providing they are stable for the 
specified period of time prior to the first dose of study medication and are not permitted 
to change (dose reduction or increase) during the study treatment period.
5.8.2.1. Methotrexate
All subjects entering the study must have taken MTX continuously for at least 4 months 
prior to the first dose of study medication (baseline visit) and have been taking a stable
dose of 6.0 mg to 16 mg weekly, for at least 6 weeks prior to the baseline visit and 
continue taking that dose throughout the study, unless modification is clinically indicated.
5.8.2.2. Folate Supplementation
Subjects must receive either folic acid or folinic acid as folate supplementation according 
to MTX labeling, practice guidelines and standard of care.
5.8.2.3. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Other Analgesics
Subjects may continue taking stable daily doses of NSAIDs and other analgesics provided 
that the dose is stable for at least 4 weeks prior to the baseline visit and for the duration of 
the study. 
Subjects who require intermittent therapy for symptom relief, may use short-acting 
analgesics including NSAIDs and acetaminophen. However, these medications are not 
permitted within 24 hours of the scheduled joint assessments. Topical NSAIDs and other 
topical analgesics are allowed at any time during the study.
5.8.2.4. Corticosteroid
Oral corticosteroids are allowed during the study up to the dose of 10 mg/day of oral
prednisone or equivalent providing that the dose is stable for at least 4 weeks prior to the
baseline visit; dose should also remain stable for the duration of study treatment.
Reductions in oral corticosteroid dose are only allowed as needed to protect a subject’s 
safety.  
5.8.3. Prohibited Concomitant Treatment(s)
The following treatments are prohibited throughout the double-blind study treatment 
period. Prohibited concomitant treatments include, but not limited to, the following:

DMARDs excepting of MTX


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
Other investigational or marketed immunosuppressants or biologics with
immunomodulatory properties

Moderate to potent cytochrome (CYP)3A and CYP2C19 inhibitors and CYP3A 
inducers (Refer to Appendix 3)

Herbal medicines

Parenteral injections of corticosteroids and hyaluronic acid (e.g. intravenous, 
intra-articular, soft tissue, intra-muscle), articular drainage, articular local 
anesthetic and nerve block

Cytotoxic (immunosuppressive) drugs (e.g., cyclophosphamide)

Plasma exchange therapy

Surgery which affects the efficacy assessments, such as Synovectomy, Artificial 
joint replacement, etc.

Any live (attenuated) vaccines

LCAP
Specific medications and required discontinuation times are listed below.  A list of 
prohibited concomitant medications is provided in Appendix 3.
Any investigational treatment must be discontinued a minimum of 12 weeks or 5 half-life 
(whichever is longer) prior to the baseline visit.  
For investigational drugs which half-life is unknown or pharmacological effect possibly 
persist beyond 5 half-life (e.g. receptor activator of nuclear factor kappa-β ligand 
[RANKL] inhibitors), investigator should consult with sponsor to determine the washout 
period.   
5.8.3.1. Disease Modifying Antirheumatic Drugs (DMARDs)
Subjects who have received biologic or non-biologic DMARDs excepting MTX are 
eligible to participate in the study, providing the following discontinuation periods are 
observed prior to baseline visit (Table 3). 
Table 3.
DMARDs - Required Washout Period Prior to Baseline Visit 
Washout period
Drugs
20 weeks
oral gold and injectable gold 
12 weeks
abatacept, certolizumab pegol, leflunomide*, tocilizumab
10 weeks
golimumab 
8 weeks
infliximab (including biosimilar)
6 weeks
adalimumab (including biosimilar)
4 weeks
azathioprine, cyclosporine, etanercept (including biosimilar), minocycline, 
penicillamine, sulfasalazine, tacrolimus, other DMARDs (e.g., bucillamine, 
mizoribin,etc.)


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12 weeks or 5 half-life 
(whichever is longer)
Other investigational drugs (excluding drugs listed above)
* Leflunomide may be discontinued 4 weeks prior to baseline visit when discontinued using an elimination 
procedure (i.e., 4 grams cholestyramine, 3 times daily, for approximately 17 days). Administration duration of 
cholestyramine may be adjusted based on the patient’s condition and findings of clinical testing.
5.8.3.2. Immune-Modulating Biologic Products
While receiving study drug, no immune-modulating biologic products are allowed to be 
administered concomitantly, including other biologic DMARDs (refer to Appendix 3).
5.8.3.3. CYP3A and CYP2C19 Inhibitors and CYP3A Inducers
Tofacitinib exposure is increased when co-administered with medications that are potent 
inhibitors of CYP 3A (e.g., ketoconazole) and medications that result in both moderate 
inhibition of CYP3A and potent inhibition of CYP2C19 (e.g., fluconazole). 
Tofacitinib exposure is decreased when co-administered with potent CYP3A inducers 
(e.g., rifampicin). 
All prohibited drugs that are CYP3A/CYP2C19 inhibitors require at least a 7 day or 5 
half-lives (whichever is longer) washout prior to the first dose of study drug. Note: 
Amiodarone requires discontinuation at least 290 days (~5 half-lives, half-life averages 
~58 days) prior to the first dose of study drug.
All prohibited drugs that are CYP3A inducers require at least a 28 day or 5 half-lives 
(whichever is longer) washout prior to the first dose of study drug.
If a medication that is a potent CYP3A inhibitor or is both a moderate inhibitor of 
CYP3A4 and potent inhibitor of CYP2C19 needs to be administered during the study for 
any reason, including the treatment of an adverse event, all study medication should be 
interrupted during treatment. 
6. STUDY PROCEDURES 
6.1. Screening (Week −4: Day −34 to Day 0)
Subjects must complete the screening procedures and have test results available prior to 
the baseline visit to confirm that they meet the entrance criteria for the study. All 
screening procedures must be completed within a 4 weeks window, unless otherwise 
noted.
Subjects who do not have all tests completed within the 4 weeks screening period or who 
temporarily do not meet study entry criteria (e.g., treatment with antibiotics during the 
screening period or for administrative reasons) may re-screen; the subject’s prior study 
subject identification (SSID) number and reason for re-screening must be documented. 
Subjects should be fasting for at least 9 hours prior to the visit.
Subjects who do not meet screening criteria or do not re-screen, must be discontinued and 
the reason for screening-failure must be documented in the CRF.


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Procedures to be performed during the screening period (day −34 to day 0) include:

Informed consent

Confirmation of RA diagnosis: subject must meet the American Rheumatism 
Association 1987 revised criteria for classification of RA at least 6 months prior to 
screening (refer to Appendix 1).

Medical history: include previous vaccination (including zoster vaccine) history, 
smoking status, average weekly alcohol consumption, family history of premature 
coronary heart disease (CHD), and history of any prior episodes of herpes zoster.

Prior treatments/medications (refer to Section 5.8.1): This includes start dates and 
stop dates with reason for discontinuation (if appropriate), dosage and frequency of 
administration, and indication treated (make sure all indications are listed in the 
medical history) for all current medications, any medications taken within the 4 weeks 
prior to screening procedures, and a complete history of all DMARDs ever taken 
including the dates of administration and the reasons for discontinuation.

Review of Inclusion/Exclusion criteria.

Complete physical examination: height, weight, general appearance, skin (presence of 
rash), HEENT (head, eyes, ears, nose and throat), lungs (auscultation), heart 
(auscultation for presence of murmurs, gallops, rubs), lower extremities (peripheral 
edema), abdominal (palpation and auscultation), neurologic (mental status, station, 
gait, reflexes, motor and sensory function, coordination) and lymph nodes.

Vital signs (blood pressure and pulse rate) and body temperature (axilla).

Whole blood IFN-γ release assay: Quantiferon-3G/QuantiFERON®-TB Gold In Tube 
test or T-SPOT unless the subject has previously received an adequate course of 
therapy for either latent or active TB infection.

12-lead ECG.

Chest X-ray (PA and lateral) or chest CT scan must show no evidence of active 
tuberculosis or other finding that would exclude the subject from the study (refer to
Section 7.2.5).

Laboratory tests: Rheumatoid factor, hematology, chemistry panel (including fasting 
lipid profile), serum pregnancy tests (-human chorionic gonadotropin [HCG], female 
subjects who have child-bearing potential only), urinalysis, serum -D-glucan, KL-6, 
serology (HIV, HBV, HCV), varicella-zoster virus (VZV) titer, CRP and ESR (refer 
to Section 7.2.6).
All required laboratory testing must be complete and reported; any invalid specimens 
must be retested and reported prior to the baseline visit.

RA Activity: 68/66 tender/painful and swollen joint counts performed and the number 
of swollen joints and the number of tender/painful joints meet the criteria for
inclusion.


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
Concomitant treatments/medication (refer Section 5.8.2 and 5.8.3).
6.2. Study Period
Eligible subjects will be randomized and treated in a double-blind fashion. Refer to 
SCHEDULE OF ACTIVITIES for the detail overview of the procedures.
Subjects who discontinue assigned investigational drug are required to continue in the 
study and perform all study tests and procedures until the study is complete.
6.2.1. Visit 2, Baseline Visit (Day 1)
Subjects are required to fast for at least 9 hours prior to the visit. Subjects who have met 
all the inclusion criteria and have no exclusion criteria present may participate in the 
study.
Procedures that will be performed prior to the first dose of study drug include:

Review of inclusion/exclusion criteria.

Targeted physical examination: weight, examination of heart, lungs, lower extremities 
for peripheral edema, abdomen and lymph nodes. 

Vital signs/temperature.

Laboratory tests: Hematology, chemistry panel (including fasting lipid profile), urine 
pregnancy tests (-HCG, female subjects who have child-bearing potential only), 
urinalysis, lymphocyte subset markers, CRP and ESR (refer to Section 7.2.6).

Banked biospecimens (refer to section 7.3) .

Joint assessment: tender/painful joint count (68 joints) and swollen joint count (66
joints).

Completion of the following assessments:

Patient assessment of arthritis pain

Patient global assessment of arthritis

Physician global assessment of arthritis

Patient reported outcome (PRO): 

HAQ-DI

SF-36 (ver.2, acute)

FACIT-Fatigue

EQ-5D


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
Concomitant treatments/medications review.

Randomize: Investigators have to confirm that all screening procedures have been 
completed and the subject is eligible for randomization.

Dispense of investigational product and dosing diary

Safety assessment and AE reporting

Schedule the subject to return for Visit 3 (Week 4) 
6.2.2. Visit 3 (Week 4: Day 29 3 days)
Subjects are required to fast for at least 9 hours prior to the visit. Procedures that will be 
performed on Visit 3 include:

Targeted physical examination: weight, examination of heart, lungs, lower extremities 
for peripheral edema, abdomen and lymph nodes.

Vital signs/temperature.

Laboratory tests: Hematology, chemistry panel (including fasting lipid profile), urine 
pregnancy tests (-HCG, female subjects who have child-bearing potential only), 
urinalysis, lymphocyte subset markers, CRP and ESR (refer to Section 7.2.6).

Joint assessment: tender/painful joint count (68 joints) and swollen joint count (66 
joints).

Completion of the following assessments:

Patient assessment of arthritis pain

Patient global assessment of arthritis

Physician global assessment of arthritis

Patient reported outcome (PRO): 

HAQ-DI

SF-36 (ver.2, acute)

Drug accountability (include review of dosing diary) and dispense of new 
investigational product and dispense dosing diary

Concomitant treatments/medications review

Safety assessment and AE reporting

Schedule the subject to return for Visit 4 (Week 8)


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6.2.3. Visit 4 (Week 8: Day 57 3 days)
Procedures that will be performed on Visit 4 include:

Drug accountability (include review of dosing diary) and dispense of new 
investigational product and dispense dosing diary

Concomitant treatments/medication review

Safety assessment and AE reporting

Schedule the subject to return for Visit 5 (Week 12)
6.2.4. Visit 5 (Week 12: Day 85 3 days) End of Study or Early Termination
Subjects are required to fast for at least 9 hours prior to the visit. Procedures that will be 
performed on Visit 5 include:

Targeted physical examination: weight, examination of heart, lungs, lower extremities 
for peripheral edema, abdomen and lymph nodes. Assessment of new physical 
findings.

Vital signs/temperature.

Laboratory tests: Hematology, chemistry panel (including fasting lipid profile), 
urine pregnancy tests (-HCG, female subjects who have child-bearing potential 
only), urinalysis, lymphocyte subset markers, CRP and ESR (refer to Section 
7.2.6).

Joint assessment: tender/painful joint count (68 joints) and swollen joint count (66 
joints).

Completion of the following assessments:

Patient assessment of arthritis pain

Patient global assessment of arthritis

Physician global assessment of arthritis

Patient reported outcome (PRO): 

HAQ-DI

SF-36 (ver.2, acute)

FACIT-Fatigue

EQ-5D

Drug accountability (include review of dosing daily)


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
Concomitant treatments/medications review

Safety assessment and AE reporting
6.3. Follow-up Visit
A follow-up visit is not planned in this study.  However, when a follow-up visit is 
necessary due to an adverse event or abnormal test finding, the investigator may arrange 
follow-up at investigator’s discretion for subjects.
6.4. Subject Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or 
behavioral reasons, or the inability of the subject to comply with the protocol required 
schedule of study visits or procedures at a given study site.
If subjects withdraw prior to Week 12 (Visit 5), the subject should complete the 
procedures for Week 12 (Visit 5) (refer to section 6.2.4). 
It is important to continue all subjects in the study and perform all tests and procedures 
until the study is completed to enable collection of safety data, even if a subject 
withdraws from the study assigned treatment, unless the subject withdraws their consent 
to continue participation. 
If a subject does not return for a scheduled visit, every effort should be made to contact 
the subject and document their current status.  All attempts to contact the subject and 
information received during contact attempts must be documented in the subject’s 
medical record.  In any circumstance, every effort should be made to document subject 
outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
request the subject to return all unused investigational products, request the subject to 
return for a final visit, if applicable, and follow up with the subject regarding any 
unresolved Adverse Events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of 
future information, no further evaluations should be performed, and no additional data 
should be collected.  The sponsor may retain and continue to use any data collected 
before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed,
the investigator will document the reason for this and any corrective and preventive 
actions 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 fashion.


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7.1. Efficacy
7.1.1. Assessments of Disease Activity
Individual components for the following indicators of disease activity will be collected 
throughout the study as described in Table 4.
Table 4.
Disease Activity Indicators
Indicator
Definition/Calculation
DAS28-4(CRP)
0.56*√(TJC28) + 0.28*√(SJC28) + 0.36*ln(CRP in mg/L +1) + 
0.014*PtGA in mm+ 0.96
DAS28-4(ESR)
0.56*√(TJC28) + 0.28*√(SJC28) + 0.70*In(ESR in mm/hour) + 
0.014*PtGA in mm
ACR Response Rates
The ACR’s definition for calculating a 20% improvement in 
RA (ACR20) is as follows: a 20% improvement in tender and swollen 
joint counts and 20% improvement in 3 of the 5 remaining ACR-core 
set measures: patient and physician global assessments, pain, disability, 
and an acute-phase reactant (e.g., CRP).  Similarly, ACR50 and 70 are 
calculated with the respective percent improvements.
DAS = Disease Activity Score; CRP = C-reactive protein in mg/L; TJC = tender joint count; SJC = 
swollen joint count; ESR = erythrocyte sedimentation rate in mm/first hour, PtGA = patient’s global 
assessment of health; ACR = American College of Rheumatology
7.1.2. DAS Assessments
The Disease Activity Score (DAS) assessment is a derived measurement with differential
weighting given to each component12. The DAS 28-4(CRP) and the DAS28-4(ESR) will 
be calculated.
The components of the DAS 28 arthritis assessment are:
1. Tender/Painful Joint Count (28 joints);
2. Swollen Joint Count (28 joints);
3. CRP or ESR;
4. Patient Global Assessment of Arthritis.
7.1.2.1. Tender/Painful Joint Count (28 joints)
Twenty-eight (28) joints will be assessed by investigator to determine the number of
joints that are considered tender or painful. The response to pressure/motion on each 
joint will be assessed using the following scale:

Present/Absent/Not Done/Not Applicable (to be used for artificial joints).
The 28 joints to be assessed are the shoulders, elbows, wrists, metacarpophalangeal 
(MCP) joints, proximal interphalangeal (PIP) joints, and knees. Artificial joints will not 
be assessed. As a general rule, the same investigator should perform these assessments 
throughout the term of study.
7.1.2.2. Swollen Joint Count (28 joints)
The investigator will also assess these joints for swelling using the following scale:


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
Present/Absent/Not Done/Not Applicable (to be used for artificial joints).
The 28 swollen joint count includes the following joints: shoulders, elbows, wrists, MCP
joints, PIP joints and knees. Artificial joints will not be assessed.  As a general rule, the 
same investigator should perform these assessments throughout the term of study.
7.1.2.3. C-Reactive Protein (CRP)
The CRP will be analyzed by a central laboratory. It will be used in the calculation of 
several efficacy parameters.  CRP results will not be blinded and will be provided to the 
investigator for all visits. 
7.1.2.4. Erythrocyte Sedimentation Rate (ESR) (At Participating Sites)
The ESR will be analyzed by a local laboratory using the Westergren method or other 
methods that yield results comparable to the Westergren method (the same ESR 
assessment method should be used consistently for a subject throughout the study). ESR 
results will be used in the calculation of several efficacy parameters.  ESR results will not 
be blinded.
7.1.3. ACR Assessments
The American College of Rheumatology’s definition for calculating improvement in RA 
(ACR20) is calculated as a 20% improvement in tender and swollen joint counts and 20% 
improvement in 3 of the 5 remaining ACR-core set measures: patient and physician
global assessments, pain, disability, and an acute-phase reactant. Similarly, ACR50 and
70 are calculated with the respective percent improvements.
The specific components of the ACR Assessments that will be used in this study are:
1. Tender/Painful Joint count (68 joints);
2. Swollen Joint Count (66 joints);
3. Patient Assessment of Arthritis Pain;
4. Patient Global Assessment of Arthritis;
5. Physician Global Assessment of Arthritis;
6. CRP;
7. HAQ-DI.
7.1.3.1. Tender/Painful Joint Count (68 joints)
Sixty-eight (68) joints will be assessed by investigator to determine the number of joints 
that are considered tender/painful.  The response to pressure/motion on each joint will be 
assessed using the following scale:

Present/Absent/Not Done/Not Applicable (to be used for artificial joints).


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As a general rule, the same investigator performed these assessments throughout the term 
of study.
The 68 joints to be assessed are the following (Artificial joints will not be assessed):

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).
7.1.3.2. Swollen Joint Count (66 joints)
Investigator will also assess these joints for swelling using the following scale:

Present/ Absent/Not Done/Not Applicable (to be used for artificial 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. As a general rule, the same investigator 
should perform these assessments throughout the term of study.
7.1.3.3. Patient Assessment of Arthritis Pain
Subjects will assess the severity of their arthritis pain using a 100 mm visual analog scale 
(VAS) placing a mark on the scale between 0 (no pain) and 100 (most severe pain), which 
corresponds to the magnitude of their pain.
7.1.3.4. Patient Global Assessment of Arthritis
Subjects will answer the following question, “Considering all the ways your arthritis 
affects you, how are you feeling today?”  The subject’s response will be recorded using a 
100 mm VAS.
7.1.3.5. Physician Global Assessment of Arthritis
The investigator will assess how the subject’s overall arthritis appears at the time of the 
visit.  This is an evaluation based on the subject’s disease signs, functional capacity and 
physical examination, and should be independent of the Patient Global Assessment of 
Arthritis.  The investigator’s response will be recorded using a 100 mm VAS.
7.1.4. Patient Reported Outcomes
7.1.4.1. Health Assessment Questionnaire-Disability Index (HAQ-DI)
The HAQ-DI assesses the degree of difficulty a subject has experienced during the past 
week in 8 domains of daily living activities: dressing and grooming, arising, eating, 


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walking, hygiene, reach, grip, and other activities13. Each activity category consists of 2-3 
items.  For each question in the questionnaire, the level of difficulty is scored from 0 to 3 
with 0 representing “no difficulty,” 1 as “some difficulty,” 2 as “much difficulty,” and 3 
as “unable to do”.  Any activity that requires assistance from another individual or 
requires the use of an assistive device adjusts to a minimum score of 2 to represent a more 
limited functional status.  The form should then be checked by the site staff for 
completeness (refer to Appendix 6).
7.1.4.2. SF-36 Health Survey (Version 2, Acute)
The SF-36 is a widely used general health status questionnaire that assesses 8 domains of
functional health and well-being: Physical Functioning, Role Limitations due to Physical
Health Problems, Bodily Pain, Social Functioning, Mental Health, Role Limitations due 
to Emotional Problems, Vitality, and General Health Perceptions14. A Physical health 
component summary score and Mental health component summary score are calculated
from the 8 domain scores. The acute form uses a recall period of one week. The SF-36 is 
a psychometrically valid and reliable instrument that has been translated into many 
languages, and the scores have been shown to be responsive to change. Higher scores 
indicate a better health-related quality of life. On the specified study visit days, subjects 
should complete the SF-36. The SF-36 should be checked for completeness by the study 
site staff (refer to Appendix 7).
7.1.4.3. Functional assessment of chronic illness therapy (FACIT)-Fatigue
The FACIT-Fatigue Scale is a subject completed questionnaire consisting of 13 items that 
assess fatigue15.  Instrument scoring yields a range from 0 to 52, with higher scores 
representing better subject status (less fatigue).  This questionnaire should be completed 
by the subject prior to any procedures being performed at the visit, if possible.  The form 
should then be checked by site staff for completeness (refer to Appendix 8).
7.1.4.4. Euro Quality of Life Questionnaire (EQ-5D)
The EQ-5D is a patient completed instrument designed to assess impact on quality of life 
in five domains: mobility, self-care, usual activities, pain/discomfort, and
anxiety/depression16. Additionally, scores from the five domains may be used to calculate 
a single index value. The instrument provides a simple descriptive profile and a single 
index value for health status, and is applicable to a wide range of health conditions and 
treatments. On the specified study visit days, subjects should complete the EQ-5D at the 
clinic. The EQ-5D should be checked for completeness by the study site staff (refer to
Appendix 9).
7.2. Safety
7.2.1. Complete Physical Examination
A standard physical examination will be performed at the screening visit.  The following 
parameters and body systems will be examined and any abnormalities described: height, 
weight, general appearance, skin (presence of rash), HEENT (head, eyes, ears, nose and 
throat), lungs (auscultation), heart (auscultation for presence of murmurs, gallops, rubs), 
lower extremities (peripheral edema), abdominal (palpation and auscultation), neurologic 
(mental status, station, gait, reflexes, motor and sensory function, coordination) and 
lymph nodes.  


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7.2.2. Targeted Physical Examinations
At Visit 2, 3 and 5, a targeted physical examination will be performed assessing the 
following: weight, lungs, heart, lower extremities for peripheral edema, abdomen and 
lymph nodes.  Any clinically significant changes from the last complete physical 
examination should be recorded as AEs; ongoing AEs should be updated, as appropriate.
7.2.3. Vital signs and body temperature
Blood pressure should be measured in the subject’s dominant arm and recorded to the 
nearest mmHg. The same arm will be used throughout the study. All blood pressure in 
this study will be measured with the subject in the sitting position after resting for at least 
5 minutes. The use of automated devices for measuring blood pressure and pulse rate are 
acceptable, although, when done manually, pulse rate will be measured in the 
brachial/radial artery for at least 30 seconds. When the timing of these measurements 
coincides with a blood collection, blood pressure and pulse rate should be obtained first.
Temperature will be collected as axillary temperature.
7.2.4. 12-lead electrocardiogram
A 12-lead ECG will be obtained on all subjects at the screening visit.  All ECGs should
be performed after the subject has rested quietly for at least 10 minutes.  ECGs will be 
read locally. Screening ECG results will be used as a screening tool and should be 
maintained in the subject’s source documentation.  Subjects with a screening 12-lead 
electrocardiogram that demonstrates clinically significant abnormalities requiring urgent 
treatment (e.g., acute myocardial infarction, serious tachy- or bradyarrhythmias) or that is 
indicative of serious underlying heart disease (e.g., cardiomyopathy, major congenital 
heart disease, low voltage in all leads) should not be enrolled in the study.
7.2.5. Chest Radiograph or chest CT scan 
Subject must have a chest radiograph (PA and lateral views) or chest CT scan 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 or respiratologist. Documentation of the official reading must be 
located and available in the source documentation.
If necessary, a chest CT scan (with or without IV contrast) may be performed during 
screening following initial performance of chest radiographs (PA and lateral) at the 
clinical discretion of the investigator. If pulmonary signs and symptoms are observed at 
and after baseline visit, unscheduled imaging tests (e.g. chest X-ray or chest CT scan) 
may be performed based on the judgment by investigator as appropriate.
7.2.6. Clinical Laboratory Tests
Blood and urine samples will be collected at the time points identified in Table 5.
Unscheduled clinical laboratory tests may be obtained at any time during the study to 
assess any perceived safety concerns.


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Table 5.
Clinical Laboratory Tests
Tests
Visits
Comments
Chemistry
blood urea nitrogen, creatinine, 
glucose, calcium, sodium, 
potassium, bicarbonate, chloride, 
total protein, total bilirubin, direct 
bilirubin, indirect bilirubin, ALT, 
AST, ALP, gamma-glutamyl 
transferase (GGT), albumin, 
creatine kinase (CK)
Visit 1, Visit 2, Visit 3 and 
Visit 5
Creatinine clearance is calculated 
by the central laboratory according 
to the Cockcroft-Gault Formula at 
screening Visit (Appendix 4).
Refer to Section 7.5 for retesting 
requirements for ALT and AST 
elevated 3 × ULN.
Hematology
Hemoglobin
Hematocrit
RBC
WBC
Neutrophils (%, abs)
Lymphocytes (%, abs)
Monocytes (%, abs)
Eosinophils (%, abs)
Basophils (%, abs)
Platelets
Visit 1, Visit 2, Visit 3 and 
Visit 5
Refer to Section 7.5 for monitoring 
requirements related to
hemoglobin, neutrophil and 
lymphocyte counts.
C-reactive Protein (CRP)
Visit 1, Visit 2, Visit 3 and 
Visit 5
Refer to Section 7.1.2.3.
Erythrocyte sedimentation ratio (ESR)
Visit 1, Visit 2, Visit 3 and 
Visit 5
Refer to Section 7.1.2.4.
Rheumatoid Factor
Visit 1
Banked Biospecimens
Visit 2
Refer to Section 7.3.
Serum β-D-glucan and KL-6
Visit 1
HIV Serology
Visit 1
Hepatitis B Surface antigen (HBsAg)
Hepatitis B Core Antibody (HBcAb)
Hepatitis B Surface Antibody (HBsAb)
Visit 1
Refer to Section 7.2.6.2 and 
Appendix 5.
Hepatitis B virus DNA (HBV DNA)
Visit 1, recommended every 4 
weeks
Refer to Section 7.2.6.2 and 
Appendix 5 to determine when 
necessary.
Hepatitis C virus antibody (HCV Ab)
Hepatitis C RNA (HCV RNA)
Visit 1
HCV RNA assay will be 
performed, if HCV Ab is positive. 
Lipids (fasting)
Triglycerides
Total Cholesterol
HDL Cholesterol
LDL Cholesterol
Visit 1, Visit 2, Visit 3 and 
Visit 5
Subjects should be fasting for at 
least 9 hours prior to each visit.  
Refer to Section 7.2.6.4.
Serum Pregnancy Testing
Visit 1
All female subjects of childbearing 
potential, regardless of whether or 
not they are sexually active.  Refer 
to Section 7.2.6.1 .
Whole blood IFN-γ release assay  
(Quantiferon-3G/QuantiFERON® -TB 
Gold In-Tube or T-SPOT)
Visit 1
If there are two consective 
indeterminate results of QFT-
G/QuantiFERON® -TB Gold In-Tube
or T-SPOT test, a Mantoux 
Purified Protein Derivative (PPD) 
tuberculin skin test can be 
performed during screening period.  
Refer to Section 7.2.6.3.1.


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Table 5.
Clinical Laboratory Tests
Tests
Visits
Comments
Varicella-Zoster Virus (VZV)
Visit 1
Lymphocyte subset markers
Visit 2, Visit 3 and Visit 5
Lymphocyte subset markers 
include: CD3+, CD3−CD19+,
CD3+CD4+CD8−,
CD3+CD4−CD8+, 
CD3+CD16+CD56+, 
CD3−CD16+CD56+, 
CD3−CD16+CD56−, 
CD3−CD16−CD56+, 
CD3−CD16−CD56−, CD4/CD8
Urinalysis
Specific Gravity
pH
Protein
Glucose
Ketones
Blood
Nitrite
Leukocyte Esterase
Pregnancy test (excluding visit 1)
Urine sediment (microscopy)
Urine culture (if clinically 
indicated)
Visit 1, Visit 2, Visit 3 and 
Visit 5
Tests to include when repeat AST 
and/or ALT are required:
Albumin
Creatine kinase (CK)
Total bilirubin
Direct bilirubin
Indirect bilirubin,
GGT
PT/INR
ALP
At same time as AST and/or 
ALT are repeated for 
elevations as noted in Section 
7.5
Refer to Section 8.7.2 for further 
details on management of 
elevations. 
ALT = alanine aminotransferase (SGPT); AST = aspartate aminotransferase (SGOT) ; ALP = alkaline 
phosphatase; HDL = high density lipoprotein; HIV = human immunodeficiency virus; LDL = low density 
lipoprotein; SGOT = serum glutamic-oxaloacetic transaminase (AST); SGPT = serum glutamic pyruvate 
transaminase (ALT); TB = tuberculosis; 
× ULN = times the upper limit of normal; 
7.2.6.1. Pregnancy Testing
For female subjects of childbearing potential, a serum pregnancy test will be performed at
the screening visit. For female subjects of childbearing potential, urine pregnancy test 
with sensitivity of at least 25 mIU/mL will be performed prior to starting study therapy  
(before investigational product administration at the baseline visit), visit 3 (week 4) and 
visit 5 (week 12).  A negative pregnancy result is required before the subject may receive 
the investigational product. Urine pregnancy test may be repeated more frequently if a 
menstrual cycle is missed or if potential pregnancy is otherwise suspected.
7.2.6.2. Hepatitis B virus screening
All subjects must undergo testing for hepatitis B surface antigen (HBsAg), hepatitis B
core antibody (HBcAb) and hepatitis B surface antibody (HBsAb). Subjects who have 


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negative HBsAg, negative HBcAb and positive HBsAb without documentation of prior 
HBV vaccination, and subjects who have negative HBsAg, positive HBcAb and positive 
HBsAb are required to undergo HBV DNA testing at the screening visit.  Refer to
Appendix 5 for the detail of HBV screening.
7.2.6.3. Tuberculosis Screening
During the screening period, it must be determined and documented that a subject does 
not have evidence of active or latent or inadequately treated infection with TB per the 
inclusion criteria. The results of TB screening conducted in 12 weeks prior to Screening 
or during the screening period must be documented in study records prior to Baseline/Day 
1.
7.2.6.3.1. Whole blood IFN-γ release assay
QFT-G is an in vitro diagnostic test using a peptide cocktail simulating ESAT-6, CFP-10 
and TB 7.7 proteins to stimulate cells in heparinized whole blood. Detection of IFN-γ
performed by Enzyme-Linked Immunosorbent Assay (ELISA) is used to identify in vitro 
responses to these peptide antigens that are associated with Mycobacterium tuberculosis
infection. QFT-G is an indirect test for M. tuberculosis infection (including disease) and 
is intended for use in conjunction with risk assessment, radiography and other medical 
and diagnostic evaluations.
The T-SPOT® TB test is an IFN-γ release assay, and enumerates the response of effector 
T cells that have been sensitized to Mycobacterium tuberculosis.  IFN-γ is captured and 
presented as spots from T cells sensitized to Mycobacterium tuberculosis antigens.  The 
results are interpreted by subtracting the spot count in the negative (NIL) control from the 
spot count in Panels A (ESAT-6) and B (CFP-10).
A negative QFT-G and/or T-SPOT test result is required to meet the inclusion criterion. 
QFT-G and T-SPOT test results will be reported as positive, negative or indeterminate.
In the case of an indeterminate result, repeat tests should be permitted for the purpose of 
determining eligibility of subjects to enroll in this study. Mantoux/PPD testing will be 
allowed, if there are two consecutive indeterminate results in subjects who have been 
received BCG vaccination. Subjects with a history of BCG vaccination will be tested with 
the QFT-G and/or T-SPOT test. 
7.2.6.3.2. Mantoux/Purified Protein Derivative (PPD) Tuberculin Skin Test
Mantoux Purified Protein Derivative (PPD) tuberculin skin test will be allowed during 
screening period, if there are two consecutive indeterminate results of QFT-G or T-SPOT
test in subjects who have not received BCG vaccination. Subjects must have a
Mantoux/PPD tuberculin skin test administered and then evaluated by a health care
professional 48 to 72 hours later. If performed, a negative Mantoux/PPD tuberculin skin 
test result is required to meet the inclusion criterion.
The Tuberculin Test consists of intracutaneous injection of PPD in 0.1 mL of solution on 
the volar aspect of the forearm, using a short beveled 26-or 27-gauge needle (Mantoux
test). The test is positive if the diameter of the erythema is over 10 mm in 48 to 72 hours 
after injection.


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7.2.6.4. Serum Lipid Profile
Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides will be measured
during the study requiring subjects to be fasting at least 9 hours prior to Visit 1, Visit 2,
Visit 3 and Visit 5. Refer to Appendix 10 for recommended clinical management of 
cholesterol.
7.2.6.5. Creatinine Clearance
A commonly used surrogate marker for actual creatinine clearance is the Cockcroft-Gault
formula (refer to Appendix 4), which employs creatinine measurements and a subject’s 
weight to predict the clearance. For subjects to be eligible for the study, GFR needs to be 
>40 mL/min based on Cockcroft-Gault calculation. Cockcroft-Gault GFR calculation 
will be done as part of clinical laboratory tests in Visit 1.
7.2.7. Adjudicated Adverse Events 
Specific safety events such as cardiovascular (CV) events, malignancies, opportunistic
infections (OI), hepatic events and interstitial lung disease (ILD) in this study will be 
adjudicated by external or internal committees to harmonize and to standardize selected 
safety event assessments (Refer to Section 9.6).
Subjects will be monitored for development of any CV events, malignancies, infections
(viral, bacterial, and fungal), liver disease and lung disease during the study.
The study site has responsibility to obtain and submit the event documentation to related 
committee. Event documentation will vary with the event requiring adjudication and may 
include (but not be limited to): hospital discharge summaries, operative reports, clinic 
notes, ECGs, diagnostic tests, pathology reports, autopsy reports and death certificate 
information, as applicable.  Criteria for defining specific events will be provided to 
investigators in a separate study document.
Refer to Appendix 11 for the steps to take in the event of potentially malignant tumors, 
lymphadenopathy or possible extra-nodal lymphoproliferative disorder (LPD) which 
might arise in the course of this study.
7.3. Banked Biospecimens
7.3.1. Markers of Drug Response
Studying the variation in genetic markers and other biomarkers may help to explain some 
of the variability in response seen with some drugs among different individuals.  This is 
referred to as pharmacogenomic/biomarker research.  Comparing the deoxyribonucleic 
acid (DNA), ribonucleic acid (RNA), protein, and metabolite variation patterns of 
subjects who respond well and those who respond poorly to treatment may help to better 
define the most appropriate group of patients in which to target a given treatment.  
Collecting biospecimens for exploratory pharmacogenomic/biomarker analyses and 
retaining them in the Pfizer BioBank makes it possible to better understand the drug’s 
mechanism of action and to seek explanations for differences in, for example, exposure, 
efficacy, tolerability, or safety not anticipated prior to the beginning of the study.  
Providing these biospecimens is a required study activity for study sites and subjects, 
unless prohibited as such by local regulations or ethics committee (EC) decision.  


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


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natural variation amongst people in genes, RNA, proteins, and metabolites; and 
use in developing new technologies related to pharmacogenomics/biomarkers.  
Subjects need not provide additional biospecimens for the uses described in this section; 
the biospecimen specified in the Markers of Drug Response section will be used.  
Subjects may still participate in the clinical study if they elect not to allow their banked 
biospecimens to be used for the additional purposes described in this section.
7.4. Assessment of Suicidal Ideation and Behavior (SIB)
There are no current medically significant suicidality concerns for the study drug (ie, 
tofacitinib) in this study or their respective mechanisms of action. Ongoing and aggregate 
cumulative safety reviews and pharmacovigilance activities will be conducted; if any 
concerns are identified that would warrant changes to these assessments, surveillance 
tools will be implemented, as appropriate.
7.5. Triggered Requirements
The following laboratory abnormalities require re-testing ideally within 3-5 days, prompt 
retesting, withdrawal of study treatment or withdrawal from this study.
Condition
Action
Neutrophil counts <1000 cells/mm3
The subject should return to the study 
site for prompt retesting, ideally within 
3-5 days.
Platelet counts <100,000 platelets/mm3
The subject should return to the study 
site for prompt retesting, ideally within 
3-5 days.
Lymphocyte counts <500 lymphocytes/mm3
The subject should return to the study 
site for prompt retesting, ideally within 
3-5 days.
Any single AST and/or ALT elevation 
≥3 × ULN *
The subject should return to the study 
site for prompt retesting, ideally within 
3-5 days. 
Any single hemoglobin value <8.0 g/dL or one 
that drops 2 gm/dL below baseline. 
The subject should return to the study 
site for prompt retesting, ideally within 
3-5 days.
Any serum creatinine increase >50% over the 
average of screening (most recent value prior 
to baseline) and baseline values OR an 
absolute increase in serum creatinine 
>0.5 mg/dL (>44.2 mol/L) over the average 
of screening (most recent value prior to 
baseline) and baseline values
The subject should return to the study 
site for prompt retesting, ideally within 
3-5 days.
* The subject must return to the study site for prompt retesting and include the following tests: albumin, 
creatine kinase (CK), total bilirubin, direct and indirect bilirubin, GGT, PT/INR, and ALP. 
Additional investigations include a detailed history, occupational exposure, sexual history, travel history, 
history of contact with a jaundiced subject, surgery, blood transfusion, history of liver or allergic disease, 
work exposure, history of ethanol, recreational drug and dietary supplement consumption.  Testing for acute 
hepatitis A, B or C infection and biliary tract imaging may be considered.


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


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Condition
Action
Increase lipid parameters (total cholesterol, 
LDL cholesterol, HDL cholesterol, 
triglycerides)
Monitor and treat according to local 
guidance (eg, diet and behavior 
modification, statin therapy).
Pregnancy or refusal to use appropriate 
contraception
Permanently withdraw the subject from 
the study drug and follow any pregnancy 
to resolution.
Anaphylactic or other serious allergic reaction
Immediately discontinue study drug and 
institute appropriate therapy.  
Symptoms suggestive of a lupus-like syndrome
Discontinue study drug and institute 
appropriate therapy.
Detection of HBV-DNA by the two sequential 
quantitative tests (for subjects who have HBV-
DNA assay at screening)
Immediately discontinue study drug and 
institute appropriate therapy.  
Other serious or severe AEs, after consultation 
with the sponsor.
Treatment with all study drugs will be 
discontinued and the subject withdrawn 
from this study.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase; DNA = 
deoxyribonucleic acid; g/dL = grams per deciliter; GGT = gamma-glutamyl transferase; HBV = hepatitis B 
virus; PT/INR = Prothrombin Time/International Normalized Ratio; mm = millimeter; × ULN = times the 
upper limit of normal
Additional individual subject safety monitoring in above actions is at the discretion of the 
investigator and dependent on any perceived safety concerns.  Unscheduled laboratory 
testing through the central laboratory 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.
Because of the potential higher risk of interstitial pneumonia in Japanese patients than in 
Western patients, investigators should carefully evaluate all patients who exhibit 
symptoms, especially fever and cough. 
If a patient develops fever, cough, or dyspnea, temporary discontinuation of study drug 
should be considered.  The differential diagnosis should include assessment for 
pneumonia, TB, pneumocystis pneumonia (PCP), and invasive fungal infection. 
Additionally, if a patient’s absolute lymphocyte count is decreased to <1000/mm3, please 
consider appropriate action based on the patient’s condition, such as retest of lymphocyte 
counts, as warranted. If the absolute lymphocyte count is decreased to <500/mm3, prompt 
retesting, ideally within 3-5 days from the awareness, is required and please consider 
temporary discontinuation of study drug while the patient is under evaluation for the 
cause of the abnormality (ies), e.g., pneumonia, TB or PCP.  
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 


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For all AEs, the investigator must pursue and obtain information adequate both to 
determine the outcome of the AE and to assess whether it meets the criteria for 
classification as an serious adverse event (SAE) requiring immediate notification to Pfizer 
or its designated representative.  For all AEs, sufficient information should be obtained by 
the investigator to determine the causality of the AE.  The investigator is required to 
assess causality.  Follow-up by the investigator may be required until the event or its 
sequelae resolve or stabilize at a level acceptable to the investigator, and Pfizer concurs 
with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the 
clinical study.  
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins 
from the time that the subject provides informed consent, which is obtained prior to the 
subject’s participation in the study, ie, prior to undergoing any study-related procedure 
and/or receiving investigational product, through and including 28 calendar days after the 
last administration of the investigational product.  SAEs occurring to a subject after the 
active reporting period has ended should be reported to the sponsor if the investigator 
becomes aware of them; at a minimum, all SAEs that the investigator believes have at 
least a reasonable possibility of being related to study drug are to be reported to the 
sponsor.
AEs (serious and nonserious) should be recorded on the Case Report Form (CRF) from 
the time the subject has taken at least 1 dose of study treatment through the subject’s last 
visit.  
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.


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Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the 
medication error case report form (CRF) which is a specific version of the adverse event 
(AE) page, and on the SAE form when appropriate.  In the event of medication dosing 
error, the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the 
adverse event (AE) page and, if applicable, any associated AE(s) are captured on an AE 
CRF page.
All overdoses are medication errors.  For the purpose of this study, medication errors will 
be reported as protocol deviations if the subject reported taking 2-fold or more of their 
prescribed dose for one or more days or were identified as consuming more than 120% of 
their prescribed dose over the visit interval.
The following is an example of tofacitinib overdose:


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8.4.1. Tofacitinib Overdose
There is no experience with overdose of tofacitinib.  Pharmacokinetic data up to and 
including a single dose of 100 mg in healthy volunteers indicate that more than 95% of 
the administered dose is expected to be eliminated within 24 hours.  There is no specific 
antidote for overdose with tofacitinib.  In case of an overdose, it is recommended that the 
subject be monitored for signs and symptoms of adverse reactions.  Subjects who develop 
adverse reactions should receive appropriate treatment.
Overdoses of tofacitinib are defined by doses and duration of dosing not administered in 
the tofacitinib development program.  The following doses and duration of dosing have 
been administered in tofacitinib rheumatoid arthritis clinical trials without evidence of 
dose-limiting symptoms and are not considered overdoses: 

≤100 mg tofacitinib daily for up to 2 weeks

≤60 mg tofacitinib daily for up to 6 weeks

≤30 mg tofacitinib daily for up to 6 months
8.5. Infections 
All treated infections occurring during the study, including, but not limited to, respiratory 
infections, cutaneous infections, urinary tract infections and episodes of suspicious or 
febrile diarrhea, should be cultured if possible and any identified organisms noted in the 
CRF. 
Infections should be classified as either serious infections or treated infections, as defined 
below.
8.5.1. Treated Infections
A treated infection is any infection that requires antimicrobial therapy by any route of 
administration or any surgical intervention (eg, incision and drainage).  Subjects who 
experience infections that require treatment can have their study drug temporarily 
discontinued during antimicrobial therapy.  This information should be noted in the CRF.
8.5.2. Serious Infections
A serious infection is any treated infection that requires hospitalization for treatment or 
requires parenteral antimicrobial therapy or meets other criteria that require it to be 
classified as a serious adverse event.  A patient who experiences a serious infection 
should be discontinued from the study and the serious adverse event should be listed as 
the reason for discontinuation in the eCRF.  Appropriate laboratory investigations, 
including but not limited to cultures should be performed to establish the etiology of any 
serious infection.  All adverse events, including serious adverse events, should be 
reported as described in Section 8.2 on Adverse Event Reporting.
8.6. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be 
reported as an AE are as follows: 


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
Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing (e.g., temporary discontinuation of 
study drug) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does 
not constitute an AE.  Any abnormal test result that is determined to be an error does not 
require reporting as an AE.
8.7. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of 
the ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
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.
8.7.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (refer to section on Serious Adverse Event Reporting Requirements).
8.7.2. Potential Cases of Drug-Induced Liver Injury 
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in 
this study.  However, should an investigator deem it necessary to run LFTs because of
clinical sign/symptom presentation in a subject, such LFT results should be handled and 
followed up as described below.  


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Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver 
injury are considered potential cases of drug-induced liver injury (potential Hy’s law 
cases) and should always be considered important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects 
who present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal 
range who subsequently present with AST or ALT values 3 times the upper limit 
of normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no 
evidence of hemolysis and an ALP value 2 × ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 × ULN, or 
8 × ULN (whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN
or if the value reaches ≥3 × ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation 
should include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/ international normalized ratio (INR), and ALP.  A 
detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced 
person, surgery, blood transfusion, history of liver or allergic disease, and work exposure, 
should be collected.  Further testing for acute hepatitis A, B, or C infection and liver 
imaging (e.g., biliary tract) may be warranted. All cases confirmed on repeat testing as 
meeting the laboratory criteria defined above, with no other cause for liver function test 
(LFT) abnormalities identified at the time, should be considered potential Hy’s law cases 
irrespective of availability of all the results of the investigations performed to determine 
etiology of the abnormal LFTs.  Such potential Hy’s law cases should be reported as 
SAEs.


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8.8. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital 
or equivalent healthcare facility or any prolongation of an existing admission. Admission 
also includes transfer within the hospital to an acute/intensive care unit (e.g., from the 
psychiatric wing to a medical floor, medical floor to a coronary care unit, or neurological 
floor to a tuberculosis unit). An emergency room visit does not necessarily constitute a 
hospitalization; however, the event leading to the emergency room visit should be 
assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (e.g., 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 (e.g., 
for workup of persistent pre-treatment laboratory abnormality);

Social admission (e.g., subject has no place to sleep);

Administrative admission (e.g., for yearly physical examination);

Protocol-specified admission during a study (e.g., for a procedure required by the 
study protocol);

Optional admission not associated with a precipitating clinical AE (e.g., for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the 
baseline documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should 
not be reported as AEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE, and 
the resulting appendectomy should be recorded as treatment of the AE.


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8.9. Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, 
or SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, 
these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is 
not necessarily an SAE.  For example, a headache may be severe (interferes significantly 
with the subject's usual function) but would not be classified as serious unless it met one 
of the criteria for SAEs, listed above.
8.10. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product caused or 
contributed to an AE; generally the facts (evidence) or arguments to suggest a causal 
relationship should be provided.  If the investigator does not know whether or not the 
investigational product caused the event, then the event will be handled as “related to 
investigational product” for reporting purposes, as defined by the sponsor (refer to section 
on Reporting Requirements).  If the investigator's causality assessment is "unknown but 
not related to investigational product," this should be clearly documented on study 
records.  
In addition, if the investigator determines that an SAE is associated with study 
procedures, the investigator must record this causal relationship in the source documents 
and CRF, as appropriate, and report such an assessment in accordance with the SAE
reporting requirements, if applicable.
8.11. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having 
been exposed (e.g., 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 (e.g., a nurse reports that she is 
pregnant and has been exposed to chemotherapeutic products).


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2. A male has been exposed (e.g., because of treatment or environmental exposure) 
to the investigational product prior to or around the time of conception and/or is 
exposed during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit 
this information to the Pfizer drug safety unit on a Serious Adverse Event (SAE) Report
Form and Exposure During Pregnancy (EDP) supplemental form, regardless of whether 
an SAE has occurred.  In addition, the investigator must submit information regarding 
environmental exposure to a Pfizer product in a pregnant woman (e.g., a subject reports 
that she is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) 
using the EDP supplemental form.  This must be done irrespective of whether an AE has 
occurred and within 24 hours of awareness of the exposure. The information submitted 
should include the anticipated date of delivery (refer to below for information related to 
termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome 
for all EDP reports with an unknown outcome.  The investigator will follow the 
pregnancy until completion or until pregnancy termination) and notify Pfizer of the 
outcome as a follow-up to the initial EDP supplemental form.  In the case of a live birth, 
the structural integrity of the neonate can be assessed at the time of birth.  In the event of 
a termination, the reason(s) for termination should be specified and, if clinically possible, 
the structural integrity of the terminated fetus should be assessed by gross visual 
inspection (unless preprocedure test findings are conclusive for a congenital anomaly and 
the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in 
a live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs.  In addition, infant deaths after 1 month should be 
reported as SAEs when the investigator assesses the infant death as related or 
possibly related to exposure to the investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(e.g., follow-up on preterm infants to identify developmental delays). In the case of 
paternal exposure, the investigator will provide the study subject with the Pregnant 
Partner Release of Information Form to deliver to his partner. The investigator must 
document in the source documents that the subject was given the Pregnant Partner 
Release of Information Form to provide to his partner.


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8.12. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event.
An occupational exposure is reported to the drug safety unit within 24 hours of the
Investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the 
study, the information is not reported on a Case Report Form (CRF), however a copy of 
the completed SAE Report form is maintained in the investigator site file.
8.13. Withdrawal Due to Adverse Events (Refer to Also the Section on Subject
Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  
When a subject withdraws because of an SAE, the SAE must be reported in accordance 
with the reporting requirements defined below.
8.14. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported 
by the study subject.  In addition, each study subject will be questioned about AEs.
8.15. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE
occurs, expedited reporting will follow local and international regulations, as appropriate.
8.15.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of exposure during pregnancy, exposure 
via breastfeeding and occupational exposure cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (e.g., if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the 
time of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an 
investigator may be requested by Pfizer to obtain specific additional follow-up 
information in an expedited fashion.  This information collected for SAEs is more 
detailed than that captured on the AE CRF.  In general, this will include a description of 


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the AE in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality.  Information on other possible causes of 
the event, such as concomitant medications, vaccines, and/or illnesses, must be provided.  
In the case of a subject death, a summary of available autopsy findings must be submitted 
as soon as possible to Pfizer or its designated representative. 
8.15.2. Non-serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form 
for collection of SAE information is not the same as the AE CRF.  Where the same data 
are collected, the forms must be completed in a consistent manner.  For example, the 
same AE term should be used on both forms.  AEs should be reported using concise 
medical terminology on the CRFs as well as on the form for collection of SAE
information.
8.15.3. Sponsor Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried 
out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP), which will be maintained 
by the Sponsor.  This document may modify the plans outlined in the protocol; however, 
any major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment.
9.1. Sample Size Determination
The primary objective of the study is to demonstrate the non-inferiority in efficacy of 
tofacitinib 11 mg MR QD to 5 mg IR BID for the treatment of signs and symptoms in 
patients with active RA on a stable background of MTX, as measured by DAS28-4(CRP) 
change from baseline at Week 12.
The following assumptions in treatment comparison for the primary endpoint have been 
applied: (1) one-sided type-I error (alpha) of 0.025, (2) subjects assigned to tofacitinib 
MR 11 mg QD and IR 5 mg BID groups in a 1:1 ratio, (3) difference of treatment means 
is zero, (4) a common standard deviation of 1.3 based on the previous tofacitinib studies. 
Based on the forgoing assumptions, a total of at least 200 evaluable subjects (100 in each 
treatment arm) will be required to demonstrate non-inferiority with a power of 90% and a 
non-inferiority margin of 0.6, which is equal to the minimum improvement in disease 
activity by DAS consistent with a “moderate response” by the European League Against 
Rheumatism (EULAR) criteria.17
It is anticipated that the sample size of 100 subjects in each formulation group will 
provide 0.36 half-width of 2-sided 95% confidence interval for the difference on the 
change from baseline in DAS28-4(CRP) at Week 12 assuming a common standard 
deviation of 1.3.


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9.2. Efficacy Analysis
9.2.1. Statistical Hypothesis
The primary hypothesis associated with the statistical objective is to demonstrate non-
inferiority of tofacitinib MR 11 mg QD to IR 5 mg BID as measured by DAS28-4(CRP) 
change from baseline at Week 12.  The null hypothesis is that the treatment difference 
(tofacitinib MR 11 mg QD – IR 5 mg BID) is 0.6 or more, and the alternative hypothesis 
is that the treatment difference is less than 0.6.
9.2.2. Statistical Decision Rule
If the lower bound of the 2-sided 95% confidence interval (type-I error [alpha] of 0.025 in 
each tail) for the difference in change from baseline in DAS28-4(CRP) between the two 
arms (MR 11 mg QD – IR 5 mg BID) is less than 0.6, then the treatment of tofacitinib 
MR 11 mg QD will be declared to be non-inferior to that of tofacitinib IR 5 mg BID.
9.2.3. Analysis of Primary Efficacy Endpoint 
The primary efficacy variable of DAS28-4(CRP) will be expressed as a change from 
baseline. The analysis will be conducted using a linear mixed effect model with repeated 
measures (MMRM), which will include baseline as a covariate, treatment, visit (week 4 
and 12), and treatment by visit interaction as fixed effects.  Subjects will be a random 
effect and unstructured covariance will be assumed. The estimate of treatment difference 
and the associated 2-sided 95% confidence interval (type-I error [alpha] of 0.025 in each 
tail) at the primary time point of week 12 will be constructed based on the model.  The 
statistical decision rule is described in Section 9.2.2.
The primary efficacy analysis will use the full analysis set (FAS) which will include all
subjects who were randomized and received at least one dose of the randomized
investigational drug.
9.2.4. Robustness Analysis
To support the interpretation of the primary analysis, robustness analyses will be 
performed for the primary endpoint.  However, the conclusions will be purely based on 
the results of the primary analysis. 
The robustness analyses will be conducted using the ‘Per Protocol’ analysis set rather 
than the FAS. 
The ‘Per Protocol’ analysis set will include all randomized subjects who completed the 12 
week study with no important protocol deviations that could impact the efficacy analysis. 
The list of potentially important protocol deviations (pIPDs) and the subjects to be 
excluded from the ‘Per Protocol’ analysis set will be identified, reviewed, and finalized 
prior to the release of the database.
9.2.5. Analysis of Secondary and Other Efficacy Endpoints
For each endpoint, treatment comparisons are performed at Week 12 and other time 
points when assessed. There is no non-inferiority testing in these analyses.  The point 
estimate of the treatment difference and the associated 2-sided 95% confidence intervals
(CIs) will be calculated, for descriptive purposes.


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All the secondary and other efficacy analyses are based on FAS. 
The continuous data, i.e., change from baseline in DAS28-4(ESR) and HAQ-DI will be 
analyzed in a similar manner as described for change from baseline in DAS28-4(CRP) in 
the primary analysis. 
Dichotomized data will be summarized and compared between two treatment groups 
using the normal approximation to the difference in proportions.  The 2 sided 95% 
confidence interval of the treatment difference will be constructed.  Examples of the 
secondary and other efficacy endpoints for each scheduled post-baseline measurement 
are:

ACR20, ACR50 and ACR70 response.

Remission, as assessed by: DAS28-4(CRP) < 2.6 and DAS28-4(ESR) < 2.6.

LDA, as assessed by: DAS28-4(CRP) ≤ 3.2 and DAS28-4(ESR) ≤3.2.

HAQ-DI response (decrease of at least 0.22).
Subjects who drop-out for any reason will be considered as a non-responder (non-
responder imputation [NRI]). For the composite endpoint, the last observation carried 
forward (LOCF) mixed components method will be used to impute any missing 
components before drop-out. Only post-baseline values will be carried forward in the 
latter case.
Descriptive statistics of the patient-reported outcome instruments for baseline and for 
each scheduled post-baseline measurement will be provided.
Remaining secondary and other efficacy analyses will be detailed in the analysis plan.
9.3. Safety Analysis
All the safety data will be summarized descriptively through appropriate data tabulations, 
descriptive statistics, and graphical presentations, including:

All AEs, including SAEs.

Clinically significant abnormal laboratory parameters.
The safety analysis will be conducted on the safety analysis set (SAFETY), which is 
defined as all subjects who were randomized and received at least one dose of the 
investigational drug.  By definition, it is identical to the full analysis set defined above.
9.4. Interim Analysis
No interim analysis of the study data will be performed for use outside the data 
monitoring committee (DMC).
9.5. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC). 


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The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the 
study according to the charter.  The recommendations made by the E-DMC to alter the 
conduct of the study will be forwarded to Pfizer for final decision.  Pfizer will forward 
such decisions, which may include summaries of aggregate analyses of endpoint events 
and of safety data that are not endpoints, to regulatory authorities, as appropriate.  
9.6. Safety Event Adjudication/Review Committees
To help assess specific safety events in this study adjudication committees have been 
established to harmonize and standardize selected safety event assessment.  Members of 
these safety event adjudication committees will be blinded to treatment assignment in 
order to allow for unbiased assessments.  These committees include a Cardiovascular 
Endpoint Adjudication Committee (CV EAC), Malignancy Adjudication Committee 
(MAC), Opportunistic Infection Review Committee (OIRC), Hepatic Event Review 
Committee (HERC) and Gastrointestinal Perforation Review Committee (GIPRC).  In 
addition to these external committees, an internal committee of medically qualified Pfizer 
personnel with expertise in the assessment and diagnosis of respiratory disease will 
review and categorize potential events of interstitial lung disease (Interstitial Lung 
Disease Review Committee [ILDRC]).
Further information about these committees can be found in the respective charters, 
including specific descriptions of the scope of their responsibilities and the processes and 
definitions used to review and assess specific safety events. 
Additional safety event adjudication committees may be established to harmonize and 
standardize selected safety event assessments.  As described above, individual committee 
charters will provide specific descriptions of the scope of responsibilities and the 
processes and definitions used to review and assess specific safety events.
In addition to the event adjudication or review committees described above, all biopsies 
of potentially malignant tumors, suspicious lymphadenopathy, or possible extranodal 
lymphoproliferative disorder (LPD) should be submitted to the central laboratory for 
review by central laboratory pathologists.  In some instances, additional expert pathology 
review of submitted samples may be performed.  Description of the scope of review and 
the processes used to obtain and assess biopsies is described in the Histopathology 
Review for Potential Malignancy charter.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors 
may review source documents to confirm that the data recorded on CRFs 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.
The study site may be subject to review by the institutional review board (IRB)/ethics 
committee (EC), and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.


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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's or the physician's subject chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and 
clearly identify those data that will be recorded in the CRF, and for which the CRF will 
stand as the source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, e.g., 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 (e.g., letters, meeting minutes, and telephone call reports).  The records 
should be retained by the investigator according to International Conference on 
Harmonisation (ICH), 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 (e.g., 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 (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study 
protocol, protocol amendments, informed consent documents, and other relevant 
documents, e.g., recruitment advertisements, if applicable, from the IRB/EC.  All 
correspondence with the IRB/EC should be retained in the investigator file.  Copies of 
IRB/EC approvals should be forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval 
is where the change is necessary to eliminate apparent immediate hazards to the subjects.  
In that event, the investigator must notify the IRB/EC and Pfizer in writing immediately 
after the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as 
well as the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations 
of Medical Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of 
Helsinki (World Medical Association 1996 and 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH
guideline on GCP, and applicable local regulatory requirements and laws.
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 is compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code 
consisting of a numbering system provided by Pfizer in order to de-identify study
subjects. The study site will maintain a confidential list of subjects who participated in the 
study linking their numerical code to the subject’s actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of subject personal 
data consistent with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for 
inspection.


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The investigator must ensure that each study subject is fully informed about the nature 
and objectives of the study and possible risks associated with participation.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed. The 
investigator will retain the original of each subject's signed consent document.
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, as permitted by the IRB/EC and consistent with local regulatory and legal 
requirements, then 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/her own 
consent, the source documents must record why the subject did not provide consent (e.g., 
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 (e.g., 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.
12.4. Subject Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information 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 All Participating Countries
End of Trial in all participating countries is defined as Last Subject Last Visit (LSLV) for 
the last subject.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of tofacitinib at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects 


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and the hospital pharmacy (if applicable) within one week.  As directed by Pfizer, all 
study materials must be collected and all CRFs completed to the greatest extent possible.
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 patients that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  
US Basic Results are submitted for posting within 1 year of the primary completion date 
for studies in adult populations or within 6 months of the primary completion date for 
studies in pediatric populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary 
outcome, whether the clinical study concluded according to the prespecified protocol or 
was terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies 
that are in scope of EU requirements.  EU Basic Results are submitted for posting within 
1 year of the primary completion date for studies in adult populations or within 6 months 
of the primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients 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 has no objection to publication by an investigator of any information collected or 
generated by the investigator, whether or not the results are favorable to the 
investigational drug. 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 before it is submitted or 
otherwise disclosed.


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The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc) to 
Pfizer at least 30 days before they are submitted for publication or otherwise disclosed. If 
any patent action is required to protect intellectual property rights, 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 (other than the study results themselves) before disclosure.
If the study is part of a multicenter study, the investigator agrees that the first publication 
is to be a joint publication covering all centers. However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, 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.


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16. REFERENCES
1 Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor 
selectivity. Nat Biotechnol 2008;26:127-32.
2 Meyer DM, Jesson MI. Anti-inflammatory activity and neutrophil reductions mediated 
by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm 
(Lond) 2010;7:41.
3 Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol 
2007;178(5):2623-9.
4 O’Sullivan LA, Liongue C, Lewis RS, et al. Cytokine receptor signaling through the 
JAK
STAT-Socs pathway in disease. Mol Immunol 2007;44(10):2497-506.
5 Strand V, Singh JA. Improved health-related quality of life with effective disease-
modifying antirheumatic drugs: evidence from randomized controlled trials. The 
American journal of managed care. 2007;13 Suppl 9:S237-51. Epub 2008/01/12.
6 Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, et al. Phase IIb 
dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab 
monotherapy versus placebo in patients with active rheumatoid arthritis with an 
inadequate response to disease-modifying antirheumatic drugs. Arthritis and rheumatism. 
2012;64(3):617-29. Epub 2011/09/29.
7 Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, et al. A 
phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus 
placebo in combination with background methotrexate in patients with active rheumatoid 
arthritis and an inadequate response to methotrexate alone. Arthritis and rheumatism. 
2012;64(4):970-81. Epub 2011/10/19.
8 Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. 
Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. The New 
England journal of medicine. 2012;367(6):495-507. Epub 2012/08/10.
9 Burmester GR, Benda B, Gruben D, Bradley J, Mebus C. Tofacitinib for rheumatoid 
arthritis - Authors' reply. Lancet. 2013;381(9880):1812-3. Epub 2013/05/28.
10 van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garcia Meijide JA, Wagner S, 
et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. The New England 
journal of medicine. 2012;367(6):508-19. Epub 2012/08/10.
11 Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, et al. 
Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in 
patients with active rheumatoid arthritis: a randomized trial. Annals of internal medicine. 
2013;159(4):253-61. Epub 2013/09/13.
12 DAS-score.nl: Disease activity score in rheumatoid arthritis. Available online at:
http://www.das-score.nl/das28/en/. Accessed on 27 June 2014.


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13 Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the health
assessment questionnaire, disability and pain scales. The Journal of rheumatology.
1982;9(5):789-93. Epub 1982/09/01.
14 Ware JE KM, Dewey JE. . How to score Version 2 of the SF 36 Health Survey
(Standard & Acute forms). In: How to score Version 2 of the SF 36 Health Survey
(Standard & Acute forms). Lincoln, Rhode Island: QualityMetric, Incorporated. 2000.
15 Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in cancer patients compared
with fatigue in the general United States population. Cancer. 2002;94(2):528-38. Epub
2002/03/20.
16 Hurst NP, Kind P, Ruta D, Hunter M, Stubbings A. Measuring health-related quality of 
life in rheumatoid arthritis: validity, responsiveness and reliability of EuroQol (EQ-5D). 
British journal of rheumatology. 1997;36(5):551-9. Epub 1997/05/01.
17 van Gestel AM, Prevoo ML, van 't Hof MA, van Rijswijk MH, van de Putte LB, van 
Riel PL. Development and validation of the European League Against Rheumatism 
response criteria for rheumatoid arthritis. Arthritis Rheum. 1996;39 (1):34-40.
18 Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association
1987 revised criteria for the classification of rheumatoid arthritis. Arth Rheum 1988; 31
(3) :315-24.
19 Hochberg MC, Chang RW, Dwosh I, et al. The American College of Rheumatology
1991 revised criteria for the classification of global functional status in rheumatoid
arthritis. Arthritis Rheum 1992; 35 (5):498-502.
20 Japan Society of Hepatology (JSH). JSH Guidelines for the Management of Hepatitis B 
Virus Infection. Hepatology Research 2014; 44 (Suppl. 1):1-58.
21 Anonymous. National Cholesterol Education Program Expert Panel. Detection, 
evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III):  
Final Report. National Heart, Lung, and Blood Institute. National Institutes of Health. 
NIH Publication No.02-5215. September 2002.
22 Japan Atherosclerosis Society (JAS). Guidelines for Prevention of Atherosclerotic
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23 National Cholesterol Education Program ATP III Guidelines At-A-Glance Quick Desk 
Reference. National Heart, Lung, and Blood Institute. National Institutes of Health. NIH 
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Appendix 1. American College of Rheumatology (ACR) 1987 Revised Classification
Criteria18
Patients must have a diagnosis of rheumatoid arthritis (RA) according to the American
College of Rheumatology (ACR) 1987 Revised Criteria. These criteria require that patients
fulfill at least four (4) of the seven (7) criteria; criteria 1 through 4 must have been present for
at least 6 weeks.
1. Morning Stiffness.
Morning stiffness in and around the joints, lasting at least 1 hour before maximal
improvement.
2. Arthritis of three or more joint areas.
At least three joint areas simultaneously have had soft tissue swelling or fluid (not bony 
overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, 
MCP, wrist, elbow, knee, ankle, and MTP joints.
3. Arthritis of hand joints.
At least one area swollen (as defined above) in a wrist, MCP, or PIP joint.
4. Symmetric arthritis.
Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the 
body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute 
symmetry).
5. Rheumatoid nodules.
Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular 
regions, observed by a physician.
6. Serum rheumatoid factor.
Demonstration of abnormal amounts of serum rheumatoid factor by any method for 
which the result has been positive in <5% of normal control subjects.
7. Radiographic changes.
Radiographic changes typical of rheumatoid arthritis on PA hand and wrist radiographs, 
which must include erosions or unequivocal bony decalcification localized in or most 
marked adjacent to the involved joints (osteoarthritis changes alone do not qualify).


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Appendix 2. Criteria for Classification of Functional Status in Rheumatoid Arthritis19
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)


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Appendix 3. Prohibited Concomitant Medications
Moderate or potent CYP3A/CYP2C19 inhibitors and moderate or potent CYP3A inducers
may include, but are not limited to, those listed below.  Only systemically administered drugs 
listed below are prohibited; topical, ophthalmic, or intra vaginal administration is allowed.
This listing of prohibited concomitant treatments is not considered all inclusive.
Prohibited Concomitant Medications
Moderate or Potent CYP3A/CYP2C19 
Inhibitors* 
Moderate or Potent CYP3A Inducers**
Protease inhibitors:
Protease inhibitors:
indinavir 
efavirenz
nelfinavir
nevirapine
ritonavir 
Anticonvulsants:
delavirdine
saquinavir
atazanavir
barbiturates
phenobarbital
phenytoin
carbamazepine
Macrolide antibiotics:
Antibiotics:
clarithromycin
rifampicin
telithromycin
erythromycin,
rifabutin
Other antibiotics:
Antidepressants:
chloramphenicol
norfloxacin
St.  John's Wort
Antifungals:
Other compounds:
modafinil
troglitazone
fluconazole
ketoconazole
itraconazole
clotrimazole
voriconazole
Antidepressants:
fluvoxamine
nefazodone
Other compounds:
amiodarone, cimetidine, diethyl-
dithiocarbamate, diltiazem, imatinib,
mifepristone (RU-486) , verapamil
Prohibited Concomitant DMARDs***
Biologic DMARDs 
Nonbiologic DMARDs
etanercept, adalimumab, infliximab, 
abatacept, tocilizumab (including 
oral gold, injectable gold, sulfasalazine,
D-penicillamine, bucillamine, mizoribin, 


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biosimilar), etc.
azathioprine, leflunomide, cyclosporine, 
tacrolimus, etc.
* All prohibited drugs that are CYP3A/CYP2C19 inhibitors require at least a 7 day or 5 half-
lives (whichever is longer) washout prior to the first dose of study drug. Note: Amiodarone 
requires discontinuation at least 290 days (~5 half-lives, half-life averages ~58 days) prior to 
the first dose of study drug.
** All prohibited drugs that are CYP3A inducers require at least a 28 day or 5 half-lives 
(whichever is longer) washout prior to the first dose of study drug.
*** Refer to Section 5.8.3 for specific washout requirements.


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Appendix 4. Cockcroft-Gault Formula for Estimating GFR
Creatinine Clearance (estimated) / Conventional mL/min =
((140 - Age (years)) × Weight (kg) × Factora) / (72 × Serum Creatinine (mg/dL))
a Factor is equal to 0.85 in females and 1.00 in males.


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Appendix 5. Screening Procedure of Hepatitis B virus Infection   
A subject will be screened for HBV infection. All patients must undergo testing for hepatitis 
B surface antigen (HBsAg), hepatitis B core antbody (HBcAb) and hepatitis B surface 
antibody (HBsAb). Refer to the following figure for the detail of screening procedure of 
HBV infection20.
1) HBV DNA assay is recommended to perform every 4 weeks.


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Appendix 6. Health Assessment Questionnaire-Disability Index (HAQ-DI)


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Appendix 7. Short Form -36, version 2, acute (SF-36)
Please answer every question. Some questions may look like others, but each one is different.
Please take the time to read and answer each question carefully by filling in the bubble that
best represents your response.


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Appendix 8. FACIT-Fatigue


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Appendix 9. EQ-5D
By placing a checkmark in one box in each group below, please indicate which statements 
best describe your own health state today.


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Appendix 10. Recommended Clinical Management of Cholesterol
Safety monitoring of a subject’s lipid panel results is recommended to include an assessment 
of individual subject risk for cardiovascular disease.  Management of lipid levels should be 
determined on an individual subject level due to the individualized nature of cholesterol 
treatment recommendations.  The Third Report of the Expert Panel on Detection, Evaluation, 
and Treatment of High Blood Cholesterol in Adults (ATP III, National Cholesterol Education 
Program 2002) 21 provides guiding principles for the intensity of lipid lowering therapy based 
on an individual’s absolute risk for coronary heart disease (CHD).  ATP III guidelines and/or 
Japan Atherosclerosis Society(JAS) Guidelines for Prevention of Atherosclerotic
Cardiovascular Diseases 2014 22 should be used to determine if any lipid lowering 
intervention is required for a subject.  Such assessments should occur throughout the study, 
including during the screening period and prior to randomization into the study, in light of 
the known co-morbidities associated with RA (e.g., metabolic syndrome, cardiovascular 
morbidity and mortality) and the observed increases in lipid levels in previous clinical trials 
with CP-690,550.  Subject management of lipid elevations may be referred to the primary 
care physician at the discretion of the investigator. 
A copy of the ATP III guidelines At-A-Glance Quick Desk Reference23 will be provided to 
each study site for reference.


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Appendix 11. Evaluation of Potentially Malignant Tumors, Suspicious 
Lymphadenopathy or Possible Extra-nodal Lymphoproliferative Disorder (LPD)
In the event of potentially malignant tumors, lymphadenopathy or possible extra-nodal 
lymphoproliferative disorder (LPD), which might arise in the course of this study, the 
following steps are to be taken.
When there is a decision to biopsy a potentially malignant tumor, lymph node, or other 
tissue, the investigator and/or consultants should contact the sponsor to discuss the issue and 
any decisions as soon as possible.  It is recommended that specialists with experience in the 
evaluation of immunosuppressed patients be consulted.
If a biopsy for lymphadenopathy or lymphoma is to be performed, the investigator or 
consultant should refer to the study biopsy procedures instructions and review the following 
points with the surgeon and pathologist:

Fine needle aspiration and core needle biopsy are strongly discouraged; excisional 
biopsy is required for accurate diagnosis;

Tissue must be sent fresh to the pathology laboratory; the pathologist must be 
consulted before the procedure;

Archive multiple frozen tissue samples, if possible;

Include flow cytometry and cytogenetics as part of the pathologic evaluation;

Culture for mycobacterium and fungi, if indicated;

Collect and snap freeze peripheral blood lymphocytes for germ line evaluation 
(DNA);

Archive multiple aliquots of serum samples.
For all biopsies of potentially malignant tumors, suspicious lymphadenopathy, or possible 
extranodal lymphoproliferative disorder (LPD), please request the pathologist to send the 
original slides used to make the definitive diagnosis, ancillary study reports, and the 
pathologist’s report to the central laboratory for a blinded review by a central pathologist, to 
be paid for by Pfizer.  Should the central pathologist make a diagnosis that is not essentially 
similar to the local pathologist’s diagnosis, the site and the local pathologist will be notified 
and provided with an opportunity to consult with the central pathologist (paid for by Pfizer).  
Translation during this consultation, if needed, will be provided by the staff of the Pfizer 
Clinical Country Office or designee.
Both the local pathologist’s diagnosis and the central pathologist’s diagnosis will be reported 
in the study database.


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SAP_000.pdf: 
Protocol A3921215 Statistical Analysis Plan
Page 1
Protocol A3921215
A RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, PHASE 3 STUDY TO 
DEMONSTRATE NON-INFERIORITY FOR THE EFFICACY OF A  ONCE DAILY 
DOSE OF TOFACITINIB MODIFIED RELEASE TABLET TO A TWICE DAILY 
DOSE OF THE IMMEDIATE RELEASE TABLET IN ADULT PATIENTS WITH 
RHEUMATOID ARTHRITIS ON BACKGROUND METHOTREXATE
Statistical Analysis Plan 
(SAP)
Version:
3.0
Author:
(EPS Corporation – Tokyo, Japan)
 (Clinical Statistics – Tokyo, Japan)
Date:
28-Mar-2017
PPD
PPD


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TABLE OF CONTENTS 
LIST OF TABLES...........................................................................................................................3
LIST OF FIGURES .........................................................................................................................3
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................5
2. INTRODUCTION .......................................................................................................................6
2.1. Study Design ...................................................................................................................6
2.2. Study Objectives .............................................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING........................................8
4. HYPOTHESES AND DECISION RULES.................................................................................8
4.1. Statistical Hypotheses .....................................................................................................8
4.2. Statistical Decision Rules................................................................................................8
5. ANALYSIS SETS .......................................................................................................................8
5.1. Full Analysis Set .............................................................................................................8
5.2. ‘Per Protocol’ Analysis Set .............................................................................................8
5.3. Safety Analysis Set..........................................................................................................9
5.4. Other Analysis Sets .........................................................................................................9
5.5. Treatment Misallocations................................................................................................9
5.6. Protocol Deviations.........................................................................................................9
5.6.1. Deviations Assessed Prior to Randomization.....................................................9
5.6.2. Deviations Assessed Post-Randomization..........................................................9
6. ENDPOINTS AND COVARIATES .........................................................................................10
6.1. Efficacy Endpoints ........................................................................................................10
6.1.1. Primary Efficacy Endpoint ...............................................................................10
6.1.2. Secondary Efficacy Endpoints..........................................................................10
6.1.3. Other Efficacy Endpoints .................................................................................11
6.2. Safety Endpoints ...........................................................................................................11
6.3. Other Endpoints.............................................................................................................11
6.4. Covariates......................................................................................................................11
7. HANDLING OF MISSING VALUES ......................................................................................11
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................12
8.1. Statistical Methods ........................................................................................................12
8.1.1. Analysis of Longitudinal Continuous Data ......................................................12


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8.1.2. Analysis of Non Longitudinal Continuous Data ..............................................12
8.1.3. Analysis of Binary Data....................................................................................12
8.2. Statistical Analyses .......................................................................................................13
8.2.1. Analysis of Primary Efficacy Endpoints ..........................................................13
8.2.1.1. Sensitivity/Robustness Analyses.....................................................13
8.2.1.2. Subset Analysis ...............................................................................13
8.2.2. Analysis of Secondary and Other Efficacy Endpoints .....................................14
8.2.3. Analysis of Safety Data ....................................................................................14
8.2.3.1. Adverse Events................................................................................15
8.2.3.2. Laboratory Data...............................................................................16
8.2.3.3. Vital Signs.......................................................................................17
8.2.3.4. Electrocardiogram ...........................................................................18
8.2.3.5. Physical Examination......................................................................18
8.2.4. Analysis of Other Data .....................................................................................18
8.2.4.1. Baseline Summaries ........................................................................18
8.2.4.2. Study Treatment Exposure..............................................................18
8.2.4.3. Concomitant Medications and Non-Drug Treatments ....................18
9. REFERENCES ..........................................................................................................................19
LIST OF TABLES
Table 1.
Laboratory Tests for Absolute and (Percent) Change from Baseline Values.............16
Table 2.
Details of Visit Windows............................................................................................20
LIST OF FIGURES
Figure 1.
Study Design.................................................................................................................7
APPENDICES
Appendix 1. DETAILS OF VISIT WINDOWS............................................................................20
Appendix 2. DATA DERIVATION DETAILS ............................................................................21
Appendix 2.1. Miscellaneous Notes Regarding Endpoints ...........................................................21
Appendix 2.2. Handling Missing Joint Counts..............................................................................22


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Appendix 3. ATP III SCREEN SHOTS ........................................................................................24
Appendix 4. HERPES ZOSTER....................................................................................................30


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
NOTE: This Statistical Analysis Plan was amended after blinded data had been sent to the
University of Wisconsin, which analyzed the data to report to the Data Safety
Monitoring Board (DSMB). The data sets were sent on March 5 2015. None of the 
amended text resulted from or is otherwise based upon the review of data by DSMB.
Amendment 2
Changes from the previous version (version 2.0, December 2, 2016) have been made for 
results of blinded data review.

Corrected the method of multiple imputation for DAS28 missing values in Section 7.

Added analysis of herpes zoster events defined by MedDRA Preferred Terms in Section 
8.2.3.1 and Appendix 4.

Added creatine kinase for descriptive, model analysis and summary of abnormalities in 
Section 8.2.3.2.

Changed the use of percent change from baseline value instead of change from baseline 
value in triglyceride in Section 8.2.3.2.
Amendment 1
Changes from the previous version (version 1.0, January 14, 2015) have been made for the 
issuance of a protocol amendment, results of blinded data review and observation of
document review at Quality Gate.

Statistical null hypothesis and alternative hypothesis were added in Section 4.1.

Corrected definition of the difference between treatment groups in primary endpoint to in 
Section 4.2 and Section 8.2.1 as per protocol amendment.

Definition of subgroups was clarified in Section 8.2.1.2.

Analyses of safety data were clarified in Section 8.2.3.1 for adverse events, Section 
8.2.3.2 for laboratory data, Section 8.2.3.3 for vital signs, Section 8.2.3.4 for 
electrocardiogram and Section 8.2.3.5 for physical examination.

New Section 8.2.4 was added for analyses of other data and clarified in Section 8.2.4.1
for baseline summaries, Section 8.2.4.2 for study treatment exposure and Section 8.2.4.3
for concomitant medications and non-drug treatments.

Added the definition of DAS28-3(CRP), DAS28-3(ESR), SDAI and CDAI as versions of 
the disease activity score in Appendix 2.1. Although these two endpoints are not pre-
defined efficacy endpoint but will be available for further analysis if need be.


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
Added Definition of Hyperlipidemia (Screen Shots) by ATP III in Appendix 3.

Other minor revisions.
2. INTRODUCTION
Note: in this document any text taken directly from the protocol is italicised.
Tofacitinib is a potent, selective inhibitor of the Janus Kinase (JAK) family of kinases with a 
high degree of selectivity against other kinases in the human genome. The immediate release 
(IR) formulation of tofacitinib has been approved for the treatment of rheumatoid arthritis 
(RA) as a twice daily (BID) regimen.  Tofacitinib is being developed for the treatment of 
psoriasis (PsO, oral and topical), spondylarthropathies (ankylosing spondylitis [AS] and 
psoriatic arthritis [PsA]) and inflammatory bowel disease (Crohn’s disease [CD] and 
ulcerative colitis [UC]).
The modified release (MR) formulation of tofacitinib is being studied as a disease-modifying 
antirheumatic drug (DMARD) for the once daily (QD) treatment of RA. The MR QD regimen 
has the potential to improve drug compliance of patients, patient convenience, and to offer 
additional dosing options for patients.
This study will seek to compare the efficacy and safety of the MR 11 mg QD regimen to the
IR 5 mg BID regimen for the treatment of RA.
2.1. Study Design
This is a multicenter, randomized, double blind, parallel group, phase 3 study to evaluate
efficacy and safety of tofacitinib MR 11 mg QD tablet compared to IR 5 mg BID tablet 
following 12 weeks treatment in patients with moderate to severe RA on a stable background 
of methotrexate (MTX).
Subjects will be randomized in a 1:1 ratio for the 2 treatment arms with a total sample size of 
approximately 200 subjects; there will be approximately 100 subjects randomized into the 
11 mg MR QD group and approximately 100 patients into the 5 mg IR BID group.
The study design schematic for the study is represented in Figure 1.


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Figure 1.
Study Design
Approximately 100 per arm, N=200
2.2. Study Objectives
Primary Objective
1. To demonstrate the non-inferiority for efficacy of tofacitinib MR 11 mg QD to IR 5 mg 
BID for the treatment of signs and symptoms in patients with active RA on a stable 
background of MTX, as measured by Disease Activity Score 28-4 (C-reactive protein) 
[DAS28-4(CRP)] change from Baseline at Week 12.
Secondary Objectives
1. To evaluate the similarity in efficacy of tofacitinib MR 11 mg QD and IR 5 mg BID for 
the treatment of signs and symptoms of RA, as measured by DAS28-4 erythrocyte 
sedimentation rate (ESR) change from Baseline, American College of Rheumatology 20% 
improvement (ACR20), ACR50, ACR70 responses, remission, and Low Disease Activity 
(LDA), at Week 12.
2. To evaluate the similarity in efficacy of tofacitinib MR 11 mg QD and IR 5 mg BID for  
physical function status as measured by health assessment questionnaire-disability index 
(HAQ-DI) change from Baseline at Week 12.
3. To evaluate the similarity in effects on patient’s health outcome measures (change from 
Baseline in short form 36 health survey (SF-36), functional assessment of chronic illness 
therapy (FACIT) fatigue and euro quality of life-5 dimensions questionnaire [EQ-5D]) of 
tofacitinib MR 11 mg QD and IR 5 mg BID at Week 12.
4. To evaluate the safety and tolerability of tofacitinib MR 11 mg QD in comparison with IR 
5 mg BID in patients.
Randomization 1:1
Tofacitinib MR 11 mg Tablet, Once Daily 
Tofacitinib IR 5 mg Tablet, Twice Daily
Screening
−4                           0                          4                           8                           12 (Weeks)


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Other Objective
The efficacy and health outcome objectives will also be evaluated at other post-Baseline 
visits.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No interim analysis of the study data will be performed for use outside the data monitoring 
committee (DMC).
Final analyses will follow the official database release.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
The primary hypothesis associated with the statistical objective is to demonstrate non-
inferiority of tofacitinib MR 11 mg QD to IR 5 mg BID as measured by DAS28-4(CRP) 
change from baseline at Week 12. The null hypothesis is that the treatment difference 
(tofacitinib MR 11 mg QD – IR 5 mg BID) is 0.6 or more, and the alternative hypothesis is 
that the treatment difference is less than 0.6.
4.2. Statistical Decision Rules
If the upper bound of the 2-sided 95% confidence interval (type-I error [alpha] of 0.025 in 
each tail) for the difference in change from baseline in DAS28-4(CRP) between the two arms 
(MR 11 mg QD – IR 5 mg BID) is less than 0.6, then the treatment of tofacitinib MR 11 mg 
QD will be declared to be non-inferior to that of tofacitinib IR 5 mg BID.
5. ANALYSIS SETS
5.1. Full Analysis Set
The full analysis set (FAS) will include all subjects who were randomized and received at 
least one dose of the randomized investigational drug.
5.2. ‘Per Protocol’ Analysis Set 
The Per Protocol Analysis Set (PPAS) will be a subset of the FAS dataset. The PPAS will 
include all randomized subjects who completed the 12 week study with no important protocol 
deviations that could impact the efficacy analysis.  The list of potentially important protocol 
deviations (pIPDs) and the subjects to be excluded from the ‘Per Protocol’ analysis set will 
be identified, reviewed, and finalized prior to the release of the database.


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5.3. Safety Analysis Set
The Safety Analysis Set will include all subjects who were randomized and received at least 
one dose of the randomized investigational drug. By definition, it is identical to the full 
analysis set defined above.
5.4. Other Analysis Sets
None.
5.5. Treatment Misallocations 
If a patient was:

Randomized but not treated, then the patient will be excluded from all analyses 
according to the definitions of FAS, PPAS and Safety Analysis Set given above.  The 
patient will be included in the disposition summaries.

Treated but not randomized, then the patient will be excluded from all analyses 
according to the definitions of FAS, PPAS and Safety Analysis Set given above. The 
patient will be included in safety data listings.

Randomized but took incorrect treatment, then the patient will be reported under 
his/her randomized treatment group for all analyses based on FAS and Safety 
Analysis Set, but will be omitted from analyses based on PPAS. Medication errors 
will be listed.
5.6. Protocol Deviations
The following sections describe any protocol deviations that relate to the statistical analyses.
It is possible that unexpected deviations will arise, becoming known only after the study has 
been active for a long period of time; hence more deviations may be added.  A full list of 
protocol deviations for the study report will be compiled prior to database closure.  As of this 
writing, the protocol deviations can all be found in Sections 5.6.1 and 5.6.2 below.
The list of patients along with the excluding protocol deviation will be put into the trial 
master file.
5.6.1. Deviations Assessed Prior to Randomization
Granted exceptions to the inclusion or exclusion criteria are not expected to occur.  Any 
patient who enters the study when the inclusion or exclusion criteria would have prevented 
entry will be considered to have had a protocol deviation.
5.6.2. Deviations Assessed Post-Randomization
Only protocol deviations that are thought to effect the efficacy of tofacitinib will be 
considered.  Each of the cases will be reviewed by the team and a clinical judgment made in 


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each particular circumstance as to whether efficacy would have been effected in the cases of 
these specific classes of protocol deviations assessed post randomization:

Patients who receive prohibited concomitant medications;

Patients who interrupt therapy for longer than allowed (less than 80% compliant
during the double-blind study treatment period);

Patients who were randomized but took incorrect treatment;

Patients whose background RA medications are changed in violation of protocol.
Each patient’s presence on the list of exclusion from the per-protocol analysis means that 
there was at least one deviation for that patient clinically judged to effect efficacy.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoints
6.1.1. Primary Efficacy Endpoint

Change from Baseline in DAS28-4(CRP) at Week 12.
6.1.2. Secondary Efficacy Endpoints

Change from Baseline in DAS28-4(ESR) at Week 12.

ACR20, ACR50 and ACR70 response at Week 12.

Remission at Week 12, as assessed by: DAS28-4(CRP) < 2.6 and DAS28-4(ESR) < 
2.6.

LDA at Week 12, as assessed by: DAS28-4(CRP) ≤ 3.2 and DAS28-4(ESR) ≤ 3.2.

Change from Baseline in HAQ-DI at Week 12.

HAQ-DI response (decrease of at least 0.22) at Week 12.

Change from Baseline in the SF-36 8 domain scores and 2 component scores at Week 
12.

Change from Baseline in the FACIT-Fatigue scale at Week 12.

Change from Baseline in the EQ-5D at Week 12.


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6.1.3. Other Efficacy Endpoints

Primary and secondary efficacy endpoints at other selected post-baseline scheduled 
visits.
6.2. Safety Endpoints

All adverse events (AEs), including serious adverse events (SAEs).

Clinically significant abnormal laboratory parameters.
6.3. Other Endpoints
None.
6.4. Covariates 
The baseline values of the efficacy endpoint will be used as covariates when the treatment 
effect is assessed on the change from baseline for the efficacy endpoints. 
7. HANDLING OF MISSING VALUES
In general, missing values will not be imputed for descriptive statistics.
For continuous efficacy endpoints, 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.
In addition, if the DAS28 values post-baseline are missing, method of multiple imputation
(MI) will be used to impute any missing DAS28 values. The SAS MI procedure will be used 
to impute missing DAS28 values for each group. One thousand (1000) complete data sets 
will be generated and analyzed using the SAS MIANALYZE procedure to combine results 
from these complete sets.
For binary efficacy endpoints, last observation carried forward (LOCF) mixed components 
method will be used to impute any missing components in binary composite endpoints before 
dropout for any reason. Only post-baseline values will be carried forward. Any subject 
whose response status at any time cannot be determined even after the imputation above will 
be counted as a non-responder at that time (non-responder imputation, NRI). This includes 
all visits after dropout for any reason.
Also as a sensitivity check, the “as-is” values of the binary efficacy endpoints will be 
analyzed.  That is, the values of binary composite endpoints will be calculated without 
applying any imputation to the components.
In addition, missing values for safety endpoints will not be imputed.


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8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
In general, number and percent will be presented for binary variables, and number, mean, 
standard deviation, standard error of the mean, minimum, 1st, 2nd and 3rd quartiles and 
maximum will be presented for continuous variables. In addition, graphics may be used to 
present the data.
8.1. Statistical Methods 
8.1.1. Analysis of Longitudinal Continuous Data
The analysis will be conducted using a linear mixed effect model with repeated measures 
(MMRM), which will include treatment (tofacitinib MR 11 mg QD and IR 5 mg BID), visit, 
and treatment by visit interaction as fixed effects.  Subjects will be a random effect and 
unstructured covariance will be assumed for the within-subject errors.  If there are 
convergence problems with this model, sequential structures will be applied until the 
problems resolved; autoregressive 1 and compound symmetry.
If there is modeling of actual values, the explanatory variable of visit will include baseline as 
one of the longitudinal values.  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, the mean differences 
between the treatment groups and the associated 2-sided 95% confidence interval (type-I 
error [alpha] of 0.025 in each tail) will be derived from the model.
8.1.2. Analysis of Non Longitudinal Continuous Data
The same approach as in Section 8.1.1 will be applied, except that the model will not include 
visit, treatment-by-visit interaction, or patient as a random effect.  In this case, the model is 
an analysis of covariance (ANCOVA) model.
8.1.3. Analysis of Binary Data
The normal approximation for the difference in binomial proportions will be used to estimate 
the 95% confidence interval.
The normal-approximation to the test statistic for the difference in binomial random variables 
is calculated as
c
c
c
i
i
i
c
i
i
n
p
p
n
p
p
p
p
Z
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
ˆ
ˆ





where pˆ refers to the relative frequency, n to sample size, the subscript c refers to a 
comparator group (i.e., tofacitinib IR 5 mg BID) and the subscript i refers to a test group (i.e., 
tofacitinib MR 11 mg QD).


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Two-sided 95% confidence intervals are formed by:
c
c
c
i
i
i
c
i
n
p
p
n
p
p
p
p
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
96
.1
)
ˆ
ˆ
(





In addition, this method will also be used in all secondary analyses involving binary 
variables.
8.2. Statistical Analyses 
8.2.1. Analysis of Primary Efficacy Endpoints
The primary endpoint DAS28-4(CRP) change from baseline will be analyzed using MMRM 
described in Section 8.1.1 on the FAS. The patient is required to have a baseline and at least 
one non-missing on-study assessment of DAS28-4(CRP) to be included the analysis.  
Missing values will not be imputed.
Non-inferiority of tofacitinib MR 11 mg QD to IR 5 mg BID will be concluded if the upper
bound of the 2-sided 95% confidence interval of differences between the treatment groups
(MR 11 mg QD – IR 5 mg BID) at Week 12 is less than the pre-specified non-inferiority 
margin of 0.6.
8.2.1.1. Sensitivity/Robustness Analyses
To support the interpretation of the primary analyses, some robustness or sensitivity analyses 
will be performed for the primary endpoint.  However, the conclusions (non-inferiority) for 
comparison of the primary endpoint between tofacitinib MR 11 mg QD and IR 5 mg BID
group is purely based on results of the primary analysis.
One of the robustness analyses is ‘Per Protocol’ analysis, that is, the same primary analysis 
for the primary endpoint will be conducted using PPAS rather than the FAS.
Other robustness analyses will be performed using the FAS as follows:

MMRM model described in Section 8.1.1 with compound symmetry instead of 
unstructured covariance.  Missing values will not be imputed.

MMRM model described in Section 8.1.1 with unstructured covariance. Missing 
values will be imputed using the method of MI as described in Section 7.

ANCOVA model described in Section 8.1.2 at Week 12.  Missing values will not be
imputed.
8.2.1.2. Subset Analysis
For DAS28-4(CRP) change from baseline, subgroup analysis will be performed by following
subsets at baseline/screening:


Protocol A3921215 Statistical Analysis Plan
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
Sex (Male, Female), 

Body weight (<55 kg, ≥55 kg), 

Age (<65 years old, ≥65 years old), 

Rheumatoid factor at screening (Negative, Positive), 

Disease duration (<5 years, ≥5 years), 

Methotrexate dose at baseline (≤8 mg/week, >8 mg/week) and 

DAS28-4(CRP) at baseline (≤5.1, >5.1). 
8.2.2. Analysis of Secondary and Other Efficacy Endpoints
All analyses of secondary and other efficacy endpoints are based on the FAS.
The change from baseline in longitudinal continuous variables (i.e. DAS28-4(ESR), HAQ-DI, 
other 6 components of the ACR criteria, the 8 domains and 2 component scores of SF-36)
will each be analyzed using the MMRM model as described in Section 8.1.1 and the missing 
values will not be imputed.
The change from baseline in non-longitudinal continuous variables (i.e. EQ-5D utility score 
and FACIT fatigue scale) will each be analyzed using ANCOVA model as described in 
Section 8.1.2 and the missing values will not be imputed.
Binary variables (i.e. the ACR variables [ACR20, ACR50 and ACR70], DAS28 responses 
[DAS28 3.2, DAS28 <2.6] which include DAS28-4[CRP] and DAS28-4[ESR], and 
decrease [at least 0.22] in HAQ-DI) will be analyzed using the normal approximation to the 
difference in response rates, as described in Section 8.1.3.  The missing values will be 
handled according to the approach described in Section 7.
8.2.3. Analysis of Safety Data
The safety analysis will be conducted on the safety analysis set.
The Sponsor has standard (i.e., used for all its clinical trials) summary displays and listings 
for MedDRA-coded adverse events, demography, medical history, length of time in study 
and discontinuation, concomitant and concurrent medications, physical examination, ECG, 
laboratory tests, weight, pulse rate, and blood pressure.  These standards, called Pfizer Data 
Standards, will be utilized in the reporting of these routine safety variables (Pfizer Data 
Standards Rulebook). 


Protocol A3921215 Statistical Analysis Plan
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8.2.3.1. Adverse Events
Adverse events will be listed and summarized within treatment group in accordance with the 
Pfizer Data Standards.  Adverse events, serious adverse events and discontinuation due to 
adverse event will also be summarized by subsets described in Section 8.2.1.2.
Adverse events met following the Standardised MedDRA Queries (SMQs) will be 
summarized within treatment group.

Hypertension

Congestive Heart Failure

Dyslipidaemia

Erythropenia

Leukopenia

Acute Renal Failure

Ischemic Heart Disease

Ischemic Cerebrovascular Disease

Myocardial Infarction

Possible Drug-Related Hepatic Disorders
Serious infection events and treated infection events will be summarized per visit, 
respectively.
Herpes zoster events defined by MedDRA Preferred Terms in Appendix 4 will be 
summarized within treatment group. 
Adverse events reviewed in the following adjudication/review committees will be listed.

Cardiovascular safety endpoints adjudicated by the Cardiovascular Endpoint 
Adjudication Committee (CV-EAC). 

Malignancies adjudicated by Malignancy Adjudication Committee (MAC)

Opportunistic infections reviewed by the Opportunistic Infection Review Committee 
(OIRC).

Hepatic events reviewed by the Hepatic Event Review Committee (HERC).


Protocol A3921215 Statistical Analysis Plan
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
Gastrointestinal perforation events reviewed by Gastrointestinal Perforation Review 
Committee (GIPRC).

Interstitial lung disease (ILD) events reviewed by the Interstitial Lung Disease 
Review Committee (ILDRC).

Potentially malignant tumors, suspicious lymphadenopathy, possible extranodal 
lymphoproliferative disorder (LPD) reviewed by the central pathologists. 
8.2.3.2. Laboratory Data
Laboratory data will be listed and summarized within treatment group in accordance with the 
Pfizer Data Standards. Incidence of laboratory test abnormalities (including without regard 
to baseline abnormality) will be summarized within each treatment group.
For each planned time point, actual values and changes from baseline values will be 
summarized within each treatment with descriptive statistics. The changes from baseline
values will be analyzed using the MMRM model as described in Section 8.1.1. Instead of
changes form baseline, percent changes from baseline will be analyzed in lipid tests (total 
cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)
cholesterol and triglyceride).  Laboratory tests to be analyzed for absolute and (percent) 
changes from baseline values are listed in Table 1.
Table 1.
Laboratory Tests for Absolute and (Percent) Change from Baseline 
Values
Descriptive Statisticsa
Descriptive Statisticsa and Model Analysisb
Platelet
Neutrophil Count
Hemoglobin
Lymphocyte Count
Creatinine Clearance (Cockcroft-Gault)
Serum Creatinine
ALT
Total Cholesterol
AST
LDL-C
Bilirubin
HDL-C
Lymphocyte Subset Count CD3+
Triglyceride
Lymphocyte Subset Count CD3−CD19+
Ratio of Total Cholesterol/HDL-C
Lymphocyte Subset Count CD3+CD4+CD8−
Ratio of LDL-C/HDL-C
Lymphocyte Subset Count CD3+CD4−CD8+
Creatine Kinase
Lymphocyte Subset Count CD3+CD16+CD56+
Lymphocyte Subset Count CD3−CD16+CD56+
Lymphocyte Subset Count CD3−CD16+CD56−
Lymphocyte Subset Count CD3−CD16−CD56+
Lymphocyte Subset Count CD3−CD16−CD56−
Ratio of Lymphocyte Subset Count CD4/CD8
ALT = alanine transaminase , AST = aspartate transaminase, LDL-C = low density lipoprotein-cholesterol, 
HDL-C = high density lipoprotein-cholesterol, CD = cluster of differentiation
a. Descriptive statistics of actual and change from baseline values per visit
b. MMRM model analysis of change from baseline values per visit


Protocol A3921215 Statistical Analysis Plan
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The following laboratory test abnormalities will be listed and summarized within each 
treatment group.

Neutropenia

Lymphopenia

Decreased hemoglobin

Hyperlipidemia classified by ATP III criteria defined in Appendix 3

Increased liver function test values as multiple of upper limit of normal in patients 
with normal at baseline and without regard to baseline abnormality

Drug-induced Liver Injury (DILI) in patients with normal at baseline and without 
regard to baseline abnormality

Laboratory values met protocol criteria for monitoring and discontinuation

Increased creatine kinase values as multiple of upper limit of normal in patients with 
normal at baseline and with abnormal at baseline
Maximum LDL-cholesterol value on-treatment versus baseline value will be summarized in 
shift table.
8.2.3.3. Vital Signs
For each planned time point, actual values and change from baseline values in blood pressure, 
weight and body mass index will be summarized within each treatment with descriptive 
statistics.
The changes from baseline values in blood pressure will be analyzed using the MMRM 
model as described in Section 8.1.1.
Subjects with hypertension will be listed and summarized per visits classified by JNC73
criteria;

Stage 1 (140 systolic blood pressure (SBP) 159 mmHg or 90 diastolic blood 
pressure (DBP) 99),

Stage 2 (SBP 160 or DBP 100).
All values in blood pressure meeting the categorical criteria of potential clinical concern will 
be listed. All planned and unplanned post-dose time points will be counted in these 
categorical summaries.
All vital signs values will be listed.


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8.2.3.4. Electrocardiogram
Interpretation and comments on findings in ECG at Screening will be listed.
8.2.3.5. Physical Examination
Physical examination data will be listed within treatment group in accordance with the Pfizer 
Data Standards. New/intensified physical examination findings from Screening to Week 
12/End of Treatment will also be presented.
8.2.4. Analysis of Other Data
8.2.4.1. Baseline Summaries
A breakdown of demographic data will be provided for age, race, weight, body mass index 
and height. Each will be summarized by sex at birth and ‘All Subjects’ with tables and 
listings presented in accordance with the Pfizer Data Standards. Use adult age categories for 
the demographic summaries (<18, 18-44, 45-64, and ≥65).
Also, medical history and primary diagnosis will be tabulated and listed in in accordance 
with the Pfizer Data Standards.
The following pre-treatment characteristic will be summarized:

Rheumatoid Factor at screening (Positive and Negative)
8.2.4.2. Study Treatment Exposure
Duration of exposure will be presented in tables and listings in accordance with the Pfizer 
Data Standards.  
8.2.4.3. Concomitant Medications and Non-Drug Treatments
All prior and concomitant medications as well as non-drug treatments will be provided in 
tables and listings in accordance with the Pfizer Data Standards. 
The following rheumatoid arthritis medications use will be summarized by treatment group:

Previously taken anti-TNF inhibitors

Previously taken other biologic DMARDs

Previously taken traditional (conventional synthetic) DMARDs other than 
methrotrexate

Previously taken glucocorticoids

New lipid lowering medications taken


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
New DMARDs taken (that may have been Protocol Violations)

New NSAIDs/COX-2 inhibitors taken

New hypertension medications taken

Concomitant glucocorticoids taken

New glucocorticoids taken
Frequency and type of medication will be summarized categorically by treatment group. 
Descriptive statistics of doses of background methrotrexate at baseline will also be 
summarized.
9. REFERENCES 
1. Pfizer Inflammation Statistics Rulebook For Rheumatoid Arthritis Version 2.0
2. Pfizer Data Standards Rulebook.
3. U.S. NIH - Seventh Report of the Joint National Committee on Prevention, Detection, 
Evaluation, and Treatment of High Blood Pressure (JNC 7)


Protocol A3921215 Statistical Analysis Plan
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Appendix 1. DETAILS OF VISIT WINDOWS
Visit windows will be used for efficacy and safety summaries that will conduct evaluations 
or assessments in schedule visits and display by visit.
Table 2.
Details of Visit Windows
Visit Label
Target Day
Definition [Day window]
Screening
0
Days −34 to 0
Baseline
Day 1, Randomization
Day 1
Week 4
29
Days 2 to 43
Week 8
57
Days 44 to 71
Week 12
85
Days 72 to 
If the calculated study day for the labeled 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 values fall into the same visit window, keep the one closest to the Target Day.  
If the study day of two values are equal distant from the Target Day in absolute value, the 
later value should be used.
Subjects’ observations will be excluded from visit windows if the data was collected more 
than 7 days off study drug.
(Safety analysis may follow Pfizer standard)


Protocol A3921215 Statistical Analysis Plan
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Appendix 2. DATA DERIVATION DETAILS
Appendix 2.1. Miscellaneous Notes Regarding Endpoints
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

A 20% improvement from baseline in the swollen joint count

A 20% improvement from baseline in at least 3 of the following 5 variables:
1. Patient’s Global Assessment of Arthritis (VAS)
2. Physician’s Global Assessment of Arthritis (VAS)
3. Patient’s Assessment of Arthritis Pain (VAS)
4. HAQ disability index
5. C-Reactive Protein (CRP)
ACR50 and ACR70 are defined analogously.
There are many forms of the DAS.  The DAS used in this protocol is the DAS using the the 
28-count subsets of tender/painful joints and swollen joints, together with either CRP or 
erythrocyte sedimentation rate ESR, to derive the DAS28-4(CRP), DAS28-3(CRP) or 
DAS28-4(ESR) and DAS28-3(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.
DAS28 improvement in RA† are categorized using the following EULAR response criteria:
                                                
+ 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.
† See http://www.das-score.nl/ as of  30 November, 2016


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EULAR Response Criteria
DAS28 improvement (decline in DAS)
DAS28
(at current visit)
≤0.6
0.6 < - ≤1.2
>1.2
≤3.2
none
moderate
good
3.2 < - ≤5.1
none
moderate
moderate
> 5.1
none
none
moderate
There are three categories then, in order: no improvement, moderate improvement, and good 
improvement.  That is, good improvement is the highest kind of improvement.  Implicitly, 
the category “no improvement” also includes a worsening of RA.  Hence, relative to 
Baseline, a patient can only have: a 0 change in categories; a change of “1” category or a 
change of “2” categories.
The Simplified Disease Activity Index (SDAI) will be calculated per the following formula:
SDAI= TJC28+SJC28+GH/10+PGA/10+CRP/10;
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, PGA stands for Physician’s Global Assessment of Arthritis on a 100 mm 
VAS and CRP is in mg/L.
The Clinical Disease Activity Index (CDAI) will be derived similarly, except that the CRP 
component will not be part of the calculation.
Appendix 2.2. 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”

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”


Protocol A3921215 Statistical Analysis Plan
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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.


Protocol A3921215 Statistical Analysis Plan
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Appendix 3. ATP III SCREEN SHOTS
ATP III “At A Glance” is available here at this link: 
http://www.nhlbi.nih.gov/guidelines/cholesterol/atglance.htm  That page at this link is pasted 
below.
ATP III At-A-Glance: Quick Desk Reference

STEP 1: Determine lipoprotein levels - obtain complete lipoprotein profile after 9- to 12-
hour fast

STEP 2: Identify presence of clinical atherosclerotic disease that confers high risk for 
coronary heart disease (CHD) events (CHD risk equivalent)

STEP 3: Determine presence of major risk factors (other than LDL)

STEP 4: If 2+ risk factors (other than LDL) are present without CHD or CHD risk 
equivalent, assess 10-year (short-term) CHD risk

STEP 5: Determine risk category

STEP 6: Initiate therapeutic lifestyle changes (TLC) if LDL is above goal

STEP 7: Consider adding drug therapy if LDL exceeds levels shown in Step 5 table

STEP 8: Identify metabolic syndrome and treat, if present, after 3 months of TLC

STEP 9: Treat elevated triglycerides
STEP 1: Determine lipoprotein levels - obtain complete lipoprotein profile after 9- to 
12-hour fast.
ATP III Classification of LDL, Total, and HDL Cholesterol (mg/dL)

LDL Cholesterol - Primary Target of Therapy
<100
Optimal
100-129
Near Optimal/Above Optimal
130-159
Borderline High
160-189
High
190
Very high


Protocol A3921215 Statistical Analysis Plan
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
Total Cholesterol
<200
Desirable
200-239
Borderline High
240
High

HDL Cholesterol
<40
Low
60
High
STEP 2: Identify presence of clinical atherosclerotic disease that confers high risk for 
coronary heart disease (CHD) events (CHD risk equivalent):

Clinical CHD

Symptomatic carotid artery disease

Peripheral arterial disease

Abdominal aortic aneurysm.
STEP 3: Determine presence of major risk factors (other than LDL):
Major Risk Factors (Exclusive of LDL Cholesterol) That Modify LDL Goals

Cigarette smoking

Hypertension (BP 140/90 mmHg or on antihypertensive medication)

Low HDL cholesterol (<40 mg/dl)*

Family history of premature CHD (CHD in male first degree relative <55 years; CHD in 
female first degree relative <65 years)

Age (men 45 years; women 55 years)
* HDL cholesterol 60 mg/dL counts as a "negative" risk factor; its presence removes one risk factor from the 
total count. 
Note: in ATP III, diabetes is regarded as a CHD risk equivalent.
STEP 4: If 2+ risk factors (other than LDL) are present without CHD or CHD risk 
equivalent, assess 10-year (short-term) CHD risk (see Framingham tables).
Three levels of 10-year risk:

>20% -- CHD risk equivalent 

10-20% 


Protocol A3921215 Statistical Analysis Plan
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
<10%
STEP 5: Determine risk category:

Establish LDL goal of therapy

Determine need for therapeutic lifestyle changes (TLC)

Determine level for drug consideration
LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug 
Therapy in Different Risk Categories.
Risk Category
LDL Goal
LDL Level at Which to 
Initiate Therapeutic 
Lifestyle Changes (TLC)
LDL Level at Which to Consider Drug 
Therapy
CHD or CHD Risk Equivalents 
(10-year risk >20%)
<100 mg/dL 100 mg/dL
130 mg/dL (100-129 mg/dL: drug optional)*
2+ Risk Factors
(10-year risk 20%)
<130 mg/dL 130 mg/dL
10-year risk 10-20%: 130 mg/dL 
10-year risk <10%: 160 mg/dL
0-1 Risk Factor**
<160 mg/dL 160 mg/dL
190 mg/dL
(160-189 mg/dL: LDL-lowering drug optional)
* Some authorities recommend use of LDL-lowering drugs in this category if an LDL cholesterol <100 mg/dL cannot be 
achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL, e.g., 
nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory.
** Almost all people with 0-1 risk factor have a 10-year risk <10%, thus 10-year risk assessment in people with 0-1 risk 
factor is not necessary.
STEP 6: Initiate therapeutic lifestyle changes (TLC) if LDL is above goal.
TLC Features

TLC Diet: 

Saturated fat <7% of calories, cholesterol <200 mg/day

Consider increased viscous (soluble) fiber (10-25 g/day) and plant stanols/sterols 
(2g/day) as therapeutic options to enhance LDL lowering

Weight management

Increased physical activity
STEP 7: Consider adding drug therapy if LDL exceeds levels shown in Step 5 table:

Consider drug simultaneously with TLC for CHD and CHD equivalents

Consider adding drug to TLC after 3 months for other risk categories.
Drugs Affecting Lipoprotein Metabolism


Protocol A3921215 Statistical Analysis Plan
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Drug Class 
Agents and Daily Doses
Lipid/Lipoprotein 
Effects
Side Effects
Contraindications
HMG CoA 
reductase 
inhibitors 
(statins)
Lovastatin (20-80 mg), 
Pravastatin (20-40 mg), 
Simvastatin (20-80 mg), 
Fluvastatin (20-80 mg), 
Atorvastatin (10-80 mg), 
Cerivastatin (0.4-0.8 mg)
LDL-C 18-55%
HDL-C 5-15%
TG
7-30%
Myopathy
Increased liver 
enzymes
Absolute: 

Active or chronic 
liver disease 
Relative: 

Concomitant use 
of certain drugs*
Bile acid 
Sequestrants
Cholestyramine (4-16 g) 
Colestipol (5-20 g) 
Colesevelam (2.6-3.8 g)
LDL-C 15-30%
HDL-C 3-5%
TG
No change or 
increase
Gastrointestinal distress
Constipation
Decreased absorption 
of other drugs
Absolute: 

dysbeta-
lipoproteinemia 

TG >400 mg/dL 
Relative: 

TG >200 mg/dL
Nicotinic acid
Immediate release 
(crystalline) nicotinic acid 
(1.5-3 gm), extended release 
nicotinic acid (Niaspan ®) (1-
2 g), sustained release 
nicotinic acid (1-2 g)
LDL-C 5-25%
HDL-C 15-35%
TG
20-50%
Flushing
Hyperglycemia
Hyperuricemia (or 
gout)
Upper GI distress
Hepatotoxicity
Absolute: 

Chronic liver 
disease 

Severe gout 
Relative: 

Diabetes 

Hyperuricemia 

Peptic ulcer 
disease
Fibric acids
Gemfibrozil (600 mg BID)
Fenofibrate (200 mg) 
Clofibrate (1000 mg BID)
LDL-C 5-20% (may be 
increased in patients with 
high TG)
HDL-C 10-20%
TG
20-50%
Dyspepsia
Gallstones
Myopathy
Absolute: 

Severe renal 
disease

Severe hepatic 
disease
* Cyclosporine, macrolide antibiotics, various anti-fungal agents, and cytochrome P-450 inhibitors (fibrates and niacin 
should be used with appropriate caution).
STEP 8: Identify metabolic syndrome and treat, if present, after 3 months of TLC.
Clinical Identification of the Metabolic Syndrome - Any 3 of the Following:
Risk Factor
Defining Level
Abdominal obesity*
Men
Women
Waist circumference**
>102 cm (>40 in)
>88 cm (>35 in)
Triglycerides
150 mg/dL
HDL cholesterol
Men
Women
<40 mg/dl
<50 mg/dl
blood pressure
130/85 mmHg
Fasting glucose
110 mg/dL
* Overweight and obesity are associated with insulin resistance and the metabolic syndrome. However, the presence of 
abdominal obesity is more highly correlated with the metabolic risk factors than is an elevated body mass index (BMI). 
Therefore, the simple measure of waist circumference is recommended to identify the body weight component of the 
metabolic syndrome.
** Some male patients can develop multiple metabolic risk factors when the waist circumference is only marginally 
increased, e.g., 94-102 cm (37-39 in). Such patients may have a strong genetic contribution to insulin resistance. They 
should benefit from changes in life habits, similarly to men with categorical increases in waist circumference.
Treatment of the metabolic syndrome


Protocol A3921215 Statistical Analysis Plan
Page 28

Treat underlying causes (overweight/obesity and physical inactivity): 

Intensify weight management

Increase physical activity

Treat lipid and non-lipid risk factors if they persist despite these lifestyle therapies: 

Treat hypertension

Use aspirin for CHD patients to reduce prothrombotic state

Treat elevated triglycerides and/or low HDL (as shown in Step 9 below)
STEP 9: Treat elevated triglycerides.
ATP III Classification of Serum Triglycerides (mg/dL)
<150
Normal
150-199
Borderline high
200-499
High
500
Very high
Treatment of elevated triglycerides (150 mg/dL)

Primary aim of therapy is to reach LDL goal.

Intensify weight management.

Increase physical activity.

If triglycerides are 200 mg/dL after LDL goal is reached, set secondary goal for non-
HDL cholesterol (total - HDL) 30 mg/dL higher than LDL goal.
Comparison of LDL Cholesterol and Non-HDL Cholesterol Goals for Three Risk Categories
Risk Category
LDL Goal (mg/dL) Non-HDL Goal (mg/dL)
CHD and CHD Risk Equivalent (10-year risk for CHD >20%) <100
<130
Multiple (2+) Risk Factors and 10-year risk 20%
<130 
<160
0-1 Risk Factor
<160 
<190 
If triglycerides 200-499 mg/dL after LDL goal is reached, consider adding drug if needed to 
reach non-HDL goal:

intensify therapy with LDL-lowering drug, or

add nicotinic acid or fibrate to further lower VLDL.
If triglycerides 500 mg/dL, first lower triglycerides to prevent pancreatitis:


Protocol A3921215 Statistical Analysis Plan
Page 29

very low-fat diet (15% of calories from fat)

weight management and physical activity

fibrate or nicotinic acid

when triglycerides <500 mg/dL, turn to LDL-lowering therapy.
Treatment of low HDL cholesterol (<40 mg/dL)

First reach LDL goal, then:

Intensify weight management and increase physical activity. 

If triglycerides 200-499 mg/dL, achieve non-HDL goal.

If triglycerides <200 mg/dL (isolated low HDL) in CHD or CHD equivalent, consider 
nicotinic acid or fibrate.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
National Institutes of Health
National Heart, Lung, and Blood Institute
NIH Publication No. 01-3305
May 2001


Protocol A3921215 Statistical Analysis Plan
Page 30
Appendix 4. HERPES ZOSTER
Herpes zoster is defined as an adverse event with one of the following MedDRA version 19.1 
Preferred Terms (Preferred Codes):

Genital herpes zoster (10072210)

Herpes zoster (10019974)

Herpes zoster cutaneous disseminated (10074297)

Herpes zoster disseminated (10065038)

Herpes zoster infection neurological (10061208)

Herpes zoster meningitis (10074259) 

Herpes zoster meningoencephalitis (10074248) 

Herpes zoster meningomyelitis (10074251) 

Herpes zoster necrotising retinopathy (10074253) 

Herpes zoster oticus (10063491)

Herpes zoster pharyngitis (10074245)

Ophthalmic herpes zoster (10030865)
Additionally, if there are any events that are adjudicated as any type of herpes zoster 
(including herpes zoster, two adjacent dermatomes which is considered a special interest 
infection rather than an opportunistic infection), the events will be included in the herpes 
zoster analyses, regardless of the reported MedDRA Preferred Terms.