Clinical trial NCT03502616
Conditions: Ankylosing Spondylitis
Sponsor: Pfizer
Start date: 2018-06-07; Completion date: 2020-08-20
Enrollment: 270 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if tofacitinib is safe and effective in subjects with active ankylosing spondylitis.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Tofacitinib
Intervention descriptions: intervention 1: Oral administration twice per day

Protocol documents:
Prot_000.pdf: 
Tofacitinib (CP-690,550)
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A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, STUDY 
OF THE EFFICACY AND SAFETY OF TOFACITINIB IN SUBJECTS WITH
ACTIVE ANKYLOSING SPONDYLITIS (AS)
Investigational Product Number:
CP-690,550
Investigational Product Name:
Tofacitinib
United States (US) Investigational New Drug 
(IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2018-000226-58
Protocol Number:
A3921120
Phase:
3
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.
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 3
03-April-2020
This global amendment incorporates venous 
thromboembolism (VTE) risk factor checks.
Pfizer has determined that VTE is identified as 
an important identified risk/dose dependent 
adverse drug reaction for tofacitinib.
The following sections have been updated to 
reflect these changes:
Protocol Summary, Schedule of Activities, 
Section 3 (Study Design), Section 5.5
(Administration), Section 6.2 (Study Period), 
Section 6.3 (Follow-up Visit), Section 6.4
(Subjects Discontinuation from the 
Investigational Product), Section 6.4.2
(Discontinuation from Investigational Product), 
Section 7.1.14 (Risk Factor Check for VTE), 
References Section and Appendix 1.  
Amendment 2 
10-April-2019
1. Summary of Changes: Corrected a 
typographical error under Amendment 1 
(bullet #8).
2. Protocol Summary, Section 1.2, 
Section 1.2.3.2, Section 1.2.6, Section 2, 
Section 4.1, Section 5.8, Section 6.1,
Section 6.3, Section 6.4, Section 7.2.5.5, 
Section 7.2.9.7, Section 9.6 and Appendix 2, 
Appendix 4: Made clarifications and 
corrected typographical or formatting errors.
3. Protocol Summary, Section 3, Section 5.1, 
Section 5.2, Section 7.2.3, Section 9.2 and 
Section 9.4: Added new analysis conducted 
at Week 16 when all applicable subjects have 
completed their Week 16 visits and clarified 
information about blinding due to the 
addition of the Week 16 analysis.  
 
 
 
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4. Protocol Summary, Section 2 and Section 16: 
removed reference 63 as it is no longer 
applicable. 
5. Schedule of Activities and Section 6.2.4: 
Removed reference to allowing the subject a 
light snack as this is a non-fasting visit.
6. Protocol Summary, Section 3, Section 4.2, 
Section 5.1, and Section 5.8.1: Changed to 
not exclude subjects with prior bDMARD 
use (non-IR) based on the available 
population to improve the recruitment in the 
study.
7. Protocol Summary, Section 2 and 
Section 9.2: Moved the ASQol in sequence 
for global type 1 error control before the 
SF-36v2 PCS.  Added the FACIT-F Total 
score to the global type I error control 
scheme.  Disease specific ASQoL score was 
moved before generic SF-36v2 PCS score 
and FACIT-F total score was added to the 
type I error control scheme because of the 
importance of fatigue to patients and as a key 
core domain to measure in AS clinical 
studies.  Also, updated the related objective.
8. Schedule of Activities, Section 4.4, 
Section 5.5, Section 6 and Section 7.5: Edited 
language to accommodate visits that may 
occur in the afternoon or evening.
9. Schedule of Activities and Section 6.2.6: 
Edited language to clarify in-clinic dosing for 
Week 16 visit is from the newly dispensed 
open-label supply.  Rearranged visit 
procedures to ensure relevant data is 
collected prior to patient being dosed with 
open-label IP supply.
10. Section 1.2 and Section 1.2.2: Updated 
protocol with the most recent information of 
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the tofacitinib program.
11. Section 3: Replaced the schema with a 
picture to address formatting issues.
12. Section 4.1: Removed the requirement for 
prior approval of sponsor for inclusion of 
subjects being treated for latent TB. Due to 
the removal of potential Sponsor waiver for 
the requirement of the protocol, in addition to 
consistency with other tofacitinib studies.  
13. Section 4.2 (exclusion criteria #26) and 
Section 4.4.6: Updated contraception 
language to include 1 highly effective 
method of contraception to be consistent with 
the updated investigator’s brochure, other 
tofacitinib programs as well as aligning with 
new protocol template requirements for
contraception.  Male subjects are no longer 
required to use contraception.  The risk of the 
partner due to drug exposure in the ejaculate 
was low.  Also, contraception language 
specific for subjects from Canada requiring 
WOCBP to use two contraceptive methods at 
the same time as per agreement with the 
Health Authority of Canada and Canada 
Guidance document.
14. Section 6.2.6: Revised the study procedures 
to ensure all data was collected before 
subjects begin administration of the
open-label IP.
15. Section 8.1: Removed optional protocol 
template language regarding the efficacy 
endpoint adjudication committee as the 
efficacy endpoints will not be adjudicated.
16. Section 8.2.5: Changed discontinuation from 
study to discontinuation from the
investigational product to align with changes 
made in Amendment 1.
17. Section 9.2.3: Clarified some language to be 


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more precise.
18. Appendix 1: Added or clarified relevant 
abbreviations.
19. Appendix 8: Added country specific 
appendix required by France.
Amendment 1
06-September-2018
1. Protocol Summary, Sections 2, 9.2.1 and 
Section 9.2.3: Clarified the role of ASAS40 
response at 16 weeks as a key secondary 
endpoint.  Replaced ∆SF-36v2 Physical 
Functioning domain by ∆SF-36v2 PCS as a Type 
I error controlled endpoint.  Added ∆Ankylosing 
Spondylitis Quality of Life (ASQoL) as an 
additional Type I error controlled endpoint.  
Moved AS-HCRU from a secondary to tertiary 
endpoint as it is supportive data.
2. Protocol Summary and Section 2: Added 
Inflammation, Patients Assessment of Spinal 
Pain and PGA to the secondary endpoints as 
these were not included in the original protocol.  
Clarified the BASMI secondary endpoint 
includes the 5 components.  Realigned secondary 
endpoints to be consistent with the statistical 
testing (ie, TypeI error control).
3. Protocol Summary and Section 3: Administrative 
changes to clarify blinding.  Removed mention 
of last treatment visit per FDA feedback for 
subject discontinuation of investigational product 
and withdrawal from study.
4. Protocol Summary, SOA, Section 2, Section 6, 
Section 7.2.9.6 and 7.2.9.7: Updated names of 
the SF-36v2 and EQ-5D-3L.
5. Schedule of Activities, Section 6.1 and 
Section 7.1.12: Added clarification that SI joint 
radiographs will be performed at screening if 
previous radiographs cannot be interpreted by the 
central reader.
6. Schedule of Activities, Section 6 and Section 7: 


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Added waist circumference at the Baseline visit, 
CV risk at the Screening visit and a check of the 
skin for the presence of rash to the targeted 
physical exam.  These assessments were missing 
from the original protocol. 
7. Schedule of Activities: Corrected the definition 
of TNFi-IR in the abbreviations list.
8. Schedule of Activities (footnote 11, removal of 
ET visit), Sections 4.4.1, 5.5, 6.2.11, 6.3, 6.4, 
6.4.2, 7.1.4, 7.1.7, 7.2.4, 8.1.3, and 8.2.2:
Updated sections based upon FDA feedback for 
subject discontinuation of investigational product 
and withdrawal from study.
9. Schedule of Activities, Sections 5.3, 5.5, 5.1, 6.3, 
6.4, 6.4.2, 8.1.3, 8.2, and Appendix 6: Updated 
the term study drug or study treatment to 
investigational product to maintain consistency 
throughout the protocol.
10. Schedule of Activities and Sections 7.2.9, 7.2.9.3 
and 7.2.9.4: Administrative update, removed 
quotations marks from PROs.
11. Sections 1.2 and 1.2.1.3: Added approval 
information for tofacitinib for UC.
12. Section 1.2.1.2: Corrected a typographical error 
and added date of approval and the approved 
dose for PsA.
13. Section 1.2.6: Included UC as an approved 
indication for the 5 mg dose.
14. Section 3: Corrected an error in the study design
schematic figure.
15. Section 4.1, 8.1.2: Updated by removing 
reference to a legally acceptable representative 
(all subjects are required to comprehend all 
pertinent aspects of the study).
16. Section 4.1: Updated inclusion criteria #3 to 


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address countries whose majority age is 
18 years. 
17. Section 4.1: Updated Inclusion Criteria #5 to 
clarify that radiographs would be obtained during 
the screening period, instead of at the Screening 
visit. 
18. Section 4.1: Inclusion criteria #7 updated the 
definition of inadequate response and clarified 
the definition of intolerance.  Corrected a 
typographical error in inclusion criteria #7 and 
#8.
19. Section 4.1: Updated inclusion criteria #9 to 
align with section 5.8.1 (Subject must be on a 
stable dose of corticosteroids for 1 week prior to 
first dose of investigational product).
20. Section 4.1; Updated inclusion criteria #13 to 
remove subjects that have been or are being 
treated for an active TB infection.
21. Section 4.2: Updated Exclusion criteria #1 for 
clarity.
22. Section 4.2 Updated exclusion criteria #4 to 
correct an administrative error in the protocol. 
23. Section 4.2: Updated exclusion criteria #5 to 
exclude targeted synthetic DMARDs (including 
tofacitinib) and subjects that have been 
previously exposed to conventional synthetic, 
targeted synthetic, or biological DMARDs to 
provide further clarification. 
24. Section 4.2: Updated exclusion criteria #6 to add 
the exclusion of subjects with a history of 
allergies or hypersensitivity to lactose or 
tofacitinib which was missing from the original 
protocol.
25. Section 4.2: Removed the following sentence: 
“Documentation in the source of the typical
results to allow a repeat lab is required” from 


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Exclusion criteria #9 for clarity.
26. Section 4.2: Removed exclusion criteria #26 as it 
is now covered by updated exclusion criteria #5. 
27. Sections 4.2, 4.4.6 and 6.4.1: Corrected 
typographical errors.
28. Section 4.3: Clarified the randomization criteria 
for participation in the study with addition that 
subjects should not meet any of the exclusion 
criteria.
29. Sections 4.1 and 5.8.1.1: Updated methotrexate 
use to 25 mg/week.  The 20 mg maximum 
MTX dose was carried over from the A3921119 
Phase 2 study of AS, which originally had a 
higher dose of tofacitinib that was later removed 
from the protocol.  Since many investigators use 
25 mg/week MTX, and the A3921120 protocol 
has only a tofacitinib 5 mg BID dose, it is 
deemed safe to allow the combination.  This 
observation is based on sponsor’s tofacitinib RA 
clinical studies, which did allow 25 mg/week
MTX.
30. Section 5.1: Added rationale on stratification 
which was missing in the original protocol.
31. Sections 5.8.2, 5.8.1.2 and Appendix 4: 
Corrected language to clear up inconsistencies.
32. Sections 6.2.1, 6.2.6, 6.2.10: Administrative 
change to provide clarity for the investigators 
that the EQ-5D-3L and the EQ-VAS are on the 
same questionnaire. 
33. Section 7.1: Approximate total blood volume 
revised to be consistent with updated total blood 
volumes received from Central Laboratory.
34. Section 7.2.9.8: Clarified FACIT fatigue scale.
35. Section 7.4: Clarified rater qualifications per new 


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protocol template guidance.
36. Sections 8.2.4 and 8.2.6: Removed Treated 
Infections Section.  Final tables and listings will 
describe safety data using industry wide standard 
terms: MedDRA(Infections and Infestations) and 
serious infection events (SIE).  These will be 
compared with other tofacitinib studies (eg, RA, 
PsA, UC) as well as external databases which 
include the same standardized terms.  There is no 
industry standard definition of a "treated 
infection" nor a consistent internal definition that 
could be used for comparison.
37. Sections 11.1, 11.2 and 12.3: Corrected a 
typographical error (Section 11.1) and updated to 
revise sponsor’s protocol template language to 
comply with new EU general data protection 
regulation (GDPR) guidelines.
38. Section 13.1: Edited to reflect sponsor’s updated 
protocol template language.
39. Section 16: Corrected page numbers for 
reference #18.  Added reference #63.
40. Appendix 1: Added abbreviations used in 
updated protocol text (oz, PBO, CHD and 
tsDMARD).  Updated abbreviations for 
consistency (bDMARD, csDMARD, DMARD, 
HBsAB, HBsAG).
Original 
protocol
22 February 2018
Not applicable (N/A).
This amendment incorporates all revisions to date, including amendments made at the 
request of the country health authorities and institutional review boards (IRBs)/ethics 
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................15
LIST OF FIGURES .................................................................................................................15
APPENDICES .........................................................................................................................16
1. INTRODUCTION ...............................................................................................................28
1.1. Mechanism of Action/Indication.............................................................................28
1.2. Background and Rationale ......................................................................................28
1.2.1. Summary of Efficacy..................................................................................30
1.2.1.1. Rheumatoid Arthritis.................................................................30
1.2.1.2. Psoriatic Arthritis ......................................................................30
1.2.1.3. Ulcerative Colitis.......................................................................30
1.2.1.4. AS..............................................................................................31
1.2.2. Summary of Safety .....................................................................................31
1.2.3. Overall Risk-Benefit...................................................................................31
1.2.3.1. Potential Benefits.......................................................................31
1.2.3.2. Potential Risks...........................................................................32
1.2.4. ClinicalPharmacokinetics...........................................................................33
1.2.5. Drug Development and Study Rationale ....................................................34
1.2.6. Dose Selection Rationale ............................................................................35
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................36
3. STUDY DESIGN.................................................................................................................37
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................40
4.1. Inclusion Criteria.....................................................................................................40
4.2. Exclusion Criteria....................................................................................................43
4.3. Randomization Criteria ...........................................................................................46
4.4. Lifestyle Requirements ...........................................................................................46
4.4.1. Fasting Visit Requirements.........................................................................47
4.4.2. Non-Pharmacologic Interventions ..............................................................47
4.4.3. Dietary Supplements...................................................................................47
4.4.4. Vaccine Guidelines .....................................................................................48
4.4.5. Elective Surgery..........................................................................................48
4.4.6. Contraception..............................................................................................48


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4.4.7. Sponsor’s Qualified Medical Personnel......................................................50
5. STUDY TREATMENTS.....................................................................................................51
5.1. Allocation to Treatment...........................................................................................51
5.2. Breaking the Blind...................................................................................................52
5.3. Subject Compliance.................................................................................................53
5.4. Investigational Product Supplies .............................................................................53
5.4.1. Dosage Form(s) and Packaging ..................................................................53
5.4.2. Preparation and Dispensing ........................................................................53
5.5. Administration.........................................................................................................54
5.6. Investigational Product Storage ..............................................................................55
5.7. Investigational Product Accountability...................................................................56
5.7.1. Destruction of Investigational Product Supplies ........................................56
5.8. Concomitant Treatment(s).......................................................................................56
5.8.1. Biologic Medications..................................................................................56
5.8.2. Stable Background Pain or Other AS Therapy...........................................57
5.8.3. Rescue Therapy ..........................................................................................58
5.8.4. Prohibited Medications ...............................................................................58
6. STUDY PROCEDURES .....................................................................................................59
6.1. Screening.................................................................................................................59
6.2. Study Period ............................................................................................................61
6.2.1. Baseline Day 1 (Randomization)................................................................61
6.2.2. Week 2 ........................................................................................................63
6.2.3. Week 4 ........................................................................................................64
6.2.4. Week 8........................................................................................................66
6.2.5. Week 12......................................................................................................67
6.2.6. Week 16......................................................................................................69
6.2.7. Week 24 ......................................................................................................70
6.2.8. Week 32......................................................................................................72
6.2.9. Week 40......................................................................................................73
6.2.10. Week 48....................................................................................................75
6.3. Follow-up Visit........................................................................................................76
6.4. Subjects Discontinuation from the Investigational Product ....................................78


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6.4.1. Monitoring Criteria .....................................................................................79
6.4.2. Discontinuation Criteria (from the Investigational Product)......................79
7. ASSESSMENTS..................................................................................................................81
7.1. Safety Assessments .................................................................................................81
7.1.1. Hepatitis B and C Virus Testing .................................................................82
7.1.2. Pregnancy Testing.......................................................................................82
7.1.3. Cardiovascular (CV) Risk Factor Assessment ...........................................83
7.1.4. Complete Physical Examination..................................................................83
7.1.4.1. Targeted Physical Examination .................................................83
7.1.5. Weight, Height and Waist Circumference..................................................83
7.1.6. Vital Signs...................................................................................................84
7.1.7. 12-Lead Electrocardiogram (ECG).............................................................84
7.1.8. TB Testing ..................................................................................................84
7.1.9. QuantiFERON- TB Gold In-Tube Test.....................................................84
7.1.10. Chest Radiograph......................................................................................85
7.1.11. Radiograph of Sacroiliac (SI) Joints.........................................................85
7.1.12. Historical Radiograph...............................................................................85
7.1.13. New Radiograph at Screening ..................................................................85
7.1.14. Risk Factor Check for Venous Thromboembolism..................................86
7.2. Efficacy Assessments..............................................................................................86
7.2.1. ASAS Improvement Criteria ......................................................................86
7.2.2. Ankylosing Spondylitis Disease Activity Score (ASDASCRP).................87
7.2.3. High Sensitivity C-Reactive Protein (hsCRP) ............................................87
7.2.4. Specific Medical History and Peripheral Articular Involvement................87
7.2.5. Bath Ankylosing Spondylitis Metrology Index (BASMI)..........................87
7.2.5.1. Lateral Spinal Flexion................................................................88
7.2.5.2. Tragus-to-Wall Distance............................................................88
7.2.5.3. Lumbar Flexion (Modified Schober).........................................88
7.2.5.4. Maximal Intermalleolar Distance ..............................................89
7.2.5.5. Cervical Rotation.......................................................................89
7.2.6. Spinal Mobility: Chest Expansion ..............................................................89
7.2.7. Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) .................89


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7.2.8. Swollen Joint Count (44) ............................................................................89
7.2.9. Patient Reported Outcomes.........................................................................90
7.2.9.1. Bath Ankylosing Spondylitis Disease Activity Index
(BASDAI)..........................................................................................90
7.2.9.2. Bath Ankylosing Spondylitis Functional Index (BASFI) .........90
7.2.9.3. Patient Global Assessment of Disease.......................................91
7.2.9.4. Patient Assessment of Spinal Pain.............................................91
7.2.9.5. Ankylosing Spondylitis Quality of Life ....................................91
7.2.9.6. SF-36v2 Health Survey)............................................................91
7.2.9.7. EuroQol 5 Dimensions 3 Levels (EQ-5D-3L) Health State
Profile ................................................................................................91
7.2.9.8. Functional Assessment of Chronic Illness Therapy –
Fatigue Scale......................................................................................92
7.2.9.9. Work Productivity & Activity Impairment Questionnaire:
Spondyloarthritis ...............................................................................92
7.2.9.10. Ankylosing Spondylitis Healthcare Resource Utilization
Questionnaire.....................................................................................92
7.3. Imaging Assessments (Chest and SI joint radiographs)..........................................92
7.4. Rater Qualifications.................................................................................................93
........................................................................................93
8. ADVERSE EVENT REPORTING......................................................................................95
8.1. Requirements...........................................................................................................95
8.1.1. Additional Details on Recording Adverse Events on the CRF...................96
8.1.2. Eliciting Adverse Event Information..........................................................96
8.1.3. Withdrawal due to Adverse Events (see also the Subjects
Discontinuation from the Investigational Product section) .............................96
8.1.4. Time Period for Collecting AE/SAE Information......................................96
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................97
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................97
8.1.5. Causality Assessment .................................................................................97
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................98
8.2. Definitions...............................................................................................................98
8.2.1. Adverse Events ...........................................................................................98
8.2.2. Abnormal Test Findings .............................................................................99


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8.2.3. Serious Adverse Events ..............................................................................99
8.2.4. Infections ..................................................................................................100
8.2.5. Serious Infections .....................................................................................100
8.2.6. Hospitalization..........................................................................................100
8.3. Special Situations ..................................................................................................101
8.3.1. Protocol-Specified Serious Adverse Events .............................................101
8.3.2. Potential Cases of Drug-Induced Liver Injury..........................................101
8.3.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................103
8.3.3.1. Exposure During Pregnancy....................................................103
8.3.3.2. Exposure During Breastfeeding ..............................................105
8.3.3.3. Occupational Exposure ...........................................................105
8.3.4. Medication Errors .....................................................................................105
8.3.4.1. Medication Errors....................................................................105
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................106
9.1. Sample Size Determination ...................................................................................106
9.2. Efficacy Analysis...................................................................................................106
9.2.1. Analysis of Primary Endpoint...................................................................107
9.2.2. Analysis of Secondary and Other Endpoints ............................................107
9.2.3. Control for Type I Error Rate ...................................................................107
9.3. Safety Analysis......................................................................................................109
9.4. Interim Analysis ....................................................................................................109
9.5. Data Monitoring Committee .................................................................................109
9.6. Safety Event Adjudication/Review Committees...................................................110
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................111
11. DATA HANDLING AND RECORD KEEPING ...........................................................112
11.1. Case Report Forms/Electronic Data Record .......................................................112
11.2. Record Retention.................................................................................................112
12. ETHICS............................................................................................................................113
12.1. Institutional Review Board/Ethics Committee....................................................113
12.2. Ethical Conduct of the Study ..............................................................................113
12.3. Subject Information and Consent........................................................................113


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12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................114
13. DEFINITION OF END OF TRIAL.................................................................................114
13.1. End of Trial in All Participating Countries .........................................................114
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................114
15. PUBLICATION OF STUDY RESULTS........................................................................115
15.1. Communication of Results by Pfizer ..................................................................115
15.2. Publications by Investigators ..............................................................................115
16. REFERENCES ................................................................................................................117
LIST OF TABLES
.......................................................94
LIST OF FIGURES
Figure 1.
Study Design Schematic...........................................................................38
Figure 2.
44 Swollen Joint Count Mannequin..........................................................90


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APPENDICES
Appendix 1. Abbreviations....................................................................................................122
Appendix 2. Modified New York Criteria for Ankylosing Spondylitis (1984).....................126
Appendix 3. Cockcroft-Gault Calculation .............................................................................127
Appendix 4. Prohibited Concomitant Medications................................................................128
Appendix 5. Approximate Equivalent Morphine Doses of Opioid Analgesics .....................130
Appendix 6. Rescue Therapy.................................................................................................131
Appendix 7. Evaluation of Potentially Malignant Tumors, Suspicious 
Lymphadenopathy, Possible Extranodal Lymphoproliferative 
Disorder (LPD) .......................................................................................133
Appendix 8. France Appendix...............................................................................................134


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PROTOCOL SUMMARY
Background and Rationale
Ankylosing Spondylitis (AS) is prevalent among spondyloarthropathies, a group of arthritic 
conditions affecting the spine.  This under recognized disease is often not diagnosed for 
many years and typically presents in people between 20 and 40 years of age leading to 
progressive disability and adverse effects on quality of life.  Tofacitinib inhibits signaling of
cytokines that are integral to lymphocyte activation, proliferation, and function and may thus 
result in suppression of multiple aspects of the immune response.  This forms the basis of the 
rationale to investigate the effect of tofacitinib in active AS.
This study is a follow-up to the A3921119 Phase 2b study of tofacitinib in active AS.
Objectives and Endpoints
Primary Objectives:
Primary Endpoint:

To compare the efficacy of tofacitinib 5 mg BID versus
placebo on the ASAS20 response rate at Week 16 in
subjects with active AS that have had an inadequate
response to previous treatment.

ASAS20 response at Week 16.
Key Secondary Objective:
Key Secondary Endpoint:

To compare the efficacy of tofacitinib 5 mg BID versus
placebo on the ASAS40 response rate at Week 16 in 
subjects with active AS that have had an inadequate 
response to previous treatment.

ASAS40 response at Week 16.
Other Secondary Objectives:
Other Secondary Endpoints:

To compare the safety and tolerability of tofacitinib 
5 mg BID versus placebo in subjects with active AS that have
had an inadequate response to previous treatment.

Incidence and severity of Adverse Events (AE).

Clinical laboratory tests, vital signs, physical
examination and 12-lead ECG parameters.

To compare the efficacy (including health-related 
quality of life, function, pain, and fatigue) of tofacitinib 
5 mg BID versus placebo at all time points in subjects 
with active AS that have had an inadequate response to 
previous treatment.

ASAS20 response at all other time points.

ASAS40 response at all other time points.

Change from baseline in Ankylosing Spondylitis
Disease Activity Score using C-Reactive Protein
(ASDASCRP) at all time points.

Change from baseline in hsCRP at all time points.

Change from baseline in Ankylosing Spondylitis
Quality of Life (ASQoL) at all time points collected.

Change from baseline in Short-Form-36 Health
Survey-Version 2 Acute (SF-36v2) at all time points 
collected.

Change from baseline in Bath Ankylosing Spondylitis
Metrology Index (BASMI) including the 5 components 
(lateral spine flexion, tragus-to-wall distance, lumbar 
flexion, maximal intermalleolar distance and cervical 
rotation) at all time points.

Change from baseline in Functional Assessment of
Chronic Illness Therapy-Fatigue (FACIT-F) 
(3 endpoints: total score, experience domain and 
impact domain scores) at all time points

Change from baseline in Patients Global Assessment of 
Disease (PGA) at all time points collected.


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
Change from baseline in Patient’s Assessment of 
Spinal Pain (Total Back Pain, Nocturnal Spinal Pain) 
at all time points collected.

Change in from baseline Bath Ankylosing Spondylitis
Functional Index (BASFI) at all time points.

Change from baseline in inflammation (mean of the 
answers to questions 5 and 6 of the BASDAI) at all 
time points collected.

ASAS 5/6 response at all time points.

ASAS partial remission criteria at all time points.

Change from baseline in Bath Ankylosing Spondylitis
Disease Activity Index (BASDAI) at all time points.

BASDAI50 response at all time points.

ASDAS clinically important improvement, ASDAS
major improvement and ASDAS inactive disease at all
time points.

Change from baseline in Maastricht Ankylosing
Spondylitis Enthesitis Score (MASES) at all time points
collected.

Change from baseline in extra-articular Involvement
(Specific Medical History and peripheral articular
involvement [as assessed by change from baseline in 
swollen joint count]) at all time points collected.

Change from baseline in spinal mobility at all time
points collected.

Change from baseline in EuroQol EQ-5D Health State
Profile 3 level (EQ-5D-3L) and Your own health state 
today (EQ-VAS), at all time points collected.

Change from baseline in Work Productivity and
Activity Impairment (WPAI) Questionnaire:
Spondyloarthritis at all time points collected.
Tertiary/Exploratory Objectives:
Tertiary/Exploratory Endpoints:

 


To evaluate the effect of tofacitinib 5 mg BID on
lymphocyte subsets using FACS analysis.

Fluorescence Activated Cell Sorting (FACS) analysis
of lymphocyte subsets.

To measure the effect of tofacitinib 5 mg BID on 
healthcare resource utilization at all collected time 
points.

AS HealthCare Resource Utilization Questionnaire
(AS-HCRU) at all time points collected.


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Study Design
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled efficacy and
safety study designed to compare tofacitinib to placebo in subjects with active AS.  An 
estimate of approximately 480 AS subjects will be screened globally in order that 
approximately 240 eligible subjects (120 per arm) will be randomized in a 1:1 ratio to 
tofacitinib 5 mg BID (twice daily) or matching placebo BID.  Active disease is required for 
entry into this study and is defined as: Modified New York Criteria for Ankylosing 
Spondylitis (1984), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 
4 and back pain score (BASDAI Question 2) of 4 despite an adequate therapeutic trial 
with 2 or more non-steroidal anti-inflammatory drugs (NSAIDS) (or intolerance to NSAIDs).
Eligible subjects will be treated with one of the two sequences for 16 weeks followed by 
treatment with tofacitinib 5 mg BID for an additional 32 weeks.
The duration of participation for eligible subjects will be approximately 56 weeks.  This will 
include a screening period of approximately 30 days, a 16-week double-blind treatment 
period, a 32-week open-label treatment period and a 28 day follow-up period.  During the 
16-week treatment period subjects will visit the clinic every two weeks (3 days) until the 
Week 4 visit and then every 4 weeks (7 days) until completion of Week 16.  At the 
Week 16 visit all subjects will be assigned to open-label tofacitinib and will visit the clinic 
every two months (7 days) until week 48.  Subjects will then return to the clinic for a 
Follow-up visit approximately 28 days after the week 48 visit.  The investigators, subjects 
and sponsor study team will remain blinded to the first 16 weeks of treatment assignment
through the entire duration of the trial until database release.
Amendment 3
All subjects in the study will be evaluated for risk factors for venous thromboembolism
(VTE) (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).
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 VTE.
A subject may be at high risk for VTE if he/she:
•
has heart failure or prior myocardial infarction within the past 3 months;
•
has inherited coagulation disorders;
•
has had VTE, either deep venous thrombosis or pulmonary embolism;
•
is taking combined hormonal contraceptives or hormone replacement therapy;


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•
has a malignancy (association is strongest with cancers other than non-
melanoma skin cancers);
•
is undergoing major surgery or is immobilized.
Additional risk factors for VTE, such as age, diabetes, obesity (body mass index [BMI≥30
kg/m2), smoking status, hypertension, and first degree family history of VTE 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 discontinue from open-label 5 mg BID
dose of tofacitinib.
See Risk Factor Check for VTE in Section 7.1.14 for tofacitinib dosing guidance when a risk 
factor is identified.
If a subject has 1 or more of the risk factors for VTE listed above and is receiving tofacitinib 
5 mg BID, they may remain on tofacitinib 5 mg BID after careful investigator assessment of 
benefit: risk. For subjects who do not have any of the risk factors for VTE listed above, 
he/she will remain on their open-label tofacitinib dose of 5 mg BID.
Study Treatments
Subjects will be randomized at the Baseline visit in a 1:1 ratio to one of the following two
treatment sequences for a total of 16 weeks of treatment. Randomization will be stratified by 
prior treatment history: (1) Biological disease-modifying anti-rheumatic drug-naive
(bDMARD-naïve) and (2) Tumor Necrosis Factor inhibitor inadequate responders (TNFi-IR)
or bDMARD use (non-IR).
Strata (Patient 
Population)
Sequence
Treatment Sequence and Description
Planned 
Number of 
Randomized 
Subjects
bDMARD-naive
1
Blinded Tofacitinib 5 mg BID for 16 weeks 
followed by open-label tofacitinib for 32 
weeks
One-tofacitinib 5 mg tablet in AM & PM
96
bDMARD-naive
2
Placebo BID for 16 weeks followed by
open-label 5 mg BID tofacitinib for 
32 weeks
One-5 mg matching placebo tablet in AM & 
PM for the first 16 weeks followed by 
one-tofacitinib 5 mg tablet in the AM & PM 
for 32 weeks
96
TNFi-IR or 
bDMARD use 
(non-IR)
1
Blinded Tofacitinib 5 mg BID for 16 weeks 
followed by open-label tofacitinib for 32 
weeks
One-tofacitinib 5 mg tablet in AM & PM
24


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Strata (Patient 
Population)
Sequence
Treatment Sequence and Description
Planned 
Number of 
Randomized 
Subjects
TNFi-IR or 
bDMARD use 
(non-IR)
2
Placebo BID for 16 weeks followed by 
open-label 5 mg BID tofacitinib for 
32 weeks
One-5 mg matching placebo tablet in AM & 
PM for the first 16 weeks followed by 
One-tofacitinib 5 mg tablet in the AM & PM 
for 32 weeks
24
Subjects will receive one tablet in the morning and one tablet in the evening for a total of
two tablets per day. Placebo tablets will match the 5 mg tablets in order to maintain the
blind.
At the end of the 16 week double-blinded treatment period, all subjects will be assigned to 
open-label tofacitinib 5 mg BID to Week 48.  The investigators, subjects and sponsor study 
team will remain blinded to the first 16 weeks of treatment assignment through the entire 
duration of the trial until database release.
Statistical Methods
The Assessment of the SpondyloArthritis International Society 20% improvement 
(ASAS20) response rate at Week 16 is the primary efficacy endpoint in this trial.  The 
analysis of the primary endpoint will be based on the full analysis set.  The normal 
approximation for the difference in binomial proportions adjusting for the prior treatment 
history at randomization (bDMARD-naïve vs TNFi-IR) via the Cochran–Mantel–Haenszel 
approach will be used to estimate the treatment effect (treatment difference, standard error, 
95% confidence interval) and to test (Normal Z-test) the superiority of tofacitinib to placebo. 
Approximately 120 subjects per arm will be randomized.  A sample size of 120 per arm will 
yield about 89% power to detect a difference of at least 20% between tofacitinib 5 mg BID 
and placebo at a two-sided significance level of 5%, assuming a placebo response rate of 
40% for ASAS20 response at Week 16. 
The family-wise Type I error rate will be controlled at the 2-sided 5% (or equivalently
1-sided 2.5%) significance level using a step-down testing procedure for the primary 
endpoint of ASAS20, the key secondary endpoint of Assessment of the SpondyloArthritis 
International Society 40% improvement (ASAS40) and a select set of secondary endpoints 
at Week 16 tested in the sequence below: ASAS20, ASAS40, change from baseline in 
Ankylosing Spondylitis Disease Activity Score (ASDASCRP), change from baseline in High 
Sensitivity C-Reactive Protein (hsCRP), change from baseline in Ankylosing Spondylitis 
Quality of Life (ASQoL), change from baseline in SF-36 Health Survey Version 2, Acute 
(SF-36v2) Physical Component Summary (PCS), , and change from baseline in Bath 
Ankylosing Spondylitis Metrology Index (BASMI), and change from baseline in Functional 


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Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Total score (See Section 9.2.3 for 
additional Type I error control procedures).
There will be a total of 2 planned analyses conducted when all applicable subjects have 
completed their Week 16 and Week 48 (including follow-up) visits, respectively. 
 
 
 (see Section 9.2 for details).  
CCI


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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to STUDY PROCEDURES
(Section 6) and ASSESSMENTS (Section 7) for detailed information on each procedure and assessment required for compliance with
the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Protocol Activity
Visit Window (days)
Screening1
Treatment Period
Follow 
–up11
30 days
Baseline 
Day 1
Week 2
Week 4
Week 8
Week 12
Week 16
Week 24 Week 32
Week 40
Week 48
3
3
7
7
7
7
7
7
7
7
Informed Consent/Assent
X
AS Diagnosis2
X
X
Demographics
X
General Medical History 
(includes previous 
vaccinations, family history of 
AS, herpes zoster history, 
smoking and alcohol use, CV 
X
Determination of 
“bDMARD-naïve” or 
“TNFi-IR” status
X
Complete Physical Exam3
X
X
X
X
Targeted Physical Exam4
X
X
X
X
X
X
X
X
Height, Weight5 and 
Waist circumference5
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (blood 
pressure, pulse rate, 
temperature)
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG6
X
X
X
Chest Radiograph
X
Radiographs of SI joints7
X
Prior/Concomitant 
Treatments(s)
X
X
X
X
X
X
X
X
X
X
X
X


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Protocol Activity
Visit Window (days)
Screening1
Treatment Period
Follow 
–up11
30 days
Baseline 
Day 1
Week 2
Week 4
Week 8
Week 12
Week 16
Week 24 Week 32
Week 40
Week 48
3
3
7
7
7
7
7
7
7
7
LABORATORY 
TESTING
Hematology
X
X
X
X
X
X
X
X
X
X
Chemistry Panel
X
X
X
X
X
X
X
X
X
X
Lipid Panel (fasting)8
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
QuantiFERONTB Gold
X
Urine Pregnancy Test 
(HCG)9
X10
X
X
X
X
X
X
X
X
X
X
X
C-Reactive Protein 
(hsCRP)12
X
X
X
X
X
X
X
X
X
X
X
X
HIV serology, HBsAg, 
HBcAb, HCV Ab
X
Prothrombin Time (INR)
X
HLA-B27 Sample
X
FACS Analysis:
Lymphocyte Markers
X
X
X
X
X
EVALUATION OF DISEASE 
ACTIVITY
Specific Medical History:
Uveitis, IBD, Psoriasis,
Peripheral Articular
Involvement*
X
X
X
X
X
X
X
ASAS, ASDASCRP
X
X
X
X
X
X
X
X
X
X
X
BASMI (linear
function)14,15
X
X
X
X
X
X
X
X
X
X
X
Spinal Mobility14,16
X
X
X
X
X
X
X
X
X
X
X


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Protocol Activity
Visit Window (days)
Screening1
Treatment Period
Follow 
–up11
30 days
Baseline 
Day 1
Week 2
Week 4
Week 8
Week 12
Week 16
Week 24 Week 32
Week 40
Week 48
3
3
7
7
7
7
7
7
7
7
Enthesitis Evaluation
(MASES)14
X
X
X
X
X
X
X
X
X
Number of swollen joints
(44 joint count)14
X
X
X
X
X
X
X
X
X
X
PATIENT 
REPORTED
OUTCOMES
Patient Global Assessment
of Disease
X
X
X
X
X
X
X
X
X
X
X
Patient Assessment of
Spinal Pain17
X
X
X
X
X
X
X
X
X
X
X
BASDAI, BASFI
X
X
X
X
X
X
X
X
X
X
X
ASQoL, SF-36v2, 
EQ-5D-3Lincluding 
EQ-VAS
X
X
X
FACIT-F
X
X
X
X
X
X
X
X
X
X
Work Productivity &
Activity Impairment
Questionnaire (WPAI):
X
X
X
AS HealthCare Resource
Utilization Questionnaire
(AS-HCRU)
X
X
X
OTHER ACTIVITIES
   Randomization
X
Assignment to Open-label 
Treatment
X
Dosing in Clinic18
X
X
X
X
X
X
X
X
X
X
Drug Dispensing
X
X
X
X
X19
X
X
X
Dosing Instructions20
X
X
X13
X13
X
X
X
X
X
  Drug Accountability
X
X
X
X
X
X
X
X
X


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Protocol Activity
Visit Window (days)
Screening1
Treatment Period
Follow 
–up11
30 days
Baseline 
Day 1
Week 2
Week 4
Week 8
Week 12
Week 16
Week 24 Week 32
Week 40
Week 48
3
3
7
7
7
7
7
7
7
7
Serious and non-serious 
adverse Event Reporting
X
X
X
X
X
X
X
X
X
X
X
X
Contraception Check21
X
X
X
X
X
X
X
X
X
X
X
X
Risk Factor Check for 
Venous 
Thromboembolism22
X
X
X
X
AS=Ankylosing Spondylitis; bDMARD= Biological Disease-modifying anti-rheumatic drugs, TNFi-IR= Tumor Necrosis Factor inhibitor-Inadequate Responder, 
IBD=Inflammatory Bowel Disease; HCG=Human Chorionic Gonadotrophinhs; hsCRP= High-Sensitivity C-Reactive Protein; FACS=Fluorescence-Activated 
Cell Sorting; FSH=Follicule Stimulating Hormone; ASAS=Assessment in Ankylosing Spondylitis; ASDAS=Ankylosing Spondylitis Disease Activity Score; 
BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; BASFI=Bath Ankylosing Spondylitis Functional Index; BASMI=Bath Ankylosing Spondylitis 
Metrology Index; MASES=Maastricht Ankylosing Spondylitis Enthesitis Score; ASQoL=Ankylosing Spondylitis Quality of Life; SF-36v2=Short Form 36; 
EQ-5D-3L=EuroQol Health State Profile; EQ-VAS=”Your own health state today”; FACIT-F=Functional Assessment of Chronic Illness Therapy-Fatigue; 
SI=Sacroiliac; WOCBP = women of childbearing potential*as assessed by swollen joint count.
1.
Screening visit occurs within 30 days prior to administration of the investigational product at the Baseline (Day 1) visit.
2.
Prior to randomization confirm diagnosis of active AS: Modified New York Criteria for Ankylosing Spondylitis (1984), BASDAI score of 4 and back pain
score (BASDAI Question 2) of 4. 
3.
The following parameters and body systems will be examined and any abnormalities described: general appearance, skin (presence of rash), HEENT (head,
ears, eyes, nose, throat), lungs (auscultation), heart (auscultation for presence of murmurs, gallops, rubs), lower extremity exam (for peripheral edema), abdominal
(palpation and auscultation), neurologic (mental status, station, gait, reflexes, motor and sensory function, coordination) and lymph nodes.  Any clinically
significant change(s) from Baseline/Day 1 should be recorded as an adverse event(s). 
4.
Targeted physical examination will be performed assessing the following: lungs, heart, abdomen, lower extremities (for peripheral edema), skin (presence of
rash) and lymph nodes.  Any clinically significant change(s) from Baseline (Day 1) should be recorded as an adverse event(s).
5.
Height is collected at Screening visit only, waist circumference is collected at Baseline visit only. After Baseline visit, only weight is required. 
6.
ECG to be read centrally.
7.
Radiographs to be read centrally. Previous radiographs (up to 2 years old) of the SI joints documenting the diagnosis of AS will be acceptable if they can be
obtained and sent to the central reader for confirmation. If radiographs are not available or cannot be interpreted by the central reader, new radiograph
(AP pelvis) should be obtained during the screening period and submitted to the central reader.
8.
The lipid panel will include apolipoprotein A-1 and B, total cholesterol, HDL, LDL, and triglycerides. Other lipoprotein tests potentially include particle size
measurements.
9.
Urine pregnancy test is required only for WOCBP; may be repeated more frequently if required by local regulation/practice, if a menstrual cycle is missed, or
if a potential pregnancy is suspected.
10. Women of non-childbearing potential must meet one of the following criteria: undergone hysterectomy and/or bilateral oophorectomy, medically confirmed


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Protocol Activity
Visit Window (days)
Screening1
Treatment Period
Follow 
–up11
30 days
Baseline 
Day 1
Week 2
Week 4
Week 8
Week 12
Week 16
Week 24 Week 32
Week 40
Week 48
3
3
7
7
7
7
7
7
7
7
ovarian failure or confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or
physiological cause); status may be confirmed with/and have a central laboratory confirmation of FSH level indicative of postmenopausal state. 
11. The Follow-up Visit is required of all subjects who complete the study or are withdrawn from the investigational product after the Week 40 visit.  These 
subjects must have a Follow-up visit within 28 days (7 days) of the Week 48 visit.  Subjects who are withdrawn from the investigational product prior to the 
Week 40 visit are not required to have a follow-up visit after they complete the study at the Week 48 visit.
12. hsCRP will be blinded after the Screening visit.
 
14. Qualified blinded assessor (blinded to previous assessments both of efficacy and safety) must be used.  It is recommended that the same qualified personnel
be used for each visit.
15. The combined index score will be calculated by the Sponsor using the individual scores from the following measures: lateral spinal flexion, tragus-to-wall
distance, lumbar flexion (modified Schober), maximal intermalleolar distance, and cervical rotation.
16. Chest expansion will be measured for spinal mobility.
17. Spinal pain assessment includes both Total Back Pain and Nocturnal Spinal Pain.
18. At all visits, the scheduled dose of investigational product will be taken by the subject in the clinic.
19. All blinded investigational product will be collected at the start of the Week 16 visit and subjects will receive new investigational product as a part of the 
open-label portion of the study at the Week 16 visit and will receive the first dose of open-label investigational product in the clinic.
20. Instruct subject not to take the in-clinic dose of investigational product the day of the next study visit and to bring the drug supply with them to the visit.
21. Confirm and document that contraception, if assigned, is used consistently and correctly.
22. Per Amendment 3, all subjects will be asked at every remaining study visit if they have any newly-developed risk factors for VTE as described in
Section 7.1.14


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Tofacitinib is being developed for the treatment of adult subjects with active ankylosing
spondylitis (AS) who have had an inadequate response to previous non-steroidal 
anti-inflammatory drug (NSAID) or tumor necrosis factor inhibitor (TNFi) treatment.
Tofacitinib is a potent, selective inhibitor of the Janus Kinase (JAK) family of kinases with a 
high degree of selectivity against other kinases in the human genome.  In kinase assays, 
tofacitinib, inhibits JAK1, JAK2, JAK3, and to a lesser extent TyK2.  In cellular settings
where JAK kinases signal in pairs, tofacitinib preferentially inhibits signaling by 
heterodimeric receptors associated with JAK3 and/or JAK1 with functional selectivity over 
receptors that signal via pairs of JAK2.1,2,3  This affects signaling via IL-17, IL-21 and 
IL-23 which have been implicated in AS pathology.3 Antibodies to IL-17 have demonstrated 
efficacy in AS.3
Through direct and indirect inhibition of cytokine pathways, tofacitinib can modulate immune 
responses and reduce or prevent inflammation.3  
1.2. Background and Rationale
AS is prevalent among spondyloarthropathies, a group of arthritic conditions affecting the
spine.  AS causes bone erosions in the axial skeleton and chronic inflammation at the
insertion of ligaments and tendons which results in new bone formation and eventual
ankylosis of the joints. The diagnosis is confirmed by pelvic x-rays that meet Modified New 
York Criteria for Ankylosing Spondylitis (1984) (See Appendix 2). AS usually progresses
from sacral inflammation initiating in the sacroiliac joints to progressive spine ankylosis over
time leading to back pain, loss of mobility, fatigue, stiffness and functional impairment.  AS
is frequently associated with peripheral arthritis, enthesitis, osteoporosis and extraarticular
manifestations such as anterior uveitis and inflammatory bowel disease (IBD).  This
under-recognized disease is often not diagnosed for many years and typically presents in
people between 20 and 40 years of age with a slightly higher prevalence in males leading to
progressive disability and adverse effects on quality of life.4,5  It is estimated that this
condition affects approximately 0.1-1.1% of the Caucasian adult population globally.5,6
The etiology of AS is currently unknown but a genetic link was noted in 90-95% of people
with AS who are positive for HLA-B27 allele and risk increases with HLA-B27-positive
relatives.5,7,8  There is currently no cure for AS. As a result patients with AS face a poor 
quality of life with increased rates of work disability and unemployment and an ever
increasing cost to society.9,10
In the past several years there has been significant progress in the management of AS.  With 
the advent of new consensus-based criteria issued by Assessments in Ankylosing Spondylitis 
International Society (ASAS)/the European League Against Rheumatism (EULAR) group, 
the earlier identification of patients with AS is possible.11  Magnetic Resonance Imaging 
(MRI) has proven valuable in identifying early sacroiliitis and spondylitis with detection of 
enthesitis and synovitis in the axial skeleton.12


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For many decades, the mainstay of treatment of AS has been NSAIDs and structured exercise 
programs including physical therapy with the aim of relieving clinical symptoms. However, 
gastrointestinal and other adverse effects limit the tolerability of NSAIDs including some 
COX-2 selective inhibitors.  In addition, AS patients report insufficient control with NSAIDs
alone.11  Treatment with conventional synthetic disease-modifying anti-rheumatic drugs
(csDMARDs) that have shown efficacy in rheumatoid arthritis have not shown similar 
efficacy in AS.13,14  Sulfasalazine may provide some benefits for peripheral arthritis but does
not impact axial disease.15,16
TNF-α (Tumor Necrosis Factor alpha) antagonists, also known as TNF inhibitors (TNFi),
have demonstrated efficacy and are approved for the reduction of clinical signs and symptoms,
in patients with AS.  A recent recommendation from the ASAS recommends that anti-TNF
therapy is indicated for those patients with persistently high disease activity despite
conventional treatment.18  However, parenteral administration of TNF inhibitors limit the use
of TNFi in AS, and there is a substantial proportion of patients who have an inadequate 
response to TNFi.19-21  Additional biological DMARDs (bDMARDs) have been subsequently 
approved but these remain parenteral.  There remains an unmet medical need for an effective
oral treatment for AS.
Tofacitinib has previously demonstrated efficacy and safety in Phase 221-26 and Phase 325
randomized controlled clinical trials of rheumatoid arthritis (RA) with up to 24 months duration 
and in long-term extension studies (LTE) with up to 105 months of observation.33-35  Tofacitinib 
is approved by the FDA (Food and Drug Administration) and the European Medicines Agency 
(EMA) for the treatment of moderate to severe RA.  In psoriatic arthritis (PsA), tofacitinib 
was safe and effective in phase 336,37 and long-term extension studies.  Tofacitinib was 
approved by the FDA in December 2017 and the EMA in June 2018 for the treatment of PsA.
Efficacy and safety was demonstrated in phase 2 and phase 3 studies of other chronic
inflammatory diseases such as psoriasis (PsO)38-41 and was approved for the treatment of 
ulcerative colitis (UC) by the FDA and Japan in May 2018.42
A previous Phase 2 study, A3921119, was conducted in AS patients with an inadequate 
response to NSAIDs.4  This study, A3921120, will evaluate the efficacy and safety of
tofacitinib in patients with active AS in a double-blind 16-week, placebo-controlled,
randomized, multicenter study in subjects that have an inadequate response to previous
treatment with NSAIDs or with TNFi.
This study is a follow-up to the A3921119 Phase 2b study of tofacitinib in active AS.  This trial
will use placebo control in the study design.  Subjects who are enrolled in this study will be
allowed to remain on their concomitant NSAIDs/csDMARDs as noted in the inclusion and
exclusion criteria.  In addition, subjects may be offered an appropriate rescue medication (see 
Appendix 6) during the study if there is an increase in pain.  The placebo-controlled phase of 
the study is of short duration (16 weeks), if some subjects do experience increased or 
persistent clinical disease activity, worsening or persistent high disease activity should be 
clinically apparent given the frequency of visits and they will have the option to withdraw 
from the investigational product at any time.  Finally, all subjects will be advanced to 
open-label tofacitinib 5 mg BID after the 16-week double-blind treatment period.  Subjects 


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will remain blinded to the sequence whether or not they were on placebo or tofacitinib 
throughout the study.  Given these considerations, it is appropriate to investigate tofacitinib 
in a bDMARD naïve population, as well as those who have had an inadequate response to 
TNFi. 
1.2.1. Summary of Efficacy
1.2.1.1. Rheumatoid Arthritis
Tofacitinib has demonstrated efficacy in RA as both monotherapy and in combination with 
methotrexate in Phase 2 and 3 studies.  Efficacy in relieving signs and symptoms and in 
restoring physical function was demonstrated by American College of Rheumatology 
20% response (ACR20) primary endpoint and secondary efficacy endpoints including 
ACR50, ACR70, Disease Activity Score for 28 Joints (DAS 28) and the Health Assessment 
Questionnaire Disability Index (HAQ-DI).  Additionally, radiographic assessments showed 
tofacitinib reduced or inhibited the progression of structural damage.
Evidence of sustained efficacy of tofacitinib treatment in RA was provided from data in 
open-label extension studies.  In the long-term follow-up studies A3921024 (ongoing at the 
time of analysis) and A3921041, efficacy was maintained in these studies through at least 
96 months.  No additional long term safety issues were identified. 
1.2.1.2. Psoriatic Arthritis 
The tofacitinib Phase 3 program was designed to evaluate the safety and efficacy of 
tofacitinib 5 mg and 10 mg BID in subjects with active psoriatic arthritis (PsA).  The 
2 pivotal studies (A3921091, A3921125) compared the efficacy of both tofacitinib doses to 
that of the placebo over 3 months for improvements in multiple PsA domains, examined the 
onset of efficacy, and assessed the persistence of efficacy (over a period of greater than 
3 months) of both tofacitinib doses in csDMARD inadequate responder (csDMARD-IR) 
TNFi-naïve and TNFi-IR populations.  For both studies the ACR20 response rate and the 
mean HAQ-DI (decrease) were statistically higher for both tofacitinib 5 mg and 10 mg BID 
dose treatment groups than the placebo treatment group at Month 3.  For both studies, early 
onset of efficacy in ACR20 response was shown with both tofacitinib doses as demonstrated 
by a statistically significant superior response to placebo at Week 2, Month 1, and Month 2.  
ACR50 response rates demonstrated superiority to placebo at Month 3 for both studies.  
Tofacitinib 5 mg BID was approved by the FDA for the treatment of PsA as of 14 December 
2017 and by the EMA as of 25 June 2018. 
1.2.1.3. Ulcerative Colitis
Efficacy in UC was shown in Phase 2 and 3 studies.  In Phase 3 induction studies (A3921094 
and A3921095) the proportion of subjects showing remission by Week 8 was statistically 
significantly greater in the tofacitinib 10 mg BID group as compared with the placebo group.  
Mucosal healing at Week 8 also showed statistically significant improvement over the 
placebo.  In maintenance study A3921096, efficacy of tofacitinib 5 mg BID and 10 mg BID 
was demonstrated with statistically significant greater treatment effects for both treatment 
groups versus placebo at Week 52 for remission, mucosal healing and sustained 


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corticosteroid-free remission. Tofacitinib 5 and 10 mg BID was approved for the treatment
of UC in the US as of 30 May 2018 and in Japan as of 25 May 2018.
1.2.1.4. AS
A dose-ranging Phase 2 study, A3921119, evaluated the efficacy and safety of tofacitinib in 
AS subjects with an inadequate response to NSAIDs.  The primary endpoint estimated the 
dose-response relationship using the Emax model for the ASAS20 response rate at Week 12.  
Tofacitinib 5 mg and 10 mg BID had response rates with model based estimated differences 
from placebo of 22.9% and 27.3% respectively.  Normal approximation analysis of the 
ASAS20 at Week 12 demonstrated tofacitinib 5 mg BID was the only dose statistically 
superior to the placebo.  Secondary endpoints generally demonstrated greater improvements 
with tofacitinib 5 and 10 mg BID than the placebo. 
1.2.2. Summary of Safety
The clinical development program for tofacitinib (oral administration) has included patients 
with RA, juvenile idiopathic arthritis (JIA), PsA, UC, PsO, renal transplant rejection, Crohn’s 
disease (CD) and AS, enrolled in 48 Phase 2, Phase 3 and LTE studies.
Cumulatively through 05 May 2018, it is estimated that 23,038 subjects have participated in 
tofacitinib clinical trials worldwide, with more than 14,473 subjects receiving at least 1 study 
dose of oral tofacitinib, in either a randomized clinical study or LTE study.  Of these 
subjects, approximately 8700 subjects continue to receive tofacitinib by participating in LTE
or other types of continuation studies.
Potential safety risks for subjects treated with tofacitinib are based on the totality of the data 
including nonclinical observations, clinical observations, as well as safety risks reported for 
other therapies that may share common pathways with tofacitinib. These risks are discussed 
briefly in the following section.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure. 
1.2.3. Overall Risk-Benefit
1.2.3.1. Potential Benefits
Given the chronic nature of this disorder and the limited available therapies, there remains an
unmet medical need for an effective oral treatment for AS.  In addition, patients may have an 
inadequate response to available treatment options such as TNFi.
The benefits to individual subjects participating in this study will be the potential control of
the disease activity by improving signs and symptoms.  All subjects may also benefit from
gaining knowledge about their health status through study tests and physician assessments, as
well as having close monitoring of their disease.


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1.2.3.2. Potential Risks
The risks associated with tofacitinib are similar to the risks associated with the use of other 
bDMARDS, including a potential risk for development of serious and other infections, 
eg, tuberculosis and viral reactivation such as herpes zoster (HZ).  In the RA program, the 
serious infection rate in the tofacitinib-treated subjects was consistent with the rates of 
serious infections in patients treated with other therapeutic interventions including 
bDMARDs.  Serious infections were more frequent among the elderly (>65 years), subjects 
with diabetes mellitus and subjects treated previously with biological agents.  Rates of HZ 
infections in tofacitinib-treated subjects with RA were increased compared with 
placebo-treated RA subjects and historical controls; this included an increased risk of HZ 
infections in Asian RA subjects compared with non-Asian RA subjects.  In the tofacitinib RA 
clinical development program, the rate of HZ varied significantly across countries and 
regions.  The incidence rates of HZ in Japan and Korea were notably higher than the rates 
observed in other regions/countries.  The reason for the increased risk of HZ in Japan and 
Korea is unclear.
Decreases in white blood cell counts, particularly neutrophils and lymphocytes, and 
decreased in hemoglobin have been observed.  These effects are usually mild to moderate 
and returned to normal after discontinuation of therapy.  Anemia is a possible consequence of 
JAK2 inhibition.  Experience to date indicates that anemia is easily monitored, usually 
manageable without discontinuation of treatment, and reversible on discontinuation of 
tofacitinib.  Neutropenia is of primary concern by virtue of its relationship to an increased 
risk of infection.  Thus far no association between the occurrence of neutropenia and 
infection has been observed in the tofacitinib program.
Treatment with tofacitinib was associated with increases in levels of Low Density 
Lipoprotein (LDL) and High Density Lipoprotein (HDL) cholesterol, with the ratios of mean 
LDL/HDL cholesterol unchanged.  In the previous controlled trials, elevation of LDL 
cholesterol generally returned to pre-treatment levels after discontinuation of tofacitinib.  In 
light of the association of RA and accelerated atherosclerosis, cardiovascular (CV) mortality 
and morbidity CV events were evaluated by an independent adjudication committee.  Review 
of cardiovascular events by the committee reported in RA and PsO studies suggest that 
tofacitinib was not associated with an increase in major adverse cardiovascular events.
Also observed in previous studies were slight increases in measured serum creatinine and 
serum transaminases.  This effect generally returned to normal after discontinuation of 
therapy.  A single RA subject experienced possible drug-induced liver injury (DILI) while 
being treated with tofacitinib and methotrexate.  Tofacitinib was discontinued and the subject 
recovered following treatment with prednisone and azathioprine.  The time course of the 
subject’s biochemical abnormalities were atypical for DILI, however investigation did not 
reveal an alternative etiology.  No additional possible DILI cases and no confirmed Hy’s 
Law cases have been identified during adjudication by the Hepatic Event Review Committee
(HERC).


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Non-melanoma skin cancer (NMSC) has been acknowledged as an adverse drug reaction for 
tofacitinib based on review of data in RA subjects.  There has been no identified increased 
risk for other types of malignancy for tofacitinib, although an increased risk of 
post-transplant lymphoproliferative disorders (PTLD) were observed in tofacitinib-treated 
subjects in a renal transplant study where combination of multiple potent 
immunosuppressants were used in conjunction with tofacitinib.  Other malignancies observed 
(at varying frequencies depending on the population under study) include breast cancer, 
lymphoma, melanomas, colon and prostate cancer.  Pancreatic and other cancers have also 
been reported less frequently.
Cases of gastrointestinal (GI) perforation were observed in RA subjects taking tofacitinib, 
often in the setting of diverticulitis.  All affected subjects had underlying risk factors, 
including a history of concomitant drug treatment with (NSAIDS) and/or corticosteroids that 
have been associated with an increased risk of GI tract injury.43,44  Isolated events of GI
perforation have also been reported in clinical trials in other tofacitinib indications including
one (preferred term: appendicitis) in the PsA program, 8 in the UC program, 3 in the CD 
program and 2 in the renal transplant program.
Interstitial lung disease (ILD), a complex co-morbidity in RA subjects, has also been 
reported in RA subjects receiving tofacitinib.  While data from the RA development program 
do not identify a pulmonary toxicity for tofacitinib, an increased risk of ILD was observed in 
Asian RA subjects as compared to non-Asian subjects but there was no consistent dose 
relationship.
Based on nonclinical data, there is a potential risk for teratogenicity with tofacitinib.
A more detailed discussion of tofacitinib safety can be found in the Investigator’s Brochure.
1.2.4. ClinicalPharmacokinetics
The pharmacokinetic (PK) profile of tofacitinib is characterized by rapid absorption, rapid 
elimination (terminal half-life of ~3 hours) and dose proportional PK.  Co-administration 
with a high fat meal increased the tofacitinib AUC by 14% and decreased Cmax by 26%; no 
dosage adjustments or meal restrictions during chronic dosing are warranted.  The clearance 
mechanisms for tofacitinib in humans appear to be both non-renal and renal excretion of the 
parent drug, the former accounting for approximately 2/3 of the total clearance.  The 
metabolism of tofacitinib appears to be primarily mediated by Cytochrome P450 enzyme 
3A4 (CYP3A4) with minor contribution from CYP2C19 as suggested by data from poor 
metabolizers of CYP2C19.
The PK of tofacitinib is similar between Caucasians and Japanese healthy volunteers.
In vitro studies have shown that tofacitinib does not significantly inhibit the major drug 
metabolizing CYPs, indicating a low potential for tofacitinib to increase the exposure of
other drugs.  This was demonstrated in a clinical study where tofacitinib did not have an 
effect on the pharmacokinetics of an oral dose of midazolam (a highly sensitive CYP3A 
substrate) in healthy volunteers.  On the other hand, inhibitors and inducers of CYP3A4/5 are 


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likely to alter the disposition of tofacitinib.  Co-administration of tofacitinib with 
fluconazole, a moderately potent inhibitor of CYP3A4 and a potent inhibitor of CYP2C19, 
resulted in 79% and 27% increases in the AUC and Cmax of tofacitinib, respectively.  
Co-administration of tofacitinib with methotrexate had no effect on the PK of tofacitinib and 
resulted in an approximate 10% decrease in the AUC of methotrexate.  The extent of 
decrease in methotrexate exposure does not warrant modifications to the individualized 
dosing of methotrexate.  Co-administration of tofacitinib with cyclosporine and oral 
tacrolimus, moderate and weak CYP3A4 inhibitors, respectively, resulted in increases of 
73% and 21% in AUCinf of tofacitinib.  In both cases, tofacitinib Cmax was decreased 
slightly; ratio 91%, for tacrolimus and 83%, for cyclosporine.
Consistent with the ~30% contribution of renal clearance to the total clearance of tofacitinib, 
mean exposure in end stage renal disease (ESRD) subjects (on a non-dialysis day) was 
approximately 40% higher compared with historical healthy subject data. In contrast, in a 
separate study, mean exposure was approximately 125% higher in subjects with severe renal 
impairment compared with healthy subjects.  Mild and moderate renal impaired subjects had 
37% and 43% higher exposure, respectively, compared with healthy subjects.
Based on these data, subjects with estimated creatinine clearance <40 mL/min will be
excluded from this study as will concomitant use of moderate to potent inhibitors of 
CYP3A4/5. 
Further clinical pharmacology background information on tofacitinib can be found in the 
current version of the Investigator’s Brochure.
1.2.5. Drug Development and Study Rationale
The effects of tofacitinib on cytokines (including the cross over to JAK1 which may result in 
some attenuation of signaling by additional cytokines, such as IL-6 and IFN-γ) that are 
integral to lymphocyte activation, proliferation, and function and inhibition of their signaling 
may thus result in suppression of multiple aspects of the immune response.  Cytokines IL-17, 
IL-21 and IL-23 have been implicated in AS pathology and antibodies to IL-17 have
demonstrated efficacy in AS.3  This forms the basis of the rationale to investigate the effect 
of tofacitinib in active AS.
Ankylosing Spondylitis as a chronic inflammatory disease shares many characteristics with 
RA and PsA such as inflammation and bone erosions.  The axial inflammation that is specific 
to AS, is the inflammation in the spine.  This can lead to bone erosions, new bone formation 
and ankylosis of the spine.  In addition, RA, PsA, and AS share many similar circulating pro 
inflammatory cytokines, including IL-6, IL-17, IL-23, TNF-and TNF-.45  Increased 
concentrations of IL-6 have been observed in patients with chronic inflammatory conditions 
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Phase 2 study A3921119 assessed the safety and efficacy of tofacitinib in subjects with active 
AS at 2 mg BID, 5 mg BID and 10 mg BID. Approximately 200 subjects (~50 per arm) were 
randomized in a 1:1:1:1 ratio to one of 4 treatment sequences for a total of 12 weeks of
treatment.  At Week 12 the primary endpoint Emax model ASAS20 response rates for the 
tofacitinib 2 mg BID, 5 mg BID and 10 mg BID treatment groups and placebo treatment 
group were 56.0%, 63.0%, 67.4% and 40.1%, respectively.  The tofacitinib 5 mg and 10 mg 
BID treatment groups had numerically greater ASAS20 response rates than the placebo 
treated group at Week 12, and greater mean improvement from Baseline in Patient Global 
Assessment (PGA) of disease score, total back pain, inflammation score, and nocturnal spinal 
pain than the placebo group.  There was statistically significant greater improvement in 
ASAS40 rates, ASDASCRP values, ASDASCRP clinically important improvement, 
improvement in mean BASDAI values, and BASDAI50 response rate at Week 12 for all 
tofacitinib treatment groups compared to the placebo. 
Secondary endpoints such as BASDAI50 and Bath Ankylosing Spondylitis Functional Index 
(BASFI), as well as patient-reported outcomes such as AS Quality of Life (ASQoL) were 
also met.  Efficacy was also demonstrated through objective measures such as the 
Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index of disease activity 
scores. There was statistically significant greater improvement from Baseline for LS mean 
SPARCC MRI index of disease activity score of the SI joints compared to placebo for the 
tofacitinib 5 mg BID and 10 mg BID treatment groups.  There was also statistically 
significant greater improvement from Baseline for LS mean SPARCC MRI index of disease 
activity score of the spine compared to placebo for the tofacitinib 2 mg BID, 5 mg BID and 
10 mg BID treatment groups, with the 5 and 10 mg doses showing statistical significance.  
The safety profiles for both the tofacitinib treated and placebo treated groups were similar.  
The totality of these results forms the basis of our decision to move to Phase 3.
1.2.6. Dose Selection Rationale
Tofacitinib 5 mg BID will be evaluated in this Phase 3 study in AS.
Tofacitinib doses of 5 and 10 mg BID were demonstrated to be efficacious in RA and PsA 
subjects in those respective clinical development programs.  The primary endpoint Emax 
model analysis estimated an ASAS20 response rate of 63.0% after tofacitinib 5 mg BID, a 
22.9% rate higher than placebo.  Supportive normal approximation analysis demonstrated an 
ASAS20 response rate after tofacitinib 5 mg BID significantly higher than placebo
(80.8% vs 41.2%; p<0.001); tofacitinib 2 mg and 10 mg BID demonstrated greater response 
rate than placebo but were not significant (51.9% and 55.8%, respectively).  A consistent 
magnitude of efficacy was not observed after the lowest dose (2 mg BID) of tofacitinib, 
especially with more objective endpoints such as MRI.  Compared to 5 mg BID, the 10 mg 
tofacitinib dose did not demonstrate consistent or clinically meaningful additional 
improvements in efficacy across study endpoints.  No new safety concerns were identified in 
the Phase 2 AS study at any dose of tofacitinib.


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Tofacitinib 5 mg BID is the currently approved dose in the United States Prescribing 
Information (USPI) for use in RA, PsA, and UC.  Given the results of the Phase 2 study of 
tofacitinib in AS subjects as well as taking into consideration the current BID posology for 
tofacitinib in other rheumatologic diseases, 5 mg BID of tofacitinib was selected to be 
evaluated in this Phase 3 study in AS subjects.
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objectives:
Primary Endpoint:

To compare the efficacy of tofacitinib 5 mg BID versus
placebo on the ASAS20 response rate at Week 16 in
subjects with active AS that have had an inadequate
response to previous treatment.

ASAS20 response at Week 16.
Key Secondary Objective:
Key Secondary Endpoint:

To compare the efficacy of tofacitinib 5 mg BID versus 
placebo on the ASAS40 response rate at Week 16 in 
subjects with active AS that have had an inadequate 
response to previous treatment.

ASAS40 response at Week 16.
Other Secondary Objectives:
Other Secondary Endpoints:

To compare the safety and tolerability of tofacitinib 
5 mg BID versus placebo in subjects with active AS that have
had an inadequate response to previous treatment.

Incidence and severity of Adverse Events (AE).

Clinical laboratory tests, vital signs, physical
examination and 12-lead ECG parameters.

To compare the efficacy (including health-related 
quality of life, function, pain, and fatigue) of tofacitinib 
5 mg BID versus placebo at all time points in subjects 
with active AS that have had an inadequate response to 
previous treatment.

ASAS20 response at all other time points.

ASAS40 response at all other time points.

Change from baseline in Ankylosing Spondylitis
Disease Activity Score using C-Reactive Protein
(ASDASCRP) at all time points.

Change from baseline in hsCRP at all time points.

Change from baseline in Ankylosing Spondylitis
Quality of Life (ASQoL) at all time points collected.

Change from baseline in Short-Form-36 Health
Survey-Version 2 Acute (SF-36v2) at all time points 
collected.

Change from baseline in Bath Ankylosing Spondylitis
Metrology Index (BASMI) including the 5 components 
(lateral spine flexion, tragus-to-wall distance, lumbar 
flexion, maximal intermalleolar distance and cervical 
rotation) at all time points.

Change from baseline in Functional Assessment of
Chronic Illness Therapy-Fatigue (FACIT-F) 
(3 endpoints: total score, experience domain and 
impact domain scores) at all time points.

Change from baseline in Patients Global Assessment of 
Disease (PGA) at all time points collected.

Change from baseline in Patient’s Assessment of 
Spinal Pain (Total Back Pain, Nocturnal Spinal Pain) 
at all time points collected.

Change from baseline in Bath Ankylosing Spondylitis
Functional Index (BASFI) at all time points.

Change from baseline in inflammation (mean of the 
answers to questions 5 and 6 of the BASDAI) at all 
time points collected.


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•
ASAS 5/6 response at all time points.
•
ASAS partial remission criteria at all time points.
•
Change from baseline in Bath Ankylosing Spondylitis
Disease Activity Index (BASDAI) at all time points.
•
BASDAI50 response at all time points.
•
ASDAS clinically important improvement, ASDAS
major improvement and ASDAS inactive disease at all
time points.
•
Change from baseline in Maastricht Ankylosing
Spondylitis Enthesitis Score (MASES) at all time points
collected.
•
Change from baseline in extra-articular Involvement
(Specific Medical History and peripheral articular
involvement [as assessed by change from baseline in 
swollen joint count]) at all time points collected.
•
Change from baseline in spinal mobility at all time
points collected.
•
Change from baseline in EuroQol EQ-5D Health State
Profile 3 level (EQ-5D-3L) and Your own health state 
today (EQ-VAS), at all time points collected.
•
Change from baseline in Work Productivity and
Activity Impairment (WPAI) Questionnaire:
Spondyloarthritis at all time points collected.
Tertiary/Exploratory Objectives:
Tertiary/Exploratory Endpoints:
•
 
•
.
•
To evaluate the effect of tofacitinib 5 mg BID on 
lymphocyte subsets using FACS analysis.
•
Fluorescence Activated Cell Sorting (FACS) analysis
of lymphocyte subsets.
•
To measure the effect of tofacitinib 5 mg BID on 
healthcare resource utilization at all collected time 
points.
•
AS HealthCare Resource Utilization Questionnaire
(AS-HCRU) at all time points collected.
3. STUDY DESIGN
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, efficacy and 
safety study of tofacitinib in subjects with active AS.  Approximately 480 AS subjects will be 
screened globally in order that approximately 240 eligible subjects (120 per arm) will be 
randomized in a 1:1 ratio to tofacitinib 5 mg BID or matching placebo BID for a total of 
16 weeks of blinded treatment.  During the 16-week treatment period subjects will visit the 
clinic every two weeks (±3 days) until the Week 4 visit and then every 4 weeks (±7 days) 
until the completion of Week 16.  At the Week 16 visit all subjects will be assigned to 
open-label tofacitinib and will visit the clinic every two months (±7 days) until Week 48.  
Subjects will then return to the clinic for a Follow-up visit approximately 28 days after the 
Week 48 visit.  There will be a total of 2 planned analyses conducted when all applicable 
subjects have completed their Week 16 and Week 48 (including follow-up) visits, 
respectively. 
 
 The first analysis will be conducted when all applicable subjects 
CCI


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have completed their Week 16 visit (see Section 9.2).  The investigators, subjects and 
sponsor study team will remain blinded to the first 16 weeks of treatment assignment through 
the entire duration of the trial until database release.  
Randomization will be stratified by prior treatment history: (1) bDMARD-naive and (2) 
Tumor Necrosis Factor inhibitor-inadequate responder (TNFi-IR) or bDMARD use (non-IR).  
Approximately 80% of the subjects will be bDMARD-naïve and have an inadequate response 
to at least 2 NSAIDs (designed as Stratum bDMARD-naïve), and the other 
approximately 20% of subjects who had an inadequate response to at least one but not more 
than 2 TNFi and have an inadequate response to at least 2 NSAIDs or bDMARD use 
(non-IR) [designed as Stratum TNFi-IR or bDMARD use (non-IR)].  Subjects who had prior 
bDMARD use (non-IR) will be eligible to participate in the study and will be included in the 
TNFi-IR or bDMARD use (non-IR) stratum.  An inadequate response to NSAID or TNFi 
treatment is defined as having a treatment related adverse event or lack of response to 
NSAID or TNFi treatment that was administered in accordance with its labeling 
recommendations. The sponsor may limit enrollment of subjects with baseline hsCRP below 
0.287 mg/dl to match their estimated prevalence in AS.  See Figure 1.
Figure 1.
Study Design Schematic
0*
       PBO BID                 Tofacitinib 5mg BID
48
Active 
AS: 
stratify 
80% 
bDMARD 
naïve; 
20% TNFi 
IR or 
bDMARD 
use 
(non-IR)
Tofacitinib 5mg BID      Tofacitinib 5mg BID  
*Randomize 1:1; N=120 perarm
Screen
16
Follow
-up
Primary endpoint: 
Proportion of subjects 
achieving ASAS20 at 16 
weeks
weeks
Active disease is required for entry into this study and is defined as: Modified New York 
Criteria for Ankylosing Spondylitis (1984), Bath Ankylosing Spondylitis Disease Activity 
Index (BASDAI) score of 4 and back pain score (BASDAI Question 2) of 4.  If subjects 
have fulfilled entry criteria, they will be randomized to receive either tofacitinib 5 mg BID or 
placebo.


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Including the Screening visit, subjects will return to the clinic site at above noted intervals for 
a total of 12 visits.  If the subject completes the Follow-up visit, the minimum duration of 
participation will be approximately 56 weeks (Screening: 30 days, 16 week double blind 
treatment period, 32 week open-label treatment period, Follow-up visit: 28 days 7 days) 
without inclusion of any alterations in the visit schedule according to the protocol.
Selected assessments during the study will need to be completed by a qualified blinded 
assessor.  This blinded assessor should be blinded to subject’s baseline treatment assignment, 
all previously completed efficacy assessments (including patient’s global assessment) and all 
safety data (eg, laboratory results, adverse events) in order that the current assessments are 
completed in an objective manner throughout the study.
Amendment 3
All subjects in the study will be evaluated for risk factors for VTE50.
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 VTE.
A subject may be at high risk for VTE if he/she:
•
has heart failure or prior myocardial infarction within past 3 months;
•
has inherited coagulation disorders;
•
has had VTE, either deep venous thrombosis or pulmonary embolism;
•
is taking combined hormonal contraceptives or hormone replacement therapy;
•
has a malignancy (association is strongest with cancers other than non-
melanoma skin cancers);
•
is undergoing major surgery or is immobilized.
Additional risk factors for VTE, such as age, diabetes, obesity (BMI≥30 kg/m2), smoking 
status, hypertension, and first degree family history of VTE 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 discontinue from open-label 5 mg BID
dose of tofacitinib.
See Risk Factor Check for VTE in Section 7.1.14 for tofacitinib dosing guidance when a risk 
factor is identified.
If a subject has one or more of the risk factors for VTE listed above under Amendment 3 and 
is receiving tofacitinib 5 mg BID, they may remain on tofacitinib 5 mg BID after careful 
investigator assessment of benefit: risk. For subjects who do not have any of the risk factors 


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for VTE listed above under Amendment 3, he/she will remain on their open-label tofacitinib 
dose of 5 mg BID.
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 non-medical 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 appropriately qualified member
of the investigator’s study team before subjects are included in the study.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the
study:
1. Evidence of a personally signed and dated informed consent document indicating that
the subject has been informed of and is capable of comprehending all pertinent
aspects of the study.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and
other study procedures.
3. Subject is at least 18 years old (or the minimum country-specific age of consent if 
>18) at the screening visit.
4. The subject has a diagnosis of AS based on the Modified New York Criteria for
Ankylosing Spondylitis (1984). See Appendix 2.
5. The subject must have a radiograph of the SI joints (AP Pelvis) documenting diagnosis of 
AS.  Previous radiographs (up to 2 years old) can be used if they are accepted by the 
central reader.  Otherwise, a new radiograph will be obtained during the screening period.
6. Subject has active AS Screening and Baseline (Day 1) visits defined as:

BASDAI score of 4; and

Back pain score (BASDAI Question 2) of 4.
7. Subject has active disease despite nonsteroidal anti-inflammatory drug (NSAID)
therapy or is intolerant to NSAIDs as defined by:
Subject must have had at least a total of 2 occurrences of an inadequate clinical 
response (minimum of 4 week trial) or intolerance to at least 2 different oral NSAIDs.  
An inadequate response to a previous NSAID or TNFi is defined as a lack of 
sufficient clinical response based on a clinical judgment or based on a related adverse 


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event (eg an adverse drug reaction requiring discontinuation) to the subject’s previous 
treatment for AS.  This will be documented on the relevant case report form (CRF).
Intolerance is defined as having discontinued NSAID treatment due to a related
adverse event (eg, allergic reaction, gastrointestinal symptoms or signs, hypertension,
etc).  
8. Subjects who are designated as TNFi-IR must have received at least 1, but not more
than 2 approved TNF inhibiting biologic agent that was administered in accordance 
with its labeling recommendations and was inadequately effective after the minimum 
treatment times listed below and/or not tolerated after one or more doses.

At least 3 months of adalimumab treatment;

At least 3 months of etanercept treatment;

At least 4 infusions of infliximab;

At least 3 injections of golimumab;

At least 3 months of certolizumab treatment.
Intolerance is defined as having experienced a treatment-related AE 
(eg, infusion/injection reactions, infections, laboratory test changes, etc).  
Discontinuation for economic reasons is not considered intolerance. 
NOTE: The washout period required for study entry for TNFi at Baseline (Day 1) is 
discussed in Section 5.8.1.
9. Subjects may be receiving the following csDMARDs at the time of the screening 
visit.  These medications should be continued throughout the entire study and doses 
should remain unchanged.  Any other Disease-Modifying Anti-Rheumatic Drugs 
(DMARDs) require discussion prior to enrollment with the sponsor for washout 
timeframe.


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
Methotrexate (MTX): Maximum dose of 25 mg/week.  Minimum duration of
therapy 4 months and dose stable for 4 weeks prior to first dose of investigational 
product.  Subjects on MTX should be on an adequate and stable dose of folate 
supplementation per local standards/regulatory approval (eg, not less than 5 mg 
weekly based on folic acid, unless such doses would violate the local label 
guidelines or standard of care) for at least 4 weeks prior to the first dose of 
investigational product.  Subject must not have had previous serious toxicity 
while on MTX and not be expected to require evaluation for possible 
methotrexate toxicity (eg, require a liver biopsy for methotrexate toxicity) during 
the study;

Sulfasalazine (Azulfidine, Salazopyrin): Maximum dose of 3 gm/day.  
Minimum duration of therapy 2 months and dose stable for 4 weeks prior to first 
dose of investigational product.
10. Subjects who are already taking oral corticosteroids (not injectables) may participate in
the study:

Oral corticosteroids: Subjects who are already receiving oral corticosteroids must
be on a stable dose of 10 mg/day of prednisone or equivalent for 1 week prior to
the first dose of investigational product;

Injected (eg, intraarticular, intramuscular, epidural or intravenous) corticosteroids
must be discontinued 4 weeks prior to the first dose of investigational product;

Topical and intra-rectal corticosteroids will be allowed during the study.
11. Subject has discontinued all disallowed concomitant medication for the required time
prior to the first dose of investigational product.
12. Subjects who are receiving any investigational or marketed treatment for AS, arthritis
or back pain not mentioned elsewhere must have that treatment discontinued for
4 weeks or 5 half-lives, whichever is longer.
13. Subjects receiving non-prohibited concomitant medications for any reason must be
willing to stay on a stable regimen (doses and frequency) as defined in the protocol.
14. No evidence of active or latent or inadequately treated infection with Mycobacterium
tuberculosis (TB) as defined by all of the following:

A negative QuantiFERON-TB Gold (QFT G) In Tube test performed at or
within 3 months prior to the Screening visit.  Subjects with a history of Bacille 
Calmette Guérin (BCG) vaccination will be tested with the QFT G test; 

No local QTF G testing will be accepted for meeting this inclusion criterion;


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
A chest radiograph taken at or within the 3 months prior to screening and 
reviewed by a radiologist or pulmonologist as per local standard of care and 
documented to be without changes of suggestive active TB infection;

No history of either untreated or inadequately treated latent or active TB 
infection.
NOTE: If a subject has previously received an adequate course of therapy for latent 
(eg, 9 months of isoniazid in a locale where rates of primary multi drug resistant TB 
infection are <5% or an acceptable alternative regimen) TB infection, a 
QuantiFERON-TB Gold In Tube (QFT Gold test) need not be obtained, but a chest 
radiograph must still be obtained if not done so within the prior 3 months.  A subject 
who is currently being treated for latent TB infection can only be enrolled with 
confirmation of current incidence rates of multi drug resistant TB infection and
documentation of an adequate treatment regimen.
15. Women of childbearing potential must test negative for pregnancy prior to enrollment
in this study.
16. Female subjects of non-childbearing potential must meet at least 1 of the following
criteria:

Achieved post-menopausal 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/and have a central laboratory
confirmation of serum follicle-stimulating hormone (FSH) level confirming the
postmenopausal state;

Have undergone a documented hysterectomy and/or bilateral oophorectomy; 

Have medically confirmed ovarian failure. 
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential. 
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or subjects 
who are Pfizer employees, including their family members, directly involved in the
conduct of the study.  Persons who are dependent upon the sponsor, investigator or 
the study site are excluded.


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2. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
study entry and/or during study participation (excluding non-interventional follow-up
during the screening period).
3. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
4. History of known or suspected complete ankylosis of the spine.
5. Subjects that have been exposed to or are currently receiving targeted synthetic 
DMARDS (including JAK inhibitors) or those currently on biological DMARDS 
(ie, washout from any current bDMARD required per Section 5.8.1), thalidomide
(including previous use) and other prohibited concomitant medications noted in 
Appendix 4.
6. History of allergies, intolerance or hypersensitivity to lactose or tofacitinib 
(CP-690,550).  This includes subjects with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. The 
investigators of potential subjects with acquired lactose intolerance should consider 
whether this is sufficiently concerning so as to preclude participation.
7. Blood dyscrasias at screening or within 3 months prior to the first dose of
investigational product includingconfirmed:

Hemoglobin <10 g/dL;

Absolute white blood cell count (WBC) <3.0 x 109/L (<3000 mm3);

Absolute neutrophil count (ANC) <1.5 x 109/L (<1500 mm3);

Absolute lymphocyte count <1.0 x 109/L (<1000/mm3);

Platelet count <100 x 109/L (<100,000/mm3).
8. Estimated Creatinine Clearance <40 mL/min based on Cockcroft Gault equation at 
Screening visit (see Appendix 3).
9. Total bilirubin, AST or ALT more than 1.5 times the upper limit of normal (ULN) at 
screening visit. 


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One re-testing of a laboratory-acceptable specimen (eg, appropriately labeled, within
stability parameters, not hemolyzed, appropriate type (tube and reagent) and volume)
is allowed of any above parameters if the abnormal lab(s) was an uncharacteristic
result(s).
Re-test must be completed within the screening period.
10. History of any other autoimmune rheumatic disease.
11. History of an infected joint prosthesis at any time, with the prosthesis still in situ.
12. History of any lymphoproliferative disorder, such as Epstein Barr Virus related 
lymphoproliferative disease (EBV-LPD), history of lymphoma, leukemia, or signs
and symptoms suggestive of current lymphatic disease.
13. History of recurrent (more than one episode) herpes zoster or 
disseminated/multi-dermatomal (a single episode) herpes zoster or disseminated (a 
single episode) herpes simplex.
14. History of infection requiring hospitalization, parenteral antimicrobial therapy, or as 
otherwise judged clinically significant by the investigator, within the 3 months prior 
to the first dose of investigational product.
15. History of infection requiring antimicrobial therapy within 2 weeks prior to the first 
dose of investigational product.
16. Any prior treatment with non-B cell specific lymphocyte depleting agents/therapies 
(eg, alemtuzamab, efalizumab), alkylating agents (eg, cyclophosphamide or 
chlorambucil), or total lymphoid irradiation. 
17. Any subject who has been vaccinated with live or attenuated vaccines within the 
6 weeks prior to the first dose of investigational product or is to be vaccinated with 
these vaccines at any time during treatment or within 6 weeks after last dose of 
investigational product.
18. A subject with any condition possibly affecting oral drug absorption, eg, gastrectomy, 
clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery 
such as gastric bypass.  Procedures such as gastric banding, that simply divide the 
stomach into separate chambers, are NOT exclusionary.
19. A subject that is considered at risk for GI perforation by the investigator or Sponsor.
20. History of alcohol or drug abuse unless in full remission for greater than 6 months 
prior to first dose of investigational product.  Subjects currently using marijuana.


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21. Screening 12-lead electrocardiogram (ECG) that demonstrates clinically relevant 
abnormalities which may affect subject safety (eg, pattern of acute myocardial 
infarction, acute ischemia or serious arrhythmia) or interpretation of study results 
(eg, continuously paced ventricular rhythm or complete left bundle branch block).
22. A subject with a known immunodeficiency disorder or a first degree relative with a 
hereditary immunodeficiency.
23. A subject with a malignancy or with a history of malignancy, with the exception of 
adequately treated or excised non metastatic basal cell or squamous cell cancer of the 
skin or cervical carcinoma in situ.
24. Significant trauma or surgery procedure within 1 month prior to first dose of study 
medication, or any planned elective surgery during the study period.
25. A subject known to be infected with human immunodeficiency virus (HIV), hepatitis 
B virus or hepatitis C virus or any chronic infection.

Hepatitis B Surface Antigen positive (HBsAg+) is exclusionary; subjects who are
HBsAg- but Hepatitis B core antibody positive (HBcAb+) must undergo further
testing for HBsAb to be considered for enrollment. If HBsAb+, subject may
enroll; if HBsAb-, subject is excluded.

Subjects who are Hepatitis C Virus Antibody Positive (HCV Ab+) must undergo
further testing for Hepatitis C Virus Ribonucleic Acid (HCV RNA).  Subjects
who are HCV RNA- may enroll.
26. Pregnant female subjects; breastfeeding female subjects; female subjects of 
childbearing potential, who are unwilling or unable to use 1 highly effective method 
of contraception as outlined in this protocol for the duration of the study and for at 
least 28 days after last dose of investigational product.  Note: This is 2 methods of 
contraception for female subjects of childbearing potential from Canada.
27. A subject who, in the opinion of the investigator or Pfizer (or designee), will be 
uncooperative or unable to comply with study procedures.
4.3. Randomization Criteria
A subject who has signed an informed consent document to participate in the study, has
undergone all screening procedures, and has met all inclusion and none of the exclusion criteria
for participation in the study at the Baseline visit.
4.4. Lifestyle Requirements
In order to participate in the study, subjects must be made aware of the following lifestyle 
guidelines and restrictions that apply during the study period.  Details of these life style 
guidelines are provided in the sections as noted.


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
On designated study visit days, comply with fasting requirements for at least 9 hours
prior to visit (See Section 6).  On study visit days, subject should not take the 
in-clinic dose of study medication before the clinic visit.

On study visit days, do not smoke or ingest caffeine (eg, tea, coffee, some soft
drinks/colas/energy drinks and power bars) during the 30 minutes prior to blood
pressure and pulse (heart) rate measurements.

On study visit days, take prescribed permitted concomitant medication, as needed,
prior to the study visit, if it can be administered with water only.

Avoid vaccinations with live or attenuated live vaccines and contact with individuals
who have recently received live or attenuated live vaccines (See Section 4.4.4).

Discontinue and avoid using certain medications and treatments (see Inclusion Criteria
and list of prohibited medications in Section 5.8.4 and Appendix 4).

Contact the study site investigator if there are any changes or additions to concomitant
medications.

Avoid having elective surgery (See Section 4.4.5).

Agree to use highly effective contraceptive methods per Section 4.4.6.
4.4.1. Fasting Visit Requirements
On visit days when fasting lipid panels are scheduled to be collected, all subjects should
refrain from all food and liquids (water and regular medications permitted;
) for at least 9 hours prior to scheduled
safety laboratory tests. Visits that require fasting are Baseline/Day 1, Weeks 4, 16, 32, 48 and 
Follow-up.
4.4.2. Non-Pharmacologic Interventions
The subject should continue all non-pharmacological therapies, such as physical therapy, as
indicated. However, the subject should avoid changing the type or intensity of therapy, or
initiating new therapy, until after the Week 16 visit.
4.4.3. Dietary Supplements
For the purposes of this protocol, dietary supplements are defined as vitamins, minerals, 
purified food substances, and herbals with pharmaceutical properties.
Vitamins, minerals and purified food substances are allowed in amounts not known to be 
associated with adverse effects (such as hypervitaminosis).  Herbals with pharmaceutical 
properties are allowed only if there is acceptable evidence of no CYP3A inhibition or 
induction.  Otherwise, herbals with pharmaceutical properties must be discontinued for at 
least 4 weeks prior to first dose of investigational product, unless there is sufficient data 


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available regarding the duration of an herbal medication’s pharmacokinetic and 
pharmacodynamic effects to allow a shorter washout to be specified (eg, 5 half-lives).  Please 
direct any questions to the Sponsor.
Glucosamine sulfate and chondroitin sulfate are allowed in the study but subjects should be 
on a stable dose for 1 week prior to first dose of investigational product and throughout the 
study.
4.4.4. Vaccine Guidelines
Vaccination with live or live attenuated components is prohibited during the study and for
6 weeks after last dose of investigational product.  Similarly, current routine household 
contact with children and others vaccinated with live vaccine components should be avoided 
during treatment and for 6 weeks following completion of the study.  Some of these vaccines 
include varicella (“chickenpox or shingles”) vaccine, oral polio vaccine, and the inhaled flu 
vaccine.  Following vaccination with live component vaccines, the virus may be shed in 
bodily fluids, including stool, and there is a potential risk that the virus may be transmitted.  
General guidelines suggest that exposure should be avoided following vaccination with these 
vaccines for the stated time period:

Varicella or attenuated typhoid fever vaccination for 4 weeks following vaccination;

Oral polio vaccination for 6 weeks following vaccination;

Attenuated rotavirus vaccine for 10 days following vaccination;

FluMist(inhaled flu vaccine) for 1 week following vaccination.
4.4.5. Elective Surgery
During the course of this study, elective surgery should be delayed until the end of the 
placebo-controlled period. No elective surgery should be scheduled without first consulting 
with the Pfizer Medical Monitor.
Subjects who do require surgery should temporarily discontinue investigational product for 
one week prior to the surgical procedure and remain off investigational product after the 
surgical procedure until sutures/staples are removed. If absorbing sutures or chemical 
closure methods are utilized, investigational product can be resumed when the operative site 
is sufficiently healed and risk of infection is minimal.
4.4.6. Contraception
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 and 
his/her partner(s) 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 


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conversation, and the subject’s affirmation, in the subject’s chart (subjects need 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 partner.  Subjects in Canada who are women of childbearing potential (WOCBP) 
and sexually active are required to use two contraceptive methods at the same time, one 
highly effective contraceptive method and one additional effective contraceptive method.
A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least 
1 of the following conditions applies:

Is not a woman of childbearing potential (WOCBP).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described 
below during the intervention period and for at least 28 days after the last dose of 
study intervention, which corresponds to the time needed to eliminate any study 
intervention(s).  The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
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:
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.
5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception
should be used.  The spermatogenesis cycle is approximately 90 days.


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Highly Effective Methods That Are User Dependent
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal;

Injectable.
2. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.
3. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
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.  
No effects of tofacitinib have been seen in male fertility or offspring of dosed males in any 
preclinical studies conducted to date.  However, male subjects who are on background 
medications (including DMARDs) that require male contraceptive precautions according to 
the local drug label must do so if they are sexually active with women of child bearing 
potential during the study and after therapy for 3 months or for the duration specified in the
local drug label.  Subjects who are receiving concomitant drugs (eg, methotrexate) that 
require contraceptive precautions in their labeling should follow the most stringent 
precautions.
4.4.7. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the
trial is documented in the study contact list located in the study team repository site.


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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 
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 products are tofacitinib and placebo. 
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, patient population (bDMARD-naïve or TNFi-IR or bDMARD use 
[non-IR]) and the subject number. The site personnel will then be provided with a treatment 
assignment, randomization number, and dispensable unit (DU) or container number when 
investigational product is being supplied via the IRT system. The IRT system will provide a 
confirmation report containing the subject number, randomization number, and DU or 
container number assigned. The confirmation report must be stored in the site’s files.
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
Subjects will be randomized at the Baseline visit in a 1:1 ratio to one of the following two
parallel blinded treatment sequences for a total of 16 weeks of treatment.  Eligible subjects 
will be treated with one of the two sequences for 16 weeks followed by treatment with 
tofacitinib 5 mg BID for an additional 32 weeks.


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Randomization will be stratified by prior treatment history: (1) bDMARD-naive and 
(2) TNFi-IR or bDMARD use (non-IR). During the feasibility phase of clinical trial 
preparation, the sponsor conducted a survey of the countries and sites likely to participate in 
the study.  While there was country-to-country variability, the overall proportion of 
bDMARD-naïve and TNFi-IR or bDMARD use (non-IR) was approximately 80%/20% 
respectively.  The clinical trial was thus designed to reflect this prevalence.  Subjects with 
more than 2 TNFi failures were excluded due to the higher likelihood that they could be 
refractory to tofacitinib therapy, an observation noted in other tofacitinib trials in RA and 
PsA.
At the end of the 16 week double-blinded treatment period, all subjects will be assigned to 
open-label tofacitinib 5 mg BID to Week 48.  The investigators, subjects and sponsor study 
team will remain blinded to the first 16 weeks of treatment assignment through the entire 
duration of the trial until database release.
5.2. Breaking the Blind
This study will be subject-, investigator-, and sponsor-blinded.  For the open-label treatment 
period, subjects, investigator and sponsor study team will remain blinded to the double-blind 
treatment period study sequence. 
Strata (Patient 
Population)
Sequence
Treatment Sequence and Description
Planned 
Number of 
Randomized 
Subjects
bDMARD-naive
1
Blinded Tofacitinib 5 mg BID for 
16 weeks followed by open-label 
tofacitinib for 32 weeks
One-tofacitinib 5 mg tablet in AM & PM
96
bDMARD-naive
2
Placebo BID for 16 weeks followed by 
open-label 5 mg BID tofacitinib for 
32 weeks
One- 5 mg matching placebo tablet in 
AM & PM for the first 16 weeks followed 
by one-tofacitinib 5 mg tablet in the AM 
& PM for 32 weeks
96
TNFi-IR or bDMARD use 
(non-IR)
1
Blinded Tofacitinib 5 mg BID for 16 
weeks followed by open-label tofacitinib 
for 32 weeks
One-tofacitinib 5 mg tablet in AM & PM
24
TNFi-IR or bDMARD use 
(non-IR)
2
Placebo BID for 16 weeks followed by 
open-label 5 mg BID tofacitinib for 
32 weeks
One- 5 mg matching placebo tablet in 
AM & PM for the first 16 weeks followed 
by one-tofacitinib 5 mg tablet in the AM 
& PM for 32 weeks
24


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At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process.  Blinding codes should be 
broken only in exceptional circumstances when knowledge of the actual treatment code is 
absolutely essential for further management of the subject.  Investigators are encouraged to 
discuss with a member of the study team if they believe that unblinding is necessary.  When 
the blinding code is broken, the reason must be fully documented and entered on the 
electronic case report form (eCRF).
5.3. Subject Compliance
Subject compliance with dosing administration will be verified by accounting of returned 
containers and investigational product at each visit.  Compliance for the tablets will be 
calculated by each bottle and documented.  If compliance is <80%, the investigator or 
designee is to counsel the subject and ensure steps are taken to improve compliance.  
Subjects, who are less than 80% compliant with the dosage regimen for any two consecutive 
visit periods, should be withdrawn from the investigational product.  In the event that the 
investigational product is held due to an AE, infection or elective surgery, in accordance with 
the protocol-specified time frames, compliance should still be calculated for the visit period, 
but withdrawal from the investigational product would be assessed.  If the subject is 
over-compliant with the investigational product (intentional or accidental) the investigator or 
designee is to counsel the subject and ensure correct understanding of the investigational 
product dosing regimen.  The investigator should contact the Pfizer Medical Monitor or 
designee promptly with any over-compliance (>120%) that may potentially impact the safe 
use of the investigational product or that may result in a serious adverse event.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
During the double-blind treatment period, blinded tofacitinib and matched placebo will be
provided as tablets for oral administration. The tofacitinib 5 mg tablets or placebo tablets 
will be supplied in bottles and labeled according to local regulatory requirements.  The 
investigational product will be labeled in such a manner that the subject and study staff will be
unable to determine from the dispensed packaging to which treatment sequence the subject is 
assigned.  All blinded investigational product will be collected at the Week 16 visit and subjects 
will receive new investigational product as part of the open-label portion of the study at the 
Week 16 visit and will receive the first dose of open-label investigational product in the clinic.  
At the Week 16 visit, all subjects will receive tofacitinib 5 mg tablets supplied in containers 
and labeled according to local regulatory requirements.  Supplies will be labeled as
appropriate for this two-arm placebo-controlled, double-blind trial and the open-label 
treatment period.
5.4.2. Preparation and Dispensing
The investigational product will be dispensed using an IRT drug management system at each 
visit from Baseline to Week 40 (excluding Week 2).  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 


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maintain the product in the bottle provided throughout the course of dosing and return the 
bottle to the site at the next study visit. 
The investigational product will be packaged and labeled in such a manner that the subject 
and study staff will be unable to determine from the dispensed packaging to which treatment 
arm the subject is assigned during the double-blind treatment period.  At study visits 
sufficient investigational product will be dispensed to complete dosing until the next
scheduled visit.  The amount of investigational product dispensed at each visit must be 
recorded.  At study visits the subject must return all investigational product and the amount 
of investigational product returned will be recorded to account for all dispensed 
investigational product.
5.5. Administration
Investigational product will be dispensed to subjects to self-administer after appropriate
training and specific instructions are provided.  Instructions on dosing will be provided on the 
Subject Dosing Card. At all visits, the scheduled dose of investigational product will be taken
by the subject in the clinic.  At the end of each visit, sites will instruct subjects, when to take 
their investigational product prior to their next study visit.  
 
  Subjects should receive 
open-label investigational product at the Week 16 visit and should receive the first dose of 
the open-label investigational product at the clinic.
Tofacitinib tablets or matching placebo for oral administration 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. 
Subjects will be instructed to take their tablet investigational product twice daily (once in the
morning and once in the evening approximately 12 hours apart) for a total of two tablets per 
day.  Placebo tablets will match the 5 mg tablets in order to maintain the blind.
During the double-blind treatment period, if the investigator deems it necessary to withhold 
the investigational product to treat a non-serious infection or other medical condition, 
temporary withholding is permitted for up to 5 days.  If temporary withholding of the 
investigational product exceeding 5 days is required for a medical reason (eg, elective 
surgery), the investigator must contact the Pfizer Medical Monitor for approval.
Temporary withholding of the investigational product, as described above, is permitted once 
during the study without obtaining prior approval from the Pfizer Medical Monitor.  Any 
additional request(s) for temporary withholding of the investigational product during the 
double blind period require(s) documented approval by the Pfizer Medical Monitor.
Per Amendment 3, for subjects with suspected VTE, treatment with tofacitinib should be 
temporarily withheld while the subject is evaluated. If VTE is confirmed, discontinue 
treatment with tofacitinib (see Section 6.4: Subjects Discontinuation from the Investigational 
Product).


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During the open-label period of the study, tofacitinib 5 mg BID may be temporarily 
discontinued for up to 28 consecutive days for laboratory abnormalities, for infections which 
do not meet criteria for serious infections (those requiring parenteral antimicrobial therapy or 
hospitalization), for surgical procedures or other moderately severe AEs.  If treatment must 
be discontinued for more than 28 days, the subject should be withdrawn from the 
investigational product permanently (see Section 6.4.2). 
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 Investigator’s Brochure will be superseded by the 
storage conditions stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations. The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Site staff will instruct subjects on the proper storage requirements for take home 
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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 containers of the investigational 
product must be returned to the investigator by the subject at every visit and at the end of the 
trial.
5.7.1. Destruction of Investigational Product Supplies
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented. 
5.8. Concomitant Treatment(s)
It is important to be aware of, and document, all concomitant medications including:
prescription, non-prescription (ie, over-the-counter) and herbal medications.
All local standard-of-care practices for the administration of permitted therapy 
(ie, background DMARD, contraceptives, rescue medication) including laboratory testing, 
follow-up care and contraindications should be performed according to local standards of 
care throughout the study.  A subject who is receiving an allowed concomitant medication 
for any reason must be on a locally-approved medication and dose that is considered 
standard-of-care for the treated indication, and this must be documented in the case report
form.  It is recommended that subjects avoid changing non-prohibited prescription or 
non-prescription drugs, vitamins, and dietary supplements within 7 days or 5 half-lives 
(whichever is longer) prior to the first dose of investigational product and prior to study visits 
unless otherwise noted below, throughout the study.
Medications that are taken during the screening period (after informed consent is obtained
and before the first dose of investigational product) will be documented as prior medications.  
Medications taken after the first dose of investigational product has been administered will 
be documented as concomitant medications.  All concomitant medications taken during the 
study must be recorded in the study records with indication (as appropriate), daily dose and 
start and stop dates of administration.  Subjects will be queried about concomitant 
medications at each study visit.  Minimum guidelines for folate supplementation during 
study: Subjects on methotrexate must receive folate supplementation according to local 
methotrexate label guidelines and standard of care.  A minimum of 5 mg weekly based on 
folic acid should be given unless local guidelines or standard of care state otherwise.
5.8.1. Biologic Medications
Prior treatment with bDMARDs including TNF inhibitors is permitted if they have been 
discontinued for at least five half-lives before randomization.  See also Section 4.1 for 
definition of a TNF inhibitor nonresponder.  Subjects on bDMARDs including TNF inhibitors 
must be discontinued according to the following criteria:


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
Etanercept (Enbrel): Discontinued at least 4 weeks prior to the first dose of 
investigational product;

Adalimumab (Humira): Discontinued at least 10 weeks prior to the first dose of 
investigational product;

Infliximab (Remicade): Discontinued at least 8 weeks prior to the first dose of 
investigational product;

Golimumab (Simponi): Discontinued at least 10 weeks prior to the first dose of 
investigational product;

Certolizumab (Cimzia): Discontinued at least 10 weeks prior to the first dose of 
investigational product;

Other bDMARDs: Discontinued at least 4 weeks or 5 half-lives (whichever is longer) 
washout period prior to first dose of study treatment after discussion with Sponsor.
5.8.2. Stable Background Pain or Other AS Therapy
Subjects taking permitted csDMARDs (eg, methotrexate (25 mg/week) or sulfasalazine
(3 gm/day)), nonsteroidal anti-inflammatory drugs including selective 
cyclooxygenase-2 inhibitors (COX-2 inhibitors), and/or corticosteroids (10 mg prednisone 
mg/day) must remain on the same dose regimen throughout the study.  Daily dosages of 
NSAIDs/COX-2 inhibitors, corticosteroids, opioids, and acetaminophen/paracetamol must be 
stable for 1 week prior to first study dose and must remain so during the study treatment 
period (Week 48) except if adjustment is needed to protect a subject’s safety.  Daily dosage 
of NSAIDs/COX-2 inhibitors, corticosteroids, opioids and acetaminophen/paracetamol must 
not be modified within the 24 hours prior to any study visit, except if adjustment is needed to 
protect a subject’s safety.
Subjects using topical NSAIDs or anesthetics (ie, Ben-Gay) on peripheral joints are allowed 
if stable for 1 week prior to the first study dose and must remain so during the study 
treatment period.
Glucosamine sulfate and chondroitin sulfate are allowed in the study but subjects should be 
on a stable dose for 1 week prior to first dose of investigational product and throughout the 
study.
The total daily dose of acetaminophen may not exceed 2.6 grams per day, and the total daily 
dose of opioid may not exceed the potency equivalent of 30 mg of orally-administered 
morphine (See Appendix 5).


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5.8.3. Rescue Therapy
The only medications that are allowed for rescue are listed in Appendix 6.
Increases of acetaminophen/paracetamol and opioids are allowable as rescue medication for 
no more than 10 consecutive days.  Acetaminophen/paracetamol may be added or increased 
to a maximum of 2.6 gm/day.  Combination products such as over-the-counter “cold 
remedies” or pain medications should be assessed for acetaminophen/paracetamol content so 
as the total dose will not exceed 2.6 gm/day.  Opioids may be added or increased to a 
maximum potency equivalent of 30 mg of orally-administered morphine. 
Subjects who require rescue for more than 10 consecutive days will be discontinued from the 
investigational product and be designated as discontinued from the investigational product 
for lack of efficacy.  There is no limit to the duration of nonconsecutive use of rescue
medications.  In addition, subjects may not be dosed with rescue medication during the 
24 hours prior to a study visit.  In the judgement of the investigator, if rescue therapy has any 
effect on efficacy data collected during a study visit, this will constitute a protocol deviation.  
Baseline stable use of acetaminophen/paracetamol or opioids should NOT be discontinued in 
advance of study visits.
5.8.4. Prohibited Medications
Prohibited drugs and dietary supplements not otherwise specified herein or in Appendix 4
must be discontinued at least 30 days or 5 half-lives (whichever is longer) before the first 
dose of investigational product.  A list of prohibited drugs with specific discontinuation 
recommendations can be found in Appendix 4.

Any DMARDs (synthetic or biologic) except for methotrexate or sulfasalazine. 
Subjects receiving any other investigational or marketed treatment for AS, arthritis or
back pain other than permitted in Appendix 4.  Subjects receiving any other
investigational drug during the study.

Injected (intravenous, intramuscular, intraarticular or epidural) corticosteroids are not
allowed during the blinded portion of the study either as a stable concomitant
medication or as rescue medication.

Herbals with pharmaceutical properties are allowed only if there is acceptable
evidence of no CYP3A inhibition or induction and must be reported as a concomitant
medication. Otherwise, herbals with pharmaceutical properties must be discontinued
for at least 4 weeks prior to first dose of study drug, unless there is sufficient data
available regarding the duration of an herbal medication’s pharmacokinetic and
pharmacodynamic effects to allow a shorter washout to be specified (eg, 5 half-lives).

Vaccinations with live components are prohibited during the study and for 6 weeks 
after last dose of investigational product.

Currently receiving or previously used thalidomide.


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Acetaminophen/paracetamol is not permitted as a part of combination products such as
over-the-counter “cold remedies” or in combination with opioids if the
acetaminophen/paracetamol dose will exceed 2.6 gm/day.
6. STUDY PROCEDURES
6.1. Screening
Subjects will be screened within 30 days prior to administration of investigational product to 
confirm that they meet the entrance criteria for the study. 
Rescreening of subjects will be allowed in a limited number of circumstances as determined
by the Pfizer Medical Monitor (eg, requires antimicrobial therapy within 2 weeks prior to the 
first dose of investigational product, requires emergency surgery) and should be confirmed 
with the Pfizer Medical Monitor when rescreening can occur.
The study investigator or a sub-investigator will discuss with each subject the nature of the 
study, its requirements, and its restrictions.  Written informed consent/assent must be 
obtained prior to performance of any protocol-specific procedures.
Subjects, who are on prohibited medications and are deriving a beneficial response from the 
medication, should not be entered into this study.  However, there may be subjects taking a 
prohibited medication who have experienced an ineffectual/suboptimal response or side 
effects and wish to enter the study. These subjects may require a washout period that extends 
beyond the screening duration.  For these subjects, written informed consent and a unique 
subject number obtained through the IRT system must be obtained prior to initiation of the 
washout period.  No other screening activities should be performed at this time.  These 
subjects should return for a Screening visit within the allowed window, at which time all 
screening procedures should be completed.
At all visits, subjects should complete the “Patient Reported Outcome” (PRO) questionnaires 
at the clinic prior to any other study procedures outside of the informed consent process. 
The following procedures will be performed:

Informed consent;

Collect demographic information (sex, date of birth, race, and ethnicity);

ASAS/ASDASCRP Component: “Patient Global Assessment of Disease” (NRS), 
“Patient Assessment of Spinal Pain” which include Total Back Pain(NRS) and 
Nocturnal Spinal Pain (NRS), BASDAI (NRS), BASFI (NRS);

Confirmation of diagnosis of active AS: based on the Modified New York Criteria for
Ankylosing Spondylitis (1984) and BASDAI score of 4 and back pain score 
(BASDAI Question 2) of 4;


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
General Medical History: Should include history of previous vaccinations, 
specifically influenza, pneumococcal and herpes zoster as well as family history of 
AS, herpes zoster history, CV risk factor assessment, smoking history and average
weekly alcohol consumption;

Specific Medical History: History of uveitis, psoriasis, inflammatory bowel disease 
and peripheral articular involvement as assessed by swollen joint count;

Prior/Concomitant treatments: Current and prior medications (noting exclusions and 
required csDMARD restrictions), including a complete history of all DMARDs 
(synthetic/biologic) ever taken with reasons for discontinuation (those taken during
the 1 year prior to the first dose of investigational product should include the dose and 
duration of treatment).  Complete history of all drugs (including non-prescription 
drugs, vitamins and dietary supplements) taken within 4 weeks prior to the screening 
procedures;

Vital Signs: Blood pressure (seated), pulse rate and temperature (via tympanic, oral or 
temporal, preferred);

Complete Physical Examination: General appearance, skin (presence of rash), 
HEENT (head, eyes, ears, nose and throat), lungs (auscultation), heart (auscultation 
for presence of murmurs, gallops, rubs), lower extremities (presence of peripheral
edema), abdominal (palpation and auscultation), neurologic (mental status, station, 
gait, reflexes, motor and sensory function, coordination) and lymph nodes;

Height, weight (without shoes preferred); 

12-lead electrocardiogram submitted to central reader;

BASMI (linear function) obtained by qualified blinded assessor: Lateral spinal 
flexion, tragus-to-wall distance, lumbar flexion (modified Schober), maximal 
intermalleolar distance and cervical rotation;

Spinal Mobility obtained by qualified blinded assessor: chest expansion;

Laboratory testing: Central laboratory tests include: Hematology, Urinalysis, 
Chemistry Panel, HIV Serology, hepatitis testing (HBsAg, HBcAb, HCV Ab), high 
sensitivity C-Reactive Protein (hsCRP), and Prothrombin time (PT/INR); FSH and
hepatitis reflex testing, if applicable.  Screening lab tests as noted in the 
inclusion/exclusion criteria may be repeated a single time if the initial result is 
inconsistent with previous subject laboratory history;

Urine Pregnancy Test (for women of childbearing potential only);


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
QuantiFERON-TB Gold: Must be performed unless previously tested and 
documented within 3 months of screening visit OR unless subject has previously 
received an adequate course of therapy for either latent or active TB infection; 

Radiograph of chest: Unless performed within 3 months of Screening visit and 
documented;

Radiograph of SI joints (read centrally).  If documentation of AS has been obtained 
with prior radiographs, obtain radiographs for submission to the central reader.  If not, 
perform after all other screening procedures and only perform radiograph of SI joints 
if subject does not fail to meet other study criteria;

If radiographs are not available or unable to be read by the central reader, new
radiograph (AP pelvis) should be obtained at the Screening visit and submitted to the 
central reader;

Monitoring for adverse events;

Contraception check: Confirm and document that proper contraception is being used.
6.2. Study Period
Subjects who have met all the inclusion criteria and have no exclusion criteria present may 
participate in the study.  Blood collection for laboratory testing requiring a fasting state (at 
least 9 hours) may be taken up to 48 hours prior to the Baseline/Day 1 visit.  For 
post-baseline double-blind study period visits blood collection for laboratory testing 
requiring a fasting state (at least 9 hours) up to 48 hours prior to or following as necessary to 
ensure samples are collected in a fasting state.  If the subject has not fasted for at least 
9 hours, the visit should be rescheduled to occur within 48 hours in the fasting state.
Subjects will complete the PRO questionnaires at the clinic prior to any other study 
procedures.  This sequence of study procedures will reduce the risk of inadvertently 
introducing bias in a subject’s responses through study staff interactions.  In the unlikely
event that a PRO questionnaire(s) is not able to be administered by the study site staff and 
completed by the subject at the clinic visit, the PRO questionnaire(s) should not be
administered.
6.2.1. Baseline Day 1 (Randomization)
Subjects are required to fast for at least 9 hours prior to the, visit; however, blood 
collection for laboratory testing may be taken up to 48 hours prior to the Baseline/Day 1 visit
as necessary to ensure the samples are collected in a fasting state.  If the blood collection is 
completed in advance of the clinic visit, the PROs should not be done with the blood 
collection but at the clinic visit.


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
All PROs should be performed before any other study procedures at the clinic visit.  
These include the following: ASAS/ASDASCRP Component: “Patient Global 
Assessment of Disease (NRS)”, “Patient Assessment of Spinal Pain” which includes 
Total Back Pain (NRS) and Nocturnal Spinal Pain (NRS), BASDAI (NRS), BASFI 
(NRS), ASQoL, SF-36v2, EuroQol EQ-5D Health State Profile 3 Level (EQ-5D-3L) 
and Your own health state today (EQ-VAS), Functional Assessment of Chronic 
Illness Therapy-Fatigue Scale (FACIT-F), - WPAI and AS HealthCare Resource 
Utilization Questionnaire (AS-HCRU) Questionnaire.
Prior to the first dose the following procedures will be completed:

Confirmation of diagnosis of active AS: based on the Modified New York Criteria for 
Ankylosing Spondylitis (1984) and BASDAI score of 4 and back pain score 
(BASDAI Question 2) of 4;

Determination and confirmation of either “bDMARD-naive” or “TNFi-IR” or
“bDMARD use (non-IR)” status for randomization;

Prior/Concomitant treatments: Current and prior medications (noting exclusions and 
required DMARD restrictions) will be reviewed to ensure no concomitant 
medications (including non-prescription drugs, vitamins and dietary supplements) 
have been added that are prohibited;

Vital Signs: Blood pressure (seated), pulse rate and temperature (via tympanic, oral or 
temporal, preferred);

Complete Physical Examination: General appearance, skin (presence of rash), 
HEENT (head, eyes, ears, nose and throat), lungs (auscultation), heart (auscultation 
for presence of murmurs, gallops, rubs), lower extremities (presence of peripheral 
edema), abdominal (palpation and auscultation), neurologic (mental status, station, 
gait, reflexes, motor and sensory function, coordination) and lymph nodes;

Weight (without shoes preferred) and waist circumference;

Specific Medical History: History of uveitis, psoriasis, inflammatory bowel disease 
and peripheral articular involvement as assessed by swollen joint count;

BASMI (linear function) obtained by qualified blinded assessor: Lateral spinal 
flexion, tragus-to-wall distance, lumbar flexion (modified Schober), maximal 
intermalleolar distance and cervical rotation;

Spinal mobility obtained by qualified blinded assessor: chest expansion;

Laboratory testing: Central laboratory tests include: Hematology, Urinalysis, 
Chemistry Panel, Lipid Profile (fasting), Urine Pregnancy Test (for women of 
childbearing potential only), hsCRP;


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
Blood sample for HLA-B27;

Blood sample for Fluorescence Activated Cell Sorting (FACS) Analysis;

Assessment of swollen joints (44-joint count) by qualified blinded assessor;

Assessment of enthesitis using the Maastricht Ankylosing Spondylitis Enthesitis 
Score (MASES) Index by qualified blinded assessor;

Contact Interactive Web Response System (IWRS) to randomize subject;

Dispense the investigational product to subject as described in Section 5.5 and as 
noted in the Administration and Compliance Sections.  Instruct subject on correct 
investigational product administration.  All subsequent scheduled doses on clinic visit 
days will be taken in the clinic;

Monitoring for adverse events;

Contraception check: Confirm and document that proper contraception is being used;

Instruct subject not to take the in-clinic dose of investigational product the day of the 
next study visit and to bring the drug supply with them to the visit.
6.2.2. Week 2
There is a 3 day window for this visit.
 

All PROs should be completed prior to any other study procedures. These include the 
following: ASAS/ASDASCRP Component: “Patient Global Assessment of Disease 
(NRS)”, “Patient Assessment of Spinal Pain” which includes Total Back Pain (NRS)
and Nocturnal Spinal Pain (NRS), BASDAI (NRS), BASFI (NRS), and FACIT-F.
After the PROs have been obtained, the following procedures should be completed:

Verify morning dose of investigational product was not administered by subject.  If 
the dose was administered, continue with visit but re-instruct subject on the 
requirement for in-clinic dosing;
Note: For subjects where the visit is conducted in the afternoon or evening, verify the 
afternoon or evening dose of investigational product was not administered by the 
subject.


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
Targeted physical examination (examination of heart, lungs, abdomen, lower
extremities, skin (presence of rash) and lymph nodes);

Weight (without shoes preferred);

BASMI (linear function) obtained by qualified blinded assessor: Lateral spinal flexion,
tragus-to-wall distance, lumbar flexion (modified Schober), maximal intermalleolar
distance and cervical rotation;

Spinal mobility obtained by qualified blinded assessor: chest expansion;

Vital signs: Blood pressure (seated), pulse rate and temperature (via tympanic, oral or
temporal, preferred);

Laboratory testing: Urine Pregnancy Test (for women of childbearing potential only),
hsCRP;

Assessment of swollen joints (44-joint count) by qualified blinded assessor;

Administer investigational product from the previously dispensed study drug supplies
unless subject had already administered dose at home;

Complete drug accountability;

Monitoring of adverse events and concomitant treatments.
Record any 
modifications, deletions or additions;

Contraception check: Confirm and document that proper contraception is being used;

Instruct subject not to take the in-clinic dose of investigational product the day of the
next study visit and to bring the drug supply with them to the visit.
6.2.3. Week 4
There is a 3 day window for this visit.
Subjects are required to fast for at least 9 hours prior to the visit; however, blood
collection for laboratory testing may be taken up to 48 hours prior to or following this visit as 
necessary to ensure the samples are collected in a fasting state. If the blood collection is
completed in advance of the clinic visit, the PROs should not be done with the blood
collection but at the clinic visit.
 


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
All PROs should be completed prior to any other study procedures. These include the
following: ASAS/ASDASCRP Component: “Patient Global Assessment of Disease
(NRS)”, “Patient Assessment of Spinal Pain” which includes Total Back Pain (NRS)
and Nocturnal Spinal Pain (NRS), BASDAI (NRS), BASFI (NRS), and FACIT-F.
After the PROs are obtained, the following procedures should be completed prior to dosing:

Verify morning dose of investigational product was not administered by the subject
and previous day’s dosing was administered;
Note: For subjects where the visit is conducted in the afternoon or evening, verify the 
afternoon or evening dose of investigational product was not administered by the subject.

Vital signs: Blood pressure (seated), pulse rate and temperature (via tympanic, oral or
temporal, preferred);

Laboratory testing: Central laboratory tests include: Hematology, Urinalysis,
Chemistry Panel, Lipid Profile (fasting), Urine Pregnancy Test (for women of
childbearing potential only), hsCRP;


Blood sample for FACS Analysis;

The following procedures can be done before or after dosing depending upon the clinic’s
schedule but is recommended that they be done at the same time (before or after dosing)
consistently across all subsequent subject clinic visits:

Targeted physical examination (examination of heart, lungs, abdomen, lower
extremities, skin (presence of rash) and lymph nodes);

Weight (without shoes preferred);

BASMI (linear function) obtained by qualified blinded assessor: Lateral spinal flexion,
tragus-to-wall distance, lumbar flexion (modified Schober), maximal intermalleolar
distance and cervical rotation;

Spinal mobility obtained by qualified blinded assessor: chest expansion;

Assessment of swollen joints (44-joint count) by qualified blinded assessor;

Assessment of enthesitis using the MASES Index by qualified blinded assessor;

Complete drug accountability.


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Procedures to be performed after dosing:


Contact IWRS and dispense new supply of investigational product to subject;

Monitoring of adverse events and concomitant treatments.  Record any
modifications, deletions or additions;

Contraception check: Confirm and document that proper contraception is being used;

Instruct subject not to take the in-clinic dose of investigational product the day of the
next study visit and to bring the drug supply with them to the visit.
6.2.4. Week 8
There is a 7 day window for this visit.
 
 

All PROs should be completed prior to any other study procedures.  These include the 
following: ASAS/ASDASCRP Component: “Patient Global Assessment of Disease 
(NRS)”, “Patient Assessment of Spinal Pain” which includes Total Back Pain (NRS) 
and Nocturnal Spinal Pain (NRS), BASDAI (NRS), BASFI (NRS), and FACIT-F.
After the PROs have been obtained, the following procedures should be completed:

Verify morning dose of investigational product was not administered by the subject 
and previous day’s dosing was administered;
Note: For subjects where the visit is conducted in the afternoon or evening, verify the 
afternoon or evening dose of investigational product was not administered by the 
subject.

Vital signs: Blood pressure, pulse rate and temperature (via tympanic, oral or 
temporal, preferred);

Laboratory testing: Urine Pregnancy Test (for women of childbearing potential only), 
hsCRP;


 


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The following procedures can be done before or after dosing depending upon the clinic’s 
schedule but it is recommended that they be done at the same time (before or after dosing) 
consistently across all subsequent subject clinic visits:

Targeted physical examination (examination of heart, lungs, abdomen, lower 
extremities, skin (presence of rash) and lymph nodes);

Weight (without shoes preferred);

Specific Medical History: History of uveitis, psoriasis, inflammatory bowel disease 
and peripheral articular involvement as assessed by swollen joint count;

BASMI (linear function) by qualified blinded assessor: Lateral spinal flexion, 
tragus-to-wall distance, lumbar flexion (modified Schober), maximal intermalleolar
distance and cervical rotation;

Spinal mobility obtained by qualified blinded assessor: chest expansion;

Assessment of swollen joints (44-joint count) by qualified blinded assessor;

Assessment of enthesitis using the MASES Index by qualified blinded assessor;

Complete drug accountability. 
After dosing:


Monitoring of adverse events and concomitant medications.  Record any 
modifications, deletions or additions;

Contraception check: Confirm and document that proper contraception is being used;

Contact IWRS and dispense new supply of investigational product to subject;

Instruct subject not to take the in-clinic dose of investigational product the day of the 
next study visit and to bring the drug supply with them to the visit.
6.2.5. Week 12
There is a 7 day window for this visit.

All PROs should be completed prior to any other study procedures.  These include the 
following: ASAS/ASDASCRP Component: “Patient Global Assessment of Disease 
(NRS)”, “Patient Assessment of Spinal Pain” which includes Total Back Pain (NRS) 
and Nocturnal Spinal Pain (NRS), BASDAI (NRS), BASFI (NRS), and FACIT-F.


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After the PROs are obtained, the following procedures should be completed prior to dosing:

Verify morning dose of investigational product was not administered by subject.  If 
the dose was administered, continue with visit but re-instruct subject on the 
requirement for in-clinic dosing;
Note: For subjects where the visit is conducted in the afternoon or evening, verify the 
afternoon or evening dose of investigational product was not administered by the 
subject.

Vital signs: Blood pressure (seated), pulse rate and temperature (via tympanic, oral or 
temporal, preferred);

Laboratory testing: Hematology, Chemistry Panel, Urinalysis, Urine Pregnancy Test 
(for women of childbearing potential only), hsCRP;

Administer in-clinic dose of investigational product from previously dispensed study 
drug supplies.
The following procedures can be done before or after dosing depending upon the clinic’s
schedule but it is recommended that they be done at the same time (before or after dosing) 
consistently across all subsequent subject clinic visits:

Targeted physical examination (examination of heart, lungs, abdomen, lower 
extremities, skin (presence of rash) and lymph nodes);

Weight (without shoes preferred);

BASMI (linear function) by qualified blinded assessor: Lateral spinal flexion, 
tragus-to-wall distance, lumbar flexion (modified Schober), maximal intermalleolar 
distance and cervical rotation;

Spinal mobility obtained by qualified blinded assessor: chest expansion;

Assessment of swollen joints (44-joint count) by qualified blinded assessor;

Assessment of enthesitis using the MASES Index by qualified blinded assessor;

Complete drug accountability. 
After dosing:

Monitoring of adverse events and concomitant treatments.  Record any modifications, 
deletions or additions;

Contraception check: Confirm and document that proper contraception is being used;


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
Contact IWRS and dispense new supply of investigational product to subject;

Instruct subject not to take the in-clinic dose of investigational product the day of the 
next study visit but to bring the drug supply with them to the visit.
6.2.6. Week 16
There is a 7 day window for this visit.
Subjects are required to fast for at least 9 hours prior to the visit; however, blood
collection for laboratory testing may be taken up to 48 hours prior to or following this visit as 
necessary to ensure the samples are collected in a fasting state. If the blood collection is
completed in advance of the clinic visit, the PROs should not be done with the blood
collection but at the clinic visit.

All PROs should be performed before any other study procedures at the clinic visit.  
These include the following: ASAS/ASDASCRP Component: “Patient Global
Assessment of Disease (NRS)”, “Patient Assessment of Spinal Pain” which includes
Total Back Pain (NRS) and Nocturnal Spinal Pain (NRS), BASDAI (NRS), BASFI
(NRS), ASQoL, SF-36v2, EQ-5D-3L and EQ-VAS, FACIT-F, - WPAI and
AS-HCRU Questionnaire.

Verify morning dose of investigational product was not administered by subject.  If
the dose was administered, continue with visit but re-instruct subject on the
requirement for in-clinic dosing;
Note: For subjects where the visit is conducted in the afternoon or evening, verify the 
afternoon or evening dose of investigational product was not administered by the 
subject.

Blood pressure (seated), pulse rate and temperature (via tympanic, oral or temporal,
preferred);

12-lead electrocardiogram submitted to central reader;

Laboratory testing: Central laboratory tests include: Hematology, Urinalysis,
Chemistry Panel, Lipid Profile (fasting), Urine Pregnancy Test (for women of
childbearing potential only), hsCRP;

Blood sample for FACS Analysis;

Complete Physical Examination: General appearance, skin (presence of rash), HEENT
(head, eyes, ears, nose and throat), lungs (auscultation), heart (auscultation for
presence of murmurs, gallops, rubs), lower extremities (presence of peripheral
edema), abdominal (palpation and auscultation), neurologic (mental status, station,
gait, reflexes, motor and sensory function, coordination) and lymph nodes;


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
Weight (without shoes preferred);

Specific Medical History: History of uveitis, psoriasis, inflammatory bowel disease
and peripheral articular involvement as assessed by swollen joint count;

BASMI (linear function) by qualified blinded assessor: Lateral spinal flexion,
tragus-to-wall distance, lumbar flexion (modified Schober), maximal intermalleolar
distance and cervical rotation;

Spinal mobility obtained by qualified blinded assessor: chest expansion;

Assessment of swollen joints (44-joint count) by qualified blinded assessor;

Assessment of enthesitis using the MASES Index by qualified blinded
assessor;Complete drug accountability;

Monitoring of adverse events and concomitant treatments.  Record any
modifications, deletions or additions;

Contraception check: Confirm and document that proper contraception is being used;
Subjects will be switched to open-label tofacitinib 5 mg BID for the remainder of the study.

Contact IWRS and dispense new supply of open-label investigational product to
subject;

Administer in-clinic dose of investigational product from open-label study drug 
supply.

Instruct subject not to take the in-clinic dose of investigational product the day of the
next study visit but to bring the drug supply with them to the visit.
6.2.7. Week 24
There is a 7 day window for this visit.

All PROs should be completed prior to any other study procedures. These include the
following: ASAS/ASDASCRP Component: “Patient Global Assessment of Disease
(NRS)”, “Patient Assessment of Spinal Pain” which includes Total Back Pain (NRS)
and Nocturnal Spinal Pain (NRS), BASDAI (NRS), BASFI (NRS), and FACIT-F.
After the PROs are obtained, the following procedures should be completed prior to dosing:

Verify morning dose of investigational product was not administered by subject.  If
the dose was administered, continue with visit but re-instruct subject on the
requirement for in-clinic dosing;


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
Note: For subjects where the visit is conducted in the afternoon or evening, verify the 
afternoon or evening dose of investigational product was not administered by the 
subject.  Vital signs: Blood pressure (seated), pulse rate and temperature (via
tympanic, oral or temporal, preferred);

Laboratory testing: Hematology, Chemistry Panel, Urinalysis, Urine Pregnancy Test
(for women of childbearing potential only), hsCRP;

Administer in-clinic dose of investigational product from previously dispensed study
drug supplies.
The following procedures can be done before or after dosing depending upon the clinic’s
schedule but it is recommended that they be done at the same time (before or after dosing)
consistently across all subsequent subject clinic visits:

Targeted physical examination (examination of heart, lungs, abdomen, lower
extremities, skin (presence of rash) and lymph nodes);

Weight (without shoes preferred);

BASMI (linear function) by qualified blinded assessor: Lateral spinal flexion,
tragus-to-wall distance, lumbar flexion (modified Schober), maximal intermalleolar
distance and cervical rotation;

Spinal mobility obtained by qualified blinded assessor: chest expansion;

Assessment of swollen joints (44-joint count) by qualified blinded assessor;

Assessment of enthesitis using the MASES Index by qualified blinded assessor;

Complete drug accountability.
After dosing:

Monitoring of adverse events and concomitant treatments.  Record any
modifications, deletions or additions;

Contraception check: Confirm and document that proper contraception is being used;

Contact IWRS and dispense new supply of investigational product to subject;

Instruct subject not to take the in-clinic dose of investigational product the day of the
next study visit but to bring the drug supply with them to the visit.


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6.2.8. Week 32
There is a 7 day window for this visit.
Subjects are required to fast for at least 9 hours prior to the visit; however, blood
collection for laboratory testing may be taken up to 48 hours prior to or following this visit as 
necessary to ensure the samples are collected in a fasting state. If the blood collection is
completed in advance of the clinic visit, the PROs should not be done with the blood
collection but at the clinic visit.

All PROs should be completed prior to any other study procedures. These include the
following: ASAS/ASDASCRP Component: “Patient Global Assessment of Disease
(NRS)”, “Patient Assessment of Spinal Pain” which includes Total Back Pain (NRS)
and Nocturnal Spinal Pain (NRS), BASDAI (NRS), BASFI (NRS), and FACIT-F.
After the PROs are obtained, the following procedures should be completed prior to dosing:

Verify morning dose of investigational product was not administered by subject.  If
the dose was administered, continue with visit but re-instruct subject on the
requirement for in-clinic dosing;
Note: For subjects where the visit is conducted in the afternoon or evening, verify 
the afternoon or evening dose of investigational product was not administered by the 
subject.  

Vital signs: Blood pressure (seated), pulse rate and temperature (via tympanic, oral or 
temporal, preferred);

Laboratory testing: Central laboratory tests include: Hematology, Urinalysis,
Chemistry Panel, Lipid Profile (fasting), Urine Pregnancy Test (for women of
childbearing potential only), hsCRP;

Blood sample for FACS Analysis;

Administer investigational product to the subject from the previously dispensed study
drug supplies.
The following procedures can be done before or after dosing depending upon the clinic’s
schedule but is recommended that they be done at the same time (before or after dosing)
consistently across all subsequent subject clinic visits:

Targeted physical examination (examination of heart, lungs, abdomen, lower
extremities, skin (presence of rash) and lymph nodes);

Weight (without shoes preferred);


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
Specific Medical History: History of uveitis, psoriasis, inflammatory bowel disease
and peripheral articular involvement as assessed by swollen joint count;

BASMI (linear function) obtained by qualified blinded assessor: Lateral spinal flexion,
tragus-to-wall distance, lumbar flexion (modified Schober), maximal intermalleolar
distance and cervical rotation;

Spinal mobility obtained by qualified blinded assessor: chest expansion;

Assessment of swollen joints (44-joint count) by qualified blinded assessor;

Assessment of enthesitis using the MASES Index by qualified blinded assessor;

Complete drug accountability.
Procedures to be performed after dosing:

Monitoring of adverse events and concomitant treatments. Record any modifications,
deletions or additions;

Contraception check: Confirm and document that proper contraception is being used;

Risk factor check for VTE (Section 7.1.14);

Contact IWRS and dispense new supply of study medication to subject;

Instruct subject not to take the in-clinic dose of investigational product the day of the
next study visit but to bring the drug supply with them to the visit.
6.2.9. Week 40
There is a 7 day window for this visit.

All PROs should be completed prior to any other study procedures. These include the
following: ASAS/ASDASCRP Component: “Patient Global Assessment of Disease
(NRS)”, “Patient Assessment of Spinal Pain” which includes Total Back Pain (NRS)
and Nocturnal Spinal Pain (NRS), BASDAI (NRS), BASFI (NRS), and FACIT-F.
After the PROs are obtained, the following procedures should be completed prior to dosing:

Verify morning dose of investigational product was not administered by subject.  If
the dose was administered, continue with visit but re-instruct subject on the
requirement for in-clinic dosing;
Note: For subjects where the visit is conducted in the afternoon or evening, verify 
the afternoon or evening dose of investigational product was not administered by the 


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subject.  Vital signs: Blood pressure (seated), pulse rate and temperature (via
tympanic, oral or temporal, preferred);

Laboratory testing: Hematology, Chemistry Panel, Urinalysis, Urine Pregnancy Test
(for women of childbearing potential only), hsCRP;

Administer in-clinic dose of investigational product from previously dispensed study
drug supplies.
The following procedures can be done before or after dosing depending upon the clinic’s
schedule but it is recommended that they be done at the same time (before or after dosing)
consistently across all subsequent subject clinic visits:

Targeted physical examination (examination of heart, lungs, abdomen, lower
extremities, skin (presence of rash) and lymph nodes);

Weight (without shoes preferred);

BASMI (linear function) by qualified blinded assessor: Lateral spinal flexion,
tragus-to-wall distance, lumbar flexion (modified Schober), maximal intermalleolar
distance and cervical rotation;

Spinal mobility obtained by qualified blinded assessor: chest expansion;

Assessment of swollen joints (44-joint count) by qualified blinded assessor;

Assessment of enthesitis using the MASES Index by qualified blinded assessor;

Complete drug accountability.
After dosing:

Monitoring of adverse events and concomitant treatments. Record any modifications,
deletions or additions;

Contraception check: Confirm and document that proper contraception is being used;

Risk factor check for VTE (Section 7.1.14);

Contact IWRS and dispense new supply of study medication to subject;

Instruct subject not to take the in-clinic dose of investigational product the day of the
next study visit but to bring the drug supply with them to the visit.


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6.2.10. Week 48
There is a 7 day window for this visit.
Subjects are required to fast for at least 9 hours prior to the visit; however, blood
collection for laboratory testing may be taken up to 48 hours prior to or following this visit as 
necessary to ensure the samples are collected in a fasting state. If the blood collection is
completed in advance of the clinic visit, the PROs should not be done with the blood
collection but at the clinic visit.

All PROs should be performed before any other study procedures at the clinic visit.  
These include the following: ASAS/ASDASCRP Component: “Patient Global
Assessment of Disease (NRS)”, “Patient Assessment of Spinal Pain” which includes
Total Back Pain (NRS) and Nocturnal Spinal Pain (NRS), BASDAI (NRS), BASFI
(NRS), ASQoL, SF-36v2, EQ-5D-3L and EQ-VAS, FACIT-F, WPAI and AS-HCRU
Questionnaire;

Vital signs: Blood pressure (seated), pulse rate and temperature (via tympanic, oral or
temporal, preferred);

12-lead electrocardiogram submitted to central reader;

Laboratory testing: Central laboratory tests include: Hematology, Urinalysis,
Chemistry Panel, Lipid Profile (fasting), Urine Pregnancy Test (for women of
childbearing potential only), hsCRP;

Blood sample for FACS Analysis;

Complete Physical Examination: General appearance, skin (presence of rash), HEENT
(head, eyes, ears, nose and throat), lungs (auscultation), heart (auscultation for
presence of murmurs, gallops, rubs), lower extremities (presence of peripheral
edema), abdominal (palpation and auscultation), neurologic (mental status, station,
gait, reflexes, motor and sensory function, coordination) and lymph nodes;

Weight (without shoes preferred);

Specific Medical History: History of uveitis, psoriasis, inflammatory bowel disease
and peripheral articular involvement as assessed by swollen joint count;

BASMI (linear function) by qualified blinded assessor: Lateral spinal flexion,
tragus-to-wall distance, lumbar flexion (modified Schober), maximal intermalleolar
distance and cervical rotation;

Spinal mobility obtained by qualified blinded assessor: chest expansion;

Assessment of swollen joints (44-joint count) by qualified blinded assessor;


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
Assessment of enthesitis using the MASES Index by qualified blinded assessor;

Administer in-clinic dose of investigational product from previously dispensed study
drug supplies;

Complete drug accountability;

Contraception check: Confirm and document that proper contraception is being used;

Risk factor check for VTE (Section 7.1.14);

Monitoring of adverse events and concomitant treatments.  Record any
modifications, deletions or additions.
6.3. Follow-up Visit
The Follow-up visit is required of all subjects who complete the study or are withdrawn from 
the investigational product after the Week 40 visit.  These subjects must have a Follow-up 
visit within 28 days (7 days) of the Week 48 visit.  Subjects who are withdrawn from the 
investigational product prior to the Week 40 visit are not required to have a follow-up visit 
after they complete the study at the Week 48 visit.  There is a 7 day window for this visit.
All subjects who complete or discontinue early from the investigational product after Week 40 
must have a Follow-up visit within 28 days (7 days) of the Week 48 visit. 
Subjects are required to fast for at least 9 hours prior to the visit; however, blood
collection for laboratory testing may be taken up to 48 hours prior to or following this visit as 
necessary to ensure the samples are collected in a fasting state.
The following procedures will be performed:

Targeted physical examination (examination of heart, lungs, abdomen, lower
extremities, skin (presence of rash) and lymph nodes);

Weight (without shoes preferred);

Specific Medical History: History of uveitis, psoriasis, inflammatory bowel disease
and peripheral articular involvement as assessed by swollen joint count;

Vital Signs and temperature: Blood pressure (seated), pulse rate and temperature (via
tympanic, oral or temporal, preferred);

Laboratory testing: Central laboratory tests include: Hematology, Urinalysis,
Chemistry Panel, Lipid Profile (fasting), Urine Pregnancy Test (for women of
childbearing potential only), hsCRP;

Adverse event reporting and concomitant treatment use;


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
Risk factor check for VTE (Section 7.1.14);

Contraception check: Confirm and document that proper contraception is being used.
If abnormalities in hematology or chemistry results or adverse events with a causal
relationship to the study medication are still observed/ongoing at the follow-up visit, the
subject must continue to be followed until the laboratory abnormality or adverse event
stabilizes or returns to baseline levels as approved by the Sponsor.


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6.4. Subjects Discontinuation from the Investigational Product
Subjects may discontinue from the investigational product at any time at their own request, 
or they may be withdrawn from the investigational product at any time at the discretion of the 
investigator or sponsor for safety (see also the (MonitoringCriteria/Discontinuation Criteria 
(from the Investigational Product)) or the Withdrawal due to Adverse Events) 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.  Subjects who discontinue the investigational 
product early should continue to be followed for all regularly scheduled visits for safety and 
efficacy assessments.  Those subjects that discontinue from the investigational product prior 
to Week 40 visit will not be required to have a follow–up visit.
Per Amendment 3, for subjects with suspected VTE, treatment with tofacitinib should be 
temporarily withheld while the subject is evaluated. If VTE is confirmed, discontinue 
treatment with tofacitinib [see Section 6.4.2, Discontinuation Criteria (from the 
Investigational Product)].
Lost to Follow-up:
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  Withdrawal due to a subject being no longer willing to participate in the study 
should be distinguished from withdrawal due to “lost to follow-up” (LTFU).  Every effort 
should be made to identify and contact subjects who are potentially LTFU.  A subject should 
not be considered a withdrawal due to LTFU until at least 3 attempts to contact the subject by 
multiple methods (conducted in accordance with local rules and regulations) have been 
unsuccessful.  All methods of attempted contact with the subject must be clearly documented 
in the subject’s source documents and the eCRF.  All potential LTFU subjects must be 
discussed with the study team or designee prior to assigning LTFU status.
In any circumstance, every effort should be made to document subject outcome, if possible.  
The investigator should inquire about the reason for withdrawal, requests the subject to 
returns all unused investigational product(s), request the subject to return for a final visit, if 
applicable, and follow-up with the subject regarding any unresolved adverse events (AEs).
Withdrawal of Consent:
If the subject withdraws from the investigational product, and also withdraws consent for 
disclosure of future information, no further evaluations should be performed, and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
If a subject has any clinically significant, treatment-emergent, abnormalities at the conclusion 
of the study, the Pfizer Medical Monitor (or designated representative) should be notified and 
every effort should be made to arrange follow-up evaluations at appropriate intervals to 
document the cause of the abnormality.  All abnormal laboratory events of clinical 
significance should be followed until the laboratory values have returned to normal or 
baseline levels.


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6.4.1. Monitoring Criteria
The following laboratory abnormalities require prompt retesting, ideally within 3- 5 days:

Any single hemoglobin value that drops >2 g/dL (or 20 g/L) below baseline, if 
indicated after review by the Pfizer Medical Monitor or investigator.  Factors that will 
be considered include stability of hemoglobin values, and their relationship to the 
standard reference range;

Absolute neutrophil count <1.2 x 109/L (<1200/mm3);

Absolute lymphocyte count <0.5 x 109/L (<500/mm3);

Platelet count <100 x 109/L (<100,000/mm3);

Serum creatinine increase >50% over the average of screening and baseline values OR
an absolute increase in serum creatinine >0.5 mg/dL (or 44 μmol/l) over the average 
of screening and baseline values, if indicated after review by the Pfizer Medical 
Monitor or investigator.  Factors that will be considered include stability of the 
creatinine values, and their relationship to the standard reference range;

Any creatine kinase (CK) >5x upper limit of normal (ULN) (repeat laboratory testing
should also include cardiac troponin).
If the abnormality is confirmed after re-test, follow-up should be discussed with the Sponsor 
and frequency of monitoring increased.  Confirmation should be done based upon central 
laboratory results, but local laboratory results will be acceptable, particularly if these may be 
done more promptly.
For additional laboratory abnormalities that require prompt retesting, preferably within 
48 hours from awareness of the abnormal results see Section 8.3.2 Potential Cases of 
Drug-Induced Liver Injury.
6.4.2. Discontinuation Criteria (from the Investigational Product)
The investigational product will be discontinued in the event of any of the following:

Serious infections, defined as any infection (viral, bacterial, and fungal) requiring
parenteral antimicrobial therapy or hospitalization for treatment, or meeting other
criteria that require the infection to be classified as a serious adverse event;

Two sequential absolute neutrophil counts <1.0 x 109/L (<1000/mm3);

Two sequential absolute lymphocyte counts <500 lymphocytes/mm3;

Two sequential hemoglobin values <8.0 g/dL (80 g/L) or decreases of >30% from
baseline value;


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
Two sequential platelet counts <75 x 109/L (<75,000/mm3);

Two sequential AST or ALT elevations 3 times the upper limit of normal with at
least one total bilirubin value 2 times the upper limit of normal;1

Two sequential AST or ALT elevations 3 times the upper limit of normal
accompanied by signs or symptoms consistent with hepatic injury (eg, new onset
elevated PT/INR);1

Two sequential AST or ALT elevations >5 times the upper limit of normal, regardless
of total bilirubin or accompanying signs or symptoms;1

Two sequential increases in serum creatinine >50% AND an absolute increase in
serum creatinine >0.5 mg/dL (44 μmol/L) over the average of screening and baseline
values;

Two sequential creatine kinase (CK) elevations >10 times the upper limit of normal,
unless the causality is known not to be medically serious (eg, exercise or trauma
induced);

A confirmed positive urine pregnancy test in a woman of childbearing potential;

Any opportunisticinfections considered significant by the investigator or the Sponsor;

Requirement of rescue medication for more than 10 consecutive days;

Subjects interrupting investigational product for more than 5 consecutive days during 
the double-blind portion or 28 consecutive days during the open-label treatment period
or subjects who are less than 80% compliant with the dosage regimen for any two
consecutive visit periods;

Other serious or severe adverse events, in the opinion of the investigator or sponsor.  
Whenever possible, the investigator should consult with a member of the study team
before discontinuation of the subject from the investigational product;

If VTE is confirmed, discontinue treatment with tofacitinib.
                                                
1. 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 Sponsor or designee.


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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. Safety Assessments
Clinical Laboratory Samples
Blood and urine samples will be collected at the time points identified in the protocol.  
Unscheduled clinical laboratory tests may be performed at any time during the study to 
assess any perceived safety concerns or for required monitoring.  Any laboratory test that is 
not analyzable should be repeated as soon as possible, but no later than the next visit.  If a 
subject completes the entire study without any retesting required, approximately 150 mL of 
blood will be taken.
Laboratory Testing Profile
Tests Included
Laboratory Tests Required at Screening Only QuantiFERON-TB Gold In-Tube, HIV-1/HIV-2 antibody screen,
hepatitis B surface antigen (HBsAg), hepatitis B core antibody
(HBcAb) *HBsAb only required for reflex testing in cases of
HBsAg- and HBcAb+, hepatitis C virus antibody (HCV Ab), HCV
RNA reflex testing for HCV Ab+, Prothrombin time (PT/INR),a
FSH (If applicable, for post- menopausal women only).
Hematology
Hemoglobin, hematocrit, RBC, RBC morphology, reticulocyte
(abs); White blood cell (WBC) count and differential, [neutrophils
(%, abs), lymphocytes (%, abs), monocytes (%, abs), eosinophils
(%, abs), basophils (%, abs)], platelet count.
Chemistry Panel
Urea nitrogen, creatinine, glucose, calcium, sodium, potassium,
bicarbonate, chloride, total protein, total bilirubin, direct bilirubin,
indirect bilirubin, alanine transaminase (ALT), aspartate
transaminase (AST), alkaline phosphatase, gamma-glutamyl
transferase (GGT), albumin, creatine kinase (CK).
Lipid Panel (fasting)
Total cholesterol, HDL, LDL, triglyceride; apolipoprotein
A-1, B and other lipoprotein tests potentially including particle
size measurements.


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Laboratory Testing Profile
Tests Included
Urinalysis
Specific gravity, pH, protein, glucose, ketones, blood, leukocyte
esterase.
Microscopy and/or culture to be performed if clinically indicated
or if urinalysis results positive (blood, protein or leukocyte
esterase/WBC).
Urine HCG pregnancy testing for women of childbearing
potential; may be repeated more frequently than indicated if
required by local regulation/practices, if a menstrual cycle is
missed, or if potential pregnancy is suspected.
Samples at Baseline Only
HLA-B27.
Acute Phase Reactants
High sensitivity C-reactive protein (hsCRP, tested centrally and
results blinded except at Screening visit).
FACS Analysis of Lymphocyte Markers
CD3+(%, abs), CD3+CD4+ (%, abs), CD3+CD8+ (%, abs),
CD19+ (%, abs), CD56+/CD16+ (%, abs).
a.
All subjects will be screened for normal prothrombin time (PT/INR).  PT should also be evaluated to rule
out acute hepatic injury in cases of hepatic enzyme elevations (see Section 8.3.2).
7.1.1. Hepatitis B and C Virus Testing
Subjects will be excluded with a known hepatitis B infection.  All subjects will be tested for 
HBsAg and HBcAb at the Screening visit.  Any subject who is HBsAg+ is excluded from 
study participation.  Subjects who are HBsAg- but HBcAb+ must undergo further testing for 
HBsAb by the central laboratory to be considered for enrollment.  Subjects who are 
HBsAg-/HBcAb+/HBsAb+ may be eligible for enrollment.  Subjects who are 
HBsAg-/HBcAb+/HBsAb- are excluded from study participation.
Subjects will be excluded with a known hepatitis C infection.  At the Screening visit all 
subjects will be tested for HCV Ab.  Subjects that are HCV Ab+ must undergo further testing 
for HCV RNA by the central laboratory to be considered for enrollment.  HCV RNA must be 
negative per the central laboratory to allow entry into the study.
7.1.2. Pregnancy Testing
A woman of childbearing potential must have a negative highly sensitive pregnancy test 
(urine, serum) as required by local regulations within 24 hours before the first dose of 
investigational product.  If a urine test cannot be confirmed as negative (eg, an ambiguous 
result), a serum pregnancy test is required.  In such cases, the participant must be excluded 
from participation if the serum pregnancy result is positive.  Pregnancy tests will also be
repeated at all visits and at the end of the study to confirm that the subject has not become 
pregnant during the study.  Pregnancy tests will also be done whenever 1 menstrual cycle is 
missed; during the active treatment period and when potential pregnancy is otherwise 
suspected, and may be repeated if requested by institutional review boards (IRBs)/ethics 
committees (ECs) or if required by local regulations.  In the case of a positive confirmed 
pregnancy, the subject will be withdrawn from administration of investigational product and 
all the necessary follow up will be conducted.


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7.1.3. Cardiovascular (CV) Risk Factor Assessment
CV risk factor assessment will be obtained at the Screening Visit.  The assessment includes: 

Smoking status;

Average weekly alcohol consumption: units/week, where a unit contains 14 g of pure 
alcohol, an amount equivalent to that contained in 5 oz (a glass) of wine at 
12% alcohol, 8-9 oz of malt liquor at 7% alcohol, 12 oz of beer at 5 % alcohol, or 
1.5 oz of drinks containing 40% alcohol; 

Family history of premature coronary heart disease (CHD): CHD in a male first 
degree relative <55 years of age, CHD in a female first degree relative <65 years of 
age.
7.1.4. Complete Physical Examination
A standard complete physical examination will be performed at Screening, Baseline/Day 1, 
Week 16, and Week 48.  The following parameters and body systems will be examined and 
any abnormalities described: general appearance, skin (presence of rash), HEENT (head, 
ears, eyes, nose, throat), lungs (auscultation), heart (auscultation for presence of murmurs, 
gallops, rubs), lower extremity exam (for peripheral edema), abdominal (palpation and 
auscultation), neurologic (mental status, station, gait, reflexes, motor and sensory function, 
coordination) and lymph nodes.  Any clinically significant change(s) from Baseline/Day 1 
should be recorded as an adverse event(s).
7.1.4.1. Targeted Physical Examination
At all other visits, an abbreviated physical examination will be performed assessing the
following: lungs, heart, abdomen, lower extremities (for peripheral edema), skin (presence of
rash) and lymph nodes.  Any clinically significant change(s) from Baseline (Day 1) should be
recorded as an adverse event(s).
7.1.5. Weight, Height and Waist Circumference
Weight will be measured at each study visit.  It is preferred that weight be measured in 
kilograms (kg) with shoes removed.  Weight should be measured to the nearest 0.1 kg.
Height will be measured at the Screening visit. It is preferred that height be measured in 
centimeters (cm) with shoes removed.
Waist circumference will be measured at the Baseline visit.  Waist measurement should be 
taken directly on the skin without clothing, in the standing position, and at the end of normal 
expiration.  Waist circumference should be measured immediately above the iliac crest.  
Waist measurement should be measured to the nearest 0.1 cm.


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7.1.6. Vital Signs
Body temperature, blood pressure and pulse rate will be measured at every study visit.
It is preferred that body temperature be collected using the tympanic, oral or temporal 
methods.  The method chosen should be used consistently by the investigational site 
throughout the study.
Blood pressure (BP) will be measured using a standard calibrated blood pressure measuring 
device.  The following method should be used to record the blood pressure:

Subjects should be seated in a chair with feet flat on the floor, back supported and their
arms bared (free of restrictions, such as rolled up sleeves, etc) and supported at heart
level;

Measurements should be taken on the same arm at each visit (preferably nondominant
arm);

Subjects should refrain from smoking or ingesting caffeine during the 30 minutes
preceding the measurements;

Measurements should begin after at least 5 minutes of rest;

BP should be recorded to the nearest mmHg value.
When the timing of BP and pulse rate measurements coincides with a blood collection or
other study procedures, BP and pulse rate should be obtained first.
7.1.7. 12-Lead Electrocardiogram (ECG)
Twelve-lead electrocardiograms (ECGs) will be obtained on all subjects at the Screening,
Week 16, Week 48 visits. All ECGs should be performed after the subject has rested quietly
for at least 10 minutes. ECG data will be submitted to a central reader for measurement.  
Any clinically significant changes from the Screening ECG will be recorded as adverse
events and evaluated further, as clinically warranted.
7.1.8. TB Testing
During the Screening period, it must be determined and documented that a subject does not
have evidence of active or latent or inadequately treated infection with Mycobacterium
tuberculosis (TB) per the inclusion criteria. The results of TB screening conducted in the
3 months prior to Screening or during the Screening period must be documented in study
records prior to Baseline/Day 1.
7.1.9. QuantiFERON- TB Gold In-Tube Test
QuantiFERON-TB Gold In-Tube is an in vitro diagnostic test using a peptide cocktail
simulating ESAT-6, CFP-10 and TB 7.7 proteins to stimulate cells in heparinized whole
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identify in vitro responses to these peptide antigens that are associated with Mycobacterium 
tuberculosis infection.  QuantiFERON-TB Gold In-Tube is an indirect test for 
M. tuberculosis infection (including disease) and is intended for use in conjunction with risk 
assessment, radiography and other medical and diagnostic evaluations.
Test results will be reported as positive, negative or indeterminate. In the case of an
indeterminate result, repeat tests may be permitted for the purpose of determining eligibility
of subjects to enroll in this study.  The procedure for using this test and interpreting results is 
described fully in the laboratory manual, which will be provided to investigators.
In addition, annual screening for latent and/or active TB will be conducted using QFT for
those subjects in the countries for which TB incidence has been reported at a rate of 
>50 cases per 100,000 persons.  All subjects with a new positive QFT must have a chest 
radiograph reviewed by a radiologist or pulmonologist as per local standard of care and the 
radiograph must be negative for active TB infection for the subject to remain in the study.
7.1.10. Chest Radiograph
A chest radiograph will be obtained at the Screening visit in all subjects unless it has been
previously taken and documented within the 3 months prior. To be considered eligible for
the study, the radiograph must be reviewed by a radiologist or pulmonologist as per local standard 
of care and documented as negative for active tuberculosis infection.
7.1.11. Radiograph of Sacroiliac (SI) Joints
A radiograph of the SI joints is required to meet inclusion criteria of documented AS and
must meet the Modified New York criteria 198451 for ankylosing spondylitis (Appendix 2) for
a subject to be enrolled in the study.  Regardless of whether the radiograph is newly obtained 
or historical, it must be submitted to the central reader for evaluation of suitability of quality 
and confirmation of diagnosis at the screening visit.  Subjects should not be scheduled for 
Baseline visit until confirmation is received from the central reader.
7.1.12. Historical Radiograph
Previous radiographs (up to 2 years old) of the sacroiliac (SI) joints (ideally AP view of the 
pelvis) documenting the diagnosis of AS will be acceptable and should be used in lieu of 
performing screening radiographs if they can be obtained and sent to the central reader for 
confirmation.  The original films, or a copy, must be on site and a copy should be sent to the 
central reader.  If the radiograph is a digital image, a copy can be sent to the central reader.  
If the results are considered unevaluable by the central reader, the x-ray must be repeated.
7.1.13. New Radiograph at Screening
If a historical radiograph cannot be obtained or interpreted by the central reader, x-ray of the
anterior-posterior (AP) pelvis view at the screening visit must be obtained to visualize the SI
joints. This should be done after all screening activities have been completed and if subject
does not fail to meet other study criteria.


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7.1.14. Risk Factor Check for Venous Thromboembolism
All subjects will undergo a risk factor check at each applicable study visit to check for newly 
developed risk factors for VTE50. This information is to be captured in the subject’s source
file.
A subject may be at high risk for VTE if he/she:

has heart failure or prior myocardial infarction within the past 3 months;

has inherited coagulation disorders;

has had VTE, either deep venous thrombosis or pulmonary embolism;

is taking combined hormonal contraceptives or hormone replacement therapy;

has a malignancy (association is strongest with cancers other than non-melanoma skin 
cancers);

is undergoing major surgery or is immobilized.
Additional risk factors for VTE, such as age, diabetes, obesity (BMI≥30 kg/m2), smoking 
status, hypertension, and first degree family history of VTE 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 discontinue from open-label 5 mg BID
dose of tofacitinib.
If a subject has 1 or more of the risk factors for VTE listed above and is receiving tofacitinib 
5 mg BID, they may remain on tofacitinib 5 mg BID after careful investigator assessment of 
benefit: risk. For subjects who do not have any of the risk factors for VTE listed above, 
he/she will remain on their open-label tofacitinib dose of 5 mg BID.
7.2. Efficacy Assessments
7.2.1. ASAS Improvement Criteria
The Assessment of SpondyloArthritis International Society (ASAS) has developed 
improvement criteria for clinical trials in AS which include the ASAS20, ASAS40, ASAS 
5/6 assessments52 and partial remission.53  These composite scores are derived from several 
of the “Patient Reported Outcome” measures or disease activity assessments.  The composite 
score will be calculated by the sponsor.  In order for this calculation to be completed, the 
investigator is responsible to ensure completeness of the PROs and appropriately conduct the 
assessments that comprise this endpoint.
ASAS20 and ASAS40 assess 4 domains: the “Patient Global Assessment of Disease”, Spinal 
Pain (total back pain), Function (BASFI) and Inflammation (from the BASDAI).  ASAS20 
improvement is defined as 20% and 1 unit in at least 3 domains on a scale of 0-10 and no 
worsening of 20% and 1 unit in the remaining domain.  ASAS40 improvement criteria are 


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classified as 40% and 2 units in at least 3 domains on a scale of 0-10 and no worsening at
all in the remaining domain.
ASAS 5/6 assesses 6 domains: the domains as noted in the ASAS20 and 40, CRP and Spinal 
mobility, specifically lateral spinal flexion (from the BASMI).  Improvement is defined as 
20% in at least 5 domains.
ASAS partial remission is based on the same 4 ASAS domains noted above.  Partial 
remission is defined as a response if a score of 2 or less (on a scale of 0-10) for each of the 
4 domains.
7.2.2. Ankylosing Spondylitis Disease Activity Score (ASDASCRP)
The ASDASCRP endpoint is derived from several patient reported outcomes and CRP which 
will be calculated by the sponsor.  In order for this calculation to be completed, the 
investigator is responsible to ensure completeness of the PROs and appropriately conduct the 
assessments that comprise this endpoint.  Following is the formula used for calculating the 
ASDASCRP.53
ASDASCRP = 0.121 × Back Pain + 0.058 × Duration of Morning Stiffness + 0.110 × Patient
Global + 0.073 × Peripheral Pain/Swelling + 0.579×Ln(CRP mg/L+1).52
Question 2 of the BASDAI provides the data for Back Pain, Question 6 of the BASDAI
provides the data for Duration of Morning Stiffness, the score from the Patient Global
Assessment of Disease is utilized for the Patient Global and Question 3 of the BASDAI
contributes the data for Peripheral Pain/Swelling.
The ASDAS clinically important improvement, major improvement and inactive disease will
be calculated from the ASDAS data.53
7.2.3. High Sensitivity C-Reactive Protein (hsCRP)
Blood samples will be collected at each visit for analysis of hsCRP using an assay analyzed 
by the central laboratory.  The investigator, study site personnel and Sponsor study team will 
be kept blinded to the results of this test at all visits except the Screening visit.
7.2.4. Specific Medical History and Peripheral Articular Involvement
Subjects will be assessed at Screening, Baseline/Day 1, Week 8, Week 16, Week 32, 
Week 48, and at Follow-up to determine if they have experienced an adverse event of IBD, 
psoriasis or uveitis as well as any complaints suggestive of peripheral articular involvement
(as assessed by swollen joint count) since the last visit.
7.2.5. Bath Ankylosing Spondylitis Metrology Index (BASMI)
The Bath Ankylosing Spondylitis Metrology Index (BASMI)54 is used to assess the axial
status and mobility (cervical, dorsal and lumbar spine, hips and pelvic soft tissue). Five
clinical measures comprise this scale and in this clinical study the linear function method55
will be used; these measures will be obtained by the qualified blinded assessor.  It is


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recommended that the same qualified personnel be used for each visit.  The combined index
score will be calculated by the sponsor using the individual scores from the following
measures: lateral spinal flexion, tragus-to-wall distance, lumbar flexion (modified Schober),
maximal intermalleolar distance, and cervical rotation.
Constricting clothing should be removed to ensure the subject can adequately move for the
examinations and visualization of anatomical positions where necessary.
7.2.5.1. Lateral Spinal Flexion
The subject should stand upright and the subject’s head and back should rest against the wall
as close as possible with shoulders level and feet 30 cm apart and feet parallel.  There should 
be no flexion in the knees, no bending forward.  Subject’s hands should be resting on his/her 
lateral thighs.  At the tip of the middle finger, place a mark on the thigh.  This is the neutral 
position mark. Measure and record the neutral position.  Have the subject bend sideways 
without bending knees or lifting heels while attempting to keep the shoulders in the same 
position (flexion position).  Place a second mark and record the lateral flexion (left or right as 
appropriate) using a centimeter tape measure.  Measure and record two tries for the left and 
two tries for the right.  The results of the two tries are recorded for left and right separately in
cm to the nearest 0.1 cm.  The difference between the neutral position and the lateral flexion 
for each side will be calculated by the sponsor and the better of two tries will be used in the 
analysis of the data.
Alternatively, measure the distance between the subject’s middle fingertip and the floor 
before (this is the neutral position) and after bending sideways.  Record the neutral position 
in cm to the nearest 0.1 cm.  Measure and record two tries for the left and two tries for the 
right.  The results of the two tries are recorded for the left and right separately in cm to the 
nearest 0.1 cm.  The difference between the neutral position and the lateral flexion for each 
site will be calculated by the sponsor and the better of two tries will be used in the analysis.  
If this technique is used, it must be consistently used for the entire time this subject is 
participating.  If marks are placed on the subject, ensure marks are not visible at the next 
clinic visit.
7.2.5.2. Tragus-to-Wall Distance
Place the subject standing with his/her back against the wall; knees straight; scapulae,
buttocks, and heels against wall; and head in as neutral position as possible.  Measure the 
distance between the tragus and wall in cm (to the nearest 0.1 cm) from both the right side 
and left side at the maximum effort to touch the head against the wall.  Measure two tries on 
the right side and two tries on the left side.  Record both tries on the appropriate eCRF.
7.2.5.3. Lumbar Flexion (Modified Schober)
With the subject standing erect and outer edges of feet 30 cm apart, place a mark in the 
midpoint of a line that joins the posterior superior iliac spines (baseline mark).  Place a 
second mark (A) 10 cm above the baseline mark and a third mark (B) 5 cm below the 
baseline mark.  Then have the subject maximally bend forward, keeping the knees fully 
extended.  With the subject’s spine in full flexion, re-measure the distance between marks 


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A and B (in cm to the nearest 0.1 cm).  This measurement should include the original 15 cm.  
Measure two tries. Record both tries on the appropriate eCRF.
7.2.5.4. Maximal Intermalleolar Distance
The subject should lie supine with the knees straight and feet/toes pointing straight up.  The 
subject is asked to separate the legs as far as possible and the distance between the medial 
malleoli is measured (in cm to the nearest 0.1 cm).  Measure and record two tries on the 
appropriate eCRF.
7.2.5.5. Cervical Rotation
Subject should be sitting straight on a chair with chin level and hands on their knees.  The 
qualified blinded assessor places a goniometer at the top of the head in line with the nose.  
The qualified blinded assessor asks the subject to rotate the neck maximally to the left, 
follows with the goniometer and records the angle between the sagittal plane and the new 
plane after rotation.  Ensure the subject keeps shoulders still and no neck or shoulder flexion 
occurs.  A second reading is obtained and the both of the readings are recorded.  The 
procedure is repeated for the right side and the both of the readings are recorded for the right 
side.  The better of the two for each side is selected for scoring.  Scoring is done by 
calculating the mean of the left and right measurement and is recorded in degrees (0-90).
7.2.6. Spinal Mobility: Chest Expansion
This assessment is performed by the qualified blinded assessor.  It is recommended that the 
same qualified personnel be used for each visit.  Spinal Mobility includes the measures 
collected in the BASMI and Chest Expansion.  For collecting chest expansion the subject 
should have their hands rest on or behind the head.  With the subject standing and at maximal 
inspiration, measure the chest circumference at nipple line or at the 4th intercostal space (in 
cm to the nearest 0.1 cm) anteriorly.  Re-measure the chest circumference at maximal 
expiration.  The difference between maximal inspiration and expiration of the two attempts 
will be obtained and recorded.  The better of the two attempts will be utilized for data 
reporting.
7.2.7. Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)
Enthesitis will be evaluated by the qualified blinded assessor using the Maastricht Ankylosing
Spondylitis Enthesitis Score (MASES).56  It is recommended that the same qualified
personnel be used for each visit.  Thirteen sites (right and left) will be assessed for tenderness:
costochondral 1 (right and left), costochondral 7 (right and left), spina iliaca anterior superior
(right and left), crista iliaca (right and left), spina iliaca posterior (right and left), processus
spinosus at L5 and Achilles tendon proximal insertion (right and left).
Scoring at each site will be 0 for no tenderness or 1 for tenderness.
7.2.8. Swollen Joint Count (44)
The qualified blinded assessor will also assess joints for swelling using the following scale:
Present/Absent/Not Done/Not Applicable (to be used for artificial or missing joints) for


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determination of the total number of swollen joints.  It is recommended that the same
qualified personnel be used for each visit.  Forty-four (44) joints will be assessed for swelling
as noted in Figure 211 below and will include the following: sternoclaviculars,
acromioclaviculars, shoulders, elbows, wrists, metacarpophalangeals (MCP I, II, III, IV, V),
thumb interphalangeal (IP), proximal interphalangeals (PIP II, III, IV, V), knees, ankles, and
metatarsophalangeals (MTP I, II, III, IV, V).  Artificial joints will not be assessed.
Figure 2.
44 Swollen Joint Count Mannequin
7.2.9. Patient Reported Outcomes
7.2.9.1. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
The BASDAI is a validated questionnaire that consists of 6 questions pertaining to the 
5 major symptoms of AS: fatigue; spinal pain; peripheral arthritis; enthesitis, intensity of
morning stiffness and duration of morning stiffness.57  Each question will be rated using a 
numerical rating scale from 0 (none) to 10 (very severe).  The BASDAI score is calculated 
by computing the mean of questions 5 and 6 and adding it to the sum of questions (Q)1-4. 
This score is then divided by 5.  See following equation:
BASDAI = ((Q1 + Q2 + Q3 + Q4) + ((Q5 + Q6) / 2)) / 5
Q=Question
The total score and the response to Question 2 will be used for entry into the study. See 
Inclusion Criteria, Section 4.1.
7.2.9.2. Bath Ankylosing Spondylitis Functional Index (BASFI)
The BASFI is a set of 10 questions designed to determine the degree of functional limitation
in those with AS.58  The ten questions were chosen with a major input from patients with AS.


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The first 8 questions consider activities related to functional anatomy.  The final 2 questions 
assess the subjects’ ability to cope with everyday life.  A 0-10 numerical rating scale is used 
to answer the questions with 0 being “Easy” and 10 being “Impossible.”  The score will be 
derived from the mean of the 10 items by the sponsor and is indicative of the subject’s level 
of ability.
7.2.9.3. Patient Global Assessment of Disease
Subjects will assess their overall disease activity over the last week using a numerical rating
scale between 0 (Not Active) and 10 (Very Active) to the question, “How active was your
spondylitis on average during the last week?” Results of this assessment will be used to
calculate the ASAS improvement criteria.
7.2.9.4. Patient Assessment of Spinal Pain
Two NRS scales will be used to assess the subject’s spinal pain: level of nocturnal pain and
total back pain on average during the last week. For each of these scales, subjects will mark
their level of pain on a 0-10 NRS anchored by 0 for “No Pain” to 10 “Most Severe Pain.”
Results of total back pain will be used to calculate the ASAS improvement criteria.
7.2.9.5. Ankylosing Spondylitis Quality of Life
The Ankylosing Spondylitis Quality of Life (ASQoL) is an 18-item questionnaire assessing
the amount of restriction the subject is experiencing in daily activities, level of pain and
fatigue, and the impact on the subject’s emotional state.59  Each item is scored as 0 (no 
impact) or 1 (yes - impact).  A total score is calculated by summing the items.  The total 
score ranges from 0 to 18, with higher values indicating more impaired health-related quality 
of life.
7.2.9.6. SF-36v2 Health Survey)
The SF-36 v.2 (Acute) is a 36-item generic health status measure.  It measures 8 general 
health domains: physical functioning, role limitations due to physical health, bodily pain, 
general health perceptions, vitality, social functioning, role limitations due to emotional 
problems, and mental health.60  These domains can also be summarized as physical and 
mental component summary scores.  This questionnaire should be completed by the subject 
prior to any procedures being performed at the visit.  The form should be checked for 
completeness by the site staff.
7.2.9.7. EuroQol 5 Dimensions 3 Levels (EQ-5D-3L) Health State Profile
The EuroQol 3 Levels EQ-5D-3L Health State Profile (3 levels) is a subject completed
instrument designed to assess impact on health related quality of life in five domains:
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.61 Additionally, 
scores from the five domains may be used to calculate a single index value, also known as a 
utility score.  The validity and reliability of the EuroQol 3 Levels EQ-5D-3L has been 
established in a number of disease states, including rheumatoid arthritis.  In addition, “Your 
own health state today” (EQ-VAS) records the subject’s self-rated health, a score ranging 
from 0 to 100 mm will be recorded, with higher scores representing better health state today.


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This questionnaire should be completed by the subject prior to any procedures being 
performed at the visit.  The form should then be checked by site staff for completeness.
7.2.9.8. Functional Assessment of Chronic Illness Therapy – Fatigue Scale
The FACIT – Fatigue Scale is a subject completed questionnaire consisting of 13 items that
assess fatigue.62  Instrument scoring yields a range from 0 to 52 for the total score, with 
higher scores representing better subject status (less fatigue).  The FACIT - Fatigue Scale 
will also be summarized as FACIT-Fatigue experience domain score and FACIT-Fatigue 
impact domain score.  This questionnaire should be completed by the subject prior to any 
procedures being performed at the visit.  The form should then be checked by site staff for 
completeness.
7.2.9.9. Work Productivity & Activity Impairment Questionnaire: Spondyloarthritis
The Work Productivity & Activity Impairment Questionnaire (WPAI): Spondyloarthritis is a
6-item questionnaire that is specific for spondyloarthritis which yields four types of scores:
absenteeism, presenteesism (impairment at work/reduced job effectiveness), work
productivity loss and activity impairment.63 WPAI outcomes are expressed as impairment 
percentages with higher numbers indicating greater impairment and less productivity.  This 
questionnaire should be completed by the subject prior to any procedures being performed at 
the visit, if possible.  The form should be checked for completeness by the site staff.
7.2.9.10. Ankylosing Spondylitis Healthcare Resource Utilization Questionnaire
The AS Healthcare Resource Utilization Questionnaire (AS-HCRU) is a seventeen item scale 
that is designed to assess healthcare usage during the previous three months across a wide 
number of direct medical cost domains.  The scale also assesses indirect costs associated with 
functional disability and impaired productivity at home and at work.  This questionnaire 
should be completed by the subject prior to any procedures being performed at the visit, if 
possible.  The form should be checked for completeness by the site staff.
7.3. Imaging Assessments (Chest and SI joint radiographs)
Management of incidental findings
An incidental finding is one unknown to the subject that has potential health or reproductive 
importance, which is discovered unexpectedly in the course of a research study, but is 
unrelated to the purpose and beyond the aims of the study.
Radiograph images will be reviewed by a central review facility. The purpose of this review 
is to evaluate images for TB screening or diagnosis of AS. Central image review is not a 
complete medical review of the subject and no incidental findings will be shared with the 
principal investigator, site staff, or the subject. All safety reviews will be the sole 
responsibility of site staff.


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7.4. Rater Qualifications
For specific rating assessments, only qualified raters will be allowed to evaluate and/or rate 
subjects in this study.  It is a strong preference that the same rater perform all assessments for
a subject throughout the study.  However, if a situation arises where this is not feasible and a 
back-up rater must conduct the assessments this will not be considered a protocol deviation.  
The minimum qualifications a rater must meet for each study rating assessment will be 
outlined in the study Rater Experience Questionnaire for Blinded Assessors provided to each 
participating site.  The level of experience with the target population (or equivalent), and 
certification required (if applicable) will be listed and used to determine whether a rater is 
approved for a given assessment.  Proposed raters who do not meet specific criteria but who
may be qualified based on unique circumstances may be individually reviewed by the study 
clinical team to determine whether or not they are qualified to perform the assessments.  
Documentation that the rater is certified to perform selected study assessments before he or 
she can participate in the conduct of the study is required.  The raters who administer specific 
study assessments will be documented in a centralized location and all site staff who 
administer ratings will be verified in the site study documentation during the conduct of the 
study.
The following procedures require a health care professional who is competent to perform the 
assessments: swollen joint count; Bath Ankylosing Spondylitis Metrology Index (BASMI); 
Maastricht Ankylosing Spondylitis Enthesitis Score (MASES); spinal mobility.
 
 
 
 
 
 
 
 


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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether
associated with an AE), except 
occupational exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the Clinical Trial 
Serious Adverse Event (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 


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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.
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 due to Adverse Events (see also the Subjects Discontinuation from 
the Investigational Product 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 investigational product because of an SAE, the SAE 
must be recorded on the eCRF and reported, as appropriate, on the CT SAE Report Form, in 
accordance with the Requirements section above.
Subjects that are withdrawn due to an AE 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. In this case, no further 
evaluation 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.
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 


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study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.


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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;

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.


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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 investigational product, significant 
additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.


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8.2.4. Infections
Some infections may be classified as serious infections, as defined below.
8.2.5. Serious Infections
A serious infection is any infection (viral, bacterial, and fungal) that requires hospitalization
for treatment or requires parenteral antimicrobial therapy or meets other criteria that require it
to be classified as a serious adverse event. A subject who experiences a serious infection
should be discontinued from the investigational product and the serious adverse event should
be listed as the reason for discontinuation in the CRF.  Appropriate laboratory investigations,
including but not limited to cultures should be performed to establish the etiology of any
serious infection. All adverse events, including serious adverse events, should be reported as 
described in Section 8 on Adverse Event Reporting.
8.2.6. 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;

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);


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
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.
Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.3. Special Situations
8.3.1. 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.
8.3.2. 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 


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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:

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. 


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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 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.
8.3.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.3.1. 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).


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
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.
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 


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subject was given the Pregnant Partner Release of Information Form to provide to his
partner.
8.3.3.2. 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.
8.3.3.3. 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 an CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.4. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether
associated with an AE)
Only if associated with an 
SAE
8.3.4.1. 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;


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•
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
Methodology for summary and statistical analyses of the data collected in this trial are given 
here and further detailed in a statistical analysis plan (SAP), which will be dated and 
maintained by Pfizer.
This analysis plan may modify what is outlined in the protocol; however, any major 
modifications of the primary endpoint definition or its analyses will also be reflected in a
protocol amendment.
9.1. Sample Size Determination
The primary efficacy analysis is to compare the ASAS20 response rate at Week 16 of the 
tofacitinib 5 mg BID and placebo via the normal approximation for the difference in 
binomial proportions.  Assuming a placebo response rate of 40% for ASAS20 response at 
Week 16, a sample size of 120 per arm will yield about 89% power to detect a difference of 
at least 20% between tofacitinib 5 mg BID and placebo at a two-sided significance level of 
5%.  In the Phase 2 proof of concept trial A3921119, ASAS20 response rates at Week 12
were 63% and 40% for tofacitinib 5 mg BID and placebo, respectively. 
9.2. Efficacy Analysis
There will be a total of 2 planned analyses conducted when all applicable subjects have 
completed their Week 16 and Week 48 (including follow-up) visits, respectively. The 
investigators, subjects and sponsor study team will remain blinded to the first 16 weeks of
treatment assignment through the entire duration of the trial until database release at
Week 48. The first analysis (Week 16 analysis) will include all efficacy data through 
Week 16 and the safety data through the data cutoff date. As the primary endpoint 
(ASAS20), the key secondary endpoint (ASAS40) and the other Type I error controlled 
secondary endpoints are at Week 16, there will be no additional adjustment made for Type I 
error rate at the final analysis at Week 48. The efficacy analysis results through Week 16 
obtained from the Week 16 analysis will be considered final and definitive. 
 
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The Week 48 analysis will be conducted when all the applicable subjects have completed 
their Week 48 (including follow-up) visit and the database is released.  All the Week 48 
analysis results will be secondary in nature.  The Week 48 analysis will contain results for 
earlier visits prior to or at Week 16 including those for the primary endpoint and the key 
secondary endpoint; however they will serve as a sensitivity analysis only to ensure there are 
no major changes to the definitive results for the primary endpoint and the key secondary 
endpoint obtained at the Week 16 analysis.
9.2.1. Analysis of Primary Endpoint
The ASAS20 response rate at Week 16 is the primary efficacy endpoint in this trial.  The 
analysis of primary endpoint will be based on the full analysis set, which includes all 
randomized subjects who take at least 1 dose of investigational product.  For the primary 
analysis, the normal approximation for the difference in binomial proportions adjusting for 
the stratification factor (ie, prior treatment history: bDMARD-naïve vs TNFi-IR) at 
randomization via the Cochran–Mantel–Haenszel approach will be used to estimate the 
treatment effect (treatment difference, standard error, 95% confidence interval) and to test 
(Normal Z-test) test the superiority of tofacitinib 5 mg BID to placebo and to generate 
confidence interval for the difference.  Missing values for any reason will be handled by 
setting the ASAS20 value to nonresponsive.  Note that this can be viewed as a composite 
endpoint in the sense that a response requires the subject completes a visit of interest eg, 
Week 16, and achieves a response per the defined ASAS20 response criteria (otherwise it is 
considered a nonresponse).
Sensitivity analyses will be performed to assess robustness of the primary analysis due to 
missing data and will be detailed in the SAP.
9.2.2. Analysis of Secondary and Other Endpoints
Methods for the analysis of secondary endpoints and other endpoints will be enumerated in 
the SAP.  Briefly, binary variables will follow the analyses using the normal approximation 
to estimating binomial proportions as described for the ASAS20 and continuous endpoints 
will be analyzed as change from baseline as appropriate with a mixed model for repeated 
measures (MMRM) that include fixed effects of treatment group, visit, and treatment-group 
by visit interaction, stratification factor (ie, prior treatment history: bDMARD-naïve vs 
TNFi-IR) at randomization, and baseline value.  An unstructured variance covariance matrix 
will be used, provided the model converges, otherwise an alternative covariance structure
will be attempted.  Descriptive statistics may also be calculated and displayed.
9.2.3. Control for Type I Error Rate
This protocol is designed to establish the superiority of tofacitinib 5 mg BID to placebo for 
the treatment of active AS based on the primary endpoint of ASAS20 at Week 16 in subjects 
who have had an inadequate response to previous treatments.
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All statistical tests will be conducted at the 2-sided 5% (or equivalently 1-sided 2.5%) 
significance level for comparing tofacitinib 5 mg BID to placebo.  Type I error will be 
controlled at 2-sided 5% or equivalently 1-sided 2.5%. 
For the primary endpoint of ASAS20 at Week 16, if the 2-sided p value is 5%, the 
superiority of tofacitinib 5 mg BID to placebo will be declared for this primary endpoint and 
the primary objective of this study is met.Hypothesis testing will continue to the global 
family of select set of secondary endpoints stated below (Global Type I Error Control (for 
the primary endpoint and a select set of secondary endpoints)).  For each of the endpoints
within this family, superiority of tofacitinib 5 mg BID to placebo will be declared if 
statistical significance is achieved under the step-down testing procedure.  In addition, three 
other families of hypotheses, ASAS family endpoints (Type I Error Control for Endpoints in 
the ASAS Family), ASAS20’s earlier time points (Type I Error Control for ASAS20 at Earlier 
Time Points) and ASAS40’s earlier time points (Type I Error Control for ASAS40 at Earlier 
Time Points) will also be tested.  For each of the endpoints or time points of 
ASAS20/ASAS40, superiority of tofacitinib 5 mg BID to placebo will be declared if 
statistical significance is achieved under its respective step-down testing procedure.
Global Type I Error Control (for the primary endpoint and a select set of secondary 
endpoints): The family-wise Type I error rate will be controlled at the 2-sided 5% (or 
equivalently 1-sided 2.5%) significance level using a step-down testing procedure for the 
primary endpoint of ASAS20, the key secondary endpoint of ASAS40 and a select set of 
secondary endpoints at Week 16 tested in the sequence below: ASAS20, ASAS40, change 
from baseline in ASDASCRP,  change from baseline in hsCRP, change from baseline in
ASQoL, change from baseline in SF-36v2 Physical Component Summary (PCS), change 
from baseline in BASMI, and change from baseline in the FACIT-F Total score.  When an 
endpoint fails to declare statistical significance, this endpoint and the remaining endpoints 
lower in the hierarchy will be considered non-significant. The rationale for the selection and 
ordering of the select set of secondary endpoints are clinical importance, precedence and 
likelihood of statistical success based on the results of the A3921119 study.
Type I Error Control for Endpoints in the ASAS Family: ∆ in Patient Global Assessment 
(PGA) of disease, change from baseline in total back pain, ∆BASFI, and change from 
baseline in in inflammation (average of questions 5 and 6 of BASDAI) are the 4 ASAS 
components used in deriving ASAS20, thus they are considered belonging to the ASAS 
family of endpoints. A step-down testing procedure will be applied to them and tested in the 
sequence below: ASAS20, change from baseline in PGA, change from baseline in total back 
pain, change from baseline in BASFI, and change from baseline in inflammation (average of 
questions 5 and 6 of BASDAI) at Week 16.  When an endpoint fails to declare statistical 
significance, this endpoint and the remaining endpoints lower in the hierarchy will be 
considered non-significant.  Though this testing scheme does not protect the Type I error for 
the family of all possible comparisons, it will provide Type I error protection for testing the 
family of ASAS endpoints.
Type I Error Control for ASAS20 at Earlier Time Points: In order to be more rigorous about 
establishing the onset of efficacy as measured by ASAS20 at the earliest time point at which 


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there is statistical separation between tofacitinib 5 mg BID and placebo, a step-down 
approach with the ASAS20 from Week 16 to earlier time points (order of testing: Weeks 16, 
12, 8, 4, and 2) will also be used for each time point.  Though this testing scheme does not 
protect the Type I error for the family of all possible comparisons, it will provide Type I error 
protection for testing the family of ASAS20 time points.
Type I Error Control for ASAS40 at Earlier Time Points: In order to be more rigorous about 
establishing the onset of efficacy as measured by ASAS40 at the earliest time point at which 
there is statistical separation between tofacitinib 5 mg BID and placebo, a step-down 
approach with the ASAS40 from Week 16 to earlier time points (order of testing: Weeks 16, 
12, 8, 4, and 2) will also be used for each time point.  Though this testing scheme does not 
protect the Type I error for the family of all possible comparisons, it will provide Type I error 
protection for testing the family of ASAS40 time points.
9.3. Safety Analysis
All the safety data will be summarized descriptively through appropriate data tabulations,
descriptive statistics, and graphical presentations:

Incidence and severity of adverse events;

Categorical summary of absolute vital signs and vital sign changes compared to
baseline by subject;

Serious infections, defined as any infection (viral, bacterial, and fungal) requiring
hospitalization or parenteral antimicrobials, will be summarized;

Any safety events that trigger withdrawal of a subject;

Safety laboratory tests will be summarized according to Pfizer standards.
Special attention will be given to the following safety criteria: neutrophil counts, lymphocyte
counts, serum creatinine levels, platelet counts, transaminase levels, bilirubin levels (and other
measures of liver function), events of anemia.
9.4. Interim Analysis
No formal interim analysis will be conducted for this study. The analysis of the primary, key 
secondary endpoint and the other Type I error controlled secondary endpoints conducted at 
Week 16 is the final analysis for these endpoints (see Section 9.2).
9.5. 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, 


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which may include summaries of aggregate analyses of safety data that are not endpoints, to 
regulatory authorities, as appropriate.
Information about the E-DMC can be found in the E-DMC Charter, which outlines the 
operating procedures of the committee, including specific description of the scope of their 
responsibilities, including a plan where communication timelines are defined. 
9.6. Safety Event Adjudication/Review Committees
To help assess the specific safety events in this and other Phase 3 studies for the oral 
tofacitinib AS 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), Opportunistic Infection review Committee (OIRC), Malignancy Adjudication 
Committee (MAC), Hepatic Event Review Committee (HERC) and Gastrointestinal 
Perforation Review Committee (GIPRC).  In addition to these external committees, an 
internal committee of medically trained qualified Pfizer personnel with expertise in the 
assessment and diagnosis of respiratory disease will review and categorize potential events of 
interstitial lung disease (Interstitial Lung Disease Review Committee, ILDRC).  Further 
information about these committees can be found in their respective charters, including 
specific descriptions of the scope of their responsibilities and the process and definitions to 
review and assess specific safety events.
Additional safety event adjudication review committees may be established as considered 
appropriate. As described above, individual committee charters will provide specific 
descriptions of the scope of the responsibilities and the processes and definitions used to 
review and assess specific safety events.
In addition to the event adjudication or review committees described above, all biopsies of 
potentially malignant tumors, suspicious lymphadenopathy, or possible extranodal 
lymphoproliferative disorder (LPD), should be submitted to the central laboratory for review 
by the central laboratory pathologists.  In some instances, additional expert pathology review 
of submitted samples may be performed.  Description of the scope of the review and the 
processes used to obtain and assess biopsies is described in the Histopathology Review for 
Potential Malignancy charters.  Further details on central laboratory review of biopsies of 
suspected malignancies are found in Appendix 7.


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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 
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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 shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and/or paper form and will 
be password protected or secured in a locked room to prevent access by unauthorized third 
parties.
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/assent 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.  
The investigator must ensure that the records continue to be stored securely for so long as 
they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 


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Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records,
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.  In addition, the study will be conducted in accordance with applicable local
regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 


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to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
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 the Clinical Study Agreement and 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.
The investigator must ensure that each study subject, is fully informed about the nature and 
objectives of the study, the sharing of data relating to the study and possible risks associated 
with participation, including the risks associated with the processing of the subject’s personal
data.  The investigator further must ensure that each study subject, is fully informed about his 
or her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
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 All Participating Countries
End of trial in all participating countries is defined as Last Subject Last Visit.
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 5 business days.  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 investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
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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26.
Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofacitinib (CP-690,550) 
combined with methotrexate in patients with rheumatoid arthritis and an inadequate 
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Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in 
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inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. 
Lancet 2013; 381(9865):451-60.
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monotherapy in rheumatoid arthritis. N Engl J Med 2012; 367(6):495-507.
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disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis a 
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arthritis. N Engl J Med 2014; 370(25):2377-86.
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van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients 
with rheumatoid arthritis receiving methotrexate: twelve-month data from a 
twenty-four-month phase III randomized radiographic study. Arthritis Rheum 2013;
65(3):559-70.
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placebo in rheumatoid arthritis. N Engl J Med 2012; 367(6):508-19.
33.
Yamanaka H, Tanaka Y, Takeuchi T, et al. Tofacitinib, an oral Janus kinase inhibitor, 
as monotherapy or with background methotrexate, in Japanese patients with rheumatoid 
arthritis: an open-label, long-term extension study. Arthritis Res Ther 2016; 18:34.
34.
Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral 
janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm 
extension studies. J Rheumatol 2014; 41(5):837-52.
35.
Wollenhaupt J, Silverfield J, Lee EB, et al. Tofacitinib, an oral janus kinase inhibitor, in 
the treatment of rheumatoid arthritis: safety and efficacy in open-label, long-term 
extension studies over 9 years. Arthritis Rheumatol 2017; 69(Suppl 10):Abstr 522.
36.
Gladman D, Rigby W, Azevedo VF, et al. Tofacitinib for psoriatic arthritis in patients 
with an inadequate response to TNF inhibitors. N Engl J Med 2017; 377(16):1525-36.
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Mease P, Hall S, FitzGerald O, et al. Tofacitinib or adalimumab versus placebo for 
psoriatic arthritis. N Engl J Med 2017; 377(16):1537-50.


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38.
Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus 
kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled 
dose-ranging study. Br J Dermatol 2012; 167(3):668-77.
39.
Bachelez H, van de Kerkhof PC, Strohal R, et al. Tofacitinib versus etanercept or 
placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised 
non-inferiority trial. Lancet 2015; 386(9993):552-61. 
40.
Bissonnette R, Iversen L, Sofen H, et al. Tofacitinib withdrawal and retreatment in 
moderate-to-severe chronic plaque psoriasis: a randomized controlled trial. Br J 
Dermatol 2015; 172(5):1395-406.
41.
Papp KA, Menter MA, Abe M, et al. Tofacitinib, an oral Janus kinase inhibitor, for the 
treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled,
phase III trials. Br J Dermatol 2015; 173(4):949-61.
42.
Sandborn WJ, Su C, Panes J. Tofacitinib as induction and maintenance therapy for 
ulcerative colitis. N Engl J Med 2017; 377(5):496-7.
43.
van Vollenhoven RF, Keystone EC, Furie R, et al. Gastrointestinal safety in patients 
with rheumatoid arthritis treated with tocilizumab: data from Roche clinical trials 
[abstract]. Arthritis Rheum 2009; 60(10):1613.
44.
Curtis JR, Xie F, Chen L, et al. The incidence of gastrointestinal perforations among 
rheumatoid arthritis patients. Arthritis Rheum 2011; 63(2):346-51.
45.
Van Roon JAG, Bijlsma JWJ. Rheumatoid arthritis and spondyloarthropathies: the Th2 
mediated regulation in RA and the spondyloarthropathies. Ann Rheum Dis 2002; 
61:951-4.
46.
Gratacos J, Collado A, Filella X, et al. Serum cytokines (IL-6, TNF-alpha, IL-1 beta and 
IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and 
disease activity and severity. Br J Rheumatol 1994; 33(10):927-31.
47.
Tutuncu ZN, Bilgie A, Kennedy LG, et al. Interleukin-6, acute phase reactants and 
clinical status in ankylosing spondylitis. Ann Rheum Dis 1994; 53(6):425-6.
48.
Visvanathan S, Wagner C, Marini JC, et al. Inflammatory biomarkers, disease activity 
and spinal disease measures in patients with ankylosing spondylitis after treatment with 
infliximab. Ann Rheum Dis 2008; 67(4):511-7.
49.
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http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm.
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developed in collaboration with the ERS. European Heart Journal (2020) 41;543-603.


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51.
van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for 
ankylosing spondylitis. A proposal for modification of the New York criteria. Arth 
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Sieper J, Rudwaleit M, Baraliakos X, et al. The Assessment of SpondyloArthritis 
International Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann 
Rheum Dis 2009; 68 Suppl 2:ii1-44.
53.
Machado P, Landewe R, Lie E, et al. Ankylosing Spondylitis Disease Activity Score 
(ASDAS): defining cut-off values for disease activity states and improvement scores. 
Ann Rheum Dis 2011; 70(1):47-53.
54.
Jenkinson TR, Mallorie PA, Whitelock HC, et al. Defining spinal mobility in 
ankylosing spondylitis (AS). The Bath AS Metrology Index. J Rheumatol 1994; 
21(9):1694-8.
55.
van der Heijde D, Landewe R, Feldtkeller E. Proposal of a linear definition of the Bath 
Ankylosing Spondylitis Metrology Index (BASMI) and comparison with the 2-step and 
10-step definitions. Ann Rheum Dis 2008; 67(4):489-493.
56.
Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, et al. Assessment of enthesitis 
in ankylosing spondylitis. Ann Rheum Dis 2003; 62(2):127-32.
57.
Garrett S, Jenkinson T, Kennedy LG, et al. A new approach to defining disease status in 
ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J 
Rheumatol 1994; 21(12):2286-91.
58.
Calin A, Garrett S, Whitelock H, et al. A new approach to defining functional ability in 
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59.
Doward LC, Spoorenberg A, Cook SA, et al. Development of the ASQoL: a quality of 
life instrument specific to ankylosing spondylitis. Ann Rheum Dis 2003; 62(1):20-6.
60.
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Hurst NP, Kind P, Ruta D, et al. Measuring health-related quality of life in rheumatoid 
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62.
Cella D, Lai JS, Chang CH, et al. Fatigue in cancer patients compared with fatigue in 
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Reilly MC, Gooch KL, Wong RL, et al. Validity, reliability and responsiveness of the
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Rheumatology (Oxford)2010; 49(4):812-9.


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Appendix 1. Abbreviations
This is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AE
Adverse Event
ACR
American College of Rheumatology
ACR20
American College of Rheumatology 20% improvement
ACR50
American College of Rheumatology 50% improvement
ACR70
American College of Rheumatology 70% improvement
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AS
Ankylosing Spondylitis
AP
Anterior-Posterior
ASAS
Assessment in Ankylosing Spondylitis
ASAS 20/40
Assessment in Ankylosing Spondylitis 20%/40% improvement
ASDASCRP
Ankylosing Spondylitis Disease Activity Score using CRP
AS-HCRU
AS HealthCare Resource Utilization Questionnaire
ASQoL
Ankylosing Spondylitis Quality of Life
AST
AspartateAminotransferase
AUC
Area under the concentration-time curve
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
BCG
Bacille Calmette Guérin
bDMARD
Biological Disease-Modifying Anti-Rheumatic Drug
BID
Twice daily
BMI
Body mass index
BP
Blood pressure
bpm
Beats per minute
BUN
Blood urea nitrogen
CD
Crohn’s Disease
CHD
Coronary heart disease
CK
Creatine Kinase
cm
centimeter
COX-2
Cyclooxygenase-2
CRF
Case Report Form
CRP
C-reactive Protein
CRO
Contract Research Organization
CSA
Clinical Study Agreement
csDMARD
Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug
CTA
Clinical Trial Application 
CT SAE
Clinical Trial Serious Adverse Advent Form
CYP3A4
Cytochrome P450 enzyme 3A4


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Abbreviation
Term
CYP2C19
Cytochrome P450 enzyme 2C19
CYP450
Cytochrome P450
CV
Cardiovascular
CV EAC
Cardiovascular Endpoint Adjudication Committee
DAS
Disease Activity Score
DILI
Drug-induced liver injury
DMARD
Disease-Modifying Anti-Rheumatic Drug
DMC
Data Monitoring Committee
EBV
Epstein-Barr Virus
EBV-LPD
Epstein-Barr Virus induced lymphoproliferative disease
eCRF
Electronic case report form
ECG
Electrocardiogram
EDP
Exposure During Pregnancy
EMA
European Medicines Agency
Emax
Maximal effect
EIU
Exposure in Utero
EQ-5D-3L
The EuroQol 5 Dimensions 3 Level Health State Profile
EQ-VAS
Your Own Health State Today Questionnaire
ER
Exposure Response
ESRD
End stage renal disease
EC
Ethics committees
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
EULAR
The European League Against Rheumatism
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FACS
Fluorescence Activated Cell Sorting
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GI
Gastrointestinal
GIPRC
Gastrointestinal Perforation Review Committee
gm
gram
HAQ-DI
Health Assessment Questionnaire-Disability Index
HBcAb
Hepatitis B core antibody
HBsAb
Hepatitis B Surface Antibody
HBsAg
Hepatitis B Surface Antigen
HCG
Human Chorionic Gonadotrophin
HCV
Hepatitis C Virus
HCVAb+
Hepatitis C Virus Antibody Postitive
HDL
High Density Lipoprotein
HEENT
Head, eyes, ears, nose, throat
HERC
Hepatic Event Review Committee
HDL-c
High Density Lipoprotein cholesterol


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Abbreviation
Term
HIV
Human Immunodeficiency Virus
hsCRP
High Sensitivity C-Reactive Protein
HZ
Herpes Zoster
IB
Investigator brochure
IBD
Inflammatory Bowel Disease
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
IND
Investigational New Drug Application
ILDRC
Interstitial Lung Disease Review Committee
IP
Interphalangeal
IRB
Institutional Review Board
IRC
Internal Review Committee
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine hormone-releasing system
IWR
Interactive Web-based response
IWRS
Interactive Web-based response system
JAK
Janus Kinase
JIA
Juvenile Idiopathic Arthritis
LDL
Low Density Lipoprotein
LFT
Liver function test
LPD
Lymphoproliferative Disease
LTE
Long-term Extension
LTFU
Lost to Follow-Up
MAC
Malignancy Adjudication Committee
MASES
Maastricht Ankylosing Spondylitis Enthesitis Score
MCP
Metacarpophalangeal
mg
Milligrams
MRI
Magnetic Resonance Imaging
MTP
Metatarsophalangeal
MTX
Methotrexate
N/A
Not Applicable
NMSC
Non-melanoma skin cancer
NRS
Numerical Rating Scale
NSAIDs
Non-Steroidal Anti-Inflammatory Drugs
OIRC
Opportunistic Infection review Committee
Oz
Ounce
PBO
Placebo
PCD
Primary Completion Date
PCS
physical component summary
PD
Pharmacodynamics


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Abbreviation
Term
PIP
Proximal Interphalangeals
PRO
Patient Reported Outcome
PsA
Psoriatic Arthritis
PsO
Psoriasis
PTLD
Post-Transplant Lymphoproliferative Disorders
PT-INR
Prothrombin Time- International Normalized Rate
Q
Question
QA/QC
Quality Assurance/Quality Control
QFT-G
Quantiferon Gold
RA
Rheumatoid Arthritis
RBC
Red Blood Cell
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SF-36v2
36-Item Short-Form Health Survey Version 2
SI
Sacroiliac
SIJ
Sacroiliac joint
SPARCC
Spondyloarthritis Research Consortium of Canada
SRSD
Single Reference Safety Document
TB
Tuberculosis
TBili
Total bilirubin
TNF-
Tumor Necrosis Factor alpha
TNFi
Tumor Necrosis Factor Inhibitor(s)
TNFi IR
Tumor Necrosis Factor Inhibitor(s) Inadequate Responder
tsDMARD
Targeted synthetic Disease-Modifying Anti-Rheumatic Drug
UC
Ulcerative Colitis
ULN
Upper Limit of Normal
US
United States
VAS
Visual Analog Scale
VTE
Venous thromboembolism 
WHO
World Health Organization
WOCBP
Woman of childbearing potential
WPAI
Work Productivity and Activity Impairment


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Appendix 2. Modified New York Criteria for Ankylosing Spondylitis (1984)
Following describes the Modified New York Criteria for Ankylosing Spondylitis
(1984)47 that will be used in this study:
Clinical Criteria:

Low back pain and stiffness for more than 3 months that improves with exercise but it
is not relieved by rest;

Limitation of motion of the lumbar spine in the sagittal and frontal planes;

Limitation of chest expansion relative to normal values correlated for age and sex. 
Radiological Criterion:

Sacroiliitis grade 2 bilaterally or grade 3-4 unilaterally.
Definite AS if the radiological criterion is associated with at least one clinical criterion.  
Modified New York Grading Criteria:

Grade 0: normal SI joints within thin sharp cortical margins and normal cartilage
space;

Grade 1: non-specific “suspicious” findings;

Grade 2: minimal sacroiliitis and consists of loss of definition of the SI joint margins.  
There may be minimal sclerosis and erosions.  There may or may not be joint space
narrowing;

Grade 3: definite sclerosis on both sides of the joint, erosions, and loss of joint space;

Grade 4: complete bony ankylosis of the SI joints.


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


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Appendix 4. Prohibited Concomitant Medications
All biologic agents and TNF inhibitors are prohibited and subjects currently using these
medications should not be enrolled in the study.
Other DMARDs
The following DMARDs are prohibited:
Auranofin (oral gold), aurothioglucose (injectable gold), aurothiomalate (injectable gold)
must be discontinued for 8 weeks prior to the first dose of the study drug.
d-penicillamine, bucillamine, mizoribin, azathioprine, chloroquine, hydroxychloroquine,
cyclosporine, tacrolimus, and staphylococcal protein A immuno-absorbant pheresis
columns (eg, PROSORBAdevice/column) must be discontinued for 4 weeks prior to the
first dose of study drug.
Leflunomide (Arava) must be discontinued 8 weeks prior to the first dose of study drug if no
elimination procedure is followed.  Alternately, it should be discontinued with the following
elimination procedure at least 4 weeks prior to the first dose of study drug:

Cholestyramine at a dosage of 8 grams three times daily for at least 24 hours, or
activated charcoal at a dosage of 50 grams 4 times a day for at least 24 hours (US PI,
Elimination Procedure to significantly lower leflunomide drug levels).
Tetracyclines, unless prescribed for the treatment of acne or other dermatologic disorders,
must be discontinued for 4 weeks prior to the first dose of study drug.
Live or attenuated live vaccines are prohibited during the study and for 6 weeks after last dose
of study drug.
All Investigational Drugs not otherwise specified are prohibited and require a 4 week
(5 half-lives) washout period prior to first dose of study treatment.
In the table below those drugs requiring washout longer than 7 days are in bold and 
italicized.  Please note that efavirenz, nevirapine, barbiturates, carbamazepine, phenobarbital, 
St. John’s Wort, rifabutin and rifapentine should be discontinued at least 30 days prior to first 
dose of study based on the half-life of these drugs, and that amiodarone should be 
discontinued at least 290 days prior to the first dose of study drug based on a half-life of 
58 days.
All other prohibited drugs in the table below require at least a 7 day or 5 half-life (whichever
is longer) washout period prior to the first dose of study treatment.

Topical (including skin or mucous membranes) application of antibacterial (eg,
clarithromycin, erythromycin and norfloxacin) and antifungal (fluconazole,
ketoconazole and itraconazole) medications is permitted.

Potent inhibitors and inducers of CYP3A (shown below) are not permitted in the study
except in emergency situations requiring no more than one day of administration.


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Potent CYP3A Inhibitors
Potent CYP3A Inducers
HIV antivirals:
-indinavir (Crixivan)
-nelfinavir (Viracept)
-ritonavir (Kaletra, Norvir)
efavirenz (Sustiva)
clarithromycin (Biaxin, Prevpac)
nevirapine (Viramune)
itraconazole (Sporanox)
barbiturates
ketoconazole (Nizoral)
carbamazepine (Carbatrol, Tegretol)
nefazodone (Serzone)
modafinil (Provigil)
phenobarbital
phenytoin (Dilantin, Phenytek)
rifabutin (Mycobutin)
rifampin (Rifadin, Rifamate, Rifater)
Rifapentine(Priftin)
Subjects may be initiated on moderate inhibitors (except amiodarone) and inducers (shown
below), as required, if the total duration of treatment lasts less than or equal to 7 days.
Moderate CYP3A Inhibitors
Moderate CYP3A Inducers
HIV antivirals:
atazanavir (Reyataz)
delavirdine (Rescriptor)
saquinavir (Fortovase)
St. John’s wort
amiodarone (Cordarone, Pacerone)
cimetidine (Tagamet)
Clotrimazole
diethyl-dithiocarbamate
diltiazem (Cardizem, Tiazac)
Erythromycin
fluconazole (Diflucan)
fluvoxamine (Luvox)
grapefruit or grapefruit-related citrus fruits, juices (eg,
Seville oranges, pomelos)*
Mibefradil
mifepristone (Mifeprex, RU486)
norfloxacin (Shibroxin, Noroxin)
verapamil (Calan SR, Covera HS, Isoptin SR, Tarka,
Verelan)
Voriconazole
*Consumption of juice from grapefruit, pomelos and Seville oranges is permitted up to 8 ounces (total) in a day. 
It is recommended to separate their coadministration with study medication by at least 1 hour.


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Appendix 5. Approximate Equivalent Morphine Doses of Opioid Analgesics
Common Opioid Analgesics
Drug
Maximum Allowed Total
Daily Dose
Relative potency to oral
morphine
Half-Life
Morphine
30 mg
1
1.5 – 4 hrs
Hydrocodone (Vicodin, Lortab)
30 mg
1
3.8 – 4.5 hrs
Hydromorphone (Dilaudid)
7.5 mg
4
2.5 hrs
Meperidine (Demerol, Pethidine)
300 mg
0.1
3.2 – 3.7 hrs
Methadone (Dolophine, 
Methadose, Physeptone)
10 mg
3.0
23 hrs
Codeine (Paveral, Tylenol
#2 and #3)
200 mg
0.15
2.5 – 3.5 hrs
Oxycodone [Roxicodone; 
Percocet, Tylox]
15 mg
~2
3.2 hrs
Tramadol [Ultram, Zydol; 
Zamadol, Ultracet, Tramal]
300 mg
~0.1
4.7 – 5.1 hrs
Propoxyphene HCl (Darvon, 
Darvocet, Doloxene) 
Propoxyphene napsylate 
(Darvon-N, Darvocet-N 100)
300 mg propoxyphene 
HCl
400 mg propoxyphene 
napsylate
~0.1
6-12 hrs; 30-36 hrs. 
for active metabolite 
(norpropoxyphene)
Sites should contact the study team for acceptable alternative preparations and related data.  References:
Twycross R, Wilcock A, Thorp S. Palliative Care Formulary. Abingdon: Radcliffe Medical Press, 1998.
Twycross R. Pain relief in advanced cancer. Edinburgh: Churchill Livingstone, 1994.


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Appendix 6. Rescue Therapy
Acetaminophen/paracetamol is allowable as rescue medication if dosed no more than 
2.6 gm/day for no more than 10 consecutive days.  If a subject is already taking stable
background doses of acetaminophen/ paracetamol, s/he may increase the dose up to 
2.6 gm/day for up to 10 consecutive days for rescue purposes.
THE FOLLOWING PARADIGM SHOULD BE USED TO DETERMINE
APPROPRIATE OPIOID RESCUE THERAPY:
For subjects who are NOT on stable, background opioid therapy: any of the following
single opioid agents may be given as rescue medication (with or without
acetaminophen/paracetamol) for no more than 10 consecutive days in the following total daily
doses:
1. Hydrocodone (with or without acetaminophen/paracetamol), not to exceed 30 mg total
daily dose.
2. Oxycodone (with or without acetaminophen/paracetamol), not to exceed 15 mg total
daily dose.
3. Tramadol (with or without acetaminophen/paracetamol), not to exceed 300 mg total
daily dose.
For subjects who ARE on stable, background opioid therapy:

They may NOT add a second opioid agent for rescue;

If their background medication is 1 of the 3 listed above, they may, within the above
maximum total dosage limits, increase the dosage for up to 10 consecutive days for
rescue purposes;

If their background medication is a short-acting (half-life <5 hrs, (Appendix 5) opioid
that is not one of those listed above, they may increase the dosage for up to 
10 consecutive days (up to a total daily dose which must not exceed the potency
equivalent of 30 mg of orally-administered morphine [Appendix 5]) for rescue
purposes;

Sustained release opioid formulations (eg, OxyContin®, MS Contin®) and opioids with
half-lives greater than 5 hours (eg, methadone, propoxyphene) may NOT be USED for
rescue medication.
Sustained release opioid formulations (eg, OxyContin®, MS Contin®) and opioids with
half-lives greater than 5 hours (eg, methadone, propoxyphene; see also Appendix 5) may
NOT be INCREASED for rescue purposes.


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Acetaminophen/paracetamol is not permitted as a part of combination products such as 
over-the-counter “cold remedies” or in combination with opioids if the 
acetaminophen/paracetamol dose will exceed 2.6 gm/day.  Subjects who require rescue 
medication for more than 10 consecutive days should be discontinued from the 
investigational product.  In addition, subjects should not be dosed with rescue 
acetaminophen/paracetamol or opioids within 24 hours prior to a study visit.  Baseline stable 
acetaminophen/paracetamol or opioids should NOT be discontinued in advance of study 
visits.
SUBJECTS SHOULD NOT BE DOSED WITH ANY RESCUE INTERVENTION
WITHIN 24 HOURS PRIOR TO A STUDY VISIT. 


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Appendix 7. Evaluation of Potentially Malignant Tumors, Suspicious 
Lymphadenopathy, Possible Extranodal Lymphoproliferative Disorder (LPD)
The following steps should be taken in the event of potentially malignant tumors, suspicious 
lymphadenopathy or possible extranodal lymphoproliferative disorder (LPD) which might 
arise in the course of this study.
When there is a decision to biopsy a potentially malignant tumor, lymph node, or other 
tissue, the investigator and/or consultants should contact the Pfizer study team to discuss the 
issue and any decisions made as soon as possible.  It is recommended that a specialist with 
experience in the evaluation of immunosuppressed patients be consulted.
If a biopsy for the lymphadenopathy or lymphoma is to be performed, the investigator or 
consultant should refer to the instructional slide deck in the Lymph Node Biopsy kit and 
review the following points with the surgeon and pathologist:

Fine needle aspiration and core needle aspiration 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;

Collect and snap freeze peripheral blood lymphocytes for germ line evaluation 
(DNA);

Archive multiple aliquots of serum samples.
For all biopsies, please request the pathologist to send the original slides used to make the 
definitive diagnosis, ancillary study reports, and the pathologist’s report to the central 
laboratory.


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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.

SAP_001.pdf: 
Protocol A3921120 (Tofacitinib (CP-690,550)) Statistical Analysis Plan
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Protocol A3921120
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, STUDY 
OF THE EFFICACY AND SAFETY OF TOFACITINIB IN SUBJECTS WITH
ACTIVE ANKYLOSING SPONDYLITIS (AS)
Statistical Analysis Plan 
(SAP)
Version:
4
Date:
17 Dec 2019


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TABLE OF CONTENTS
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION ...............................................................................................................14
2.1. Study Objectives and Estimands.............................................................................14
2.1.1. Estimands for ASAS20 and ASAS40 at Week 16......................................15
2.1.2. Estimands for Continuous Secondary Endpoints .......................................16
2.2. Study Design ...........................................................................................................17
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................19
3.1. Primary Endpoint ....................................................................................................19
3.2. Secondary Endpoints...............................................................................................19
3.2.1. Key Secondary Endpoint............................................................................19
3.2.2. Other Secondary Endpoints........................................................................19
3.3. Tertiary/Exploratory Endpoints...............................................................................22
3.4. Baseline Variables...................................................................................................22
3.4.1. Stratification Factor ....................................................................................22
3.5. Safety Endpoints .....................................................................................................22
......................................................................................23
4. ANALYSIS SETS ...............................................................................................................23
4.1. Full Analysis Set .....................................................................................................23
4.2. Per Protocol Analysis Set........................................................................................23
4.2.1. Protocol Deviations ....................................................................................24
4.2.2. Deviations Assessed Prior to Randomization.............................................24
4.2.3. Deviations Assessed Post-Randomization..................................................25
4.3. Safety Analysis Set..................................................................................................25
4.4. Other Analysis Sets .................................................................................................25
4.4.1. Endpoint Specific Analysis Sets.................................................................25
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................26
5.1. Hypotheses and Decision Rules ..............................................................................27
5.2. General Methods .....................................................................................................28
5.2.1. Analyses for Binary Endpoints...................................................................29
5.2.1.1. Cochran-Mantel Haenszel (CMH) Approach............................29


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5.2.1.2. Generalized Marginal Model for Repeated Measures 
(GMMRM) ........................................................................................30
5.2.1.3. Tipping Point Analysis..............................................................31
5.2.2. Analyses for Continuous (Repeated) Data .................................................32
5.2.3. Analyses for Continuous (Single Visit) Data .............................................32
5.3. Methods to Manage Missing Data ..........................................................................32
6 . ANALYSES AND SUMMARIES.....................................................................................33
6.1. Primary Endpoint: ASAS20 at Week 16.................................................................34
6.1.1. Primary Analysis ........................................................................................34
6.1.2. Supportive Analyses ...................................................................................34
6.2. Key Secondary Endpoint: ASAS40 at Week 16 .....................................................37
6.3. Other Secondary Endpoints and Tertiary/Exploratory Endpoints...........................37
6.4. Subset (Subgroup) Analyses ...................................................................................40
6.4.1. Subgroup Analyses for Primary Endpoint of ASAS20 at Week 16...........40
6.4.2. Subgroup Analyses for Key Secondary Endpoint of ASAS40 at 
Week 16 ...........................................................................................................42
6.5. Baseline and Other Summaries and Analyses.........................................................42
6.5.1. Baseline Summaries....................................................................................42
6.5.2. Prior and Baseline Treatments for Ankylosing Spondylitis .......................45
6.5.3. Concomitant Medications...........................................................................45
6.6. Safety Summaries and Analyses .............................................................................46
6.6.1. Adverse Events...........................................................................................46
6.6.2. Laboratory Data..........................................................................................46
7. INTERIM ANALYSES.......................................................................................................47
8. REFERENCES ....................................................................................................................48
9. APPENDICES .....................................................................................................................50
9.1. Data Set Description: On-Drug vs. On-Study Data ................................................50
9.2. Endpoint Definitions and Data Derivation Details .................................................50
9.2.1. ASAS Improvement Criteria ......................................................................50
9.2.2. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) & 
BASDAI50.......................................................................................................51
9.2.3. Bath Ankylosing Spondylitis Metrology Index (BASMI)..........................52
9.2.4. Ankylosing Spondylitis Disease Activity Score (ASDASCRP)...................53


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9.2.5. Swollen Joint Count (44)............................................................................54
9.2.6. Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) .................55
9.2.7. 36-Item Short Form Survey Version 2 (SF-36v2) Acute ...........................55
9.2.8. EuroQol-5D Health Questionnaire – 3 Level Version (EQ-5D-3L) ..........61
9.2.9. Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-F)........................................................................................................62
9.2.10. Work Productivity and Activity Impairment Questionnaire: 
Spondyloarthritis (WPAI)................................................................................63
9.3. Tipping Point Analysis for Longitudinal Binary Data............................................64
9.4. Definition and Use of Visit Windows in Reporting................................................66
9.5. Range of Values for Continuous Efficacy Endpoints .............................................68
9.6. Lists of DMARDs and NSAIDs..............................................................................70
9.7. Metabolic Syndrome and Diabetes Mellitus at Baseline ........................................72
9.7.1. Criteria for Clinical Diagnosis of Metabolic Syndrome.............................72
9.7.2. Definition of Diabetes Mellitus at Baseline................................................74
9.8. Summary of Efficacy Analyses...............................................................................75
9.9. Abbreviations Used in SAP.....................................................................................82
9.10. Definition of NSAID-Inadequate Response (NSAID-IR) ....................................84
9.11. Derivation of the Stratification Factor ..................................................................85
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................6
Table 2.
Endpoint Specific Analysis Sets...............................................................26
Table 3.
Mock Table of ASAS20 Response at Week 16 and Reasons for 
Study Drug Discontinuation Prior to Week 16 (Estimand 1, FAS, 
MR=NR, On-Drug Data)..........................................................................36
Table 4.
Mock Table of ASAS20 Response at Week 16 and Reasons for 
Study  Discontinuation Prior to Week 16 (Estimand 2, FAS, 
MR=NR, On-Study  Data)........................................................................37
Table 5.
Visit Windowing.......................................................................................67
Table 6.
Numerical Characteristics of Select Continuous Efficacy Endpoints ......68
Table 7.
List of DMARDs and NSAIDs.................................................................70
Table 8.
Summary of Efficacy Analyses ................................................................75
Table 9.
Abbreviations Used in SAP......................................................................82


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LIST OF FIGURES
Figure 1.
Schematic of Study Design.......................................................................18


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version, 
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1 (05 
March
2018)
Original 
(22 February 
2018)
First version.
None.
2 (21 
September
2018)
1
(06 September 
2018)
Revision to align with 
study protocol 
amendment 1 which 
was revised based on 
regulatory input on 
Type I error controlled 
secondary endpoints 
and mandate to follow 
up subjects after 
discontinuation of 
investigational 
products.
1.
Updated Section 2.1 to 
have study objectives 
aligned with protocol’s 
study objectives.
2.
Updated the study 
schematic and clarified 
the investigators, subjects 
and sponsor will remain 
blinded to the first 
16 weeks of treatment 
through the entire 
duration of the trial until 
database release in 
Section 2.2.
3.
Updated ASAS40 at 
Week 16 as key 
secondary endpoint, re-
ordered the other 
secondary endpoints to 
have same order of 
hierarchy in Type I error 
controlled hypothesis
testing in Section 3.2. 
4.
Clarified the derivation of 
prior treatment history as 
a randomization factor in 
Section 3.4.1.
5.
Added prior exposure to 
non-TNFi bDMARD as a
protocol deviation for 
exclusion from Per 


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Protocol Analysis Set in 
Section 4.2.2.
6.
Updated the terminology 
of “study treatment” to 
“investigational product” 
to be consistent with 
protocol in Section 4.2.3.
7.
Removed the statements
regarding EMA’s 
consideration of ASAS40 
as primary endpoint in 
Section 5.1.
8.
For global type I error 
controlled endpoints in 
Section 5.1, changed 
SF-36v2 Physical 
Functioning domain to 
Physical Component 
Summary and added 
ASQoL to the hierarchy 
of testing. Also clarified 
the step-down testing 
procedure.  
9.
Added descriptions of 
analyses of ASAS20 at 
Week 16 for subjects 
who discontinued 
investigational product or 
study early in 
Section 6.1.2.
10. Clarified/Added 
EQ-5D-3L Utility Score 
(UK) to the list of 
endpoints in Sections 
3.2.2, 6.3 and 9.8
(Table 8) as an endpoint, 
provided method of its 
derivation in 
Section 9.2.8 and data 
range in Section 9.5.


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11. Updated country list in 
defining subgroup of 
geographic region in 
Section 6.4; added waist 
circumference to the list 
of baseline characteristics 
in Section 6.5.
12. Updated list of references 
in Section 8.
13. Clarified the names of 
CRF forms referred in 
Section 9.1 (On/Off-Drug 
Data) and Section 9.7 
(Baseline Metabolic 
Syndrome).
14. Clarified the use of CRF-
calculated BASDAI and 
inflammation scores at 
Screening and Baseline 
visits in Section 9.2.2.
15. Provided clarification for
windowing observations 
for subjects who 
discontinue from study 
prior to Week 48 in 
Section 9.4.
16. Added abbreviations to
Table 9 in Section 9.9.
17. Corrected minor 
typographical errors 
throughout the SAP.
3 (23 May
2019)
2
(10 April 2019)
Revision to incorporate 
suggestions from US 
FDA and to align with 
changes in study 
protocol amendment 2.
1.
Clarified terminology in 
study objectives and 
added definitions of 
estimands in Section 2.1 
according to suggestions 
from FDA.
2.
Updated study design in 
Section 2.2 to describe 


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the Week 16 and 
Week 48 analyses and the 
expanded inclusion of 
subjects with prior 
bDMARD use without IR
per protocol amendment 
2. 
3.
Updated the stratum's 
label of the stratification 
factor from "TNFi-IR" to 
"TNFi-IR or bDMARD 
Use (Non-IR)" 
throughout the document. 
Also updated the study 
schematic in Section 2.2. 
4.
Re-ordered the endpoints 
in Section 3 to align with 
the updated sequence of 
endpoints under Type I 
error control testing per
protocol amendment 2.
5.
Removed the exclusion 
criterion of the per 
protocol analysis set: 
"Subject who were 
exposed to prior 
non-TNFi biological 
DMARD" in 
Section 4.2.2 per
expanded inclusion under
protocol amendment 2.
6.
Provided descriptions and 
scopes of Week 16 and 
Week 48 analyses for 
efficacy and safety in 
Section 5 and Section 6 
per protocol amendment 
2.
7.
Updated Global Type I 
Error Control testing in 
Section 5.1: moved 
∆ASQoL up and added 


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∆FACIT-F Total Score 
per protocol amendment 
2.
8.
Clarified the application 
of statistical adjustment 
for binary endpoints 
when 0%/100% response 
rate observed in 
treatments by stratum in 
Section 5.2.1.1.
9.
Updated the MMRM 
model for continuous 
endpoints including 
interaction terms of 
stratification factor and 
baseline value with visit 
in the model in Section 
5.2.2.
10. Added the ANCOVA 
model in Section 5.2 to 
analyze data of a single 
visit for some continuous 
endpoints in the Week 16 
analysis.
11. Clarified the methods of 
handling missing data 
under the estimands for 
both binary and 
continuous endpoints in 
Section 5.3.
12. Updated the supportive 
analyses for the primary 
endpoint of ASAS20 at 
Week 16, key secondary 
endpoint of ASAS40 at 
Week 16 and other 
secondary binary and 
continuous endpoints in 
Sections 6.1, 6.2 and 6.3 
and aligned these 
analyses with the 


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estimand framework
described in Section 2.1.
13. Added subgroup analyses 
of 3-category prior 
treatment history and 
baseline AS disease 
activity (with literature 
reference); updated
subgroup definition of 
geographic region in 
Section 6.4. Updated a 
few baseline disease 
characteristics in 
Section 6.5.
14. Updated the definition of 
treatment-emergent 
adverse event to remove 
the restriction of 
worsening severity from 
baseline in Section 6.6.1
per Sponsor’s new data 
standard.
15. Clarified the derivation of 
Modified Schober's test 
score using CRF value 
for BASMI in Section 
9.2.3.
16. Re-formatted the 
descriptions of Tipping 
Point Analysis in Section 
9.3 into a step-by-step 
format and pre-specified 
the number of multiple 
imputations and the 
values of MNAR 
adjustment (ߜ) according
to suggestion from FDA.
17. Updated the list of 
DMARDs and NSAIDs 
in Section 9.6, noting that 


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this is not an exhaustive 
list.
18. Updated the summary 
table of efficacy analyses 
in Section 9.8 and 
updated abbreviation in 
Section 9.9.
19. Added definition of 
NSAID inadequate 
response (NSAID-IR) in 
Appendix Section 9.10 
and derivation of 
stratification factor in 
Appendix Section 9.11.
4 (17 Dec
2019)
2
(10 April 2019)
Revision to provide 
additional clarification 
after study's blinded 
data review.
1. Corrected typo to remove 
Week 2 for endpoint of 
MASES as it is not 
assessed at Week 2 per 
protocol (Section 3.2.2, 
Section 6.3, Section 9.8 
Table 8);
2. Clarified Tier-2 adverse 
events in Section 3.5; 
3. Clarified the handling of a 
case when a subject has an 
assessment prior to or on
the date of the 
investigational product 
discontinuation in the 
same visit window as the 
discontinuation (see 
Section 9.4, Table 5), this 
assessment will be 
considered as on-drug and 
used in the analysis for 
that visit window
(Section 5.3);
4. Removed adverse event 
analyses for the 
incremental period: 
Week 16 to Week 48 as 


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analyses for Baseline to 
Week 16 and Baseline to 
Week 48 are sufficient 
(Section 6.6.1);
5. Clarified the handling of 
LLOQ for hsCRP is 
applicable to all efficacy 
and safety analyses, not 
just ASDASCRP
(Section 9.2.4);
6. Clarified the treatment 
switch date as the start 
date from the first entry of 
dosing log for the period 
between Week 16 to 
Week 24 (Section 9.4, 
Table 5);
7. Removed Metamizole 
Sodium from the NSAID 
list as it is confirmed as an 
analgesic (Section 9.6, 
Table 7);
8. Corrected typographical 
errors throughout the 
SAP.


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2. INTRODUCTION
Ankylosing Spondylitis (AS) is prevalent among spondyloarthropathies, a group of arthritic 
conditions affecting the spine.  This under recognized disease is often not diagnosed for 
many years and typically presents in people between 20 and 40 years of age leading to 
progressive disability and adverse effects on health-related quality of life.  Tofacitinib 
inhibits signaling of cytokines that are integral to lymphocyte activation, proliferation, and 
function and may thus result in suppression of multiple aspects of the immune response.  
This forms the basis of the rationale to investigate the effect of tofacitinib in active AS.  This 
study is a follow-up to the A3921119 phase 2b study of tofacitinib in active AS. 
2.1. Study Objectives and Estimands
Primary Objective
1. To compare the efficacy of tofacitinib 5 mg BID versus placebo on the ASAS20
response rate at Week 16 in subjects with active AS that have had an inadequate
response to previous treatment.
Key Secondary Objective
1. To compare the efficacy of tofacitinib 5 mg BID versus placebo on the ASAS40 
response rate at Week 16 in subjects with active AS that have had an inadequate
response to previous treatment.
Other Secondary Objectives
1. To compare the safety and tolerability of tofacitinib 5 mg BID versus placebo in 
subjects with active AS that have had an inadequate response to previous treatment.
2. To compare the efficacy (including health-related quality of life, function, pain, and 
fatigue) of tofacitinib 5 mg BID versus placebo at all time points in subjects with 
active AS that have had an inadequate response to previous treatment.
Tertiary/Exploratory Objectives
1.
2. To evaluate the effect of tofacitinib 5 mg BID on lymphocyte subsets using FACS 
analysis.
3. To measure the effect of tofacitinib 5 mg BID on healthcare resource utilization at all 
collected time points.


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2.1.1. Estimands for ASAS20 and ASAS40 at Week 16
Only discontinuation of the investigational product will be considered as an intercurrent 
event to define the estimands for this study. There are three estimands for the primary 
endpoint of ASAS20 at Week 16.
Estimand 1:
The first estimand of ASAS20 at Week 16 is a composite estimand that accounts for both 
treatment adherence and response. A responder is defined as having a response without 
discontinuation of the investigational product prior to Week 16. This is also called the 
Primary Estimand defined according to the primary objective. It includes the following four 
attributes:

Population: Subjects who have active AS; 

Variable: ASAS20 response at Week 16. A subject after an intercurrent event of 
discontinuation of investigational product will be considered a non-responder for the 
visit of interest;

Intercurrent event: The intercurrent event of discontinuation of the investigational 
product prior to Week 16 is captured through the definition of the composite variable. 
Data collected after discontinuation of the investigational product prior to Week 16 
(ie, off-drug data) are not included to derive the response, ie, only On-Drug data are 
used (see Section 9.1);

Population-level summary: The difference in ASAS20 response rates between 
tofacitinib 5 mg BID and placebo at Week 16.
Estimand 2:
The second estimand of ASAS20 at Week 16 is supportive to Estimand 1 and is a treatment 
policy estimand. It estimates the effect regardless of treatment adherence. It includes the 
following four attributes:

Population: Subjects who have active AS; 

Variable: ASAS20 response at Week 16;

Intercurrent event: The intercurrent event of discontinuation of the investigational 
product prior to Week 16 is not considered here for data exclusion. Data collected 
after discontinuation of the investigational product prior to Week 16 (ie, off-drug 
data) are also included to derive the response, ie, On-Study data are used (see 
Section 9.1);

Population-level summary: The difference in ASAS20 response rates between 
tofacitinib 5 mg BID and placebo at Week 16.


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The difference between Estimand 1 and Estimand 2 is that Estimand 2 disregards treatment 
adherence and includes the additional data collected after the intercurrent event of 
discontinuation of the investigational product, ie, On-Study data. (see Section 9.1).
Estimand 3:
The third estimand of ASAS20 at Week 16 is supportive to Estimand 1 and is a hypothetical 
estimand. It estimates the treatment effect as if the intercurrent event of discontinuation of 
investigational product prior to Week 16 has not occurred. This includes the following four 
attributes:

Population: Subjects who have active AS;

Variable: ASAS20 response at Week 16;

Intercurrent event: Only data collected before the intercurrent event of 
discontinuation of the investigational product prior to Week 16 are included to derive 
the response, ie, On-Drug data (see Section 9.1);

Population-level summary: The odds ratio of ASAS20 response between tofacitinib 
5 mg BID and placebo at Week 16.
The main difference between Estimand 1 and Estimand 3 is that Estimand 3 assumes the 
intercurrent event of discontinuation of investigational product prior to Week 16 has not 
occurred, while Estimand 1 considers the response after discontinuation of investigational 
product as non-response via the composite strategy. Also, the population-level summary in 
Estimand 3 is an odds ratio instead of difference in response rates as in Estimand 1.
The same three estimand definitions for ASAS20 at Week 16 described above are also 
applicable to ASAS40 at Week 16 with ASAS20 substituted by ASAS40 in the definitions. 
Specifically, Estimand 1 for ASAS40 at Week 16 is called the Key Secondary Estimand, 
defined according to the key secondary objective. Estimand 1 will be used for other binary 
secondary endpoints by appropriately substituting the endpoint.
2.1.2. Estimands for Continuous Secondary Endpoints
Only discontinuation of the investigational product will be considered as an intercurrent 
event to define the estimands for this study.  The endpoint of change from baseline (Δ) in 
Patient Global Assessment of Disease (PGA) will be used as an example in defining the 
estimands. Estimand 4 will be used for other continuous secondary endpoints by 
appropriately substituting the endpoint.  Estimand 5 will be used only for the Type I error 
controlled continuous secondary endpoints as supportive analyses.


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Estimand 4:
This estimand of ΔPGA at Week 16 is a hypothetical estimand. It estimates the treatment 
effect as if the intercurrent event of discontinuation of investigational product prior to 
Week 16 has not occurred. This includes the following four attributes:

Population: Subjects who have active AS; 

Variable: ΔPGA at Week 16;

Intercurrent event: Only data collected before the intercurrent event of 
discontinuation of the investigational product prior to Week 16 are included, 
ie, On-Drug data (see Section 9.1);

Population-level summary: The mean difference in ΔPGA between tofacitinib 5 mg 
BID and placebo at Week 16.
Estimand 5:
This estimand of ΔPGA at Week 16 is supportive to Estimand 4 and is a treatment policy
estimand. It estimates the effect regardless of treatment adherence. It includes the following 
four attributes:

Population: Subjects who have active AS; 

Variable: ΔPGA at Week 16;

Intercurrent event: The intercurrent event of discontinuation of the investigational 
product prior to Week 16 is not considered here for data exclusion. Data collected 
after the discontinuation of the investigational product prior to Week 16 (ie, off-drug 
data) are also included, ie, On-Study data are used (see Section 9.1);

Population-level summary: The mean difference in ΔPGA between tofacitinib 5 mg 
BID and placebo at Week 16.
The difference between Estimand 5 and Estimand 4 is that Estimand 5 disregards treatment 
adherence and includes the additional data collected after the intercurrent event of 
discontinuation of the investigational product prior to Week 16, ie, On-Study data are used. 
(see Section 9.1).
2.2. Study Design
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled efficacy and 
safety study designed to compare tofacitinib to placebo in subjects with active AS.  An 
estimate of approximately 480 AS subjects will be screened globally in order that 
approximately 240 eligible subjects (120 per arm) will be randomized in a 1:1 ratio to 
tofacitinib 5 mg BID (twice daily) or matching placebo BID.  Figure 1 shows the schematic 
of the study design.  


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Figure 1.
Schematic of Study Design
Abbreviations: AS = Ankylosing Spondylitis; ASAS20 = Assessment of SpondyloArthritis International 
Society 20; bDMARD = biological disease-modifying antirheumatic drug; BID = twice daily; IR = inadequate 
responder; N = number of subjects; PBO = placebo; TNFi = tumor necrosis factor inhibitor.
The duration of participation for eligible subjects will be approximately 56 weeks. This will 
include a screening period of approximately 30 days, a 16-week double-blind treatment 
period, a 32-week open-label treatment period and a 28-day follow-up period. During the 
16-week treatment period subjects will visit the clinic every two weeks (3 days) until the 
Week 4 visit and then every 4 weeks (7 days) until the completion of Week 16. At the 
Week 16 visit all subjects will be assigned to open-label tofacitinib and will visit the clinic 
every two months (7 days) until Week 48. Subjects will then return to the clinic for a 
Follow-up visit approximately 28 days after the Week 48 visit. There will be a total of 
2 planned analyses conducted when all applicable subjects have completed their Week 16 and 
Week 48 (including follow-up) visits, respectively. The first analysis will be conducted when 
all applicable subjects have completed their Week 16 visit. The investigators, subjects, and 
sponsor study team will remain blinded to the first 16 weeks of treatment assignment through 
the entire duration of trial until database release. Randomization will be stratified by prior 
treatment history: (1) bDMARD-naïve and (2) Tumor Necrosis Factor inhibitor-inadequate 
responder (TNFi-IR) or bDMARD Use (Non-IR). Subjects who had prior bDMARD use 
(Non-IR) will be eligible to participate in the study after washout and will be included in the 
"TNFi-IR or bDMARD Use (Non-IR)" stratum. Approximately 80% of the subjects will be 
bDMARD-naïve (designed as Stratum "bDMARD-naïve"), and the other approximately 


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20% of subjects who had an inadequate response to at least one but not more than 2 TNF 
inhibitors or who had prior bDMARD use (Non-IR) (designed as Stratum "TNFi-IR or
bDMARD Use [Non-IR]").  All subjects will have an inadequate response to at least 
2 NSAIDs. An inadequate response to NSAID or TNFi treatment is defined as having a 
treatment related adverse event or lack of response to NSAID or TNFi treatment that was 
administered in accordance with its labeling recommendations.  
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint

ASAS20 response at Week 16 (see Section 9.2.1).
3.2. Secondary Endpoints
3.2.1. Key Secondary Endpoint

ASAS40 response at Week 16 (see Section 9.2.1).
3.2.2. Other Secondary Endpoints

ASAS20 response at all other time points (Weeks 2, 4, 8, 12, 24, 32, 40, and 48) (see 
Section 9.2.1);

ASAS40 response at all other time points (Weeks 2, 4, 8, 12, 24, 32, 40, and 48) (see 
Section 9.2.1);

Change from Baseline (Δ) in Ankylosing Spondylitis Disease Activity Score using 
C-Reactive Protein (ΔASDASCRP) at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, 
and 48) (see Section 9.2.4);

Δ in High Sensitivity C-Reactive Protein (ΔhsCRP, mg/L) at all time points
(Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);

Δ in Ankylosing Spondylitis Quality of Life (ΔASQoL) at Weeks 16 & 48;
A total score is calculated by summing the 18 items. The total score ranges from 0 to
18, with higher values indicating more impaired health-related quality of life.

Δ in 36-Item Short Form Health Survey Version 2 (ΔSF-36v2), Acute at Weeks 16 
& 48;
This survey yields 10 endpoints: 8 general health domains: physical functioning, role 
limitations due to physical health, bodily pain, general health perceptions, vitality, 
social functioning, role limitations due to emotional problems, and mental health.  
These domains can also be summarized as physical and mental component summary
scores (see Section 9.2.7).


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
Δ in Bath Ankylosing Spondylitis Metrology Index (ΔBASMI) and its 5 components 
(Δ in Lateral Spinal Flexion, Tragus-to-Wall Distance, Lumbar Flexion [as measured 
by Modified Schober’s test score], Maximal Intermalleolar Distance, and Cervical 
Rotation) at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48) (see 
Section 9.2.3);

Δ in Functional Assessment of Chronic Illness Therapy-Fatigue (ΔFACIT-F) (Total 
Score, Experience Domain Score, and Impact Domain Score) at all time points 
(Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);
This instrument has 13 items that assess fatigue. Instrument scoring yields a range
from 0 to 52 for Total Score, with higher scores representing better subject status (less
fatigue). For Experience Domain Score, range is 0-20; for Impact Domain Score, 
range is 0-32 (see Section 9.2.9).  

Δ in Patient Global Assessment of Disease (ΔPGA) at all time points (Weeks 2, 4, 8, 
12, 16, 24, 32, 40, and 48). PGA is one of the 4 ASAS20/ASAS40 components;

Δ in Patient Assessment of Spinal Pain (two numerical rating scales [NRS]: Δ in
Nocturnal Spinal Pain and Total Back Pain, respectively) at all time points (Weeks 2, 
4, 8, 12, 16, 24, 32, 40, and 48). Total Back Pain is one of the 4 ASAS20/ASAS40 
components;

Δ in Bath Ankylosing Spondylitis Functional Index (ΔBASFI) at all time points
(Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);
This instrument consists of 10 questions. BASFI is the average of these 10 scores and 
it ranges from 0 to 10, with higher scores indicating greater functional limitation. If 
the number of missing scores is ≤3, then BASFI is calculated based on the average of 
the remaining non-missing scores, otherwise if the number of missing scores is 
>3, then BASFI is considered missing (Ramiro et al., 2014).1 BASFI is one of the 
4 ASAS20/ASAS40 components.

Δ in Inflammation at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);
Inflammation is one of the 4 ASAS20/ASAS40 components, which is the average of 
the answers to questions 5 & 6 of BASDAI (see Section 9.2.2). If answer to one of 
the two questions is missing, the other non-missing answer will be used as 
inflammation. If both answers are missing, inflammation is considered missing 
(Ramiro et al., 2014).1

ASAS 5/6 response at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48) (see 
Section 9.2.1);

ASAS Partial Remission response at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, 
and 48) (see Section 9.2.1);


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
Δ in Bath Ankylosing Spondylitis Disease Activity Index (ΔBASDAI) at all time 
points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48) (see Section 9.2.2);

BASDAI50 response at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48) (see 
Section 9.2.2);

ASDASCRP Clinically Important Improvement response at all time points (Weeks 2, 
4, 8, 12, 16, 24, 32, 40, and 48) (see Section 9.2.4);

ASDASCRP Major Improvement response at all time points (Weeks 2, 4, 8, 12, 16, 24, 
32, 40, and 48) (see Section 9.2.4);

ASDASCRP Inactive Disease response at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 
40, and 48) (see Section 9.2.4);

Δ in Maastricht Ankylosing Spondylitis Enthesitis Score (ΔMASES) at all time points
(Weeks 4, 8, 12, 16, 24, 32, 40, and 48) (see Section 9.2.6);

Δ in extra-articular involvement (Specific Medical History and peripheral articular
involvement [as assessed by Swollen Joint Count (44) (ΔSJC[44])]) at all time points
(Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48) (see Section 9.2.5);

Δ in Spinal Mobility: Chest Expansion at all time points (Weeks 2, 4, 8, 12, 16, 24, 
32, 40, and 48);
The chest expansion (cm) is measured as the difference between maximal inspiration 
and expiration. Two attempts will be performed and the better (ie, larger) of the two 
attempts will be utilized for data analysis.

Δ in EuroQol-5D Health State Profile – 3 Level Version (ΔEQ-5D-3L)
(5 Dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort and 
Anxiety/Depression, “Your own health state today” [ΔEQ-VAS], and EQ-5D-3L
Utility score based on United Kingdom (UK) weights) at Weeks 16 & 48 (see 
Section 9.2.8);

Δ in Work Productivity & Activity Impairment (ΔWPAI) Questionnaire: 
Spondyloarthritis (4 subscale scores in range of 0-100%) at Weeks 16 & 48 (see 
Section 9.2.10).
The 4 subscales are (1) percent work time missed due to health problem, (2) percent 
impairment while working due to health problem, (3) percent overall work 
impairment due to health problem, and (4) percent activity impairment due to health 
problem.


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3.3. Tertiary/Exploratory Endpoints

 

Fluorescence Activated Cell Sorting (FACS) analysis of lymphocyte subsets;

Ankylosing Spondylitis HealthCare Resource Utilization Questionnaire (AS-HCRU
and ΔAS-HCRU Self-Rating of Job Performance at Work which is question 14 with 
range of 0-10) at Weeks 16 & 48.
3.4. Baseline Variables
Baseline value of an endpoint is the value obtained on Day 1 (ie, Baseline visit) or prior
before the first dose of the investigational product. A subject’s prior treatment history at 
randomization, defined by two categories: "bDMARD-naïve" and "TNFi-IR or bDMARD 
Use (Non-IR)" (see Section 3.4.1), which is used as a factor for stratified randomization, is 
described in more detail below and also in Appendix Section 9.11. 
3.4.1. Stratification Factor
Subjects will be stratified by prior treatment history (strata of "bDMARD-naïve" and
"TNFi-IR or bDMARD Use [Non-IR]") at randomization. The stratum derived from data 
collected on prior medications taken and on the reasons for their discontinuation in the 
clinical database will be used for analysis. Specifically, prior medications taken before 
Day 1 collected on the Prior and Concomitant Medications DMARD CRF pages (bDMARDs 
subcategory) will be used to derive the strata. An inadequate response to a medication is 
defined when its discontinuation was due to either adverse event or lack of efficacy (see 
Appendix Section 9.11 for additional details to derive this stratification factor). For the 
primary endpoint of ASAS20 at Week 16 and the key secondary endpoint of ASAS40 at 
Week 16 only, a sensitivity analysis may need to be performed using the stratum from the 
randomization system (if there are differences between that from the randomization system 
and that derived from the clinical database) (see Section 6.1.2 and Section 6.2). 
3.5. Safety Endpoints

Incidence and severity of Adverse Events (AE);

Clinical laboratory tests, vital signs, physical examination and 12-lead ECG 
parameters;

Fluorescence Activated Cell Sorting (FACS) analysis of lymphocyte subsets.
In addition to standard safety displays, a 3-tier approach will be used to summarize AEs.  
Under this approach, AEs are classified into 1 of 3 tiers. 

Tier-1 events: These are pre-specified events of clinical importance and are 
maintained in a list in the product’s Safety Surveillance Review Plan. This is a set of 
AEs of special interest that has been identified for the tofacitinib compound.


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
Tier-2 events: These are events that are not Tier-1 but are “common” (ie, occurring 
≥4 subjects in any treatment group).  A Medical Dictionary for Regulatory Activities
(MedDRA) Preferred Term (PT) is defined as a Tier-2 event if there are at least 
4 subjects in any treatment group reporting an event.

Tier-3 events: These are events that are neither Tier-1 nor Tier-2 events.
The 3 tiers are mutually exclusive.  Tier-3 events will be included in standard safety displays 
and not separately displayed in specific Tier-3 tables.
 
 
 
4. ANALYSIS SETS
Below are descriptions of the Analysis Sets defined for this study. 
4.1. Full Analysis Set
The full analysis set (FAS) will include all subjects who were randomized to the study and 
received at least one dose of the randomized investigational product (ie, tofacitinib or 
placebo). The primary efficacy population for this study is defined by the FAS of subjects.  
Subjects will be analyzed in the treatment groups as they are randomized. If a subject is 
treated but not randomized, then the subject will be excluded from the FAS. A narrative will 
be provided for this subject in the clinical study report (CSR).
Continuous and ordered-categorical (analyzed as continuous) endpoints for which change or 
percent change from Baseline is the measure to be analyzed, would require that a subject has 
a Baseline value and at least one post-baseline value to be included in the FAS for that 
endpoint.  It is anticipated that there should be little bias due to excluding subjects with no 
Baseline value since the missingness mechanism is likely to be missing completely at 
random (MCAR) (Rubin, 1987).2  Excluding a subject with no post-baseline would likely 
cause a more favorable estimate of the mean change from Baseline for that endpoint for the 
treatment group in which that subject was assigned. However, it is anticipated that very few 
subjects will be excluded for this reason minimizing any potential bias. 
4.2. Per Protocol Analysis Set 
The Per-Protocol (PP) analysis set will exclude all subjects from the FAS who had a protocol 
deviation (see Section 4.2.1 below) thought to have a material impact on the primary efficacy 
analysis.  The PP analysis set will be used in conjunction with Estimand 1 as a supportive 
analysis for the primary endpoint of ASAS20 at Week 16 and the key secondary endpoint of 
ASAS40 at Week 16 (see Section 2.1.1).


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4.2.1. Protocol Deviations
Only protocol deviations that are thought to affect the primary efficacy endpoint of 
ASAS20 at Week 16 and the key secondary endpoint of ASAS40 at Week 16 will be 
considered in defining the PP analysis set. The following sections describe protocol 
deviations that will lead to subject exclusion from the PP analysis set. It is possible that 
unexpected deviations will arise, becoming known only after the study has been active for a 
long period of time; hence more deviations may be added to the list at a later date. As of this 
writing, the protocol deviations that will define the PP analysis set can all be found in
Section 4.2.2 and Section 4.2.3 below.
The list of subjects along with the protocol deviation that excludes them from the PP analysis 
set will be finalized prior to the treatment unblinding for the Week 16 analysis and put into 
the Trial Master File (TMF). 
4.2.2. Deviations Assessed Prior to Randomization
Exceptions to the inclusion or exclusion criteria are not expected to occur; but any subject 
who fails meeting any of the following protocol inclusion criteria will be excluded from the 
PP analysis set. 

Subjects who failed to meet the Modified New York Criteria for Ankylosing 
Spondylitis (1984) at screening. The AS diagnosis at screening is recorded on the 
Case Report Form (CRF) page for primary diagnosis. A subject who did not have 
this CRF page filled out will be considered having this exclusion criterion for 
PP analysis set met.

Subjects who had BASDAI score <4 or back pain score (BASDAI Question 2) 
<4 assessed at either screening or Baseline (ie, Day 1) visit. The BASDAI CRF 
pages at screening and Baseline will be used to check this condition. 

Subject who failed to meet the criteria of at least 2 NSAIDs-IR (see definition of 
inadequate response to NSAID in Appendix Section 9.10).

Subjects who failed to meet the criteria of:

Being naïve to prior bDMARD, or

Having an inadequate clinical response or intolerance due to treatment-related 
AE to at least 1, but not more than 2 approved TNFi’s (ie, 1 or 2 TNFi-IR) or
having bDMARD Use (Non-IR).
Appendix Section 9.11 provides more details on how to check these criteria and to 
derive the stratification factor.
Full lists of DMARDs and NSAIDs can be found in Section 9.6.


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4.2.3. Deviations Assessed Post-Randomization
These specific classes of protocol deviations will be assessed post randomization up to 
Week 16 only:

Subjects who were randomized but took or received incorrect treatment other than the 
randomized treatment for the entire duration from Baseline through Week 16. This 
will be checked manually since there is no CRF page for this condition.

Subjects who had <80% compliance on the investigational product’s tablets on 
2 consecutive visits (ie, 2 dosing periods) for the period from Baseline through 
Week 16. The investigational product compliance (%) will be derived from the total 
number of doses actually taken divided by the total number of doses expected to take 
per dosing period as recorded in Oral Dosing CRF page. Both the randomized 
treatments (ie, tofacitinib and placebo) will be taken into account.

Subjects who were dosed with rescue medication for AS on the preceding day or the 
same day of the primary endpoint assessment at the Week 16 study visit. The rescue 
medication is recorded on the Concomitant Medications – Rescue Medications CRF 
page.
Each subject’s presence on the list of exclusion from the PP analysis set means that there was 
at least one deviation for that subject.
4.3. Safety Analysis Set
The safety analysis set (SAFETY) will include all subjects who were randomized and 
received at least one dose of the investigational product (ie, tofacitinib or placebo). Subjects 
will be analyzed in the treatment groups as they received. If a subject is treated but not 
randomized, then the subject will be excluded from the SAFETY analysis set. A narrative 
will be provided for this subject in the CSR.
4.4. Other Analysis Sets
4.4.1. Endpoint Specific Analysis Sets
Subjects will be excluded from the FAS for analyzing a specific endpoint if the criterion for 
inclusion is not met for the endpoint.


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Table 2.
Endpoint Specific Analysis Sets
Endpoint
Inclusion
Rationale
ASDASCRP Clinically 
Important Improvement 
(improvement 
[decrease] from 
Baseline in ASDASCRP
≥1.1 units)
Include subjects with 
Baseline ASDASCRP
≥1.1 units in FAS
Restrict Baseline ASDASCRP ≥1.1 units to allow 
room for response
ASDASCRP Major 
Improvement
(improvement 
[decrease] from 
Baseline in ASDASCRP
≥2.0 units)
Include subjects with 
Baseline ASDASCRP
≥2.0 units in FAS
Restrict Baseline ASDASCRP ≥2.0 units to allow 
room for response
ASDASCRP Inactive 
Disease
(ie, ASDASCRP
<1.3 units)
Include subjects with 
Baseline ASDASCRP
≥1.3 units in FAS
Restrict Baseline ASDASCRP ≥1.3 units to allow 
room for response
Δ in Swollen Joint 
Count (44)
Include subjects with 
Baseline swollen joint 
count (44) >0 in FAS
Having swollen joints is not an enrollment criterion, 
it is expected only a subset of subjects will have 
swollen joints at Baseline.
ΔMASES
Include subjects with 
Baseline MASES >0 in 
FAS
Enthesitis is not an enrollment criterion, it is 
expected only a subset of subjects will have 
enthesitis at Baseline.
Abbreviations: Δ = change from Baseline, ASDASCRP = Ankylosing Spondylitis Disease Activity Score
- C-Reactive Protein, FAS = Full Analysis Set, MASES = Maastricht Ankylosing Spondylitis Enthesitis 
Score.
5. GENERAL METHODOLOGY AND CONVENTIONS
There will be a total of 2 planned analyses conducted when all applicable subjects have 
completed their Week 16 and Week 48 (including follow-up) visits, respectively. The 
investigators, subjects and sponsor study team will remain blinded to the first 16 weeks of 
treatment assignment through the entire duration of the trial until database release at 
Week 48. The Week 16 analysis will include all efficacy data through Week 16 and the 
safety data through the data cutoff date (for those subjects who have passed the Week 16 
visit). As the primary endpoint (ASAS20), the key secondary endpoint (ASAS40) and the 
other Type I error controlled secondary endpoints are at Week 16, there will be no additional 
adjustment made for Type I error rate at the final analysis at Week 48. The efficacy analysis 
results through Week 16 obtained from the Week 16 analysis will be considered final and 
definitive. 
 
The Week 48 analysis will be conducted when all the applicable subjects have completed 
their Week 48 (including follow-up) visit and the database is released.  All the Week 48 
analysis results will be secondary in nature.  The Week 48 analysis will contain results for 
earlier visits prior to or at Week 16 including those for the primary endpoint and the key 
secondary endpoint; however, they will serve as a sensitivity analysis only to ensure there are 
CCI


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no major changes to the definitive results for the primary endpoint and the key secondary 
endpoint obtained at the Week 16 analysis.
5.1. Hypotheses and Decision Rules
This protocol is designed to establish the superiority of tofacitinib 5 mg BID to placebo for 
the treatment of active AS based on the primary endpoint of ASAS20 at Week 16 in subjects 
who have had an inadequate response to previous treatments. 
All statistical tests will be conducted at the 2-sided 5% (or equivalently 1-sided 2.5%) 
significance level for comparing tofacitinib 5 mg BID to placebo. Type I error will be 
controlled at 2-sided 5% or equivalently 1-sided 2.5%. 
For the primary endpoint of ASAS20 at Week 16, if the 2-sided p-value is ≤5%, the 
superiority of tofacitinib 5 mg BID to placebo will be declared for this primary endpoint and 
the primary objective of this study is met.
Hypothesis testing will continue to the global family of select set of secondary endpoints 
stated below [Global Type I Error Control (for the primary endpoint and a select set of 
secondary endpoints)]. For each of the endpoints within this family, superiority of tofacitinib 
5 mg BID to placebo will be declared if statistical significance is achieved under the step-
down testing procedure.
In addition, three other families of hypotheses, ASAS family endpoints (Type I Error Control 
for Endpoints in the ASAS Family), ASAS20’s earlier time points (Type I Error Control for 
ASAS20 at Earlier Time Points) and ASAS40’s earlier time points (Type I Error Control for 
ASAS40 at Earlier Time Points) will also be tested. For each of the endpoints or time points 
of ASAS20/ASAS40, superiority of tofacitinib 5 mg BID to placebo will be declared if 
statistical significance is achieved under its respective step-down testing procedure.
Global Type I Error Control (for the primary endpoint and a select set of secondary 
endpoints): The family-wise Type I error rate will be controlled at the 2-sided 5% (or 
equivalently 1-sided 2.5%) significance level using a step-down testing procedure for the 
primary endpoint of ASAS20 at Week 16, the key secondary endpoint of ASAS40 at 
Week 16, and a select set of secondary endpoints at Week 16 tested in the sequence below: 
ASAS20, ASAS40, ASDASCRP, ∆hsCRP, ΔASQoL, SF-36v2 Physical Component 
Summary (PCS), ΔBASMI, and ΔFACIT-F Total Score.  When an endpoint fails to declare 
statistical significance, this endpoint and the remaining endpoints lower in the hierarchy will 
be considered non-significant. The rationale for the selection and ordering of the select set of 
secondary endpoints are clinical importance, precedence and likelihood of statistical success 
based on the results of the A3921119 study.
Type I Error Control for Endpoints in the ASAS Family: ∆PGA, ∆ in total back pain, 
∆BASFI, and ∆in inflammation (average of questions 5 and 6 of BASDAI) are the 4 ASAS 
components used in deriving ASAS20, thus they are considered belonging to the ASAS 
family of endpoints. A step-down testing procedure will be applied to them and tested in the 
sequence below: ASAS20, ∆PGA, ∆ in total back pain, ∆BASFI, and ∆in inflammation 
(average of questions 5 and 6 of BASDAI) at Week 16. When an endpoint fails to declare 


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statistical significance, this endpoint and the remaining endpoints lower in the hierarchy will 
be considered non-significant. Though this testing scheme does not protect the Type I error 
for the family of all possible comparisons, it will provide Type I error protection for testing 
the family of ASAS endpoints.
Type I Error Control for ASAS20 at Earlier Time Points: In order to be more rigorous about 
establishing the onset of efficacy as measured by ASAS20 at the earliest time point at which 
there is statistical separation between tofacitinib 5 mg BID and placebo, a step-down 
approach with the ASAS20 from Week 16 to earlier time points (order of testing: Weeks 16, 
12, 8, 4, and 2) will also be used for each time point. Though this testing scheme does not 
protect the Type I error for the family of all possible comparisons, it will provide Type I error 
protection for testing the family of ASAS20 time points.
Type I Error Control for ASAS40 at Earlier Time Points: In order to be more rigorous about 
establishing the onset of efficacy as measured by ASAS40 at the earliest time point at which 
there is statistical separation between tofacitinib 5 mg BID and placebo, a step-down 
approach with the ASAS40 from Week 16 to earlier time points (order of testing: Weeks 16, 
12, 8, 4, and 2) will also be used for each time point. Though this testing scheme does not 
protect the Type I error for the family of all possible comparisons, it will provide Type I error 
protection for testing the family of ASAS40 time points.
5.2. General Methods 
As subjects randomized to treatment group of placebo → tofacitinib 5 mg BID (ie, →means 
switching to) will advance from placebo to open-label treatment of tofacitinib 5 mg BID at 
Week 16, the treatment label used for reporting visits up to Week 16 will be “Placebo” and 
treatment label for reporting visits after Week 16 through Week 48 will be 
“Placebo → Tofacitinib 5 mg BID”. For analyses through Week 16, the following treatment 
comparison will be made at each time point, where applicable:

Tofacitinib 5 mg BID vs. Placebo.
For analyses after Week 16 through Week 48, the following treatment comparison will be 
made at each time point,

Tofacitinib 5 mg BID vs. Placebo → Tofacitinib 5 mg BID.
The primary efficacy comparison for the primary endpoint of ASAS20 will be between 
tofacitinib 5 mg BID and placebo at Week 16. 
Descriptive Summaries
In general, the data for all continuous endpoints will be summarized by treatment group 
(ie, 2 groups) and by time point in tables containing descriptive statistics (N [which is the 
number of subjects evaluable for the endpoint at the time point], mean, standard deviation, 
standard error of the mean, minimum, 1st, 2nd (ie, median) and 3rd quartiles and maximum) 
for actual and change from Baseline (or percent change from Baseline) values for those 
endpoints measured at Baseline. In case when N=1 (ie, only one subject is 


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available/evaluable for summary), standard deviation and standard error will be reported as 
“NA” (not applicable) while the remaining statistical parameters will have the same value as 
the mean. The data for all response-type endpoints will be summarized by treatment group 
and by time point in tables showing descriptive statistics: N, n (ie, number of responders), 
response rate (%), standard error of the response rate, and 95% confidence interval (CI) 
based on normal approximation. If ݌̂ is the estimated response rate, then the 95% CI is 
calculated as:
݌̂ േݖ଴.ଽ଻ହඨ݌̂ሺ1 െ݌̂ሻ
ܰ
where z0.975 is the 97.5th percentile of the standard normal distribution and N is the number of 
subjects evaluable for the endpoint at the time point. If the lower bound is calculated to be 
negative, it will be set to 0%; if the upper bound is calculated to be larger than 100%, it will 
be set to 100%. In case when response rate is 0 or 100%, standard error will be reported as 
“NA” and the 95% CI bounds will be the same as the response rate.  The displays described 
above for continuous and response-type endpoints will only use available data with no 
imputation. Therefore, the calculation of response rates will use the number of evaluable 
subjects as denominators. 
5.2.1. Analyses for Binary Endpoints
5.2.1.1. Cochran-Mantel Haenszel (CMH) Approach
For a single time point (eg, ASAS20 response rate at Week 16), difference in response 
proportion between tofacitinib 5 mg BID and placebo groups will be estimated using the 
Cochran-Mantel Haenszel (CMH) approach adjusting for stratification factor of prior 
treatment history (strata of "bDMARD-naïve" and "TNFi-IR or bDMARD Use [Non-IR]")
(Cochran, 1954; Mantel and Haenszel, 1959).3,4 Large sample approximation will be used 
for testing the superiority of tofacitinib 5 mg BID to placebo at Week 16 and prior time 
points and for forming 95% CI’s and calculating p-values. This approach will be referred to 
as CMH.
Explicitly, let 
and 
represent the estimated response rates for tofacitinib 5 mg BID 
(A) and placebo (B), respectively, of the ݅th stratum. Using the CMH weights, the weighted 
difference in proportions between tofacitinib 5 mg BID and placebo groups, d, is expressed 
by:
where
∑
+
+
=
i
Bi
Ai
Bi
Ai
Bi
Ai
Bi
Ai
i
n
n
n
n
n
n
n
n
w
)
/(
)
(
)
/(
)
(
, is the CMH weight for the ݅th stratum, with 
and 
equal the numbers of subjects in the tofacitinib 5 mg BID and placebo groups, respectively, 
per stratum. The weights are normalized such that the sum across strata adds up to 1.
Ai
pˆ
Bi
pˆ
)
ˆ
ˆ
(
d
Bi
Ai
i
i
p
p
w
−
= ∑
Ai
n
Bi
n


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The variance of d is:
,
with
Bi
Bi
Bi
Ai
Ai
Ai
Bi
Ai
n
p
p
n
p
p
p
p
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
)
ˆ
ˆ
var(
−
+
−
=
−
.
Two-sided 95% CI will be estimated using the normal approximation to the binomial 
distribution via the following method, 
݀േൣݖଵିఈ/ଶඥݒܽݎሺ݀ሻ൧.
Two-sided p-value for the test of the 0 difference between tofacitinib 5 mg BID and placebo 
groups will be calculated as:
݌ൌ2ሺ1 െߔሺ|ܼ|ሻሻ,
where Φ(.) is the Gaussian cumulative density function and 
is the Normal 
Z-test statistic.
If there is no (ie, 0) response or 100% response in any one or both of the two treatment 
groups for the comparison in a stratum, eg, tofacitinib 5 mg BID vs. placebo, when 
calculating the proportions above, 0.5 will be added to the number of responses (ie, 
numerator) and 1 will be added to the denominator in each treatment in that stratum 
corresponding to the pair of comparison for calculating the treatment difference, standard 
error (ie, ඥݒܽݎሺ݀ሻ), 95% CI and 2-sided p-value (Agresti, 2002).5
When response rate of 0% or 100% is observed in both treatments in comparison and in both 
strata, no formal comparison will be performed. Estimated response rate of 0% or 100% will 
be reported as observed. Standard error will be reported as 0.
The final results will be expressed in percentages, ie, (proportions x 100)%.
5.2.1.2. Generalized Marginal Model for Repeated Measures (GMMRM)
As a supportive analysis of ASAS20 (or ASAS40) for Estimand 3 (Section 2.1.1) scheduled 
to be collected multiple times during the first 16 weeks of placebo-controlled period
(Weeks 2, 4, 8, 12 and 16) of the study, a generalized marginal linear model for repeated 
measures (GMMRM) will be used. This model will have fixed effects for treatment, visit
(discrete), and treatment-by-visit interaction; the dependent variable will be the logit of the 
probability of ASAS20 (or ASAS40) response. Note that the model includes fixed effects of 
treatment, visit, and treatment-by-visit interaction only to ensure the estimated response rates 
and the treatment difference have a population average or marginal interpretation. A 
common autoregressive of order 1 [AR(1)] variance-covariance matrix for the two treatment 
groups will be used to model the variability among observations within a subject. If AR(1) 
)
ˆ
ˆ
var(
var(d)
2
Bi
Ai
i
i
p
p
w
−
= ∑
)
var(d
d
Z =


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matrix fails to converge, compound symmetry will be attempted. The parameters of the 
model will be estimated with pseudo-likelihood type methods.  Simulations investigating 
generalized linear models (GLM) for correlated binary data fit with generalized linear mixed 
effect model indicate good performance as measured by Type I error, CI coverage and bias 
even in the presence of data that is MAR (Liu and Zhan, 2011).6  From this model, one can 
obtain estimates of response rates for each treatment group at each time point (at 
Week 16 and prior) as well as inferential comparisons between treatment groups (odds ratio 
[OR], 95% CI, and p-value).  In the unlikely event that a response rate is 0 or 100% at a 
particular visit for a treatment group that may lead to convergence issues, data from that visit 
for both treatment groups will be removed from the model fitting in order to overcome any 
numerical difficulty.
5.2.1.3. Tipping Point Analysis
A method to analyze the longitudinal data of a binary endpoint measured during the placebo-
controlled period (eg, ASAS20 [or ASAS40] response rates at Weeks 2, 4, 8, 12 and 16) 
under the missing not at random (MNAR) assumption is called the tipping point analysis. 
This analysis is used as a supportive analysis for the primary endpoint of ASAS20 and the 
key secondary endpoint of ASAS40 both at Week 16. It assesses the robustness of the binary 
data to potential deviations from the missing at random (MAR) assumption for both 
tofacitinib 5 mg BID and placebo groups and it is based on multiple imputation (Yan, Lee 
and Li, 2009; Ratitch, O’Kelly and Tosiello, 2013).7,8
In this tipping point analysis, a single saturated generalized linear mixed effect model is used 
as the imputation model. The normal approximation of the difference in binomial 
proportions using the CMH method adjusting for prior treatment history at randomization 
("bDMARD-naïve" vs. "TNFi-IR or bDMARD Use [Non-IR]") is used as the analysis 
model, which is the same as the method of analyzing response-type endpoint at a single time 
point described in Section 5.2.1.1. The generalized linear mixed effect model includes the 
fixed effects of treatment, visit, treatment-by-visit interaction, prior treatment history at 
randomization ("bDMARD-naïve" vs. "TNFi-IR or bDMARD Use [Non-IR]"), and a latent 
subject-level random effect. The logit link is used to model the ASAS20 (or ASAS40)
response rate as dependent variable for all visits. Estimation of the model parameters is 
performed under the Bayesian framework using Markov Chain Monte Carlo (MCMC) 
methods. Only the available on-drug data (see Appendix Section 9.1) without imputation are 
included in this generalized linear mixed effect model to estimate the model parameters.
Imputation of missing ASAS20 (or ASAS40) response is performed only at Week 16 based 
on the predictive distribution of the generalized linear mixed effect model. Under missing 
not at random (MNAR) assumption, a fixed MNAR quantity (favorable or unfavorable) will 
be applied to the probability of the ASAS20 (or ASAS40) response at Week 16 for subjects 
with missing response in the tofacitinib 5 mg BID group and placebo group independently 
(ie, the analysis will be two-dimensional applied to both tofacitinib 5 mg BID and placebo).  
A series of fixed quantities will be applied to the probability of the ASAS20 (or ASAS40) 
response at Week 16 for subjects with missing response in the tofacitinib 5 mg BID group or 
placebo group independently to assess when the conclusion might change (ie, tipping). A 
scenario included in the tipping point analysis framework is an analysis under MAR, if there 
is no fixed quantity applied to the mean of the missing response for subjects in the tofacitinib 


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5 mg BID group and placebo group. The Rubin’s rules (Rubin, 1987)2 will be used to 
combine the results of multiple imputed samples for inference. More detailed step-by-step
descriptions are provided in the Appendix (Section 9.3).
5.2.2. Analyses for Continuous (Repeated) Data
Repeated measures data for continuous or order-categorical (analyzed as continuous) endpoints
will be analyzed as change from baseline as appropriate with a mixed model for repeated
measures (MMRM) that includes fixed effects of treatment group, visit, treatment-group by
visit interaction, stratification factor (ie, prior treatment history: "bDMARD-naïve"
vs "TNFi-IR or bDMARD Use [Non-IR]") at randomization, stratification-factor by visit 
interaction, baseline value, and baseline-value by visit interaction. A common unstructured
variance-covariance matrix will be used, provided the model converges, otherwise an 
alternative covariance structure, eg, heterogeneous compound symmetry (CSH), will be 
attempted. The Kenward-Roger degrees of freedom approximation will be used.  This model 
is referred to as MMRM. Comparison of tofacitinib 5 mg BID to placebo (providing least 
squares means [LSM] of the treatments, LSM of the treatment difference, 2-sided p-value 
and 95% CI) at each time point during the first 16 weeks will be generated using this 
MMRM. Comparisons of tofacitinib 5 mg BID and placebo → tofacitinib 5 mg BID for 
visits after Week 16 through Week 48 are also reported from the same model. For each 
endpoint, the number of subjects by treatment group in the FAS, the number of subjects by 
treatment group included in the MMRM and the number of subjects by treatment group 
evaluable at each of the visits are also to be reported. If the Baseline is missing or if there are 
no post-baseline measurements, the subject will be excluded from this analysis (see
Section 4.1).
5.2.3. Analyses for Continuous (Single Visit) Data
For continuous or order-categorical (analyzed as continuous) endpoints, when the analysis 
includes only a single post-baseline visit, these endpoints will be analyzed as change from
baseline with an analysis of covariance (ANCOVA) model that includes fixed effects of 
treatment group, stratification factor (ie, prior treatment history: "bDMARD-naïve"
vs "TNFi-IR or bDMARD Use [Non-IR]") at randomization, and baseline value. This model 
is referred to as ANCOVA. Comparison of tofacitinib 5 mg BID to placebo (providing LSM 
of the treatments, LSM of the treatment difference, 2-sided p-value and 95% CI) at this visit 
will be generated using this ANCOVA. For this visit, the number of subjects by treatment 
group in the FAS and the number of subjects by treatment group included in the ANCOVA at 
this visit are also to be reported. If the Baseline is missing or if there is no post-baseline 
measurement at this visit, the subject will be excluded from this analysis (see Section 4.1). 
5.3. Methods to Manage Missing Data
As described in Section 2.1.1, Estimands 1, 2 and 3 will be used for analyses of ASAS20 at 
Week 16.  After accounting for the intercurrent event of discontinuation of investigational 
product (Section 2.1.1), missing ASAS20 values at Week 16 will be handled by setting the
ASAS20 values to nonresponsive (in conjunction with Estimand 1 and Estimand 2). This
method of handling missing response is known as missing response as non-response 
(MR=NR). Note that for Estimand 1 which employs the composite strategy (Section 2.1.1),
this can be viewed as a composite endpoint in the sense that a response requires the subject 


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completes a visit of interest while receiving investigational product eg, Week 16, and 
achieves a response per the defined ASAS20 response criteria (otherwise it is considered a 
nonresponse). Note that when a subject has an ASAS20 assessment prior to or on the same
date as the discontinuation of the investigational product within the Week 16 visit window, 
this ASAS20 assessment will be used to evaluate ASAS20 response as on-drug observation 
for Week 16 (this same rule will be applied to other visits and other applicable binary 
endpoints). For Estimand 3, missing response will not be explicitly imputed but will be 
implicitly handled in the GMMRM analysis. The above methods will also be applied to 
ASAS40 response at Week 16 as well as time points prior to Week 16 for both ASAS20 and 
ASAS40. The MR=NR in conjunction with Estimand 1 using on-drug data will be applied to 
all other response-type secondary endpoints (not Type I error controlled) including ASAS 
5/6, ASAS partial remission, ASDASCRP clinically important improvement, ASDASCRP
major improvement, ASDASCRP inactive disease, and BASDAI50 at all time points collected.
Repeated measures data for continuous and ordered-categorical (analyzed as continuous) 
endpoints will be analyzed with a MMRM model.  This model will yield unbiased estimates 
and valid inferences in the presence of data that is MCAR or MAR (Rubin, 1987).2 Hence 
missing values will not be explicitly imputed in the routine analysis using the repeated 
measures model. Continuous and ordered-categorical (analyzed as continuous) endpoints 
with only a single post-baseline visit will be analyzed with an ANCOVA model. Missing 
values will not be imputed when using the ANCOVA model.
Tipping point analyses will be conducted to address impact of missing values on the 
conclusions for ASAS20 and ASAS40 at Week 16 (Section 5.2.1.3). 
For the SF-36v2, ASQoL, EQ-5D-3L (including EQ-VAS and EQ-5D-3L Utility Score 
[UK]), WPAI, AS-HCRU, and FACIT-F instruments, rules suggested by the developers of 
these instruments will be followed in calculating scores when individual question/items may 
be missing.  If these rules are not enough for calculating a score, then the endpoint will be 
considered to have a missing value, and this missing value will be addressed as specified in 
the paragraph above. For BASDAI, inflammation based on BASDAI’s questions 5 and 6, 
and BASFI, methods of handling missing scores follow the those suggested by Ramiro et al. 
(2014)1 (see Sections 3.2.2 and 9.2.2). Specific methods of handling missing components for 
BASMI, missing joints for SJC(44), and missing sites for MASES can be found in 
Appendix (see Sections 9.2.3, 9.2.5, and 9.2.6 respectively).
In general, missing values in any of the endpoints will not be imputed when summarizing 
these endpoints using descriptive statistics. 
In addition, missing values for safety endpoints will not be imputed.
6 . ANALYSES AND SUMMARIES
All efficacy analysis will use FAS (Section 4.1) or FAS with some subjects excluded from 
analyses for certain endpoints (Section 4.4.1) except where indicated otherwise.  For each 
endpoint, comparison (Section 5.2) of tofacitinib 5 mg BID group to the placebo group at 
Week 16, which is the primary interest of the treatment comparison will be provided (point 
estimate, SE, p-value, and 95% CI). Treatment comparisons at other visits will be provided 


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as well. The Week 16 analysis will include efficacy data through Week 16 only, while safety 
data through Week 16 and beyond for those subjects who have passed the Week 16 visit at 
data cut. The Week 48 analysis will include efficacy and safety data through the Week 48 
visit including follow-up visit (Section 5).
6.1. Primary Endpoint: ASAS20 at Week 16
6.1.1. Primary Analysis
The ASAS20 response rate at Week 16 is the primary efficacy endpoint in this trial.  The 
analysis of primary endpoint will be based on the FAS, which includes all randomized 
subjects who take at least 1 dose of investigational product (ie, tofacitinib or placebo).  For 
the primary analysis, the normal approximation for the difference in binomial proportions 
adjusting for the stratification factor (ie, prior treatment history: "bDMARD-naïve" vs 
"TNFi-IR or bDMARD Use [Non-IR]") at randomization (prior treatment history will be 
derived from the clinical database and used in the analysis; see Section 3.4.1 and 
Section 9.11) via the CMH approach will be used to test the superiority of tofacitinib 5 mg 
BID to placebo and to generate 95% CI for the difference (see Section 5.2.1.1). Missing 
values for any reason will be handled by setting the ASAS20 value to nonresponsive, 
MR=NR (see Section 5.3).  This is the primary analysis for the ASAS20 response rate at 
Week 16. This analysis uses the on-drug data only (see Appendix Section 9.1). This 
corresponds to Estimand 1 or the Primary Estimand (see Section 2.1.1). Analysis of 
ASAS20 at other time points will also be analyzed using the same method and the on-drug 
data on the FAS.
6.1.2. Supportive Analyses
Supportive Analysis 1: As a supportive analysis based on Estimand 2 of ASAS20 at Week 16
(see Section 2.1.1), ASAS20 at Week 16 will be analyzed using the on-study data (see 
Appendix Section 9.1). Analysis of ASAS20 at other time points will also be analyzed using 
the same method as in the primary analysis (Section 6.1.1) but using the on-study data on the 
FAS.
Supportive Analysis 2: The same analysis as the primary analysis for ASAS20 response rate 
at Week 16 (see Section 5.2.1.1) will be conducted on the PP analysis set (see Section 4.2) as 
a supportive analysis based on Estimand 1 of ASAS20 at Week 16 (see Section 2.1.1) since 
the FAS may include instances of protocol deviations which may have material impact on the 
primary efficacy endpoint. Missing values will be handled by setting the ASAS20 value to 
non-responsive, ie, MR=NR (see Section 5.3). This analysis uses the on-drug data only (see 
Appendix Section 9.1).
Supportive Analysis 3: As a supportive analysis based on Estimand 3 of ASAS20 at Week 16
(see Section 2.1.1), GMMRM without imputation for missing responses will be applied to the 
available ASAS20 data collected at Weeks 2, 4, 8, 12, and 16. The FAS will be used for this 
analysis (see Section 5.2.1.2). Missing ASAS20 response status will not be imputed and will
be treated as missing. This analysis uses the on-drug data only (see Appendix Section 9.1).
Supportive Analysis 4: Another supportive analysis on the ASAS20 response rate at Week 16 
is performed to assess the robustness of the data to the departures from the MAR assumption. 


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This analysis is called tipping point analysis and its methodology is briefly described in
Section 5.2.1.3 and further detailed in the Appendix (Section 9.3). The FAS will be used and 
the analysis will include both tofacitinib 5 mg BID and placebo groups. The available 
on-drug data of ASAS20 without imputation from the following five time points: Weeks 2, 4, 
8, 12, and 16 are included in the imputation model to estimate the parameters. The missing 
ASAS20 at Week 16 with respect to the on-drug data will be subject to multiple imputation. 
The tipping point analysis includes MAR for both treatment groups as a special case. Both 
parameter estimation and multiple imputation use only the on-drug data (see 
Appendix Section 9.1).
Supportive Analysis 5: Similar to Supportive Analysis 4 above, the tipping point analysis is 
repeated on the On-Study data (see Appendix Section 9.1 regarding the scope of on-study 
data). The same available on-drug data of ASAS20 without imputation from the following 
five time points: Weeks 2, 4, 8, 12, and 16 are included in the imputation model to estimate 
the parameters using the on-drug data only. However, the missing ASAS20 at Week 16 with 
respect to the on-study (both available on-drug and off-drug taken into account together) will 
be subject to multiple imputation. Therefore, parameter estimation uses only on-drug data, 
but multiple imputation for missing ASAS20 response accounts for on-study data which 
includes both on-drug and off-drug data (see Appendix Section 9.1). 
Supportive Analysis 6: MMRM without imputation for missing data described in
Section 5.2.2 will be used to analyze the change from Baseline for the 4 ASAS20/ASAS40 
component endpoints [∆PGA, ∆ in total back pain, ∆BASFI, and ∆in inflammation (average 
of questions 5 and 6 of BASDAI)] on the FAS using the on-study data (including both 
on-drug and off-drug data, see Appendix Section 9.1). These analyses of the
4 ASAS20/ASAS40 component endpoints at Week 16 correspond to Estimand 5 (see 
Section 2.1.2). The model will include the time points of Weeks 2, 4, 8, 12, and 16 for the 
Week 16 analysis only. Only comparisons between tofacitinib 5 mg BID with placebo for 
visits up to Week 16 will be reported. Prior treatment history will be derived from the 
clinical database and used in the analysis (see Section 3.4.1).
Note that MMRM analyses of the 4 ASAS20/ASAS40 component endpoints [∆PGA, ∆ in 
total back pain, ∆BASFI, and ∆in inflammation (average of questions 5 and 6 of BASDAI)]
on the FAS using the on-drug data are detailed in Section 6.3. These endpoints at Week 16 
correspond to Estimand 4 (see Section 2.1.2). These are secondary endpoints/analyses 
themselves but can be viewed supportive to the primary endpoint as well. 
In addition, a summary of subjects will be produced for those who complete the Week 16 
visit by their ASAS20 response status at Week 16 and those who discontinue from the 
investigational product prior to Week 16 visit by their reason (ie, status) of discontinuation 
using the Disposition – End of Treatment CRF page and the on-drug data (Appendix
Section 9.1).  A mock table is given below.


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Table 3.
Mock Table of ASAS20 Response at Week 16 and Reasons for Study Drug 
Discontinuation Prior to Week 16 (Estimand 1, FAS, MR=NR, On-Drug 
Data)
ASAS20 Response Outcome at Week 16 – Estimand 1, FAS, MR=NR, On-Drug Data
Status - n (%)
Tofacitinib 5 mg 
BID (N=xxx)
Placebo 
(N=xxx)
ASAS20 Responders
xx (xx.xx)
xx (xx.xx)
ASAS20 Non-Responders
xx (xx.xx)
xx (xx.xx)
ASAS20 Non-Responders – Who Completed 
the Week 16 Visit with Observed On-Drug Data
xx (xx.xx)
xx (xx.xx)
ASAS20 Non-Responders – Who Completed 
the Week 16 Visit with Missing On-Drug Data
xx (xx.xx)
xx (xx.xx)
ASAS20 Non-Responders – Who Discontinued 
Investigational Product Prior to Week 16 Visit
xx (xx.xx)
xx (xx.xx)
Reasons for Discontinuation of Investigational 
Product
             Lack of Efficacy
xx (xx.xx)
xx (xx.xx)
             Adverse Event
xx (xx.xx)
xx (xx.xx)
             Death
xx (xx.xx)
xx (xx.xx)
             Lost to Follow-up
xx (xx.xx)
xx (xx.xx)
             Withdrawal by Subject
xx (xx.xx)
xx (xx.xx)
            Non-Compliance with Study Drug
xx (xx.xx)
xx (xx.xx)
             Protocol Deviation
xx (xx.xx)
xx (xx.xx)
             Pregnancy
xx (xx.xx)
xx (xx.xx)
             Physician Decision
xx (xx.xx)
xx (xx.xx)
             Medication Error without Associated Adverse 
            Event
xx (xx.xx)
xx (xx.xx)
             Study Terminated by Sponsor
xx (xx.xx)
xx (xx.xx)
             Other
xx (xx.xx)
xx (xx.xx)
Another summary of subjects will also be produced for those who complete the Week 16 
visit by their ASAS20 response status at Week 16 and those who permanently discontinue 
from the study prior to Week 16 visit by their reason (ie, status) of discontinuation using 
Disposition – Follow-Up CRF page and on-study data (Appendix Section 9.1). 


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Table 4.
Mock Table of ASAS20 Response at Week 16 and Reasons for Study 
Discontinuation Prior to Week 16 (Estimand 2, FAS, MR=NR, On-Study 
Data)
ASAS20 Response Outcome at Week 16 – Estimand 2, FAS, MR=NR, On-Study Data 
Status - n (%)
Tofa 5 mg BID 
(N=xxx)
Placebo 
(N=xxx)
ASAS20 Responders 
xx (xx.xx)
xx (xx.xx)
ASAS20 Non-Responders
xx (xx.xx)
xx (xx.xx)
ASAS20 Non-Responders – Who Completed the 
Week 16 Visit with Observed On-Study Data
xx (xx.xx)
xx (xx.xx)
ASAS20 Non-Responders – Who Completed the 
Week 16 Visit with Missing On-Study Data
xx (xx.xx)
xx (xx.xx)
ASAS20 Non-Responders – Missing On-Study 
Data due to Discontinuation from Study 
Participation Prior to Week 16 Visit
xx (xx.xx)
xx (xx.xx)
Reasons for Discontinuation from Study
           Death
xx (xx.xx)
xx (xx.xx)
           Lost to Follow-up
xx (xx.xx)
xx (xx.xx)
           Withdrawal by Subject
xx (xx.xx)
xx (xx.xx)
           Study Terminated by Sponsor
xx (xx.xx)
xx (xx.xx)
           Other
xx (xx.xx)
xx (xx.xx)
6.2. Key Secondary Endpoint: ASAS40 at Week 16
ASAS40 at Week 16 will be analyzed using the same methods as those for the primary 
endpoint ASAS20 detailed in Section 6.1. Analysis of ASAS40 at other time points will also 
be analyzed using the same method as for ASAS20 on the FAS. These include the analyses 
for Estimand 1 (also known as the Key Secondary Estimand for Key Secondary Analysis), 
Estimand 2 (Supportive Analysis 1), Estimand 1 on the Per Protocol Analysis Set 
(Supportive Analysis 2), Estimand 3 (Supportive Analysis 3) (see Section 2.1.1), and 
supportive tipping point analyses (Supportive Analysis 4 and Supportive Analysis 5).
6.3. Other Secondary Endpoints and Tertiary/Exploratory Endpoints
Analyses of all endpoints listed in this section will use the FAS (Section 4.1) or FAS with 
certain subjects excluded for some endpoints (Section 4.4.1) using the on-drug data (main)
and are also repeated using the on-study data for the following Type I error controlled 
secondary endpoints only: ∆ASDASCRP, ∆hsCRP, ∆ASQoL, ∆SF-36v2 (PCS score as well as 
the non-Type I error controlled endpoints of MCS and 8 norm-based domain scores), 
∆BASMI (as well as the 5 non-Type I error controlled components), ∆FACIT-F (Total score 
as well as the non-Type I error controlled endpoints of Experience Domain and Impact 
Domain Scores), ∆PGA, ∆in Total Back Pain, ∆BASFI and ∆Inflammation (supportive)
(Appendix Section 9.1).
For the binary endpoints listed below, the observed response rates and SEs of these observed 
response rates, without imputation for missing data, will be provided descriptively for the 
two treatment groups at the time points indicated per Section 5.2. For treatment comparisons 
at all time points, the normal approximation for the difference in binomial proportions 


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adjusting for the stratification factor (ie, prior treatment history: "bDMARD naïve" vs. 
"TNFi-IR or bDMARD Use [Non-IR]") at randomization (prior treatment history will be 
derived from the clinical database and used in the analysis; see Section 3.4.1) via the CMH 
approach will be used for both testing and forming 95% CI’s for the treatment difference 
between tofacitinib 5 mg BID and placebo as described in Section 5.2.1.1. Setting missing 
responses to non-responses (ie, MR=NR) will be used for missing data.
•
ASAS20 response at all other time points (Weeks 2, 4, 8, 12, 24, 32, 40, and 48);
•
ASAS40 response at all other time points (Weeks 2, 4, 8, 12, 24, 32, 40, and 48) (see
Section 6.2);
•
ASAS 5/6 response at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);
•
ASAS partial remission response at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, 
and 48);
•
ASDASCRP Clinically Important Improvement response, ASDASCRP Major 
Improvement response and ASDASCRP Inactive Disease response at all time points
(Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48); and
•
BASDAI50 response at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48).
When using the on-drug data, the treatment comparisons of these binary endpoints 
correspond to Estimand 1 (Section 2.1.1). Only ASAS20 and ASAS40 (the only two binary 
endpoints under Type I Error Control at earlier time points) will be repeated using the on-
study data (Section 9.1), and the treatment comparisons of these two binary endpoints 
correspond to Estimand 2 (Section 2.1.1).
MMRM without imputation for missing data described in Section 5.2.2 will be used to
analyze the change from Baseline for the following endpoints. The model will include up to 
Week 16 (Weeks 2, 4, 8, 12, and 16) for the Week 16 analysis while all the time points of the 
entire study duration (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48) for the Week 48 analysis as 
indicated below for each of the endpoints. Prior treatment history will be derived from the 
clinical database and used in the analysis (see Section 3.4.1 and Section 9.11). When the
on-drug data is used (Section 9.1), the treatment comparisons of these endpoints correspond 
to Estimand 4 (Section 2.1.2) for both Week 16 and Week 48 analyses. These same analyses 
will be repeated only for the following Type I error controlled secondary endpoints: 
∆ASDASCRP, ∆hsCRP, ∆BASMI (as well as the 5 non-Type I error controlled components), 
∆FACIT-F (Total score as well as the non-Type I error controlled endpoints of Experience 
Domain and Impact Domain Scores), ∆PGA, ∆in Total Back Pain, ∆BASFI and 
∆Inflammation (supportive) (Section 6.1.2) using the on-study data (Section 9.1) for the 
Week 16 analysis only, and the treatment comparisons of these endpoints correspond to the 
Estimand 5 (Section 2.1.2).
•
ΔASDASCRP at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);


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
ΔhsCRP (mg/L) at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);

ΔBASDAI at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);

ΔBASMI and its 5 components (Δ in Lateral Spinal Flexion, Tragus-to-Wall 
Distance, Lumbar Flexion [as measured by Modified Schober’s test score], Maximal 
Intermalleolar Distance, and Cervical Rotation) at all time points (Weeks 2, 4, 8, 12, 
16, 24, 32, 40, and 48);

ΔBASFI at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);

ΔMASES at all time points (Weeks 4, 8, 12, 16, 24, 32, 40, and 48);

ΔSJC(44) at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);

Δ in Spinal Mobility: Chest Expansion at all time points (Weeks 2, 4, 8, 12, 16, 24, 
32, 40, and 48);

ΔPGA at all time points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);

Δ in Patient Assessment of Spinal Pain (two numerical rating scales [NRS]: Δ in
Nocturnal Spinal Pain and Total Back Pain) at all time points (Weeks 2, 4, 8, 12, 16, 
24, 32, 40, and 48);

Δ in Inflammation (defined as the average of questions 5 & 6 of BASDAI) at all time 
points (Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48);

ΔFACIT-F Total, Experience Domain, and Impact Domain Scores at all time points 
(Weeks 2, 4, 8, 12, 16, 24, 32, 40, and 48).
For the Week 16 analysis, the ANCOVA model will include Week 16 as indicated below for 
each of the endpoints. When the on-drug data is used (Section 9.1), the treatment 
comparisons of these endpoints correspond to Estimand 4 (Section 2.1.2). These same 
analyses will be repeated only for the following Type I error controlled secondary endpoints: 
ΔSF-36v2 (PCS, as well as non-Type I error controlled MCS and 8 norm-based domains) and 
ΔASQoL using the on-study data (Section 9.1) for the Week 16 analysis only, and the 
treatment comparisons of these endpoints correspond to the Estimand 5 (Section 2.1.2). The 
Week 48 analysis will use the MMRM model. The MMRM model will include all the time 
points of the entire study duration (Weeks 16 & 48) using the on-drug data only
corresponding to Estimand 4 (Section 9.1) as indicated below for each of the endpoints.
Prior treatment history will be derived from the clinical database and used in the analysis (see
Section 3.4.1 and Section 9.11).

ΔSF-36v2, Acute (8 domains (norm-based), PCS, and MCS scores) at Weeks 16 & 
48;


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
ΔEQ-5D-3L (5 dimensions), ΔEQ-VAS, and ΔEQ-5D-3L Utility Score (UK) at 
Weeks 16 & 48;

ΔASQoL at Weeks 16 & 48;

ΔWPAI Questionnaire: Spondyloarthritis (4 subscale scores in range of 0-100%) at 
Weeks 16 & 48;

ΔAS-HCRU Self-Rating of Job Performance at Work at Weeks 16 & 48.
However, AS-HCRU will only be summarized descriptively for Baseline, Weeks 16 
& 48.
6.4. Subset (Subgroup) Analyses
6.4.1. Subgroup Analyses for Primary Endpoint of ASAS20 at Week 16
All subgroup comparisons for the primary endpoint ASAS20 at Week 16 will be made on the 
FAS with missing value handled by MR=NR using the on-drug data corresponding to 
Estimand 1 for the following comparison only:

Tofacitinib 5 mg BID vs. Placebo.
Subgroup analysis will be performed for each of the following subgroup variables and their 
categories in parentheses:

Prior treatment history - 2 categories ("bDMARD-naïve", "TNFi-IR or bDMARD 
Use [Non-IR]") where prior treatment history is derived from the clinical database
(see Appendix Section 9.11);

Prior treatment history – 3 categories ("bDMARD-naïve", "TNFi-IR", "bDMARD 
Use [Non-IR]") where prior treatment history – 3 categories is derived from the 
clinical database. Subjects under "bDMARD Use (Non-IR)" category are not 
TNFi-IR and have prior bDMARD Use without IR. This subgroup analysis is only 
done when there is sufficient number of subjects in the "bDMARD Use (Non-IR)"
category (see Appendix Section 9.11);

Geographic region – 4 regions ("North America (US and Canada)" [United States, 
Canada], "European Union" [Bulgaria, Czech Republic, France, Hungary, Poland], 
"Rest of World" [Ukraine, Russia, Australia, Turkey], "Asia" [China, South Korea]);

Gender (Female, Male);

Race (White, Asian, Other), when a subject selects more than one race category, this 
subject will be grouped to the “Other”;

Age at Baseline (<65, ≥65 years);

Baseline weight (<60, ≥60 to ≤100, >100 kg);


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•
Baseline Body Mass Index (BMI) (<25, ≥25 to <30, ≥30 to <40, and ≥40 kg/m2);
•
AS disease symptom duration (<5, ≥5 years);
•
Baseline AS disease activity (ASDASCRP <1.3 [inactive disease], ≥1.3 to <2.1 [low 
disease activity], ≥2.1 to ≤3.5 [high disease activity], > 3.5 [very high disease 
activity] units, and continuous) (van der Heijde et al. 2016; Machodo et al., 2018);9
•
Baseline hsCRP (≤2.87, >2.87 mg/L), where 2.87 mg/L (the upper limit of normal) is 
defined in this study as elevated;
•
Baseline smoking status (Never Smoked, Former Smoker, Current Smoker);
•
Day 1 Concomitant csDMARD Use (Yes, No);
•
HLA-B27 (Positive, Negative).
Estimates of the treatment difference between tofacitinib 5 mg BID and placebo at Week 16 
along with the 95% CI without p-value, will be presented for each category of a subgroup 
variable. The normal approximation using CMH approach adjusting for prior treatment 
history ("bDMARD-naïve" vs. "TNFi-IR or bDMARD Use [Non-IR]") (see Sections 3.4.1
and 5.2.1.1 as well as Section 9.11) will be used for each category of a subgroup variable, 
except for the subgroup of prior treatment history. 
In addition to Week 16, subgroup analysis of ASAS20 by prior treatment history (2 category 
definition: "bDMARD-naïve", "TNFi-IR or bDMARD Use [Non-IR]") and (3-category 
definition: "bDMARD-naïve", "TNFi-IR", and "bDMARD Use [Non-IR]" provided there is 
sufficient number of subjects in the category of bDMARD Use [Non-IR]) will be conducted
at each visit prior to Week 16. ASAS20 will be analyzed separately by prior treatment 
history (both 2-category and 3-category definitions) using the normal approximation 
approach to the difference in binomial proportions on the FAS (Section 4.1) with missing 
value considered as non-responsive (ie, MR=NR). For each category of "bDMARD-naïve"
and "TNFi-IR or bDMARD Use (Non-IR)" of the 2-category definition, as an example, the 
95% CI of the treatment difference is calculated as:
ሺ݌̂஺െ݌̂஻ሻേݖ଴.ଽ଻ହඨ݌̂஺ሺ1 െ݌̂஺ሻ
݊஺
൅݌̂஻ሺ1 െ݌̂஻ሻ
݊஻
where ݌̂஺and ݌̂஻represent the estimated response rates for tofacitinib 5 mg BID and placebo 
respectively, and ݊஺and ݊஻are their respective sample sizes. ݖ଴.ଽ଻ହis the 97.5th percentile of 
the standard normal distribution. No p-value will be produced. The method of handling 0 or 
100% response rate in either or both treatment groups can be found in Section 5.2.1.1.


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The primary purpose of subgroup analyses is to check for consistency of the primary 
endpoint results across subgroup categories, ie, making sure overall results are not driven by 
some subset of subjects (ie, particular categories of a subgroup). Graphical display (eg,
forest plots) of the treatment differences in ASAS20 at Week 16 between tofacitinib 5 mg 
BID and placebo will be presented. There is no intention to have any specific inference 
within subgroup variables, therefore only 95% CI’s are produced without corresponding 
p-values.
6.4.2. Subgroup Analyses for Key Secondary Endpoint of ASAS40 at Week 16
As ASAS40 at Week 16 is the key secondary endpoint, all of the subgroup analyses 
described for ASAS20 in Section 6.4.1 will also be performed on ASAS40 at Week 16. The 
analysis by prior treatment history described for ASAS20 in Section 6.4.1 will also be 
performed on ASAS40. Only the on-drug data corresponding to Estimand 1 will be used (see 
Appendix Section 9.1). The other Type 1 controlled secondary endpoints will not be
included in subgroup analyses.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Baseline characteristics will include but may not be limited to the ones listed below and will 
be summarized descriptively. For continuous variables, the summary will include N (which 
is the number of subjects evaluable for the baseline characteristics), mean, median, SD and 
range (ie, minimum and maximum); for binary and categorical variables, the summary will 
include frequencies and percentages. A missing category will be included for those subjects 
with missing value. In addition to displays by treatment groups, the summaries will also be 
provided for all the treatment groups combined.
Demographic characteristics:

Baseline age (2 categorizations: <18, ≥18 to ≤44, ≥45 to ≤64, ≥65 years; <18, ≥18 to 
≤44, ≥45 to ≤64, ≥65 to ≤74, ≥75 to ≤84, ≥85 years; and continuous in years);

Gender (Female, Male);

Race (White, Black, Asian, Other);

Geographic region (see Section 6.4.1 for definition);

Ethnicity (Hispanic/Latino, non-Hispanic/Latino);

Baseline body weight (<60, ≥60 to ≤100, >100 kg; and continuous in kg);

Baseline height (continuous in cm);

Baseline waist circumference (continuous in cm);


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
Baseline BMI (<18.5, ≥18.5 to <25, ≥25 to <30, ≥30 to <40, and 40 kg/m2; and 
continuous kg/m2);

Baseline smoking status (Never Smoked, Former Smoker, Current Smoker);

Duration of smoking started (continuous in years) for subjects who are Current 
Smokers or Former Smokers;

Duration of smoking stopped (continuous in years) for subjects who are Former 
Smokers only;

Baseline pack-year (continuous in pack-year) for subjects who are Current Smokers 
or Former Smokers;

Baseline Alcohol use (Yes, No; continuous in units/week for subjects who have 
Current Alcohol use at Baseline); Yes is defined for subjects who have Current 
Alcohol use at Baseline, else No.
Baseline disease characteristics:

Prior treatment history at randomization ("bDMARD-naïve", "TNFi-IR or bDMARD 
Use [Non-IR]") where prior treatment history is derived from the clinical database
(see Section 9.11). Under the "TNFi-IR or bDMARD Use (Non-IR)" category, two 
subcategories: "TNFi-IR" and "bDMARD Use (Non-IR)" will be summarized. 
Subjects under "bDMARD Use (Non-IR)" are not TNFi-IR and have prior bDMARD
Use without IR (see Section 9.11);

AS disease symptom duration (<5, ≥5 years; and continuous in years);

AS disease duration since diagnosis (<5, ≥5 years; continuous in years);

Family history of Spondyloarthritis (Yes, No);

History of Uveitis (Yes, No);

Current symptom of Uveitis (Yes, No) for subjects with history of uveitis;

History of Psoriasis (Yes, No);

Current symptom of Psoriasis (Yes, No) for subjects with history of psoriasis; 

History of Inflammatory Bowel Disease (IBD) (Yes, No);

Current symptom of IBD (Yes, No) for subjects with history of IBD;

HLA-B27 (Positive, Negative);

Baseline hsCRP (≤2.87, >2.87 mg/L [ie, Elevated hsCRP]; and continuous in mg/L);


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
Baseline metabolic syndrome (Yes, No) (see Section 9.7.1 for definition);

Baseline diabetes mellitus (Yes, No) (see Section 9.7.2 for definition);

Baseline PGA (continuous);

Baseline Patient Assessment of Pain – Total Back Pain (continuous);

Baseline Patient Assessment of Pain – Nocturnal Spinal Pain (continuous);

Baseline BASFI (continuous);

Baseline BASDAI Total score (continuous);

Baseline Inflammation (Average of questions 5 and 6 of BASDAI) (continuous);

Baseline BASMI and its 5 components (continuous);

Baseline Spinal Mobility – Chest Expansion (continuous in cm)

Baseline AS disease activity (ASDASCRP <1.3 [inactive disease], ≥1.3 to <2.1 [low 
disease activity], ≥2.1 to ≤3.5 [high disease activity], >3.5 [very high disease activity] 
units, and continuous) (van der Heijde et al. 2016; Machodo et al., 2018);9,10

Baseline presence of enthesitis based on MASES (Yes, No). Yes is defined for those 
subjects with Baseline MASES >0;

Baseline MASES (continuous) for those subjects with Baseline MASES >0;

Baseline presence of swollen joints (Yes, No). Yes is defined for those subjects with 
Baseline SJC(44) >0;

Baseline SJC(44) (continuous) for those subject with Baseline SJC(44) >0;

Baseline SF-36v2 – 8 domain scale (ie, norm-based), PCS, MCS scores (continuous);

Baseline EQ-5D-3L – 5 dimension scores (continuous), EQ-VAS (Your own health 
state today) (continuous in mm) and EQ-5D-3L Utility score (UK) (continuous);

Baseline FACIT-F – Total score, Impact domain and Experience domain scores
(continuous);

Baseline WPAI – 4 subscores (continuous in %);

Baseline ASQoL Total score (continuous).


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6.5.2. Prior and Baseline Treatments for Ankylosing Spondylitis
Prior use denotes any relevant drug use prior to Day 1. If there are missing values for any of 
the characteristics, add a “Missing” category to capture these subjects unless noted otherwise.

Prior oral corticosteroids use (oral only: Yes, No, Missing is considered as No);

Number of prior NSAIDs-IR (2 NSAID-IR, ≥3 NSAID-IR) for all subjects (see 
Appendix Section 9.10 for definition of NSAID-IR);

Number of prior TNFi-IR (1 TNFi-IR, 2 TNFi-IR) for subjects who have prior 
inadequate response to TNFi (ie, with prior treatment history of "TNFi-IR" derived 
from the clinical database, see Appendix Section 9.11 for definition of TNFi-IR);

Number of prior bDMARD Use (1 bDMARD Use, ≥2 bMDARDs Use) for subjects 
who are not grouped to "TNFi-IR" stratum but have prior bDMARD Use without 
IR (ie, bDMARD Use [Non-IR] derived from clinical database, see Appendix
Section 9.11).
6.5.3. Concomitant Medications
Concomitant treatments are those treatments that are taken on Day 1 or after. These 
treatments can be summarized based on the periods of assessment and the summary will 
include only those subjects who received any concomitant medications post-baseline. 

Taken on Day 1 (at Baseline) only;

Taken on Day 1 up to Week 16;

Taken on Day 1 up to Week 48.
Concomitant medications for primary diagnosis:

Concomitant csDMARDs (for any csDMARDs use [n, %] and for each csDMARD
use, eg, Methotrexate, Sulfasalazine, etc. Full but non-exhaustive list of csDMARDs 
can be found in Section 9.6 Table 7. List of DMARDs and NSAIDs); Note that 
csDMARD is defined as non-bDMARD.

Concomitant NSAIDs (for any NSAIDs use [n, %] and for each NSAID use. Full but 
non-exhaustive list of NSAIDs can be found in Section 9.6 Table 7. List of 
DMARDs and NSAIDs);

Corticosteroids (for any Corticosteroids use [n, %] and for each corticosteroid use, eg,
Glucocorticoids);

Pain Management/Analgesics (for any Pain Management/Analgesics use [n, %] and 
for each pain management/analgesics use).


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6.6. Safety Summaries and Analyses
All the safety data will be summarized descriptively through appropriate data tabulations, 
descriptive statistics, and graphical presentations.  AEs, vital signs, 12-lead ECG parameters, 
and laboratory tests will be summarized according to the Clinical Data Interchange Standards 
Consortium (CDISC) and Pfizer Standards (CaPS).
6.6.1. Adverse Events
AEs will be reported as treatment-emergent all causality and treatment-emergent 
treatment-related.  A treatment-emergent AE is any event that starts on or after the first 
dosing day. The algorithm will not consider any events that start prior to the first dose date.
The relationship to study treatment is assessed by the investigator.
AEs will be displayed by two analysis periods: (1) Baseline to Week 16; and (2) Baseline to 
Week 48 (end of study including follow-up).
Tier-1 events, ie, AEs of special interest will be summarized descriptively. 
Tier-2 events will be analyzed using asymptotic methods proposed by Miettinen and 
Nurminen (1985).11 Risk ratios (tofacitinib 5 mg BID compared to placebo) and 2-sided
95% CI will be reported.  P-values will not be reported for Tier-2 events. This analysis is 
applicable for the period of Baseline to Week 16 only.
6.6.2. Laboratory Data
For laboratory tests, 12-lead ECG parameters and vital signs, these summaries include 
categorical tables (eg, normal, high, low), and descriptive statistics for change or percent 
change (for fasting lipids) from Baseline by treatment group and visit. For the FACS, the 
endpoints to be summarized, which are subsets of lymphocytes and are measured at Baseline, 
Week 4, Week 16, Week 32, and Week 48, are as follows: CD3+(%, abs), CD3+CD4+ 
(%, abs), CD3+CD8+ (%, abs), CD19+ (%, abs), CD56+/CD16+ (%, abs).  Raw values as 
well as percent change from Baseline will be summarized with descriptive statistics by 
treatment group and visit.
The number and percent of subjects reporting specific past and present medical histories at 
screening will be summarized by medical history reporting term (from MedDRA) and 
treatment group following CaPS. 
Clinical findings on any physical examination during the study will be tabulated by treatment 
group following CaPS. 
Previous and concomitant medication usage by medication type will be tabulated by 
treatment group using the WHO-Drug dictionary following CaPS. 


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7. INTERIM ANALYSES
No formal interim analysis will be conducted for this study. The analysis of the primary
endpoint, key secondary endpoint and other Type I error controlled secondary endpoints 
conducted at Week 16 is the final analysis (ie, Week 16 analysis) for these endpoints. 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.  Information about the E-DMC can 
be found in the E-DMC Charter, which outlines the operating procedures of the committee, 
including specific description of the scope of their responsibilities, including a plan where 
communication timelines are defined.  
The final analysis (ie, Week 48 analysis) will be performed at the official database release.


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8. REFERENCES 
1.
Ramiro S, van Tubergen A, van der Heijde D, van den Bosch F, Dougados M, Landewé 
R. (2014). How to deal with missing items in BASDAI and BASFI. Rheumatology. 53: 
374-376.
2.
Rubin DB. (1987). Multiple imputation for nonresponse in surveys.  New York: Wiley.
3.
Cochran WG. (1954). Some methods of strengthening the common X2 tests. Biometrics.
10: 417-451.
4.
Mantel N, Haenszel, W. (1959). Statistical aspects of the analysis of data from 
retrospective studies of disease. J. Natl. Cancer Inst. 22:719-748.
5.
Agresti A. (2002). Categorical Data Analysis, 2nd Edition, New York: John Wiley & 
Sons.
6.
Liu GR, Zhan X. (2011). Comparisons of methods for analysis of repeated binary 
responses with missing data.  Journal of Biopharmaceutical Statistics. 21: 371-392.
7.
Yan X, Lee S, Li N. (2009). Missing data handling methods in medical device clinical 
trials. Journal of Biopharmaceutical Statistics. 19: 1085-1098.
8.
Ratitch B, O’Kelly M, Tosiello R. (2013). Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models. Pharmaceutical 
Statistics. 12: 337–347.
9.
van de Heijde D, Joshi A, Pangan AL, Chen N, Betts K, Mittal M, Bao Y. (2016). 
ASAS40 and ASDAS clinical responses in the ABILITY-1 clinical trial translate to 
meaningful improvements in physical function, health-related quality of life and work 
productivity in patients with non-radiographic axial spondyloarthritis. Rheumatology. 
55: 80-88.
10.
Machodo PM, Landewé R, van der Heijde D, et al. (2018). Ankylosing Spondylitis 
Disease Activity Score (ASDAS): 2018 update of the nomenclature for disease activity 
states. Ann. Rheum. Dis. 77: 1539-1540.
11.
Miettinen O, Nurminen M. (1985). Comparative analysis of two rates. Statistics in 
Medicine. 4: 213-226. 
12.
Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargas R, Dougados 
M, Hermann KG, Landewe R, Maksymowych W, van der Heijde D. (2009). The 
assessment of spondyloarthritis international society (ASAS) handbook: a guide to 
assess spondyloarthritis. Ann. Rheum. Dis. 68 (Suppl. II): ii1-ii44.
13.
Machado P, Landewe R, Lie E, et al. (2011). Ankylosing Spondylitis Disease Activity 
Score (ASDAS): defining cut-off values for disease activity states and improvement 
scores. Ann. Rheum. Dis. 70(1):47-53.


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14.
van der Heijde D, Landewe R, Feldtkeller E. (2008). Proposal of a linear definition of 
the Bath Ankylosing Spondylitis Metrology Index (BASMI) and comparison with the 2-
step and 10-step definitions. Ann. Rheum. Dis. 67:489–493. 
15.
Lukas C, Landewe R, Sieper J, Dougados M, Davis J, Braun J, van der Linden S, van 
der Heijde D, for the Assessment of SpondyloArthritis International Society. (2009). 
Development of an ASAS-endorsed disease activity score (ASDAS) in patients with 
ankylosing spondylitis. Ann. Rheum. Dis. 68: 18-24.
16.
Ware Jr JE, Kosinski M, Bjorner JB, Turner-Bowker DM, Gandek B, Maruish ME.
(2007). User’s Manual for the SF-36v2® Health Survey (2nd ed.). Lincoln, RI: 
QualityMetric Incorporated.
17.
Dolan P. (1997). Modeling valuations for EuroQol Health States. Medical Care. 35(11): 
1095-1108.
18.
Szende A, Oppe M, Devlin N. (2007). EQ-5D value sets: inventory, comparative review 
and user guide. 2nd ed., Dordrecht, The Netherlands: Springer.
19.
Cella D, Lai JS, Chang CH, Peterman A, Slavin M. (2002). Fatigue in cancer patients 
compared with fatigue in the general United States population. Cancer, 94 (2): 528-538.
20.
Cella D, Lai JS, Stone A. (2011). Self-reported fatigue: one dimension or more? 
Lessons from the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-
F) questionnaire. Support Care Cancer, 19: 1441-1450.
21.
Reilly MC, Gooch KL, Wong RL, Kupper H, van der Heijde D. (2010). Validity, 
reliability and responsiveness of the work productivity and activity impairment 
questionnaire in ankylosing spondylitis. Rheumatology (Oxford), 49: 812-819.
22.
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, 
James PT, Loria CM, Smith SC. (2009). Harmonizing the metabolic syndrome: a joint 
interim statement of the International Diabetes Federation Task Force on Epidemiology 
and Prevention; National Heart, Lung, and Blood Institute; American Heart 
Association; World Heart Federation; International Atherosclerosis Society; and 
International Association for the Study of Obesity. Circulation, 120: 1640-1645.


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9. APPENDICES 
9.1. Data Set Description: On-Drug vs. On-Study Data
If for any reason, when subjects have prematurely and permanently discontinued the 
investigational product (ie, tofacitinib or placebo) during the course of the study, every effort 
will be made by the study sites and investigators to engage these subjects to follow through 
the remaining planned study visits and to collect both efficacy and safety data through the 
end of the study while they are off-drug. It is important that subjects are still blinded to the 
treatment they receive through the end of the study. For a subject who prematurely 
discontinues the investigational product (ie, tofacitinib or placebo), the date of the permanent 
drug discontinuation as recorded on the Disposition – End of Treatment CRF page will be 
used to separate the efficacy data collected in visits on or before this date as this subject’s on-
drug data and data collected in visits after this date as this subject’s off-drug data. 
Because of this data differentiation, there will be two different datasets included for analyses. 
The first dataset, referred to as On-Drug Data, includes only data that are collected in visits 
on or before the permanent drug discontinuation. The second dataset, referred to as 
On-Study Data, includes both the data collected in visits on or before as well as visits after 
the permanent drug discontinuation. Data that are collected during the on-drug period will be 
flagged as on-drug data and data collected during the off-drug period will be flagged as 
off-drug data. Therefore, both on-drug and off-drug data constitute the on-study data. All of 
the analyses specified in this SAP will use the On-Drug Data unless otherwise specified 
when using the On-Study Data. The On-Study data will only be used for specific supportive 
analyses of the primary endpoint (ASAS20), key secondary endpoint (ASAS40) and their 
4 components (see Section 2.1, Section 6.1.2 and Section 6.2) as well as other Type I error 
controlled secondary endpoints. 
All safety data will be analyzed regardless of investigational product discontinuation.
9.2. Endpoint Definitions and Data Derivation Details
9.2.1. ASAS Improvement Criteria
The Assessment of SpondyloArthritis International Society (ASAS) has developed 
improvement criteria for clinical trials in AS which include the ASAS20, ASAS40, 
ASAS 5/6 (Sieper et al., 2009)12 assessments and partial remission (Machado et al., 2011).13  
These composite scores are derived from several of the Patient Reported Outcome (PRO)
measures or disease activity assessments.  The composite score will be calculated by the 
sponsor.  In order for this calculation to be completed, the investigator is responsible to 
ensure completeness of the PROs and appropriately conduct the assessments that comprise 
this endpoint.
ASAS20 and ASAS40 assess 4 domains: the “Patient Global Assessment of Disease” (PGA, 
from the CRF of Patient Global Assessment of Disease, range 0-10, with higher scores 
indicating greater disease activity), Spinal Pain (from the CRF of Total Back Pain, range 
0-10, with higher scores indicating greater pain), Function (which is the mean of the 
10 questions from the BASFI CRF, range 0-10, with higher scores indicating greater 


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functional limitation) and Inflammation (which is the mean of questions 5 and 6 from the 
BASDAI CRF, range 0-10, with higher scores indicating greater inflammation).
ASAS20 improvement (response) is defined as 20% improvement (decrease) from Baseline 
and 1 unit improvement (decrease) from Baseline in at least 3 domains on a scale of 
0-10 and no worsening from Baseline of 20% and 1 unit in the remaining domain.  
ASAS40 improvement (response) criteria are classified as 40% improvement (decrease)
from Baseline and 2 units improvement (decrease) from Baseline in at least 3 domains on a 
scale of 0-10 and no worsening from Baseline at all in the remaining domain.
ASAS partial remission is based on the same 4 domains noted above.  Partial remission is 
defined as a response if a score of 2 or less (on a scale of 0-10) for each of the 4 domains.
ASAS20, ASAS40, and ASAS partial remission will be considered missing if at least one of 
the 4 domain scores is missing.
ASAS 5/6 assesses 6 domains: the 4 domains as noted in the ASAS20 and 40 (ie, PGA, Total 
Back Pain, BASFI, and Inflammation), and additionally two more domains, hsCRP (mg/L)
and Spinal mobility, specifically lateral flexion (from the BASMI). Computation details for 
lateral flexion (cm) can be found in Section 9.2.3 for BASMI. ASAS 5/6 response is defined 
as 20% improvement (decrease) from Baseline in at least 5 domains.  
In order to avoid numerical difficulty, if the Baseline value of any domain is equal to 0, the 
following algorithm will be used in evaluating the percent change from Baseline:
1. If change from Baseline is also equal to 0, then percent change from Baseline is set to 
be 0%;
2. If change from Baseline is > 0, then percent change from Baseline is set to be 
999999%.
These percentages will be used to derive the ASAS20, ASAS40, and ASAS 5/6 responses
and will be reported in listings. Change from Baseline cannot be <0 if Baseline is equal to 
0 since the range of values in these domains is 0-10.
9.2.2. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) & BASDAI50
The BASDAI score is obtained by computing the mean score for the 2 questions related to 
morning stiffness (questions 5 and 6) and then adding that value to the sum of the scores for 
the first 4 questions and then dividing the total by 5.  This can be written as:
BASDAI=(Q1+Q2+Q3+Q4+(Q5+Q6)/2)/5.
The total score will range from 0 to 10, with higher scores indicating greater disease activity. 


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If answer to only one question is missing, BASDAI score will be calculated using the 
remaining 5 non-missing answers; otherwise if answers to two or more questions are missing, 
BASDAI will be considered missing (Ramiro et al., 2014).1 Specifically, if the answer to 
either question 5 or 6 is missing, then the score for the one available question can be used.  If 
both are missing, then the BASDAI is considered missing. Regarding the other 4 questions, 
if only 1 is missing, then the other 3 non-missing answers are used; else if more than 1 of 
these 4 answers is missing, then the BASDAI is considered missing. Explicitly, the 
calculation of BASDAI score for any one missing answer is detailed in the table below:
Missing Q5 or Q6
Missing any Q1-Q4
Formula
No
Yes
BASDAI=[sum of the 3 non-missing of 
(Q1,Q2,Q3,Q4)+(Q5+Q6)/2]/4
Yes
No
BASDAI=[Q1+Q2+Q3+Q4+(non-missing of Q5 or Q6)]/5
At a given visit, BASDAI50 response is defined as an improvement (decrease) from Baseline 
in BASDAI score ≥50%. 
As one of the 4 domains to derive ASAS improvement criteria, the mean score of the 
2 questions related to morning stiffness (questions 5 and 6) is used as a measure of 
inflammation. If one of the 2 scores is missing, the non-missing one is used for 
inflammation; else if both scores are missing, inflammation is set as missing (Ramiro et al., 
2014).1 This score will range from 0 to 10, with higher scores indicating greater 
inflammation.
The BASDAI score and the inflammation score (mean of questions 5 and 6) at all visits will 
be derived using the algorithm described above to account for missing values. The BASDAI 
score and the inflammation score obtained from the CRF page at Screening and Baseline 
visits are calculated only for the purpose of determining subject’s eligibility and protocol 
deviation status (see Section 4.2.2) and will not be used for statistical analyses for these two 
visits. BASDAI score and inflammation score at Screening and Baseline visits will be 
re-calculated using the above algorithm accounting for missing answers above and will be 
used for all BASDAI and BASDAI50 statistical analyses.
9.2.3. Bath Ankylosing Spondylitis Metrology Index (BASMI)
The BASMI consists of 5 components: cervical rotation (left and right, degree), 
intermalleolar distance (cm), lumbar flexion as measured by Modified Schober’s test score 
(cm) (note: This score is obtained by subtracting 15 cm from the value entered on the CRF 
page which intentionally includes the 15 cm.), tragus-to-wall distance (left and right, cm) and 
lateral flexion (left and right, neutral and flexion, cm).  Cervical rotation, tragus-to-wall 
distance and lateral flexion have multiple measurements while intermalleolar distance and 
Modified Schober’s test score have single measurement. Each measurement is done twice
(ie, two trials) at a visit. 


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The calculation of BASMI follows the algorithm published by van der Heijde et al. (2008).9
The algorithm is reproduced in the table below. In order to obtain the lateral flexion for each 
side (left or right) from the measures recorded on the CRFs, one needs to compute the 
following difference: [(lateral flexion-neutral) – (lateral flexion-flexion)].  This is done for 
each of the two trials. For tragus-to-wall distance, the better (ie, smaller) of two trials, while 
for cervical rotation and lateral flexion, the better (ie, larger) of two trials will be chosen for 
left and right separately. Then the mean of left and right of those chosen (denoted as A) will 
be used to compute scores in range of 0-10 (denoted as S). For Modified Schober’s test score 
and intermalleolar distance, the better (ie, larger) of the two trials (denoted as A) will be used 
to compute scores in range of 0-10 (denoted as S). It is important to note that the better 
values of the measurements do not necessarily all come from the same trial, meaning better 
one of the measurements is separately chosen between the two trials.
Each of the score obtained for cervical rotation, intermalleolar distance, Modified Schober’s
test score, tragus-to-wall distance and lateral flexion (A in the table below), will be mapped
via linear functions to a score in range of 0-10 (S in the table below).  To obtain the BASMI 
score, one takes the mean of the five component scores (ie, five S) that range between 0-10, 
with higher scores indicating more severe the patient’s limitation of movement due to their 
AS. If the number of missing component scores ≤2, BASMI score is computed using the 
mean of the remaining non-missing component scores, otherwise if the number of missing 
component scores >2, BASMI is considered as missing.
Components
S=0 if
0 <S <10 if
S=10 if
Lateral lumbar flexion (cm)
A ≥21.1
S = (21.1-A)/2.1
A ≤ 0.1
Tragus-to-wall distance (cm)
A ≤8
S=(A-8)/3
A ≥38
Lumbar flexion (modified Schober) 
(cm)
A ≥7.4
S=(7.4-A)/0.7
A ≤0.4
Intermalleolar distance (cm)
A ≥124.5
S=(124.5-A)/10
A ≤24.5
Cervical rotation angle (degree, °)
A ≥89.3
S=(89.3-A)/8.5
A ≤4.3
9.2.4. Ankylosing Spondylitis Disease Activity Score (ASDASCRP)
The ASDASCRP endpoint is derived from several patient reported outcomes and hsCRP
(mg/L) which will be calculated by the sponsor.  Following is the formula used for 
calculating the ASDASCRP (Sieper et al., 2009; Lukas et al., 2009).12,15
ASDASCRP = 0.121 × Back Pain + 0.058 × Duration of Morning Stiffness + 0.110 × Patient 
Global + 0.073 × Peripheral Pain/Swelling + 0.579×Ln(hsCRP+1).
Question 2 of the BASDAI provides the data for Back Pain, Question 6 of the BASDAI 
provides the data for Duration of Morning Stiffness, the score from the Patient Global 
Assessment of Disease (PGA) is utilized for the Patient Global and Question 3 of the 
BASDAI contributes the data for Peripheral Pain/Swelling. If any one of the five 
components is missing, ASDASCRP is considered missing. The range of the ASDASCRP is 
≥0, with higher scores indicating greater disease activity.


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hsCRP will be set to 0.199 mg/L in the formula above and in all efficacy and safety analyses, 
where 0.2 mg/L is the lower limit of quantification (LLOQ) of the assay.
The ASDASCRP clinically important improvement, major improvement and inactive disease 
will be calculated from the ASDASCRP data (van de Heijde et al. 2016).9

ASDASCRP clinically important improvement is defined as a response if improvement 
(decrease) from Baseline in ASDASCRP ≥1.1 units. 

ASDASCRP major improvement is defined as a response if improvement (decrease) 
from Baseline in ASDASCRP ≥2.0 units. 

ASDASCRP inactive disease is defined as a response if actual ASDASCRP <1.3 units. 
9.2.5. Swollen Joint Count (44)
Swollen joints are recorded in the CRF page of joint swelling. This page is to be completed 
if answer to the question, “Does this subject exhibit any joint swelling in the physical exam?” 
is “Yes.” For each of the 44 joints, swelling can be recorded as “Present”, “Absent”, “Not 
Done”, “Not Applicable” or this joint assessment is simply missing. Before calculating the 
swollen joint count, the following pre-processing steps for each joint should be performed:

If a joint receives an intra-articular injection (either at Baseline or post-baseline 
visits), set the joint status to “Present” on or after the date of injection regardless of 
the assessment of the joint recorded on the CRF page.

If there is no associated injection record available, a joint recorded as “Not Done” is 
set to missing.

A joint recorded as “Not Applicable” means that measurement cannot be made and 
this joint is set to missing.
After this pre-processing, a joint assessment that is set to missing is to be imputed by the 
average of the non-missing values of the other joints, with the restriction that the number of 
missing joint assessments cannot exceed 50% of the expected total number of joints 
evaluated for the swollen joint count (ie, 22, 50% of 44). In that case, the swollen joint count
is set to missing.
Explicitly after pre-processing, let:

N1=number of joints recorded as “Present”;

N2=number of joints recorded as “Absent”;

N3=number of joints with missing values.


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The total number of joints assessed is N1+ N2+ N3 (ie, 44). The imputed swollen joint count 
is therefore N1+ N3×( N1/( N1+ N2)) if N1+ N2 > 22; otherwise the swollen joint count is set 
to missing. It can be noted that the swollen joint count may not be a whole number. Note
that if there is no missing joint assessment, the swollen joint count will be the number of 
joints recorded as “Present” (ie, N1).
9.2.6. Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)
Thirteen sites are assessed for tenderness on the MASES CRF page. For each site, 
tenderness can be recorded as “Present”, “Absent”, “Not Done”, or this site assessment is 
simply missing. Before calculating MASES, the following pre-processing step for each site 
will be performed:

If a site is recorded as “Not Done”, set the site to missing.
After this pre-processing, a site assessment that is set to missing is to be imputed by the 
average of the non-missing values of the other sites, with the restriction that the number of 
missing site assessments cannot exceed 50% of the expected total number of sites evaluated 
for the MASES (ie, 6.5, 50% of 13). In that case, the MASES is set to missing.
Explicitly after pre-processing, let:

N1=number of sites recorded as “Present”;

N2=number of sites recorded as “Absent”;

N3=number of sites with missing values.
The total number of sites assessed is N1+ N2+ N3 (ie, 13). The imputed MASES is therefore 
N1+ N3× (N1/( N1+ N2)) if N1+ N2 >6.5; otherwise the MASES is set to missing. It can be 
noted that the MASES may not be a whole number. Note that if there is no missing site 
assessment, the MASES will be the number of sites recorded as “Present” (ie, N1).
9.2.7. 36-Item Short Form Survey Version 2 (SF-36v2) Acute
The SF-36 v.2 (Acute) is a 36-item generic health status measure. It measures 8 general
health domains: physical functioning, role limitation due to physical health, bodily pain,
general health perceptions, vitality, social functioning, role limitations due to emotional 
problems and mental health.  These domains can also be summarized as physical and mental 
component summary scores (Ware Jr et al., 2007).16
For each of the 8 domains, the raw score is first transformed into a score within the range of 
0-100. This score will then be standardized into a Z-score using the domain’s mean and 
standard deviation based on the 1998 general U.S. population (ie, norm). This Z-score is 
finally re-scaled to a scale score (or norm-based score) with mean of 50 and standard 
deviation of 10. The scale scores (ie, norm-based scores) of the 8 domains are used for 
analyses. These 8 domains are as follows:


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a.
Physical Functioning (PF).  This score is based on the responses to the 10 items that 
compose Question 3 and reflects the degree to which various physical activities have 
been limited in the previous week by the subject’s health.
b. Role-Physical (RP).  This score is based on the responses to the four items that 
compose Question 4 and reflects the relative amount of time that the subject has had 
problems with work or other regular daily activities as a result of their physical health 
during the previous week.
c.
Bodily Pain (BP).  This score is based on the responses to Questions 7 and 8 and 
reflects bodily pain and its effects on normal work during the previous week.
d. General Health (GH).  This score is based on responses to Question 1 and the four 
items in Question 11 and reflects the subject’s perception of their general health
during the previous week.
e.
Vitality (VT).  This score is based on responses to Question 9 items a, e and g, and 
reflects the subject’s physical energy level relative to time during the previous week.
f.
Social Functioning (SF).  This score is based on responses to Questions 6 and reflects 
how physical health or emotional problems have interfered with social activities 
during the previous week.
g. Role-Emotional (RE).  This score is based on responses to the three items in Question 
5 and reflects the amount of time during the previous week that emotional problems 
have interfered with work or regular daily activities.
h. Mental Health (MH).  This score is based on responses to Question 9 items b, c, d, f, 
and h and reflects various mental/emotional states relative to time during the previous 
week.
The summary component scores are:

Physical Component Summary (PCS).

Mental Component Summary (MCS).
In addition, there is another subscale in the SF-36: Health Transition (TR). This score is 
based on the response to Question 2 and is a rating of current general health compared to one
week previous.
The summary component summary (PCS, MCS) scores are based on a normalized sum of the 
8 scale scores (ie, norm-based scores): PF, RP, BP, GH, VT, SF, RE, and MH.  All domains 
and summary components are scored such that a higher score indicates a higher functioning 
or health level.


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VARIABLE
DERIVATION
SF-36 PF scale score
raw score = sum (items 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I,
3J)
PF = (raw score -10) * 5
PF_Z = (PF – 82.62455)/24.43176
PF scale score = (PF_Z*10) + 50
When calculating the raw score, if 5 or more of the items are non-missing
then replace any missing values as follows:
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores.
Otherwise, if less than 5 of the items are non-missing then PF scale score
is missing.
The response scale for each activity ranges from 1 to 3 where 1=limited a
lot, 2=limited a little, and 3=not limited at all.
A higher PF scale score indicates better physical functioning.
SF-36 RP scale score
raw score = sum (items 4A, 4B, 4C, and 4D)
RP = [(raw score -4)/16] * 100
RP_Z= (RP – 82.65109)/26.19282
RP scale score = (RP_Z * 10) + 50
When calculating the raw score, if 2 or more of the items are non-missing
then replace any missing values as follows:
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator.  Substitute the mean for any 
missing scores.
Otherwise, if less than 2 of the items are non-missing then RP scale score
is missing.
The response scale for each item ranges from 1 to 5 where 1=All of the 
time, 2=Most of the time, 3=Some of the time, 4=A little of the time, and 
5=None of the time. A higher RP scale score indicates better role-physical 
functioning.


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SF-36 BP scale score
raw score = sum (reversed item 7 and reversed item 8)
BP = (raw score -2) * 10
BP_Z = (BP – 73.86999)/24.00884
BP scale score = (BP_Z * 10) + 50
Reverse direction of Item 7 as follows if 
=1, set to 6
if =2, set to 5.4
if =3, set to 4.2
if =4, set to 3.1
if =5, set to 2.2
if =6, set to 1
Reverse direction of item 8 as follows:
if =1 and original value of item 7=1, set to 6
if =1 and original value of item 7>=2, set to 5 
if =2, set to 4
if =3, set to 3
if =4, set to 2
if =5, set to 1
If item 7 is answered and item 8 is missing, set 8 = reversed 7 as defined 
above. If 8 is answered and 7 is missing, set 7 as reverse item 8 as follows:
if =1, set to 6
if =2, set to 4.75 
if=3, set to 3.5 
if=4, set to 2.25
if=5, set to 1
If 1 or more questions were answered, calculate BP scale score as defined 
above. If neither question was answered then BP scale score is missing.
The scale for Question 7, amount of bodily pain, ranges from 1 to 6 where 
1=None, 2=Very mild, 3=mild, 4=Moderate, 5=Severe, and 6=Very 
severe. 
The scale for Question 8, the degree to which pain interfered with normal 
work, ranges from 1 to 5 where 1=Not at all, 2=A little bit, 3=Moderately, 
4=Quite a bit, and 5=Extremely. A higher BP scale score indicates lack of 
bodily pain.
SF-36 GH scale score
raw score = sum (reversed item 1, item 11A, reversed 11B,
11C and reversed 11D) 
GH = (raw score -5) * 5
GH_Z = (GH – 70.78372)/21.28902
GH scale score = (GH_Z * 10) + 50
Reverse direction of Item 1 as follows:
if =1, set to 5
if =2, set to 4.4
if =3, set to 3.4
if =4, set to 2
if =5, set to 1
Reverse direction of item 11B and 11D by subtracting score from 6.
When calculating the raw score, if 3 or more of the items are non-missing 
then replace any missing values as follows:


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Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores.
Otherwise, if less than 3 of the items are non-missing then GH scale score 
is missing.
Responses for Question 1, an assessment of self-perceived health status, 
range from 1 to 5 where 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 
5=Poor. 
Responses for the items in Question 11 range from 1 to 5 where 
1=Definitely true, 2=Mostly true, 3=Don’t know, 4=Mostly false, and 
5=Definitely false and reflect the subject’s perception of their relative 
health and expectations of their future health status.
A higher GH scale score indicates better general health perceptions.
SF-36 VT scale score
raw score = sum (reversed item 9a, reversed 9e, 9g and 9i)
VT = [(raw score -4)/16] * 100
VT_Z = (VT – 58.41968)/20.87823
VT scale score = (VT_Z * 10) + 50
Reverse direction of Items 9a and 9e by subtracting score from 6.
When calculating the raw score, if 2 or more of the items are non-missing 
then replace any missing values as follows:
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores.
Otherwise, if less than 2 of the items are non-missing then VT scale score 
is missing.
The scale for these items ranges from 1 to 5 where 1=All of the time, 
2=Most of the time, 3=Some of the time, 4=A little of the time, and 
5=None of the time. A higher VT scale score indicates more vitality.
SF-36 SF scale score
raw score = sum (reversed 6 and 10)
SF = [(raw score -2)/8] * 100
SF_Z = (SF – 85.11568) / 23.24464
SF scale score = (SF_Z * 10) + 50
Reverse direction of score for item 6 by subtracting score from 6.
When calculating the raw score, if 1 of the items is missing then substitute 
the missing score with the score on the non-missing item.  If both items 
are missing then SF scale score is missing.
Responses to Question 6, an assessment of the extent to which 
health/emotional problems interfered with social activities, range from 1 to 
5 where 1=Not at all, 2=Slightly, 3=Moderately, 4=Quite a bit, and 
5=Extremely. Responses to Question 10 reflect the amount of time that 
health/emotional problems interfered with social activities and range from 
1 to 5 where 1=All of the time, 2=Most of the time, 3=Some of the time, 
4=A little of the time, and 5=None of the time. A higher SF scale score 
indicates better social functioning.


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SF-36 RE scale score
raw score = sum (items 5A, 5B, and 5C)
RE = [(raw score -3) / 12] * 100
RE_Z = (RE – 87.50009) / 22.01216
RE scale score = (RE_Z * 10) + 50
When calculating the raw score, if 2 or more of the items are non-missing 
then replace any missing values as follows:
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores.
Otherwise, if less than 2 of the items are non-missing then RE scale score 
is missing.
Responses to the items in Question 5 range from 1 to 5 where 1=All of the 
time, 2=Most of the time, 3=Some of the time, 4=A little of the time, and 
5=None of the time. A higher RE scale score indicates better 
role-emotional functioning.
SF-36 MH scale score
raw score = sum (items 9B, 9C, reversed 9D, 9F and reversed 9H)
MH = (raw score - 5) * 5
MH_Z = (MH – 75.76034)/18.04746
MH scale score = (MH_Z * 10) + 50
Reverse direction of scores for 9D and 9H, by subtracting score from 6.
If 3 or more of the items are non-missing then replace any missing values 
as follows:
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores.
Otherwise, if less than 3 of the items are non-missing then MH scale score 
is missing.
The scale for these items ranges from 1 to 5 where 1=All of the time, 
2=Most of the time, 3=Some of the time, 4=A little of the time, and 
5=None of the time. A higher MH scale score indicates better mental 
health.


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SF-36 PCS score
PCS score includes the 8 scales for GH, PF,
RP, RE, SF, MH, BP, and VT.
PF1= (PF-82.62455)/24.43176; RP1=(RP-82.65109)/26.19282; 
BP1=(BP-73.86999)/24.00884; 
GH1 = (GH-70.78372)/21.28902; VT1= (VT-58.41968)/20.87823; 
SF1=(SF-85.11568)/23.24464; RE1= (RE-87.50009)/22.01216; 
MH1=(MH-75.76034)/18.04746;
Raw Score = ((GH1*.24954)+(PF1* .42402)+(RP1*.35119)
+ (RE1*-.19206)+(SF1*-.00753)+(MH1*-.22069)+(BP1*.31754)
+ (VT1*.02877))
PCS Summary Scale Score = (raw score *10) + 50
Raw Score is missing if one of the component scale scores is missing.
SF-36 MCS score
MCS score includes the 8 scales for GH,
PF, RP, RE, SF, MH, BP, and VT.
PF1= (PF-82.62455)/24.43176; RP1=(RP-82.65109)/26.19282; 
BP1=(BP-73.86999)/24.00884; 
GH1 = (GH-70.78372)/21.28902; VT1= (VT-58.41968)/20.87823; 
SF1=(SF-85.11568)/23.24464; RE1= (RE-87.50009)/22.01216; 
MH1=(MH-75.76034)/18.04746;
Raw Score =((GH1*-.01571)+(PF1*-.22999)+(RP1*-.12329)
+ (RE1*.43407)+(SF1*.26876)+(MH1*.48581)+(BP1*- 0.09731)
+ (VT1*.23534)) 
MCS Summary Scale Score = (raw score*10)+50
Raw score is missing if one of the component scale scores in missing.
9.2.8. EuroQol-5D Health Questionnaire – 3 Level Version (EQ-5D-3L)
There are 5 health dimensions on the EQ-5D-3L Health Questionnaire CRF page: Mobility, 
Self-care, Usual Activities, Pain/Discomfort and Anxiety/Depression.  Each dimension has 
three possible levels of response (no problem, some problems, and extreme problems).  If a 
subject reports no problem in a dimension, the score is coded as 1; if some problems, the 
score is coded as 2; and if extreme problems, the score is coded as 3. An ambiguous value 
such as when two boxes are checked, it will be treated as missing.
“Your own health state today” (EQ-VAS) records the subject’s self-rated health, a score 
ranging from 0 to 100 mm is recorded, with higher scores representing better health state 
today. The raw VAS data will need to be rescaled to a 100 mm scale prior to any calculation.
In addition, EQ-5D-3L Utility score based on United Kingdom (UK) sample in 1993 will be 
derived (Dolan, 1997; Szende, Oppe, and Delvin, 2007).17,18 The time trade-off (TTO) value 
set is used for scoring. The following table provides the scoring algorithm for a subject’s 
health state coded in 5 digits in the order of Mobility, Self-care, Usual Activities, 
Pain/Discomfort and Anxiety/Depression. If any dimension is coded as 1, nothing (ie, 0) will 
be subtracted. Therefore, if a subject has a health state of 11111, the Utility score will be


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1 (ie, maximum Utility score). An example of a health state of 21232 has Utility score of 
0.088, as illustrated below. If any of the 5 dimension scores is missing, the Utility score is 
set to missing.
UK TTO value set
Example: the value for health 
state 21232
Full health (11111)
1
Full health
= 1
At least one 2 or 3
- 0.081
Minus a constant
- 0.081
At least one 3
- 0.269
Minus a constant
- 0.269
Mobility = 2
- 0.069
Minus Mobility 
level 2
- 0.069
Mobility = 3
- 0.314
Self-care = 2
- 0.104
Minus Self-care 
level 1
- 0.000
Self-care = 3
- 0.214
Usual Activities = 2
- 0.036
Minus Usual 
Activities level 2
- 0.036
Usual Activities = 3
- 0.094
Pain/Discomfort = 2
- 0.123
Pain/Discomfort = 3
- 0.386
Minus 
Pain/Discomfort 
level 3
- 0.386
Anxiety/Depression = 2
- 0.071
Minus 
Anxiety/Depression 
level 2
- 0.071
Anxiety/Depression = 3
- 0.236
State 21232
= 0.088
9.2.9. Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F)
FACIT-F is a 13-item questionnaire (each item score ranges from 0 to 4).  There will be 
3 endpoints derived: FACIT-F total score, FACIT-F experience domain score and FACIT-F 
impact domain score (Cella et al., 2002; Cella, Lai, and Stone, 2011).19,20  FACIT-F total 
score (range 0-52) is calculated by summing the 13 items.  FACIT-F experience domain 
score (range 0-20) is calculated by summing 5 items of Q1 I feel fatigued, Q2 I feel weak all 
over, Q3 I feel listless (“washed out”), Q4 I feel tired and Q7 I have energy, while FACIT-F 
impact domain score (range 032) is calculated by summing the remaining 8 items.  Note that 
all the scores except for Q7 & Q8 should be reversed (ie, 0 →4, 1→3, 3→1, 4→0) prior to 


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summing for both the total score and the domain scores such that higher scores represent 
better functioning (ie- less fatigue).
All responses are added with equal weight to obtain the total score.  In cases where some 
answers are missing, a total score is prorated from the score of the answered items, so long as 
more than 50% of the items (ie, at least 7 of 13 for FACIT-F total score, at least 3 of 5 for 
FACIT-F experience domain score, and at least 5 of 8 for FACIT-F impact domain score) are 
answered.
9.2.10. Work Productivity and Activity Impairment Questionnaire: Spondyloarthritis
(WPAI)
The WPAI assesses work productivity and impairment (Reilly et al., 2010).21  It is a 6-item 
questionnaire used to assess the degree to which Ankylosing Spondylitis affected work 
productivity and regular activities over the past 7 days.  The questions are as follows: 
Q1 = currently employed;
Q2 = hours missed due to health problems;
Q3 = hours missed due to other reasons;
Q4 = hours actually worked;
Q5 = degree health affected productivity while working (0-10 scale, with higher numbers 
indicating less productivity);
Q6 = degree health affected regular activities (0-10 scale, with higher numbers indicating
greater impairment of regular activities).
Subscale scores that are calculated from these questions are: 

Percent work time missed due to health problem: Q2/(Q2+Q4) for those who were 
currently employed;

Percent impairment while working due to health problem: Q5/10 for those who were 
currently employed and actually worked in the past 7 days;

Percent overall work impairment due to health problem: Q2/(Q2+Q4)+[(1-
Q2/(Q2+Q4))×(Q5/10)] for those who were currently employed;

Percent activity impairment due to health problem: Q6/10 for all respondents.
Each subscale score is expressed as an impairment percentage (range: 0-100%) where higher 
numbers indicate greater impairment and less productivity.


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9.3. Tipping Point Analysis for Longitudinal Binary Data
A method to analyze the longitudinal data of a binary endpoint measured during the 
placebo-controlled period (eg, ASAS20 [or ASAS40] response rates at Weeks 2, 4, 8, 12 and 
16) under the MNAR assumption is called the tipping point analysis. This analysis is used as 
a supportive analysis for the primary endpoint of ASAS20 and the key secondary endpoint of 
ASAS40 both at Week 16. It assesses the robustness of the binary data to potential 
deviations from the MAR assumption for both tofacitinib 5 mg BID and placebo groups and 
it is based on multiple imputation (Yan, Lee and Li 2009; Ratitch, O’Kelly and Tosiello, 
2013).7,8
In this tipping point analysis, a single saturated generalized linear mixed effect model is used 
as the imputation model. The normal approximation of the difference in binomial 
proportions using the CMH method adjusting for prior treatment history at randomization 
("bDMARD-naïve" vs. "TNFi-IR or bDMARD Use [Non-IR]") (prior treatment history will 
be derived from the clinical database and used in the analysis, see Section 3.4.1) is used as 
the analysis model, which is the same as the method of analyzing binary endpoint at a single 
time point described in Section 5.2.1.1. This tipping point analysis will be implemented in 
the following steps.
Step 1: Specification of the imputation model. 
The generalized linear mixed effect model includes the fixed effects of treatment, visit
(discrete), treatment-by-visit interaction, prior treatment history at randomization 
("bDMARD-naïve" vs "TNFi-IR or bDMARD Use [Non-IR]"), and a latent subject-level 
random effect. The logit link is used to model the ASAS20 (or ASAS40) response rate as 
dependent variable for all visits. Estimation of the model parameters is performed under the
Bayesian framework using MCMC methods. Only the available on-drug data (see Appendix
Section 9.1) without imputation are included in this generalized linear mixed effect model to 
estimate the model parameters. If the binary response is denoted by ܻ௜for subject ݅, then the 
saturated generalized linear mixed effect model for two treatment groups and the five 
post-baseline visits is parameterized as:
݈݋݃݅ݐሺߨ௜ሻൌ݈݋݃݅ݐ൫ܲሺܻ௜ൌ1ሻ൯ൌߚ଴൅ߚௗ௢௦௘݀݋ݏ݁൅ߚ௧௜௠௘ଵݐ݅݉݁1 ൅ߚ௧௜௠௘ଶݐ݅݉݁2 ൅ߚ௧௜௠௘ଷݐ݅݉݁3 ൅
ߚ௧௜௠௘ସݐ݅݉݁4 ൅ߚ௜௡௧ଵ݀݋ݏ݁∗ݐ݅݉݁1 ൅ߚ௜௡௧ଶ݀݋ݏ݁∗ݐ݅݉݁2 ൅
ߚ௜௡௧ଷ݀݋ݏ݁∗ݐ݅݉݁3 ൅ߚ௜௡௧ସ݀݋ݏ݁∗ݐ݅݉݁4 ൅ߚ௦௧௥௔௧௔ݏݐݎܽݐܽ൅߶௜∙
In this model, using reference coding, ݀݋ݏ݁is a dummy variable representing treatment 
assignment. When it is 0, it represents the placebo group; 1 represents tofacitinib 5 mg BID. 
Similarly, ݐ݅݉݁1, ݐ݅݉݁2, ݐ݅݉݁3, and ݐ݅݉݁4 are dummy variables. When all of them are 0, it 
represents Week 2; ݐ݅݉݁1 ൌ1 and all others being 0 represent Week 4; ݐ݅݉݁2 ൌ1 and all 
others being 0 represent Week 8; ݐ݅݉݁3 ൌ1 and all others being 0 represent Week 12, and 
ݐ݅݉݁4 ൌ1 and all others being 0 represent Week 16. ݏݐݎܽݐܽis a dummy variable representing 
prior treatment history with two strata: "bDMARD-naïve" and "TNFi-IR or bDMARD Use 
(Non-IR)". When it is 0, it represents "bDMARD-naïve"; 1 represents "TNFi-IR or 
bDMARD Use (Non-IR)". Interaction terms between the treatment and time point are also 


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included in the model, leading to a saturated model. ߶௜’s represent the subject-specific 
random effects.
Step 2: Estimating the imputation model. 
Estimation of the model parameters is performed under the Bayesian framework using 
MCMC methods. All of the ߚ’s are the respective effect parameters and they are all assigned 
the same non-informative prior Normal distribution, ܰሺߤఉൌ0, ߪఉ
ଶൌ9ሻ.  The variance of 9 on 
the logit scale ensures this prior is non-informative on the probability scale over its support 
of [0, 1]. ߶௜’s are the subject-specific random effects and they are all assigned a common 
prior Normal distribution, ܰሺ0, ߪଶሻ. ߪଶis the common variance and it is further assigned a 
weakly informative Inverse-Gamma distribution with shape=1 and scale=1. In this prior 
distribution, the prior 90th percentile for ߪଶis approximately 9. 
Step 3: Imputation of missing response at Week 16.
A single imputation of missing ASAS20 (or ASAS40) response at Week 16 is performed 
based on the predictive distribution of the generalized linear mixed effect model. Inferences 
at earlier time points are not of interest, thus imputation of missing ASAS20 (or ASAS40) at 
earlier time points will not be performed. The following model parameters pertinent to the 
assessment of treatment difference at Week 16: ߚ଴
∗, ߚௗ௢௦௘
∗
, ߚ௧௜௠௘ସ
∗
, ߚ௜௡௧ସ
∗
, ߚ௦௧௥௔௧௔
∗
, and ߶௜
∗can be 
sampled from their posterior distributions. Multiply imputed datasets can be generated using 
multiple samples from the MCMC of these parameters. The number of imputations (R) is
specified as 100.
Step 4: MNAR parameter (ߜ) and predictive distribution.
For example, for a subject ݅randomized to tofacitinib 5 mg BID with prior treatment history 
of "TNFi-IR or bDMARD Use (Non-IR)" with missing ASAS20 (or ASAS40) response at 
Week 16, the probability of response of this subject ߨ௜
∗(derived from sampled parameters) is 
subtracted by a fixed MNAR quantity (favorable or unfavorable) of ߜሺെ1 ൏ߜ൏1ሻto become 
ߨ௜
௣,
ߨ௜
௣ൌߨ௜
∗െߜ
where ߨ௜
∗ൌ
ୣ୶୮ሺఉబ∗ାఉ೏೚ೞ೐
∗
ାఉ೟೔೘೐ర
∗
ାఉ೔೙೟ర
∗
ାఉೞ೟ೝೌ೟ೌ
∗
ାథ೔
∗ሻ
ଵାୣ୶୮ሺఉబ∗ାఉ೏೚ೞ೐
∗
ାఉ೟೔೘೐ర
∗
ାఉ೔೙೟ర
∗
ାఉೞ೟ೝೌ೟ೌ
∗
ାథ೔
∗ሻ. In the situation when ߨ௜
௣൏0, ߨ௜
௣will be set to 0; 
similarly when ߨ௜
௣൐1, ߨ௜
௣will be set to 1.  For a given ߜ, the missing ASAS20 (or ASAS40)
response at Week 16 for this subject in the tofacitinib 5mg BID group with prior treatment 
history of "TNFi-IR or bDMARD Use (Non-IR)" will be imputed based on Bernoulli model 
with the probability of ߨ௜
௣. This is similarly done for a subject in the placebo group. A series 
of fixed MNAR quantity ߜincluding 0 (ie, MAR) will be applied to both treatment groups.
The same series of ߜvalues is used for both treatment groups: 
-0.9, -0.7, -0.5, -0.3, -0.1, 0, 0.1, 0.3, 0.5, 0.7, 0.9. The ߜvalues may be adjusted as 
appropriate. The value of 0 represents MAR assumption, while positive values represent
unfavorable scenarios (ie, penalizing the subject’s probability of response) and negative 
values represent favorable scenarios. Once all subjects with missing ASAS20 (or ASAS40)


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responses at Week 16 are imputed, this step results in a single complete imputed data set for 
Week 16.
Step 5: Analysis of complete imputed data set.
Analysis of an imputed data set will produce an estimate as well as standard error of the 
treatment difference applying the normal approximation of the difference in binomial 
proportions using the CMH approach adjusting for prior treatment history at randomization 
("bDMARD-naïve" vs. "TNFi-IR or bDMARD Use [Non-IR]"). For a given value of 
MNAR quantity, this is repeated for R=100 times to generate R=100 complete imputed data 
sets and these R=100 sets of estimates are combined using the Rubin’s rules (Rubin, 1987).2
The analysis method is the same as that used for the primary analysis. 
Step 6: Assessment of tipping point 
Steps 4-5 can then be repeated for different values of MNAR quantities ߜto evaluate their
impact on the treatment difference for subjects with missing ASAS20 (or ASAS40)
responses at Week 16 between tofacitinib 5 mg BID and placebo. The specific 
implementation (ie, seed for random number generation, burn-in and thinning of the MCMC 
samples) of this tipping point analysis will be pre-specified in the statistical programming 
plan. Note that there is no need to repeat Steps 1-3 for different values of ߜ.
9.4. Definition and Use of Visit Windows in Reporting
For reporting purposes, the following visit windows will be used for efficacy, patient-
reported outcomes and safety display that show by scheduled visits. If two or more 
observations fall into the same visit window, the observation closest to the target day will be 
used in the analyses. If there is a tie, the later observation will be used. However, for a 
subject who discontinues from the study early prior to the Week 48 visit and who does not 
have an observation within the Week 48 visit window, if two or more observations fall in the 
same visit window (ie, a visit window prior to Week 48), then the latest observation (rather 
than the observation closest to the target day) within this visit window will be used in the 
analysis for that visit window.
The visit windows will be applied to on-drug data and on-study data separately (see 
Section 9.1).


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Table 5.
Visit Windowing
Visit Label
Target Daya
Window Definition
Screening
< Day 1
Baseline
Day 1
Last non-missing assessment on or before Day 1 and prior to first 
dose of investigational product (ie, tofacitinib or placebo)
Week 2
Day 15
Day 2 to Day 21
Week 4
Day 29
Day 22 to Day 42
Week 8
Day 57
Day 43 to Day 70
Week 12
Day 85
Day 71 to Day 98
Week 16c
Day 113
Day 99 to [Treatment Switch Dayb or Day 140, whichever is smaller]
Week 24
Day 169
[Treatment Switch Dayb+1 or Day 141, whichever is smaller] to 
Day 196
Week 32
Day 225
Day 197 to Day 252
Week 40
Day 281
Day 253 to Day 308
Week 48
Day 337
≥ Day 309
a.
Target day is equal to the target week×7 days + 1 day.
b.
Treatment switch day = day of the first dose of treatment switch at Week 16 (ie, treatment switch day = treatment 
switch date – date of the first dose +1), where treatment switch date is taken from the Oral Dosing CRF, as the start 
date in the first entry of the dosing log for the period of Week 16 to Week 24. 
c.
All the data collected on treatment switch day will be counted in ≤ Week 16 except for the AE data.  Any new 
treatment emergent AE occurred on the day of treatment switch will be counted in ≥ Week 24.
Note that the upper limit of the Week 16 visit window and the lower limit of the 
Week 24 visit window are defined uniquely for each of the subjects in the study regardless of 
which treatment group the subjects are randomized to, since per the study protocol, subjects 
randomized to the placebo → tofacitinib 5 mg BID treatment group will advance to the 
predetermined treatment (tofacitinib 5 mg BID) in a blinded fashion for the remainder of the 
study.  Further details for the Week 16/Week 24 visit windows are in order.
1. If treatment switch day falls between Day 99 and Day 140, then the upper limit of the 
Week 16 visit window is the smaller of treatment switch day or Day 140 and the 
lower limit of the Week 24 visit window is the smaller of treatment switch day+1 or 
Day 141;
2. If treatment switch day < 99, >140, or missing, then the upper limit of the Week 
16 visit window will be set to Day 140 and the lower limit of the Week 24 visit will 
be set to Day 141.


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Effects of Bullets 1 and 2 above are further illustrated as follows.
If treatment switch day is
Missing
<99
99-140
>140
Visit label
Week 16
Week 24
Week 16
Week 24
Week 16
Week 24
Week 16
Week 24
Day 
window
99 to 140
141-196
99 to 140
141-196
from
[99 to 99]
up to
[99 to 140]
from
[100 to 
196]
up to
[141 to 
196]
99 to 140
141-196
9.5. Range of Values for Continuous Efficacy Endpoints
The following table displays the unit, theoretical range of values, and the direction of 
improvement for each of the select continuous efficacy endpoints.
Table 6.
Numerical Characteristics of Select Continuous Efficacy Endpoints
Endpoint
Unit
Theoretical Range of 
Values
Direction of 
Improvement from 
Baseline
Patient Global Assessment of 
Disease
None
0-10
Decrease from 
Baseline 
Patient Assessment of Spinal Pain 
(Total Back Pain, Nocturnal Spinal 
Pain)
None
All: 0-10
Decrease from 
Baseline 
BASFI
None
0-10
Decrease from 
Baseline 
BASDAI 
None
0-10
Decrease from 
Baseline 
Inflammation Score (ie, Average of 
Q5 and Q6 of BASDAI)
None
0-10
Decrease from 
Baseline 
hsCRP
mg/L
≥0
Decrease from 
Baseline 
BASMI score and its 5 component 
scores (A, S) (A is the unmapped 
component score, S is the mapped 
component score [range 0-10] via 
linear method, see Section 9.2.3)
BASMI, 5 
components 
(S): None 
Lateral flexion, 
Tragus-to-wall
distance, 
lumbar flexion, 
and 
intermalleolar 
distance (A): 
cm
Cervical 
rotation angle 
(A): degree (°)
BASMI, 5 components 
(S): 0-10
5 components (A): ≥0
BASMI, 5 
components (S), 
Tragus-to-wall 
distance (A): 
Decrease from 
Baseline 
Lateral flexion, 
lumbar flexion, 
intermalleolar 
distance, and 
cervical rotation 
(A): Increase from 
Baseline.
Spinal Mobility – Chest Expansion
cm
≥0
Increase from 
Baseline (ie, higher 


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score represents 
more spinal 
mobility)
ASDASCRP
None
≥0
Decrease from 
Baseline 
MASES
None
0-13
Decrease from 
Baseline 
Swollen Joint Count (44)
None
0-44
Decrease from 
Baseline 
SF-36v2, 8 domain scale (ie, norm-
based), PCS, and MCS scores
None
All: Real values 
(Mean=50, SD=10)
Increase from 
Baseline 
EQ-5D-3L, 5 dimension scores 
None
All: 1, 2, 3
Decrease from 
Baseline 
EQ-VAS
mm
0-100
Increase from 
Baseline 
EQ-5D-3L, Utility Score (UK)
None
-0.594 - 1
Increase from 
Baseline
FACIT-F (Total, Impact domain, 
Experience domain scores)
None
Total: 0-52
Impact domain: 0-32
Experience domain: 0-20
Increase from 
Baseline (ie, higher 
score represents less 
fatigue)
ASQoL
None
0-18
Decrease from 
Baseline 
WPAI 4 subscale scores
%
All: 0-100
Decrease from 
Baseline 
AS-HCRU Self-Rating of Job 
Performance
None
0-10
Decrease from 
Baseline 
Abbreviations: % = percent; ASDASCRP = Ankylosing Spondylitis Disease Activity Score using C-Reactive 
Protein; AS-HCRU = Ankylosing Spondylitis – HealthCare Resource Utilization Questionnaire; 
ASQoL = Ankylosing Spondylitis Quality of Life; BASDAI = Bath Ankylosing Spondylitis Disease Activity 
Index; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMI = Bath Ankylosing Spondylitis 
Metrology Index; cm = centimeter; EQ-5D-3L = EuroQol Health State Profile – 5 Dimensions – 3 Levels; 
EQ-VAS = EuroQol Your own health state today-Visual Analog Scale; FACIT-F = Functional Assessment 
of Chronic Illness Therapy - Fatigue; hsCRP = high sensitivity C-Reactive Protein; MASES = Maastricht 
Ankylosing Spondylitis Enthesitis Score; 
MCS = mental component summary; mg/L = milligrams per liter; PCS = physical component summary; SD 
= standard deviation; SF-36v2 = 36-Item Short Form Survey Version 2 Acute; UK = United Kingdom; 
WPAI = Work Productivity & Activity Impairment. 


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9.6. Lists of DMARDs and NSAIDs
The following table enlists the generic names of biological DMARDs (bDMARDs) including 
both TNFi bDMARDs and non-TNFi bDMARDs, csDMARDs (also known as 
non-bDMARDs), and NSAIDs. This list is not an exhaustive list and additional terms may 
be present in the clinical database. 
Table 7.
List of DMARDs and NSAIDs
WHODrug Preferred Term
bDMARDs
csDMARDs1
NSAIDs
TNFi
Non-TNFi
ABATACEPT
x
ACECLOFENAC
x
ACEMETACIN
x
ADALIMUMAB2
x
ANAKINRA
x
APREMILAST3
x
AZATHIOPRINE
x
CELECOXIB
x
CERTOLIZUMAB2
x
CERTOLIZUMAB PEGOL2
x
CHLOROQUINE
x
CICLOSPORIN
x
DEXKETOPROFEN
x
DEXKETOPROFEN TRAMADOL
x
DEXKETOPROFEN TROMETAMOL
x
DICLOFENAC
x
DICLOFENAC DIETHYLAMINE
x
DICLOFENAC POTASSIUM
x
DICLOFENAC SODIUM
x
DICLOFENAC 
SODIUM/MISOPROSTOL
x
ETANERCEPT2
x
ETODOLAC
x
ETORICOXIB
x
FLURBIPROFEN
x
GOLIMUMAB2
x
GUSELKUMAB
x
HYDROXYCHLOROQUINE
x


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WHODrug Preferred Term
bDMARDs
csDMARDs1
NSAIDs
TNFi
Non-TNFi
HYDROXYCHLOROQUINE 
PHOSPHATE
x
IBUPROFEN
x
IBUPROFEN W/PARACETAMOL
x
INDOMETACIN
x
INFLIXIMAB2
x
IXEKIZUMAB
x
KETOPROFEN
x
KETOROLAC
x
LEFLUNOMIDE
x
LORNOXICAM
x
MELOXICAM
x
METHOTREXATE
x
METHOTREXATE SODIUM
.
x
NABUMETONE
x
NAPROXEN
x
NAPROXEN SODIUM
x
NIFLUMIC ACID
x
NIMESULIDE
x
PELUBIPROFEN
x
PHENYLBUTAZONE
x
PIROXICAM
x
PIROXICAM BETADEX
x
RITUXIMAB
x
ROFECOXIB
x
SALSALATE
x
SECUKINUMAB
x
SULFASALAZINE
x
SULINDAC
x
TALNIFLUMATE
x
TENOXICAM
x
TIAPROFENIC ACID
x
TOCILIZUMAB
x
USTEKINUMAB
x


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WHODrug Preferred Term
bDMARDs
csDMARDs1
NSAIDs
TNFi
Non-TNFi
Abbreviations: TNFi = tumor necrosis factor inhibitor; bDMARD = biological disease-modifying 
antirheumatic drug; csDMARD = conventional synthetic disease-modifying antirheumatic drug.
1.
csDMARD is also defined as non-biological DMARD (ie, non-bDMARD).
2.
TNFi approved for Ankylosing Spondylitis by the US FDA.
3.
Apremilast is a targeted synthetic DMARD (tsDMARD), but is considered as a csDMARD in the analysis. A 
footnote, “Apremilast is considered as a csDMARD”, will be added to any display where applicable.
9.7. Metabolic Syndrome and Diabetes Mellitus at Baseline
9.7.1. Criteria for Clinical Diagnosis of Metabolic Syndrome
Criteria for clinical diagnosis of the metabolic syndrome will be based on the 2009 Joint 
Statement Harmonizing the Metabolic Syndrome (Alberti et al., 2009).22  There are 
5 measures or risk factors as detailed in Table 1 of the 2009 Joint statement and excerpted 
below: 


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Any 3 abnormal findings out of the 5 measures will qualify a subject for the metabolic 
syndrome. A missing measure is considered as its criteria not satisfied and thus not counted 
as an abnormal finding. The baseline (ie, Day -1 per CaPS) value will be used in the 
derivation. If the Day -1 value is not available, a value prior to Day -1 will be used.

Any drug treatment taken on Day -1 recorded on the Prior and Concomitant
Medications – Anti-Diabetic Agents CRF will be considered having the drug 
treatment of elevated glucose criterion satisfied. 

Any drug treatment taken on Day -1 recorded on the Prior and Concomitant
Medications – Anti-Hypertension Agents CRF will be considered having the drug 
treatment of elevated blood pressure criterion satisfied.

Any drug treatment taken on Day -1 recorded on the Prior and Concomitant
Medications – Lipid Lowering Agents CRF will be considered having the drug 
treatment of elevated triglycerides criterion satisfied. 

For the HDL-C criterion, only the lab categorical cutpoints will be considered and 
drug treatment will not be considered. 

The waist circumference thresholds will be population and country specific per 
Table 2 of the 2009 Joint Statement excerpted below. Explicitly, the US specific 
threshold will be used for the subjects enrolled from US, the Canada threshold for the 
subjects enrolled from Canada, the European threshold for the subjects enrolled from 
Western Europe, Eastern Europe and Russia, the Asian (including Japanese) threshold 
for the subjects enrolled from Asia, and Ethnic Central and South American threshold 
for the subjects enrolled from Central and South America.


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9.7.2. Definition of Diabetes Mellitus at Baseline
A subject is considered having diabetes mellitus at baseline, if any of the conditions below is 
met. The baseline (ie, Day -1 per CaPS) value will be used in the derivation. If the 
Day -1 value is not available, a value prior to Day -1 will be used.

Subject had a diagnosis of diabetes mellitus recorded on the Cardiovascular Risk 
Factors CRF or on the General Medical History CRF at screening;

Subject received any drug treatment taken on Day -1 recorded on the Prior and 
Concomitant Medications – Anti-Diabetic Agents CRF;

Subject’s HbA1c ≥6.5% at baseline or, if HbA1c is not available, baseline fasting 
plasma glucose ≥126 mg/dL. 


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9.8. Summary of Efficacy Analyses
The following table provides a summary of all of the efficacy analyses to be performed for the comparison of treatments across visits.
Table 8.
Summary of Efficacy Analyses
Endpoint
Week 16
Estimand
Week 16
Analysis
Week 
16 or 48
Analysis 
Report
Visits to 
Report
Data
Inclusion
Analysis 
Set
Analysis 
Method
Adjustment to 
Stratification at 
Randomization 
Missing 
Data 
Handling
Treatment
Comparison
Endpoint 
Type
Interpretation
Section 
references
Section 2.1
Section 6
Section 5
Section 9.1
Section 
4
Section 5
Section 5
Section 5.3
Section 5.2
Section 5
1. ASAS20
(Primary 
endpoint at 
Week 16)
2. ASAS40 
(Key 
secondary 
endpoint at 
Week 16)
(Type I 
Error 
Controlled)
Estimand 1
(ASAS20: 
Primary 
Estimand; 
ASAS40: Key 
Secondary 
Estimand)
ASAS20: 
Primary 
analysis;
ASAS40:
Key 
Secondary 
analysis
Week 16
Weeks 2, 
4, 8, 12, 
16
On-drug 
data
FAS
CMH Normal 
Approximation
Stratified by prior 
treatment history as 
CMH stratification 
factor
MR=NR
Tofacitinib 5 
versus 
Placebo 
(Week 2 to 
Week 16)
Binary
ASAS20 at 
Week 16 
primary, 
ASAS40 at 
Week 16 Key 
secondary, all 
others 
secondary
Estimand 1
(ASAS20: 
Primary 
Estimand; 
ASAS40: Key 
Secondary 
Estimand)
ASAS20: 
Primary 
analysis;
ASAS40:
Key 
Secondary 
analysis
Week 48
Weeks 2, 
4, 8, 12, 
16, 24, 32, 
40, 48
On-drug 
data
FAS
CMH Normal 
Approximation
Stratified by prior 
treatment history as 
CMH stratification 
factor
MR=NR
1. Tofacitinib 
5 versus 
Placebo 
(Week 2 to 
Week 16)
2. Tofacitinib 
5 versus 
Placebo → 
Tofacitinib 5 
(After Week 
16)
Binary
Supportive for 
≤16 weeks and 
secondary for 
>16 weeks 
Estimand 2
Supportive 
analysis 1
Week 16
Weeks 2, 
4, 8, 12, 
16
On-study 
data
FAS
CMH Normal 
Approximation
Stratified by prior 
treatment history as 
CMH stratification 
factor
MR=NR
Tofacitinib 5 
versus 
Placebo 
(Week 2 to 
Week 16)
Binary
Supportive
Estimand 2
Supportive 
analysis 1
Week 48
Weeks 2, 
4, 8, 12, 
16, 24, 32, 
40, 48
On-study 
data
FAS
CMH Normal 
Approximation
Stratified by prior 
treatment history as 
CMH stratification 
factor
MR=NR
1. Tofacitinib 
5 versus 
Placebo 
(Week 2 to 
Week 16)
Binary
Supportive


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Endpoint
Week 16
Estimand
Week 16
Analysis
Week 
16 or 48
Analysis 
Report
Visits to 
Report
Data
Inclusion
Analysis 
Set
Analysis 
Method
Adjustment to 
Stratification at 
Randomization 
Missing 
Data 
Handling
Treatment
Comparison
Endpoint 
Type
Interpretation
2. Tofacitinib 
5 versus 
Placebo → 
Tofacitinib 5 
(After Week 
16)
Estimand 1
Supportive 
analysis 2
Week 16
Week 16
On-drug 
data
PP
CMH Normal 
Approximation
Stratified by prior 
treatment history as 
CMH stratification 
factor
MR=NR
Tofacitinib 5 
versus 
Placebo at 
Week 16
Binary
Supportive
Estimand 3
Supportive 
analysis 3
Week 16
Weeks 2, 
4, 8, 12, 
16
On-drug 
data
FAS
GMMRM
Stratification factor 
not used in model
No 
imputation
Tofacitinib 5 
versus 
Placebo 
(Week 2 to 
Week 16) 
reporting 
Odds Ratio
Binary
Supportive
NA
Supportive 
analysis 4
Week 16
Estimatio
n: Weeks 
2, 4, 8, 12, 
16;
Report: 
Week 16
On-drug 
data for 
both 
parameter 
estimation 
and 
multiple 
imputation
FAS
Tipping Point 
Analysis
Prior treatment 
history as a 
covariate in the 
saturated 
generalized linear 
mixed effect model 
(ie, imputation 
model). Stratified 
by prior treatment 
history as CMH 
stratification factor 
in the analysis 
model.
Only missing 
data at Week 
16 will be 
imputed 
using 
multiple 
imputation
Tofacitinib 5 
versus 
Placebo at 
Week 16 for 
different 
values of 
MNAR 
adjustment ߜ
Binary
Supportive
NA
Supportive 
analysis 5
Week 16
Estimatio
n: Weeks 
2, 4, 8, 12, 
16;
Report: 
Week 16
On-drug 
data for 
parameter 
estimation 
but on-
study data 
for multiple 
imputation
FAS
Tipping Point 
Analysis
Prior treatment 
history as a 
covariate in the 
saturated 
generalized linear 
mixed effect model 
(ie, imputation 
model). Stratified 
by prior treatment 
history as CMH 
stratification factor 
in the analysis 
model.
Only missing 
data at Week 
16 will be 
imputed 
using 
multiple 
imputation
Tofacitinib 5 
versus 
Placebo at 
Week 16 for 
different 
values of 
MNAR 
adjustment ߜ
Binary
Supportive


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Endpoint
Week 16
Estimand
Week 16
Analysis
Week 
16 or 48
Analysis 
Report
Visits to 
Report
Data
Inclusion
Analysis 
Set
Analysis 
Method
Adjustment to 
Stratification at 
Randomization 
Missing 
Data 
Handling
Treatment
Comparison
Endpoint 
Type
Interpretation
Estimand 1
Subgroup 
analysis of 
prior 
treatment 
history (2 
categories): 
"bDMARD-
naïve" and 
"TNFi-IR or 
bDMARD 
Use (Non-IR)"
Week 16
Weeks 2, 
4, 8, 12, 
16
On-drug 
data
FAS for 
each 
category 
of 
"bDMA
RD-
naïve" 
and 
"TNFi-
IR or 
bDMAR
D Use 
(Non-
IR)"
Normal 
Approximation
NA
MR=NR
Tofacitinib 5 
versus 
Placebo 
(Week 2 to 
Week 16)
Note: no p-
values
Binary
Supportive
Estimand 1
Subgroup 
analysis of 
prior 
treatment 
history (3 
categories): 
"bDMARD-
naïve", 
"TNFi-IR", 
and 
"bDMARD 
Use (Non-IR)"
Week 16
Weeks 2, 
4, 8, 12, 
16
On-drug 
data
FAS for 
each 
category 
of 
"bDMA
RD-
naïve", 
"TNFi-
IR", and 
"bDMA
RD Use 
(Non-
IR)"
Normal 
Approximation
NA
MR=NR
Tofacitinib 5 
versus 
Placebo 
(Week 2 to
Week 16)
Note: no p-
values
Binary
Supportive
Estimand 1
Other 
subgroup 
analyses
Week 16
Week 16 
only
On-drug 
data
FAS for 
each 
category 
of a 
subgrou
p 
variable
CMH Normal 
Approximation
Stratified by prior 
treatment history as 
CMH stratification 
factor
MR=NR
Tofacitinib 5 
versus 
Placebo at 
Week 16
Note: no p-
values
Binary
Supportive
Four ASAS 
components
:
1. ∆PGA
2. ∆Patient 
Assessment 
of Spinal 
Pain (Total 
Back Pain)
Estimand 4
Secondary 
analysis
Week 16
Weeks 2, 
4, 8, 12, 
16
On-drug 
data
FAS**
MMRM
MMRM*
No 
imputation
Tofacitinib 5 
versus 
Placebo 
(Week 2 to 
Week 16)
Continuou
s
Secondary
Estimand 4
Secondary 
analysis
Week 48
Weeks 2, 
4, 8, 12, 
16, 24, 32, 
40, 48
On-drug 
data
FAS**
MMRM
MMRM*
No 
imputation
1. Tofacitinib 
5 versus 
Placebo 
Continuou
s
Supportive for 
≤16 weeks and 
secondary for 
>16 weeks 


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Endpoint
Week 16
Estimand
Week 16
Analysis
Week 
16 or 48
Analysis 
Report
Visits to 
Report
Data
Inclusion
Analysis 
Set
Analysis 
Method
Adjustment to 
Stratification at 
Randomization 
Missing 
Data 
Handling
Treatment
Comparison
Endpoint 
Type
Interpretation
3. ∆BASFI
4. 
∆Inflammat
ion
(All 
secondary 
endpoints, 
Type I 
Error 
Controlled)
(Week 2 to 
Week 16)
2. Tofacitinib 
5 versus 
Placebo → 
Tofacitinib 5 
(After Week 
16)
Estimand 5
Supportive 
analysis 6
Week 16
Weeks 2, 
4, 8, 12, 
16
On-study 
data
FAS**
MMRM
MMRM*
No 
imputation
Tofacitinib 5 
versus 
Placebo 
(Week 2 to 
Week 16)
Continuou
s
Supportive 
1. ASAS 
5/6
2. ASAS 
partial 
remission
3. 
ASDASCRP
clinically 
important 
improveme
nt
4. 
ASDASCRP
major 
improveme
nt
5. 
ASDASCRP
inactive 
disease
6. 
BASDAI50
(All 
secondary 
endpoints)
Estimand 1
Secondary 
analysis
Week 16
Weeks 2, 
4, 8, 12, 
16
On-drug 
data
FAS/En
dpoint-
specific 
FAS 
CMH Normal 
Approximation
Stratified by prior 
treatment history as 
CMH stratification 
factor
MR=NR
Tofacitinib 5 
versus 
Placebo 
(Week 2 to 
Week 16)
Binary
Secondary
Estimand 1
Secondary 
analysis
Week 48
Weeks 2, 
4, 8, 12, 
16, 24, 32, 
40, 48
On-drug 
data
FAS/En
dpoint-
specific 
FAS
CMH Normal 
Approximation
Stratified by prior
treatment history as 
CMH stratification 
factor
MR=NR
1. Tofacitinib 
5 versus 
Placebo 
(Week 2 to 
Week 16)
2. Tofacitinib 
5 versus 
Placebo → 
Tofacitinib 5 
(After Week 
16)
Binary
Supportive for 
≤16 weeks and 
secondary for 
>16 weeks


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Endpoint
Week 16
Estimand
Week 16
Analysis
Week 
16 or 48
Analysis 
Report
Visits to 
Report
Data
Inclusion
Analysis 
Set
Analysis 
Method
Adjustment to 
Stratification at 
Randomization 
Missing 
Data 
Handling
Treatment
Comparison
Endpoint 
Type
Interpretation
1. 
∆ASDASCR
P
2. ∆hsCRP
3. ∆BASMI 
and ∆in 5 
components
4. ∆FACIT-
F (Total, 
Experience 
Domain, 
Impact 
Domain 
Scores)
5. 
∆BASDAI
6. ∆MASES
7. ∆Swollen 
Joint Count 
(44)
8. ∆Spinal 
Mobility -
Chest 
Expansion
9. ∆Patient 
Assessment 
of Spinal 
Pain 
(Nocturnal 
Spinal Pain)
(All 
secondary 
endpoints)
Estimand 4
Secondary 
analysis
Week 16
Weeks 2, 
4, 8, 12, 
16 (note: 
MASES 
has no 
Week 2)
On-drug 
data
FAS/En
dpoint-
specific 
FAS**
MMRM
MMRM*
No 
imputation
Tofacitinib 5 
versus 
Placebo 
(Week 2 to 
Week 16)
Continuou
s
Secondary
Estimand 4
Secondary 
analysis
Week 48
Weeks 2, 
4, 8, 12, 
16, 24, 32, 
40, 48
(note: 
MASES 
has no 
Week 2)
On-drug 
data
FAS/En
dpoint-
specific 
FAS**
MMRM
MMRM*
No 
imputation
1. Tofacitinib 
5 versus 
Placebo 
(Week 2 to 
Week 16)
2. Tofacitinib 
5 versus 
Placebo → 
Tofacitinib 5 
(After Week 
16)
Continuou
s
Supportive for 
≤16 weeks and 
secondary for 
>16 weeks
Estimand 5
(Only for the 
following 
four: 
∆ASDASCRP, 
∆hsCRP,
∆BASMI 
and 5 
components,
∆FACIT-F 
(Total, 
Experience 
Domain, 
Impact 
Domain 
Scores)
(Type I Error 
Controlled
except 
FACIT-F 
Impact,
Experience 
Domain 
Scores, and
BASMI 5 
components)
NA
Week 16
Weeks 2, 
4, 8, 12, 
16
On-study 
data
FAS/En
dpoint-
specific 
FAS**
MMRM
MMRM*
No 
imputation
Tofacitinib 5 
versus 
Placebo 
(Week 2 to 
Week 16)
Continuou
s
Supportive


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Endpoint
Week 16
Estimand
Week 16
Analysis
Week 
16 or 48
Analysis 
Report
Visits to 
Report
Data
Inclusion
Analysis 
Set
Analysis 
Method
Adjustment to 
Stratification at 
Randomization 
Missing 
Data 
Handling
Treatment
Comparison
Endpoint 
Type
Interpretation
1. ∆ASQoL 
2. ∆SF-
36v2 (PCS, 
MCS, 8 
domains, 
norm-
based)
3. ∆EQ-5D-
3L (5 
dimensions, 
EQ-VAS, 
Utility 
Score [UK])
4. ∆WPAI 
(4 subscale 
scores)
(All 
secondary 
endpoints)
Estimand 4
Secondary 
analysis
Week 16
Week 16
On-drug 
data
FAS**
ANCOVA
ANCOVA includes 
fixed effects of 
treatment, 
stratification factor 
(ie, prior treatment 
history) at 
randomization and 
baseline value
No 
imputation
Tofacitinib 5 
versus 
Placebo at 
Week 16
Continuou
s
Secondary
Estimand 4
Secondary 
analysis
Week 48
Weeks 16, 
48
On-drug 
data
FAS**
MMRM
MMRM*
No 
imputation
1. Tofacitinib 
5 versus 
Placebo at 
Week 16
2. Tofacitinib 
5 versus 
Placebo → 
Tofacitinib 5 
at Week 48
Continuou
s
Supportive for 
≤16 weeks and 
secondary for 
>16 weeks
Estimand 5
(Only for the 
following two: 
∆ASQoL,  
∆SF-36v2 
PCS, MCS, 8 
domains, 
norm-based) 
(Type I Error 
Controlled
except SF-
36v2 MCS 
and 8 domain 
scores)
NA
Week 16
Week 16
On-study 
data
FAS**
ANCOVA
ANCOVA includes 
fixed effects of 
treatment, 
stratification factor 
(ie, prior treatment 
history) at 
randomization and 
baseline value
No 
imputation
Tofacitinib 5 
versus 
Placebo at 
Week 16
Continuou
s
Supportive
1. ∆AS-
HCRU Self-
Rating of 
Job 
Performanc
e at Work
(Tertiary
/Explorator
y endpoint)
Estimand 4
Tertiary /
Exploratory
analysis
Week 16
Week 16
On-drug 
data
FAS**
ANCOVA
ANCOVA includes 
fixed effects of 
treatment, 
stratification factor 
(ie, prior treatment 
history) at 
randomization and 
baseline value
No 
imputation
Tofacitinib 5 
versus 
Placebo at 
Week 16
Continuou
s
Exploratory
Estimand 4
Tertiary /
Exploratory
analysis
Week 48
Weeks 16, 
48
On-drug 
data
FAS**
MMRM
MMRM*
No 
imputation
1. Tofacitinib 
5 versus 
Placebo at 
Week 16
Continuou
s
Supportive for 
≤16 weeks and 
exploratory for
>16 weeks


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Endpoint
Week 16
Estimand
Week 16
Analysis
Week 
16 or 48
Analysis 
Report
Visits to 
Report
Data
Inclusion
Analysis 
Set
Analysis 
Method
Adjustment to 
Stratification at 
Randomization 
Missing 
Data 
Handling
Treatment
Comparison
Endpoint 
Type
Interpretation
2. Tofacitinib 
5 versus 
Placebo → 
Tofacitinib 5 
at Week 48
For complete list of abbreviations used for this table, please see Section 9.9.
In all the analyses, stratification factor (ie, prior treatment history: "bDMARD-naïve" vs. "TNFi-IR or bDMARD Use [Non-IR]") at randomization will be derived from the 
clinical database (Section 3.4.1, Section 9.11).
*MMRM includes fixed effects of treatment, visit, treatment-by-visit interaction, stratification factor (ie, prior treatment history) at randomization, 
stratification-factor-by-visit interaction, baseline value, and baseline-value-by-visit interaction.
**Subjects are included in model if they have non-missing baseline values and at least one non-missing post-baseline value.


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9.9. Abbreviations Used in SAP
The following table lists out the abbreviations used in this SAP except some mathematical 
notations and formulae.
Table 9.
Abbreviations Used in SAP
Term or Abbreviation
Definition
Δ
Change from Baseline
AE
Adverse Event
ANCOVA
Analysis of Covariance
AR(1)
Autoregressive of order 1 type covariance structure
AS
Ankylosing Spondylitis
ASAS
Assessment of SpondyloArthritis International Society
ASAS20
Assessment of SpondyloArthritis International Society improvement 
(response) is defined as 20% improvement (decrease) from Baseline 
and 1 unit improvement (decrease) from Baseline in at least 
3 domains on a scale of 0-10 and no worsening from Baseline of 
20% and 1 unit in the remaining domain
ASAS40
Assessment of SpondyloArthritis International Society improvement 
(response) criteria are classified as 40% improvement (decrease) 
from Baseline and 2 units improvement (decrease) from Baseline in 
at least 3 domains on a scale of 0-10 and no worsening from Baseline 
at all in the remaining domain.
AS-HCRU
Ankylosing Spondylitis – HealthCare Resource Utilization 
Questionnaire
ASDASCRP
Ankylosing Spondylitis Disease Activity Score using C-Reactive 
Protein
ASQoL
Ankylosing Spondylitis Quality of Life
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASDAI50
Bath Ankylosing Spondylitis Disease Activity Index improvement 
(response) is defined as decrease from Baseline in BASDAI score 
≥50%
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
bDMARD
biological disease-modifying antirheumatic drug
BID
twice daily
BMI
Body Mass Index
BP
Bodily Pain
CaPS
CDISC and Pfizer Standards
CDISC
Clinical Data Interchange Standards Consortium
cm
centimeter
CMH
Cochran–Mantel–Haenszel
CP-690,550
Tofacitinib
CRF
Case Report Form
CSR
Clinical Study Report
CI
Confidence Interval
csDMARD
Conventional synthetic disease-modifying antirheumatic drug
CSH
Heterogeneous Compound Symmetry type covariance structure
DMARD
Disease-modifying antirheumatic drug
ECG
Electrocardiogram
EMA
European Medicines Agency
EQ-5D-3L
EuroQol Health State Profile – 5 Dimensions – 3 Levels


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EQ-VAS
EuroQol Your own health state today - Visual Analog Scale 
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FACS
Fluorescence-activated cell sorting
FAS
Full Analysis Set
GMMRM
Generalized Marginal Model for Repeated Measures
GLM
Generalized Linear Model
GH
General Health
hsCRP
High Sensitive C-reactive protein
HLA-B27
Human leukocyte antigen - B27
IBD
Inflammatory Bowel Disease
IR
Inadequate Response, Inadequate Responder
kg
kilogram
kg/m2
kilogram per meter squared
LLOQ
Lower limit of quantification
LSM
Least squares mean
Ln
Natural logarithm
MAR
Missing at random
MASES
Maastricht Ankylosing Spondylitis Enthesitis Score
MCAR
Missing completely at random
MCMC
Markov Chain Monte Carlo
MCS
Mental component summary
MedDRA
Medical Dictionary for Regulatory Activities
mg/L
milligram per liter
MH
Mental Health
MMRM
Mixed Model for Repeated Measures
MNAR
Missing not at random
MR=NR
Missing response as non-response
N
Number of subjects
NA
Not Applicable
NRS
Numerical Rating Scale
NSAID
Nonsteroidal anti-inflammatory drug
NSAID-IR
Inadequate response to nonsteroidal anti-inflammatory drug treatment
OR
Odds ratio
PBO
Placebo
PCS
Physical component summary
PF
Physical Functioning
PGA
Patient Global Assessment of Disease
PRO
Patient-reported outcome
PP
Per Protocol
PT
Preferred Term
RP
Role-Physical
RE
Role-Emotional
SAFETY
Safety Analysis Set
SAP
Statistical analysis plan
SD
Standard deviation
SE
Standard error
SF
Social Functioning
SF-36v2
36-Item Short-Form Health Survey Version 2 Acute
SI
Sacroiliac
SJC
Swollen Joint Count
TMF
Trial Master File
TNF
Tumor necrosis factor


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9.10. Definition of NSAID-Inadequate Response (NSAID-IR)
For prior use of a given NSAID, the criterion of an inadequate response (NSAID-IR) can be 
satisfied in any one of the following three possible conditions:
1. Discontinued due to adverse event or intolerability: NSAID was taken and was 
discontinued due to adverse event prior to Day 1 of the study. This will be checked 
using Prior and Concomitant Medications NSAID CRF page where the start date and 
end date were before Day 1 of the study and "Adverse Event" was checked under 
Reason for Discontinuation;
2. Discontinued due to lack of efficacy: NSAID was taken and was discontinued due to 
lack of efficacy prior to Day 1 of the study with at least a 4-week (ie, 28 days) trial 
prior to discontinuation. This will be checked using Prior and Concomitant 
Medications NSAID CRF page where the start date and end date were before Day 1 
of the study, the NSAID treatment duration met the minimum duration: end date -
start date + 1 ≥28 days, and "Lack of Efficacy" was checked under Reason for 
Discontinuation; or
3. Ongoing but with lack of efficacy: NSAID was taken and was ongoing through Day 1 
of the study with at least a 4-week (ie, 28 days) trial prior to Day 1 of the study, with 
active AS at Screening and Day 1 (ie, Baseline). This will be checked using (a) Prior 
and Concomitant Medications NSAID CRF page where the start date was before Day 
1, the "Ongoing?" box was checked Yes, the NSAID treatment duration met the 
minimum duration: date of first dose of the study (ie Day 1) - start date + 1 ≥28 days, 
(b) the date of diagnosis of Ankylosing Spondylitis was present on the Primary 
Diagnosis CRF page at Screening visit, and (c) BASDAI score of ≥4 and back pain 
score (BASDAI question 2) of ≥4 at both Screening and Baseline (ie Day 1) visits on 
the BASDAI CRF page.
Multiple occurrences of the above three conditions for the same NSAID whether in different 
doses or different dosing frequency are counted as only one unique NSAID-IR.  Based on all 
NSAIDs entered into the Prior and Concomitant Medications NSAID CRF page, the Primary 
Diagnosis CRF page (for condition 3), and the BASDAI CRF page (for condition 3) for each 
TNFi
Tumor necrosis factor inhibitor
TNFi-IR
Inadequate response to tumor necrosis factor inhibitor treatment
Tofa
Tofacitinib
TR
Health Transition
tsDMARD
targeted synthetic disease-modifying antirheumatic drug
TTO
Time Trade-Off
UK
United Kingdom
VT
Vitality
WPAI
Work Productivity & Activity Impairment
vs.
versus
WHO-Drug
International classification of medicines created by World Health 
Organization Programme for International Drug Monitoring
z0.975
97.5th percentile of the standard normal distribution


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subject, the number of NSAIDs-IR per this subject will be counted. A subject has to meet at 
least 2 NSAIDs-IR to enroll.
9.11. Derivation of the Stratification Factor
The stratification factor will be derived from the Prior and Concomitant Medications 
DMARD CRF page, and specifically from the biologic DMARD (bDMARD) subcategory.
Each of the strata will be derived as follows.
1. bDMARD-naïve: subjects who had no prior exposure to any bDMARD prior to 
Day 1 of the study. This will be checked using the DMARD CRF page where 
subjects should have no entry on the bDMARD subcategory.
2. TNFi-IR: subjects who had inadequate response to one or at most two different TNFi 
therapies. For prior use of a given TNFi, an inadequate response is defined in one of 
the following two possible conditions:
a.
Discontinued due to adverse event or intolerability: TNFi was taken and was 
discontinued due to adverse event prior to Day 1 of the study. This will be 
checked using the Prior and Concomitant Medications DMARD CRF page 
(bDMARD subcategory) where the start date and end date were before Day 1 of 
the study and "Adverse Event" was checked under Reason for Discontinuation; or
b. Discontinued due to lack of efficacy: TNFi was taken and was discontinued due 
to lack of efficacy prior to Day 1 of the study. This will be checked using the 
Prior and Concomitant Medications DMARD CRF page (bDMARD subcategory)
where the start date and end date were before Day 1 of the study and "Lack of 
Efficacy" was checked under Reason for Discontinuation.
3. bDMARD Use (Non-IR): subjects who had prior exposure to any bDMARD (TNFi or 
non-TNFi bDMARD) prior to Day 1 of the study documented on the DMARD CRF 
page (bDMARD subcategory). 
Subjects in (1) above are grouped to the "bDMARD-naïve" stratum and subjects in (2) and 
(3) are grouped to the "TNFi-IR or bDMARD Use (Non-IR)" stratum.
Any subjects with three or more TNFi-IR or with non-TNFi bDMARD-IR due to protocol 
deviation will be included in the stratum of "TNFi-IR or bDMARD Use (Non-IR)" for 
analysis purpose.