Clinical trial NCT03281304
Conditions: Ulcerative Colitis
Keywords: ulcerative colitis inflammatory bowel disease
Sponsor: Pfizer
Start date: 2017-11-16; Completion date: 2022-03-18
Enrollment: 140 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a follow up study for subjects with Ulcerative Colitis (UC) in stable remission designed to evaluate flexible dosing of CP-690,550.

Detailed description:

Arms: arm 1: CP-690,550 5 mg tablet by mouth twice a day (BID) arm 2: CP-690,550 10 mg BID
Interventions: intervention 1: CP-690,500 5 mg intervention 2: CP-690,550 10 mg
Intervention descriptions: intervention 1: CP-690,550 5 mg tablet BID intervention 2: CP-690,550 10 mg tablet BID

Protocol documents:
Prot_001.pdf: 
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A PHASE 3B/4, MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, PARALLEL 
GROUP STUDY OF TOFACITINIB (CP-690,550) IN SUBJECTS WITH 
ULCERATIVE COLITIS IN STABLE REMISSION
Investigational Product Number:
CP-690,550
Investigational Product Name:
Tofacitinib
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2017-002274-39
Protocol Number:
A3921288
Phase*:
3b/4
*Designation of Phase 3b is for countries where approval of tofacitinib for ulcerative colitis has not yet 
been granted; Phase 4 designation is for countries where approval of tofacitinib for ulcerative colitis has 
been granted.
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
CCI


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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 3
11 May 2020
This global amendment incorporates monitoring and 
discontinuation guidelines for venous 
thromboembolism. 
Pfizer has determined that venous thromboembolism
is an important identified risk/dose dependent 
adverse drug reaction for tofacitinib.
The following sections have been updated to reflect 
these changes:
Schedule of Activities, Section 3 (Study Design),
Section 4.2 (Exclusion Criteria), Section 5 (Study 
Treatments), Section 5.5 (Administration) 
Section 5.11 (Tofacitinib Dose Adjustment
Guidelines), Section 5.12 (Tofacitinib Temporary 
Withholding), Section 6 (Study Procedures), 
Section 6.4 (Subject Withdrawal), Section 7.3.3 
(Clinical Laboratory Tests), Section 7.3.6 (Risk 
Factor Check for Venous Thromboembolism), 
Section 16 (References), Appendix 1 and 
Appendix 4.
Protocol Administrative Clarification Letter dated 
19 August 2019 have been incorporated.
Lastly, the changes described in the Protocol 
Administrative Clarification Letter for 
Amendment 2 due to COVID-19 have been 
incorporated in newly added Appendix 9.
Amendment 2
19 June 2019
This global amendment incorporates the provisional 
measures on the restrictions for prescriptions of 
tofacitinib set forth on 17 May 2019 by the 
European Medicines Agency’s (EMA) 
Pharmacovigilance Risk Assessment Committee 
(PRAC) in the European Union.
Subjects who are identified as having one or more of 
the contraindicated risk factors for pulmonary 
embolism as described by PRAC will have their 
tofacitinib dose adjusted to open-label 5 mg BID.


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Any subject identified as having one or more of the
contraindicated risk factors for pulmonary embolism
as described by PRAC will not be permitted to 
receive tofacitinib 10 mg BID.  
A risk factor check for pulmonary embolism is 
added for all study visits.  At the time of 
Amendment 2, 138 subjects have been enrolled in 
the study and have each completed various durations 
of participation.  Therefore, this new procedure will 
only be collected at visits applicable to each 
subject’s individual participation.
Lastly, the changes described in the Protocol 
Administrative Clarification Letter for 
Amendment 1 have been incorporated; namely the 
addition of an ‘X’ in the Schedule of Activities at 
Month 18 for the procedure of Investigational 
Product Dispensing and the corresponding 
correction in Section 6.2.8, Month 18 Visit.
The following sections have been updated in this 
protocol amendment:

Protocol Summary Study Design, Schedule of 
Activities, Section 3 (Study Design), Section 4.2 
(Exclusion Criteria), Section 5 (Study 
Treatments), Section 5.5 (Administration), 
Section 5.8 (Concomitant Medications), 
Section 5.11 (Tofacitinib Dose Adjustment
Guidelines), Section 6 (Study Visit Procedures),
newly added Section 7.3.6 (Risk Factor Check
for Pulmonary Embolism), Section 9.1 (Sample 
Size Determination), and Appendix 1 
(Abbreviations).
Amendment 1 
30 November 
2018

Protocol Summary and Section 3, Study Design 
revised to change treatment duration from 
18 months to 42 months.  The increased 
treatment duration includes 8 additional visits to 
the study site at Months 21, 24, 27, 30, 33, 36, 
39 and 42. 
Rationale: This protocol is being amended to 
extend subject participation an additional 
2 years, from 18 months to 42 months. The 


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study is being extended from 18 to 42 months to 
gather additional long term safety data.  In 
addition, the increase in duration provides a 
longer time horizon to observe any potential 
divergence of efficacy between the two dose 
groups.

Protocol Summary, Section 3, Study Design and 
Section 9.1, Sample Size Determination have 
been revised to clarify that the final sample size 
may exceed 130 subjects.
Rationale: These revisions were made to 
optimize recruitment of potentially eligible 
subjects from Study A3921139.

Collection of demography information at 
Baseline has been added to the Schedule of 
Activities and Section 6.2.1, Baseline (Visit 1).
Rationale: Collection of demography 
information at Baseline is included as an 
administrative change that was communicated 
via a Protocol Administrative Clarification 
Letter dated 20 September 2017.

Schedule of Activities for Months 21 through 42 
included.  Assessments will be the same as those 
done during Month 1 through Month 18; no new 
assessments are introduced.  Sections 6.2.9, 
6.2.10, 6.2.11 and 6.2.12 have been added to 
describe study procedures during Months 21 
through 42.
Rationale: The Schedule of Activities and 
subsequent Procedures sections are updated to 
reflect the increased treatment duration of the 
study to 42 months.

Schedule of Activities, Sections 6 and 7.3.3.2 
have been revised to reflect the change in 
tuberculosis test name from QuantiFERONTB 
Gold In-Tube test to QuantiFERONTB Gold 
Plus test.
Rationale: The name of the tuberculosis assay 
utilized by the central laboratory has changed. 


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
Removed all references to legally acceptable 
representative throughout the protocol.  Subjects 
must be able to provide their own consent to 
participate in this study.
Rationale: All references to legally authorized 
representative have been removed throughout 
the protocol as all subjects recruited into this 
study are only those subjects who are already 
participated in Study A3921139 and provided 
their own consent to participate.

Section 4, Subject Eligibility Criteria revised 
Inclusion criterion #1 and removed Exclusion 
criterion #1 to allow subjects who have received 
tofacitinib 10 mg BID for a minimum of 
2 consecutive years in Study A3921139 to be 
eligible for this study. 
Rationale: Revising the Eligibility Criteria will 
enable more patients to be considered for study 
entry that are aligned with clinical practice. 

Section 4.4.4, Contraception revised to clearly 
state that male condom or female condom used 
WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository) is not 
appropriate or accepted in the European Union 
(EU); an alternate form of contraception must be 
selected.
Rationale: Contraception section is revised in 
response to a request from the Voluntary 
Harmonization Process to align with Heads of 
Medicines Agencies (HMA) guidance and 
clearly note within the protocol that male 
condom or female condom used with a 
spermicide is not an appropriate method in the 
whole EU.

Section 7.3.3.2, Tuberculosis Testing revised to 
reflect additional testing done at Months 24 and 
36 in high TB prevalence countries.  
Rationale: The additional TB testing is updated 
to reflect the increased treatment duration of the 
study to 42 months while still ensuring annual 


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testing in high TB prevalence countries.

Section 7.3.4, Infections revised to clarify that if 
high-risk behaviour(s) or environmental 
exposures are identified, subjects may be tested 
to provide evidence that pre-specified infections 
(eg, HIV, HCV, HBV) are not present.
Rationale: Section 7.3.4 is revised in response 
to competent authority feedback for continued 
subject safety.

Appendix 4, Guidelines for Monitoring and 
Discontinuation revised to clarify references to 
changes from baseline.
Rationale: Revisions to the guidelines and 
monitoring criteria are made to clarify which 
study baseline is used for comparison.

Appendix 8, France Appendix included 
satisfying the requirements of Contrat Unique in 
France. 
Editorial and administrative changes throughout.
Original protocol
13 July 2017
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................11
APPENDICES .........................................................................................................................11
PROTOCOL SUMMARY.......................................................................................................12
SCHEDULE OF ACTIVITIES (BASELINE THROUGH MONTH 18) ...............................17
1. INTRODUCTION ...............................................................................................................22
1.1. Mechanism of Action/Indication.............................................................................22
1.2. Background and Rationale ......................................................................................22
1.3. Clinical Pharmacokinetics.......................................................................................24
1.4. Rationale of Dose Selection ....................................................................................25
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................25
2.1. Objectives................................................................................................................25
2.2. Endpoints.................................................................................................................25
3. STUDY DESIGN.................................................................................................................26
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................30
4.1. Inclusion Criteria.....................................................................................................30
4.2. Exclusion Criteria....................................................................................................31
4.3. Randomization Criteria ...........................................................................................32
4.4. Lifestyle Requirements ...........................................................................................32
4.4.1. Tobacco.......................................................................................................32
4.4.2. Diet and Dietary Supplements....................................................................33
4.4.3. Vaccination.................................................................................................33
4.4.4. Contraception..............................................................................................33
4.4.5. Reproductive Status of Male Subjects........................................................35
4.4.6. Surgery........................................................................................................35
4.5. Sponsor’s Qualified Medical Personnel..................................................................35
5. STUDY TREATMENTS.....................................................................................................35
5.1. Allocation to Treatment ..........................................................................................36
5.2. Breaking the Blind ..................................................................................................36
5.3. Subject Compliance.................................................................................................37
5.4. Investigational Product Supplies.............................................................................37
5.4.1. Dosage Form(s) and Packaging..................................................................37


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5.4.2. Preparation and Dispensing........................................................................37
5.5. Administration.........................................................................................................37
5.6. Investigational Product Storage ..............................................................................38
5.7. Investigational Product Accountability...................................................................39
5.7.1. Destruction of Investigational Product Supplies ........................................39
5.8. Concomitant Medication(s).....................................................................................39
5.9. Prohibited Concomitant Medications......................................................................40
5.10. Rescue Medication ................................................................................................41
5.11. Tofacitinib Dose Adjustment Guidelines..............................................................41
5.12. Tofacitinib Temporary Withholding.....................................................................42
6. STUDY PROCEDURES .....................................................................................................42
6.1. Screening.................................................................................................................42
6.2. Study Period ............................................................................................................42
6.2.1. Baseline (Visit 1)........................................................................................42
6.2.2. Month 1 (7 days, Visit 2)..........................................................................44
6.2.3. Month 3 (7 days, Visit 3)..........................................................................45
6.2.4. Month 6 (7 days, Visit 4)..........................................................................46
6.2.5. Month 9 (7 days, Visit 5)..........................................................................47
6.2.6. Month 12 (7 days, Visit 6)........................................................................47
6.2.7. Month 15 (7 days, Visit 7)........................................................................48
6.2.8. Month 18 (7 days, Visit 8) Visit...............................................................49
6.2.9. Months 21 and 33 (7 days, Visits 9 and 13).............................................50
6.2.10. Months 24 and 36 (7 days, Visits 10 and 14).........................................51
6.2.11. Months 27 and 39 (7 days, Visits 11 and 15).........................................52
6.2.12. Months 30 and 42 (7 days, Visits 12 and 16) or Early Termination 
(ET) Visit .........................................................................................................53
6.3. Follow-up Visit (4 weeks after last dose 7 days, Visit 17) ...................................54
6.4. Subject Withdrawal.................................................................................................54
7. ASSESSMENTS..................................................................................................................56
7.1. Pregnancy Testing...................................................................................................56
7.2. Ulcerative Colitis Assessments ...............................................................................57
7.2.1. Subject Bowel Movement Diary ................................................................57


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7.2.2. Partial Mayo Score .....................................................................................57
7.2.3. Mayo Score.................................................................................................58
7.3. Safety.......................................................................................................................59
7.3.1. Vital Signs ..................................................................................................59
7.3.2. Physical Examinations................................................................................60
7.3.3. Clinical Laboratory Tests ...........................................................................60
7.3.3.1. Stool Samples for Fecal Calprotectin........................................61
7.3.3.2. Tuberculosis Testing .................................................................62
7.3.3.3. Serum Lipids .............................................................................62
7.3.4. Infections ....................................................................................................62
7.3.5. Safety Events of Interest.............................................................................63
7.3.6. Risk Factor Check for Venous Thromboembolism....................................63
8. ADVERSE EVENT REPORTING......................................................................................64
8.1. Requirements...........................................................................................................64
8.1.1. Additional Details On Recording Adverse Events on the CRF..................66
8.1.2. Eliciting Adverse Event Information..........................................................66
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................66
8.1.4. Time Period for Collecting AE/SAE Information......................................66
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................66
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................67
8.1.5. Causality Assessment .................................................................................67
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................67
8.2. Definitions...............................................................................................................67
8.2.1. Adverse Events...........................................................................................67
8.2.2. Abnormal Test Findings .............................................................................68
8.2.3. Serious Adverse Events ..............................................................................69
8.2.4. Hospitalization............................................................................................69
8.3. Severity Assessment................................................................................................70
8.4. Special Situations ....................................................................................................71
8.4.1. Protocol-Specified Serious Adverse Events ...............................................71
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................71


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8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................72
8.4.3.1. Exposure During Pregnancy......................................................73
8.4.3.2. Exposure During Breastfeeding ................................................74
8.4.3.3. Occupational Exposure .............................................................74
8.4.4. Medication Errors .......................................................................................74
8.4.4.1. Medication Errors......................................................................75
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................75
9.1. Sample Size Determination.....................................................................................75
9.2. Efficacy Analysis ....................................................................................................76
9.2.1. Analysis Population....................................................................................76
9.2.2. Primary Analysis ........................................................................................76
9.2.3. Secondary Analysis ....................................................................................76
9.3. Analysis of Biomarker Endpoints ...........................................................................78
9.4. Safety Analysis........................................................................................................78
9.5. Interim Analysis ......................................................................................................78
9.6. Data Monitoring Committee ...................................................................................78
9.7. Safety Event Adjudication Committees ..................................................................78
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................79
11. DATA HANDLING AND RECORD KEEPING .............................................................80
11.1. Case Report Forms/Electronic Data Record .........................................................80
11.2. Record Retention...................................................................................................80
12. ETHICS..............................................................................................................................81
12.1. Institutional Review Board/Ethics Committee......................................................81
12.2. Ethical Conduct of the Study ................................................................................81
12.3. Subject Information and Consent..........................................................................81
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................82
13. DEFINITION OF END OF TRIAL...................................................................................82
13.1. End of Trial in a Member State.............................................................................82
13.2. End of Trial in All Other Participating Countries.................................................82
14. SPONSOR DISCONTINUATION CRITERIA ................................................................82
15. PUBLICATION OF STUDY RESULTS..........................................................................83


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15.1. Communication of Results by Pfizer ....................................................................83
15.2. Publications by Investigators ................................................................................83
16. REFERENCES ..................................................................................................................85
LIST OF TABLES
Table 1.
Investigational Product Administration................................................................38
Table 2.
Concomitant Medications.....................................................................................40
Table 3.
Laboratory Test Parameters..................................................................................60
APPENDICES
Appendix 1. Abbreviations......................................................................................................86
Appendix 2. Mayo Scoring System* .......................................................................................89
Appendix 3. Prohibited Concomitant Medications..................................................................90
Appendix 4. Guidelines for Monitoring and Discontinuations................................................92
Appendix 5. Evaluation of Potentially Malignant Tumors, Suspicious
Lymphadenopathy or Possible Extranodal Lymphoproliferative Disorder 
(LPD)....................................................................................................................95
Appendix 6. Evaluation of Gastrointestinal Tract Biopsies ....................................................96
Appendix 7. Recommended Clinical Management of Cholesterol .........................................97
Appendix 8. France Appendix.................................................................................................98
Appendix 9. Protocol Administrative Changes and Clarification for Study A3921288 
During COVID-19 Pandemic ...............................................................................99


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PROTOCOL SUMMARY
Background and Rationale
The tofacitinib Phase 3 ulcerative colitis (UC) program evaluated the efficacy and safety of 
tofacitinib in patients with moderately to severely active UC who had prior failure or 
intolerance to corticosteroids, azathioprine/6-mercaptopurine (AZA/6-MP), and/or tumor 
necrosis factor inhibitor (TNFi) agents.  The program consists of 2 completed, identically 
designed 8-week induction studies (A3921094 and A3921095) with tofacitinib 10 mg twice 
daily (BID) or placebo, 1 completed 52-week maintenance study (A3921096) with tofacitinib 
5 mg BID, tofacitinib 10 mg BID or placebo, and 1 ongoing open-label long-term extension 
(LTE) study (A3921139) with tofacitinib 5 mg BID and tofacitinib 10 mg BID. 
This study is designed to evaluate (1) the efficacy and safety of tofacitinib in subjects in 
stable remission on 10 mg BID who decrease the dose to 5 mg BID compared to subjects 
remaining on 10 mg BID; (2) the efficacy and safety of tofacitinib in subjects in stable 
remission on 10 mg BID who decrease the dose to 5 mg BID with option for dose escalation 
for flare (“flexible dosing regimen”) compared to subjects staying on 10 mg BID; and (3) the 
efficacy and safety of the subset of subjects who have flare on maintenance tofacitinib 5 mg 
BID and are re-treated with 10 mg BID.
Objectives
Primary Objective

To evaluate the efficacy and safety of tofacitinib in subjects in stable remission on 
10 mg BID who decrease the dose to and remain on 5 mg BID (“5 mg BID dose 
group”) compared to subjects remaining on 10 mg BID.
Secondary Objectives

To evaluate the efficacy and safety of tofacitinib in subjects in stable remission on 
10 mg BID who decrease the dose to 5 mg BID with option for dose escalation for 
flare (“flexible dosing regimen”) compared to subjects staying on 10 mg BID.

To evaluate the efficacy and safety of the subset of subjects in stable remission on
10 mg BID who have flare after dose decrease to tofacitinib 5 mg BID and are 
re-treated with 10 mg BID.
Endpoints
Primary Efficacy Endpoint

Remission based on modified Mayo score at Month 6.
Secondary Efficacy Endpoints

Time to loss of remission based on modified Mayo score.


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
Remission at all applicable scheduled visits based on the following: modified Mayo 
score (excluding Month 6), modified partial Mayo score, total Mayo score, and partial 
Mayo score.

Change from baseline (of Study A3921288) at all applicable scheduled visits in the 
following: modified Mayo score, modified partial Mayo score, total Mayo score, and 
partial Mayo score.

Mucosal healing at all applicable scheduled visits.

Clinical response based on Mayo score at all applicable scheduled visits.

Change from baseline at all applicable scheduled visits in fecal calprotectin and 
hs-CRP levels.
Safety Endpoints

Incidence and severity of adverse events (AEs).

Incidence of serious infections.

Incidence and severity of clinical laboratory abnormalities, and change from baseline 
in clinical laboratory values.

Incidence of vital sign abnormalities and change from baseline in vital signs.

Incidence of clinically significant changes in physical examinations from baseline.

Adjudicated safety events (eg, opportunistic infections, malignancy, gastrointestinal 
perforation, and cardiovascular events).
STUDY DESIGN
This is a Phase 3b/4, multi-center, randomized double-blind study.  Designation of Phase 3b 
is for countries where approval of tofacitinib for UC has not yet been granted; Phase 4 
designation is for countries where approval of tofacitinib for UC has been granted.  This
study will enroll subjects from currently enrolled subjects in Study A3921139 who are in 
stable remission on tofacitinib 10 mg BID for at least 6 months prior to enrollment.  Subjects 
must have received tofacitinib 10 mg BID for a minimum of 2 consecutive years in
Study A3921139, and not be receiving any corticosteroids to treat their UC for at least 
4 weeks prior to baseline in order to be eligible for this study.  Subjects enrolling under 
Amendment 2 must not have any risk factors for pulmonary embolism as described in
Section 4.2, exclusion criterion #12.


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Although approximately 130 subjects are estimated to be enrolled into this study (based on 
availability of eligible subjects from Study A3921139 and based on the conservative 
assumptions of the attrition rate of 50% -60% in Study A3921139), the final sample size may 
exceed 130 subjects.  The Sponsor will continue to engage with investigative sites 
participating in Study A3921139 to assess the ability to enroll additional eligible subjects.
This study will have a total of 42 months of treatment duration.  The primary analysis will be 
conducted after the last subject enrolled reaches their Month 6 study visit.  This study will 
remain double-blinded to the site and the subject to the initial treatment assignment at 
baseline.
Study visits will occur at baseline (enrollment), and at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 
27, 30, 33, 36, 39 and 42.  All subjects, who withdraw early or who complete this study, will 
have a 4-week safety follow-up evaluation after the last dose of investigational product.
If during the course of the study, a subject experiences an increase in clinical symptoms, such 
as an increase in rectal bleeding or an increase in stool frequency, then an endoscopy should 
be performed to assess if the subject is experiencing flare.  Flare must be confirmed prior to
performing any dose adjustments.  In addition, subjects who experience atypical symptoms 
or features of their usual UC disease course or have significantly worsening disease activity 
assessments from the previous visit, or have the presence of risk factors such as recent 
antibiotic use or a recent history of C. difficile infection should have Clostridium difficile
(C. difficile) toxin testing performed before assessing for flare and performing any dose 
adjustments.  
Please refer to Section 5.11 for tofacitinib dose adjustment guidelines and definition of flare. 
STUDY TREATMENTS
Subjects will be randomized to one of two dosing groups at baseline of Study A3921288:

Tofacitinib 5 mg BID.

Tofacitinib 10 mg BID.
STATISTICAL METHODS
Sample Size Determination
Although approximately 130 subjects are estimated to be enrolled into this study (based on 
availability of eligible subjects from the open label Study A3921139 and based on the 
conservative assumptions of the attrition rate of 50% - 60% in Study A3921139).  The final 
sample size may exceed 130 subjects and may equal up to 200 subjects if the actual attrition 
rate is lower than the assumed one.  The Sponsor will continue to engage with investigative
sites participating in Study A3921139 to assess the ability to enroll additional eligible 
subjects.  


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With 130 (65 per group) subjects, the estimated half width of the 95% confidence for 
treatment difference between tofacitinib 10 mg BID and 5 mg BID in proportion of remission 
at Month 6 based on the modified Mayo score is about 16%, assuming the remission rates are 
greater than 70% in both groups.
Efficacy Analysis
Analysis Population
The primary analysis population will be the Full Analysis Set (FAS) defined as all subjects 
who are randomized into the study and receive at least 1 dose of investigational product.
Primary Analysis
The primary endpoint is remission based on the modified Mayo score at Month 6.  The 
primary analysis will be performed at Month 6 based on the FAS for the estimation of 
treatment difference between the following two dose groups:

Tofacitinib 10 mg BID Dose Group: subjects who are initially assigned to tofacitinib 
10 mg BID at randomization.

Tofacitinib 5 mg BID Dose Group: subjects who are initially assigned to tofacitinib 
5 mg BID at randomization, regardless of whether the dose is escalated back to 
tofacitinib 10 mg BID or not.
The stratified estimation of the treatment difference between tofacitinib 10 mg BID and 
5 mg BID in the proportion of subjects with remission at Month 6 will be presented along 
with its 95% confidence interval (CI). The Cochran-Mantel-Haenszel (CMH) weight method 
will be used for the stratified estimation of the treatment difference.  The stratified CI will be 
constructed using the NewCombe method.  Subjects with dose escalation prior to Month 6 or 
with missing values at Month 6 will be treated as non-responders at Month 6.  Sensitivity 
analyses for handling with missing data will be performed and further details will be 
provided in the statistical analysis plan.
Secondary Analysis
Dose comparison between tofacitinib 5 mg BID and 10 mg BID 
For the primary objective, the treatment difference for the binary secondary efficacy 
endpoints will also be estimated based on the FAS, using the same approach as described 
above for the primary endpoint.  For continuous endpoints, the change from baseline will be 
analyzed using linear mixed-effects model with baseline value, dose group, the endoscopic 
subscore at baseline (0 versus 1), visit, and dose group by visit interaction all as fixed effects,
and subject as a random effect.  The adjusted estimations and associated 95% CI for the 
overall difference between the two dose groups will be computed.  Kaplan-Meier estimates at 
the scheduled visits will be computed for time to event endpoint. The log-rank test stratified 


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by endoscopic subscore at baseline (0 versus 1) will also be performed for the comparison 
between dose groups. 
If a subject has a dose escalation back to tofacitinib 10 mg BID, then

For binary efficacy endpoints, the subject will be considered as a non-responder for 
any visit after the dose escalation visit.

For continuous efficacy endpoints, the data collected for any visit after the dose 
escalation visit will be considered as missing.

For time to loss of remission, the subject will be considered as having an event at the 
visit with a dose escalation if the event criteria are met or having a censor time at the 
visit with a dose escalation if the event criteria are not met.
For continuous endpoints that are measured repeatedly over time, the missing values will be 
handled in a linear mixed-effects model where the mechanism of missingness is assumed to
be missing at random. 
Regimen comparison between flexible dosing and fixed dosing 
For the first secondary objective, analyses will be performed based on the FAS for 
comparisons of the following two dose regimens:

Tofacitinib fixed 10 mg BID Dose Regimen: subjects who are initially assigned to 
tofacitinib 10 mg BID at randomization and stay on tofacitinib 10 mg BID until 
completion or discontinuation.

Tofacitinib flexible 5 mg/10 mg BID Dose Regimen: subjects who are initially 
assigned to tofacitinib 5 mg BID at randomization, staying on tofacitinib 5 mg BID or
having dose escalation from tofacitinib 5 mg BID to 10 mg BID.
Analysis methods are the same as the ones described above for comparison between dose 
groups except that data from subjects with dose escalation back to tofacitinib 10 mg BID will 
be treated as it is.  Only the visits with missing data will be treated as non-responders.
For the second secondary objective, summary descriptive statistics will be reported for the 
sub-group of subjects who are initially assigned to tofacitinib 5 mg BID and later are 
retreated with tofacitinib 10 mg BID.  Missing data will not be imputed.
Safety Analysis
The safety data will be summarized in accordance with Pfizer Data Standards based on the 
safety analysis set defined as all subjects who receive at least 1 dose of investigational 
product.
Summaries will be performed by dose group and dose regimens as defined in the efficacy 
sub-section.


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SCHEDULE OF ACTIVITIES (BASELINE THROUGH MONTH 18)
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
All study visits after Baseline will have a visit window of 7 days.
Refer to Appendix 9 for permitted alternative measures for certain study procedures in response to the ongoing global COVID-19 
pandemic.
Study Procedure
Baseline
Treatment Period
Day 11
Month 1
(7 days)
Month 3
(7 days)
Month 6
(7 days)
Month 9
(7 days)
Month 12
(7 days)
Month 15
(7 days)
Month 18
(7 days) 
Visit Number 
1
2
3
4
5
6
7
8
Informed Consent
X
Medical History2
X
Demography10
X
Targeted Physical Examination3
OLE
X
X
X
X
X
X
X
Vital Signs, Including Temperature 
OLE
X
X
X
X
X
X
X
Laboratory
Hematology
OLE
X
X
X
X
X
X
X
Serum Chemistry
OLE
X
X
X
X
X
X
X
Lipid Profile, Fasting
OLE
X
X
X
Urine -hCG4
OLE
X
X
X
X
X
X
X
Dispense Stool Sample 
Collection Kit
X
X
X
X
X
X
X
X
Collect Stool Sample for Fecal 
Calprotectin5
X
X
X
X
X
X
X
X
High-Sensitivity CRP
OLE
X
X
X
X
X
X
X
Tuberculosis Testing/Chest 
Radiograph, if necessary in 
Specific Countries6
X


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Study Procedure
Baseline
Treatment Period
Day 11
Month 1
(7 days)
Month 3
(7 days)
Month 6
(7 days)
Month 9
(7 days)
Month 12
(7 days)
Month 15
(7 days)
Month 18
(7 days) 
HBV DNA Testing (Japan 
Only)7
OLE
X
X
X
X
X
X
X
Endoscopic Procedure
Flexible Sigmoidoscopy/ 
Colonoscopy (if preferred)8
OLE
X
X
Eligibility Assessment
X
Randomization
X
Investigational Product Dispensing
X
X
X
X
X
X
X
Investigational Product
Accountability
X
X
X
X
X
X
X
Ulcerative Colitis Assessments
Bowel Movement Diary Data9
X
X
X
X
X
X
X
X
Partial Mayo Score
X
X
X
X
X
Mayo Score
OLE
X
X
Contraception Check For Females of 
Childbearing Potential
X
X
X
X
X
X
X
X
Adverse Event Monitoring
X
X
X
X
X
X
X
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
Risk Factor Check for Venous 
Thromboembolism11
X
X
X
X
X
X
X
X
Abbreviations: ET = early termination; -hCG = beta-human chorionic gonadotropin; OLE = open-label extension study (A3921139).
1.
The baseline visit of Study A3921288 is the same visit as the last visit in Study A3921139.  All procedures done at the last visit in A3921139 for subjects 
enrolled into Study A3921288 will be used as the baseline data for Study A3921288.  Procedures listed as OLE procedures will NOT BE REPEATED at 
baseline of Study A3921288.  Only those procedures marked with an ‘X’ will be performed at the baseline visit of Study A3921288.
2.
Medical history from Study A3921139, including resolved adverse events (AEs) will be used for Study A3921288.  Ongoing AEs from Study A3921139 
will be followed throughout Study A3921288.
3.
The targeted physical examination consists of weight, general appearance, and examinations of eyes, mouth, lungs, heart, abdomen, musculoskeletal, 
extremities, skin and lymph nodes.
4.
Urine -hCG to be performed only for females of childbearing potential.  Pregnancy testing may be performed more frequently per local regulations.
5.
Stool samples will be collected at baseline and at each scheduled study visit to measure fecal calprotectin (see Section 7.3.3.1).  In addition, stool samples 
should be obtained at the time of worsening disease and/or flare when possible.


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6.
Tuberculosis (TB) screening will be conducted at Month 12 using Quantiferon-TBGold Plus test (QFT) only for subjects in those countries in which TB 
prevalence has been reported at a rate of >50 cases per 100,000 persons (see Section 7.3.3.2). All subjects with positive results must have chest radiograph 
performed.  Note: QFT should not be performed in subjects who had positive result during prior testing (screening visit in Induction Study A3921094 or 
A3921095 or prior annual visits in Study A3921139) and/or previously received adequate treatment for TB.
7.
Safety monitoring for a subset of subjects in Japan only.  See Appendix 4 for details.
8.
Flexible sigmoidoscopy/colonoscopy (if preferred) will be performed at Month 6, Month 18 and at ET for all subjects.  In order for a subject to eligible for 
Study A3921288, they must have an endoscopy performed in Study A3921139 6 months prior to baseline of Study A3921288 with an endoscopic subscore 
of 0 or 1.  Mayo endoscopic subscore will only be assessed by local site read. 
9.
Bowel movement (BM) diary data will be collected through a phone-based interactive voice recording system (IVRS) tool.  Subjects will be instructed in its 
use at the Baseline visit.  Subjects should start completing the BM diary daily approximately 7 days prior to their next scheduled visit.  Study site staff 
should contact the subjects 7 days prior to the scheduled visit to ensure compliance.  In addition, subjects should be instructed to start completing the BM 
diary whenever he/she experiences any worsening of UC symptoms anytime during the study.
10. Demography, including birth date, sex/gender, ethnicity and race will be collected at the Baseline/Day 1 visit and provided in the case report form as allowed 
by local regulations.
11. Per Amendment 2, all subjects will be asked at every study visit if they have any newly-developed risk factors for pulmonary embolism as described 
in Section 7.3.6.  At the time of Amendment 2, 138 subjects have been enrolled in the study and have each completed various durations of 
participation.  Per Amendment 3, all subjects will be asked at each applicable visit if they have any newly developed risk factors for venous
thromboembolism as described in Section 7.3.6.  At the time of Amendment 3, all subjects were enrolled and completed the Month 6 study visit.  
Therefore, this procedure will only be collected at visits applicable to each subject’s individual participation. If a subject has a newly identified risk 
factor for venous thromboembolism, the subject’s tofacitinib dose will be adjusted to open-label 5 mg BID.


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SCHEDULE OF ACTIVITIES (MONTH 21 THROUGH MONTH 42)
Study Procedure
Treatment Period
Follow-Up
Month 21
(7 days)
Month 24
(7 days)
Month 27
(7 days)
Month 30
(7 days)
Month 33
(7 days)
Month 36
(7 days)
Month 39
(7 days)
Month 
42/ET1
(7 days) 
4-weeks 
after last 
dose 
(7 days)
Visit Number 
9
10
11
12
13
14
15
16
17
Targeted Physical Examination2
X
X
X
X
X
X
X
X
X
Vital Signs, Including Temperature 
X
X
X
X
X
X
X
X
X
Laboratory
Hematology
X
X
X
X
X
X
X
X
X
Serum Chemistry
X
X
X
X
X
X
X
X
X
Lipid Profile, Fasting
X
X
X
X
X
Urine -hCG3
X
X
X
X
X
X
X
X
X
Dispense Stool Sample 
Collection Kit
X
X
X
X
X
X
X
Collect Stool Sample for Fecal 
Calprotectin4
X
X
X
X
X
X
X
X
High-Sensitivity CRP
X
X
X
X
X
X
X
X
Tuberculosis Testing/Chest 
Radiograph, if necessary in 
Specific Countries5
X
X
HBV DNA Testing (Japan 
Only)6
X
X
X
X
X
X
X
X
X
Endoscopic Procedure
Flexible Sigmoidoscopy/ 
Colonoscopy (if preferred)7
X
X
Investigational Product Dispensing
X
X
X
X
X
X
X
Investigational Product 
Accountability
X
X
X
X
X
X
X
X
Ulcerative Colitis Assessments
Bowel Movement Diary Data8
X
X
X
X
X
X
X
X
Partial Mayo Score
X
X
X
X
X
X
Mayo Score
X
X
Contraception Check For Females of 
Childbearing Potential
X
X
X
X
X
X
X
X
X
Adverse Event Monitoring
X
X
X
X
X
X
X
X
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X


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Study Procedure
Treatment Period
Follow-Up
Month 21
(7 days)
Month 24
(7 days)
Month 27
(7 days)
Month 30
(7 days)
Month 33
(7 days)
Month 36
(7 days)
Month 39
(7 days)
Month 
42/ET1
(7 days) 
4-weeks 
after last 
dose 
(7 days)
Risk Factor Check for Venous 
Thromboembolism9
X
X
X
X
X
X
X
X
Abbreviations: -hCG = beta-human chorionic gonadotropin.
1.
Subjects who discontinue treatment early from the study will have an early termination (ET) visit and all procedures listed at Month 42/ET will be performed 
on the last day the subject takes the investigational product or as soon as possible thereafter.
2.
The targeted physical examination consists of weight, general appearance, and examinations of eyes, mouth, lungs, heart, abdomen, musculoskeletal,
extremities, skin and lymph nodes.
3.
Urine -hCG to be performed only for females of childbearing potential.  Pregnancy testing may be performed more frequently per local regulations.
4.
Stool samples will be collected at baseline and at each scheduled study visit to measure fecal calprotectin (see Section 7.3.3.1).  In addition, stool samples 
should be obtained at the time of worsening disease and/or flare when possible.
5.
Tuberculosis (TB) screening will be conducted at Month 24 and 36 using Quantiferon-TBGold Plus test (QFT) only for subjects in those countries in 
which TB prevalence has been reported at a rate of >50 cases per 100,000 persons (see Section 7.3.3.2).  All subjects with positive results must have chest 
radiograph performed.  Note: QFT should not be performed in subjects who had positive result during prior testing (screening visit in Induction 
Study A3921094 or A3921095 or prior annual visits in Study A3921139) and/or previously received adequate treatment for TB.
6.
Safety monitoring for a subset of subjects in Japan only.  See Appendix 4 for details.
7.
Flexible sigmoidoscopy/colonoscopy (if preferred) will be performed at Month 30, Month 42 and at ET for all subjects.  Mayo endoscopic subscore will 
only be assessed by local site read. 
8.
Bowel movement (BM) diary data will be collected through a phone-based interactive voice recording system (IVRS) tool.  Subjects will be instructed in its 
use at the Baseline visit.  Subjects should start completing the BM diary daily approximately 7 days prior to their next scheduled visit.  Study site staff 
should contact the subjects 7 days prior to the scheduled visit to ensure compliance.  In addition, subjects should be instructed to start completing the BM 
diary whenever he/she experiences any worsening of UC symptoms anytime during the study.
9.
Per Amendment 2, all subjects will be asked at every study visit if they have any newly-developed risk factors for pulmonary embolism as described 
in Section 7.3.6.  At the time of Amendment 2, 138 subjects have been enrolled in the study and have each completed various durations of 
participation. Per Amendment 3, all subjects will be asked at each applicable visit if they have any newly developed risk factors for venous
thromboembolism as described in Section 7.3.6.  At the time of Amendment 3, all subjects were enrolled and completed the Month 6 study visit.  
Therefore, this procedure will only be collected at visits applicable to each subject’s individual participation.  If a subject has a newly identified risk 
factor for venous thromboembolism, the subject’s tofacitinib dose will be adjusted to open-label 5 mg BID.


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1. INTRODUCTION
Ulcerative colitis (UC) is a chronic, inflammatory disease of the colon characterized 
clinically by intermittent flares interposed between variable periods of remission and 
pathologically by inflammation confined to the mucosa.  Patients with moderately to severely 
active UC are challenged with few treatment options for a life-long chronic condition with 
high disease burden, reduced quality-of-life, and associated comorbidities.
1.1. Mechanism of Action/Indication
Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a 
high degree of selectivity against other kinases.1  In kinase assays, tofacitinib inhibits JAK1, 
JAK2, JAK3, and to a lesser extent tyrosine kinase 2 (TyK2).  In cellular settings where JAK 
kinases signal in pairs, tofacitinib preferentially inhibits signaling by heterodimers containing 
JAK3 and/or JAK1 with functional selectivity over JAK2 homodimer signaling.2  Inhibition
of JAK1 and JAK3 by tofacitinib blocks signaling through the common gamma chain 
containing receptors for several cytokines, including interleukin (IL) -2, -4,-7,-9, -15 and -21.  
These cytokines are integral to lymphocyte activation, proliferation, and function, and 
inhibition of their signaling may thus 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 gamma (IFN).3  At higher
exposures, inhibition of erythropoietin, prolactin and other hormones could occur via 
inhibition of JAK2 homodimer signaling.
The broad effects of JAK1/3 inhibition on multiple cytokine pathways provides the rationale 
for developing tofacitinib as treatment for several diseases, including UC, in which 
lymphocyte activation/proliferation plays a pathogenic role.
Tofacitinib is currently being studied as an oral treatment for UC, rheumatoid arthritis (RA) 
and Psoriatic Arthritis (PsA).
1.2. Background and Rationale
The tofacitinib Phase 3 UC program evaluated the efficacy and safety of tofacitinib in 
patients with moderately to severely active UC who had prior failure or intolerance to 
corticosteroids, azathioprine/6-mercaptopurine (AZA/6-MP), and/or tumor necrosis factor 
inhibitor (TNFi) agents.  The program consists of 2 completed, identically designed 8-week 
induction studies (A3921094 and A3921095) with tofacitinib 10 mg twice daily (BID) or 
placebo, 1 completed 52-week maintenance study (A3921096) with tofacitinib 5 mg BID, 
tofacitinib 10 mg BID or placebo, and 1 ongoing open-label long-term extension (LTE) study 
(A3921139) with tofacitinib 5 mg BID and tofacitinib 10 mg BID. 
In both induction studies (A3921094 and A3921095), statistically significantly higher 
proportions of subjects in the tofacitinib 10 mg BID group achieved the primary endpoint of 
remission as well as the key secondary endpoint of mucosal healing at Week 8 compared 
with placebo based on the centrally read endoscopy data.  The tofacitinib 10 mg BID group 
also had statistically significantly higher proportions of subjects with the secondary 
endpoints of clinical response and endoscopic remission at Week 8 as compared with 


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placebo.  These results were supported by all other secondary and exploratory efficacy 
endpoints, biomarkers, and patient-reported outcomes (PROs).  The observed treatment 
effects were consistent regardless of prior TNFi treatment.
In addition, tofacitinib 10 mg BID showed significantly greater improvement from baseline 
in partial Mayo score compared with placebo by Week 2, which was the first post-baseline 
timepoint assessed and these improvements continued to increase at Week 4 and Week 8.  In 
these 8-week induction studies, the tofacitinib 10 mg BID dose appeared to be well tolerated.  
Most adverse events (AEs) were mild or moderate in severity, and the most frequent 
treatment-emergent adverse events (TEAEs) were headache and nasopharyngitis, with 
similar rates between the tofacitinib and placebo group.
In the maintenance study (A3921096), both tofacitinib 5 mg BID and 10 mg BID
demonstrated statistically significantly greater treatment effects versus placebo for remission 
at Week 52 (primary endpoint), mucosal healing at Week 52, and sustained corticosteroid 
free remission among subjects in remission at baseline (key secondary endpoints).  
Tofacitinib 5 mg BID and 10 mg BID also demonstrated statistically significantly higher 
proportions of subjects with clinical response compared with placebo.  Time to treatment 
failure was statistically significantly different in the tofacitinib 5 mg BID and 10 mg BID 
treatment groups compared with placebo, with earlier and more frequent events in the 
placebo group. The efficacy of tofacitinib 5 mg BID and 10 mg BID was supported by all 
other secondary and exploratory efficacy endpoints and PROs.
The observed treatment effect was higher in the tofacitinib 10 mg BID group than the 
tofacitinib 5 mg BID group in the overall population for primary and key secondary 
endpoints, and was generally consistent across subgroups. 
In the 52-week maintenance study, both the tofacitinib 5 mg BID and 10 mg BID doses 
appeared to be well tolerated.  Most AEs were mild or moderate in severity, and the most 
frequent TEAEs were colitis ulcerative (higher incidence in the placebo group) and 
nasopharyngitis (higher incidence in the tofacitinib groups).  Discontinuation from the study
due to AEs occurred more frequently in the placebo group compared with the tofacitinib 
5 mg BID and 10 mg BID groups, with the most frequent AE leading to discontinuation 
being colitis ulcerative (worsening of UC).  Serious adverse event (SAEs) occurred at similar 
frequencies across treatment groups.  More subjects in the tofacitinib treatment groups 
experienced infection AEs compared with placebo, though serious infections occurred at 
similar rates across treatment groups.  The most frequent infection AE in all treatment groups 
was nasopharyngitis.  There was a dose-dependent increase in the rate of herpes zoster (HZ).
The safety profile of tofacitinib in UC has been well characterized based on a substantial
safety database in UC as well as an extensive safety database from other indications, mostly 
RA.  The safety data from the overall UC clinical program showed that the safety profile of 
tofacitinib treatment in the UC population was consistent with that of the RA population.  
There was evidence of dose effect for HZ, consistent with other indications.  Overall, rates of 
events of special interest were similar to the rates in RA and psoriasis, except for a higher 
incidence rate of HZ.  The overall safety profile of tofacitinib was also similar to that of 


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TNFi agents except for a higher rate of HZ.  The majority of HZ events were cutaneous 
zoster involving 1 or 2 adjacent dermatomes.  The totality of data supports an overall 
acceptable safety profile for both tofacitinib 5 mg BID and 10 mg BID maintenance therapy 
in moderately to severely active UC patients.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure (IB).
The open-label LTE study (A3921139) is ongoing and the main objective of the study is to 
collect long term safety data for both tofacitinib 5 mg BID and 10 mg BID doses.  Subjects 
who completed the induction studies but did not achieve clinical response were eligible to 
enter into the open-label LTE study.  Subjects who either completed the maintenance study 
treatment period or who withdrew early from the maintenance study by meeting prespecified 
protocol defined criteria for treatment failure were also potentially eligible to enter the 
open-label LTE study.  Subjects completing maintenance Study A3921096 in remission who 
enrolled into open-label LTE study were assigned to receive tofacitinib 5 mg BID at baseline.  
All other subjects were assigned to tofacitinib 10 mg BID at baseline.  Among those subjects 
entering the open-label LTE Study A3921139 in remission who received tofacitinib 
10 mg BID during maintenance treatment, 72.7% of these subjects remained in remission and 
81.8% had mucosal healing after 12 months of open-label treatment with tofacitinib 
5 mg BID.
Based on the Phase 3 data, the observed treatment effect was higher with tofacitinib 
10 mg BID than tofacitinib 5 mg BID maintenance therapy and a dose-dependent response 
observed in the rate of herpes zoster.  While the data from the uncontrolled open-label LTE 
study suggest maintenance of efficacy with dose reduction to 5 mg BID for subjects who are 
in remission after 52 weeks of receiving tofacitinib 10 mg BID, this double-blind, 
randomized study may help to further evaluate the benefits of dosing flexibility with 
tofacitinib, and provide additional data for selecting the most appropriate regimen for an 
individual subject.
This study is designed to evaluate (1) the efficacy and safety of tofacitinib in subjects in 
stable remission on 10 mg BID who decrease the dose to 5 mg BID compared to subjects 
remaining on 10 mg BID; (2) the efficacy and safety of tofacitinib in subjects in stable 
remission on 10 mg BID who decrease the dose to 5 mg BID with option for dose escalation 
for flare (“flexible dosing regimen”) compared to subjects staying on 10 mg BID; and (3) the 
efficacy and safety of the subset of subjects who have flare on maintenance tofacitinib 
5 mg BID and are re-treated with 10 mg BID.
1.3. Clinical Pharmacokinetics
The pharmacokinetics of tofacitinib in humans is characterized by rapid absorption and 
elimination, with a time to peak concentration (Tmax) of approximately 0.5 hour and a 
half-life (t1/2) of approximately 3 hours.  Steady state pharmacokinetics is predictable from
single dose data, with minimal accumulation with twice daily dosing.  In general, systemic 
exposure of tofacitinib increases with dose in a dose-proportional manner. 


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The clearance mechanisms for tofacitinib in humans include both non-renal (hepatic 
metabolism) and renal excretion of the parent drug, the former accounting for approximately 
70% of the total clearance.  The metabolism of tofacitinib appears to be primarily mediated 
by CYP3A4 with minor contribution from CYP2C19 (based on data from poor metabolizers 
of CYP2C19).
1.4. Rationale of Dose Selection
In the UC Phase 3 program, tofacitinib 10 mg BID was evaluated for 8 weeks of induction 
therapy, followed by 5 mg or 10 mg BID for 52 weeks for maintenance therapy in patients 
with moderate to severe UC.  These studies showed tofacitinib 10 mg BID as an induction 
therapy and both tofacitinib 5 mg BID and 10 mg BID as a maintenance therapy were 
efficacious, relative to placebo, and had an acceptable safety and tolerability profile. Based 
on exposure response modeling of the maintenance data, there was a significant trend for 
increase in efficacy response, as well as a trend for increase in some AE rates, with 
increasing tofacitinib dose and exposure.  Patients enrolled in the ongoing open label LTE 
Study A3921139 have continued to demonstrate efficacy and acceptable safety and 
tolerability at both 5 mg BID and 10 mg BID doses.  Therefore, the doses selected for this 
study are consistent with the primary study objective of evaluating whether UC patients in 
stable remission on tofacitinib 10 mg BID are able to maintain efficacy when switched to 
tofacitinib 5 mg BID.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective

To evaluate the efficacy and safety of tofacitinib in subjects in stable remission on 
10 mg BID who decrease the dose to and remain on 5 mg BID (“5 mg BID dose 
group”) compared to subjects remaining on 10 mg BID. 
Secondary Objectives

To evaluate the efficacy and safety of tofacitinib in subjects in stable remission on 
10 mg BID who decrease the dose to 5 mg BID with option for dose escalation for 
flare (“flexible dosing regimen”) compared to subjects staying on 10 mg BID.

To evaluate the efficacy and safety of the subset of subjects in stable remission on 
10 mg BID who have flare after dose decrease to tofacitinib 5 mg BID and are 
re-treated with 10 mg BID.
2.2. Endpoints
Primary Efficacy Endpoint

Remission based on modified Mayo score at Month 6.


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Secondary Efficacy Endpoints

Time to loss of remission based on modified Mayo score.

Remission at all applicable scheduled visits based on the following: modified Mayo 
score (excluding Month 6), modified partial Mayo score, total Mayo score, and partial 
Mayo score.

Change from baseline (of Study A3921288) at all applicable scheduled visits in the 
following: modified Mayo score, modified partial Mayo score, total Mayo score, and 
partial Mayo score.

Mucosal healing at all applicable scheduled visits.

Clinical response based on Mayo score at all applicable scheduled visits.

Change from baseline at all applicable scheduled visits in fecal calprotectin and 
hs-CRP levels.
Safety Endpoints

Incidence and severity of adverse events (AEs).

Incidence of serious infections.

Incidence and severity of clinical laboratory abnormalities, and change from baseline 
in clinical laboratory values.

Incidence of vital sign abnormalities and change from baseline in vital signs.

Incidence of clinically significant changes in physical examinations from baseline.

Adjudicated safety events (eg, opportunistic infections, malignancy, gastrointestinal 
perforation, and cardiovascular events).
3. STUDY DESIGN
This is a Phase 3b/4, multi-center, randomized double-blind study.  Designation of Phase 3b 
is for countries where approval of tofacitinib for UC has not yet been granted; Phase 4 
designation is for countries where approval of tofacitinib for UC has been granted.  This 
study will enroll subjects from currently enrolled subjects in Study A3921139 who are in 
stable remission on tofacitinib 10 mg BID for at least 6 months prior to enrollment.  Subjects 
must have received tofacitinib 10 mg BID for a minimum of 2 consecutive years in
Study A3921139, not be receiving any corticosteroids to treat their UC for at least 4 weeks 
prior to baseline in order to be eligible for this study.  Subjects enrolling under Amendment 2 
must not have any risk factors for pulmonary embolism as described in Section 4.2, exclusion 
criterion #12.


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Although approximately 130 subjects are estimated to be enrolled into this study (based on 
availability of eligible subjects from Study A3921139 and based on the conservative 
assumptions of the attrition rate of 50% - 60% in Study A3921139), the final sample size 
may exceed 130 subjects.  The Sponsor will continue to engage with investigative sites 
participating in Study A3921139 to assess the ability to enroll additional eligible subjects.
This study will have a total of 42 months of treatment duration. The primary analysis will be 
conducted after the last subject enrolled reaches their Month 6 study visit.  This study will 
remain double-blinded to the site and the subject to the initial treatment assignment at 
baseline.
Study visits will occur at Baseline (Day 1, enrollment), and at Months 1, 3, 6, 9, 12, 15, 18, 
21, 24, 27, 30, 33, 36, 39 and 42.  All subjects, who withdraw early or who complete this 
study, will have a 4-week safety follow-up evaluation after the last dose of investigational 
product.
* All subjects must have an endoscopy performed in Study A3921139 6 months prior to baseline of 
Study A3921288 with an endoscopic subscore of 0 or 1, in order to be eligible for enrollment.  Local site read 
of endoscopy only.


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If during the course of the study, a subject experiences an increase in clinical symptoms, such 
as an increase in rectal bleeding or an increase in stool frequency, then an endoscopy should 
be performed to assess if the subject is experiencing flare.  Flare must be confirmed prior to 
performing any dose adjustments. In addition, subjects who experience atypical symptoms 
or features of their usual UC disease course or have significantly worsening disease activity 
assessments from the previous visit, or have the presence of risk factors such as recent 
antibiotic use or a recent history of C. difficile infection should have Clostridium difficile
(C. difficile) toxin testing performed before assessing for flare and performing any dose
adjustments. 
Please refer to Section 5.11 for tofacitinib dose adjustment guidelines and definition of flare.
Amendment 2
On 17 May 2019, the European Medicines Agency’s (EMA) Pharmacovigilance Risk 
Assessment Committee (PRAC) issued interim recommendations on the restrictions for 
prescriptions of tofacitinib.  These interim recommendations on the restrictions for 
prescriptions of tofacitinib state that patients who are at high risk of blood clots in the lungs 
must not be started on tofacitinib 10 mg BID, and that such patients currently taking 
tofacitinib 10 mg BID for any condition must be switched to alternative treatments.  Updated 
guidance from PRAC will be provided to patients and their healthcare professionals in the 
European Union (EU) once PRAC has completed its review of all available data. 
In light of the PRAC interim recommendations in the EU, Study A3921288 will be modified
globally through protocol Amendment 2, which will involve the following updates:
1. The study investigator or designee will need to review each subject’s medical history 
and study records, including their concomitant medications, to determine whether 
he/she is at high risk for developing pulmonary embolism.  If he/she has any of the 
risk factors listed below, the subject’s tofacitinib dose should be adjusted to 
open-label 5 mg BID (see Section 5.11).  
A subject may be at high risk for pulmonary embolism if he/she:

has heart failure;

has inherited coagulation disorders;

has had venous thromboembolism, either deep venous thrombosis or pulmonary 
embolism;

is taking combined hormonal contraceptives or hormone replacement therapy;

has malignancy (association is strongest with cancers other than non-melanoma 
skin cancers);

is undergoing major surgery.


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1. If a subject is identified as meeting any of the above criteria, the subject’s tofacitinib 
dose will be adjusted to open-label 5 mg BID.  The subject’s initial treatment 
assignment at baseline (5 mg BID or 10 mg BID) will remain blinded in this process.  
The subject should return to the study site as soon as possible to receive new study 
medication (1 bottle of 5 mg tablets) and they should be instructed to take 
1 x 5 mg tablet in the AM and 1 x 5 mg tablet in the PM.
2. If a subject does not have any of the risk factors listed above, he/she will remain on
their current assigned tofacitinib dose. 
3. If a subject has any of the risk factors listed above, he/she will not be permitted to 
increase their dose of tofacitinib to 10 mg BID if he/she experiences a flare of their 
UC disease (see Section 5.11).
4. The study investigator or designee will be required to ask each subject at each study 
visit if he/she has any newly-developed risk factors for pulmonary embolism, and if 
one is identified, the subject will need to have their tofacitinib dose adjusted to 
open-label 5 mg BID if they are taking open label 10 mg BID or are receiving blinded
study medication (5 mg BID or 10 mg BID); see Section 7.3.6.  At the time of 
Amendment 2, 138 subjects have been enrolled in the study and have each completed 
various durations of participation.  Therefore, this new procedure will only be 
collected at visits applicable to each subject’s individual participation.
Amendment 3
Per Amendment 3, in addition to the risk factors already listed above under Amendment 2 for 
pulmonary embolism, all subjects in the study will be evaluated for risk factors for venous 
thromboembolism.5
Two additional risk factors for venous thromboembolism to be added to the list of pulmonary 
embolism risk factors above include:

Prior myocardial infarction within the past 3 months; and

Being immobilized.
If a subject has one or more of the risk factors for venous thromboembolism listed above
under Amendment 2 and 3, the subject’s tofacitinib dose will be adjusted to open-label 5 mg 
BID.  The subject’s initial treatment assignment at baseline (5 mg BID or 10 mg BID) will 
remain blinded in this process.  
For subjects who do not have any of the risk factors for venous thromboembolism listed 
above under Amendment 2 and 3, he/she will remain on their assigned tofacitinib dose.
If a subject has any of the risk factors for venous thromboembolism listed above, he/she will 
not be permitted to increase their dose of tofacitinib to 10 mg BID if he/she experiences a 
flare of their UC disease (see Section 5.11).


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Lastly, additional risk factors for venous thromboembolism, such as age, diabetes, obesity 
(BMI>30), smoking status, hypertension and first degree family history of venous 
thromboembolism should also be taken into consideration by the investigator and the 
Sponsor medical monitor when evaluating the benefit:risk for each individual subject 
whether to modify their dose of tofacitinib.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Subjects currently enrolled in Study A3921139 who have received tofacitinib 
10 mg BID for a minimum of 2 consecutive years in Study A3921139 prior to and 
including baseline of Study A3921288.
2. Subjects who are in stable remission on tofacitinib 10 mg BID for the 6 month period 
in Study A3921139 up to and including baseline of Study A3921288, defined as 
meeting all of the following criteria:
a.
A partial Mayo score 2, with no individual subscore >1 and a rectal bleeding 
subscore of 0 at each study visit where data is available during the 6 month period 
in Study A3921139 prior to and including baseline of Study A3921288;
b. AND at least one assessment of remission based on Mayo score;

If an endoscopy was not completed 6 months prior to baseline of 
Study A3921288, then an endoscopy performed in Study A3921139 with an 
endoscopic subscore of 0 or 1, will be required prior to randomization into 
Study A3921288. 

All available assessments based on Mayo score during this period must show
remission.
c.
AND subjects must not be receiving any corticosteroid therapy for their UC for at 
least 4-weeks prior to baseline.


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3. Female subjects of childbearing potential must agree to use a highly effective method 
of contraception throughout the study and for at least 28 days after the last dose of 
assigned treatment.  Subjects in Canada who are women of childbearing potential and 
sexually active must use two contraceptive methods at the same time: one highly
effective contraceptive method and one additional effective contraceptive method
(see Section 4.4.4).
4. Female subjects of childbearing potential must have a negative urine pregnancy test 
prior to randomization.
5. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, bowel movement diary calls, and other study procedures.
6. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Subjects who were initially assigned to tofacitinib 10 mg BID at baseline of 
Study A3921139 whose tofacitinib dose was reduced to 5 mg BID due to safety or 
efficacy.
2. Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious 
colitis, or clinical findings suggestive of Crohn’s disease.
3. Subjects who in the opinion of the investigator are likely to require surgery for UC 
during the study period.
4. Subjects who are expected to receive any prohibited medications, including 
medications that are either moderate to potent CYP3A inducers or inhibitors, during 
the study period as specified in the protocol (see Appendix 3). 
5. Subjects who are expected to receive live or attenuated virus vaccination during study 
period and for 6 weeks after last dose of investigational product.
6. Women who are pregnant or breastfeeding, or planning to become pregnant during 
the study period.
7. Subjects with evidence of colonic malignancy or any dysplasia (eg, “flat dysplasia”; 
polyp) identified on endoscopic exam during Study A3921139.  Subjects with 
completely resected adenomatous polyp(s) outside of (proximal to) the extent of 
colitis may be eligible upon consultation with the sponsor.  Note, pathology report 
must be reviewed prior to subject enrolment.


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8. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
9. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
10. Subjects who, in the opinion of the investigator or Pfizer, will be uncooperative or 
unable to comply with study procedures.
11. Participation in other studies, excluding study A3921139, involving investigational 
drug(s) during study participation.
12. Subjects with any of the following risk factors for pulmonary embolism at baseline as 
defined by EMA’s PRAC (per Amendment 2 only):

has heart failure;

has inherited coagulation disorders;

has had venous thromboembolism, either deep venous thrombosis or pulmonary 
embolism;

is taking combined hormonal contraceptives or hormone replacement therapy;

has malignancy (association is strongest with cancers other than non-melanoma 
skin cancers);

is undergoing major surgery.
4.3. Randomization Criteria
Eligible subjects will be randomized in a 1:1 allocation ratio to receive either tofacitinib 
5 mg BID or 10 mg BID at baseline of Study A3921288.  Subjects will be stratified at 
baseline based on the endoscopic subscore (0 versus 1) of their most recent endoscopy. 
4.4. Lifestyle Requirements
4.4.1. Tobacco
Smoking can have an influence on the severity of UC symptoms.  For that reason, subjects 
should discuss with the study investigator if they wish to make changes to their smoking 
habits during the study.  Use of nicotine patch should be recorded as a concomitant 
medication.


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4.4.2. Diet and Dietary Supplements
Subjects are encouraged to keep their diet habits constant throughout the study.  It is 
recommended that subjects avoid consumption of grapefruit juice exceeding 8 ounces 
(~240 mL) total in a day while in the study. 
For the purposes of this protocol, dietary supplements, such as vitamins, minerals, purified 
food substances, and herbals with pharmaceutical properties are considered as concomitant 
medications.  Dietary supplements and herbs are allowed in the study, provided they are 
taken at stable doses prior to the baseline visit if they are started prior to study entry, and not 
associated with known effects on CYP3A that may impact on metabolism of the 
investigational product.  Starting dietary supplements or herbs during the study as a new 
medication is permissible as long as they are not listed on the prohibited medication list (see 
Appendix 3).
4.4.3. Vaccination
Vaccination with live components is prohibited during the study and for 6 weeks after last 
dose of investigational product.  Similarly, current routine household contact with individuals 
who have been vaccinated with live vaccine components should be avoided during treatment 
and for 6 weeks following completion of study treatment.  Following vaccination with live 
component vaccines, the virus may be shed in bodily fluids, including stool, and there is a 
potential risk that the virus may be transmitted.
Some examples of live or attenuated vaccines include but are not limited to: FluMist
(intranasal influenza vaccine), attenuated rotavirus vaccine, varicella vaccine, attenuated
typhoid fever vaccine, oral polio vaccine, and Zostavax(zoster vaccine).
4.4.4. Contraception
Based on preclinical data, tofacitinib has a potential risk of teratogenicity and early fetal loss.  
Due to this potential risk, female subjects of childbearing potential should not be 
administered tofacitinib until pregnancy is excluded.
Female subjects of nonchildbearing potential must meet at least 1 of the following criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) 
level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c.
Have medically confirmed ovarian failure. 
All other female subjects (including female subjects with tubal ligations) are considered to be 
of childbearing potential.


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All female subjects who are of childbearing potential as applicable to the study who are, in 
the opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) 
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 or her designee, in consultation with the 
subject, will confirm that the subject has selected an appropriate method of contraception for 
the individual subject from the permitted list of contraception methods (see below) and will 
confirm that the subject has been instructed in its consistent and correct use.  At time points 
indicated in the Schedule of Activities, the investigator or designee will inform the subject of 
the need to use highly effective contraception consistently and correctly and document the
conversation and the subject’s affirmation in the subject’s chart (subjects needs to affirm 
their consistent and correct use of at least 1 of the selected methods of contraception).  In 
addition, the investigator or designee will instruct the subject to call immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected in the
subject or the partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal) provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository). For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.  Note: This option is not appropriate or accepted in the European 
Union (EU); an alternate form of contraception must be selected.
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).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
Subjects in Canada who are females of childbearing potential and sexually active must use 
two contraceptive methods at the same time: one highly effective contraceptive method and 
one additional effective contraceptive method as described below.


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Highly effective contraceptive methods may include hormonal contraceptives (eg, combined 
oral contraceptives, patch, vaginal ring, injectables, and implants), intrauterine device (IUD) 
or intrauterine system (IUS), vasectomy or tubal ligation.
Effective methods may include barrier methods of contraception (eg, male condom, female 
condom, cervical cap, diaphragm or contraceptive sponge).  The proper use of diaphragm or 
cervical cap includes use of spermicide and is considered one barrier method.  The cervical 
cap and contraceptive sponge are less effective in parous women.  The use of spermicide 
alone is not considered a suitable barrier method for contraception.
4.4.5. Reproductive Status of Male Subjects
No tofacitinib effects on male fertility or offspring of dosed males have been observed in any 
preclinical studies conducted to date.  Therefore, no specific contraceptive measures are 
required in male subjects during study participation.
4.4.6. Surgery
During the course of this study, no elective surgery should be scheduled without first 
consulting with the Pfizer medical monitor.  Investigators should contact the Pfizer medical 
monitor regarding subjects who undergo non-elective surgery to discuss their suitability to 
remain in the study. 
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study portal.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Council for Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 


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packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational product is tofacitinib.
Subjects will be randomized to one of two dosing groups at baseline of Study A3921288:

Tofacitinib 5 mg BID.

Tofacitinib 10 mg BID.
Subjects who meet the protocol definition for flare may have a dose increase to 10 mg BID 
or remain on 10 mg BID, depending on their initial treatment assignment (see Section 5.11), 
provided that the subject does not have any of the risk factors for venous thromboembolism
(see Section 7.3.6).
5.1. Allocation to Treatment
Allocation of subjects to treatment groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR]). The site 
personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the subject number. The site personnel will then be provided with a 
treatment assignment, randomization number, and container number(s) when investigational 
product is being supplied via the IRT system.  The IRT system will provide a confirmation 
report containing the subject number, randomization number, and container number(s)
assigned.  The confirmation report must be stored in the site’s files. 
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
5.2. Breaking the Blind
The study will be subject and investigator blinded to the initial treatment assignment at 
baseline.
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process.  Blinding codes should be 
broken only in exceptional circumstances when knowledge of the actual treatment code is 
absolutely essential for further management of the subject. If an investigator believes that 
immediate unblinding is necessary and time and circumstances allows, he/she is encouraged 
to discuss with a member of the study team. However, discussion with a member of the 
study team in advance of the unblinding is not required. When the blinding code is broken, 
the reason must be fully documented and entered on the case report form (CRF).


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5.3. Subject Compliance
Investigational product compliance will be assessed by the site at each study visit starting at 
the visit after the baseline visit (Month 1) up to the end of treatment.  Non-compliance is 
defined as taking less than 80% or more than 120% of study drug products as directed by the 
dosing instructions.  Subjects are to bring the study drug bottle(s) with any remaining study 
drug and any empty bottle(s) to each visit for review.  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 investigational products 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. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Blinded tofacitinib and its matched placebo will be provided as tablets for oral 
administration.  The 5-mg tablets and their matching placebos will be supplied in separate 
bottles and labeled according to local regulatory requirements.
5.4.2. Preparation and Dispensing
The investigational product will be dispensed using an IRT drug management system at each 
visit according to the Schedule of Activities. A qualified staff member will dispense the 
investigational product via unique container numbers in the bottles provided, in quantities 
appropriate for the study visit schedule. The subject/caregiver should be instructed to 
maintain the product in the bottles provided throughout the course of dosing and return the 
bottles to the site at the next study visit. 
5.5. Administration
Subjects receiving blinded study medication will be dispensed two (2) bottles at each 
dispensing visit and given clear dosing instructions.  Subjects should be instructed to take 
one (1) tablet from each bottle in the morning and one (1) tablet from each bottle in the 
evening, approximately 12 hours apart.  Subjects receiving blinded study medication will 
therefore be taking two (2) tablets twice a day, regardless of which blinded treatment arm 
they are randomized to receive.  
If a subject has their tofacitinib dose adjusted to open-label 5 mg BID due to having any of 
the risk factors for venous thromboembolism, they will be dispensed only one (1) bottle of 
5 mg tablets and should be instructed to take one (1) tablet from the bottle in the morning and 
one (1) tablet in the evening, approximately 12 hours apart.  Therefore, subjects will only be 
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If a tofacitinib dose is missed and the interval to the next scheduled dose is less than 6 hours, 
the missed dose of tofacitinib should not be administered.  Tofacitinib may be taken with or 
without food.  Subjects will swallow the investigational product whole and will not 
manipulate or chew the investigational product prior to swallowing.
Table 1.
Investigational Product Administration
Treatment Assignment
AM Dosing*
PM Dosing*
5 mg BID (blinded)
Bottle A 5 mg - 1 tablet
Bottle B Placebo – 1 tablet
Bottle A 5 mg - 1 tablet 
Bottle B Placebo – 1 tablet
10 mg BID (blinded or open-label)
Bottle A 5 mg - 1 tablet
Bottle B 5 mg - 1 tablet
Bottle A 5 mg - 1 tablet
Bottle B 5 mg - 1 tablet
5 mg BID (open-label)
Bottle A 5 mg - 1 tablet
Bottle A 5 mg - 1 tablet
* Bottle A and B designations are used for example purposes only.
5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 


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Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product. It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct subjects on the proper storage requirements for take home
investigational products. 
5.7. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be
accounted for using a drug accountability form/record.  All bottles of study drug must be 
returned to the investigator by the subject at every visit to assess accountability and at the end 
of the trial.
5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
For all bottles returned to the investigator by the subject, the investigator will maintain the 
returned supply until destruction is authorized. Pfizer will provide instructions as to the 
disposition of any unused investigational product.
5.8. Concomitant Medication(s)
All subjects will be questioned about concomitant medication use at each study visit.  In
addition, the following concomitant medications that the subject had been taking from Study 
A3921139 and will continue to take in this study will be recorded: 


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Table 2.
Concomitant Medications
Treatment Type
Information Recorded
Recording Period
Ulcerative colitis (UC) 
Daily dose, unit, frequency, route, 
start and stop dates
Treatment period
Follow-up period 
Lipid lowering agents
Daily dose, unit, frequency, route, 
start and stop dates
Treatment period
Follow-up period
Anti-hypertension agents
Start and stop dates 
Treatment period
Follow-up period
Anti-diabetic agents
Start and stop dates
Treatment period
Follow-up period
All other medications*
Indication, start and stop dates
Treatment period
Follow-up period
* Includes nonprescription drugs, vitamins, and dietary supplements.
The following therapies for the treatment of UC are allowed: 

Oral 5-aminosalicylic acid (5-ASA) or sulfasalazine.
Subjects receiving either concomitant combined hormonal contraceptives or hormone 
replacement therapy must have their tofacitinib dose adjusted to open-label 5 mg BID.
5.9. Prohibited Concomitant Medications
The following medications are prohibited throughout the study (see Appendix 3): 

Azathioprine, 6-mercaptopurine and methotrexate;

Cyclosporine, mycophenolate mofetil/mycophenolic acid and tacrolimus;

Interferon;

Anti-TNF alpha therapy (eg, infliximab, adalimumab, golimumab, or certolizumab);

Corticosteroids for the treatment of UC: oral, intravenous, or rectally administered;

Rectally administered 5-ASA; 

Natalizumab, vedolizumab, or any other anti-adhesion molecule therapy (including 
investigational agents);

Other investigational or marketed immunosuppressants or biologics with 
immunomodulatory properties;

Leukocyte apheresis including selective lymphocyte, monocyte or granulocyte 
apheresis (eg, Cellsorba) or plasma exchange;

Moderate to potent CYP3A inducers or inhibitors listed in Appendix 3 due to 
potential for drug interactions or confounding of data interpretation.


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5.10. Rescue Medication
If a subject requires initiation of a new therapy or re-initiation of a therapy for UC, other than 
oral 5-ASA or sulfasalazine, the subject should be withdrawn from the study and appropriate 
agents should be given at the discretion of the investigator. 
5.11. Tofacitinib Dose Adjustment Guidelines
Per Amendment 2, all subjects will be reviewed for risk factors for pulmonary embolism as 
detailed in Section 3 under Amendment 2. Per Amendment 3, all subjects will be reviewed 
for risk factors for venous thromboembolism as detailed in Section 3 under Amendment 3.  
Subjects who are identified to have one or more of the risk factors for venous 
thromboembolism (or risk factors for pulmonary embolism per Amendment 2) will need to 
have their tofacitinib dose adjusted to open-label 5 mg BID.
If during the course of the study, a subject experiences an increase in clinical symptoms, such 
as an increase in rectal bleeding or an increase in stool frequency, then an endoscopy should 
be performed to assess if the subject is experiencing flare.  Flare must be confirmed prior to 
performing any dose adjustments.
In addition, subjects who experience atypical symptoms or features of their usual UC disease 
course or have significantly worsening disease activity assessments from the previous visit, 
or have the presence of risk factors such as recent antibiotic use or a recent history of
C. difficile infection should have Clostridium difficile (C. difficile) toxin testing performed 
before assessing for flare and performing any dose adjustments.  In addition, subjects should 
be tested for C. difficile toxin prior to being discontinued due to worsening UC, if possible.  
If confirmed positive, a full course of C. difficile treatment, as defined by local practice, must 
be given to subjects with C. difficile infection to permit their continued participation in the 
study.  Subjects may continue to receive tofacitinib while undergoing treatment for 
C. difficile infection.  Subjects with C. difficile infection that meets serious infection criteria 
must be withdrawn from the study.  Additional stool testing and treatment for other enteric
pathogens is at the discretion of the investigator.
Flare is defined by meeting one of the following 4 criteria:
1. An increase in rectal bleeding subscore by at least 1 point and an increase in 
endoscopic subscore by at least 1 point; OR
2. An increase in rectal bleeding subscore by at least 2 points and an endoscopic 
subscore >0; OR
3. An increase in stool frequency subscore by at least 2 points and an increase in the 
endoscopic subscore by at least 1 point; OR
4. An increase in endoscopic subscore by at least 2 points.


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Once the subject is confirmed to meet the definition for flare, documented by site read 
endoscopy, the investigator may adjust the dose through the IRT system provided that the 
subject does not have any of the risk factors for venous thromboembolism (see 
Section 7.3.6).  Once confirmed by the investigator, subjects may have a dose increase to 
10 mg BID or remain on 10 mg BID, depending on their initial treatment assignment.  Dose 
adjustments for confirmed flare will not be permitted prior to the Month 1 study visit.
Subjects who develop one or more of the risk factors for venous thromboembolism during 
the study will not be permitted to increase their tofacitinib dose to 10 mg BID should they 
experience a flare of their UC. 
5.12. Tofacitinib Temporary Withholding
If the investigator deems it necessary to withhold tofacitinib to treat a non-serious infection 
or other medical condition, temporary withholding is permitted for up to 10 days.  If study 
drug interruption exceeding 10 days is required for a medical reason, the investigator should 
speak with the Pfizer medical monitor to determine the suitability of the subject to withhold
treatment for a longer duration and to discuss the suitability of the subject remaining in the 
trial.
Per Amendment 3, for subjects with suspected venous thromboembolism, treatment with 
tofacitinib should be temporarily withheld while the subject is evaluated.  If venous
thromboembolism is confirmed, discontinue treatment with tofacitinib and withdraw the 
subject from the study.
6. STUDY PROCEDURES
Refer to Appendix 9 for permitted alternative measures for certain study procedures in 
response to the ongoing global COVID-19 pandemic.
6.1. Screening
There will be no protocol specified screening period as part of Study A3921288.  Screening 
will occur as part of Study A3921139 and eligibility will be assessed prior to enrolling into 
Study A3921288.
6.2. Study Period
6.2.1. Baseline (Visit 1)
The baseline visit of Study A3921288 is the same visit as the last visit in Study A3921139.  
All procedures done at the last visit in A3921139 for subjects enrolled into Study A3921288 
will be used as the baseline data for Study A3921288.
The study investigator or appropriate delegate at the site will discuss with each subject the 
nature of the study, its requirements, risks and its restrictions.  Written informed consent
must be obtained prior to performing any protocol-specific procedures.


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The following procedures will be performed:

Obtain informed consent.

Review medical history and concomitant medications.  Medical history from 
Study A3921139 will be used as baseline for Study A3921288.  Resolved AEs 
occurring in Study A3921139 will be captured as part of Baseline Medical History, 
while ongoing AEs from Study A3921139 will be followed throughout 
Study A3921288.  Ongoing concomitant medications from Study A3921139 will be 
recorded in Study A3921288.

Demography, including birth date, sex/gender, ethnicity and race will be collected at 
the Baseline/Day 1 visit and provided in the case report form as allowed by local 
regulations.

Collect stool sample for fecal calprotectin. If a sample cannot be collected at the visit, 
provide subject with stool collection kit to obtain stool sample at home. Subjects 
should be instructed to make all efforts to collect the baseline sample as soon as 
possible, but no later than 7 days of the baseline visit.  The stool sample should be
returned within 24 hours of collection.

Provide subject with stool sample collection kit to obtain stool sample at home to be 
returned for the Month 1 study visit.

Risk factor check for pulmonary embolism, per Amendment 2.

Confirmation of all inclusion/exclusion criteria.

Randomization.

Investigational product dispensing.

Subjects will be reminded of instructions for using the phone based bowel movement 
(BM) diary.  Subjects should start completing the BM diary daily approximately 
7 days prior to their next scheduled visit.  Study site staff should contact the subjects
7 days prior to the scheduled visit to ensure compliance.  In addition, subjects should 
be instructed to start completing the BM diary whenever he/she experiences any 
worsening of UC symptoms anytime during the study.

Contraception check for females of childbearing potential.

Adverse event monitoring.


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The following study procedures listed as open-label extension (OLE) in the Schedule of
Activities will be performed at the final visit of Study A3921139 and will not be 
repeated at baseline of Study A3921288:

Endoscopic procedure.

Flexible sigmoidoscopy/colonoscopy (if preferred).  Endoscopy will only be 
performed in subjects who do not have an endoscopy performed within the 
6 month period prior to baseline of Study A3921288.  Endoscopic assessment will 
only be done by local site read.

UC assessments.

Mayo score.

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum Chemistry.

hs-CRP.

Lipid profile, fasting.

Urine beta human chorionic gonadotropin (–hCG) to be performed only for 
females of childbearing potential.
6.2.2. Month 1 (7 days, Visit 2)
The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum chemistry.

hs-CRP.


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
Urine –hCG to be performed only for females of childbearing potential.

Collect stool sample or fecal calprotectin.

Provide subject with stool sample collection kit to obtain stool sample at home to 
be returned for the Month 3 study visit.

UC assessments: review of BM diary and calculate partial Mayo score.

Investigational product accountability.

Contraception check for females of childbearing potential.

Adverse event monitoring.

Concomitant medication review.

Risk factor check for pulmonary embolism, per Amendment 2.
6.2.3. Month 3 (7 days, Visit 3)
The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum chemistry.

hs-CRP.

Urine –hCG to be performed only for females of childbearing potential.

Collect stool sample for fecal calprotectin.

Provide subject with stool sample collection kit to obtain stool sample at home to 
be returned for the Month 6 study visit.  Subjects should be instructed to collect 
the sample prior to the subject initiating the bowel preparation for 
endoscopy.

UC assessments: review of BM diary and calculate partial Mayo score.

Investigational product accountability.


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
Contraception check for females of childbearing potential.

Adverse event monitoring.

Concomitant medication review.

Investigational product dispensing.

Risk factor check for pulmonary embolism, per Amendment 2.
6.2.4. Month 6 (7 days, Visit 4)
Subjects are required to fast (no food or drink except water) for at least 9 hours prior to this 
visit, as required for fasting lipid profile and fasting glucose sample collection.
The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum chemistry.

hs-CRP.

Lipid profile, fasting.

Urine –hCG to be performed only for females of childbearing potential.

Collect stool sample for fecal calprotectin.

Provide subject with stool sample collection kit to obtain stool sample at home to 
be returned for the Month 9 study visit.

Endoscopy: flexible sigmoidoscopy/colonoscopy (if preferred).  Endoscopic 
assessment will only be done by local site read.

UC assessments: review of BM diary and calculate Mayo score.

Investigational product accountability.

Contraception check for females of childbearing potential.

Adverse event monitoring.


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
Concomitant medication review.

Investigational product dispensing.

Risk factor check for pulmonary embolism, per Amendment 2.
6.2.5. Month 9 (7 days, Visit 5)
The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum chemistry.

hs-CRP.

Urine –hCG to be performed only for females of childbearing potential.

Collect stool sample for fecal calprotectin.

Provide subject with stool sample collection kit to obtain stool sample at home to 
be returned for the Month 12 study visit.

UC assessments: review of BM diary and calculate partial Mayo score.

Investigational product accountability.

Contraception check for females of childbearing potential.

Adverse event monitoring.

Concomitant medication review.

Investigational product dispensing.

Risk factor check for venous thromboembolism.
6.2.6. Month 12 (7 days, Visit 6)
Subjects are required to fast (no food or drink except water) for at least 9 hours prior to this 
visit, as required for fasting lipid profile and fasting glucose sample collection.


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The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum chemistry.

hs-CRP.

Lipid profile, fasting.

Urine –hCG to be performed only for females of childbearing potential.

Collect stool sample for fecal calprotectin.

Provide subject with stool sample collection kit to obtain stool sample at home to 
be returned for the Month 15 study visit.

Tuberculosis (TB) testing using Quantiferon-TBGold Plus test (QFT) for 
subjects in specific countries (see Section 7.3.3.2).  All subjects with a positive 
result must have a chest radiograph performed.

UC assessments: review of BM diary and calculate partial Mayo score.

Investigational product accountability.

Contraception check for females of childbearing potential.

Adverse event monitoring.

Concomitant medication review.

Investigational product dispensing.

Risk factor check for venous thromboembolism.
6.2.7. Month 15 (7 days, Visit 7)
The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.


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
Laboratory:

Hematology.

Serum chemistry.

hs-CRP.

Urine –hCG to be performed only for females of childbearing potential.

Collect stool sample for fecal calprotectin.

Provide subject with stool sample collection kit to obtain stool sample at home to 
be returned for the Month 18 study visit.  Subjects should be instructed to collect 
the sample prior to the subject initiating the bowel preparation for endoscopy.

UC assessments: review of BM diary and calculate partial Mayo score.

Investigational product accountability.

Contraception check for females of childbearing potential.

Adverse event monitoring.

Concomitant medication review.

Investigational product dispensing.

Risk factor check for venous thromboembolism.
6.2.8. Month 18 (7 days, Visit 8) Visit
Subjects are required to fast (no food or drink except water) for at least 9 hours prior to this 
visit, as required for fasting lipid profile and fasting glucose sample collection.  
The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum chemistry.

hs-CRP.


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
Lipid profile, fasting.

Urine –hCG to be performed only for females of childbearing potential.

Collect stool sample for fecal calprotectin.

Provide subject with stool sample collection kit to obtain stool sample at home to 
be returned for the Month 21 study visit.

Endoscopy: flexible sigmoidoscopy/colonoscopy (if preferred).  Endoscopic 
assessment will only be done by local site read.

UC assessments: review of BM diary and calculate Mayo score.

Investigational product accountability.

Contraception check for females of childbearing potential.

Adverse event monitoring.

Concomitant medication review.

Investigational product dispensing.

Risk factor check for venous thromboembolism.
6.2.9. Months 21 and 33 (7 days, Visits 9 and 13)
The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum chemistry.

hs-CRP.

Urine –hCG to be performed only for females of childbearing potential.

Collect stool sample for fecal calprotectin.

Provide subject with stool sample collection kit to obtain stool sample at home to 
be returned for the Months 24 and 36 study visits.  


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
UC assessments: review of BM diary and calculate partial Mayo score.

Investigational product accountability.

Contraception check for females of childbearing potential.

Adverse event monitoring.

Concomitant medication review.

Investigational product dispensing.

Risk factor check for venous thromboembolism.
6.2.10. Months 24 and 36 (7 days, Visits 10 and 14)
Subjects are required to fast (no food or drink except water) for at least 9 hours prior to these
visits, as required for fasting lipid profile and fasting glucose sample collection.
The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum chemistry.

hs-CRP.

Lipid profile, fasting.

Urine –hCG to be performed only for females of childbearing potential.

Collect stool sample for fecal calprotectin.

Provide subject with stool sample collection kit to obtain stool sample at home to 
be returned for the Months 27 and 39 study visits.

Tuberculosis (TB) testing using Quantiferon-TBGold Plus test (QFT) for
subjects in specific countries (see Section 7.3.3.2).  All subjects with a positive 
result must have a chest radiograph performed.

UC assessments: review of BM diary and calculate partial Mayo score.


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
Investigational product accountability.

Contraception check for females of childbearing potential.

Adverse event monitoring.

Concomitant medication review.

Investigational product dispensing.

Risk factor check for venous thromboembolism.
6.2.11. Months 27 and 39 (7 days, Visits 11 and 15)
The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum chemistry.

hs-CRP.

Urine –hCG to be performed only for females of childbearing potential.

Collect stool sample for fecal calprotectin.

Provide subject with stool sample collection kit to obtain stool sample at home to 
be returned for the Months 30 and 42 study visits.  Subjects should be instructed
to collect the sample prior to the subject initiating the bowel preparation for
endoscopy.

UC assessments: review of BM diary and calculate partial Mayo score.

Investigational product accountability.

Contraception check for females of childbearing potential.

Adverse event monitoring.

Concomitant medication review.

Investigational product dispensing.


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
Risk factor check for venous thromboembolism.
6.2.12. Months 30 and 42 (7 days, Visits 12 and 16) or Early Termination (ET) Visit
Subjects are required to fast (no food or drink except water) for at least 9 hours prior to these
visits, as required for fasting lipid profile and fasting glucose sample collection.  Subjects 
who discontinue treatment early from the study will have an early termination (ET) visit 
performed on the last day the subject takes the investigational product or as soon as possible 
thereafter.
The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum chemistry.

hs-CRP.

Lipid profile, fasting.

Urine –hCG to be performed only for females of childbearing potential.

Collect stool sample for fecal calprotectin.

Provide subject with stool sample collection kit to obtain stool sample at home to 
be returned for the Month 33 study visit (Month 30 only).

Endoscopy: flexible sigmoidoscopy/colonoscopy (if preferred).  Endoscopic 
assessment will only be done by local site read.

UC assessments: review of BM diary and calculate Mayo score.

Investigational product accountability.

Contraception check for females of childbearing potential.

Adverse event monitoring.

Concomitant medication review.

Investigational product dispensing (Month 30 only).


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
Risk factor check for venous thromboembolism.
6.3. Follow-up Visit (4 weeks after last dose 7 days, Visit 17)
This follow-up visit is to occur 4 weeks (7 days) after the last dose of investigational 
product administration.
The following procedures will be performed:

Targeted physical examination.

Vital signs, including temperature.

Laboratory:

Hematology.

Serum chemistry.

Lipid profile, fasting.

Urine –hCG to be performed only for females of childbearing potential.

Contraception check for females of childbearing potential.

Adverse event monitoring.

Concomitant medication review.
6.4. Subject Withdrawal
Should a subject withdraw from active treatment, the subject should complete the procedures 
listed at the Month 42/ET Visit.  After completing the procedures for the ET visit, the subject 
should return for a safety evaluation to occur approximately 4 weeks after discontinuing 
investigational product as per the follow-up visit (see Section 6.2.9).
Subjects will be withdrawn from the study if any of the following occurs during the study 
treatment period:

If rescue therapy is initiated or re-initiated for UC with the exception of oral 5-ASA 
or sulfasalazine. 

If a subject undergoes surgery for UC.
A subject may be withdrawn from the study for any of the safety concerns as listed in 
Appendix 4.


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If venous thromboembolism is confirmed, discontinue treatment with tofacitinib and 
withdraw the subject from the study (Appendix 4).
Subjects who develop a serious infection during the study, defined as any infection (viral, 
bacterial, and fungal) requiring hospitalization or parenteral antimicrobials or being classified 
as a serious adverse event should be withdrawn from the study (see Section 7.3.4).
All abnormal laboratory events of clinical significance should be followed until the 
laboratory values have returned to normal or baseline levels (see Appendix 4).  Subjects who 
meet the discontinuation criteria described in Appendix 4 will be withdrawn from the study.
Subjects who are withdrawn from this study will not be permitted to return to 
Study A3921139.
Withdrawal of consent:
Subjects who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures. The only 
exception to this is when a subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.
Subjects should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate CRF page. In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up:
All reasonable efforts must be made to locate subjects to determine and report their ongoing
status. This includes follow-up with persons authorized by the subject as noted above. Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter. All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death. If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information. If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.


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Subjects may withdraw from the study at any time at their own request, or they may be
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return all unused investigational 
product, request that the subject 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 manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Pregnancy Testing
For female subjects of childbearing potential, a urine pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed before investigational product administration at the 
baseline visit, and at all study visits to confirm the subject has not become pregnant during 
the study.  Urine pregnancy testing will also be performed at the early termination visit if 
applicable and the end of study follow-up visit.
A negative pregnancy test result is required before the subject may receive tofacitinib.  
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected).  Pregnancy tests may 
also be repeated if requested by institutional review boards (IRBs)/ethics committees (ECs) 
or if required by local regulations. 


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Urine pregnancy tests must be sensitive to at least 25 mIU/mL and will be conducted with the 
test kit provided by the central laboratory in accordance with instructions provided in its 
package insert.  Subjects who have missed a menstrual period or who show an indeterminate
or positive result on the urine test may not further progress in the study until pregnancy is 
ruled out using further diagnostic testing (eg, a negative quantitative serum pregnancy test 
conducted at a certified laboratory).
In the case of a positive confirmed pregnancy, the subject will be withdrawn from
administration of tofacitinib and from the study.
7.2. Ulcerative Colitis Assessments
7.2.1. Subject Bowel Movement Diary
Subjects will use a phone-based interactive voice recording system (IVRS) tool to record 
their BM data throughout the study.  Subjects will be instructed in its use at the Baseline 
visit.  This information should be entered daily approximately 7 days prior to their study visit 
AND any time during the study that the subject experiences a worsening of UC symptoms.  
Daily diary entries are strongly encouraged.  Automatic reminders will be sent to the subject 
before their scheduled visit to remind them to record their BM data.  Also, as an additional 
reminder the site personnel should call the subject 7 days before their next scheduled visit to 
prompt them to complete their BM data in the phone-based tool.
The phone-based IVRS tool will be provided at baseline for subjects to record the following 
information during the study:

‘Normal’ number of stools per day will be carried forward based on the data 
previously collected at the baseline of the induction studies.

Number of toilet visits for bowel movements (per day).

Presence of blood in the stools (if any).

Description of blood in the stools (if any).
The data collected in the subject BM diary will be used to determine the stool frequency 
subscore and the rectal bleeding subscore for the Mayo score, modified Mayo score, partial 
Mayo score, and modified partial Mayo score.
7.2.2. Partial Mayo Score
A partial Mayo score (PMS) is an instrument designed to measure disease activity of UC
without endoscopy.  Partial Mayo score ranges from 0 to 9 points.  It consists of 3 subscores, 
each graded from 0 to 3 with higher scores indicating more severe disease.

stool frequency (0-3);

rectal bleeding (0-3);


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
physician global assessment (PGA) (0-3).
The partial Mayo score will be assessed at each specified study visit (see Schedule of 
Activities).
The PMS will be calculated based on the subject’s BM diary data (see Section 7.2.1)
recorded over the 3 prior consecutive days.
Endpoints based on partial Mayo score are defined below:

Remission: partial Mayo score of 2 points or lower, with no individual subscore 
exceeding 1 point and a rectal bleeding subscore of 0.
Modified partial Mayo score consists of stool frequency and rectal bleeding subscores 
(ie, PMS without PGA).
Endpoints based on modified partial Mayo score are defined below:

Remission: stool frequency subscore of 0 or 1, and a rectal bleeding subscore of 0.
7.2.3. Mayo Score
The Mayo score is an instrument designed to measure disease activity of UC.  Mayo score 
ranges from 0 to 12 points.  It consists of 4 subscores, each graded from 0 to 3 with higher 
scores indicating more severe disease (see Appendix 2).

stool frequency (0-3).

rectal bleeding (0-3).

findings of flexible sigmoidoscopy (0-3).

physician global assessment (PGA) (0-3).
Mayo score is assessed at Baseline, Month 6, Month 18, Month 30 and at Month 42/ET visits
per the Schedule of Activities.
The endoscopic findings will be locally read by study site investigator.  The Mayo score will 
be calculated based on the subject’s BM diary data (see Section 7.2.1) recorded over the 
3 prior consecutive days.
The mucosal appearance of the sigmoidoscopic portion of endoscopic examination will be 
assessed for the Mayo endoscopic subscore, based on the definition provided in the protocol 
(see Appendix 2).
The PGA acknowledges the three other criteria, the patient’s recollection of abdominal 
discomfort and general sense of wellbeing, and other observations, such as physical findings 
and the patient’s performance status.  The endoscopic subscore and the PGA should be 


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performed by a physician qualified to perform endoscopy, and it is recommended that the 
same physician performs all such assessments for a particular subject throughout the study,
when possible.
Endpoints based on total Mayo score are defined below:

Remission: total Mayo score of 2 points or lower, with no individual subscore 
exceeding 1 point and a rectal bleeding subscore of 0.

Clinical response: decrease from baseline in total Mayo score of the Induction study,
of at least 3 points and at least 30%, with an accompanying decrease in the subscore 
for rectal bleeding of at least 1 point, or absolute subscore for rectal bleeding of 
0 or 1.

Mucosal healing: an endoscopic subscore of 0 or 1.
Modified Mayo score consists of stool frequency subscore, rectal bleeding subscore and 
endoscopic subscore (ie, total Mayo score without PGA).
Endpoints based on modified Mayo score are defined below:

Remission: an endoscopic subscore of 0 or 1, stool frequency subscore of 0 or 1, and 
rectal bleeding subscore of 0.
7.3. Safety
Safety will be assessed by vital signs, physical examinations, clinical laboratory tests and the 
spontaneous reporting of AEs, in all subjects who received at least 1 dose of investigational 
product.  Unscheduled safety assessments may be performed at any time during the study to 
assess any perceived safety concerns.  Investigators and Pfizer Clinicians will review 
individual subject data throughout the conduct of the study to ensure subjects’ well-being.  
Subject safety monitoring and discontinuation guidelines are provided in Appendix 4.
7.3.1. Vital Signs
Vital signs will be performed at each specified visit according to the Schedule of Activities.  
As a guideline, blood pressure should be measured in the subject’s dominant arm and 
recorded to the nearest mmHg.  The same arm should be used throughout the study, when
possible.  All blood pressure in this study should be measured with the subject in the sitting 
position after resting for at least 5 minutes, when possible.
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 oral, axillary or tympanic temperature, but the same method 
should be used throughout the study, when possible.


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7.3.2. Physical Examinations
Targeted physical examination will be performed at each specified visit according to the
Schedule of Activities.  The following will be assessed: weight, general appearance, eyes, 
mouth, lungs, heart, abdomen, musculoskeletal, extremities, skin and lymph nodes.
Recommendations for evaluation of emergent lymphadenopathy or other findings suggestive 
of lymphoproliferative disorder are provided in Appendix 5.
7.3.3. Clinical Laboratory Tests
Blood, urine, and stool samples will be collected at each specified visit according to the
Schedule of Activities.  Unscheduled clinical labs may be obtained at any time during the 
study to assess any perceived safety concerns or in accordance with the guidelines for subject 
safety monitoring and discontinuation (see Appendix 4).  Clinically significant abnormal 
findings should be recorded as AEs per Section 8.2. 
The following laboratory tests will be performed during the study:
Table 3.
Laboratory Test Parameters
Hematology
Serum Chemistry
Others
Hemoglobin
Blood urea nitrogen
Follicle stimulating hormone 
(FSH)1
Hematocrit
Creatinine
-hCG urine pregnancy test2
Reticulocyte
Glucose (fasting)5
Lipid profile (fasting)3
Platelet count
Glucose (non-fasting)6
Total cholesterol
White blood cell (WBC) count
Calcium
   Low density lipoprotein 
cholesterol (LDL-C)4
Neutrophils (abs, %)
Sodium
    High density lipoprotein 
cholesterol (HDL-C)
Eosinophils (abs, %)
Potassium
 
Triglycerides4
Monocytes (abs, %)
Chloride
Hepatitis B virus (HBV)
DNA levels (Japan only)7
Basophils (abs, %)
Total carbon dioxide (CO2) or 
bicarbonate
hs-CRP
Lymphocytes (abs, %)
Aspartate aminotransferase (AST)
Fecal calprotectin
Red blood cell (RBC) count
Alanine aminotransferase (ALT)
QFT8
Mean corpuscular volume (MCV)
Total bilirubin
Mean corpuscular hemoglobin (MCH)
Direct bilirubin
Red cell distribution width (RDW)
Indirect bilirubin
Alkaline phosphatase
Gamma-glutamine transferase
(GGT)
Total protein
Albumin
Lactate dehydrogenase (LDH)
Uric acid
Creatine kinase (CK)/creatine 
phosphokinase (CPK)
1.
Follicle stimulating hormone (FSH) to confirm postmenopausal status at baseline visit or at subsequent study visits 
only if postmenopausal status has not been previously confirmed.


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2.
Urine testing performed with a sensitivity of at least 25 mIU/mL using test kits supplied by the central laboratory at 
baseline and at all study visits for females of childbearing potential.
3.
Fasting lipid profile will be obtained according to the Schedule of Activities.
4.
If triglycerides >400 mg/dl, LDL-C will be determined by direct measurement.
5.
Fasting glucose will be measured at study visits when fasting lipid profile is obtained according to the Schedule of 
Activities.
6.
Non-fasting glucose will be measured at all other study visits according to the Schedule of Activities.
7.
Safety monitoring for a subset of subjects in Japan only (see Appendix 4).
8.
TB testing (QFT) will be performed at Months 12, 24 and 36 only for subjects in those countries in which TB 
prevalence has been reported at a rate of >50 cases per 100,000 persons (see Section 7.3.3.2).
Abnormal test results determined to be caused from laboratory error should not be reported 
as adverse events.  Clinically significant laboratory findings at the final assessment should be 
followed to resolution or until determined by the Investigator to be stabilized.  Repeat tests 
may be indicated.
7.3.3.1. Stool Samples for Fecal Calprotectin
A stool sample for determination of fecal calprotectin will be obtained at the times specified
in the Schedule of Activities as well as when a subject experiences worsening of 
disease/flare, when possible.
Study site personnel will provide a sufficient number of stool sample collection kits and 
instructions to the subject on how best to collect a sufficient stool sample.  A sample 
collected and returned on the day of the visit is preferred, however if this is not possible, a 
sample may be collected at home and returned within 24 hours of collection.  If a sample is 
collected after the visit, the subject should make all efforts to collect the sample as soon as 
possible, but no later than 7 days of the Baseline visit, and within 2 weeks for all subsequent
study visits.
For stool samples collected for the Months 6, 18, 30 and 42 (ie, study visits when endoscopy 
will be performed) subjects should be instructed to collect the sample prior to the subject 
initiating the bowel preparation for endoscopy.
Stool samples collected during this study may be aliquoted and stored for future studies.  
Examples of future studies may include “multi-omic” analyses and/or targeted evaluations
for biomarkers of disease activity or predictive classifiers of response to treatment.
Sequencing of the DNA present in the stool may be performed to better understand disease 
activity and response to therapy.  DNA generally comes from microorganisms like bacteria, 
viruses, fungi and parasites that may be present in the stool.  During this process, some 
human DNA may be inadvertently sequenced, but will not be used for the final analysis.


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7.3.3.2. Tuberculosis Testing
Tuberculosis (TB) testing will be conducted at Months 12, 24 and 36 using Quantiferon-TB
Gold Plus test (QFT) for subjects in those countries in which TB prevalence has been 
reported at a rate of >50 cases per 100,000 persons (eg, Russia, Ukraine, South Africa, and 
South Korea, based on World Health Organization, 2015 
http://www.who.int/tb/country/data/profiles/en/index.html). All subjects with positive results 
must have a chest radiograph performed and the radiograph must be negative for active TB 
infection for the subject to continue study participation.  Subjects identified as having latent 
TB (positive QFT and negative chest radiograph for active TB) should be treated 
appropriately; for subjects remaining on study during their treatment, the only acceptable 
regimen is 9 months of isoniazid.  Subjects can continue to take tofacitinib without 
interruption while receiving treatment for latent TB.  Note: QFT should not be performed in 
subjects who had a positive result during prior testing (screening visit in Induction Study 
A3921094 or A3921095 or prior annual visits during A3921139) and/or previously received 
adequate treatment for TB.
7.3.3.3. Serum Lipids
Total cholesterol, low density lipoprotein cholesterol (LDL-C), direct high density 
lipoprotein cholesterol (HDL-C) and triglycerides will be measured during the study at 
specific study visits according to the Schedule of Activities requiring subjects to fast at least 
9 hours prior to sample collection.  See Appendix 7 for recommended clinical management 
of cholesterol.
7.3.4. Infections
Subjects will be monitored for development of infection.  If high-risk behaviour(s) or 
environmental exposures are identified, subjects may be tested to provide evidence that 
pre-specified infections (eg, HIV, HCV, HBV) are not present.  All treated infections 
occurring during the study should be cultured if feasible and the results (eg, any identified 
organisms or absence of growth) recorded in the CRF.
Treated infections will be further classified as serious or non-serious.  Serious infections are 
treated infections that:

Require parenteral antimicrobial therapy; or

Require hospitalization for treatment; or

Meet other criteria that require the infection to be classified as a serious adverse event 
(SAE).
A subject who experiences a treated serious infection should be discontinued from the study.  
A serious infection should be reported as a SAE and should be listed as the reason for 
discontinuation in the CRF.  All serious infections occurring during the study should undergo 
appropriate laboratory investigations, including culture, and the results (eg, any identified 
organisms or absence of growth) recorded in the CRF.


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Subjects who experience non-serious infections that require treatment may have their study 
drug temporarily discontinued during treatment (see Section 5.12).  Temporary 
discontinuation of study drug should be recorded in the CRF.
7.3.5. Safety Events of Interest
The identification of safety events of interest should be identified by the study site and 
communicated to Pfizer or designee.  These safety events may also be identified by the Pfizer 
Study Team or designee during the review of subject data listings or by site monitors during 
routine monitoring of subject study records.
The Pfizer Study Team or designee will provide a listing of specific documents needed to
support event adjudication by the Adjudication Committees (see Section 9.7 Safety Event 
Adjudication Committees).  Obtaining and submitting the documentation will be the 
responsibility of the study site.  Event documentation will vary with the event requiring 
adjudication and may include (but not be limited to): hospital discharge summaries, operative 
reports, clinic notes, electrocardiograms (ECGs), diagnostic tests, pathology reports, autopsy 
reports and death certificate information, as applicable.
When there is a decision to biopsy a potentially malignant tumour, lymph node, or other 
tissue, the investigator and/or consultant(s) should contact Pfizer or designee to discuss the 
issue and any decisions as soon as possible.  For all biopsies of potentially malignant 
tumours, suspicious lymphadenopathy, or possible extranodal lymphoproliferative disorder 
(LPD), the study site will 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. See Appendix 5 for the steps to take 
in the event of potentially malignant tumours, lymphadenopathy or possible extra-nodal LPD 
which might arise in the course of this study.  See Appendix 6 for the steps to take when 
gastrointestinal tract biopsies are obtained.
7.3.6. Risk Factor Check for Venous Thromboembolism
All subjects will undergo a risk factor check at each study visit to check for newly-developed
risk factors for venous thromboembolism.  This information is to be captured in the subject’s 
source file and on the relevant case report form.  
A subject may be at high risk for venous thromboembolism if he/she:

has heart failure or prior myocardial infarction within the past 3 months;

has inherited coagulation disorders;

has had venous thromboembolism, either deep venous thrombosis or pulmonary 
embolism;

is taking combined hormonal contraceptives or hormone replacement therapy;


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
has malignancy (association is strongest with cancers other than non-melanoma skin 
cancers);

is undergoing major surgery or is immobilized.
If a subject is receiving blinded tofacitinib or open-label 10 mg BID and has one or more of 
the risk factors for venous thromboembolism listed above, the subject’s tofacitinib dose 
should be adjusted to open-label 5 mg BID.  If a subject has any newly-developed risk 
factors for venous thromboembolism identified during the study, they will not be permitted to
receive tofacitinib 10 mg BID.
If a subject is receiving tofacitinib open-label 5 mg BID and has one or more of the risk 
factors for venous thromboembolism listed above, they may remain on tofacitinib open-label 
5 mg BID after careful investigator assessment of benefit:risk. However, he/she will not be 
permitted to increase their dose of tofacitinib to 10 mg BID if he/she experiences a flare of 
their UC disease (see Section 5.11).
Lastly, if a subject has any of the risk factors listed above, the subject will not be eligible to 
enroll in Study A3921288, per Amendment 2.
Additional risk factors for venous thromboembolism, such as age, diabetes, obesity 
(BMI>30), smoking status, hypertension, and first degree family history of venous 
thromboembolism should also be taken into consideration by the investigator and the 
Sponsor medical monitor when evaluating the benefit:risk for each individual subject
whether to modify their dose of tofacitinib.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 


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


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As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days; except as indicated below after the last administration of the 
investigational product.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.


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Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;


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
Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require
recording as an AE.


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8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;


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
Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.


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Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE. For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:


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
Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator
awareness.


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8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.


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Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.


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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
Although approximately 130 subjects are estimated to be enrolled into this study (based on 
availability of eligible subjects from the open label Study A3921139 and based on the 
conservative assumptions of the attrition rate of 50% - 50% in Study A3921139), the final 
sample size may exceed 130 subjects.  The Sponsor will continue to engage with 
investigative sites participating in Study A3921139 to assess the ability to enroll additional 
eligible subjects.


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With 130 (65 per group) subjects, the estimated half width of the 95% confidence for 
treatment difference between tofacitinib 10 mg BID and 5 mg BID in proportion of remission 
at Month 6 based on the modified Mayo score is about 16%, assuming the remission rates are 
greater than 70% in both groups.
At the time of Amendment 2, 138 subjects have been enrolled and approximately 
122 subjects have crossed their Month 6 study visit, the timepoint of the primary endpoint.
9.2. Efficacy Analysis
9.2.1. Analysis Population
The primary analysis population will be the Full Analysis Set (FAS) defined as all subjects 
who are randomized into the study and receive at least 1 dose of investigational product.
9.2.2. Primary Analysis
The primary endpoint is remission based on the modified Mayo score at Month 6. The 
primary analysis will be performed at Month 6 based on the FAS for the estimation of 
treatment difference between the following two dose groups:

Tofacitinib 10 mg BID Dose Group: subjects who are initially assigned to tofacitinib 
10 mg BID at randomization

Tofacitinib 5 mg BID Dose Group: subjects who are initially assigned to tofacitinib 
5 mg BID at randomization, regardless of whether the dose is escalated back to 
tofacitinib 10 mg BID or not.
The stratified estimation of the treatment difference between tofacitinib 10 mg BID and 
5 mg BID in the proportion of subjects with remission at Month 6 will be presented along 
with its 95% confidence interval (CI). The Cochran-Mantel-Haenszel (CMH) weight method 
will be used for the stratified estimation of the treatment difference.  The stratified CI will be 
constructed using the NewCombe method.  Subjects with dose escalation prior to Month 6 or 
with missing values at Month 6 will be treated as non-responders at Month 6.
Sensitivity analyses for handling with missing data will be performed. An analysis using a 
generalized linear mixed-effects model may be performed for the remission endpoint based
on data collected at Month 6, Month 12, Month 18, Month 30, and Month 42 if sufficient 
data are available at Month 42. Further details will be provided in the statistical analysis 
plan.
9.2.3. Secondary Analysis
Dose comparison between tofacitinib 5 mg BID and 10 mg BID 
For the primary objective, the treatment difference for the binary secondary efficacy 
endpoints will also be estimated based on the FAS, using the same approach as described 
above for the primary endpoint.  For continuous endpoints, the change from baseline will be 
analyzed using linear mixed-effects model with baseline value, dose group, the endoscopic 


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subscore at baseline (0 versus 1), visit, and dose group by visit interaction all as fixed effects, 
and subject as a random effect. The adjusted estimations and associated 95% CI for the 
overall difference between the two dose groups will be computed.  Kaplan-Meier estimates at 
the scheduled visits will be computed for time to event endpoint.  The log-rank test stratified 
by endoscopic subscore at baseline (0 versus 1) will also be performed for the comparison 
between dose groups. 
If a subject has a dose escalation back to tofacitinib 10 mg BID, then

For binary efficacy endpoints, the subject will be considered as a non-responder for
any visit after the dose escalation visit.

For continuous efficacy endpoints, the data collected for any visit after the dose
escalation visit will be considered as missing.

For time to loss of remission, the subject will be considered as having an event at the 
visit with a dose escalation if the event criteria are met or having a censor time at the 
visit with a dose escalation if the event criteria are not met.
For continuous endpoints that are measured repeatedly over time, the missing values will be 
handled in a linear mixed-effects model where the mechanism of missingness is assumed to 
be missing at random. 
Regimen comparison between flexible dosing and fixed dosing 
For the first secondary objective, analyses will be performed based on the FAS for 
comparisons of the following two dose regimens:

Tofacitinib fixed 10 mg BID Dose Regimen: subjects who are initially assigned to
tofacitinib 10 mg BID at randomization and stay on tofacitinib 10 mg BID until
completion or discontinuation.

Tofacitinib flexible 5 mg/10 mg BID Dose Regimen: subjects who are initially 
assigned to tofacitinib 5 mg BID at randomization, staying on tofacitinib 5 mg BID or 
having dose escalation from tofacitinib 5 mg BID to 10 mg BID.
Analysis methods are the same as the ones described above for comparison between dose 
groups except that data from subjects with dose escalation back to tofacitinib 10 mg BID will 
be treated as it is.  Only the visits with missing data will be treated as non-responders.
For the second secondary objective, summary descriptive statistics will be reported for the 
sub-group of subjects who are initially assigned to tofacitinib 5 mg BID and later are
retreated with tofacitinib 10 mg BID.  Missing data will not be imputed.


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9.3. Analysis of Biomarker Endpoints
Fecal calprotectin and hs-CRP data and change from baseline will be summarized 
descriptively by dose group and by dose regimen.  Fecal calprotectin and hs-CRP data will 
also be log-transformed (natural logarithm) for the analyses.  The change from baseline will
be analyzed using a linear mixed effects model with baseline value, dose group, the 
endoscopic subscore at baseline (0 versus 1), visit, and dose group by visit interaction all as
fixed effects, and subject as a random effect.
9.4. Safety Analysis
The safety data will be summarized in accordance with Pfizer Data Standards based on the 
safety analysis set defined as all subjects who receive at least 1 dose of investigational 
product.
Summaries will be performed by dose group and dose regimen as defined in the efficacy 
sub-section.
9.5. Interim Analysis
No interim analysis is planned for this study.  The primary analysis will be performed to 
assess efficacy and safety when all subjects enrolled complete their Month 6 study visit (or 
drop out before Month 6 visit) and data are cleaned and locked.  However, the final analyses 
for secondary objectives will be performed after all subjects complete the study. Initial 
treatment assignment at baseline of the study will remain double-blinded to the site and 
subject.
9.6. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC). 
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.
9.7. Safety Event Adjudication Committees
To help assess specific safety events in this and other studies for the tofacitinib program,
adjudication committees have been established to harmonize and standardize selected safety 
event assessment.  Members of these safety event adjudication committees will be blinded to 
treatment assignment in order to allow for unbiased assessments.  These committees include 
a Cardiovascular Endpoint Adjudication Committee (CV EAC), Malignancy Adjudication 
Committee (MAC), Opportunistic Infection Review Committee (OIRC), Hepatic Event 
Review Committee (HERC) and Gastrointestinal Perforation Review Committee (GIPRC).  
Further information about these committees can be found in the respective charters, including 
specific descriptions of the scope of their responsibilities, and the processes and definitions 
used to review and assess specific safety events.


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In addition to the event adjudication or review committees described above, all biopsies of 
potentially malignant tumors, suspicious lymphadenopathy, or possible extranodal 
lymphoproliferative disorder, and all bowel biopsies containing dysplasia or malignancy, 
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.
In addition to these external committees, an internal committee of medically qualified Pfizer 
personnel with expertise in the assessment and diagnosis of respiratory disease will review 
and categorize potential events of interstitial lung disease (Interstitial Lung Disease Review 
Committee, ILDRC).
Additional safety event adjudication or review committees may be established to harmonize 
and standardize selected safety event assessments.  As described above, individual committee 
charters will provide specific descriptions of the scope of responsibilities and the processes 
and definitions used to review and assess specific safety events.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection. The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent. Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
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.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another
investigator, another institution, or an independent third party arranged by Pfizer. 
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.


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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The investigator
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.


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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.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as Last Subject Last Visit (LSLV) 
which is the last follow up visit 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, or investigational product 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, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 1 week.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.


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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 (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements. EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of
the PCD for studies in pediatric populations.
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 supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected
inventions, the investigator will provide Pfizer an opportunity to review any proposed 


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publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed. If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication. However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
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 
2010; 7:41.
3.
Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol 
2007; 178(5):2623-9.
4.
Schroeder KW, Tremaine WJ, Ilstrup DM.  Coated oral 5-aminosalicylic acid therapy 
for mildly to moderately active ulcerative colitis: a randomized study.  N Engl J Med 
1987; 317:1625-9.
5.
2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism 
developed in collaboration with the ERS. European Heart Journal (2020) 41;543-603.


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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
5-ASA
5-aminosalicylic acid
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATP
adult treatment panel
AZA
azathioprine
β-hCG
beta human chorionic gonadotropin 
BID
twice daily
BM
bowel movement
BMI
body mass index
CCO
Clinical Country Office
CK
creatine kinase
CHD
coronary heart disease
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus disease 2019
CPK
creatine phosphokinase
CRF
case report form
CSA
clinical study agreement
CSR
clinical study report
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV EAC
Cardiovascular Endpoint Adjudication Committee
CYP3A
Cytochrome P450, family 3, subfamily A
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EMA
European Medicines Agency
ET
early termination
EU
European Union
EudraCT
European Clinical Trials Database
FAS
full analysis set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice


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Abbreviation
Term
GGT
Gamma-glutamyl transferase
GIPRC
Gastrointestinal Perforation Review Committee
HBV
hepatitis B virus
HCV
hepatitis C virus
HERC
Hepatic Event Review Committee
HDL-C
high density lipoprotein cholesterol
HIV
human immunodeficiency virus
hs-CRP
high sensitivity C-reactive protein
HZ
herpes zoster
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ID
identification
IFN 
interferon (gamma)
IL
interleukin
ILDRC
Interstitial Lung Disease Review Committee
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine system
IV
intravenous
IVRS
interactive voice recording system
IWR
interactive web response
LDH
lactate dehydrogenase
LFT
liver function test
LTE
long-term extension
JAK
Janus kinase
LDL-C
low density lipoprotein cholesterol
LPD
lymphoproliferative disorder
LSLV
last subject last visit 
6-MP
6-mercaptopurine
MAC
Malignancy Adjudication Committee
N/A
not applicable
OIRC
Opportunistic Infection Review Committee
OLE
open-label extension
PCD
primary completion date
PCP
pneumocystis pneumonia
PGA
physician global assessment
PI
principal investigator
PK
pharmacokinetic
PMS
partial Mayo score


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Abbreviation
Term
PRAC
Pharmacovigilance Risk Assessment Committee 
PROs
patient-reported outcomes
PsA
Psoriatic Arthritis
PT
prothrombin time
QFT
Quantiferon-TBGold Plus test
RA
Rheumatoid arthritis
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TB
tuberculosis
TBili
total bilirubin
TEAE
treatment emergent adverse event
Tmax
time to maximum plasma concentration
TNFi
tumor necrosis factor inhibitor
Tyk2
tyrosine kinase 2
ULN
upper limit of normal
UC
ulcerative colitis
US
United States


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Appendix 2. Mayo Scoring System*
Stool frequency†:
0 = Normal no. of stools for this patient
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than normal
Subscore, 0 to 3
Rectal bleeding‡:
0 = No blood seen
1 = Streaks of blood with stool less than half the time
2 = Obvious blood with stool most of the time
3 = Blood alone passes
Subscore, 0 to 3
Findings on endoscopy:
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern)
2 = Moderate disease (marked erythema, absent vascular pattern, any friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Subscore, 0 to 3
Physician’s global assessment§:
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Subscore, 0 to 3
*
The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.4
†
Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency.  
Normal number of bowel movements represents the number of bowel movements when not having a flare.
‡
The daily bleeding score represents the most severe bleeding of the day.
§
The physician’s global assessment acknowledges the three other criteria, the patient’s recollection of 
abdominal discomfort and general sense of wellbeing, and other observations, such as physical findings and
the patient’s performance status.


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Appendix 3. Prohibited Concomitant Medications
This is not an all-inclusive list.  Study personnel should stay current and consult with their 
pharmacy to exclude all concomitant medications that are either moderate to potent CYP3A 
inhibitors or inducers.
Moderate to Potent CYP3A 
Inhibitors
Moderate to Potent CYP3A 
Inducers
Other Prohibited 
Medications
Amprenavir
Avasimibe#
Azathioprine
Amiodarone
Bosentan
6-Mercaptopurine
Aprepitant
Barbiturates
Methotrexate
Atazanavir
Carbamazepine#
Cyclosporine
Boceprevir
Efavirenz
Mycophenolate mofetil 
/mycophenolic acid
Casopitant
Etravirine
Tacrolimus
Cimetidine
Mitotane#
Interferon
Ciprofloxacin
Modafinil
Infliximab
Clarithromycin#
Nafcillin
Adalimumab
Certolizumab
Cobicistat#
Phenobarbital#
Golimumab
Conivaptan#
Phenytoin#
Corticosteroids (Oral, IV or 
Rectal)
Darunavir
Rifabutin#
5-ASA (Rectal)
Rifampin#
Natalizumab, vedolizumab, 
and other anti-adhesion 
molecule therapy (including 
investigational agents)
Diethyldithiocarbamate
St. John’s Wort#
Leukocyte apheresis 
including selective 
lymphocyte, monocyte or 
granulocyte apheresis 
(eg, Cellsorba) or plasma 
exchange
Diltiazem
Talviraline
Other immunosuppressants 
Dronedarone
Other biologics with 
immunomodulatory 
properties
Elvitegravir#
Erythromycin
Fluconazole
Fluvoxamine
Imatinib
Indinavir#
Itraconazole#
Ketoconazole#
Lopinavir#
Mibefradil#
Mifepristone (RU486)
Nefazodone#
Nelfinavir#
Norfloxacin
Posaconazole#


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Moderate to Potent CYP3A 
Inhibitors
Moderate to Potent CYP3A 
Inducers
Other Prohibited 
Medications
Ritonavir#
Saquinavir#
Schisandra sphenanthera
Telaprevir
Telithromycin#
Tipranavir#
Tofisopam
Troleandomycin#
Verapamil
Voriconazole#
# Notated as potent inhibitors or inducers
It is recommended that subjects avoid consumption of grapefruit juice exceeding 8 ounces 
(~240 mL) total in a day while in the study.
In a situation where appropriate medical care of a subject requires the use of a 
prohibited CYP3A inhibitor or inducer: Potent inhibitors and inducers of CYP3A are not 
permitted in the study EXCEPT in emergency situations requiring no more than one day of 
administration.  Note: Mitotane (half-life of 18-159 days) is not permitted for any duration 
due to its long half-life.  Subjects may be initiated on moderate inhibitors (except 
amiodarone) and moderate inducers (shown above), as required, if the total duration of 
treatment lasts less than or equal to 7 days.  If a subject requires multiple courses of treatment 
with a prohibited medication as described above, the investigator should contact the sponsor 
to discuss the suitability of the subject to remain in the study.  Topical (including skin or 
mucous membranes) application of antibacterial and antifungal medications is permitted.


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Appendix 4. Guidelines for Monitoring and Discontinuations
The following laboratory abnormalities require monitoring and re-testing ideally within 
3-5 days:

Absolute neutrophil count <1.2 x 109/L (<1200/mm3).

Absolute lymphocyte count <0.5 x 109/L (<500/mm3).

Any single hemoglobin value <8.0 g/dL.

Platelet count <100 x 109/L (<100,000/mm3).

An increase in serum creatinine of >50% from the A3921139 baseline value; OR an 
absolute increase in serum creatinine >0.5 mg/dL (>44.2 umol/L) from 
Study A3921139 baseline value.

Any single AST and/or ALT elevation 3 times the upper limit of normal (repeat 
laboratory testing should include albumin, creatine kinase, total bilirubin, direct and 
indirect bilirubin, GGT, PT [prothrombin time] with INR [international normalized 
ratio], and alkaline phosphatase), regardless of the total bilirubin.  (Please note that 
3 times the upper limit of normal increases in ALT, AST need confirmation on 
separate blood draw before undertaking thorough evaluation for liver injury).

Any CK >10 times the upper limit of normal (repeat laboratory testing should also 
include cardiac troponin).

For females of child-bearing potential with any positive urine -hCG test, the subject
will have study drug interrupted and a serum sample submitted to the central 
laboratory for -hCG testing.
Additional individual subject safety monitoring in addition to these guidelines 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.
Treatment with tofacitinib will be discontinued and the subject withdrawn from this 
study for:

Serious infections defined as any infection (viral, bacterial, and fungal) requiring 
parenteral antimicrobial therapy, hospitalization for treatment, or meeting other 
criteria that require the infection to be classified as serious adverse event.

Opportunistic infection judged significant by the investigator (United Kingdom only).

Two sequential absolute neutrophil counts <0.75 x 109/L (<750/mm3).


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
Two sequential absolute lymphocyte counts <0.5 x 109/L (<500/mm3).

Two sequential hemoglobin <8.0 g/dL.

Two sequential platelet counts <75 x 109/L (<75,000/ mm3).

Two sequential increases in serum creatinine >50% over the Study A3921139
baseline value AND an absolute increase in serum creatinine >0.5 mg/dL 
(>44.2 umol/L).

Two sequential AST or ALT elevation 3 times the upper limit of normal with at 
least one total bilirubin value 2 times the upper limit of normal.a

Two sequential CK elevations >10 times the upper limit of normal, unless the 
causality is known not to be medically serious (eg, exercise induced).

Two sequential AST or ALT elevation 3 times the upper limit of normal 
accompanied by signs or symptoms consistent with hepatic injury.a

Two sequential AST or ALT elevation 5 times the upper limit of normal, regardless 
of total bilirubin or accompanying signs or symptoms.a

Female subjects found to be pregnant during the study. 

Initiation of a new treatment or re-initiation of a prior treatment for UC, except for 
oral 5-ASA or sulfasalazine.

Surgery for UC.

Other serious or severe AEs, after consultation with the Pfizer medical monitor or 
designee.

Additional safety monitoring and discontinuation guidelines for JAPAN ONLY (see 
below).
Per Amendment 3, for subjects with suspected venous thromboembolism, treatment 
with tofacitinib should be temporarily withheld while the subject is evaluated.  If 
venous thromboembolism is confirmed, discontinue treatment with tofacitinib and
withdraw the subject from the study.
a.
In each case, there is a need for additional investigations, such as review of ethanol, recreational drug and dietary 
supplement consumption; testing for acute hepatitis A, B or C infection and biliary tract imaging should be promptly 
discussed with the Pfizer medical monitor or designee.


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Additional safety monitoring and discontinuation guidelines for JAPAN ONLY.
Safety monitoring for potential risk of interstitial pneumonia:
Because of the potential higher risk of interstitial pneumonia in Japanese patients than in
Western patients, investigators in Japan should carefully evaluate all subjects who exhibit
symptoms, especially fever and cough.
If a subject develops fever, cough, or dyspnea, temporary discontinuation of tofacitinib
should be considered.  The differential diagnosis should include assessment for pneumonia,
TB, pneumocystis pneumonia (PCP), and invasive fungal infection.
Additionally, if a subject’s absolute lymphocyte count is decreased to <1.0 x 109/L
(<1000/mm3), please consider appropriate action based on the subject’s condition, such as
retest of lymphocyte counts, as warranted.
If the absolute lymphocyte count is decreased to <0.5 x 109/L (<500/mm3) and a sequential
retest confirms the result, the subject has to be withdrawn from the study.
Safety monitoring for enrolled subjects who required hepatitis B virus (HBV) DNA 
testing:
Safety monitoring for subjects in Japan who are enrolled into Study A3921288, who
previously required HBV DNA testing per protocol in open-label LTE Study A3921139 and 
had undetectable HBV DNA levels, will continue to require HBV DNA testing (locally 
analyzed) and LFT (ie, ALT/AST) monitoring at all scheduled visits and at unscheduled 
visits at the investigator’s discretion. Safety monitoring and discontinuation criteria for AST 
and ALT will be applied as stated above in Appendix 4.  Subjects who have detectable HBV 
DNA levels during monitoring will be discontinued.


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Appendix 5. Evaluation of Potentially Malignant Tumors, Suspicious
Lymphadenopathy or Possible Extranodal Lymphoproliferative Disorder (LPD)
The following steps should be taken in the event of suspicious lymphadenopathy or possible
extranodal lymphoproliferative disorder (LPD) which might arise in the course of this or 
other studies of Pfizer’s experimental immunosuppressive drugs. 
Any new cases or worsening cases of existing lymphadenopathy need to be discussed with 
Pfizer study team first.  In addition, when there is a decision to biopsy a suspicious lymph 
node, the investigator and/or consultants should discuss the issue and any decisions as soon 
as possible with Pfizer study team.  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), 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.  Should the 
central pathologist make a diagnosis that is not essentially similar to the local pathologist’s 
diagnosis, the site will be notified and provided with an opportunity to consult with the 
central pathologist.  Translation during this consultation, if needed, will be provided by the 
staff of the Pfizer Clinical Country Office (CCO) or designee.


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Appendix 6. Evaluation of Gastrointestinal Tract Biopsies
For gastrointestinal tract biopsies, obtained from any gastrointestinal endoscopic procedure 
performed during the study because of a clinical suspicion of malignancy (even if the local 
pathologist reading is negative for dysplasia or malignancy) OR gastrointestinal tract 
biopsies obtained during the study for any reason that show the findings or suspicion of 
dysplasia or malignancy, the original slides will need to be sent for central pathologist over 
read in addition to the local pathologist’s diagnosis.


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Appendix 7. 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) 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 
other relevant local practices and guidelines should be used to determine if any lipid lowering 
intervention is required for a subject.  Such assessments should occur throughout the study, 
in light of the observed increases in lipid levels in previous clinical trials with tofacitinib.  As 
appropriate, lipid management decisions may be considered in collaboration with the
subject’s primary care physician or general practitioner.
A copy of the complete ATP III guidelines will be provided to each study site for reference.


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Appendix 8. France Appendix
This appendix applies to study sites located in France.
1.
GCP Training
Prior to enrollment of any subjects, the investigator and any sub-investigators will complete 
the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP Training”) or 
training deemed equivalent by Pfizer.  Any investigators who later join the study will 
complete the Pfizer GCP Training or equivalent before performing study-related duties.  For 
studies of applicable duration, the investigator and sub-investigators will complete Pfizer 
GCP Training or equivalent every three years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials.
2.
Investigational Product
No subjects or third-party payers will be charged for investigational product.


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Appendix 9. Protocol Administrative Changes and Clarification for Study A3921288
During COVID-19 Pandemic
In response to the ongoing global COVID-19 pandemic and the increasing restrictions on
travel, the requirement for social distancing, and concerns for public health, the study team 
has determined that the following changes to the A3921288 protocol study visits are 
acceptable alternative solutions.

Subjects who can attend scheduled study visits in the clinic and complete all study 
procedures as described in the protocol per the Schedule of the Activities should do
so; all other subjects should participate in study visits by telephone.  Video contact 
can be used if permitted by local regulations.

If a subject is unable to come in person to the study site to receive their study 
medication, courier delivery of the study medication from study sites will be 
permitted if allowable by law and local guidance. The study participant must provide 
verbal consent for providing the contact details for shipping purposes.  This verbal 
consent should be documented in the source document. Tracking records of shipment 
including the chain of custody of the study medication must be kept in the 
participant’s medical records.

Risk factor check for pulmonary embolism (per Amendment 2)/venous 
thromboembolism (per Amendment 3) should be performed prior to the site 
dispensing additional study medication.

When conducting a study visit by telephone or video (if permitted), the following 
procedures should be completed:

Review and record any adverse events and serious adverse events since the last 
study visit (follow protocol reporting procedures in Section 8).

Assess disease activity through review of subject’s diary entries leading up to the 
visit through ICOPhone and calculate the stool frequency and rectal bleeding 
subscores, as well as perform the physician global assessment.  Record the 
subscores on the ‘Partial Mayo Clinic Score CRF’.  If sufficient diary entries are 
not available prior to the visit, advise the subject to enter diary data post visit and 
inform the study site when available.

Review and record changes in concomitant medications.

Safety laboratory tests may be performed at a local laboratory and results should 
be documented on the ‘Local Lab Test CRF’.

Review and record contraceptive method and result of urine pregnancy tests for 
female participants who are women of childbearing potential.


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
Any deviations to the protocol, except for these approved modifications must be 
documented as protocol deviations and if related to the pandemic, the reason should 
clearly state “COVID-19”. These are not required to be reported to health authorities 
or IRB/ECs unless requested locally; this requirement is meant to allow the study 
team to quickly assess the impact of the pandemic on our study.
If the sponsor determines that the impact of COVID-19 on protocol visits and procedures and 
associated timeframe needs to be reported on a case report form (CRF), this will be 
requested. For participant discontinuation reporting in the CRF: select the most appropriate 
status for discontinuation; if the discontinuation is associated with the current COVID-19 
pandemic, enter “COVID-19” in the “Specify Status” field.

SAP_000.pdf: 
Protocol A3921288 (CP-690,550, Tofacitinib) Statistical Analysis Plan
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PROTOCOL A3921288
A PHASE 3B/4, MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, PARALLEL 
GROUP STUDY OF TOFACITINIB (CP-690,550) IN SUBJECTS WITH 
ULCERATIVE COLITIS IN STABLE REMISSION
Statistical Analysis Plan 
(SAP)
Version:
2.0
Date:
11 Mar 2020


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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives .......................................................................................................5
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoint ......................................................................................................7
3.2. Secondary Endpoints.................................................................................................7
3.4. Baseline Variables.....................................................................................................8
3.5. Safety Endpoints .......................................................................................................8
4. ANALYSIS SETS .................................................................................................................9
4.1. Full Analysis Set .......................................................................................................9
4.2. Per Protocol Analysis Set..........................................................................................9
4.3. Safety Analysis Set....................................................................................................9
4.4. Other Analysis Sets ...................................................................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................10
5.1. Hypotheses and Decision Rules ..............................................................................10
5.2. General Methods .....................................................................................................10
5.2.1. Analyses for Binary Efficacy Data.............................................................10
5.2.2. Analyses for Continuous Efficacy Data .....................................................11
5.2.3. Analyses for Categorical Efficacy Data .....................................................11
5.2.4. Analyses for Time to Event Data................................................................11
5.2.5. Analysis of Safety Data ..............................................................................12
5.3. Methods to Manage Missing Data ..........................................................................12
5.3.1. Efficacy Endpoints......................................................................................12
5.3.2. Safety Endpoints.........................................................................................13
5.3.3. Method of Handling the Data after Dose Escalation or Dose 
Reduction.........................................................................................................13
6. ANALYSES AND SUMMARIES ......................................................................................15
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6.1. Primary Efficacy Endpoint......................................................................................15
6.2. Secondary Efficacy Endpoints ................................................................................15
6.4. Subset Analyses.......................................................................................................15
6.5. Baseline and Other Summaries and Analyses.........................................................16
6.5.1. Baseline Summaries....................................................................................16
6.5.2. Study Treatment Exposure .........................................................................16
6.6. Safety Summaries and Analyses .............................................................................16
6.6.1. Adverse Events...........................................................................................16
7. INTERIM ANALYSES.......................................................................................................17
7.1. Introduction .............................................................................................................17
7.2. Interim Analyses and Summaries............................................................................18
8. REFERENCES ....................................................................................................................19
9. APPENDICES .....................................................................................................................20
LIST OF TABLES
Table 1 Summary of Major Changes in Statistical Analysis Plan (SAP) Amendments............4
Table 2 Examples on How to Handle Data After Dose Change..............................................14
LIST OF FIGURES
Figure 1.
Study Design...............................................................................................6
APPENDICES
Appendix 1. Definition of Analysis Visit Windows................................................................20
Appendix 2. Further Definition of Endpoints..........................................................................22
Appendix 2.1. Mayo Scoring System for Assessment of Ulcerative Colitis Activity.............22
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1. VERSION HISTORY
Table 1 Summary of Major Changes in Statistical Analysis Plan (SAP) Amendments
Version
/Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1.0
14 Sept 
2017
Original
13 Jul 2017
Not
Applicable
Not Applicable
2.0
11 Mar 2020
2
19 Jun 2019
Revision to
align with
protocol 
amendments
1 and 2.
1. Section 2.1 and Section 2.2 updated to 
align the study objectives and study 
design with the protocol
2. Section 3.2 updated to including detail 
of censoring rule for time to loss of 
remission; to move biomarker endpoint to 
this section to align with the protocol
3. Section 3.3.1 was removed as
biomarker endpoints were listed as
efficacy endpoints to align with the 
protocol
4. Section 3.5 definition for treatment 
emergent adverse event has been updated 
based on the new standard
5. Section 5.2 added details on reporting 
subgroups of subjects who are initially 
assigned to 5 mg BID and later are 
retreated with 10 mg BID
6. Section 5.2.1 added p-value, method for 
p-value, and sensitivity analyses
7. Section 5.2.2 modified the covariance
matrix used in the linear mixed effects 
model 
8. Section 5.3.1 modified the wording 
since the treatment duration has been 
changed to month 42.
9. Section 5.3.3 was added for method of 
handling data after dose escalation and 
dose reduction.
10. Section 6.2 moved Biomarker
endpoints from section 6.3.1
11. Section 6.3.1 was removed.
12. Section 6.4 added P-value with
method 
13. Section 6.6.1 added details to compute 
incidence rates.
14. Section 7.1 added additional 


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information about the unblinding plan.
15. Appendix 1 updated to include visits 
up to Month 42, and new windowing rule 
for retreatment subgroup. 
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study A3921288.  
2.1. Study Objectives
Primary Objective

To evaluate the efficacy and safety of tofacitinib in subjects in stable remission on 
10 mg BID who decrease the dose to and remain on 5 mg BID (“5 mg BID dose 
group”) compared to subjects remaining on 10 mg BID. 
Secondary Objectives

To evaluate the efficacy and safety of tofacitinib in subjects in stable remission on 
10 mg BID who decrease the dose to 5 mg BID with option for dose escalation for 
flare (“flexible dosing regimen”) compared to subjects staying on 10 mg BID.

To evaluate the efficacy and safety of the subset of subjects in stable remission on 
10 mg BID who have flare after dose decrease to tofacitinib 5 mg BID and are 
re-treated with 10 mg BID.
2.2. Study Design
This is a Phase 3b/4, multi center, randomized double blind study. This study will enroll 
subjects from currently ongoing Study A3921139 who are in stable remission on tofacitinib 
10 mg BID for at least 6 months and who are not receiving any corticosteroids to treat their 
UC for at least 4 weeks prior to enrollment.  Subjects must have been receiving tofacitinib 10 
mg BID for a minimum of 2 consecutive years in Study A3921139 prior to baseline in order 
to be eligible for this study. Eligible subjects will be randomized in a 1:1 allocation ratio to 
receive either tofacitinib 5 mg BID or 10 mg BID at baseline of Study A3921288. Subjects 
will be stratified at baseline based on the endoscopic subscore (0 versus 1) of their most 
recent endoscopy.


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Although approximately 130 subjects are estimated to be enrolled into this study (based on 
availability of eligible subjects from Study A3921139 and based on the conservative 
assumptions of the attrition rate of 50% - 60% in Study A3921139), the final sample size 
may exceed 130 subjects.  The Sponsor will continue to engage with investigative sites
participating in Study A3921139 to assess the ability to enroll additional eligible subjects.
This study will have a total of 42 months of treatment duration. The primary analysis will be 
conducted after the last subject enrolled reaches their Month 6 study visit. The study will 
remain double-blinded to the site and subject to the initial treatment assignment at baseline.
Study visits will occur at baseline (enrollment), and at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 
27, 30, 33, 36, 39 and 42. All subjects, who withdraw early or who complete this study, will 
have a 4 week safety follow up evaluation after the last dose of investigational product. A 
schematic of the study design is shown in Figure 1.
Figure 1.
Study Design
During the course of the study, if a subject experiences an increase in clinical symptoms, 
such as an increase in rectal bleeding or an increase in stool frequency, then an endoscopy 
should be performed to assess if the subject is experiencing flare. Flare must be confirmed 
prior to performing any dose adjustments.
Flare is defined by meeting one of the following 4 criteria:
1. An increase in rectal bleeding subscore by at least 1 point and an increase in 
endoscopic subscore by at least 1 point; OR


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2. An increase in rectal bleeding subscore by at least 2 points and an endoscopic 
subscore >0; OR
3. An increase in stool frequency subscore by at least 2 points and an increase in the 
endoscopic subscore by at least 1 point; OR
4. An increase in endoscopic subscore by at least 2 points.
Once the subject is confirmed to meet the definition for flare, documented by local read 
endoscopy, the investigator may adjust the dose through interactive response technology
system. Subjects may have a dose increase to 10 mg BID or remain on 10 mg BID, 
depending on their initial treatment assignment which will remain blinded. Dose adjustments 
will not be permitted prior to the Month 1 study visit.
Per protocol Amendment 2, version 19 June 2019, the study investigator or designee will be 
required to ask each subject at each study visit if he/she has any newly-developed risk factors 
for pulmonary embolism (PE), and if one is identified, the subject will need to have their 
tofacitinib dose adjusted to open-label 5 mg BID if they are taking open label 10 mg BID or 
are receiving blinded study medication (5 mg BID or 10 mg BID). At the time of
Amendment 2, 138 subjects have been enrolled in the study and have each completed various 
durations of participation. Therefore, this new procedure will only be collected at visits 
applicable to each subject’s individual participation.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint

Remission based on modified Mayo score at Month 6. Remission based on modified 
Mayo score is defined as an endoscopic subscore of 0 or 1, stool frequency subscore 
of 0 or 1, and rectal bleeding subscore of 0.
3.2. Secondary Endpoints

Time to loss of remission (flare) based on modified Mayo score. Loss of remission
(flare) is defined as meeting at least one of the 4 criteria for flare above in 
Section 2.2.

Remission based on modified Mayo score at scheduled visits other than Month 6 for 
dose groups.

Remission based on modified partial Mayo score. Remission based on modified 
partial Mayo score is defined as stool frequency subscore of 0 or 1, and a rectal 
bleeding subscore of 0.

Remission based on total Mayo score. Remission based on total Mayo score is 
defined as total Mayo score of 2 points or lower, with no individual subscore 
exceeding 1 point and a rectal bleeding subscore of 0.


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•
Remission based on partial Mayo score. Remission based on partial Mayo score is 
defined as partial Mayo score of 2 points or lower, with no individual subscore 
exceeding 1 point and a rectal bleeding subscore of 0.
•
Change from baseline (of Study A3921288) in modified Mayo score.
•
Change from baseline (of Study A3921288) in modified partial Mayo score.
•
Change from baseline (of Study A3921288) in total Mayo score.
•
Change from baseline (of Study A3921288) in partial Mayo score.
•
Mucosal healing. Mucosal healing is defined as an endoscopic subscore of 0 or 1.
•
Clinical response based on total Mayo score. Clinical response based on total Mayo 
score is defined as decrease from baseline in total Mayo score of the Induction study, 
of at least 3 points and at least 30%, with an accompanying decrease in the subscore 
for rectal bleeding of at least 1 point, or absolute subscore for rectal bleeding of 0 or 1.
•
Change from baseline in fecal calprotectin and change from baseline in hs-CRP 
levels.
 
3.4. Baseline Variables
Unless specifically stated otherwise, the baseline value is defined as the last non-missing 
measurement collected prior to the first administration of study medication in this study, 
A3921288, at Day 1. Baseline Mayo scores will be derived based on the baseline individual 
subscores. 
The endoscopic subscore (0 versus 1) at baseline is a stratification factor in randomization 
and will be used as a covariate or stratification factor in analyses. The endoscopic subscore 
based on the case report form will be used for the statistical analyses. 
3.5. Safety Endpoints
The safety endpoints in this study include:
•
Incidence and severity of adverse events (AEs).
•
Incidence and severity of clinical laboratory abnormalities, and change from baseline 
in clinical laboratory values.
•
Incidence of vital sign abnormalities and change from baseline in vital signs.
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
Incidence of clinically significant changes in physical examinations from baseline.

Safety events of interest including adjudicated safety events (eg, opportunistic 
infections, malignancy, gastrointestinal perforation, hepatic events, and 
cardiovascular events).
An adverse event is considered treatment emergent relative to a given treatment if the event 
starts after the first dose. The first dose is defined as the first dose in Study A3921288.
A 3-tier approach will be used to summarize AEs. Under this approach, AEs are classified 
into 1 of 3 tiers. Different analyses will be performed for different tiers (See Section 6.6.1). 
Tier-1 events: These are pre-specified events of clinical importance and are maintained in a 
list in the product’s Safety Review Plan.
Tier-2 events: These are events that are not tier-1 but are “common”.  A MedDRA Preferred 
Term is defined as a tier-2 event if there are at least 4 in any treatment group.
Tier-3 events: These are events that are neither tier-1 nor tier-2 events
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per standard operating procedures.
4.1. Full Analysis Set
The primary analysis population will be the Full Analysis Set (FAS) defined as all subjects 
who are randomized into the study and receive at least 1 dose of investigational product.
4.2. Per Protocol Analysis Set 
No per protocol analysis set will be defined.
4.3. Safety Analysis Set
The safety analysis set will be defined as all subjects who receive at least 1 dose of 
investigational product.
A randomized but not treated subject will be excluded from the safety analysis set. A treated 
but not randomized subject will be included in the safety analyses.
4.4. Other Analysis Sets
No other analysis sets will be used.


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5. GENERAL METHODOLOGY AND CONVENTIONS
The primary analysis will be performed to assess efficacy and safety when all subjects 
enrolled complete their Month 6 study visit (or drop out before Month 6 visit) and data are 
cleaned and locked.  However, the final analyses will be performed after all subjects 
complete the study.
5.1. Hypotheses and Decision Rules
No formal hypotheses are to be tested.
5.2. General Methods 
For the primary objective, analyses will be performed for comparisons of the following two 
dose groups:

Tofacitinib 10 mg BID dose group: subjects who are initially assigned to tofacitinib 
10 mg BID at randomization 

Tofacitinib 5 mg BID dose group: subjects who are initially assigned to tofacitinib 
5 mg BID at randomization, regardless of whether the dose is escalated back to 
tofacitinib 10 mg BID or not (Data collected after the dose escalation from tofacitinib 
5 mg BID to 10 mg BID will not be included in the analyses.)
For the first secondary objective, analyses will be performed for comparisons of the 
following two regimen groups:

Tofacitinib 10 mg BID regimen group: subjects who are initially assigned to 
tofacitinib 10 mg BID at randomization.

Tofacitinib 5 mg BID regimen group: subjects who are initially assigned to tofacitinib
5 mg BID at randomization, staying on tofacitinib 5 mg BID or having dose 
escalation from tofacitinib 5 mg BID to 10 mg BID. Data collected after the dose
escalation will be included in the analyses.
For the second secondary objective, summary descriptive statistics will be reported for the 
subgroup of subjects who are initially assigned to tofacitinib 5 mg BID and later are re-
treated with tofacitinib 10 mg BID based on the observed case data using the original
windowing rules. In addition, the efficacy data after the dose escalation will be summarized 
using the new windowing rule by resetting the baseline (Day 0) at the dose escalation time.
5.2.1. Analyses for Binary Efficacy Data
The number and proportion of responders will be presented by dose group, regimen group
and the subgroup of subjects who are initially assigned to tofacitinib 5 mg BID and later are 
retreated with tofacitinib 10 mg BID as described in Section 5.2.
For dose comparison between tofacitinib 10 mg BID and 5 mg BID, the stratified estimation 
of the treatment difference between tofacitinib 10 mg BID and 5 mg BID in the proportion of 
subjects will be presented along with its 95% confidence interval (CI) with the endoscopic 


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subscore at baseline (0 versus 1) as the stratification factor.  The Cochran Mantel Haenszel
(CMH) weight method will be used for the stratified estimation of the treatment difference. 
The stratified CI will be constructed using the NewCombe method by Yan and Su (2010).1 In 
addition, p-value based on CMH Chi-square test stratified by endoscopic subscore at baseline 
(0 versus 1) will be presented. The same analysis method will be used for regimen groups.
For the second secondary objective, in the subgroup of subjects who are initially assigned to 
tofacitinib 5 mg BID and later are retreated with tofacitinib 10 mg BID, the number and 
proportion of responders will be also presented overall and by the endoscopic subscore at 
baseline (0 versus 1).
As sensitivity analyses for handling of missing data, remission based on modified Mayo 
score and remission based on total Mayo score will also be analyzed using a generalized 
linear mixed-effects model with a logit link and with dose group, visit, dose group by visit 
interaction, endoscopic subscore at baseline (0 versus 1) all as fixed effects, and subject as a 
random effect based on data collected at Month 6, Month 18, Month 30 and Month 42 if 
sufficient data are available at Month 42. The estimated mean, mean difference, with p-
values and 95% confidence interval based on the model will be presented at each time point
for dose group and regimen group.
5.2.2. Analyses for Continuous Efficacy Data
The descriptive statistics will be used to summarize continuous data.  The continuous data 
and change from baseline will be summarized descriptively by visit and dose group, regimen
group and the subgroup of subjects who are initially assigned to tofacitinib 5 mg BID and 
later are retreated with tofacitinib 10 mg BID.
For continuous efficacy endpoints based on total Mayo score evaluated for primary objective
at Month 6, the change from baseline will be analyzed using an analysis of covariance 
(ANCOVA) model with dose group, the endoscopic subscore at baseline (0 versus 1) as 
factors and baseline score as a covariate.  Otherwise, for continuous efficacy endpoints, the 
change from baseline will be analyzed using linear mixed effects model with baseline value, 
dose group or regimen group, the endoscopic subscore at baseline (0 versus 1), visit, and 
dose group or regimen group by visit interaction all as fixed effects, and subject as a random 
effect.  The adjusted estimations and associated 95% CI for the overall difference between 
the two dose groups or two regimen groups will be computed at each visit.  
5.2.3. Analyses for Categorical Efficacy Data
For categorical variables, the descriptive statistics such as proportions in each category will 
be reported.
5.2.4. Analyses for Time to Event Data
Kaplan-Meier estimates at the scheduled visits will be computed for time-to-event endpoint.
Kaplan-Meier plots for the time-to-event variables will be produced for dose comparison and 
regimen comparison. 


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The median time-to-event will be reported for each dose group and each regimen group.  
Time-to-event endpoints will be tested between dose groups or regimen groups, using a 
log-rank test stratified by endoscopic subscore at baseline (0 versus 1). In addition, 
cumulative event rates and associated CIs will be estimated from the Kaplan-Meier curves 
for each dose group and each regimen group.  The dose or regimen comparison for the
proportions of the event will be made using Wald test statistics. 
5.2.5. Analysis of Safety Data
Safety data will be summarized based on observed-case data by dose group, regimen group 
and the subgroup of subjects who are initially assigned to tofacitinib 5 mg BID and later are 
retreated with tofacitinib 10 mg BID. Missing data will not be imputed.
For dose groups, data collected after the dose escalation from tofacitinib 5 mg BID to 
10 mg BID will not be included in the analyses. 
For regimen group, data from subjects with dose escalation from tofacitinib 5 mg BID to
10 mg BID will be treated as it is. 
For tier-1 adverse events, an unconditional exact method for risk difference proposed by 
Chan and Zhang (1999) 2 will be used to compare tofacitinib 10 mg BID to 5 mg BID (dose 
group), and tofacitinib fixed 10 mg BID to flexible 5 mg/10 mg BID (regimen group).  
P-values and 95% confidence intervals will be formed.  For tier-2 events, the risk difference
will be presented along with its 95% confidence interval using the normal approximation for 
the difference in binomial proportions. For tier-3 events, the risk difference will be reported.
5.3. Methods to Manage Missing Data
5.3.1. Efficacy Endpoints
For binary efficacy endpoints derived from total Mayo score or partial Mayo score, subjects 
with missing scores in an analysis window will be considered as non-responders.
For continuous endpoints that are measured repeatedly over time, the missing values will be 
handled in a linear mixed effects model where missing values are assumed to be missing at 
random. 
For continuous endpoints based on total Mayo score and modified Mayo score, data collected 
after baseline to Month 6 will be considered as Month 6 if a subject has missing data at 
Month 6; data collected after Month 6 to Month 18 will be considered as Month 18 if a 
subject has missing data at Month 18; data collected after Month 18 to Month 30 will be 
considered as Month 30 if a subject has missing data at Month 30; data collected after Month 
30 to Month 42 will be considered as Month 42 if a subject has missing data at Month 42. 
The description of the handling of missing data within individual components of the Mayo 
score is described in an Appendix 2.1.
Subjects who drop out or complete the study without meeting the flare criteria will be 
censored at the last visit with Mayo score assessment for endpoint of time to loss of 
remission (flare).


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Descriptive summary will also be presented based on observed data for efficacy data.
For the subgroup of subjects who are initially assigned to tofacitinib 5 mg BID and later are 
retreated with tofacitinib 10 mg BID, missing data will not be imputed.
For fecal calprotectin and hs-CRP, the missing values will be handled in a linear mixed 
effects model where missing values are assumed to be missing at random. 
In addition, for hs-CRP, assayed values below the limit of quantification (BLQ) will be set to 
10% less than the given assay lower limit for the specific biomarker.  In listings BLQ values 
will be reported as “<LLQ” where LLQ will be replaced with the value for the lower limits 
of quantification.  Assay values will be set to missing if a value has been collected as ND (ie, 
not done) or NS (ie, no sample).  
5.3.2. Safety Endpoints
Missing data for safety endpoints will not be imputed.
For dose groups, data collected after the dose escalation will not be included in the analyses.  
For regimen group, data from subjects with dose escalation back to tofacitinib 10 mg BID 
will be treated as it is.
5.3.3. Method of Handling the Data after Dose Escalation or Dose Reduction
For this study, subjects may have a dose escalation to 10 mg BID due to flare or dose 
reduction to 5 mg BID due to PE risk factors. The data after the dose change for the dose 
group and regimen group are handled as follows. 

For Tofacitinib 10 mg BID dose group: For subjects with dose reduction due to PE 
risk factor, data collected after the dose reduction will not be included in the safety
and efficacy analyses, and last observation carried forward (LOCF) will be used for 
binary and continuous efficacy endpoints. The subjects will be considered as censored 
at the dose reduction time for endpoint of time to loss of remission (flare).

For Tofacitinib 5 mg BID dose group: data collected after the dose escalation (with or 
without dose reduction due to PE risk factor after the dose escalation) from tofacitinib 
5 mg BID to 10 mg BID will not be included in the safety and efficacy analyses. The 
subjects will be treated as non-responders for any visit after the dose escalation visit 
for binary efficacy endpoints. For continuous efficacy endpoints, the data collected
for any visit after the dose escalation visit will be considered as missing. For time to 
loss of remission (flare), the subject will be considered as having an event at the visit 
with a dose escalation if the event criteria are met or having a censored time at the 
visit with a dose escalation if the event criteria are not met.

For Tofacitinib 10 mg BID regimen group: For subjects with dose reduction due to 
PE risk factor, data collected after the dose reduction will be included in the safety
and efficacy analyses.


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
For Tofacitinib 5 mg BID regimen group: Data collected after the dose escalation will 
be included in the analyses. For subjects with dose reduction due to PE risk factor
after the dose escalation, data collected after the dose reduction will be included in
the safety and efficacy analyses.
The following table provides some examples on how to handle the data after the dose 
escalation for flare and dose reduction for risk factors for PE:
Table 2 Examples on How to Handle Data After Dose Change 
Examples
Dose group
Regimen group
Safety analysis
Efficacy
analysis
Safety analysis
Efficacy
analysis
5 mg->10 mg at 
Month X
Data after
Month X will 
not be included
Data after 
Month X will 
not be included.
Subjects will be 
treated as non-
responders after 
Month X for 
binary, and 
missing for 
continuous
endpoints
Data after 
Month X will be 
included
Data after 
Month X will be 
included
10mg->5 mg at 
Month X
Data after 
Month X will 
not be included
Data after 
Month X will
not be included.
LOCF will be 
used
Data after 
Month X will be 
included
Data after 
Month X will be
included.
5mg->10mg at 
Month X->5mg 
at Month Y
Data after
Month X will 
not be included
Data after 
Month X will
not be included.
Subjects will be 
treated as non-
responders after 
Month X for 
binary, and 
missing for 
continuous
endpoints
Data after 
Month
X(including data
after Month Y)
will be included
Data from 
Month X
(including data 
after Month Y)
will be included.


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At the time of finalizing SAP V2, all subjects completed Month 6 and no subjects had dose 
reduction before Month 6. The data handling rules for dose reduction will not be applied for
the primary analysis performed at Month 6, however they will be applied to the final analysis 
performed at the end of the study.
6. ANALYSES AND SUMMARIES
Data will be summarized by dose group, regimen group and the subgroup of subjects who are 
initially assigned to tofacitinib 5 mg BID and later are retreated with tofacitinib 10 mg BID.
Efficacy analyses will be based on FAS and safety analyses will be based on the safety 
analysis set.  Demographics and baseline characteristics will be summarized for the FAS.
6.1. Primary Efficacy Endpoint
The primary efficacy endpoint is remission based on modified Mayo score at Month 6.
As detailed in Section 5.2.1, the number and proportion of responders will be presented by 
dose group. The stratified estimation of the treatment difference between dose groups will be 
presented along with its 95% CI.  
6.2. Secondary Efficacy Endpoints
Time to loss of remission (flare) based on modified Mayo score will be analyzed as described 
in Section 5.2.4.
Binary secondary efficacy endpoints will be analyzed using the same approach as described 
for the primary efficacy endpoint.  
Change from baseline (of Study A3921288) in modified Mayo score, modified partial Mayo 
score, total Mayo score, and partial Mayo score will be analyzed as described in 
Section 5.2.2.
Fecal calprotectin and hs-CRP, and their change from baseline will be summarized 
descriptively for each visit by dose group and by regimen group. 
The fecal calprotectin and hs-CRP data will also be log-transformed (natural logarithm) for 
the analyses.  The change from baseline will be analyzed using the same approach as the 
continuous efficacy.
6.4. Subset Analyses 
Subgroup analyses will be conducted for remission based on modified Mayo score, remission 
based on total Mayo score, remission based on partial mayo score and MH for Endoscopic
subscore at baseline (0, 1), prior TNF failure (Y/N), prior TNF exposure (Y/N). The number 
and proportion of responders will be presented by dose group, regimen group in each 
CCI


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subgroup. The difference between groups will be presented along with its 95% confidence 
interval using the normal approximation for the difference in binomial proportions. P-value 
based on the Chi-square test will be used to test for the group difference within a subgroup 
unless the cell frequencies are too small. In this case, the Fisher’s exact test will be used.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Demographics and baseline characteristics will be summarized by dose group based on FAS.  
6.5.2. Study Treatment Exposure
Subjects were expected to take 4 tablets per day (2 tablets on a BID schedule) during the 
double-blind treatment period.  However, since the number of tablets taken could be for a full 
day or only for a half day on the first treatment date or last treatment date, for simplicity, we 
assume that the first treatment date and last treatment date are days that the subjects took the 
expected number of tablets.  The study drug compliance is defined as:
Drug compliance = (Actual Number of Tablets taken / Expected number of tablets)*100%.
Where expected number of tablets is defined as (Treatment Duration – 2)*expected number 
of tablets per day+ the actual number of tablets taken on the first and the last treatment dates 
if treatment duration>=2 days.  If a subject only took drug on the first day, we assumed 
he/she took the expected number of tablets on that day, and define the compliance=100%.
Treatment duration in days is calculated as last treatment date – first treatment date +1.
6.6. Safety Summaries and Analyses
The safety data will be summarized in accordance with Pfizer Data Standards.
All safety data will be summarized descriptively by dose group, regimen group and the 
subgroup of subjects who are initially assigned to tofacitinib 5 mg BID and later are retreated 
with tofacitinib 10 mg BID in the safety analysis set.  
6.6.1. Adverse Events
The analyses of adverse events under the 3-tier approach described in Section 3.5 is 
considered exploratory.  There will be no adjustment for multiple comparisons or 
stratification factors in the analyses.  For tier-1 events, the proportion of AEs observed in 
each group will be presented along with the point estimates and associated 95% confidence
intervals of the risk difference, and p-value for dose comparison or regimen comparison
using the exact methods proposed by Chan and Zhang (1999)2 described in Section 5.2.5.  
For tier-2 events, the proportion of AEs observed in each group will be presented along with 
the point estimates and associated 95% confidence intervals of the risk difference using the 
normal approximation for the difference in binomial proportions.  In case of zero event rate 
for tier-2 events in any of group, the 95% confidence intervals will not be computed.  AEs 
will be arranged in the output sorted in descending point estimate of the risk difference 
within system organ class.  Tier 3 AEs will not be summarized separately, they are included 


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in the overall standard AE summary.  Footnotes in the outputs will include the methods used 
to derive any p-values and confidence intervals as per Pfizer standards.
A listing of subjects with dose reduction due to PE risk factors will be provided.
Incidence Rates (IR) of Adverse Events of Special Interest will be provided. Confidence
intervals (95%) will be computed using the exact Poisson method.
For regimen groups, IR will be calculated only for adverse event data for events of special 
interest only. The numerator will be the number of unique subjects with a treatment emergent 
event as defined above during the interval from the first dose in A3921288 study to last dose 
of tofacitinib + 28 days at risk period. The denominator of the incidence rate is person time 
accruing from the subject’s first dose to last dose + 28 days, or to the date of the first event, 
whichever occurs earlier. For a subject who died, the time will be the minimum of (the date 
of the last dose + 28 days, or death date).
For dose groups, IR will be calculated only for adverse events of special interest only. The 
numerator will be the number of unique subjects with a treatment emergent event as defined
above during the interval from the first dose in A3921288 study to dose adjustment for dose 
escalated or dose reduced subjects otherwise to last dose + 28 days at risk period. The 
denominator of the incidence rate is person time accruing from the subject’s first dose to day 
of dose escalation, or the first dose to day of dose reduction, or last dose + 28 days, or to the 
date of the first event, whichever occurs earlier. For a subject who died, the time will be the 
minimum of dose escalation day, dose reduction day, the day of the last dose + 28 days, or 
death day.
However, for mortality (death), malignancies (including NMSC), malignancies (excluding 
NMSC) and MACE related endpoints, all events regardless of their onset within 28 days or 
beyond after the last dose of tofacitinib will be included. The concept of 28 days is applied to 
subjects without events that discontinued or completed the study.
7. INTERIM ANALYSES
7.1. Introduction
The data collected from this study will be analyzed at two time points. 
The primary analysis will be performed to assess efficacy and safety when all subjects 
enrolled complete their Month 6 study visit (or drop out before Month 6 visit) and data are 
cleaned and locked. The primary analysis will include efficacy data up to Month 6 and safety 
data up to the data cutoff date, and will be performed only for dose group comparison. This 
will be considered as the primary completion date. The initial treatment assignments at 
baseline will remain double-blinded to the site and subject (i.e., Pfizer will not provide the 
individual subject treatment/randomization codes to the sites until the study is 
completed). The Pfizer study team will become unblinded at the time of the Month 6 
primary analysis and will remain unblinded for the duration of the study. The Argus Safety 
Database will not be unblinded for the primary analysis. Results from the primary analysis 
may be shared with Regulatory Authorities and may be published for scientific presentation.


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The final analysis will be performed when all subjects complete the study and the database is 
cleaned and locked. This secondary analysis will be performed for all efficacy endpoints and
safety endpoints and for dose group, regimen group and the subgroup of subjects who 
escalate their dose from tofacitinib 5 mg BID back to tofacitinib 10 mg BID.
An external data monitoring committee (E-DMC) will be responsible for ongoing monitoring 
of the safety of subjects in the study according to the DMC 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.
7.2. Interim Analyses and Summaries
No interim analysis is planned for this study.


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8. REFERENCES
1.
Yan X., Su X.G. (2010). “Stratified Wilson and Newcombe confidence intervals for 
multiple binomial proportions.” Statistics in Biopharmaceutical Research 2(3), 329-
335.
2.
Chan ISF, Zhang Z. (1999). Test-based exact confidence intervals for the difference of 
two binomial proportions. Biometrics, 55:1201–1209.


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9. APPENDICES
Appendix 1. Definition of Analysis Visit Windows
Analysis visit windows will be used for efficacy and safety data that are summarized by visit. 
Visit Label
Target Day
Analysis Visit window
Baseline
Day 1 (First 
dose date)
Up to Day 1
Month 1
Day 30
Days 2-60
Month 3
Day 90
Days 61-135
Month 6
Day 180
Days 136-225
Month 9
Day 270
Days 226-315
Month 12
Day 360
Days 316-405
Month 15
Day 450
Days 406-495
Month 18
Day 540
Days 496—585
Month 21
Day 630
Days 586-675
Month 24
Day 720
Days 676-765
Month 27
Day 810
Days 766-855
Month 30
Day 900
Days 856-945
Month 33
Day 990
Days 946-1035
Month 36
Day 1080
Days 1036-1125
Month 39
Day 1170
Days 1126-1215
Month 42
Day 1260
After Day 1216
Follow-up
Follow-up visit and >last 
dose day+5
For time to event variables, there is no need to have the windowing.  The actual days will be 
used as the event time or censored time.  But the event rate at each visit will be estimated at 
the corresponding protocol schedule day +10 days using the Kaplan-Meiermethod. If more 
than one observation from the same subject falls into the same window, the value closest to 
the target day will be used as the observation for that analysis visit.  All observations will, 
however, be included in the listings. 
Analysis visit window Follow-up is defined by the visit name=FOLLOW_UP and >last dose 
day +5.  For example, if a subject had the last dose on Day 1000 and the follow-up visit at
Day 1006, then the data from Day 1006 will be treated as follow-up data instead of Month 33
data.  However, if a subject had the last dose on Day 1000 and the follow-up visit at 
Day 1003, then the data from Day 1003 will be treated as Month 33 data.


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New windowing rule for retreatment group:
Visit Label
Target Day
Analysis visit window
Baseline
Day 1 (dose escalation day)
Last observation up to Day 1
(dose escalation day)
Month 3
Day 90
Days 2-135
Month 6
Day 180
Days 136-225
Month 9
Day 270
Days 226-315
Month 12
Day 360
Days 316-405
Month 15
Day 450
Days 406-495
Month 18
Day 540
Days 496-585
Month 21
Day 630
Days 586-675
Month 24
Day 720
Days 676-765


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Appendix 2. Further Definition of Endpoints
Appendix 2.1. Mayo Scoring System for Assessment of Ulcerative Colitis Activity
The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease. It 
consists of 4 subscores. Each sub-score ranges from 0 to 3. The 4 components of the Mayo 
score are:
Stool Frequency:
0 = Normal no. of stools for this patient.
1 = 1 to 2 stools more than normal. 
2 = 3 to 4 stools more than normal. 
3 = 5 or more stools more than normal. 
Rectal Bleeding: 
0 = No blood seen.
1 = Streaks of blood with stool less than half the time. 
2 = Obvious blood with stool most of the time. 
3 = Blood alone passes. 
Findings on Endoscopy: 
0 = Normal or inactive disease. 
1 = Mild disease (erythema, decreased vascular pattern). 
2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, 
erosions). 
3 = Severe disease (spontaneous bleeding, ulceration).
Physician’s Global Assessment: 
0 = Normal. 
1 = Mild disease. 
2 = Moderate disease. 
3 = Severe disease.
The subject’s stool diary information will be captured by an interactive voice response 
system (IVRS) connected through the phone system. Subjects will report stool frequency 
and the most severe bleeding of the day for rectal bleeding subscore daily at least 
5 consecutive days prior to each study visit during the study. Stool frequency subscore will 
be calculated based on the average number (rounded to an integer) of stools over the prior 3 
days minus the normal number of stools per day reported by the subject.  The rectal bleeding 
subscore is the average number (rounded to an integer) of the 3 days prior to the study visit.
Diary data of stool frequency and rectal bleeding on bowel preparation date(s) will be 
excluded while calculating the subscores for stool frequency and rectal bleeding. If there are 
missing diary data, the average will be taken from the 3 most recently available days reported 
within 5 days prior to the study visit. If there are less than 3 available days reported within 5 
days prior to the study visit, the average will be taken from the limited available data unless 
there is no diary data reported within 5 days.  In this case, stool frequency and rectal bleeding 
subscores will be considered as missing. 


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If at least one of the 4 Mayo subscores is missing, the total Mayo score will be considered as 
missing.