EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS OF TOFACITINIB FOR TREATMENT OF SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (SJIA) WITH ACTIVE SYSTEMIC FEATURES IN CHILDREN AND ADOLESCENT SUBJECTS
Phase: PHASE3
Conditions: Arthritis Juvenile Idiopathic
Sponsor: Pfizer

Tofacitinib 
A3921165 
Final Protocol Amendment 8,  01 September 2023 
 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS OF 
TOFACITINIB FOR TREATMENT OF SYSTEMIC JUVENILE IDIOPATHIC 
ARTHRITIS (sJIA) WITH ACTIVE SYSTEMIC FEATURES IN CHILDREN AND 
ADOLESCENT SUBJECTS 
 
Compound: 
CP-690,550 
Compound Name: 
Tofacitinib 
United States (US) Investigational New 
Drug (IND) Number: 
117400 
European Clinical Trials Database 
(EudraCT) Number: 
2017-002018-29 
Protocol Number: 
A3921165 
Phase: 
3 
 
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, 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 
Amendment 8 
01 September 2023 
Amendment 7 
22 August 2022 
Amendment 6 
09 February 2022 
Amendment 5  
21 July 2021 
Amendment 4  
17 March 2021 
Amendment 3 
04 May 2020 
Amendment 2  
16 May 2019 
Amendment 1 
14 December 2018 
Original protocol 
15 March 2017 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), and any protocol administration change letters(s).   
Protocol Amendment Summary of Changes Table 
Amendment 8 (01 September 2023) 
Overall rationale for the amendment: This global amendment incorporates measures to 
further facilitate the interpretation of trial results. This includes a modification to the 
statistical analysis. Additionally, editorial and typographic changes have been made to clarify 
the wording without changing the intent.   
Section # and Name 
Description of Change 
Brief Rationale 
SUBSTANTIAL CHANGES 
 
Protocol Summary 
Statistical analysis 
Deleted text relating to number of 
flares required for analysis. 
Deleted as there will be 
potentially 2 planned 
analyses at least 20 
flares and approximately 
40 flares. 
Protocol Summary 
Statistical analysis 
 
10. Data Analysis/ 
Statistical Methods 
Power Analysis 
The statistical design of the study 
is modified to allow for 2 planned 
analyses.  The first analysis will be 
performed after at least 20 subjects 
have reported flare in the double-
blind phase (approximately 50% of 
the total flares expected).  The 
purpose of this analysis is to allow 
early stopping of the study for 
efficacy or futility, and to assess 
safety of tofacitinib. The final 
analysis will be performed after 
Describe the current 
planned analyses. 
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Section # and Name 
Description of Change 
Brief Rationale 
flares have been reported in 
approximately 40 subjects. 
 
NON-SUBSTANTIAL CHANGES 
 
Protocol Summary 
Study Design 
 
3. Study Design 
3.1. Overview 
 
Figure 2. Study Design 
 
3. Study Design 
3.3. Randomized 
Withdrawal Phase 
 
6.7. Double Blind 
Withdrawal Phase 
Removed the specific number of 
flares in the protocol body and 
referenced the Data 
Analysis/Statistical Methods 
section. 
The statistical analysis 
section describes the 
analysis plan how the 
number of flares relate 
to the end of the study. 
Protocol Summary 
Study Design 
Clarified that subjects who achieve 
ACR clinical remission will be 
considered completers in the study. 
 
 
Clarification 
Schedule of Activities 
Footnote 7 
 
4. Subject Selection 
4.1. Inclusion criteria 
4. Bullet #1 
Allow for local QuantiFERON-TB 
testing to be performed. 
 
 
Local laboratories now 
have the capability to 
perform this test. 
3. Study Design 
3.1. Overview 
Clarified that the Centralized 
Coordinating Centers will be 
blinded to study drug assignment in 
the double-blind withdrawal phase 
of the study. 
Clarification 
 
 
10. Data Analysis/ 
Statistical Methods 
10.1. Sample Size 
Determination 
Subjects who discontinue in the 
double-blind withdrawal phase due 
to clinical remission are considered 
as completers. 
  
Clarify the difference 
for analysis purposes of 
subjects who 
discontinue versus those 
that complete the study. 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
4. Subject Selection 
4.1. Inclusion criteria 
4. Bullet #1 
Added: A negative 
QuantiFERON®-TB test performed 
locally or  
Allow local lab to 
conduct a 
QuantiFERON®-TB test 
. 
6.7. Double Blind 
Withdrawal Phase 
Deleted referenced to 31 flares and 
added: until the requisite number of 
flares have been reported (refer to 
Section 10) and the study is 
considered completed. 
To align with the 
revised statistical plan. 
10. Data Analysis/ 
Statistical Methods 
10.1. Sample Size 
Determination 
Revised last paragraph: 
Subjects who discontinue 
Investigational Product in the 
double-blind phase of the study due 
to any reason will be counted as 
having an sJIA flare in the primary 
analysis for the primary endpoint 
of the study and will contribute to 
the requisite number of subjects 
with flare for the study to be 
considered complete.  Subjects 
who achieve clinical remission 
during the double blind withdrawal 
phase are completers of the study 
and will not be counted as having 
an sJIA flare in the primary 
analysis.   
Clarifying text to 
identify subjects who 
discontinue in the 
double-blind withdrawal 
phase due to clinical 
remission as completers. 
 
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TABLE OF CONTENTS 
LIST OF TABLES ...................................................................................................................11 
LIST OF FIGURES .................................................................................................................11 
APPENDICES .........................................................................................................................11 
PROTOCOL SUMMARY .......................................................................................................12 
SCHEDULE OF ACTIVITIES................................................................................................19 
1. INTRODUCTION ...............................................................................................................25 
1.1. Indication .................................................................................................................25 
1.2. Background .............................................................................................................25 
1.2.1. Tofacitinib ...................................................................................................25 
1.2.2. Systemic JIA and the Role of Inflammatory Cytokines .............................25 
1.2.3. Study Rationale ...........................................................................................26 
1.2.4. Dose Rationale ............................................................................................27 
1.3. Single Reference Safety Document .........................................................................27 
2. STUDY OBJECTIVES AND ENDPOINTS .......................................................................28 
2.1. Objectives ................................................................................................................28 
2.1.1. Primary .......................................................................................................28 
2.1.2. Secondary ...................................................................................................28 
2.1.3. Exploratory Objective .................................................................................28 
2.2. Endpoints .................................................................................................................29 
2.2.1. Primary .......................................................................................................29 
2.2.2. Secondary Efficacy Endpoints ....................................................................29 
2.2.3. Exploratory .................................................................................................30 
2.2.4. Safety Endpoints .........................................................................................30 
2.2.5. Pharmacokinetic Endpoints ........................................................................30 
2.3. Benefit/Risk Assessment .........................................................................................30 
2.3.1. Risk Assessment .........................................................................................30 
2.3.2. Benefit Assessment .....................................................................................31 
Adults with Rheumatoid Arthritis ..................................................................................32 
Pediatric Patients with Juvenile Idiopathic Arthritis ......................................................32 
2.3.3. Overall Benefit/Risk Conclusion ................................................................33 
3. STUDY DESIGN.................................................................................................................33 
3.1. Overview .................................................................................................................33 
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3.2. Open-label Phase: Variable Duration of 12 to 40 Weeks .......................................36 
3.2.1. Open-label Phase, Part 1: Treatment with Tofacitinib while on Stable 
Background Therapy ........................................................................................36 
3.2.2. Open-label Phase, Part 2: Treatment with Tofacitinib while Tapering 
Corticosteroids .................................................................................................37 
3.2.2.1. Mandatory CS Tapering before Randomization .......................37 
3.2.2.2. Two Corticosteroid Tapering Failures are Allowed ..................38 
3.2.2.3. Optional Further CS Tapering before Randomization ..............39 
3.3. Randomized Withdrawal Phase ..............................................................................39 
3.4. Sequential Evaluation of Tofacitinib 5 mg BID Dose in Cohorts in Part 1 ............40 
3.4.1. Evaluation of 5 mg BID or Equivalent Weight-based Lower Dose ...........41 
3.4.1.1. Cohort 1 .....................................................................................41 
3.4.1.2. Cohort 2 .....................................................................................42 
3.4.1.3. Open Enrollment at the 5 mg BID Dose Level .........................42 
4. SUBJECT SELECTION ......................................................................................................42 
4.1. Inclusion Criteria .....................................................................................................42 
4.2. Exclusion Criteria ....................................................................................................44 
4.3. Randomization Criteria ...........................................................................................47 
4.4. Lifestyle Guidelines ................................................................................................47 
4.4.1. Contraception ..............................................................................................47 
4.5. Vaccine and Exposure to Infections Guidelines......................................................49 
4.5.1. Subject Specific Recommendations ...........................................................49 
4.5.2. Guidance Regarding Household Contact Vaccine-Related Exposure ........49 
4.6. Non-Pharmacologic Interventions ...........................................................................50 
4.7. Elective Surgery ......................................................................................................50 
4.8. Dietary Supplements ...............................................................................................50 
4.9. Sponsor’s Qualified Medical Personnel ..................................................................50 
5. STUDY TREATMENTS .....................................................................................................51 
5.1. Allocation to Treatment ..........................................................................................51 
5.1.1. Open-Label Phase .......................................................................................52 
5.1.1.1. Enrollment in 5 mg BID Cohort ................................................52 
5.1.1.2. Open Enrollment at the 5 mg BID Dose Level .........................52 
5.1.1.3. Double-Blind Phase ...................................................................52 
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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 .........................................................................................................53 
5.6. Investigational Product Storage ..............................................................................54 
5.7. Investigational Product Accountability ...................................................................55 
5.7.1. Destruction of Investigational Product Supplies ........................................55 
5.8. Concomitant Treatment(s) .......................................................................................55 
5.8.1. Allowed sJIA Background Therapy ...........................................................55 
5.8.1.1. Corticosteroids (CSs) ................................................................56 
5.8.1.2. Disease Modifying Anti-Rheumatic Drugs (DMARDs) ...........56 
5.8.1.3. Treatment for Latent Tuberculosis ............................................57 
5.8.2. Prohibited Concomitant Medication ...........................................................57 
5.9. Rescue Therapy .......................................................................................................58 
6. STUDY PROCEDURES .....................................................................................................58 
6.1. Screening Visit ........................................................................................................58 
6.2. Open-label Phase/Part 1: Day 1 Visit ......................................................................60 
6.3. Open-Label Phase/Part 1: Day 3, Day 7 and Day 14 Visit .....................................62 
6.4. Open-label Phase/Part 1: Visits Every 4 Weeks from Week 8 up to Week 16 .......64 
6.5. Open-label Phase/Part 2: CS Tapering: Visits Every 4 Weeks after Start of 
Part 2 ..........................................................................................................................67 
6.6. Randomization Visit: Start Double-blind Withdrawal Phase .................................69 
6.7. Double-blind Withdrawal Phase: Visits Every 4 Weeks after Randomization 
Visit ...........................................................................................................................71 
6.7.1. Discontinuation from Investigational Product during Randomized 
Withdrawal Phase ............................................................................................74 
6.8. End of Study or Early Termination Visit ................................................................74 
6.9. Follow-Up Visit (Only For Subjects Not Entering Study A3921145) ....................77 
6.10. Unscheduled Study Visit or Telephone Contact ...................................................79 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...........................................................................81 
7.1. Discontinuation of Study Intervention ....................................................................81 
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7.2. Subject Withdrawal from Study ..............................................................................82 
7.2.1. Lost to Follow-Up.......................................................................................82 
7.2.2. Withdrawal of Consent ...............................................................................82 
8. ASSESSMENTS ..................................................................................................................83 
8.1. Efficacy Assessments ..............................................................................................83 
8.1.1. Number of Joints with Active Arthritis/Limitation of Motion ...................83 
8.1.2. Fever and Absence of Fever Assessment ...................................................84 
8.1.3. Physician’s Global Assessment of Overall Disease Activity .....................84 
8.1.4. Childhood Health Assessment Questionnaire (CHAQ) .............................85 
8.1.5. Child Health Questionnaire (CHQ) ............................................................86 
8.1.6. Inflammatory, Rheumatic Disease and MAS Markers ...............................86 
8.1.6.1. C-Reactive Protein (CRP) .........................................................87 
8.1.6.2. Erythrocyte Sedimentation Rate (ESR) .....................................87 
8.1.6.3. Other Inflammatory and Rheumatic Disease Markers ..............87 
8.1.6.4. Macrophage Activation Syndrome (MAS) Markers .................87 
8.1.7. Adapted ACR 30 Pediatric Criteria: JIA Core Set Variables and 
Response ..........................................................................................................87 
8.1.8. Disease Flare Criteria .................................................................................88 
8.1.9. JIA ACR Clinical Inactive Disease and Clinical Remission Criteria .........89 
8.1.10. Juvenile Arthritis Disease Activity (JADAS-27 CRP; JADAS-27 
ESR) Score .......................................................................................................89 
8.1.11. JADAS-27 Minimal Disease Activity and Inactive Disease ....................90 
8.1.12. Centralized Coordinating Center ..............................................................90 
8.2. Safety Assessments .................................................................................................91 
8.2.1. Medical and Family History .......................................................................92 
8.2.2. Physical Examination .................................................................................92 
8.2.3. Macrophage Activation Syndrome Assessment (MAS) .............................92 
8.2.4. Uveitis Assessment .....................................................................................93 
8.2.5. Vitals Signs Assessment .............................................................................93 
8.2.6. Varicella (chickenpox) and Herpes Zoster (shingles) Assessment and 
Guidance ..........................................................................................................94 
8.2.7. Pubertal Development Assessment (Tanner Stages) ..................................95 
8.2.8. Tuberculosis Testing ...................................................................................95 
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8.2.8.1. QuantiFERON®-TB Gold or Gold Plus In-Tube Test ..............96 
8.2.8.2. Purified Protein Derivative (PPD) Test or T-Spot TB Test ......96 
8.2.9. Laboratory Testing ......................................................................................96 
8.2.10. Pregnancy Testing ....................................................................................98 
8.2.11. Contraceptive Check .................................................................................99 
8.2.12. Blood Volume ...........................................................................................99 
8.2.13. Risk Factor Check for Venous Thromboembolism ................................101 
8.2.14. Temporary Withholding of Study Drug .................................................101 
8.3. Monitoring Hematology and Serum Laboratory Parameters and specific 
adverse events ..........................................................................................................102 
8.3.1. Monitoring Criteria ...................................................................................102 
8.3.2. Discontinuation of Study Drug Criteria ....................................................103 
8.4. Pharmacokinetic Assessment ................................................................................104 
8.4.1. PK Blood Sample Collection Time ..........................................................104 
8.4.2. Blood Sample Processing .........................................................................106 
8.4.3. PK Sample Shipment ................................................................................106 
8.5. Banked Biospecimens ...........................................................................................106 
8.5.1. Markers of Drug Response .......................................................................106 
8.5.2. Additional Research ..................................................................................108 
9. ADVERSE EVENT REPORTING....................................................................................108 
9.1. Adverse Events ......................................................................................................108 
9.2. Time Period and Frequency for collecting AE and SAE Information ..................108 
9.3. Definition of an Adverse Event .............................................................................109 
9.4. Medication Errors ..................................................................................................110 
9.4.1. Tofacitinib Overdose ................................................................................110 
9.5. Infections ...............................................................................................................111 
9.5.1. Serious Infections .....................................................................................111 
9.5.2. Treated Infections .....................................................................................111 
9.6. Abnormal Test Findings ........................................................................................111 
9.7. Serious Adverse Events .........................................................................................111 
9.7.1. Protocol-Specified Serious Adverse Events .............................................112 
9.7.2. Potential Cases of Drug-Induced Liver Injury ..........................................112 
9.8. Hospitalization ......................................................................................................113 
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9.9. Severity Assessment ..............................................................................................114 
9.10. Causality Assessment ..........................................................................................114 
9.11. Exposure During Pregnancy ................................................................................115 
9.12. Occupational Exposure .......................................................................................116 
9.13. Withdrawal Due to Adverse Events ....................................................................116 
9.14. Eliciting Adverse Event Information ..................................................................117 
9.15. Reporting Requirements ......................................................................................117 
9.15.1. Serious Adverse Event Reporting Requirements ...................................117 
9.15.2. Nonserious Adverse Event Reporting Requirements .............................117 
9.15.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............117 
10. DATA ANALYSIS/STATISTICAL METHODS ...........................................................118 
10.1. Sample Size Determination .................................................................................118 
10.1.1. Power Analysis .......................................................................................118 
10.2. Efficacy Analysis ................................................................................................120 
10.2.1. Analysis of Primary Endpoint ................................................................120 
10.2.2. Analysis of Secondary Endpoints ...........................................................120 
10.3. Guidance to Open Enrollment following Cohort Review ...................................121 
10.4. Population Pharmacokinetics and Exposure-Response Analyses .......................122 
10.5. Safety Analysis ....................................................................................................123 
10.6. Interim Analysis ..................................................................................................123 
10.7. Data Safety Monitoring Board (DSMB) .............................................................123 
10.8. Steering Committee .............................................................................................124 
10.9. Safety Endpoint Adjudication Committee ..........................................................124 
11. QUALITY CONTROL AND QUALITY ASSURANCE ...............................................124 
12. DATA HANDLING AND RECORD KEEPING ...........................................................125 
12.1. Case Report Forms/Electronic Data Record .......................................................125 
12.2. Record Retention .................................................................................................126 
12.3. Data Protection ....................................................................................................126 
13. ETHICS............................................................................................................................127 
13.1. Regulatory and Ethical Considerations ...............................................................127 
13.2. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................127 
13.3. Subject Information and Consent ........................................................................128 
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13.4 Subject Recruitment .............................................................................................129 
13.5 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................129 
14. DEFINITION OF END OF TRIAL .................................................................................129 
14.1. End of Trial in a Member State ...........................................................................129 
14.2. End of Trial in All Other Participating Countries ...............................................130 
15. SPONSOR DISCONTINUATION CRITERIA ..............................................................130 
16. PUBLICATION OF STUDY RESULTS ........................................................................130 
16.1. Communication of Results by Pfizer ..................................................................130 
16.2. Publications by Investigators ..............................................................................131 
17. REFERENCES ................................................................................................................132 
 
LIST OF TABLES 
Table 1. 
Mandatory Corticosteroid Tapering Required Before 
Randomization ..........................................................................................38 
Table 2. 
Optional Corticosteroid Tapering if Dose ≤0.2 mg/kg/day ......................39 
Table 3. 
Study Treatment Dosing and Administration ...........................................54 
Table 4. 
DMARDs – Required Washout Period Prior to Day 1 of Study 
Drug ..........................................................................................................57 
Table 5. 
Maximum Blood Volume Collection at Each Study Visit .......................99 
Table 6. 
95% Confidence Intervals for Adapted JIA ACR 30 Response in 
Open Label Cohorts ................................................................................122 
 
LIST OF FIGURES 
Figure 1. 
Study Design .............................................................................................16 
Figure 2. 
Study Design .............................................................................................35 
Figure 3. 
Tofacitinib Evaluation Schema .................................................................41 
 
 
APPENDICES 
Appendix 1. Allowed and Disallowed DMARDs..................................................................135 
Appendix 2. Approximate Equivalent Morphine Doses of Opioid Analgesics .....................137 
Appendix 3. Permitted Adjustments in sJIA Therapies .........................................................138 
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Appendix 4. Estimated Glomerular Filtration Rate Calculation and Creatinine 
Clearance Calculation .............................................................................139 
Appendix 5. Prohibited Concomitant Medications ................................................................140 
Appendix 6. Rescue Therapy .................................................................................................141 
Appendix 7. Guidelines For Safety Monitoring And Discontinuations ................................142 
Appendix 8. List of Abbreviations.........................................................................................144 
Appendix 9. The Degree of Burden and the Risk Threshold Assessment required at 
each visit. [article 40 (4) No. 4 of the German Medicines Act] .............147 
Appendix 10. Temporary Measures for Study Visits Occurring During Public 
Emergencies ............................................................................................148 
Appendix 11. Summary of Changes from Original Protocol through Amendment 7 ...........151 
Temporary Measures for Study Visits Occurring During Public Emergencies .....................155 
 
PROTOCOL SUMMARY 
Background and Rationale 
The safety and effectiveness of tofacitinib for the treatment of rheumatoid arthritis (RA) has 
been demonstrated in adult subjects.  The Sponsor is conducting a pediatric investigational 
program to determine the safety and efficacy of tofacitinib in subjects 2 to <18 years of age 
for the treatment of Juvenile Idiopathic Arthritis (JIA).  
As part of this pediatric investigational program, study A3921165 will evaluate efficacy, 
safety, tolerability and pharmacokinetics of tofacitinib as treatment for systemic (s)JIA.  In 
this study, after 12 to 40 weeks of treatment with open-label tofacitinib, sJIA patients who 
are able to taper corticosteroids (CS) while maintaining an Adapted JIA ACR 30 response 
will be identified as “responders”.  These responders will proceed to a double-blind 
withdrawal phase in which they will be randomized to either continue with tofacitinib 
treatment or start placebo treatment.  Sustained efficacy of tofacitinib to prevent disease flare 
will be evaluated in the randomized withdrawal phase.  
Study Objectives 
Primary: 
• To assess the sustained efficacy of tofacitinib versus placebo in sJIA patients, as 
measured by time to sJIA flare in the double-blind randomized withdrawal phase. 
Secondary: 
• To assess efficacy of tofacitinib versus placebo in sJIA patients at various time points 
in the double-blind randomized withdrawal phase, as measured by:  
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a. Percentage of subjects with sJIA disease flares; 
b. Percentage of subjects with Adapted JIA ACR 30/50/70/90/100 responses;  
c. Changes from baseline in Juvenile Arthritis Disease Activity Score (JADAS-27);  
d. Percentage of subjects achieving inactive disease and clinical remission 
(JIA ACR); 
e. Percentage of subjects with inactive disease and minimal disease activity 
(JADAS-27); 
f. Other evaluations specified under “Efficacy endpoints” for the double-blind 
phase. 
• To assess the efficacy of tofacitinib in sJIA patients in the open-label treatment phase, 
as measured by:  
a. Percentage of subjects with successful corticosteroids tapering per protocol at the 
end of the open-label phase in subjects with sJIA receiving corticosteroids at start 
of open-label phase; 
b. Percentage of subjects with Adapted JIA ACR 30/50/70/90/100 responses at 
every visit from Day 7 onward; 
c. Other evaluations specified under “Efficacy endpoints” for the open-label phase. 
• To assess the safety and tolerability of tofacitinib in sJIA patients.  
• To assess the pharmacokinetics of tofacitinib in sJIA patients in the open-label phase. 
Exploratory Objective 
• To evaluate exploratory biomarker and genomic samples to characterize the effect of 
tofacitinib.  
Study Endpoints 
Primary Efficacy Endpoint: 
• Time to sJIA disease flare in the double-blind randomized withdrawal phase. 
Secondary Efficacy Endpoints: 
• Occurrence of disease flares in the double-blind phase at each visit. 
• Achievement of corticosteroid tapering per protocol at the end of the open-label 
active treatment period in applicable subjects receiving corticosteroids on study 
Day 1 of the open-label phase. 
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• Achievement of a corticosteroid dose of ≤0.2 mg/kg/day or 10 mg/day (whichever is 
lower) at the end of the open-label treatment period in subjects receiving 
corticosteroids on Day 1 of the open-label phase. 
• Adapted JIA ACR 30/50/70/90/100 response at every visit from Day 7 onward in the 
open-label and the double-blind phase. 
• Fever (Temp >38 Degrees Celsius/100.4° F) attributed to sJIA at Day 3, Day 7 and 
Day 14 of the open-label phase. 
• CRP ≤10 mg/L at every visit of the open-label phase. 
• “Absence of fever”, defined as absence of fever due to sJIA in the week preceding the 
assessment at every visit from Day 7 onward in the open-label and double-blind 
phase. 
• Time to first Adapted JIA ACR 30 response in Part 1 of the open-label phase.  
• Change from baseline in Juvenile Arthritis Disease Activity Score (JADAS 27) at 
every visit from Day 7 onward in the open-label and double-blind phase. 
• Change from baseline in each JIA ACR core variable at every visit from Day 7 
onward in the open-label and double-blind phase. 
• Change from baseline in Child Health Questionnaire (CHQ) responses at the end of 
Part 1 and Part 2 of the open-label phase, at randomization and every 6 months 
thereafter.  
• Change from baseline in Child Health Assessment Questionnaire (CHAQ) at every 
visit from Day 7 onward in the open-label and double-blind phase. 
• Occurrence of inactive disease status and minimal disease activity at every visit from 
Day 7 onward (JADAS-27) in the open-label and double-blind phase. 
• Occurrence of inactive disease status at every visit from Day 7 onward (JIA ACR) in 
the open-label phase.  
• Occurrence of inactive disease status at every visit and clinical remission at every 
visit starting at Week 24 in the double-blind phase.  
Exploratory Endpoints: 
• Change from baseline in various genomic and serum biomarkers following treatment 
with tofacitinib.  
Safety Endpoints: 
• All adverse events (AEs), including Serious Adverse Events (SAEs). 
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• Macrophage activation syndrome (MAS) events. 
• Serious infections, including tuberculosis, varicella and herpes zoster and 
opportunistic infections. 
• Clinically significant abnormal laboratory parameters, including abnormal 
hematology parameters, lipid parameter changes, liver enzymes, serum creatinine 
elevation. 
• Malignancies, including lymphoma and non-melanoma skin cancer. 
• Gastrointestinal perforations. 
• Cardiovascular diseases. 
• Assessments of growth and pubertal development. 
Pharmacokinetic Endpoints: 
• Tofacitinib concentrations during the open-label phase. 
Study Design 
This is a 2-phase randomized withdrawal study to evaluate efficacy, safety and tolerability, 
and pharmacokinetics of tofacitinib as a treatment for sJIA.  The study will enroll 
approximately 100 subjects from 2 to <18 years of age with sJIA with active systemic 
features. 
Subjects will be enrolled into an open-label phase during which they will receive tofacitinib 
5 mg twice daily (BID) oral tablets, or an equivalent weight-based lower dose of tofacitinib 
oral solution (1 mg/mL) BID for subjects <40 kg.  The 5 mg BID dose level of tofacitinib 
will be evaluated in a staggered fashion (cohorts of 7 subjects followed by safety review), as 
described under “Dose Selection” in Section 3.4. 
The open-label phase will be divided into two parts.  In Part 1, all subjects must achieve and 
maintain a minimum level of clinical response for at least 4 weeks.  In Part 2 of the 
open-label phase, subjects treated with background CSs ˃0.2 mg/kg/day oral prednisone (or 
equivalent) must taper their CS dose to a target range.  Subjects who successfully taper their 
CS dose while maintaining the defined clinical response, will be eligible for the double-blind 
withdrawal phase of the study.  The minimum total duration of treatment with a stable dose 
of tofacitinib for subjects completing Parts 1 and 2 must be 12 weeks to qualify to enter the 
randomized withdrawal phase of the study. 
In the double-blind withdrawal phase, “responders” from the open-label phase will be 
randomized in a 1:1 ratio to either continue tofacitinib or start placebo.  The primary 
endpoint of the study is time to sJIA flare in the double-blind phase.   
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Subjects who flare or achieve ACR clinical remission (ie, maintain JIA ACR inactive disease 
during 24 consecutive weeks) will be given the opportunity to participate in A3921145 and 
be treated with open-label tofacitinib.   
Subjects who discontinue Investigational Product in the double-blind phase and who do not 
enter A3921145 will continue in A3921165 for follow up of efficacy and safety endpoints. 
Subjects will be required to perform all scheduled visits until Week 52 after randomization or 
until the study concludes, whichever comes first. Subjects should receive standard-of-care 
treatment in accordance with local treatment guidelines. 
All subjects participating in this study, including those discontinued, will have the option, if 
eligible, of enrolling in the tofacitinib long-term extension study (A3921145).  The Sponsor’s 
intent is to make tofacitinib available to pediatric subjects through Study A3921145.  
Subjects who discontinue the study in the Open-Label Phase and do not enter A3921145, will 
be required to perform a follow-up visit 28 days after the last dose of study treatment.  
A schematic of the study design is shown in Figure 1.  
Figure 1. Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Subjects <40 kg will receive an equivalent weight-based lower dose of tofacitinib 5 mg BID. 
b CS Tapering is only required for subjects treated with CS ˃0.2 mg/kg/day oral prednisone (or equivalent).  
During the active CS tapering period in Part 2 subjects must maintain an Adapted JIA ACR 50 response. 
c aJIA: Adapted JIA.  
Screening 
Up to 40 days 
Tofacitinib 5mg BIDa   
+  
Stable Dose 
Corticosteroids (CS) 
Part 1: 
Up to 16 
weeks 
Tofacitinib 5mg BIDa 
+  
Taper CSsb 
Part 2: 
Up to 24 
weeks 
Tofacitinib 5 mg 
BID 
Receive Investigational 
Product up to 1
st sJIA 
flare, 24 consecutive 
weeks inactive disease 
(clinical remission, based 
on ACR criteria) or 
ET/EOSd 
Open labele 
Double-blind 
Rollover into 
Study 1145 
Start CS tapering if 
aJIA ACR 50 achieved 
& 
aJIAc ACR 30 for 4 weeks 
Randomize if  
Stable tapered CS dose for 4 weeks 
& 
aJIA ACR 30 for 4 weeks 
Study End: 
Required Number 
of Flares 
Placebo BID 
Randomization 
Ratio 1:1 
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d  Subjects who discontinue Investigational Product in the randomized withdrawal phase continue in study 
until week 52 after randomization or until the study concludes, whichever comes first. 
e   Subjects who discontinue the study in the open-label phase and do not enter A3921145 within 4 weeks, will 
 
be required to perform a follow-up visit 28 days after the last dose of Investigational Product.  
Statistical Analysis 
Approximately 100 subjects will be enrolled in the open-label run-in phase of the study.  Of 
these subjects, at least 12 subjects are targeted to be enrolled in each of the following age 
groups: from 12 to <18 years, from 6 <12 years and from 2 to <6 years.  It is estimated that 
approximately 55 percent of subjects will enter the randomized withdrawal period of the 
study. 
At the start of the double-blind phase, qualifying subjects receiving tofacitinib 5 mg BID in 
the active treatment phase will be randomized into a 5 mg BID tofacitinib sequence 
(continuation of the same tofacitinib treatment) or the placebo sequence (withdrawal of the 
tofacitinib treatment) with a 1:1 allocation ratio, stratified by age group.   
There will be potentially 2 planned analyses.  The First Analysis will be performed after at 
least 20 subjects have reported flare in the double-blind phase (approximately 50% of the 
total flares expected).  The purpose of the First Analysis is to allow early stopping of the 
study for efficacy or futility, and to assess safety of tofacitinib.  Depending on the number of 
flares in the first analysis, up to 40 subjects with flares may be required for the Final Analysis 
to yield an overall power of 80% using a log-rank test to detect the treatment difference.  The 
investigators, subjects and sponsor study team will remain blinded to treatment assignment in 
the double-blind phase through the entire duration of the trial until final database release. 
For the primary endpoint of time to flare in the double-blind phase, superiority of tofacitinib 
to placebo will be assessed using Kaplan-Meier methods.  The median time to flare and 
corresponding 2-sided 95% confidence interval (CI) will be provided.  Difference in time to 
flare between the two treatment groups (tofacitinib 5 mg BID vs. placebo) will be assessed 
using an unstratified log-rank test.   
To protect the integrity of the study and to preserve the type I error rate at 0.025 (1-sided 
test) and overall study power at 80% (type II error rate β=0.2), a fraction of α for efficacy and 
a fraction of β for futility will be spent at the First Analysis and accounted for in the overall 
type I error rate and type II error rate, respectively.  A formal efficacy boundary for rejecting 
the null hypothesis is constructed by using the spending function methodology of the gamma 
family design with γ= 4.  Similarly, a formal futility boundary for not rejecting the null 
hypothesis is constructed by using the spending function methodology of the gamma family 
design with γ= -4.   
• If the value of the test-statistic at the First Analysis crosses the efficacy boundary 
(z≤ -2.014, 1-sided p≤ 0.022), the trial may be stopped for efficacy. 
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• If the value of the test-statistic at the First Analysis crosses the futility boundary   
(z≥ -0.286, 1-sided p≥ 0.387), the trial may be stopped for futility. 
• Otherwise, the trial will continue as planned. The Final Analysis will be performed 
after flares have been reported in approximately 40 subjects. 
Secondary binary endpoints such as: occurrence of disease flare or inactive disease, 
achieving a response of Adapted JIA 30/50/70/90/100, absence of fever, etc., will be 
analyzed using statistical methods for binary variables; eg, normal approximation to binomial 
proportions.  For the continuous endpoints, a linear mixed-model will be applied.  Treatment 
differences along with the associated 2-sided 95% CIs, will also be calculated.  In the 
double-blind analyses, descriptive/summary statistics by treatment group for the effect on the 
primary and secondary endpoints will be provided at each time point.  
Secondary endpoints in the open-label run-in phase will be summarized descriptively by 
visit. 
At the beginning of the double-blind randomized withdrawal phase, subjects from the 
open-label run-in phase will be randomized into 2 sequences: 5 mg BID tofacitinib (or 
placebo (withdrawal of tofacitinib).  In the primary and most secondary analyses, the two 
treatment groups (tofacitinib or placebo) will be compared in order to better assess the 
treatment effect.  Some descriptive analyses will be performed. 
Safety analysis will be performed on all subjects who received at least one dose of study 
drug.  Safety data will be subject to clinical review and summarized by appropriate 
descriptive statistics. 
Details of the statistical analysis are found in Section 10 and will be further described in a 
Statistical Analysis Plan (SAP). 
 
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SCHEDULE OF ACTIVITIES  
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and   
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.  
Country-specific amendment for Germany: The degree of burden and the risk threshold should be assessed at each scheduled visit 
as outlined in Appendix 9. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the subject.  
For any visits impacted by public emergencies, including the COVID-19 pandemic, refer to Appendix 10 for additional guidance and 
instructions.  
  
 
 
Open-Label Treatment Phase 
Randomized Withdrawal 
Phase 
 
EOS  
 
Or 
 
ET 
Follow-Up 
Part 1  
(Up to 16 Weeks) 
Part 2 
(Up to 24 
Weeks) 
Treat to EOS2 or Flare 
Once required number of   
flares are reported the study 
will conclude 
Follow-Up if not entered in 
A3921145 
For subjects discontinued in Open-
Label Treatment Phase and for 
Subjects completing Randomized 
Withdrawal Phase   
Protocol Activity 
Screening 
Day 11 Day 3 
Day 7 
Day 
14 
Week 4, 
8, 
12, 16 
Week 4, 
8, 12 
16, 20, 24 
Randomization 
Visit 
Every 4 
Weeks25 
 
 
 
Follow-Up 4 wks posttreatment 
discontinuation3 
 
Visit 
 
1 
2.1 
2.2 
2.3 
2.4 to 2.7 3.1 to 3.6 
4.1  
4.2 to 4.X  
 
5 
6.1 
Time Windows 
Day – 40 to
Day -1 
Day 1 ±1 day ±1 day ±1 day ±3 days 
±3 days 
±5 days 
±5 days 
±5 days 
±7 days 
Informed Consent/Assent  
X 
 
 
 
 
 
 
 
 
X26 
 
Medical History, Family History 
X 
 
 
 
 
 
 
 
 
 
 
Uveitis Status4 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Tanner Stages 
X 
 
 
 
 
 
 
 
 
X 
 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Examination23 
X 
 
 
 
 
 
 
 
 
X 
 
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Open-Label Treatment Phase 
Randomized Withdrawal 
Phase 
 
EOS  
 
Or 
 
ET 
Follow-Up 
Part 1  
(Up to 16 Weeks) 
Part 2 
(Up to 24 
Weeks) 
Treat to EOS2 or Flare 
Once required number of   
flares are reported the study 
will conclude 
Follow-Up if not entered in 
A3921145 
For subjects discontinued in Open-
Label Treatment Phase and for 
Subjects completing Randomized 
Withdrawal Phase   
Protocol Activity 
Screening 
Day 11 Day 3 
Day 7 
Day 
14 
Week 4, 
8, 
12, 16 
Week 4, 
8, 12 
16, 20, 24 
Randomization 
Visit 
Every 4 
Weeks25 
 
 
 
Follow-Up 4 wks posttreatment 
discontinuation3 
 
Targeted Physical Examination5 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs, Height, Weight6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QuantiFERON®-TB Gold or Gold Plus 
In-Tube Test7  
X 
 
 
 
 
 
 
 
 
 
 
Chest X-ray to confirm TB status (per 
local SOC) 
X 
 
 
 
 
 
 
 
 
 
 
Oral temperature and fever assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion review 
 
X 
 
 
 
 
 
 
 
 
 
“Absence of fever” Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Number of Joints With Active Arthritis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Number of Joints With Limitation of 
Motion  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Duration of Morning Stiffness 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess extra-articular sJIA 
manifestations 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician’s Global Evaluation of 
Overall Disease Activity  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Childhood Health Assessment 
Questionnaire (CHAQ)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Child Health Questionnaire (CHQ)8 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
CS tapering9 
 
 
 
 
 
 
X 
 
 
 
 
Adapted JIA ACR Baseline 
 
X 
 
 
 
 
 
 
 
 
Adapted JIA ACR 30 response 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
sJIA flare assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
C-Reactive Protein 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Erythrocyte Sedimentation Rate (ESR) 
Westergren Method 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rheumatoid Factor 
X 
 
 
 
 
 
 
 
 
 
 
Ferritin11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Open-Label Treatment Phase 
Randomized Withdrawal 
Phase 
 
EOS  
 
Or 
 
ET 
Follow-Up 
Part 1  
(Up to 16 Weeks) 
Part 2 
(Up to 24 
Weeks) 
Treat to EOS2 or Flare 
Once required number of   
flares are reported the study 
will conclude 
Follow-Up if not entered in 
A3921145 
For subjects discontinued in Open-
Label Treatment Phase and for 
Subjects completing Randomized 
Withdrawal Phase   
Protocol Activity 
Screening 
Day 11 Day 3 
Day 7 
Day 
14 
Week 4, 
8, 
12, 16 
Week 4, 
8, 12 
16, 20, 24 
Randomization 
Visit 
Every 4 
Weeks25 
 
 
 
Follow-Up 4 wks posttreatment 
discontinuation3 
 
Fibrinogen11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology12, Chemistry 13, 
Urinalysis14 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Lipid Panel15 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Blood (serum) or Urine Pregnancy 
Test16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraceptive Check16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening HIV-1, HIV-2, HBsAg, 
HbsAb, HBcAb, HCV Ab, HCV RNA  
X 
 
 
 
 
 
 
 
 
 
 
VZV-ELISA17 
X 
 
 
 
 
 
 
 
 
 
 
Only if MAS is suspected: laboratory 
testing (ferritin, fibrinogen, platelets, 
triglycerides)18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tofacitinib PK Sampling19 
 
X 
 
 
 
X 
X19 
 
 
 
 
Banked biospecimen collection20 
 
X 
 
 
 
X (Week 
8) 
 
X 
 
X 
 
Confirmation eligibility for 
Double-Blind Phase 
 
 
 
 
 
 
 
X 
 
 
 
Randomization to Double-Blind Phase  
 
 
 
 
 
 
 
X 
 
 
 
Investigational Product Dispensing21 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
Investigation Product Compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Assessment22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Risk factor check for venous 
thromboembolism24 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational Product Dosing 
 
< -----------------Active Tofacitinib --------------- > 
<- Tofacitinib/Placebo -> 
 
 
Review Entry Criteria for A3921145 
 
 
 
 
 
 
 
 
 
X 
 
1. Day 1 visit (ie, the first day of treatment with investigational product) must occur within 40 days of the first screening visit activity.  If more than 
40 days has elapsed, the subject should be screen-failed and may be re-screened, if eligible.  Sponsor approval must be obtained prior to re-screening a 
subject.  
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2. Early termination (ET) procedures should be completed if a subject does not complete to the end of study.  If a subject discontinues at a regularly 
scheduled visit, this may be considered the ET visit and all required procedures and visit-specific CRFs should be completed; please use an unplanned 
Tanner Stage assessment CRF if this occurs. 
3. This visit will only be conducted if the subject did not rollover into study A3921145 within 4 weeks.   
4. At the screening visit, a formal uveitis assessment will not be required, but documentation of previous uveitis assessment by an ophthalmologist (or 
qualified equivalent per local practice) should be reviewed to document absence/presence of uveitis.  At every visit from Day 7 onward a confirmation 
of the subject’s uveitis status will be required as part of the JIA ACR inactive disease evaluation.  
5. Targeted physical exam consists of examination of heart, lungs, skin, extremities for peripheral edema, abdomen and lymph nodes. 
6. Vital signs include blood pressure, pulse rate, and temperature (fever) assessment.  Weight is evaluated at every visit; height is evaluation on a monthly 
basis.  Subjects will be provided with a thermometer to measure their oral temperature.  Each subject will receive a diary at Day 1 to record their 
temperature.  The parent/legal guardian should complete the diary or supervise the completion of the diary by the subject.  If subjects have a fever, the 
temperature should be recorded twice daily (in the morning and evening); the highest temperature since previous diary recording should be reported in 
the diary.  Subjects will return the diary to the clinic at each study visit.  Refer to  Section 8.1.2 for further details.  
7. A negative QuantiFERON-TB test performed locally or a PPD or T-Spot test can be substituted for the QuantiFERON®-TB Gold or Gold Plus In-Tube 
test only if the central laboratory is unable to perform the QuantiFERON®-TB Gold or Gold Plus In-Tube test or cannot determine the results to be 
positive or negative and the Sponsor approves it on a case-by-case basis.  In addition to protocol required TB testing, sites should follow their local 
standards for TB status determination, which may include chest X-ray.  See Section 8.2.8 for additional details.  In countries where TB incidence has 
been reported at a rate of >50 cases per 100,000 persons, eg, China, India, Russian Federation; South Africa and Ukraine (World Health 
Organization): TB testing (QFT-TB Gold or Gold Plus) is required at screening visit and then on a yearly basis. 
8. At baseline (Day 1), the end of Part 1 and Part 2 of the open-label phase, randomization and every 6 months thereafter the parent/legal guardian or an 
adult caregiver interacting daily with the subject will be asked to complete a Child Health Questionnaire (CHQ).  
9. In Part 2 of the study CS tapering will be required in all subjects who receive CS doses ˃0.2 mg/kg/day of oral prednisone or equivalent in Part 1.  Refer 
to Section 3.2 for further details.  
10. The Erythrocyte Sedimentation Rate (ESR) will be determined locally utilizing an ESR Testing Kit provided to the investigator site by the Sponsor.  
Please refer to the ESR Testing Kit Manual for detailed instruction on how to perform this test appropriately.  The ESR result will be recorded on the 
appropriate CRF.  The ESR result also will be faxed to the Centralized Coordinating Center. A local lab ESR testing kit (Westergren method) can be 
substituted for a Sponsor kit only if supply issues have resulted in a Sponsor kit not being available at the time of the visit.   
11. At every visit, if MAS is suspected in a febrile patient, an extra blood sample will be drawn to evaluate ferritin and fibrinogen. 
12. Hematology includes: Hemoglobin, hematocrit, red blood cells, white blood cells, neutrophils (%, absolute), lymphocytes (%, absolute), monocytes 
(%, absolute), eosinophils (%, absolute), basophils (%, absolute), and platelets.  Refer to Section 8.2.12 for details on sample collection. 
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13. Chemistry includes: Sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, glucose, calcium, total protein, total bilirubin (TB), direct 
bilirubin, indirect bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transferase 
(GGT), albumin, creatine phosphokinase kinase (CPK).  Refer to Section 8.2.12 for details on sample collection. 
14. Urinalysis includes specific gravity, pH, protein, glucose, ketones, blood and leukocyte esterase, urine microscopy (only if dipstick positive for blood or 
protein, or if clinically indicated). 
15. Lipid profile testing will be required every 3 months after Day 1: includes total cholesterol, low density lipoproteins (LDL), high density lipoproteins 
(HDL), triglycerides, apolipoprotein A1, apolipoprotein B.  Subjects should be instructed to fast for approximately 9 to 12 hours, if possible, prior to 
lipid panel testing.  
16. Blood (serum) or urine pregnancy testing is required only for females who are of childbearing potential (see Section 4.4.1).  Pregnancy testing will be 
performed locally.  Pregnancy testing may be repeated more frequently if required by local practices, if a menstrual cycle is missed, or if potential 
pregnancy is otherwise suspected.  A positive urine pregnancy test will be confirmed by a blood (serum) pregnancy test performed either locally or by 
the central laboratory.  A contraceptive check also will be performed to confirm that contraception, if assigned, is being used consistently and correctly.  
Childbearing status also will be checked and contraception implemented in subjects who mature physically and behaviorally during the conduct of the 
study.  See Section 8.2.9 for details regarding viral testing and interpretation of results. 
17. Serologic testing for antibodies to varicella zoster virus (VZV) via ELISA is required for all subjects who do not have documented evidence from a 
health professional of having received 2 doses of varicella vaccine.  If a subject does not have evidence of receipt of 2 doses of varicella vaccine, then a 
VZV ELISA test at screening is required  
18. MAS laboratory testing: if MAS is suspected in a febrile subject, extra blood samples of for evaluation of ferritin and fibrinogen will need to be drawn.  
In case no hematology or lipid evaluation is done at the visit, platelets and triglycerides will also need to be assessed to confirm a MAS diagnosis.  See 
Section 8.2.3 for details.  
19. Blood samples for PK evaluation will be obtained 15 minutes (5-30 min) and 45 minutes (35-55 min) and 4 hours (3-6h) after tofacitinib administration 
on Day 1.  An additional PK blood sample will be obtained 1.5 hours (1.25-2h) post tofacitinib administration if the subject is part of the first 
14 subjects enrolled in Cohorts 1 and 2.  After 8 weeks of open-label treatment with tofacitinib, PK blood samples will be obtained pre-dose and 1 hour 
(0.5-1.5h) and 3 hours (2-4h) after tofacitinib administration.  Whenever feasible, a later time point within the last PK sample collection range is 
preferred.  This PK sample may be obtained at Week 8 of Open-Label Part 1, or at Week 4 of Open-Label Part 2 in the case a subject started 
Open-Label Part 2 after 4 weeks of tofacitinib treatment in Part 1.  See Section 8.4 for details regarding PK sampling. Subjects in India will not 
participate in PK evaluation. 
20. A banked biospecimen for future exploratory assessments will be collected at baseline, Open Label Part 1 Week 8 (or at Week 4 of Open-Label Part 2 in 
the case a subject started Open Label Part 2 after 4 weeks of tofacitinib treatment in Part 1),  at randomization, when the subject flares (at early 
termination or the end of study visit) and if/when the subject reaches inactive disease status.  See Section 8.5 for details. 
21. The first dose of study drug is to be dispensed at the study site during the Day 1 visit.  
22. Serious adverse events (SAEs) are captured from the time of informed consent at Screening; adverse events (AEs) are captured following first dose of 
investigational product. 
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23. A skin examination for the presence of varicella (chickenpox) and herpes zoster should be performed and per a country-specific amendment for EU 
sites (including UK sites): a full skin cancer examination must be performed as part of the complete physical examination. 
24. Per Amendment 3, all subjects will be asked at every study visit if they have any newly developed risk factors for venous thromboembolism as 
described in Section 8.2.13. 
25. Subjects who discontinue Investigational Product in the double-blind phase and who do not enter A3921145 will continue in A3921165 for follow up of 
efficacy and safety endpoints. Subjects will be required to perform all scheduled visits every 4 weeks until Week 52 after randomization or until 
the study concludes, whichever comes first. All visit activities should be performed with the exception of Investigational Product dispensing, 
dosing and compliance. Subjects should receive standard-of-care treatment in accordance with local treatment guidelines. 
26. For subjects considering entering A3921145 LTE study, an Informed Consent Document/Assent Document for A3921145 should be provided to the 
subject prior to the EOS visit, if possible, to allow an appropriate length of time to consider participation, . 
 
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1. INTRODUCTION 
1.1. Indication 
Tofacitinib was approved on 06 November 2012 in the United States at a dose of 5 mg twice 
daily (BID) for the treatment of adults with moderately to severely active RA who have had 
an inadequate response or intolerance to MTX (Methotrexate).  As of 03 December 2021, 
tofacitinib 5 mg BID is also approved for the treatment of adults with psoriatic arthritis, 
ulcerative colitis, and polyarticular course juvenile idiopathic arthritis who have had an 
inadequate response or intolerance to one or more TNF blockers. It may be used in 
combination with methotrexate or other non-biologic disease modifying antirheumatic drugs 
(DMARDs).  
1.2. Background 
1.2.1. Tofacitinib 
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 Tyrosine Kinase 2 (TyK2).  In 
cellular settings where JAK kinases signal in pairs, tofacitinib preferentially inhibits signaling 
by heterodimeric receptors associated with JAK3 and/or JAK1 with functional selectivity over 
receptors that signal via pairs of JAK2.  Inhibition of JAK1 and JAK3 by tofacitinib blocks 
signaling through the common gamma chain containing receptors for several cytokines, 
including interleukins (IL) IL-2, -4,-7,-9, -15 and -21.1-3  These cytokines are integral to 
lymphocyte activation, proliferation and function, and inhibition of their signaling may thus 
result in modulation of multiple aspects of the immune response.  In addition, inhibition of 
JAK1 will result in attenuation of signaling by additional pro-inflammatory cytokines, such as 
IL-6 and interferon (IFN)γ.  At higher exposures inhibition of erythropoietin signaling could 
occur via inhibition of JAK2 signaling. 
The safety and effectiveness of tofacitinib for the treatment of RA has been demonstrated in 
adult subjects.  Both 5 mg BID and 10 mg BID dose regimens have been studied in adults and 
demonstrated efficacy.  A greater number of adverse events were reported at the 10 mg BID 
dose level.  The Sponsor is conducting a pediatric development program in subjects 2 to 
<18 years of age for the treatment of JIA.  As part of this pediatric program, a Phase 1 PK 
study of tofacitinib in JIA subjects (A3921103) has been completed, and an open-label, 
non-comparative, long-term extension study (A3921145) is currently ongoing.  In addition, a 
Phase 3 study of tofacitinib in polyarticular JIA subjects (A3921104) has been completed.  
The data from studies A3921103 and A3921104 demonstrated that tofacitinib dosed at 
5 mg BID for subjects ≥40 kg, or weight based equivalent doses BID for subjects <40 kg, was 
efficacious and safe in subjects with polyarticular JIA, including supporting data from sJIA 
patients already evaluated in the A3921104/A3921145 studies.  
1.2.2. Systemic JIA and the Role of Inflammatory Cytokines 
Study A3921165 will be conducted in subjects from 2 to <18 years of age with active 
systemic Juvenile Idiopathic Arthritis (sJIA).  Patients with active sJIA are a subgroup of JIA 
patients at higher risk for severe complications of the disease, including death, compared to 
other JIA subtypes.4 
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Active sJIA is characterized by quotidian, high spiking fever often associated with an 
evanescent, non-fixed, erythematous rash.  Myalgias and abdominal pain may be intense 
during fever peaks.  Other systemic features include hepato-splenomegaly, generalized 
lymphadenopathy and serositis.  Laboratory examinations show a prominent inflammatory 
response characterized by leukocytosis (with neutrophilia), high erythrocyte sedimentation 
rate (ESR) and C-reactive protein (CRP) concentration, and thrombocytosis.  A microcytic 
anemia is common.  Arthritis is often symmetrical and polyarticular; it may be absent at onset 
and develop during disease.5 
Recent evidence supports the concept that sJIA arises due to dysregulation of the innate 
immune system.  Dysregulation of the innate immune system in sJIA results in increased 
production of inflammatory cytokines, leading to the distinctive clinical features of the 
disease.  Cytokine profile studies have demonstrated a predominant role of the 
macrophage-derived cytokines IL-6, IL-1, and IL-18 in sJIA.6  
Macrophage activation syndrome (MAS) is a potentially life-threatening complication of 
sJIA.  MAS is characterized by continual activation and expansion of T lymphocytes and 
macrophages, which results in massive hyper-secretion of pro-inflammatory cytokines.  
Characteristic clinical features of MAS are high, non-remitting fever, hepatosplenomegaly, 
generalized lymphadenopathy, central nervous system dysfunction, and hemorrhagic 
manifestations.  Typical laboratory abnormalities include pancytopenia, increased levels of 
ferritin, liver enzymes, lactate dehydrogenase, triglycerides, D-dimers, and soluble 
interleukin-2 (IL-2) receptor (also known as soluble CD25 [sCD25]), and decreased 
fibrinogen levels.7 
The recognition of the importance of interleukin (IL)-1 and IL-6 in the pathogenesis of sJIA 
has recently led to the approvals of two treatments for this indication that target these 
mechanisms, canakinumab and tocilizumab, respectively.  These treatments have proven to be 
efficacious in sJIA (Ruperto 2012, De Benedetti 2012)14,25 and provide effective therapeutic 
options for these patients.  A randomized withdrawal design has been selected to evaluate 
efficacy and safety of tofacitinib in subjects with sJIA in order to limit exposure to placebo 
treatment.  The randomized withdrawal design is commonly used in pediatric research and it 
was used recently for a pivotal registrational study with canakinumab for sJIA.14  This design 
will provide a higher level of scientific evidence as compared to the single arm design and 
minimizes the time that subjects will be exposed to placebo.  The comparison of the 
experimental drug with placebo in an enriched population of responders (ie, randomize only 
the adapted JIA ACR 30 responders) increases the power (or equivalently, reduces the sample 
size) of the comparison.28 
1.2.3. Study Rationale 
Study A3921165 will evaluate tofacitinib treatment in subjects from 2 to <18 years of age 
with active sJIA in a randomized withdrawal model, thereby limiting the risk to sJIA patients 
associated with placebo treatment.  
This Phase 3 study is intended to provide evidence of efficacy and safety of tofacitinib in 
subjects with sJIA when dosed to target exposures similar to 5 mg orally BID in adult subjects 
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with RA or weight-adjusted doses not to exceed 5 mg BID orally in pediatric subjects with 
polyarticular course JIA.  
This study will evaluate efficacy, safety and tolerability, and pharmacokinetics of tofacitinib 
as treatment for sJIA.  After 12 to 40 weeks of open-label treatment with tofacitinib, subjects 
with sJIA who are able to taper CSs to the predetermined target dose range or lower, while 
maintaining an Adapted JIA ACR 30 response, will be identified as “responders”.  These 
responders will proceed to a withdrawal phase in which they will be randomized to continue 
tofacitinib or start placebo treatment.  The primary objective of the study will be to assess 
sustained efficacy of tofacitinib to prevent disease flare in subjects with active sJIA in the 
randomized withdrawal phase of the study. 
1.2.4. Dose Rationale 
The 5 mg BID dose of tofacitinib evaluated in A3921165 was selected based on the 
pharmacokinetic (PK) characteristics of tofacitinib in polyarticular JIA (pJIA) subjects from 
PK Study A3921103 and the exposure-response relationship of tofacitinib as previously 
demonstrated in the adult RA program.  Based on tofacitinib PK in the RA population (body 
weight ranging from 40 kg-140 kg), clearance (CL) of tofacitinib is not dependent on body 
weight in adult subjects.  Thus, the dose of tofacitinib in adolescents with body weight (BW) 
≥40 kg was set to 5 mg twice daily (BID), an approved dose of tofacitinib in adult RA patients 
in most countries.  The body weight based tofacitinib dosing scheme for subjects with sJIA 
weighing ≤40 kg is selected to match the predicted steady state concentrations (Cavg,ss) in pJIA 
patients with body weight ≥40 kg after a 5 mg BID dose.  It was assumed that the PK of 
tofacitinib will be similar between pJIA and sJIA patients.  
Systemic JIA is known to be a more severe form of childhood arthritis in which doses in 
excess of those used in pJIA patients are often needed to achieve efficacy in sJIA patients 
(eg, CSs, tocilizumab).8   
There is evidence that sJIA is associated with dysregulation of the innate immune system 
leading to over-production of cytokine IL6.6  IL6 induces body temperature increases and it 
plays a major role in development of systemic features in sJIA.  Tofacitinib treatment, in 
various nonclinical and clinical studies, has shown to result in decreased level of IL-6 in the 
circulation.9  Lack of fever control with tofacitinib may therefore be indicative of insufficient 
degree of attenuation of IL6 and this clinical feature will be utilized as an indicator to evaluate 
the efficacy of the 5 mg BID dose in the early cohorts of the study.  
1.3. Single Reference Safety Document 
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the current version of the Tofacitinib Investigator 
Brochure. 
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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Objectives 
2.1.1. Primary 
• To assess the sustained efficacy of tofacitinib versus placebo in sJIA patients, as 
measured by time to sJIA flare in the double-blind randomized withdrawal phase. 
2.1.2. Secondary 
• To assess efficacy of tofacitinib versus placebo in sJIA patients at various time points 
in the double-blind randomized withdrawal phase, as measured by:  
a. Percentage of subjects with sJIA disease flares; 
b. Percentage of subjects with Adapted JIA ACR 30/50/70/90/100 responses;  
c. Changes from baseline in Juvenile Arthritis Disease Activity Score (JADAS-27);  
d. Percentage of subjects achieving inactive disease and clinical remission (JIA 
ACR); 
e. Percentage of subjects with inactive disease and minimal disease activity 
(JADAS-27); 
f. Other evaluations specified under “Efficacy endpoints” for the double-blind phase. 
• To assess the efficacy of tofacitinib in sJIA patients in the open-label treatment phase, 
as measured by:  
a. Percentage of subjects with successful corticosteroid tapering per protocol at the 
end of the open-label phase in subjects with sJIA receiving corticosteroids at start 
of open-label phase; 
b. Percentage of subjects with Adapted JIA ACR 30/50/70/90/100 responses at every 
visit from Day 7 onward; 
c. Other evaluations specified under “Efficacy endpoints” for the open-label phase. 
• To assess the safety and tolerability of tofacitinib in sJIA patients.  
• To assess the pharmacokinetics of tofacitinib in sJIA patients in the open-label phase. 
2.1.3. Exploratory Objective 
• To evaluate exploratory biomarker and genomic samples to characterize the effect of 
tofacitinib.  
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2.2. Endpoints 
2.2.1. Primary 
• Time to sJIA disease flare in the double-blind randomized withdrawal phase. 
2.2.2. Secondary Efficacy Endpoints 
Secondary: 
Efficacy endpoints: 
• Occurrence of disease flares in the double-blind phase at each visit. 
• Achievement of corticosteroid tapering per protocol at the end of the open-label active 
treatment period in applicable subjects receiving corticosteroids on study Day 1 of the 
open-label phase. 
• Achievement of a corticosteroid dose of ≤0.2 mg/kg/day or 10 mg/day (whichever is 
lower) at the end of the open-label treatment period in subjects receiving 
corticosteroids on Day 1 of the open-label phase. 
• Adapted JIA ACR 30/50/70/90/100 response at every visit from Day 7 onward in the 
open-label and double-blind phase. 
• Fever (Temp >38 Degrees Celsius/100.4° F) attributed to sJIA at Day 3, Day 7 and 
Day 14 of the open-label phase. 
• CRP ≤10 mg/L at every visit of the open-label phase. 
• “Absence of fever”, defined as absence of fever due to sJIA in the week preceding the 
assessment at every visit from Day 7 onward in the open-label and double-blind phase. 
• Time to first Adapted JIA ACR 30 response in Part 1 of the open-label phase.  
• Change from baseline in Juvenile Arthritis Disease Activity Score (JADAS 27) at 
every visit from Day 7 onward in the open-label and double-blind phase. 
• Change from baseline in each JIA ACR core variable at every visit from Day 7 onward 
in the open-label and double-blind phase. 
• Change from baseline in Child Health Questionnaire (CHQ) responses at the end of 
Part 1 and Part 2 of the open-label phase, at randomization and every 6 months 
thereafter.  
• Change from baseline in Child Health Assessment Questionnaire (CHAQ) at every 
visit from Day 7 onward in the open-label and double-blind phase. 
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• Occurrence of inactive disease status and minimal disease activity at every visit from 
Day 7 onward (JADAS-27) in the open-label and double-blind phase. 
• Occurrence of inactive disease status and clinical remission at every visit from Day 7 
onward (JIA ACR) in the open-label and double-blind phase.  
2.2.3. Exploratory 
• Change from baseline in various genomic and serum biomarkers following treatment 
with tofacitinib.  
2.2.4. Safety Endpoints 
• All adverse events (AEs), including Serious Adverse Events (SAEs). 
• Macrophage activation syndrome (MAS) events. 
• Serious infections, including tuberculosis, varicella and herpes zoster and 
opportunistic infections. 
• Clinically significant abnormal laboratory parameters, including abnormal hematology 
parameters, lipid parameter changes, liver enzymes, serum creatinine elevation. 
• Malignancies, including lymphoma and non-melanoma skin cancer. 
• Gastrointestinal perforations. 
• Cardiovascular diseases. 
• Assessments of growth and pubertal development. 
2.2.5. Pharmacokinetic Endpoints 
• Tofacitinib concentrations during the open-label phase. 
2.3. Benefit/Risk Assessment 
2.3.1. Risk Assessment 
In prior studies of juvenile idiopathic arthritis with tofacitinib, there were no new safety 
signals or issues detected that were either unique to the JIA population treated with tofacitinib 
or new to the tofacitinib safety profile. Therefore, potential safety concerns have been 
identified based on the totality of nonclinical and clinical data across the entire tofacitinib 
development programs (all indications) and/or are considered due to experience with other 
immunosuppressive agents. The nature and degree of the risk varies with the patient 
population; however, safety findings that may be associated with the use of tofacitinib include 
lipid elevations, decreases in hemoglobin, decreases in neutrophil and lymphocyte counts, 
increases in serum creatinine, increases in serum creatine kinase, infection risk, 
lymphoproliferative disorder/lymphoma risk, malignancy risk, non-melanoma skin cancer 
(NMSC), gastrointestinal perforations, viral reactivation, including herpes zoster, tuberculosis, 
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cardiovascular (CV) disease, venous thromboembolism (VTE, manifested as pulmonary 
embolism and deep vein thrombosis), transaminase elevations, drug hypersensitivity and 
effects on pregnancy and the fetus. Interstitial lung disease (ILD) is also observed; ILD is a 
serious comorbidity for some populations in which tofacitinib has been studied and has been 
reported as a potential risk associated with other disease modifying anti-rheumatic drugs 
therapies. 
Upon completion of a large randomized open-label post authorization safety surveillance 
(PASS) study in RA subjects who were 50 years or older with at least one additional 
cardiovascular (CV) risk factor, evaluating the safety profile of tofacitinib compared to TNF 
inhibitors, additional new potential risks for tofacitinib were identified. Those include Major 
Adverse Cardiovascular Events (MACE), myocardial infarction, lymphoma, lung cancer and 
fractures. 
As per the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment 
Committee (PRAC) conclusion to a recent safety signal assessment on the data from this 
study (EPITT 19382), myocardial infarction, lung cancer and lymphoma are categorized as 
important identified risks and malignancy excluding NMSC continues to be categorized as an 
important potential risk in the context of the EU risk management plan and EU Summary of 
Product Characteristics. Recommendations for use of the marketed product (Xeljanz 
[tofacitinib]) in the EU were also adopted by PRAC, advising healthcare professionals that 
tofacitinib should only be used in patients over 65 years of age, patients who are current or 
past smokers, patients with other cardiovascular risk factors, and patients with other 
malignancy risk factors if no suitable treatment alternatives are available. 
Additionally, the risk of herpes zoster in tofacitinib-treated Asian patients may be higher than 
for non-Asian patients; further analyses showed that the increased rate among Asian patients 
is largely due to an increased incidence rate in Japanese and Korean patients. The reason for 
the increased risk of HZ in Japan and Korea is unclear. 
Safety assessments, including physical examinations, skin examinations, clinical laboratory 
tests, adverse event monitoring vital signs and VTE risk assessment will be performed in this 
study at every study visit. Safety assessments, inclusion/exclusion criteria, monitoring and 
discontinuation criteria including criteria for the discontinuation of a subject with a VTE event 
were designed to manage and mitigate the safety risks associated with tofacitinib therapy. 
A complete discussion of the possible risks associated with the administration of tofacitinib is 
summarized in Section 7.2.2.3 (Special Populations), Section 7.4 (Special Warnings and 
Precautions) and Section 7.8.3 (Characterization of Select Adverse Drug Reactions) of the 
current Tofacitinib Investigator's Brochure. Interpretation of these results and the possible 
risks associated with the administration of tofacitinib are summarized in Section 6.2.3 
(Special Safety) and Section 7 (Summary of Data and Guidance for the Investigator) of the 
Investigators’ Brochure. 
2.3.2. Benefit Assessment 
Tofacitinib was approved on 06 November 2012 in the United States at a dose of 5 mg twice 
daily (BID) for the treatment of adults with moderately to severely active RA who have had 
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an inadequate response or intolerance to MTX (methotrexate).  As of 03 December 2021, 
tofacitinib 5 mg BID is also approved for the treatment of psoriatic arthritis, ulcerative colitis, 
and polyarticular course juvenile idiopathic arthritis who have had an inadequate response or 
intolerance to one or more TNF blockers. 
Adults with Rheumatoid Arthritis 
In the Phase 3 RA development program, the primary endpoint, American College of 
Rheumatology (ACR) 20 response rate at Month 3 or 6, was consistently and statistically 
significantly different for the tofacitinib 5 mg BID group compared with the placebo group. 
Tofacitinib demonstrated statistically significant and clinically meaningful reductions in signs 
and symptoms of RA over placebo. Results of ACR50 and ACR70 response rates were 
consistent with the ACR20 results in these Phase 3 studies. ACR50 and ACR70 response rates 
were consistently greater in the tofacitinib treatment groups compared with the placebo 
groups in all the Phases 3 studies. Other efficacy parameters include measures of the 
proportion of patients achieving Disease Activity Score (DAS)28-4(Erythrocyte 
Sedimentation Rate [ESR]) <2.6 (primary) and ≤3.2 [DAS28-4(ESR) is based on the tender 
joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease 
activity and erythrocyte sedimentation rate] and physical function status (as measured by 
Health Assessment Questionnaire Disability Index [HAQ-DI]). Tofacitinib may also help in 
cartilage preservation as demonstrated by reductions in modified Total Sharp Score (mTSS) 
and radiographic joint space narrowing in adults with RA.  
Pediatric Patients with Juvenile Idiopathic Arthritis 
Pfizer has undertaken a pediatric development program to determine the safety and efficacy of 
tofacitinib in subjects 2 to <18 years of age for the treatment of juvenile idiopathic arthritis 
(JIA). JIA is an umbrella term for several distinct arthritides each lasting more than 6 weeks 
and involving both autoimmune and genetic factors, but with unknown etiology. Currently, to 
be classified as juvenile, the arthritis must have had onset prior to 16 years of age. 
As part of this pediatric program, a Phase 1 pharmacokinetic (PK) study of tofacitinib in JIA 
subjects (A3921103) was completed in 2015, and an open-label, non-comparative, long-term 
extension study (A3921145) is ongoing. Subjects from Study A3921104 were eligible to enter 
Study A3921145 to continue treatment with tofacitinib 5 mg BID IR tablets or weight 
equivalent dose of oral solution. 
Study A3921104 was designed to provide evidence of efficacy and safety of tofacitinib in 
subjects with JIA. To limit exposure to placebo in this pediatric population, a randomized 
withdrawal study design was used. Selection of doses for this first efficacy study of tofacitinib 
in subjects with JIA was supported by PK data from the completed Phase 1 PK study of 
tofacitinib in JIA subjects (A3921103) and the benefit/risk profile of tofacitinib in adult 
patients with RA. 
The primary efficacy endpoint of Study A3921104 was met; subjects treated with tofacitinib 5 
mg BID had a significantly lower occurrence of disease flare by Week 44 compared to 
placebo-treated subjects. The type I error controlled (key) secondary endpoints for the study 
were also met at Week 44. A significantly greater proportion of subjects treated with 
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tofacitinib 5 mg BID achieved JIA ACR 50, 30, and 70 responses compared to subjects 
treated with placebo, and the LS mean change from the double-blind baseline in CHAQ 
disability index indicated a statistically significant treatment effect favoring tofacitinib over 
placebo. These results were supported by sensitivity analyses. The proportions of subjects 
with TEAEs, SAEs, severe TEAEs, dose reductions or temporary discontinuations due to 
TEAEs were similar between the tofacitinib 5 mg BID and placebo groups during the double-
blind phase. A larger proportion of subjects in the placebo group had TEAEs related to the 
underlying JIA disease than subjects in the tofacitinib 5 mg BID group. A smaller proportion 
of subjects treated with tofacitinib 5 mg BID discontinued the study because of an AE 
compared to subjects who received placebo. Disease progression and JIA were the most 
frequent AEs leading to study discontinuation. 
In summary, Study A3921104 showed that tofacitinib 5 mg BID treatment in subjects 2 to 
<18 years of age with JIA resulted in significant improvements in the occurrence of disease 
flare at Week 44 compared to subjects treated with placebo. Secondary efficacy results 
supported the primary conclusion.  
An interim analysis was conducted for Study A3921145, the long-term extension study for the 
pediatric studies, at the request of a health authority. At the time of data cutoff, 227 subjects 
had enrolled in the study (signed informed consent), and 2 subjects from Study A3921104 
were enrolled but not treated; 177 subjects were currently ongoing. Insufficient clinical 
response was the most common discontinuation reason to date. In general, available efficacy 
data of long-term treatment with tofacitinib showed stable improvement in JIA symptoms 
from baseline of the qualifying/index studies.  
2.3.3. Overall Benefit/Risk Conclusion 
Based on the totality of the data, the sponsor is of the opinion that the overall risk-benefit 
assessment for this study is favorable for children with sJIA. Study A3921165 provides an 
opportunity for careful evaluation of tofacitinib in sJIA patients in a clinical study 
environment, guided by risk factors specifically described in this protocol. Thorough safety 
monitoring and staggering of cohorts based on age for index studies will be used to minimize 
risk in the pediatric population.  
Further background information on tofacitinib can be obtained from the current version of the 
Tofacitinib IB. 
3. STUDY DESIGN 
3.1. Overview 
This is a 2-phase randomized withdrawal study to evaluate efficacy, safety and tolerability, 
and pharmacokinetics of tofacitinib as a treatment for sJIA.  The study will enroll 
approximately 100 subjects from 2 to <18 years of age with sJIA with active systemic 
features, defined by either: 
• Documented intermittently spiking temperature >38° C/100.4° F due to sJIA for at 
least 1 day in the screening period and within 1 week before the first dose, and 
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presence of at least 2 joints with active arthritis at screening and baseline, and ESR 
˃30 mm/hr [1.5 X ULN] at screening;  
OR 
• Presence of at least 5 joints with active arthritis at screening and baseline, and ESR 
˃30 mm/hr [1.5 X ULN] at screening. 
The study will target enrollment of at least 12 subjects in the following age groups: from 12 to 
<18 years, from 6 <12 years, and from 2 to <6 years.  
The study will conclude when the requisite number of flares are achieved during the double-
blind phase of the study as described in Section 11, Data Analysis/Statistical Methods.   
Subjects will be enrolled into an open-label phase during which they will receive tofacitinib 
5 mg BID oral tablets, or an equivalent weight-based lower dose of tofacitinib oral solution 
(1 mg/mL) BID for subjects <40 kg.  The 5 mg BID dose level of tofacitinib will be evaluated 
in a staggered fashion (cohorts of subjects followed by safety review), as described under 
“Dose Selection” in Section 3.4. 
The open-label phase will be divided into two parts.  In Part 1, all subjects must achieve and 
maintain a protocol defined minimum level of clinical response for at least 4 weeks.  In Part 2 
of the open-label phase, subjects treated with background CSs ˃0.2 mg/kg/day oral 
prednisone (or equivalent) will attempt to have their CS dose tapered to a predetermined 
target range, or lower; subjects who successfully taper their CS dose while maintaining the 
defined clinical response, will be eligible for the double-blind withdrawal phase of the study.  
The minimum total duration of treatment with a stable dose of tofacitinib for subjects 
completing Parts 1 and 2 must be 12 weeks to qualify to enter the randomized withdrawal 
phase of the study. 
In the double-blind withdrawal phase of the study, “responders” from Part 1 and Part 2 of the 
open-label phase will be randomized in a 1:1 ratio to either continue tofacitinib or start 
placebo.  The primary endpoint of the study is time to sJIA flare in the double-blind phase.  
The double-blind withdrawal phase will continue until a sufficient number of flares are 
reported as described in Section 11.  
The Sponsor will use external Centralized Coordinating Centers to review and confirm 
applicable real-time assessments of efficacy, including the Adapted JIA ACR 30/50 response, 
sJIA flare, and inactive disease status (JIA-ACR).  The Coordinating Centers will also 
monitor and offer recommendations on corticosteroid tapering of study participants.  Refer to 
Section 8.1.12 for details on the coordinating centers. The Centralized Coordinating Centers 
will be blinded to study drug assignment in the double-blind withdrawal phase of the study. 
All subjects participating in this study, including those who discontinued in the open-label or 
double-blind phase, will have the option, if eligible (based on inclusion and exclusion 
criteria), of enrolling in the tofacitinib JIA long-term extension study (A3921145) after 
completion of this study.  
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Subjects who flare in the double-blind withdrawal phase will be given the opportunity to 
participate in A3921145 and be treated with open-label tofacitinib.  Subjects who achieve 
ACR clinical remission (ie, maintain JIA ACR inactive disease during 24 consecutive weeks) 
will complete their participation in A3921165 and be given the opportunity to enter 
A3921145.  
Subjects who discontinue Investigational Product in the double-blind phase and who do not 
enter A3921145 will continue in A3921165 for follow up of efficacy and safety endpoints. 
Subjects will be required to perform all scheduled visits until Week 52 after randomization or 
until the study concludes, whichever comes first. Subjects should receive standard-of-care 
treatment in accordance with local treatment guidelines. 
Subjects who discontinue the study in the Open-Label Phase and do not enter A3921145, will 
be required to perform a follow-up visit 28 days after the last dose of study treatment.  
A schematic of the study design is shown below: 
Figure 2. Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
a  Subjects <40 kg will receive an equivalent weight-based lower dose of tofacitinib 5 mg BID. 
b  CS Tapering is only required for subjects treated with CS ˃0.2 mg/kg/day oral prednisone (or equivalent).  
During the active CS tapering period in Part 2 subjects must maintain an Adapted JIA ACR 50 response. 
c aJIA: Adapted JIA.  
d Subjects who discontinue Investigational Product in the randomized withdrawal phase continue in study until 
week 52  
after randomization, or until the study concludes, which ever comes first. 
Screening 
Up to 40 days 
Tofacitinib 5mg BIDa  
+  
Stable Dose 
Corticosteroids (CS) 
Part 1: 
Up to 16 
weeks 
Tofacitinib 5mg BIDa 
+  
Taper CSsb 
Part 2: 
Up to 24 
weeks 
Tofacitinib 5mg BID 
Receive Investigational Product  
up to 1
st sJIA flare, 24 
consecutive weeks inactive 
disease (clinical remission, 
based on ACR criteria),  
or ET/EOSd 
Open labele 
Double-blind 
Rollover into 
Study 1145 
Start CS tapering if 
aJIA ACR 50 achieved 
& 
aJIAc ACR 30 for 4 weeks 
Randomize if  
Stable tapered CS dose for 4 weeks 
& 
aJIA ACR 30 for 4 weeks 
Study End: 
Required # flares 
Placebo BID 
Randomization 
Ratio 1:1 
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e  Subjects who discontinue the study in the open-label phase and do not enter A3921145 within 4 weeks, will 
 
be required to perform a follow-up visit 28 days after the last dose of Investigational Product. 
 
3.2. Open-label Phase: Variable Duration of 12 to 40 Weeks  
The open-label active treatment period will consist of two parts: 
3.2.1. Open-label Phase, Part 1: Treatment with Tofacitinib while on Stable Background 
Therapy  
Part 1 of the open-label active treatment phase is designed to identify tofacitinib-treated 
subjects who are able to achieve and maintain an Adapted JIA ACR 30 response for at least 
4 weeks while continuing on the stable CS dose identified during the screening period prior to 
treatment with tofacitinib.  
All subjects ≥40 kg will receive tofacitinib 5 mg BID oral tablets; however, subjects who 
cannot swallow oral tablets and all subjects <40 kg will receive a weight-based dose of 
tofacitinib oral solution (1 mg/mL) BID with a maximum dose of tofacitinib 5 mg BID.  The 
5 mg BID dose of tofacitinib will be evaluated in a staggered fashion (cohorts of 7 subjects 
followed by safety review, as described under “Dose Selection” in Section 3.4. 
Clinical assessments, including laboratory testing, will be performed at Baseline (Day 1) prior 
to the start of tofacitinib treatment, on Day 3, Day 7, Day 14, Week 4, and thereafter on a 
monthly basis.  
If subjects are using CS treatment at study start, doses must be stable and ≤1.0 mg/kg/day up 
to 30 mg/day oral prednisone (or equivalent), in the last week before the first study drug dose 
(Day 1) and remain stable for the full duration of the Open-label Phase Part 1.  Subjects who 
are not taking CS or are not required to taper CS dosing (subjects taking doses of 
corticosteroids ≤0.2 mg/kg/day) must be able to maintain an Adapted JIA ACR 30 response 
for at least 4 weeks in the Open-label Phase Part 1 will be allowed to proceed to Part 2 of the 
Open-label Phase. CS doses ˃0.2 mg/kg/day must be tapered in Part 2 of the study.  Before 
CS tapering can start in the Open-label Phase Part 2, subjects will be required to achieve an 
Adapted ACR 50 response in the Open-label Phase Part 1 in addition to maintaining an 
Adapted ACR 30 response for 4 weeks.  The duration of the Open-Label Phase Part 1 for each 
subject is variable but will be no longer than 16 weeks. 
Adapted JIA ACR 30 Response/Adapted JIA ACR 50 Response are defined as absence of 
fever due to sJIA (temperature ≤38° C/100.4° F) in the preceding 7 days along with an 
improvement of at least 30% / 50% from baseline (Day 1 of study drug before first tofacitinib 
administration) in at least 3 of the 6 JIA core components, with worsening of ≥30% / ≥50% in 
no more than 1 of the remaining components, which include:  
• Number of joints with active arthritis;  
• Number of joints with limited range of motion; 
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• Physician global evaluation of disease activity (21 circle VAS); 
• Parent/legal guardian/Child evaluation of overall well-being (21 circle VAS); 
• Functional ability (Childhood Health Assessment Questionnaire [C-HAQ]) without 
aids and devices; 
• Erythrocyte Sedimentation Rate (ESR).*  
Note: *For “real-time” assessment of the Adapted JIA ACR 30 Response during a 
study visit the subject’s ESR will be used to determine the percent change in 
inflammation biomarker.  
Subjects who have recurrence of fever due to sJIA lasting more than 2 consecutive days, 
require an increase in their CS dose, fail to achieve an Adapted JIA ACR 30 response by 
Week 12, or maintain an Adapted JIA ACR 30 response for 4 weeks by the end of Part 1 will 
be discontinued from the study.  
3.2.2. Open-label Phase, Part 2: Treatment with Tofacitinib while Tapering 
Corticosteroids  
Part 2 of the open-label active treatment phase serves to taper CSs in subjects receiving CS 
doses ˃0.2 mg/kg/day to a target range as outlined in Table 1.  Subjects will have study visits 
on a monthly basis in Part 2. 
Subjects who are treated with stable oral prednisone (or equivalent) doses ≤0.2 mg/kg/day 
who are able to maintain an Adapted JIA ACR 30 response for 4 weeks in Part 1 are allowed 
to skip Part 2 and be randomized in the Double-Blind Withdrawal Phase of the study 
(12-week minimum tofacitinib treatment duration in the Open-Label Phase is required).  
The time period of Part 2 is variable, but no longer than 24 weeks, and CS tapering will only 
be allowed in the first 20 weeks.  A subject must be on the final tapered CS dose on or before 
the day after the week 20 visit in Open-label Part 2.  CS tapering in the Open-label Phase 
Part 2 can continue as long as an Adapted JIA ACR 50 response is maintained.  After CS 
tapering to the target range (Table 1), or lower (Table 2), a subject must remain on a stable 
tapered CS dose and maintain an Adapted JIA ACR 30 response (minimum) for at least 
4 weeks before randomization to the double-blind withdrawal phase. Subjects taking CS doses 
>0.2 mg/kg/day who fail to achieve an Adapted ACR 50 response during Part 2 of the Open-
label phase of the study will be discontinued from the study and will not be randomized into 
the double-blind phase of the study. 
The minimum total duration of treatment with a stable dose of tofacitinib for subjects 
completing Open-label Phase Parts 1 and 2 must be 12 weeks to qualify to enter the 
randomized withdrawal phase of the study. 
3.2.2.1. Mandatory CS Tapering before Randomization 
The CS tapering criteria in Table 1 are the minimum target criteria that a subject has to meet 
by the end of Part 2 to be eligible for randomization; however, investigators are encouraged to 
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taper down to lower CS doses (Table 2), as long as an Adapted JIA ACR 50 response is 
maintained.  
The Centralized Coordinating Centers will provide a suggested customized 4-week CS 
tapering schedule for each subject entering Part 2 based on protocol guidelines as per Table 1.  
In general, CS doses should be tapered by 0.1 mg/kg/week of oral prednisone or equivalent 
providing that subjects are able to maintain an Adapted JIA ACR 50 response.  
Table 1. 
Mandatory Corticosteroid Tapering Required Before Randomization 
Tapering criteria - Start dose at End Part 1 
End dose after tapering by End Part 2 
CS ˃0.8 mg/kg/day oral prednisone (or 
equivalent) 
≤0.5 mg/kg/day up to a maximum dose of 
15 mg/day oral prednisone (or equivalent)  
CS ≤0.8 mg/kg/day- ≥0.5 mg/kg/day oral 
prednisone (or equivalent) 
Reduction to ≤0.3 mg/kg/day up to a 
maximum of 12 mg/day oral prednisone 
(or equivalent)  
CS <0.5 mg/kg/day – CS ˃0.2 mg/kg/day 
oral prednisone (or equivalent) 
≤0.2 mg/kg/day up to a maximum dose of 
10 mg/day oral prednisone (or equivalent) 
3.2.2.2. Two Corticosteroid Tapering Failures are Allowed 
CS tapering can continue as long as: 
Between study visits the subject does not report any sJIA associated fever or flares 
according to the investigator’s judgment. 
The subject maintains an Adapted JIA ACR 50 response at time of site visits.  
CS tapering failure is defined as loss of Adapted JIA ACR 50 response.  Subjects will be 
allowed to fail the CS tapering criteria twice in Part 2.  If after 2 tapering failures the subject 
fails to taper CS a third time, they will be discontinued from the study and offered the 
possibility to enter the A3921145 study if eligible. 
If a subject has a first CS tapering failure, continuation in the study will be allowed, but the 
steroid dose will be increased to the level of the previous visit, or higher, at the judgment of 
the investigator.  The increased CS dose cannot exceed 1.0 mg/kg/day up to 30 mg/day of oral 
prednisone (or equivalent).  This increased CS dose will be maintained for at least 2 weeks.  
Subsequent attempts of steroid tapering may occur only if the subject has re-achieved an 
Adapted JIA ACR 50 response.  If after 2 weeks, the subject does not re-achieve an Adapted 
JIA ACR 50 response this will be considered a second tapering failure.  If the subject fails a 
third CS tapering attempt they will be discontinued from the study.  
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3.2.2.3. Optional Further CS Tapering before Randomization 
If and when the oral prednisone (or equivalent) dose is at 0.2 mg/kg/day (or 10 mg/day 
whichever is lower), the investigator is encouraged to consider further reduction of the CS 
dose according the criteria in Table 2, as long as the subject maintains an Adapted JIA ACR 
50 response. 
Optional CS tapering is at the Investigator’s discretion:  
Table 2. 
Optional Corticosteroid Tapering if Dose ≤0.2 mg/kg/day 
CS Start dose ≤0.2 mg/kg/day  
CS End dose after tapering by End Part 2 
˃0.1 mg/kg/day oral prednisone (or 
equivalent) 
Taper at 0.1 mg/kg per week until at dose of 
0.1 mg/kg/day 
= 0.1 mg/kg/day of oral prednisone (or 
equivalent) 
Taper to dose of 0.05 mg/kg/day for 1 week 
<0.05 mg/kg/day of oral prednisone (or 
equivalent) 
Alternate dosing days (ie, take dose every 
48 hours) for 2 weeks and then discontinue 
3.3. Randomized Withdrawal Phase  
Subjects who are able to maintain an Adapted JIA ACR 30 response for at least 4 weeks in the 
open-label phase are eligible for the double-blind withdrawal phase.  
Eligible subjects will be randomized in a 1:1 ratio to either continue on the same dose of 
tofacitinib that they received in the open-label phase or start placebo.  They will have monthly 
visits in the withdrawal phase.  The sustained efficacy of tofacitinib will be assessed during 
this period by measurement of time to sJIA flare and other efficacy endpoints.  The study will 
continue until a sufficient number of subjects have reported flare.  Refer to Section 10.1 for 
details on the estimated number of flares required and estimated duration of the double-blind 
phase. 
Subjects will continue in the double-blind phase of the study until one of the following events 
occur: 
• The subject experiences an sJIA flare during the double-blind phase 
• After randomization into the double-blind phase, the subject experiences 24 
consecutive weeks of inactive disease as assessed using JIA ACR (clinical 
remission) 
sJIA Flare is defined as at least one of the following: 
• Recurrence of fever [(>38° C/100.4° F) on 2 or more consecutive days] considered to 
be due to sJIA activity.  
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• Worsening of 30% or more in three or more of the six variables of the JIA core set 
with no more than one variable of the JIA core set improving by 30% compared to the 
day of randomization into the withdrawal phase. 
Note: For “real-time” assessment of sJIA flares during a study visit the subject’s ESR 
will be used to determine the JIA core component related to percent change in 
inflammation biomarker.  
After randomization, subjects will be required to maintain a stable dose of CSs during the 
withdrawal phase.  Subjects who flare at any time during the randomized withdrawal phase, or 
who experience 24 consecutive weeks of inactive disease as assessed using JIA ACR (clinical 
remission) (Wallace 2011)16, will complete their participation in the study. An end-of-study 
visit should be performed.  Subjects who discontinue Investigational Product in the 
double-blind phase of the study due to any reason will be counted as having an sJIA flare in 
the primary analysis for the primary endpoint of the study and will contribute to the requisite 
number of subjects with flare for the study to be considered complete.  Subjects who achieve 
clinical remission are completers of the study and will not be counted as having an sJIA flare 
in the primary analysis. Upon notification by the Sponsor, an end-of-study visit should be 
scheduled for all remaining subjects in the study in accordance with Section 6.8.  
All subjects participating in this study, including those discontinued from the study, will have 
the option, if eligible, of enrolling in the tofacitinib long-term extension study (A3921145).  
The Sponsor’s intent is to make tofacitinib available to pediatric subjects through Study 
A3921145.  
Subjects who discontinue Investigational Product in the double-blind phase for reasons other 
than sJIA flare, and who do not enter A3921145 are required to continue in the study and 
perform all scheduled visits until Week 52 after randomization or until the study concludes, 
whichever comes first. Such subjects should transition to standard-of-care treatment in 
accordance with local treatment guidelines.   
3.4. Sequential Evaluation of Tofacitinib 5 mg BID Dose in Cohorts in Part 1  
Dosing will not exceed 5 mg BID, which is the approved dose for adult RA patients. 
Tofacitinib 5 mg BID: Initially, only subjects aged ≥12 years, with active sJIA defined by the 
presence of fever (sJIA fever) and weighing ≥40 kg will be enrolled in a staggered fashion 
into 2 (or more) sequential cohorts of 7 subjects to receive tofacitinib 5 mg BID.  The 
Sponsor, with the guidance of a Steering Committee, will assess safety, efficacy and 
pharmacokinetics of the tofacitinib 5 mg BID dose in these initial cohorts.  Decisions to open 
enrollment at the 5 mg BID dose level to those weighing <40 kg, and those aged <12 years 
after completion of the initial cohorts will be based on observed safety, systemic exposure to 
tofacitinib and efficacy (based on the Adapted JIA ACR 30 response rate; Refer to 
Section 10.3 for details) in the initial cohorts.  If the Sponsor and Steering Committee 
consider open enrollment at the tofacitinib 5 mg BID dose level warranted, additional subjects 
will be enrolled without restrictions, including those without sJIA fever and those weighing 
<40 kg or less than 12 years of age.  
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The recommended progression is outlined in Figure 3. 
Figure 3. Tofacitinib Evaluation Schema 
 
*The Steering committee may review the data of initial cohorts receiving 5 mg BID before all subjects have received 
12 weeks of study treatment dependent on observed efficacy and safety.  
3.4.1. Evaluation of 5 mg BID or Equivalent Weight-based Lower Dose  
As of Amendment 6, Cohort 1 and Cohort 2 are completed; open enrollment is ongoing. 
3.4.1.1. Cohort 1 
Enrollment started in a first cohort of 7 subjects aged ≥12 years, weighing ≥40 kg and with 
sJIA fever who received tofacitinib 5 mg BID.  
The Sponsor monitored this first cohort closely to evaluate safety and preliminary efficacy. 
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3.4.1.2. Cohort 2 
As no significant safety issues were observed after 4 weeks of treatment in Cohort 1, a second 
confirmatory cohort of 7 subjects aged ≥12 years, weighing ≥40 kg and with sJIA fever were 
enrolled at the 5 mg BID dose level.   
After 12 weeks of study treatment, the Sponsor submitted the available safety and efficacy 
data of each cohort for review by the Steering Committee.  The Steering Committee provided 
guidance to the Sponsor regarding continuation of testing of tofacitinib at the 5 mg BID dose 
level.  The Steering committee reviewed the data of initial cohorts receiving 5 mg BID before 
all subjects have received 12 weeks of study treatment.  
3.4.1.3. Open Enrollment at the 5 mg BID Dose Level 
Acceptable efficacy and safety of the 5 mg BID dose level was confirmed in the 2 cohorts at 
which time, enrollment was opened to additional subjects, including subjects less than 
12 years old, without sJIA fever, and weighing less than 40 kg.  Decisions to open enrollment 
at the 5 mg BID dose level were based on observed safety, systemic exposure to tofacitinib 
and efficacy based on the Adapted JIA ACR 30 response rate (Refer to Section 10.3 for 
details) in the initial cohorts. The details of composition and scope of the Steering Committee 
is described in the Steering Committee charter. 
4. SUBJECT SELECTION 
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.  
4.1. Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study. 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the 
study: 
1. Male or female aged 2 to <18 years. 
2. Diagnosed with sJIA according to International League Against Rheumatism (ILAR) 
criteria, and, in the opinion of the investigator, have active disease prior to screening.  
Subjects with first-degree relatives with history of psoriasis, ankylosing spondylitis, 
enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s 
syndrome, or acute anterior uveitis may be allowed for enrollment after consultation 
with the sponsor.31  Subjects must have active disease at the time of enrollment, 
defined as: 
a. Documented intermittently spiking temperature >38° C/100.4° F for at least 1 day 
due to sJIA in the screening period and within 1 week before the first dose, and the 
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presence of at least 2 joints with active arthritis at screening and baseline, and an 
ESR ˃30 mm/hr. [1.5 X ULN] at screening.  
OR  
b. Only after cohort review is completed and enrollment is opened without 
restrictions: The presence of at least 5 joints with active arthritis at screening and 
baseline, and an ESR ˃30 mm/hr. [1.5 X ULN] at screening.  Refer to Section 3.4 
for details. 
3. Treatment with stable doses of methotrexate (MTX) and/or oral CSs is permitted: 
• For subjects taking MTX: Treatment for ≥3 months with MTX and with a stable 
dose of MTX (dose must be ≤25 mg/wk or ≤20 mg/m2/week, whichever is lower) 
for at least 4 weeks before the first study drug dose (Day 1).  Subjects taking MTX 
must be taking folic acid or folinic acid in accordance with local standards; 
• For subjects taking CS: Treatment with a stable dose of oral prednisone 
(≤1 mg/kg/day up to a maximum of 30 mg/day), or equivalent, for at least 1 week 
before the first study drug dose (Day 1).  
4. No evidence or history of untreated or inadequately treated active or latent 
tuberculosis (TB) infection as evidenced by the following:  
• A negative QuantiFERON®-TB Gold or Gold Plus In-Tube test performed within 
the 3 months prior to screening.  A negative QuantiFERON®-TB test performed 
locally or a negative purified protein derivative (PPD) or T-spot test can be 
substituted for the QuantiFERON®-TB Gold or Gold Plus In-Tube test only if the 
central laboratory is unable to perform the test or cannot determine the results to be 
positive or negative and the Pfizer medical monitor is informed and agrees on a 
case-by-case basis;  
• Chest radiograph without changes suggestive of active tuberculosis (TB) infection 
within 3 months prior to screening is recommended and should be performed 
according to local standards of care or country-specific guidelines;  
Note: If a subject has previously received an adequate course of therapy for either 
latent (9 months of isoniazid in a locale where rates of primary multi-drug resistant TB 
infection are <5% or an acceptable alternative regimen) or active (acceptable 
multi-drug regimen) TB infection, neither a PPD test nor a QuantiFERON®-TB Gold 
or Gold Plus test need be obtained.  A chest radiograph may be obtained to aid in TB 
status determination, according to local standards and/or in countries with a high 
incidence rate of TB (see Section 8.2.8).  To be considered eligible for the study, the 
chest radiograph must be negative for active tuberculosis infection. 
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, 
documentation of an adequate treatment regimen, and prior approval of the Sponsor.  
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The sponsor considers ongoing treatment with isoniazid or equivalent for at least 
4 weeks before the first dose of tofacitinib (Day 1) adequate, provided that local rates 
of primary multi-drug resistant TB infection are <5%. 
5. Fertile males and females who are, in the opinion of the investigator, sexually active 
and at risk for pregnancy with their partner(s) must be willing and able to use a highly 
effective method of contraception as outlined in this protocol during the study and for 
at least 28 days after the last dose of study medication (see Section 4.4.1). 
Country-specific amendment for EU sites (including UK): Subjects who are, in the 
opinion of the investigator, sexually active and at risk for pregnancy with their 
partner(s) must agree to use 2 methods of contraception (at least one of which is 
considered to be highly effective with low user dependency as defined below) 
throughout the study and for at least 28 days (90 days for male subjects) after the last 
dose of study drug where there is known or suspected teratogenicity (see 
Section 4.4.1). 
6. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures. 
7. Evidence of a personally signed and dated Informed Consent document and Assent 
document (as appropriate) indicating that the subject and a legally acceptable 
representative/parent/legal guardian has been informed of all pertinent aspects of the 
study.  
4.2. Exclusion Criteria 
Subjects with any of the following characteristics/conditions will not be included in the study: 
1. Previous JIA treatment with tofacitinib. 
2. Current symptoms or findings of myocarditis, endocarditis or more than minimal 
pericardial effusion associated with sJIA. 
3. Current symptoms or findings of more than minimal pleuritis with sJIA. 
4. Subjects who are still within the washout periods for disallowed nonbiological and 
biological DMARDs as indicated in Section 5.8.1.2.   
5. Infections: 
a. Chronic infections; 
b. Any infection requiring hospitalization, parenteral antimicrobial therapy or judged 
to be opportunistic by the investigator within the 3 months prior to the first dose of 
study drug; 
c. Any treated infections within 2 weeks of baseline; 
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d. A subject known to be infected with Human Immunodeficiency Virus (HIV), 
Hepatitis B, or Hepatitis C (see Section 8.2.9); 
e. History of infected joint prosthesis with prosthesis still in situ. 
6. History of recurrent (more than one episode) herpes zoster or disseminated (at least 
one episode) herpes zoster, or disseminated (at least one episode) herpes simplex. 
7. Diagnosis of active Macrophage Activation Syndrome (MAS) within 3 months prior to 
the first dose of study drug. 
8. Blood dyscrasias, including (see Appendix 7): 
a. Hemoglobin <9 g/dL; 
b. White Blood Cell count <3.0 x 109/L; 
c. Absolute Neutrophil count <1.2 x 109/L; 
d. Platelet count <100 x 109/L; 
e. Absolute Lymphocyte count <0.75 x 109/L. 
9. Estimated glomerular filtration rate [eGFR] <40 mL/min/1.73 m2 at Screening.  eGFR 
will be calculated by the central lab using the bedside Schwartz formula (see 
Appendix 4). 
10. Current or recent history of uncontrolled clinically significant renal, hepatic, 
hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurologic 
disease. 
11. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥1.5 times the 
upper limit of normal or any other clinically significant laboratory abnormality (see 
Appendix 7).  
12. History of any other rheumatologic disease, other than Sjogren’s syndrome. 
13. History or current symptoms suggestive of lymphoproliferative disorders (eg, Epstein 
Barr Virus [EBV] related lymphoproliferative disorder, lymphoma, leukemia, or signs 
and symptoms suggestive of current lymphatic disease). 
14. Vaccinated or exposed to a live vaccine within the 6 weeks prior to the first dose of 
study drug, or is expected to be vaccinated or there are household members that 
require oral polio vaccination (see Section 4.5.2 Vaccination in Household Members) 
during treatment or during the 6 weeks following discontinuation of study drug. 
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15. Current malignancy or history of any malignancy with the exception of adequately 
treated or excised basal cell or squamous cell carcinoma of the skin or cervical 
carcinoma in situ. 
16. Subjects with a first degree relative with a hereditary immunodeficiency; IgA 
deficiency not exclusionary.  
17. Recent (within 28 days prior to first dose of study drug) significant trauma or major 
surgery. 
18. Subjects receiving potent and moderate CYP3A4 inhibitors or inducers (Appendix 5). 
19. Prior treatment with non B cell-specific lymphocyte depleting agents/therapies (eg, 
alemtuzumab [CAMPATH®], alkylating agents [eg, cyclophosphamide or 
chlorambucil], total lymphoid irradiation, etc.).  Subjects who have received rituximab 
or other selective B lymphocyte depleting agents (including experimental agents) are 
eligible if they have not received such therapy for at least 1 year prior to study baseline 
and have normal CD 19/20+ counts by FACS analysis. 
20. Use of prohibited prescription or non-prescription drugs and dietary supplements listed 
in Appendix 1 and Appendix 5 within the specified time frame prior to the first dose of 
study medication.  
21. Herbal supplements, unless discontinued at least 28 days prior to the first dose of study 
medication. 
22. Subjects who are children of or related to investigational site staff members, site staff 
members otherwise supervised by the investigator, or Pfizer employees directly 
involved in the conduct of the study. 
23. Participation in other studies involving investigational drug(s) within 4 weeks or 
5 half-lives (whichever is longer) prior to study entry and/or during study 
participation.  Exposure to investigational biologics should be discussed with the 
Sponsor. 
24. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of study 
results and, in the judgment of the investigator, would make the subject inappropriate 
for entry into this study. 
25. Pregnant female subjects; breastfeeding female subjects; male subjects with partners 
currently pregnant; male subjects able to father children and female subjects of 
childbearing potential who are unwilling or unable to use a highly effective method of 
contraception as outlined in this protocol for the duration of the study and for at least 
28 days after the last dose of investigational product or longer based upon the 
compound’s half-life characteristics. 
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26. Any factors or clinical characteristics potentially related to the risk of venous 
thromboembolism (see Section 8.2.13, Risk Factor Check for VTE) 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. 
28. History of allergies, intolerance or hypersensitivity to lactose or CP-690,550 
(tofacitinib), or any other excipients of the investigational medicinal products, 
including placebos.  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.  As the oral 
solution does not include lactose, subjects with hereditary or acquired lactose 
intolerance may be treated with the tofacitinib oral solution, instead of the tablet, at the 
investigators request. 
4.3. Randomization Criteria 
Before randomization, all subjects enrolled in the study will receive open-label tofacitinib 
5 mg BID oral tablets or solution (1 mg/mL), or an equivalent weight-based lower dose of 
solution (1 mg/mL).  Refer to Table 3 for details. 
The time period of the open-label phase will be between 12 and 40 weeks.  Only subjects who 
are able to maintain a minimal clinical response for 4 weeks in the open-label phase at an 
allowed CS dose will proceed to randomization.  Eligibility of the subject must be confirmed 
before randomization.  
Eligible subjects will be randomized in a 1:1 ratio into the double-blind withdrawal phase to 
either continue tofacitinib treatment or withdraw the tofacitinib dose and start placebo.  
Randomization will be stratified by age group.  
4.4. Lifestyle Guidelines 
4.4.1. Contraception 
All fertile male subjects and female subjects of childbearing potential who are, in the opinion 
of the investigator, sexually active and at risk for pregnancy with their partner(s) must agree 
to use a highly effective method of contraception consistently and correctly for the duration of 
the active treatment period and for at least 28 days after the last dose of investigational 
product.  The investigator or his or her designee, in consultation with the subject and his/her 
legally acceptable representative/parent(s)/legal guardian, will confirm that the subject has 
selected an appropriate method of contraception from the list of permitted contraception 
methods (see below).  At the time points indicated in the Schedule of Activities (SOA), the 
investigator or designee will instruct the subject of the need to use highly effective 
contraception consistently and correctly and document the conversation, and the subject’s 
affirmation, in the subject’s chart.  In addition, the investigator or his or her designee will 
instruct the subject to call immediately if the selected contraception method is discontinued or 
if pregnancy is known or suspected in the subject or the subject’s partner.  
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Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following: 
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted or transdermal) provided the subject 
plans to remain on the same treatment throughout the entire study and has been using 
that hormonal contraceptive for an adequate period of time to ensure effectiveness. 
2. Correctly placed copper-containing intrauterine device (IUD).  
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate. 
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.  
All subjects who are, in the opinion of the investigator, sexually active and at risk for 
pregnancy with their partner(s), and are on background medications (including DMARDs) 
that require contraceptive measures according to the local drug label must meet those 
requirements during the study and after therapy for 3 months or for the duration specified in 
the local drug label. 
Country specific amendment for EU sites (including UK): Subjects who are, in the opinion 
of the investigator, sexually active and at risk for pregnancy with their partner(s) must agree 
to use 2 methods of contraception (at least one of which is considered to be highly effective 
with low user dependency as defined below) throughout the study and for at least 28 days (90 
days for male subjects) after the last dose of study drug where there is known or suspected 
teratogenicity. 
Highly effective methods of contraception with low user dependency (applies to female 
subjects at risk for pregnancy with their male partners):  
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (inserted, injected, and implanted).  
2. Correctly placed intrauterine device (IUD) or intrauterine system (IUS). 
3. Male sterilization with absence of sperm in the post vasectomy ejaculate. 
4. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion had been confirmed in accordance with the device’s label). 
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4.5. Vaccine and Exposure to Infections Guidelines 
4.5.1. Subject Specific Recommendations 
It is recommended that all subjects should be up-to-date with respect to standard of care 
vaccinations (as defined by their country health ministry) or JIA guidelines.   
Varicella vaccination is encouraged when appropriate, but if the participant is vaccinated, first 
dose of study drug (Day 1) may not be administered until at least 4 weeks after vaccination. 
Other live vaccines should not be administered to study subjects within the 6 weeks prior to 
the first dose of study drug and throughout the study for example: live attenuated influenza 
vaccine, MMR (measles, mumps, and rubella) vaccine, or MMR-V (measles, mumps, rubella 
and varicella) vaccine.  
For subjects who have not been vaccinated for varicella and do not have a positive VZV IgG 
Ab serology test at screening, evaluate the subject for varicella at every study visit. For those 
subjects who have been vaccinated or have a positive VZV IgG Ab serology test at screening, 
evaluate the subject for herpes zoster at every visit. Please refer to Section 9.2.6  regarding the 
diagnosis and treatment of varicella and herpes zoster in study subjects. Inactivated vaccines, 
including inactivated influenza vaccine, pneumococcal conjugate vaccine and pneumococcal 
polysaccharide vaccines, may be administered to study subjects during the conduct of the 
study.  
Administration of non-live COVID-19 vaccines that are fully approved or approved for 
emergency use is permitted during the study, provided that the vaccination is not part of 
another clinical study.  Examples include, but are not limited to, mRNA vaccines, adenovirus 
vector vaccines and inactivated COVID-19 vaccine.  If a participant receives a non-live 
COVID-19 vaccine during the study, it should be recorded as a concomitant medication and 
standard AE collection and reporting processes would be followed. 
4.5.2. Guidance Regarding Household Contact Vaccine-Related Exposure 
In accordance with the Infectious Disease Society of America’s guidance for vaccination in 
immunocompromised individuals, the following is a guide for study subjects and their 
household contacts. 
Immunocompetent individuals who live in a household with the study subject can safely 
receive inactivated vaccines based on the standard of care vaccination schedules for children 
and adults or for travel (as defined by their country health ministry) or JIA guidelines.   
Individuals who live in a household with a study subject should receive influenza vaccine 
annually. They can receive either: (a) inactivated influenza vaccine or (b) live attenuated 
influenza vaccine (LAIV) provided they are healthy and otherwise eligible.  
Healthy immunocompetent individuals who live in a household with a study subject should 
receive the following live vaccines based on the CDC annual schedule: combined measles, 
mumps, and rubella (MMR) vaccines; rotavirus vaccine in infants aged 2–7 months; varicella 
vaccine; and zoster vaccine. Also, these individuals can safely receive the following vaccines 
for travel: yellow fever vaccine and oral typhoid vaccine. 
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Oral polio vaccine (OPV) should not be administered to individuals who live in a household 
with a study subject. 
Study subjects should avoid handling diapers of infants who have been vaccinated with 
rotavirus vaccine for 4 weeks after vaccination. 
Immunocompromised patients should avoid contact with persons who develop skin lesions 
after receipt of varicella or zoster vaccination until the lesions clear. 
Subjects should avoid exposure to infected persons and contact the Investigator promptly 
should they develop signs or symptoms of infection. 
4.6. Non-Pharmacologic Interventions 
The subject may continue, add, or remove all non-pharmacological therapies, such as physical 
therapy, as indicated and deemed appropriate for his/her physical condition. 
4.7. Elective Surgery 
During the course of this trial, no elective surgery should be scheduled without first consulting 
with the Pfizer Medical Monitor. 
Subjects who do require surgery should temporarily discontinue study medication for one 
week prior to the surgical procedure and remain off study medication after the surgical 
procedure until sutures/staples are removed, if the investigator determines this is clinically 
appropriate for the subject.  If absorbing sutures or chemical closure methods are utilized, 
study medication can be resumed when the operative site is sufficiently healed, and risk of 
infection is minimal. 
4.8. 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).  
Subjects who are treated with methotrexate should be taking supplemental folic or folinic 
acid. 
Herbals supplements are prohibited (see Section 5.8, Concomitant Treatments, for additional 
details). 
4.9. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study manual.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study numbers, 
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contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact center number can also be used by 
investigational staff if they are seeking advice on medical questions or problems; however, it 
should only be used in the event that the established communication pathways between the 
investigational site and the study team are not available.  It is therefore intended to augment, 
but not replace, the established communication pathways between the investigational site and 
the study team for advice on medical questions or problems that may arise during the study.  
The contact center number is not intended for use by the subject directly, and if a subject calls 
that number, he or she will be directed back to the investigational site. 
5. STUDY TREATMENTS 
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33). 
5.1. Allocation to Treatment 
The study will enroll approximately 100 subjects from 2 to <18 years and target enrollment of 
at least 12 subjects in each of the following age groups: from 12 to <18 years, from 6 to 
<12 years, and from 2 to <6 years.  
All eligible subjects enrolled in the study will initially be assigned to receive a stable dose of 
tofacitinib for up to 40 weeks in an open-label phase (Part 1 and 2).  Only subjects who 
qualify as “responders” will afterwards be randomized in a 1:1 ratio, stratified by age group, 
into the double-blind phase to continue tofacitinib or start placebo.  
Assignment of a subject number, allocation of tofacitinib in the open-label phase and 
randomization to tofacitinib or placebo in the double-blind phase will proceed through the use 
of an Interactive Response Technology (IRT) system.  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, the subject number, the 
subject’s weight and the date of birth of the subject (where permitted by local laws and 
regulations).  The site personnel will then be provided with a treatment assignment and 
dispensable unit (DU) or container number when drug is being supplied via the IRT system.  
The IRT system will provide a confirmation report containing the subject number and DU or 
container number assigned.  The confirmation report must be stored in the site’s files.  
There is a 24 hour a day, 365 days a year IRT helpdesk available for any questions or issues.  
The study specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system.  
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The IRT system is the source of the subject number.  The IRT system will provide the subject 
number at the end of the first IRT subject transaction.  
5.1.1. Open-Label Phase 
In the open-label phase of the study subjects ≥40 kg will receive tofacitinib 5 mg BID oral 
tablets or solution (1 mg/mL) and subjects <40 kg a weight-proportional lower dose of 
tofacitinib oral solution (1 mg/mL) BID as specified in Table 3 (see Section 5.5).  
Assignment to the 5 mg BID dose of tofacitinib in the open-label will proceed through the use 
of an Interactive Response Technology (IRT) system.  
5.1.1.1. Enrollment in 5 mg BID Cohort 
Initially, the 5 mg BID dose level was evaluated in cohorts of 7 subjects each. At the start of 
the open-label phase, subjects were assigned to tofacitinib 5 mg BID via the IRT system in 2 
or more consecutive cohorts to allow for a preliminary assessment of PK, safety and clinical 
response.  These first participants enrolled at the 5 mg BID dose level had to qualify for 
enrollment based on the presence of fever, weigh at least 40 kg and be 12 years of age or 
older.  No additional subjects were allowed to enroll until the evaluation of the 5 mg BID dose 
level in the initial cohorts by the Sponsor and Steering Committee was complete. If the 5 mg 
BID dose level had not demonstrated acceptable efficacy and safety in the initial cohorts, all 
subjects treated with this dose level would have been discontinued. 
5.1.1.2. Open Enrollment at the 5 mg BID Dose Level 
After review of the 5 mg BID cohort data, the Sponsor and Steering Committee considered 
this dosing regimen to be effective and agreed that additional subjects could be enrolled 
without sJIA fever, and could include subjects weighing <40 kg or less than 12 years of age.     
5.1.1.3. Double-Blind Phase 
Subjects who enter the double-blind phase will be randomized via the IRT system in a 
1:1 ratio to either continue treatment with the 5 mg BID dose of tofacitinib tablets/oral 
solution or matching placebo.  Randomization will be stratified by age group.  
5.2. Breaking the Blind 
During the double-blind phase of the study, the Sponsor, subject and investigator site staff 
will be blinded to the subject’s treatment assignment.  At the initiation of the study, the study 
site will be instructed on the method for breaking the blind.  The method will be either a 
manual or an electronic process.  Blinding codes should be broken only in emergency 
situations for reasons of subject safety.  Whenever possible, the investigator or 
sub-investigator consults with a member of the study team prior to breaking the blind.  When 
the blinding code is broken, the reason must be fully documented and entered on the case 
report form (CRF). 
Country specific amendment for EU sites (including UK): 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 
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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 case 
report form (CRF). 
5.3. Subject Compliance 
Subject compliance will be assessed at each visit during the study and will be verified by 
interviewing subjects and through accounting of returned containers and trial medication at 
each visit.  
Non-compliance (ie, missed or incorrect dosing where compliance is calculated to be <80% or 
>110%) will be documented on the Compliance Case Report Form (CRF).  In subjects who 
demonstrate non-compliance between visit intervals, both the subject and parent/legal 
guardian will be counseled by study staff to address reasons for non-compliance.  If after 
counseling the subject continues to exhibit non-compliance over two consecutive or 
nonconsecutive study visits, the subject may be withdrawn from the study after discussion 
with the Sponsor. 
5.4. Investigational Product Supplies 
5.4.1. Dosage Form(s) and Packaging 
Tofacitinib will be provided as oral tablets (tofacitinib 5 mg) and as an oral solution 
(CP-690,550 [the compound name for tofacitinib] 1 mg/mL) by the Sponsor.  Tofacitinib 
tablets, oral solution and matching placebo, for oral administration, will be supplied in 
child-resistant bottles to the investigator site. 
Open-label bottles of tofacitinib tablets and CP-690,550 (compound name for tofacitinib) oral 
solution will be provided for the open-label phase of the study. 
Blinded-label bottles of tofacitinib tablets, CP-690,550 (compound name for tofacitinib) oral 
solution, and matching placebo, for oral administration, will be provided for the double-blind 
withdrawal phase of the study.  
5.4.2. Preparation and Dispensing 
Investigational product will be supplied to subjects in bottles, which, along with written 
dosing instructions (dosing cards), will be dispensed by an appropriately qualified member of 
the study staff (eg, physician, nurse, physician’s assistant, practitioner, or pharmacist) as 
allowed by local, state, and institutional guidance. 
Oral solution will be administered via oral dosing syringes which will be dispensed along with 
oral solution bottles. 
5.5. Administration 
During the open-label phase (12 to 40 weeks), all subjects will receive active tofacitinib oral 
tablets or oral solution twice daily (BID) orally, approximately 12 hours (±2 hours) apart, in 
the morning and evening, at a dosage based on the subject’s body weight as specified in 
Table 3.  In the open-label phase, subjects ≥40 kg will receive tofacitinib 5 mg BID as oral 
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tablets or solution (1 mg/mL).  Subjects who are unable to swallow tablets will have the 
option of taking oral solution.  All subjects <40 kg will receive an equivalent weight-based 
lower dose of tofacitinib oral solution (1 mg/mL) BID as specified in Table 3.  At each visit 
the appropriate dose will be assigned via the IRT system based on the subject’s weight.  
Subjects should swallow investigational product tablets whole and not manipulate or chew 
them prior to swallowing.  Dosing cards with clear written instructions on how to properly 
take study medication will be provided to the subject with study medication.  
Table 3. 
Study Treatment Dosing and Administration 
Body Weight (kg) 
Dosage Regimen 
(Run-In Phase: Tofacitinib, Double-Blind Phase: Tofacitinib/Placebo) 
 
5 mg BID dose level 
5 - <7 
2 mg (2 mL oral solution) BID 
7 - <10 
2.5 mg (2.5 mL oral solution) BID 
10 - <15 
3 mg (3 mL oral solution) BID 
15 - <25 
3.5 mg (3.5 mL oral solution) BID 
25 - <40 
4 mg (4 mL oral solution) BID 
≥40 
5 mg (one 5 mg tablet or 5 mL oral solution) BID 
After the 12-40 weeks open-label phase, eligible subjects will proceed to the double-blind, 
placebo-controlled phase.  They will be randomized in a 1:1 ratio to receive either active 
tofacitinib oral tablets/oral solution or matching placebo oral tablets/oral solution, twice daily 
(BID), approximately 12 hours (±2 hours) apart, in the morning and evening, at a dosage 
based on the subject’s body weight as specified in Table 3. 
5.6. Investigational Product Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparator and/or marketed products are stored in a 
secured area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements. 
Investigational product should be stored in its original container and in accordance with the 
label.  
Storage conditions stated in the SRSD will be superseded by the storage conditions stated in 
the labeling. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation for 
excursions should be available.  The operation of the temperature monitoring device should be 
regularly inspected to ensure it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
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described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion.  Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation.  Specific details regarding 
information the site should report for each excursion will be provided to the site.  
Site staff will instruct subjects on the proper storage requirements for take home 
investigational product. 
All bottles must be returned to the investigator by the subject.  
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.  To ensure adequate records, all drug 
supplies will be accounted for in the drug accountability inventory forms as instructed by 
Pfizer and will be monitored by the accounting of unused investigational product returned by 
the subjects.  
5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of any unused 
investigational product (eg, at the site).  If Pfizer authorizes destruction at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer.  Destruction must be adequately documented.  
5.8. Concomitant Treatment(s) 
All concomitant medication taken during the study must be recorded with generic name of the 
medication, indication, daily dose, and start and stop dates of administration. 
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.  Medications taken after informed consent is obtained but before the first dose of 
study medication will be documented as prior medications.  Medications taken after the first 
dose of study drug has been administered will be documented as concomitant medications.  
5.8.1. Allowed sJIA Background Therapy 
After enrollment, subjects are allowed to continue on their stable background arthritis therapy, 
which can include nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 
(COX-2) inhibitors (see Appendix 3), allowed DMARDs (methotrexate - Section 5.8.1.2), and 
Corticosteroids (CSs) (See Section 5.8.1.1). 
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See Appendix 3 for instructions on permitted adjustments in concomitant RA therapies during 
the study. 
Herbal supplements 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).  
5.8.1.1. Corticosteroids (CSs) 
Subjects who are treated with CSs before study start, will be allowed to continue CS treatment 
provided that doses are ≤1.0 mg/kg/day prednisone or equivalent (up to a maximum dose of 
30 mg/day) and stable for at least 1 week before the first dose of tofacitinib (Day 1) 
throughout the full duration of Part 1 of the open-label phase.  
For subjects who are receiving IV pulse CS during the Screening period, the last IV pulse 
should be 2 weeks prior to Baseline (Day 1) for methylprednisolone and 3 weeks prior to 
Baseline (Day 1) for dexamethasone. Maintenance oral CS may be started on the day 
following the last IV pulse. Dosing should be ≤1.0 mg/kg/day prednisone or equivalent (up to 
a maximum dose of 30 mg/day) and stable for at least 1 week prior to Baseline (Day 1). 
CS use is encouraged to be tapered down to the lowest possible dose up to discontinuation 
during Part 2 of the open-label phase prior to entry into the double-blind randomized 
withdrawal phase of the study.  The active CS tapering period will be up to 20 weeks in 
Part 2.  Refer to  Section 3.2.2 for further details about CS tapering in Part 2.  During the 
double-blind phase the subject must remain on a stable tapered CS dose.  
For use of CS intra articular injections, please refer to Appendix 3. 
5.8.1.2. Disease Modifying Anti-Rheumatic Drugs (DMARDs) 
The only nonbiological DMARD that subjects are allowed to receive during the study period 
is methotrexate (MTX).  MTX may be administered either orally or parenterally at doses not 
to exceed 25 mg/wk or 20 mg/m2/week, whichever is lower.  Subjects who are treated with 
methotrexate should be taking supplemental folic or folinic acid. 
If receiving MTX, participants must be on a stable dose of MTX for at least 4 weeks before 
the first dose of tofacitinib (Day 1 visit).  The MTX dose will be maintained throughout the 
study unless dose modification is clinically indicated for safety reasons.  All standard-of-care 
practices for administration of methotrexate, including laboratory testing and folate 
supplementation, should be performed according to local methotrexate labels.  
All other biological and nonbiological DMARDs are disallowed during the study.  The 
wash-out periods in Table 4 must be observed before the first dose of study drug (Day 1).   
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Table 4. 
DMARDs – Required Washout Period Prior to Day 1 of Study Drug 
52 weeks 
Rituximab or other selective B lymphocyte depleting agents.  Only if 
CD19/20+ counts are normal by FACS analysis. 
8 weeks 
Immunoglobulin G (IgG), Leflunomide (Arava®), Auranofin (oral gold), 
aurothioglucose (injectable gold), aurothiomalate (injectable gold). 
7 weeks 
 Canakinumab (Ilaris®). 
4 weeks 
Tocilizumab (Actemra®), Abatacept (Orencia®), Certolizumab pegol 
(Cimzia®), Golimumab (Simponi®), Baricitinib (Olumiant®), 
Upadacitinib (Rinvoq®), Thalidomide (Thalidomid®),  , d-penicillamine, 
chloroquine, hydroxychloroquine, bucillamine, mizoribine and 
staphylococcal protein A immuno-absorbant pheresis columns. 
3 weeks 
Infliximab (Remicade®) 
2 weeks 
Adalimumab (Humira®), Etanercept (Enbrel®). 
7 Days 
Cyclosporine, tacrolimus, sulfasalazine, azathioprine. 
3 Days 
Anakinra (Kineret®) 
Disallowed and allowed non-biologic and biologic DMARDS are listed in Appendix 1.  If a 
subject requires (in the opinion of the investigator) treatment with one of the disallowed 
agents, the subject should be discontinued from the study. 
5.8.1.3. Treatment for Latent Tuberculosis 
Subjects who are diagnosed as having latent tuberculosis (ie, positive tuberculosis test, chest 
x-ray negative for active tuberculosis, and no evidence of active disease) at screening or 
during the course of the study must have either been previously treated with an adequate 
course of treatment or be currently taking isoniazid.  Subjects that the Investigator considers 
to be at high-risk to develop tuberculosis (eg, residing in high-risk areas or travel to high-risk 
areas) may be started on isoniazid treatment at the discretion of the Investigator.  The sponsor 
considers ongoing treatment with isoniazid or equivalent for at least 4 weeks before the first 
dose of tofacitinib (Day 1) adequate, provided that local rates of primary multi-drug resistant 
TB infection are <5%. 
When indicated, isoniazid treatment is required to be administered in accordance with local 
standards at a maximum dose of 300 mg/day for a total of 9 months of treatment and the 
treatment must be recorded in the subject’s case report form.  If an alternate treatment regimen 
is implemented, the reason for this must be documented and a copy of the local standard of 
care guideline identifying such treatment must be provided to the study team.  Within 
approximately one month of initiating treatment with isoniazid, the subject should have 
transaminase levels checked. 
PLEASE NOTE: although commonly used in the treatment of tuberculosis, rifampin, 
rifampicin, rifabutin and rifapentine are prohibited concomitant medications in this study. 
5.8.2. Prohibited Concomitant Medication 
Examples of medications that are prohibited from use during subject participation, due to 
potential for drug interactions or confounding of data interpretation, are listed in Appendix 5, 
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Prohibited Concomitant Medications.  Topical administration, eg, cutaneous, ophthalmic, or 
intravaginal of these concomitant medications, which are prohibited if administered 
systemically, is allowed in the study.  
Any experimental or prohibited therapy must be discontinued for 4 weeks or 5 half-lives 
(whichever is longer) prior to the first dose of study drug.  No investigational compounds, 
other than tofacitinib may be taken during participation in this study. 
5.9. Rescue Therapy 
Refer to Appendix 3 for permitted adjustments in background sJIA therapies.  Permitted 
rescue therapy can be found in Appendix 6. 
6. STUDY PROCEDURES 
This section outlines study procedures and tests required to be performed at specified study 
visits.  The order in which procedures and tests are performed is left to the discretion of the 
investigator.  Please refer to Section 8 for details regarding each procedure/test. 
Country specific amendment for Germany: In accordance with article 40 (4) No. 4 of the 
German Medicines Act; the degree of burden and the risk threshold should be assessed at each 
scheduled visit as outlined in Appendix 9. 
6.1. Screening Visit 
Please note that subjects must be enrolled within 40 days of the screening visit.   
If more than 40 days has elapsed, the subject should be screen-failed and if eligible, re-
screened. All screening procedures and assessments listed below should be repeated.  
Sponsor approval must be obtained prior to re-screening a subject.  Rescreening of subjects 
will be allowed in a limited number of circumstances as determined by the Pfizer Study 
Clinician (eg, subject requires washout of prohibited medications, requires antimicrobial 
therapy within 2 weeks prior to the first dose of study medication, requires emergency 
surgery) and should be confirmed with the Pfizer Study Clinician when rescreening can 
occur.  
Following obtainment of Informed Consent from the parent/legal guardian (and Assent from 
the subject, as appropriate), the procedures and assessments listed below will be performed at 
the screening visit.  Serious adverse events (SAEs) are captured starting with the Screening 
visit from the time of informed consent (Section 9.2).  
• Medical history and family history. 
• Uveitis assessment: if applicable, documentation of previous uveitis assessment(s) by 
an ophthalmologist (or qualified equivalent per local practice) should be reviewed to 
document presence/absence of active uveitis. 
• Prior and concomitant medications.  Refer to Section 5.8. 
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• Complete physical examination, including vital signs, height and weight.  Country 
specific amendment for EU sites (including UK): A full skin cancer examination 
must be performed as part of the complete physical examination. 
• Perform a risk factor check for venous thromboembolism.  Refer to Section 8.2.13 for 
details.   
• Evaluate the pubertal development using the Tanner Stages.  
• Obtain subject’s oral temperature and assess “Fever”, defined as temperature 
>38° C/100.4° F: 
• MAS diagnosis: Only if subject has fever and Macrophage Activation Syndrome 
(MAS) is suspected: obtain blood samples to evaluate Ferritin, Platelets, 
Triglycerides and Fibrinogen levels.  Refer to Section 8.2.11 for details regarding 
these blood sample collections. 
• Assess the sJIA Disease Activity status: 
• Fever (see above); 
• Number of joints with limitation in range of motion; 
• Number of joints with active arthritis (swelling and/or pain/tenderness);  
• Assess duration of morning stiffness; 
• Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA; 
• Physician’s Global Assessment of Overall Disease Activity; 
• Administer the Childhood Health Assessment Questionnaire (CHAQ); evaluate 
Patient wellbeing as part of the CHAQ on a 21 circle VAS; 
• ESR determination (utilizing ESR test kit provided by Sponsor); record result on 
appropriate CRF.  
• Child Health Questionnaire;  
• Obtain blood sample for QuantiFERON®-TB Gold or Gold Plus In-Tube test and send 
to central laboratory.  Note: If the reference laboratory informs the investigator site 
that QuantiFERON®-TB Gold or Gold Plus In-Tube testing cannot be performed on 
the submitted sample or if the result is indeterminate, then administer a locally 
performed QuantiFERON®-TB test or Purified Protein Derivative (PPD) skin test 
(Mantoux method) or T-spot TB test with Sponsor approval.10 
• Only if according to local standards and/or in countries with a high TB incidence 
rate: Perform a chest X-ray to aid in TB status determination. 
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• Obtain blood or urine sample(s) for the following tests and send to central laboratory.  
Refer to Section 8.2.12 for sample collection details. 
Note: At screening 14.1 mL or 15.1 mL (according to Quantiferon®-TB test used) to 
maximally 25.8 mL of blood (only if serum pregnancy test, MAS laboratory evaluations, VZV 
IgG Antibody and HCV RNA test are required) will be collected.  If preferred by the 
investigator, the laboratory evaluations at screening may be done at 2 separate visits within 
40 days before enrolment on Day 1 to limit the blood volume collected in one day.  One 
re-testing of a hematology or serum chemistry laboratory parameter is allowed if the abnormal 
lab(s) was an uncharacteristic result(s).  Re-testing must be completed within the screening 
period. 
• Hematology; 
• Chemistry;  
• Inflammatory and rheumatic disease markers: CRP, Rheumatoid Factor (RF); 
• Viral testing: Human Immunodeficiency Virus (HIV), Hepatitis B (Hep B), 
Hepatitis C (Hep C); Varicella Zoster Virus (VZV) (if applicable); 
• Urinalysis. 
• For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing. 
• For subjects using contraception: perform a contraceptive check, to ensure 
contraception is consistently and correctly used. 
6.2. Open-label Phase/Part 1: Day 1 Visit 
The study will start with an open-label phase during which all subjects will receive a stable 
dose of tofacitinib oral tablets or oral solution BID.  Part 1 of the open-label is meant to 
identify tofacitinib-treated subjects who are able to maintain an Adapted JIA ACR 
30 response for 4 weeks.  
Day 1 is the day of first study drug administration.  The procedures and assessments listed 
below will be performed at the Day 1 visit. 
For the Day 1 Visit, subjects should be instructed to fast (for 9 to 12 hours prior the scheduled 
visit), if possible, for lipid panel testing.  
• Review prior and concomitant medications.  Refer to Section 5.8;  
• Targeted physical exam;  
• Perform a risk factor check for venous thromboembolism.  Refer to Section 8.2.13 for 
details.   
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• Vital signs, height and weight. 
• Obtain subject’s oral temperature and assess “Fever”, defined as temperature 
>38° C/100.4° F: 
• MAS diagnosis: Only if subject has fever and Macrophage Activation Syndrome 
(MAS) is suspected: obtain blood samples to evaluate Ferritin, Platelets, 
Triglycerides and Fibrinogen levels.  Refer to Section 8.2.11 for details regarding 
these blood sample collections. 
• Confirm that the subject meets all inclusion criteria and none of the exclusion criteria. 
• Assess the sJIA Disease Activity status: 
• Fever (see above); 
• Number of joints with limitation in range of motion; 
• Number of joints with active arthritis (swelling and/or pain/tenderness);  
• Assess duration of morning stiffness; 
• Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA; 
• Physician’s Global Assessment of Overall Disease Activity; 
• Administer the Childhood Health Assessment Questionnaire (CHAQ); evaluate 
Patient wellbeing as part of the CHAQ on a 21 circle VAS; 
• Administer the Child Health Questionnaire (CHQ);  
• ESR determination (utilizing ESR test kit provided by Sponsor); record result on 
appropriate CRF.  
• Assess the Adapted JIA ACR baseline:  
• Record result for all core components of Adapted JIA ACR baseline in the eCRF 
for calculation of the baseline Adapted JIA ACR criteria based on ESR.*  
*For “real-time” assessment of the Adapted JIA ACR baseline during a study visit 
the subject’s ESR will be used to determine the percent change in inflammation 
biomarker.  
• Fax or email the sJIA Disease Assessment worksheets and JIA ACR core 
component CRF to the Coordinating Center for confirmation of the Adapted JIA 
ACR baseline response based on ESR.  
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• Record Adapted JIA ACR baseline value on relevant eCRF after receipt of result 
from the Coordinating Center. 
• Obtain blood or urine sample(s) for the following tests and send to central laboratory.  
Refer to Section 8.2.9 for sample collection details: 
• Hematology; 
• Chemistry; 
• Lipid panel (under fasting conditions for approximately 9 to 12 hours, if possible); 
• CRP; 
• Ferritin; 
• Urinalysis. 
• For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing. 
• For subjects using contraception: perform a contraceptive check, to ensure 
contraception is consistently and correctly used. 
• Assess for adverse events. 
• Dispense investigational product; first dose to be administered at the study site. 
• Obtain blood samples for PK analysis at 15 minutes (5-30 min), 45 minutes 
(35-55 min) and 4 hours (3-6h) post tofacitinib administration.  If feasible for the 
subject, this blood sample should be drawn between 4 to 6 hours post dose, however 
any time between 3 to 6 hours post dose is allowed.  Obtain an additional PK blood 
sample 1.5 hours (1.25-2h) post tofacitinib administration if the subject is part of the 
first 14 subjects enrolled in Cohorts 1 to 2.  Refer to Section 8.4 for details. 
• Obtain blood samples for banking of biospecimens before first dose of study drug.  
This blood sample collection is optional, at the parent/legal guardian’s discretion.  
Refer to Section 8.5 for details. 
• Provide diary to record temperature.  The parent/legal guardian should complete the 
diary or supervise the completion of the diary by the subject.  If subjects have a fever, 
the temperature should be recorded twice daily (in the morning and evening); the 
highest temperature since previous diary recording should be reported in the diary.  
Subjects will return the diary to the clinic at each study visit. 
6.3. Open-Label Phase/Part 1: Day 3, Day 7 and Day 14 Visit 
Part 1 of the open-label active treatment phase is meant to identify tofacitinib-treated subjects 
who are able to maintain an Adapted JIA ACR 30 response for 4 weeks.  
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The procedures and assessments listed below will be performed at the Day 3, Day 7 and 
Day 14 visit.  The window for these visits is ±1 days. 
• Review concomitant medications.  Refer to Section 5.8. 
• Targeted physical exam, including skin examination for chickenpox or shingles. 
• Perform a risk factor check for venous thromboembolism.  Refer to Section 8.2.13 for 
details.   
• Vital signs and weight. 
• Review temperature diary and assess “Fever” and “Absence of fever”:  
• Obtain subject’s oral temperature and assess “Fever”, defined as temperature 
>38° C/100.4° F; 
• MAS diagnosis: Only if subject has fever and MAS is suspected: obtain blood 
samples to evaluate Ferritin, Platelets, Triglycerides and Fibrinogen levels.  Refer 
to Section 8.2.11 for details regarding these blood sample collections; 
• Only at the Day 7 and Day 14 visit: Evaluate “Absence of fever”, defined as 
documented absence of fever due to systemic JIA in the week preceding this visit.  
Record the outcome in the eCRF for calculation of the Adapted JIA ACR response.  
Assess the sJIA Disease Activity status: 
• Fever (see above); 
• Number of joints with limitation in range of motion; 
• Number of joints with active arthritis (swelling and/or pain/tenderness);  
• Assess duration of morning stiffness; 
• Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA. 
• Only at the Day 7 and Day 14 visit: Uveitis status: document presence/absence of 
active uveitis. 
• Physician’s Global Assessment of Overall Disease Activity: 
• Administer the Childhood Health Assessment Questionnaire (CHAQ); evaluate 
Patient wellbeing as part of the CHAQ on a 21 circle VAS; 
• ESR determination (utilizing ESR test kit provided by Sponsor); record result 
on appropriate CRF.  
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*For “real-time” assessment of the Adapted JIA ACR 30 Response during a study 
visit the subject’s ESR will be used to determine the percent change in 
inflammation biomarker. 
• Only at the Day 7 and Day 14 visit: Assess the Adapted JIA ACR response based on 
ESR:  
• Record result for the core components of JIA ACR pediatric criteria (besides 
the CRP level) on the appropriate eCRF for calculation of the Adapted JIA 
ACR 30 response based on ESR;*  
• Fax/email the sJIA Disease Assessment worksheets and JIA ACR core 
component CRF to the Coordinating Center for confirmation of the Adapted 
JIA ACR 30 response based on ESR;  
• Record Adapted JIA ACR 30 response value on relevant eCRF after receipt of 
result from the Coordinating Center. 
• Obtain blood sample for CRP evaluation and send to central laboratory;  
• For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.  
• For subjects using contraception: perform a contraceptive check, to ensure 
contraception is consistently and correctly used. 
• Assess for adverse events. 
• Assess investigational product dosing compliance. 
• Only at Day 14: Dispense investigational drug. 
6.4. Open-label Phase/Part 1: Visits Every 4 Weeks from Week 8 up to Week 16 
Part 1 of the open-label active treatment phase is meant to identify tofacitinib-treated subjects 
who are able to maintain an Adapted JIA ACR 30 response for 4 weeks.  After the Week 4 
visit, study visits will be performed on a monthly basis.  The duration of Part 1 is variable for 
each subject but no longer than 16 weeks.  
The procedures and assessments listed below will be performed at each visit.  The window for 
these visits is ±3 days. 
For each Visit, subjects should be instructed to fast (for 9 to 12 hours prior to the scheduled 
visit), if possible, for lipid panel testing. 
• Review concomitant medications.  Refer to Section 5.8. 
• Targeted physical exam, including skin examination for chickenpox or shingles. 
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• Perform a risk factor check for venous thromboembolism.  Refer to Section 8.2.13 for 
details.   
• Vital signs, height and weight. 
• Review temperature diary and assess “Fever” and “Absence of fever”:  
• Obtain subject’s oral temperature and assess “Fever”, defined as temperature 
>38° C/100.4° F; 
• MAS diagnosis: Only if subject has fever and MAS is suspected: obtain blood 
samples to evaluate Ferritin, Platelets, Triglycerides and Fibrinogen levels.  Refer 
to Section 8.2.11 for details regarding these blood sample collections; 
• Evaluate “Absence of fever”, defined as documented absence of fever due to 
systemic JIA in the week preceding this visit.  Record the outcome in the eCRF for 
calculation of the Adapted JIA ACR response. 
• Assess the sJIA Disease Activity status: 
• Fever (see above); 
• Number of joints with limitation in range of motion; 
• Number of joints with active arthritis (swelling and/or pain/tenderness); 
• Assess duration of morning stiffness; 
• Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA; 
• Uveitis status: document presence/absence of active uveitis; 
• Physician’s Global Assessment of Overall Disease Activity; 
• Administer the Childhood Health Assessment Questionnaire (CHAQ); evaluate 
Patient wellbeing as part of the CHAQ on a 21 circle VAS; 
• Only if an Adapted JIA ACR 30 response for 4 weeks is confirmed and this 
visit concludes Part 1 of the open-label phase: Administer Child Health 
Questionnaire; 
• ESR determination (utilizing ESR test kit provided by Sponsor); record result on 
appropriate CRF.* 
*For “real-time” assessment of the Adapted JIA ACR 30 Response during a study 
visit the subject’s ESR will be used to determine the percent change in 
inflammation biomarker. 
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• Assess the Adapted JIA ACR response based on ESR and record result on appropriate 
CRF:  
• Enter data for the core components of JIA ACR pediatric criteria in the eCRF to 
for calculation of the Adapted JIA ACR 30 response based on ESR;*  
• Fax or email the sJIA Disease Assessment worksheets and JIA ACR core 
component CRF to the Coordinating Center for confirmation of the Adapted JIA 
ACR 30 response based on ESR;  
• Record evaluation of the Adapted JIA ACR 30 Response on the relevant eCRF 
after receipt of faxed result from the Coordinating Center.  Once a subject is able 
to maintain the Adapted JIA ACR 30 response for 4 weeks they can start Phase 2.  
• Obtain blood or urine sample(s) for the following tests and send to central laboratory.  
Refer to Section 8.2.12 for sample collection details: 
• Hematology; 
• Chemistry; 
• Only every 3 months after Day 1: Lipid panel (under fasting conditions for 
approximately 9 to 12 hours, if possible); 
• CRP; 
• Urinalysis.  
• For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.  
• For subjects using contraception: perform a contraceptive check, to ensure 
contraception is consistently and correctly used. 
• Assess for adverse events. 
• Assess investigational product dosing compliance. 
• Only at Week 8: 
• Obtain the first blood sample for PK analysis before investigational product 
administration.  Refer to Section 8.4 for details; 
• Dispense investigational product; administer the first dose at the study site; 
• Obtain blood samples for PK analysis at 1 hour (0.5-1.5h) and 3 hours (2-4h) post 
tofacitinib administration. If feasible for the subject, this blood sample should be 
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drawn between 3 to 4 hours post dose, however any time between 2 to 4 hours post 
dose is allowed.  Refer to Section 8.4 for details.  
6.5. Open-label Phase/Part 2: CS Tapering: Visits Every 4 Weeks after Start of Part 2 
Part 2 of the open-label active treatment phase is to permit CS tapering in subjects treated 
with CSs.  Subjects will have study visits on a monthly basis in Part 2.  
The procedures and assessments listed below will be performed at every study visit.  The 
window for these visits is ±3 days. 
For each Visit, subjects should be instructed to fast (for 9 to 12 hours prior to the scheduled 
visit), if possible, for lipid panel testing. 
• Review concomitant medications.  Refer to Section 5.8.  
• Targeted physical exam, including skin examination for chickenpox or shingles. 
• Perform a risk factor check for venous thromboembolism.  Refer to Section 8.2.13 for 
details.  
• Vital signs, height and weight. 
• Review temperature diary and assess “Fever” and “Absence of fever”:  
• Obtain subject’s oral temperature and assess “Fever”, defined as temperature 
>38° C/100.4° F; 
• MAS diagnosis: Only if subject has fever and MAS is suspected: obtain blood 
samples to evaluate Ferritin, Platelets, Triglycerides and Fibrinogen levels.  Refer 
to Section 8.2.11 for details regarding these blood sample collections; 
• Evaluate “Absence of fever”, defined as documented absence of fever due to 
systemic JIA in the week preceding this visit.  Record the outcome in the eCRF for 
calculation of the Adapted JIA ACR response. 
• Assess the sJIA Disease Activity status: 
• Fever (see above); 
• Number of joints with limitation in range of motion; 
• Number of joints with active arthritis (swelling and/or pain/tenderness);  
• Assess duration of morning stiffness; 
• Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA; 
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• Uveitis status: document presence/ absence of active uveitis; 
• Physician’s Global Assessment of Overall Disease Activity; 
• Administer the Childhood Health Assessment Questionnaire (CHAQ); evaluate 
Patient wellbeing as part of the CHAQ on a 21 circle VAS; 
• Only if an Adapted JIA ACR 30 response for 4 weeks is confirmed and this 
visit concludes Part 2 of the open-label phase: Administer Child Health 
Questionnaire; 
• ESR determination (utilizing ESR test kit provided by Sponsor); record result on 
appropriate CRF.  
*For “real-time” assessment of the Adapted JIA ACR 30 Response during a study 
visit the subject’s ESR instead of CRP will be used to determine the percent 
change in inflammation biomarker.  
• Assess the Adapted JIA ACR response based on ESR:  
• Record results for the core components of JIA ACR pediatric criteria (besides the 
CRP level) in the eCRF for calculation of the Adapted JIA ACR 30 response based 
on ESR;*  
• Fax/email the sJIA Disease Assessment worksheets and JIA ACR core component 
CRF to the Coordinating Center for confirmation of the Adapted JIA ACR 
30 response based on ESR; 
• Record the evaluation of the Adapted JIA ACR 30 response on the relevant eCRF 
after receipt of faxed result from the Coordinating Center. 
• Obtain blood or urine sample(s) for the following tests and send to central laboratory.  
Refer to Section 8.2.12 for sample collection details: 
• Hematology; 
• Chemistry; 
• Only every 3 months after Day 1: Lipid panel (under fasting conditions for 
approximately 9 to 12 hours, if possible); 
• CRP; 
• Urinalysis.  
• Only at Week 4 and only if a subject started Open-Label Part 2 after 4 weeks 
of study treatment: Obtain the first blood sample for PK analysis before 
investigational product administration.  Refer to Section 8.4 for details; 
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• Dispense investigational product; administer the first dose at the study site; 
• Obtain blood samples for PK analysis at 1 hour (0.5-1.5h) and 3 hours (2-4h) post 
tofacitinib administration.  If feasible for the subject, this second blood sample 
should be drawn between 3 to 4 hours post dose, however any time between 2 to 
4 hours post dose is allowed.  Refer to Section 8.4 for details.  
• For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.  
• For subjects using contraception: perform a contraceptive check, to ensure 
contraception is consistently and correctly used. 
• Assess for adverse events. 
• Assess investigational product dosing compliance. 
• Dispense investigational product. 
6.6. Randomization Visit: Start Double-blind Withdrawal Phase 
Subjects who are able to maintain an Adapted JIA ACR 30 response for 4 weeks on a stable 
tapered CS dose in the open-label phase are eligible for randomization into the double-blind 
withdrawal phase.  At the randomization visit subjects will be assigned to continue treatment 
with a stable dose of tofacitinib or start placebo in a 1:1 ratio.  
The randomization visit can be combined with the last visit of the Open-label phase.  In such 
cases, the Randomization CRF will need to be completed, but evaluations done as part of the 
Open-label visit, do not need to be repeated. 
The procedures and assessments listed below will be performed at the Randomization visit.  
The window for this visit is ±5 days.  
• After confirmation that the subject is eligible, obtain a randomization number through 
the IRT system.  
• Review concomitant medications.  Refer to Section 5.8. 
• Targeted physical exam, including skin examination for chickenpox or shingles. 
• Perform a risk factor check for venous thromboembolism.  Refer to Section 8.2.13 for 
details.   
• Vital signs, height and weight. 
• Review temperature diary and assess “Fever” and “Absence of fever”:  
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• Obtain subject’s oral temperature and assess “Fever”, defined as temperature 
>38° C/100.4° F; 
• MAS diagnosis: Only if subject has fever and MAS is suspected: obtain blood 
samples to evaluate Ferritin, Platelets, Triglycerides and Fibrinogen levels.  Refer 
to Section 8.2.11 for details regarding these blood sample collections; 
• Evaluate “Absence of fever”, defined as documented absence of fever due to 
systemic JIA in the week preceding this visit.  Record the outcome in the eCRF for 
calculation of the Adapted JIA ACR response. 
• Assess the sJIA Disease Activity status: 
• Fever (see above); 
• Number of joints with limitation in range of motion; 
• Number of joints with active arthritis (swelling and/or pain/tenderness);  
• Assess duration of morning stiffness; 
• Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA; 
• Uveitis status: document presence/ absence of active uveitis; 
• Physician’s Global Assessment of Overall Disease Activity; 
• Administer the Childhood Health Assessment Questionnaire (CHAQ); evaluate 
Patient wellbeing as part of the CHAQ on a 21 circle VAS; 
• Administer Child Health Questionnaire; 
• ESR determination (utilizing ESR test kit provided by Sponsor); record result on 
appropriate CRF.  
*For “real-time” assessment of the Adapted JIA ACR 30 Response during a study 
visit the subject’s ESR instead of CRP will be used to determine the percent 
change in inflammation biomarker. 
• Assess the Adapted JIA ACR response based on ESR and record result on appropriate 
CRF:  
• Enter data for the core components of JIA ACR pediatric criteria in the eCRF for 
calculation of the Adapted JIA ACR 30 response based on ESR;*  
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• Fax the sJIA Disease Assessment worksheets and JIA ACR core component CRF 
to the Coordinating Center for confirmation of the Adapted JIA ACR 30 response 
based on ESR; 
• Record the evaluation of the Adapted JIA ACR 30 response on the relevant eCRF 
after receipt of faxed result from the Coordinating Center.  Once a subject is able 
to maintain the Adapted JIA ACR 30 response for 4 weeks on a stable tapered CS 
dose in the open-label phase they can start the Double-blind Phase.  
• Obtain blood or urine sample(s) for the following tests and send to central laboratory.  
Refer to Section 8.2.12 for sample collection details: 
• Hematology; 
• Chemistry; 
• Only every 3 months after Day 1: Lipid panel (under fasting conditions for 
approximately 9 to 12 hours, if possible); 
• CRP; 
• Urinalysis.  
• Obtain blood samples for banking of biospecimens.  This blood sample collection is 
optional, at the parent/legal guardian’s discretion.  Refer to Section 8.5 for details. 
• For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.  
• For subjects using contraception: perform a contraceptive check, to ensure 
contraception is consistently and correctly used. 
• Assess for adverse events. 
• Assess investigational product dosing compliance. 
• Dispense investigational product. 
6.7. Double-blind Withdrawal Phase: Visits Every 4 Weeks after Randomization Visit 
After randomization in the double-blind withdrawal phase, each subject will have visits on a 
monthly basis until they experience a sJIA flare, or experience 24 consecutive weeks of 
inactive disease as assessed using JIA ACR (clinical remission), or until the requisite number 
of flares have been reported (refer to Section 11) and the study is considered completed.  
The procedures and assessments listed below will be performed at every visit of the 
double-blind withdrawal phase.  The window for these visits is ±5 days.  
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• Evaluate concomitant medications.  Refer to Section 5.8. 
• Targeted physical exam, including skin examination for chickenpox or shingles. 
• Perform a risk factor check for venous thromboembolism.  Refer to Section 8.2.13 for 
details.   
• Vital signs, height and weight. 
• Review temperature diary and assess “Fever” and “Absence of fever”:  
• Obtain subject’s oral temperature and assess “Fever”, defined as temperature 
>38° C/100.4° F; 
• MAS diagnosis: Only if subject has fever and MAS is suspected: obtain blood 
samples to evaluate Ferritin, Platelets, Triglycerides and Fibrinogen levels.  Refer 
to Section 8.2.11 for details regarding these blood sample collections; 
• Evaluate “Absence of fever”, defined as documented absence of fever due to 
systemic JIA in the week preceding this visit.  Record the outcome in the eCRF for 
calculation of the Adapted JIA ACR response. 
• Assess the sJIA Disease Activity status: 
• Fever (see above); 
• Number of joints with limitation in range of motion; 
• Number of joints with active arthritis (swelling and/or pain/tenderness);  
• Assess duration of morning stiffness; 
• Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA; 
• Uveitis status: document presence/absence of active uveitis; 
• Physician’s Global Assessment of Overall Disease Activity; 
• Administer the Childhood Health Assessment Questionnaire (CHAQ); evaluate 
Patient wellbeing as part of the CHAQ on a 21 circle VAS; 
• Only every 6 months after the randomization visit: Administer Child Health 
Questionnaire; 
• ESR determination (utilizing ESR test kit provided by Sponsor); record result on 
appropriate CRF.  
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*For “real-time” assessment of the sJIA Flare during a study visit the subject’s 
ESR will be used to determine the percent change in inflammation biomarker.  
• Assess sJIA flare and Adapted JIA ACR response based on ESR and record result on 
appropriate CRF:  
• Enter data for the core components of JIA ACR pediatric criteria (besides the CRP 
level) in the eCRF to determine if a subject has met the criteria for sJIA flare (with 
Adapted JIA ACR 30 response based on ESR*); 
• Fax/email the sJIA Disease Assessment worksheets and JIA ACR core component 
CRF to the Coordinating Center for confirmation of the Adapted JIA ACR 
30 response based on ESR.  A subject who is confirmed to have a sJIA flare should 
be discontinued;  
• Record the sJIA flare assessment on relevant eCRF after receipt of faxed result 
from the Coordinating Center. 
• Obtain blood or urine sample(s) for the following tests and send to central laboratory.  
Refer to Section 8.2.12 for sample collection details: 
• Hematology; 
• Chemistry; 
• Only every 3 months after Day 1: Lipid panel (under fasting conditions for 
approximately 9 to 12 hours, if possible); 
• CRP; 
• Urinalysis. 
• For subjects in countries where TB incidence has been reported at a rate of 
>50 cases per 100,000 persons, eg, China, India, Russian Federation; South 
Africa and Ukraine (World Health Organization): every 12 months after screening: 
obtain blood sample for yearly TB testing (QFT-Gold or Gold Plus). 
• For subjects who meet the sJIA flare criteria or who reach inactive disease status: 
Obtain blood samples for banking of biospecimens.  This blood sample collection is 
optional, at the parent/legal guardian’s discretion.  Refer to Section 8.5 for details. 
• For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.  
• For subjects using contraception: perform a contraceptive check, to ensure 
contraception is consistently and correctly used. 
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• Assess for adverse events. 
• Assess investigational product dosing compliance. 
• Dispense investigation product. 
6.7.1. Discontinuation from Investigational Product during Randomized Withdrawal 
Phase  
Subjects who discontinue Investigational Product in the double-blind phase, for reasons other 
than sJIA flare, and who do not rollover to A3921145 LTE study, should continue with the 
regular scheduled visits every 4 weeks up to and including Week 52. All required procedures 
and assessments listed above should be performed with the exception of IP dispensing and 
compliance. Subjects should receive standard-of-care treatment as per local guidelines. There 
are no protocol restrictions on the use of DMARDs and other disallowed agents, detailed in 
Appendix 1, for subjects receiving standard of care treatment.  
6.8. End of Study or Early Termination Visit  
Each subject’s participation in the study will end once the subject experiences a first sJIA 
flare in the double-blind phase or 24 consecutive weeks of inactive disease (clinical 
remission). An end-of-study visit should be performed.   
Subjects who are not able to maintain an Adapted JIA ACR 30 response for 4 weeks in the 
open-label phase, or who have fever due to sJIA lasting more than 2 consecutive days in Part 
1, or who fail CS tapering more than twice in Part 2 of the open-label phase will need to be 
discontinued from the study.  
Subjects will have the option, if eligible (based on inclusion and exclusion criteria), of 
enrolling in the tofacitinib JIA long-term extension study (A3921145) after withdrawal or 
completion of this study.  
• Subjects who discontinue investigational product in the double-blind phase and who 
do not enter A3921145 will be required to continue in the study and perform all 
scheduled visits until Week 52 after randomization or until the study concludes, 
whichever comes first. Such subjects should transition to standard-of care treatment in 
accordance with local guidelines.  
• Subjects who discontinue in the Open-Label Phase and do not enter A3921145 will be 
required to return for a follow up visit 28 days after the last dose of study treatment.    
The study will be completed once the requisite number of subjects have reported flare in the 
double-blind withdrawal phase (refer to Section 11).  At that time and upon notification by the 
Sponsor, the investigator will be required to schedule an end-of-study visit for all remaining 
active subjects. 
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If a subject discontinues from the study at a regularly scheduled study visit, all assessments 
and procedures for that visit should be completed.  In addition, a Tanner stage assessment 
should be done as part of the study termination.  If a subject discontinues outside of a 
regularly scheduled visit, an Early Termination visit should be scheduled as soon as possible.  
The procedures and assessments listed below will be performed at the End of Study or Early 
Termination visit.  
Subjects should be instructed to fast, if possible, for lipid panel testing. 
• Review concomitant medications.  Refer to Section 5.8. 
• Complete physical exam, including skin examination for chickenpox or shingles.  
Country specific amendment for EU sites (including UK): a full skin cancer 
examination must be performed as part of the complete physical examination. 
• Perform a risk factor check for venous thromboembolism.  Refer to Section 8.2.13 for 
details.   
• Vital signs, height and weight. 
• Review temperature diary and assess “Fever” and “Absence of fever”:  
• Obtain subject’s oral temperature and assess “Fever”, defined as temperature 
>38° C/100.4° F.  
• MAS diagnosis: Only if subject has fever and MAS is suspected: obtain blood 
samples to evaluate Ferritin, Platelets, Triglycerides and Fibrinogen levels.  Refer 
to Section 8.2.11 for details regarding these blood sample collections. 
• Evaluate “Absence of fever”, defined as documented absence of fever due to 
systemic JIA in the week preceding this visit.  Record the outcome in the eCRF for 
calculation of the Adapted JIA ACR response. 
• Evaluate the pubertal development using the Tanner Stages.  
• Assess the sJIA Disease Activity status: 
• Fever (see above); 
• Number of joints with limitation in range of motion; 
• Number of joints with active arthritis (swelling and/or pain/tenderness);  
• Assess duration of morning stiffness; 
• Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA; 
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• Uveitis status: document presence/ absence of active uveitis; 
• Physician’s Global Assessment of Overall Disease Activity; 
• Administer the Childhood Health Assessment Questionnaire (CHAQ); evaluate 
Patient wellbeing as part of the CHAQ on a 21 circle VAS; 
• Administer Child Health Questionnaire; 
• ESR determination (utilizing ESR test kit provided by Sponsor); record result on 
appropriate CRF.  
• Assess Adapted JIA ACR 30 Response and sJIA flare and record result in appropriate 
CRF: 
• Record results for 6 core components of JIA ACR pediatric criteria in the eCRF 
for the calculation of the Adapted JIA ACR 30 response, JADAS-27 and sJIA 
flare. 
*For “real-time” assessment of the Adapted JIA ACR 30 Response and/or sJIA 
Flare during a study visit the subject’s ESR will be used to determine the percent 
change in inflammation biomarker.  
• Fax the sJIA Disease Assessment worksheets and JIA ACR core component CRF 
to the Coordinating Center for confirmation of the Adapted JIA ACR 30 response 
based on ESR. 
• Record the evaluation of the Adapted JIA ACR 30 Response on the relevant eCRF 
after receipt of faxed result from the Coordinating Center. 
• Obtain blood sample(s) for the following tests and send to central laboratory.  Refer to 
Section 8.2.12 for sample collection details: 
• Hematology; 
• Chemistry; 
• Lipid panel (under fasting conditions for approximately 9 to 12 hours, if possible); 
• CRP; 
• Urinalysis. 
• For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing. 
• For subjects using contraception: perform a contraceptive check, to ensure 
contraception is consistently and correctly used. 
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• For subjects who meet the sJIA flare criteria or who reach inactive disease status: 
Obtain blood samples for banking of biospecimens.  Refer to Section 8.5 for details. 
• Assess for adverse events. 
• Assess investigational product dosing compliance. 
• Review entrance criteria for long-term extension study (A3921145). 
6.9. Follow-Up Visit (Only For Subjects Not Entering Study A3921145) 
 
At least 28 days after the last dose of study medication, subjects who did not rollover into 
study A3921145 will return for a follow-up visit.  This visit will not be required for subjects 
who discontinue investigational product in the double-blind phase and remain in the study. 
There is a +7 day window for this visit.  The procedures and assessments listed below will be 
performed at this visit:  
• Review concomitant medications.  Refer to Section 5.8. 
• Targeted physical exam, including skin examination for chickenpox or shingles. 
• Perform a risk factor check for venous thromboembolism.  Refer to Section 8.2.13 for 
details.   
• Vital signs, height and weight. 
• For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing. 
• For subjects using contraception: perform a contraceptive check, to ensure 
contraception is consistently and correctly used. 
• Assess for adverse events. 
• Only if subject discontinued in the double-blind phase for other reasons than 
“flare” per protocol before Week 24 (of the double-blind phase):  
• Review temperature diary and assess “Fever” and “Absence of fever”; 
• Obtain subject’s oral temperature and assess “Fever”, defined as temperature 
>38° C/100.4° F.  
• MAS diagnosis: Only if subject has fever and MAS is suspected: obtain 
blood samples to evaluate Ferritin, Platelets, Triglycerides and Fibrinogen 
levels.  Refer to Section 8.2.11 for details regarding these blood sample 
collections; 
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• Evaluate “Absence of fever”, defined as documented absence of fever due to 
systemic JIA in the week preceding this visit.  Record the outcome in the eCRF 
for calculation of the Adapted JIA ACR response. 
• Assess the sJIA Disease Activity status: 
• Fever (see above); 
• Number of joints with limitation in range of motion; 
• Number of joints with active arthritis (swelling and/or pain/tenderness);  
• Assess duration of morning stiffness; 
• Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA; 
• Uveitis status: document presence/absence of active uveitis; 
• Physician’s Global Assessment of Overall Disease Activity; 
• Administer the Childhood Health Assessment Questionnaire (CHAQ); evaluate 
Patient wellbeing as part of the CHAQ on a 21 circle VAS; 
• ESR determination (utilizing ESR test kit provided by Sponsor); record result 
on appropriate CRF.  
• Administer Child Health Questionnaire. 
• Assess sJIA flare and record result in appropriate CRF: 
• Record results for 6 core components of JIA ACR pediatric criteria in the eCRF 
for the calculation of the sJIA flare; 
*For “real-time” assessment of the sJIA Flare during a study visit the subject’s 
ESR will be used to determine the percent change in inflammation biomarker.  
• Fax the sJIA Disease Assessment worksheets to the Coordinating Center for 
confirmation of the sJIA Flare status based on ESR; 
• Record the evaluation of the sJIA Flare status on the relevant eCRF after receipt of 
faxed result from the Coordinating Center. 
• Obtain blood and urine sample(s) for the following tests and send to central laboratory: 
• Hematology; 
• Chemistry;  
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• Lipid panel (under fasting conditions for approximately 9 to 12 hours, if possible); 
• CRP; 
• Urinalysis. 
• For subjects who meet the sJIA flare criteria or who reach inactive disease status: 
Obtain blood samples for banking of biospecimens.  Refer to Section 8.5 for details. 
6.10. Unscheduled Study Visit or Telephone Contact 
The parent/legal guardian will be requested to contact the study staff by telephone if the 
subject has sJIA fever for more than 1 consecutive day, other symptoms of a sJIA 
exacerbation/MAS, or other adverse events of concern.  The investigator will determine 
whether an additional study visit is required for further assessment of the subject’s adverse 
event.  If the subject is suspected to experience a sJIA flare, or MAS, an unscheduled visit is 
mandatory.  
The unscheduled visit assessments may include the following: 
• Complete physical exam, including skin examination for chickenpox or shingles, vital 
signs, height and weight.  Country specific amendment for EU sites (including 
UK): a full skin cancer examination must be performed as part of the complete 
physical examination. 
• Review concomitant medications.  Refer to Section 5.8. 
• Review temperature diary and assess “Fever” and “Absence of fever”:  
• Obtain subject’s oral temperature and assess “Fever”, defined as temperature 
>38° C/100.4º F; 
• MAS diagnosis: Only if subject has fever and MAS is suspected: obtain blood 
samples to evaluate Ferritin, Platelets, Triglycerides and Fibrinogen levels.  Refer 
to Section 8.2.11 for details regarding these blood sample collections; 
• Evaluate “Absence of fever”, defined as documented absence of fever due to 
systemic JIA in the week preceding this visit. Record the outcome in the eCRF for 
calculation of the Adapted JIA ACR response. 
• Assess the sJIA Disease Activity status: 
• Fever (see above); 
• Number of joints with limitation in range of motion; 
• Number of joints with active arthritis (swelling and/or pain/tenderness);  
• Assess duration of morning stiffness; 
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• Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA; 
• Uveitis status: document presence/absence of active uveitis; 
• Physician’s Global Assessment of Overall Disease Activity; 
• Administer the Childhood Health Assessment Questionnaire (CHAQ); evaluate 
Patient wellbeing as part of the CHAQ on a 21 circle VAS; 
• Administer Child Health Questionnaire; 
• ESR determination (utilizing ESR test kit provided by Sponsor); record result on 
appropriate CRF;  
• Assess Adapted JIA ACR 30 response, and/or sJIA flare and record result on 
appropriate CRF. 
• Enter data for 6 core components of JIA ACR pediatric criteria in the eCRF for 
the calculation of the Adapted JIA ACR 30 response, JADAS-27 and sJIA 
flare; 
*For “real-time” assessment of the Adapted JIA ACR 30 Response and/or sJIA 
Flare during a study visit the subject’s ESR level will be used to determine the 
percent change in inflammation biomarker.  
• Fax/email the sJIA Disease Assessment worksheets and JIA ACR core 
component CRF to the Coordinating Center for confirmation of the Adapted 
JIA ACR 30 response based on ESR; 
• Record the evaluation of the Adapted JIA ACR 30 response value on relevant 
eCRF after receipt of faxed result from the Coordinating Center. 
• Assess for adverse events. 
• Perform a risk factor check for venous thromboembolism.  Refer to Section 8.2.13 for 
details.   
• Obtain blood sample(s) for the following tests and send to central laboratory.  Refer to 
Section 8.2.12 for sample collection details: 
• Hematology; 
• Chemistry; 
• Lipid panel (under fasting conditions for approximately 9 to 12 hours, if possible); 
• CRP; 
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• Urinalysis. 
• For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing. 
• For subjects using contraception: perform a contraceptive check, to ensure 
contraception is consistently and correctly used. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following; 
• Insufficient clinical response  
• Adverse events 
• Medication error without associated adverse event 
• Subject died 
• Protocol violation 
• Lost to-follow up 
• Does not meet entrance criteria 
• No longer willing to participate in study  
• Pregnancy 
• Study terminated by sponsor 
 
The criteria for discontinuation of investigational product in the open-label phase, (part 1 and 
part 2), are detailed in Section 3.2. 
If study intervention is permanently discontinued during the double-blind phase, and the 
participant does not enter A3921145, the participant should remain in the study for follow-up 
to be evaluated for safety and efficacy endpoints. See the SCHEDULE OF ACTIVITIES and  
Section 6 for data to be collected at the time of discontinuation of study intervention and 
follow-up visit requirements.   
Subjects will have the option, if eligible (based on inclusion and exclusion criteria), of 
enrolling in the tofacitinib JIA long term extension study (A3921145) after completion of this 
study. 
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further receipt 
of study intervention or also from study procedures, posttreatment study follow-up and/or 
future collection of additional information. 
 
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7.2. Subject Withdrawal from Study 
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include; 
• Lost to follow-up  
• No longer willing to participate in study 
• Study terminated by sponsor 
• Subject died 
 
7.2.1. Lost to Follow-Up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for/attend a 
required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether the participant wishes to and/or 
should continue in the study; 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record; 
• Should the participant continue to be unreachable, the participant will be 
considered to have withdrawn from the study.  
7.2.2. Withdrawal of Consent  
Participants who request to discontinue receipt of study intervention, and who do not enter 
A3921145, 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 participant specifically withdraws 
consent/assent for any further contact with them or persons previously authorized by the 
participant to provide this information. Participants should notify the investigator in writing of 
the decision to withdraw consent from future follow-up, whenever possible. The withdrawal 
of consent should be explained in detail in the medical records by the investigator as to 
whether the withdrawal is only from further receipt of study intervention or also from study 
procedures and/or posttreatment study follow-up, and entered on the appropriate CRF page.  
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law. 
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8. ASSESSMENTS 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the 
safety and well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely fashion. 
Efficacy evaluators must receive and document protocol specific and efficacy assessment 
scales training prior to performing evaluations.  To assure consistency and reduce variability, 
the same evaluator should assess the clinical evaluations for any individual subject throughout 
the study; a back-up experienced and qualified, protocol-trained evaluator is allowed in case 
of emergency or special situation when the designated evaluator is unable to perform the 
evaluation; this must be documented.  The identity (eg, initials) of the evaluator should be 
captured on the source documentation (eg, worksheet). 
8.1. Efficacy Assessments 
Throughout the study the sJIA disease activity of each subject will be evaluated in a 
multidimensional manner and multiple signs and symptoms related to inflammation will be 
assessed.  These include biochemical markers of inflammation (eg, ESR, CRP, See 
Section 8.1.6.3 for complete details), quantifying the amount of inflammatory tissue 
(eg, evaluation of joints), and assessing the clinical consequences of inflammation (eg, health 
questionnaires, Fever, Adapted JIA ACR response).  
8.1.1. Number of Joints with Active Arthritis/Limitation of Motion 
At each study visit, joints with swelling, pain on motion, tenderness and limitation of motion 
will be assessed and recorded on the appropriate CRF.  The results will be faxed/emailed to 
the Centralized Coordinating Center (See Section 8.1.12).  
The ACR defines a joint with active arthritis as a joint with swelling or, in the absence of 
swelling, limitation of motion accompanied by pain on motion, or tenderness.  
Swelling will be assessed in the following joints: 
• Temporomandibular, Sternoclavicular, Acromioclavicular, Shoulder, Elbow, Wrist, 
Metacarpophalangeal (MCP I-V), Proximal Interphalangeal (PIP I-V), Distal 
Interphalangeal (II-V), Knee, Ankle, Subtalar joints, Intertarsal joints, 
Metatarsophalangeal (MTP I-V), Toe Interphalangeal (I-V). 
Pain/Tenderness will be assessed in the following joints: 
• Temporomandibular, Sternoclavicular, Acromioclavicular, Shoulder, Elbow, Wrist, 
Metacarpophalangeal (MCP I-V), Proximal Interphalangeal (PIP I-V), Distal 
Interphalangeal (II-V), Hip, Knee, Ankle, Subtalar joints, Intertarsal joints, 
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Metatarsophalangeal (MTP I-V), Toe interphalangeal (I-V), Cervical spine, Thoracic 
spine, Lumbar spine, Sacroiliac joints. 
Limitation of motion will be assessed in the following joints: 
• Temporomandibular, Shoulder, Elbow, Wrist, Metacarpophalangeal (MCP I-V), 
Proximal Interphalangeal (PIP I-V), Distal Interphalangeal (II-V), Hip, Knee, Ankle, 
Subtalar joints, Intertarsal joints, Metatarsophalangeal (MTP I-V), Toe Interphalangeal 
(I-V), Cervical spine, Thoracic spine, Lumbar spine. 
Duration of morning stiffness: 
• Subjects should be queried about the approximate duration of morning stiffness by 
asking “Since the last visit, or in the past 7 days, has the duration of morning stiffness 
lasted for more than 15 minutes?”  The duration (in minutes) should be recorded in the 
source/worksheet and CRF. 
8.1.2. Fever and Absence of Fever Assessment 
At each study visit, the subject’s oral temperature will be taken.  From Day 7 onward, the 
subject will also be asked if they had fever, defined as temperature ˃38° C (100.4° F), due to 
sJIA, in the last 7 days before the visit.  “Absence of fever”, defined as the documented 
absence of fever due to sJIA in the week preceding the assessment, will be evaluated at every 
visit from the Day 7 visit onward, as a key component of the Adapted JIA ACR response.  
Subjects will be provided with a thermometer to measure their oral temperature on days that 
have fever symptoms.  Each subject will receive a diary at Screening to record their 
temperature.  The parent/legal guardian should complete the diary or supervise the completion 
of the diary by the subject.  If subjects have a fever, the temperature should be recorded twice 
daily (in the morning and evening); the highest temperature since previous diary recording 
should be reported in the diary.  Subjects will return the diary to the clinic at each study visit.  
8.1.3. Physician’s Global Assessment of Overall Disease Activity 
At each study visit, following an assessment of the number of joints with swelling, 
pain/tenderness and limitation of motion, the investigator will provide an assessment of the 
subject’s overall level of disease activity.  This evaluation is based on the subject’s disease 
signs, functional capacity and physical examination.  This evaluation is based on the subject’s 
disease signs, functional capacity and physical examination.  The result will be faxed/emailed 
to the Centralized Coordinating Center (see Section 8.1.12).  
The investigator will rate the overall level of disease activity by entering a number from 0 to 
10 (in 0.5 increments), with ‘0’ as ‘No Activity’ and ‘10’ as ‘Maximum Activity’ on a 
21-numbered circle visual analog scale (VAS), as shown below. 
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8.1.4. Childhood Health Assessment Questionnaire (CHAQ) 
At each study visit, the Childhood Health Assessment Questionnaire (CHAQ) assessment will 
be administered to the parent/legal guardian or an adult caregiver interacting daily with the 
subject.  Parents/legal guardians or an adult caregiver interacting daily with the subject will 
complete this assessment for the duration of study.  The results of the questionnaire will be 
faxed/emailed to the PRCSG/PRINTO Centralized Coordinating Center (see Section 8.1.12).  
Every effort should be made to have the same individual complete the CHAQ throughout the 
course of the study. The CHAQ (Singh 1994)11 is a validated instrument and comprises two 
indices, Disability and Discomfort, and a global assessment of arthritis (overall well-being).  
The CHAQ has been cross-culturally adapted and validated in more than 30 languages by the 
PRINTO group.12  
The CHAQ assessment will be based on the responses, as confirmed by the Centralized 
Coordinating Center. 
Disability Index  
The parent/legal guardian or adult caregiver interacting daily with the subject will be asked to 
provide responses to questions designed to assesses function in 8 areas, including dressing and 
grooming, arising, eating, walking, hygiene, reach, grip, and activities-distributed, among a 
total of 30 items.  Each question is rated on a four-point scale of difficulty in performance, 
scored from 0-3.  The question with the highest score determines the score for the functional 
area.  If aids or devices are used or assistance is required, the minimum score for that 
functional area is 2.  
Discomfort Index  
For the assessment of discomfort, the parent/legal guardian or adult caregiver interacting daily 
with the subject will be asked to provide a response to the following question: 
“How much pain do you think your child had because of his or her illness IN THE PAST 
WEEK?  Please fill a circle below to indicate how severe your child’s pain has been:”   
The parent/legal guardian or adult caregiver interacting daily with the subject will rate the 
overall pain by entering a number from 0 to 10 (in 0.5 increments), with ‘0’ as ‘No Pain’ and 
‘10’ as ‘Very Severe Pain’ on a 21-circle visual analog scale (VAS), as shown below. 
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Parent/Legal Guardian/Adult Caregiver Global Assessment of Overall Well-Being   
For the assessment of overall well-being, the parent/legal guardian or adult caregiver 
interacting daily with the subject will be asked to provide a response to the following 
question: 
“Considering all the ways in which the illness affects your child AT THIS TIME, please 
indicate below how your child is doing by filling a circle.” The parent/or legal guardian or 
adult caregiver interacting daily with the subject will rate the overall well-being by entering a 
number from 0 to 10 (in 0.5 increments), with ‘0’ as ‘Very Well’ and ‘10’ as ‘Very Poorly’ on 
a 21-circle visual analog scale (VAS), as shown below. 
 
8.1.5. Child Health Questionnaire (CHQ) 
At baseline (Day 1), the end of Part 1 and Part 2 of the open-label phase, randomization and 
every 6 months thereafter the parent/legal guardian or adult caregiver interacting daily with 
the subject will be asked to complete a Child Health Questionnaire (CHQ).  Parents/legal 
guardians or adult caregiver interacting daily with the subject will complete this assessment 
for the duration of study.  
The CHQ (Landgraf 1996)13 is a validated general pediatric quality of life instrument.  The 
CHQ assesses for 14 physical and psychosocial domains: general health perceptions, physical 
functioning, role/social physical functioning, bodily pain, role/social emotional functioning, 
role/social behavioral functioning, parent/legal guardian/adult caregiver impact-time, 
parent/legal guardian/adult caregiver impact-emotional, self-esteem, mental health, behavior, 
family activities, family cohesion, and change in health.  
The response options for the CHQ are ordinal scales that vary by the item.  Each item consists 
of 4–6 response options. Additionally, each scale consists of varying numbers of items. 
The CHQ score will be determined based on the parent/legal guardian/adult caregiver’s 
questionnaire responses.  
8.1.6. Inflammatory, Rheumatic Disease and MAS Markers 
Laboratory markers of active disease in sJIA include the erythrocyte sedimentation rate (ESR) 
and C-reactive protein (CRP).  In this study, testing for both ESR and CRP will be performed 
in all subjects at each study visit. 
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8.1.6.1. C-Reactive Protein (CRP) 
At each study visit, a blood sample for CRP testing will be collected and sent to the central 
laboratory for determination.  
8.1.6.2. Erythrocyte Sedimentation Rate (ESR) 
At each study visit, ESR (Westergren Method) will be determined locally utilizing an ESR 
Testing Kit which will be provided to the investigator site by the Sponsor.  Please refer to the 
ESR Testing Kit for detailed instructions on how to perform this test appropriately. 
The ESR result will be recorded on the appropriate CRF.  The ESR result will also be 
faxed/emailed to the Centralized Coordinating Center which, along with other JIA core set 
variables, will be used to perform efficacy assessments at each visit. A local lab ESR testing 
kit (Westergren method) can be substituted for a Sponsor kit only if supply issues have 
resulted in a Sponsor kit not being available at the time of the visit.  
8.1.6.3. Other Inflammatory and Rheumatic Disease Markers  
At screening, additional inflammatory and rheumatic disease markers, such as Rheumatoid 
Factor (RF) and albumin (as part of serum chemistry) will also be assessed.  On Day 1 ferritin 
levels, will be evaluated as another marker of rheumatic disease status. 
8.1.6.4. Macrophage Activation Syndrome (MAS) Markers  
If MAS is suspected in a febrile subject during a study visit, an extra blood sample will be 
collected to assess Ferritin (1.1 mL blood), Platelets (part of hematology assessment), 
Triglycerides (part of lipid assessment) and Fibrinogen serum levels (1.4 mL blood) in order 
to confirm a diagnosis of MAS.  Refer to Section 8.2.3 for further details. 
8.1.7. Adapted ACR 30 Pediatric Criteria: JIA Core Set Variables and Response  
The disease activity of sJIA will be measured using an adaptation of the JIA American 
College of Rheumatology (ACR) 30 response.  The Adapted JIA ACR 30 Response criteria 
include the components of the pediatric ACR core set along with the absence of fever due to 
sJIA in the preceding 7 days.14  Fever is defined as temperature ˃38° C (100.4° F).  The 
Adapted JIA ACR 30, 50, 70, 90, 100 response is defined as the absence of fever due to sJIA 
in the preceding 7 days along with at least 3 out of 6 JIA core set variables improved ≥30%, 
50%, 70%, 90%, 100%, respectively, with no more than 1 out of 6 JIA core set variables 
worsened by ≥30%, which include:  
• Number of joints with active arthritis; 
• Number of joints with limited range of motion; 
• Physician global evaluation of disease activity; 
• Parent/ legal guardian/Child evaluation of overall well-being; 
• Functional ability (CHAQ Disability Index); 
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• ESR.* 
The Adapted JIA ACR 30, 50, 70, 90, 100 response rate will be determined at every visit from 
Day 7 onward based on the investigator’s and parent/legal guardian’s assessment of 
components of the JIA core set variables.  
*For “real-time” assessment of the Adapted JIA ACR 30 Response during a study visit the 
subject’s ESR will be used to determine the percent change in inflammation biomarker.  CRP 
may be used for analysis of other related endpoints (details will be provided in the Statistical 
Analysis Plan [SAP]). 
At the end of the open-label phase, only subjects who were able to maintain an Adapted JIA 
ACR 30 response for at least 4 weeks in accordance with the protocol requirements of Section 
3.2, will be randomized into the double-blind, placebo-controlled phase.  
Achievement and maintenance of an Adapted JIA ACR 30 response in the open-label phase 
will need be confirmed by the Centralized Coordinating Center.  Investigators must enter this 
confirmation in the eCRF at every study visit from the Day 7 visit onward.  
Following confirmation, the investigator site will randomize the subject utilizing the 
Sponsor’s Interactive Response Technology (IRT) system (see Section 5.1). 
8.1.8. Disease Flare Criteria 
The Disease Flare (Brunner 2002)15 determination is a derived measurement utilizing each 
component of the JIA core set variables (see Section 8.1.7). 
Flare is defined as a worsening of 30% or more in 3 or more of the 6 variables of the JIA core 
set, with no more than one variable improving by 30% or more.  In addition, for sJIA a 
Disease Flare may also constitute a recurrence of fever.  
sJIA Flare is defined as at least one of the following: 
• Recurrence of fever (>38° C/100.4° F) on 2 or more consecutive days) considered to 
be due to SJIA activity.  
• Worsening of 30% or more in three or more of the six variables of the JIA core set 
with no more than one variable of the JIA core set improving by 30% compared to the 
day of randomization into the withdrawal phase.* 
*Note: For “real-time” assessment of sJIA flares during a study visit the subject’s 
ESR will be used to determine the JIA core component related to percent change in 
inflammation biomarker.  However, CRP may be used for analysis of other related 
endpoints (details will be provided in the Statistical Analysis Plan [SAP]). 
For evaluation of sJIA flare the following applies: If the Physician or parent/legal guardian 
global scores are used in the definition of flare, then there must be an increase of at least 
2 units on a 0-10 VAS scale.  If the number of active joints or number of joints with loss of 
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motion is used in the definition of flare, then there must be an increase of at least 2 joints.  If 
the ESR is used in the definition of flare, then the value at the visit in which flare is being 
assessed must be out of the normal range (ESR ˃20 mm/hr). Investigators will be required to 
complete relevant CRF pages regarding sJIA Disease Status while the subject is at the clinic, 
and email or fax the sJIA Disease Assessment worksheets to the Coordinating Center for 
confirmation of the sJIA flare based on ESR.  The confirmation whether a subject has a sJIA 
Flare per protocol will need to be entered in the eCRF upon receipt of the assessment from the 
Coordinating Center.  At each visit in the double-blind phase, the investigator will evaluate 
the subject for evidence of disease flare.  Subjects who experience a single episode of disease 
flare in the double-blind phase (based on the investigator’s and parent/legal guardian’s 
assessment of components of the JIA core set variables), will be discontinued from the study.  
8.1.9. JIA ACR Clinical Inactive Disease and Clinical Remission Criteria 
The American College of Rheumatology (ACR) Clinical Inactive Disease and Clinical 
Remission (Wallace 2011)16 criteria are defined as follows: 
Clinical Inactive Disease: 
• No joints with active arthritis; 
• No fever, rash, serositis, splenomegaly, hepatomegaly, or generalized 
lymphadenopathy attributable to sJIA; 
• No active uveitis (as defined by the SUN Working Group); 
• Normal ESR* (within normal limits of the method used where tested) or, if elevated, 
not attributable to s JIA; 
• Physician global assessment of disease activity score of ‘best possible’ on the scale 
used; 
• Duration of morning stiffness of ≤15 minutes. 
*The subject’s ESR result will be used for “real-time” assessment.  
Clinical Remission: 
• Clinical Inactive disease for 6 months continuously while on medications. 
Inactive disease and clinical remission based on the ACR criteria will be evaluated at every 
visit from Day 7 onward based on the investigator’s and parent/legal guardian’s assessment of 
components of the sJIA disease status.  
8.1.10. Juvenile Arthritis Disease Activity (JADAS-27 CRP; JADAS-27 ESR) Score 
The Juvenile Arthritis Disease Activity score is a validated composite disease activity 
measure for JIA (Consolaro 2009).18  Recently, the scoring system was adapted to use the 
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27-joint count (Bazso 2009),20 and C-reactive protein (CRP) in place of Erythrocyte 
Sedimentation Rate [ESR]) for the inflammatory marker component (Nordal 2012).21  
JADAS-27 CRP (JADAS-27 ESR) score will be determined based on four components:  
• Physician global assessment of disease activity;  
• Parent/legal guardian global assessment of well-being (from the CHAQ);   
• Number of joints with active disease (27 joint assessment);  
• CRP or ESR as applicable. 
8.1.11. JADAS-27 Minimal Disease Activity and Inactive Disease 
The cutoff values in the JADAS-27 that correspond to inactive disease and minimal disease 
activity (Consolaro 2012)18 are defined as follows: 
Polyarthritis (>4 active joints): 
• Inactive Disease: ≤1; 
• Minimal Disease Activity: ≤3.8. 
Oligoarthritis (≤4 active joints): 
• Inactive Disease: ≤1; 
• Minimal Disease Activity: ≤2. 
The JADAS-27 score will be determined based on the investigator and parent/legal 
assessment of the above components.  
8.1.12. Centralized Coordinating Center 
This study will utilize a Centralized Coordinating Center to review and confirm, in real time, 
efficacy assessments, including sJIA fever assessment, JIA core set variables, extra-articular 
sJIA features, Adapted JIA ACR 30, 50 response, sJIA disease flare and inactive disease, 
according to validated criteria, at various time points throughout the study.  
In addition, the Centralized Coordinating Centers will review CS regimens of study 
participants.  The Centralized Coordinating Centers will suggest a customized 4-week CS 
tapering schedule for each subject entering the Open-label Phase Part 2.  Subjects are required 
to contact the investigator if they experience any symptoms of a sJIA flare; if required, an 
extra unscheduled visit will be conducted to assess the adverse event.  The tapering schedule 
will be re-evaluated in consultation with the Coordinating Centers. 
The Centralized Coordinating Center will also provide recommendations in case participants 
are not able to maintain a stable CS dose in the double-blind phase.  Furthermore, the 
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Centralized Coordinating Center will provide guidance regarding discontinuation of any 
subject based on CS regimen.  
To facilitate this evaluation, at each visit study visit the investigator site will fax/email the 
results of each of the following JIA core set variable assessments to the Centralized 
Coordinating Center: 
• Complete joint examination form; 
• Physician’s Global Assessment of Overall Disease Activity; 
• Parent’s global assessment of overall well-being (CHAQ); 
• Assessment of extra-articular sJIA manifestations; 
• Functional ability (CHAQ); 
• ESR for same-day assessment; 
• CS regimen changes since last visit (only in Part 2 of the Open-label phase). 
Evaluation of faxed results will be performed in real time (within 90 minutes of receipt) by 
independent evaluators at the Centralized Coordinating Center.  The Centralized Coordinating 
Center will provide the investigator site with confirmation of receipt of faxed information.  
The Centralized Coordinating Center may contact the investigator site directly to confirm the 
accuracy of information submitted following review and assessment.  
Faxed results of efficacy evaluations by the Centralized Coordinating Center will need to be 
entered promptly in the eCRF during a subject’s study visit.  
Please refer to the Centralized Coordinating Center manual for details regarding instructions 
relating to submission of required information and other logistical information. 
8.2. Safety Assessments 
Safety will be assessed by the spontaneous reporting of adverse events (AEs), physical 
examinations and clinical laboratory results in all subjects who received at least 1 dose of 
study medication.  
Investigators and Pfizer clinicians will review individual subject data throughout the conduct 
of the trial to ensure subjects’ well-being. 
Please refer to Appendix 7 for guidelines for safe monitoring and discontinuations due to 
laboratory abnormalities, serious infections, opportunistic infections, and malignancies. 
Please refer to Section 10.9 for the evaluation of potentially malignant tumors, suspicious 
lymphadenopathy, possible extra-nodal lymphoproliferative disorder. 
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8.2.1. Medical and Family History 
At the time of screening, a medical and family history will be obtained.  Medical history 
should include information on the subject’s primary arthritis-related diagnosis (including 
duration), any other baseline medical conditions, allergies, and tobacco and alcohol use.  
Family history should include inquiry about family members with immunodeficiency and 
premature coronary heart disease. 
8.2.2. Physical Examination 
Complete Physical Examination 
The following parameters and body systems will be examined and any abnormalities 
described: General appearance, weight and height, skin (presence of rash), HEENT (head, 
eyes, ears, nose and throat), lungs (auscultation), heart (auscultation for presence of murmurs, 
gallops, rubs), lower extremities (peripheral edema), abdominal (palpation and auscultation), 
neurologic (mental status, station, gait, reflexes, motor and sensory function, coordination) 
and lymph nodes.  
If a rash is present, the type of rash should be noted (eg, typical sJIA rash, varicella rash, 
herpes zoster lesions, or other types of rash). Please refer to Section 9.2.6. 
Country specific amendment for EU sites (including UK): a full skin cancer examination 
must be performed as part of the complete physical examination. 
Targeted Examination 
An abbreviated physical examination will be performed assessing the following: examination 
of skin (presence of rash), heart, lungs, lower extremities for peripheral edema, abdomen and 
lymph nodes.  Any clinically significant changes from the baseline examination should be 
recorded as AEs.  
If a rash is present, the type of rash should be noted (eg, typical sJIA rash, varicella rash, 
herpes zoster lesions, or other types of rash). Please refer to Section 9.2.6. 
8.2.3. Macrophage Activation Syndrome Assessment (MAS)  
Macrophage activation syndrome (MAS) is a potentially life-threatening complication of 
sJIA.  MAS is characterized by an overwhelming inflammatory reaction due to an 
uncontrolled and dysfunctional immune response involving the continual activation and 
expansion of T lymphocytes and macrophages, which results in massive hypersecretion of 
pro-inflammatory cytokines.  Characteristic clinical features of MAS are high, non-remitting 
fever, hepatosplenomegaly, generalized lymphadenopathy, central nervous system 
dysfunction, and hemorrhagic manifestations.  Typical laboratory abnormalities include 
pancytopenia, increased levels of ferritin, triglycerides, and decreased fibrinogen levels.  A 
key histopathological feature of MAS is evidence of macrophage hemophagocytosis in the 
bone marrow.7 
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Subjects are encouraged to contact the investigator by telephone if they have fever for more 
than 1 consecutive day.  If a subject is suspected to experience MAS, an unscheduled visit 
will need to be performed as soon as possible for further evaluation.  During the unscheduled 
visit an extra blood sample will be collected to assess Ferritin, Platelets, Triglycerides and 
Fibrinogen serum levels in order to confirm a diagnosis of MAS. 
In accordance with the 2016 ACR/EULAR/PRINTO Criteria,17 a subject is classified as 
having MAS if the subject has:  
• Fever plus Ferritin >684 ng/ml; 
AND at least 2 of the following 4 laboratory variables: 
• Platelets ≤181 x 109/L; 
• AST >48 U/L;  
• Triglycerides >156 mg/Dl; 
• Fibrinogen ≤360 mg/dL.  
8.2.4. Uveitis Assessment 
At screening a formal uveitis assessment will not be required, but, if applicable, 
documentation of previous uveitis assessment(s) by an ophthalmologist (or qualified 
equivalent per local practice) should be reviewed to document presence/absence of active 
uveitis.  At every visit from Day 7 onward a confirmation of the subject’s uveitis status will 
be required as part of the JIA ACR inactive disease evaluation referenced in Section 8.1.9.  
8.2.5. Vitals Signs Assessment 
Blood Pressure 
Blood pressure will be measured in the subject’s arm and recorded to the nearest mmHg.  The 
same arm should be used throughout the study using an appropriate cuff size.  All blood 
pressure readings should be measured after resting for at least 5 minutes.  The same position 
and blood pressure cuff appropriately sized, positioned and properly calibrated should be used 
to measure blood pressure each time.  When the timing of these measurements coincides with 
a blood collection, blood pressure and pulse rate should be obtained first.  It is preferred that 
blood pressure to be collected in the sitting position, supine position is allowed.  Position 
should be documented in the CRF and should be consistent throughout the study.  
Pulse Rate 
Pulse rate should be obtained after resting for at least 5 minutes. 
Temperature 
It is preferred that body temperature be collected orally using a digital thermometer and that 
the same method should be used consistently throughout the study.  
Height and Weight 
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Weight should be reported at each visit with height preferentially measured utilizing a 
Harpenden stadiometer.  Height will be evaluated on a monthly basis.  
8.2.6. Varicella (chickenpox) and Herpes Zoster (shingles) Assessment and Guidance 
All subjects should notify the investigator immediately if they exhibit any skin lesions that 
could be attributed to varicella or herpes zoster. This is especially important for subjects who 
do not have documented evidence of having received 2 doses of  VZV or evidence of previous 
varicella zoster exposure as confirmed by VZV-specific IgG Ab serological testing at 
screening. Subjects and/or their parents or guardians should be especially diligent in 
conducting self-exams between visits. Any suspicion of varicella or herpes zoster should be 
treated immediately per standard of care for immunocompromised subjects (eg, IV acyclovir 
started within 24 hours of rash appearance) and study drug must also be discontinued 
immediately. Unless confirmed not to be varicella or herpes zoster, the subject should also be 
discontinued from the study. This will be considered a serious infection event. 
At each study visit, the subject will be assessed either by direct skin examination or 
parent/legal guardian/subject questioning to identify the presence of any rash that could 
potentially indicate the presence of chickenpox or shingles. The parent/guardian/subject 
should perform at least weekly skin examinations between visits. At any time there is concern 
that the presence of any signs or symptoms may indicate chickenpox or shingles, the 
investigator should be notified immediately. 
Rash that indicates the presence of chickenpox or shingles differs from the typical sJIA rash.  
The typical sJIA rash is a spotty pale red or pinkish salmon-colored rash. It rarely occurs on 
the face and typically appears on chest, upper arms and upper thighs, although can be found 
on other parts of the body. sJIA rash usually does not recur in the same location. It is 
generally flat, but can emerge in raised, small patches. It is rarely accompanied by itching.  
The classic symptom of varicella (chickenpox) is a rash that turns into itchy, fluid-filled 
blisters that eventually turn into scabs. The rash may first show up on the chest, back, and 
face, and then spread over the entire body, including inside the mouth, eyelids, or genital area. 
It usually takes about one week for all of the blisters to become scabs. Other typical 
symptoms that may begin to appear one to two days before rash include: fever, tiredness, loss 
of appetite, and headache. 
Herpes zoster (shingles) is a painful rash that develops on one side of the face or body. The 
rash consists of blisters that typically scab over in 7 to 10 days. Before the rash appears, 
people often have pain, itching, or tingling in the area where it will develop. This may happen 
several days before the rash appears. Most commonly, the rash occurs in a single stripe around 
either the left or the right side of the body. In other cases, the rash occurs on one side of the 
face. Shingles on the face can affect the eye and cause vision loss. In rare cases (usually in 
people with weakened immune systems), the rash may be more widespread on the body and 
look similar to a chickenpox rash. Other symptoms of shingles can include: fever, headache, 
chills, and upset stomach. 
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8.2.7. Pubertal Development Assessment (Tanner Stages) 
Determination of physical and sexual maturation will be performed at the Screening and at the 
End of Study or Early Termination visit using the Tanner stages (Dorn 1990, Taylor 2001)19,26 
by a trained physician/clinician in the presence of a parent/legal guardian or clinic staff 
member.  
In the event the parent/legal guardian or subject refuses the examination for sexual maturity, 
or if not possible per site practice or local regulations, subject self-assessment of Tanner 
staging that uses photographs or line drawings corresponding to the Tanner stages will be 
offered to obtain information on pubertal status while avoiding intrusiveness. 
The Tanner stage rating will be assigned by the clinician/physician based on the exam or 
based on the subject self-report.  If the clinician believes the subject’s self-report may reflect 
an earlier or later pubertal stage than the clinician believes is correct, the clinician will review 
the self-report form with the subject and/or parent/legal guardian to clarify the subject’s 
responses.  This review will be done in the presence of another person, either the parent/legal 
guardian or a clinic staff member.  At the end of the review, the clinician will then assign a 
best estimate Tanner stage rating.  
Note that pubertal development in the United States begins as early as age 8 and completes as 
late as age 17. 
8.2.8. Tuberculosis Testing 
At the time of screening, all subjects will under tuberculosis (TB) testing.  
QuantiFERON®-TB Gold or Gold Plus (according to the country regulations and approvals) 
In-Tube Test is the preferred testing method.  If the QuantiFERON®-TB Gold or Gold Plus 
In-Tube test cannot be performed, or if the results cannot be determined by the reference 
laboratory to be either positive or negative, then subjects may be screened using a negative 
Quantiferon®-TB  test performed locally or the Purified Protein Derivative (PPD) Tuberculin 
Skin Test (Mantoux method) or T-Spot TB test with Sponsor approval. 
In addition to TB testing as specified in this clinical protocol, a chest X-ray may be performed 
to aid in TB status determination, according to local standards and/or in countries with a high 
incidence rate of TB.  
Annual TB testing: In addition to the TB testing performed at screening, annual TB testing 
(QFT-TB Gold or Gold Plus) is required in countries where TB incidence has been reported at 
a rate of >50 cases per 100,000 persons, eg, China, Russian Federation; India, South Africa 
and Ukraine. (World Health Organization).  
Country-specific amendment for EU sites (including UK): Participants who have resided 
or travelled in areas of endemic tuberculosis or endemic mycoses; or have underlying 
conditions that may predispose them to infection must be monitored closely per applicable 
local guidelines.  Consultation with a health care professional with expertise in the treatment 
of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis 
therapy is appropriate for an individual patient. 
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8.2.8.1. QuantiFERON®-TB Gold or Gold Plus In-Tube Test 
QuantiFERON®-TB (QTF-TB) Gold or Gold Plus test will be available according to the 
country regulations and approvals. 
QuantiFERON®-TB Gold and Gold Plus In-Tube test (Guidelines 2005)10 are in vitro 
diagnostic tests using a peptide cocktail simulating ESAT-6, CFP-10 proteins (QTF-TB Gold 
Plus) or ESAT-6, CFP-10 and TB7.7 proteins (QTF-TB Gold) to stimulate cells in 
heparinized whole blood.  Detection of interferon- by Enzyme-Linked Immunosorbent Assay 
is used to 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. 
A blood sample of approximately 3 mL (QTF-TB Gold) or 4 mL (QTF-TB Gold Plus) will be 
collected at screening for QuantiFERON®-TB Gold In-Tube testing.  
Following sample processing, the sample will be shipped to the Sponsor’s designated 
reference laboratory for testing.  The procedure for processing and preparing the sample for 
shipment is described fully in the laboratory manual, which will be provided to investigators. 
A negative PPD or T-Spot TB test can be substituted for the QuantiFERON®-TB Gold or 
Gold Plus In-Tube test only if the central laboratory is unable to perform the test or cannot 
determine the results to be positive or negative and the Pfizer Medical Monitor approves it, on 
a case-by-case basis. 
8.2.8.2. Purified Protein Derivative (PPD) Test or T-Spot TB Test 
If the QuantiFERON®-TB Gold or Gold Plus In-Tube test cannot be performed, or if the 
results cannot be determined to be positive or negative, then subjects can be screened using 
the Purified Protein Derivative (PPD) Tuberculin Test (Mantoux method) or T-Spot TB test, 
with the approval of the Pfizer Medical Monitor.  
Subjects must have the PPD test administered and evaluated by a health care professional 
48 to 72 hours later in order to be eligible for the study, unless performed and documented 
within the last 3 months.  The test should be performed according to local standards and 
interpreted in consultation with the Sponsor. 
8.2.9. Laboratory Testing 
Blood and/or urine samples for tests specified below will be collected at the time points 
specified in the SOA and sent to the Sponsor’s designated central laboratory for testing.  The 
shipment address of the central laboratory contact information will be provided to investigator 
sites prior to initiation of the study.  One re-testing of a screening hematology or serum 
chemistry laboratory parameter is allowed if the abnormal lab(s) was an uncharacteristic 
result(s). Re-testing must be completed within the screening period. 
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• Hematology: Hemoglobin, hematocrit, red blood cells, white blood cells, neutrophils 
(%, absolute), lymphocytes (%, absolute), monocytes (%, absolute), eosinophils 
(%, absolute), basophils (%, absolute), platelets. 
• Chemistry: Sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, 
glucose, calcium, total protein, total bilirubin (TB), direct bilirubin, indirect bilirubin, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase, gamma-glutamyl transferase (GGT), albumin, creatine phosphokinase 
(CPK). 
• Lipids (under fasting conditions for approximately 9 to 12 hours): Total 
cholesterol, direct HDL, direct LDL, triglycerides, apolipoprotein A-1 and B.  
• Urinalysis: Specific gravity, pH, protein, glucose, ketones, blood and leukocyte 
esterase, urine microscopy (only if dipstick positive for blood or protein, or if 
clinically indicated). 
• Inflammatory markers and other RA related tests: C-reactive protein (CRP), 
Rheumatoid Factor (RF), albumin, ferritin. 
** Please note, ESR will determined locally utilizing an ESR Testing Kit provided to 
the investigator site by the Sponsor (see Section 9.1.6.2).  Please refer to the ESR 
Testing Kit Manual for detailed instruction on how to perform this test appropriately.  
The ESR result will be recorded on the appropriate CRF.  The ESR result also will be 
faxed to the Centralized Coordinating Center. 
• Pregnancy testing (women of childbearing potential only): Blood (serum) or urine 
pregnancy testing (for Human Chorionic Gonadotropin [HCG]) will be performed 
locally.  A positive urine pregnancy will be confirmed by a blood (serum) pregnancy 
test performed either locally or by the central laboratory.  
• Hepatitis B testing: HB surface antigen (HBsAg), HB core antibody (HBcAb), HB 
surface antibody (HBsAb). 
Interpretation of Hepatitis B Testing Results:   
• HBsAg negative and HBcAb negative: Subject is eligible for the study; 
• HBsAg positive and HBcAb negative: Subject is excluded from study 
participation; 
• HBsAg negative and HBcAb positive and HBsAb positive: Subject is eligible for 
study; 
• HBsAg negative and HBcAb positive and HBsAb negative: Subject is excluded 
from study participation. 
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• Hepatitis C testing: Hepatitis C Antibody (HCV Ab), Hepatitis C Viral RNA (HCV 
RNA). 
Interpretation of Hepatitis C Testing Results:  
• HCV Ab positive and HCV RNA positive: Subject is excluded from study 
participation.  
• Tuberculosis testing: Please refer to Section 9.2.8. 
• VZV-specific ELISA testing: This test will be done at the screening visit in all 
subjects who do not have a health professional documented history of having received 
2 vaccinations for VZV.   
• MAS diagnostic laboratory testing: if MAS is suspected in a febrile subject, a blood 
sample will be collected to assess Ferritin and Fibrinogen serum levels in order to 
confirm the diagnosis of MAS.  Platelet and triglyceride levels from the standard 
hematology and lipid evaluations will also be reviewed for confirmation of a MAS 
diagnosis.  
• Human Immunodeficiency Virus testing: HIV-1/HIV-2 antibody. 
Interpretation of HIV Testing Results:  
• HIV-1 or HIV-2 antibody positive: Subject is excluded from study participation. 
8.2.10. Pregnancy Testing 
For female subjects of childbearing potential (those who have passed menarche), a blood 
(serum) or urine pregnancy test, with sensitivity of at least 25 mIU/mL for hCG, will be 
performed locally at screening, before investigational product administration at the baseline 
visit, at each study visit, and at the End of Study or Early Termination visit.  If preferred, 
urine and/or serum pregnancy testing may be performed at any time using the local or central 
laboratory. 
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period or when potential pregnancy is otherwise suspected.  Pregnancy tests may 
also be repeated as per request of Institutional Review Boards (IRBs)/Ethics Committees 
(ECs) or if required by local regulations.  
A negative pregnancy test (based on the local result) is required before the subject may 
receive the investigational product.  
A positive urine pregnancy test will be confirmed by a blood (serum) pregnancy test 
performed either locally or by the central laboratory.  In the case of a positive confirmed 
pregnancy test, the subject will be withdrawn from administration of investigational product 
and from the study.  Please refer to Section 10.11 for additional information regarding 
Exposure During Pregnancy. 
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8.2.11. Contraceptive Check 
A contraceptive check also will be performed to confirm that contraception, if assigned, is 
being used consistently and correctly.  Childbearing status also will be checked, and 
contraception implemented in subjects who mature physically and behaviorally during the 
conduct of the study. 
8.2.12. Blood Volume 
Every effort will made to minimize the number of blood sampling and volumes collected.  
Low volume pediatric tubes will be used where possible.  
Country specific amendment for EU sites (including UK): If blood collection is difficult 
for individual subjects, venipuncture will be limited to 3 attempts, with additional attempts 
within 3–5 business days unless there is a medical emergency.  Every effort should be made to 
ensure that blood volume collections do not exceed 1% of the total blood volume at any single 
time and 3% of the total blood volume during any period of 4 weeks. 
At screening 14.1 mL or 15.1 mL (according to QTF-TB test used) to maximally 25.8 mL 
blood (only if serum pregnancy test, MAS laboratory evaluations, VZV IgG Antibody and 
HCV RNA test are required) will be collected.  If preferred by the investigator, the laboratory 
evaluations at screening may be done at 2 separate visits within 40 days before enrolment on 
Day 1 to limit the blood volume collected in one day.  Every effort should be made to ensure 
that blood volume collections do not exceed 1% of the total blood volume at any single time 
and 3% of the total blood volume during any period of 4 weeks.  One re-testing of a 
hematology or serum chemistry laboratory parameter is allowed if the abnormal lab(s) was an 
uncharacteristic result(s).  Re-testing must be completed within the screening period.  
In the first month of the open-label phase 20.8 mL blood will be collected (including blood 
collection at Week 4), unless optional blood collection of banked biospecimens is also 
obtained, or subjects require additional serum pregnancy testing, or extra laboratory 
evaluations for diagnosis of MAS.  At Week 4 and all monthly visits thereafter, 4.6 mL to 
12.7 mL blood will be collected. 
In case of insufficient blood sample or poor sample quality (eg, due to hemolysis or clotting) 
the subject must return within 1 week for a new sample collection. 
Table 5 reflects approximate sample volumes needed for each measured endpoint.  The actual 
times of blood sampling may change.  In some instances, additional blood samples may be 
taken for safety assessments at times specified by Pfizer.  
Table 5. 
Maximum Blood Volume Collection at Each Study Visit 
 
Screening1 Day 1 Day 3 Day 7 Day 14 Week 4, 8, 
12 up to 16 
Part 1 
Open-label 
Week 4, 8, 
12, 16 up 
to 24. 
Part 2 
Open-label 
Randomization Every 4 
weeks 
until 
ET/EOS 
End of 
Study/Early 
Termination 
Chemistry, 
Lipids1 
x (1.1) 
x (1.1) 
x 
(1.1)3 
x 
(1.1)3 
x 
(1.1)3 
x (1.1) 
x (1.1) 
x (1.1) 
x (1.1) 
x (1.1) 
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Hematology 
x (1.2) 
x (1.2) 
x 
(1.2)3 
x 
(1.2)3 
x 
(1.2)3 
x (1.2) 
x (1.2) 
x (1.2) 
x (1.2) 
x (1.2) 
Quantiferon® 
TB Gold or 
Gold Plus8,9 
x (3.0 or 
4.0) 
 
 
 
 
 
 
 
 
 
Urine/Serum 
Pregnancy 
test2 
x (1.1) 
x (1.1) x (1.1) x (1.1) x (1.1) x (1.1) 
x (1.1) 
x (1.1) 
x (1.1) 
x (1.1) 
CRP 
 
x (1.1) x (1.1) x (1.1) x (1.1) x (1.1) 
x (1.1) 
x (1.1) 
x (1.1) 
x (1.1) 
CRP, RF 
x (1.1) 
 
 
 
 
 
 
 
 
 
ESR (local 
kit) 
X (1.2) X (1.2) 
X 
(1.2) 
X 
(1.2) 
X 
(1.2) 
X (1.2) 
X (1.2) 
X (1.2) 
X (1.2) 
X (1.2) 
Ferritin3  
X (1.1)3 X (1.1) 
 
X 
(1.1)3 
X 
(1.1)3 
X 
(1.1)3 
X (1.1)3 
X (1.1)3 
X (1.1)3 
X (1.1)3 
X (1.1)3 
Fibrinogen3 
X (1.4)3 X (1.4)3 
 
X 
(1.4)3 
 
X 
(1.4)3 
X 
(1.4)3 
X (1.4)3 
X (1.4)3 
X (1.4)3 
X (1.4)3 X (1.4)3 
VZV IgG Ab4  X (1.1) 
 
 
 
 
 
 
 
 
 
HIV-1, HIV-2 x (4.0) 
 
 
 
 
 
 
 
 
 
HBsAg, 
HbcAb, 
HCAb 
x (2.5) 
 
 
 
 
 
 
 
 
 
HCV RNA5 
x (6.0) 
 
 
 
 
 
 
 
 
 
PK6 
 
x (3.6 
to 4.8) 
 
 
 
x (3.6) 
x (3.6)6 
 
 
 
Banked 
biospecimens7 
 
X (4.5) 
 
 
 
X at Wk8 
(2.0) 
 
X (4.5) 
 
X (4.5) 
Total 
14.1 or 
15.1 mL 
to 
25.8mL 
9.4 mL 
to 
17.5mL 
2.3 
mL to 
8.2mL 
2.3 
mL to 
8.2mL 
2.3 
mL to 
8.2mL 
4.6 mL to 
13.8mL 
4.6 mL to 
11.8mL 
4.6 mL to 
12.7mL 
4.6 mL 
to  
8.2mL 
4.6 mL to 
12.7mL 
1. Lipid panel will be evaluated every 3 months after Day 1. 
2. For female subjects of childbearing potential, a blood (serum) or urine pregnancy test, will be performed 
locally at screening, before investigational product administration at the baseline visit, at each study visit, 
and at the End of Study or Early Termination visit. 
3. If MAS is suspected in a febrile subject, 2.5 mL additional blood will be collected for evaluation of Ferritin 
and Fibrinogen levels.  If no hematology and lipid evaluation is part of the visit (on Day 3, Day 7, Day 14, 
or at unscheduled visits), hematology and chemistry blood samples for assessment of platelets and 
triglycerides will also be required to confirm a MAS diagnosis. 
4. Serologic testing for antibodies to varicella zoster virus (VZV) via ELISA is required for all subjects who do 
not have documented evidence from a health professional of receiving 2 doses of varicella vaccine.  
5. RNA sample collection may be deferred and collected only if required to confirm eligibility based on the 
HCV Ab results. 
6. Blood samples for PK evaluation will be collected at Day 1 and after 8 weeks of study treatment.  PK testing 
will be done at 15 minutes (5-30 min), 45 minutes (35-55 min) and 4 hours (3-6h) after tofacitinib 
administration on Day 1.  In the first 14 subjects enrolled in Cohorts 1-2 (N=7 in each cohort), PK testing 
will also be done at 1.5 hours (1.25-2h) after tofacitinib administration.  After 8 weeks of study treatment, 
PK samples will be collected pre-dose and 1 hour (0.5-1.5h) and 3 hours (2-4h) after tofacitinib 
administration.  These PK samples may be obtained at Week 8 of Open-Label Part 1, or at Week 4 of 
Open-Label Part 2 in the case a subject started Open-Label Part 2 after 4 weeks of tofacitinib treatment in 
Part 1.  Whenever feasible, later time point within the last PK sample collection range is preferred.  In total 
3 samples (each 1.2 mL) will be collected for PK evaluation from all subjects enrolled after the 2nd  cohort.  
From the first 14 subjects of Cohorts 1-2, a 4th blood sample of 1.2 mL for PK will also be collected at the 
Day 1 visit. Subjects in India will not participate in PK evaluation. 
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7. 4.5 mL blood will be collected for banked biospecimens at baseline, randomization, when the subject flares 
(Early Termination visit in Open-Label phase, or End of Study visit in Double-blind phase), and if 
applicable when inactive disease status is reached.  This blood sample collection is optional. 
8. QuantiFERON®-TB Gold (3mL) or QuantiFERON®-TB Gold Plus (4 mL) test will be available according 
to the country regulations and approvals.  
9. In countries where TB incidence has been reported at a rate of >50 cases per 100,000 persons, 
eg, China, India, Russian Federation; South Africa and Ukraine (World Health Organization): TB testing 
(QFT-TB Gold or Gold Plus) is required at screening visit and then on a yearly basis.  Therefore, in addition 
of the volume listed, 4 mL of blood will be collected for TB testing on a yearly basis as long as the subject 
will remain this study.   
8.2.13. Risk Factor Check for Venous Thromboembolism 
All subjects will undergo a risk factor check at each study visit to check for newly developed 
risk factors for venous thromboembolism.27  This information is to be captured in the subject’s 
source file and on the relevant case report form. 
A subject may be at high risk for venous thromboembolism if they: 
• have heart failure or prior myocardial infarction within past 3 months; 
• have inherited coagulation disorders; 
• have had venous thromboembolism, either deep venous thrombosis or pulmonary 
embolism; 
• are taking combined hormonal contraceptives or hormone replacement therapy; 
• have malignancy (association is strongest with cancers other than nonmelanoma skin 
cancers); 
• are undergoing major surgery or is immobilized. 
Additional risk factors for venous thromboembolism, such as age, diabetes, obesity 
(BMI>30), 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 modify their dose of 
tofacitinib. 
If a subject has one or more of the risk factors for venous thromboembolism 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 for venous thromboembolism listed above 
under Amendment 3, they will remain on their assigned tofacitinib dose.  
8.2.14. Temporary Withholding of Study Drug 
Withholding of study drug is not necessary when administering non-live vaccines, including 
inactivated influenza vaccine and non-live COVID-19 vaccines. 
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Study drug may be temporarily discontinued for up to 28 consecutive days, for more severe 
cytopenia, 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.  Subjects who withhold study drug for any of these reasons will not 
be considered non-compliant with study medication and a PD will not be recorded. 
Per Amendment 3, for subjects with suspected venous thromboembolism, treatment with 
study drug should be temporarily withheld while the subject is evaluated.  If venous 
thromboembolism is confirmed, discontinue treatment with study drug.  
8.3. Monitoring Hematology and Serum Laboratory Parameters and specific adverse 
events 
8.3.1. Monitoring Criteria 
The following laboratory abnormalities require prompt retesting, ideally within 3-5 days: 
• Absolute neutrophil count (ANC) <1.0 x 109/L (<1000/mm3); 
• Absolute lymphocyte counts <0.5 x 109/L (<500/mm3); 
• Platelet count <100 x 10 9/L (<100,000/mm3); 
• Any single hemoglobin value <8.0 g/dL or one that drops ≥2 gm/dL below baseline; 
• Any single AST and/or ALT elevation ≥3 x upper limit of normal (ULN), regardless to 
total bilirubin.  Repeat testing must include the following tests: albumin, creatine 
kinase (CK), total bilirubin, direct and indirect bilirubin, GGT, PT/INR, and alkaline 
phosphatase; 
• Any single serum creatinine increase >50% over the average of screening (most recent 
value prior to baseline) and baseline values OR an absolute increase in serum 
creatinine ≥0.5 mg/dL (≥44.2 umol/L) over the average of screening (most recent 
value prior to baseline) and baseline values AND any single CrCl decrease of 
>30% over the average of screening (most recent value prior to baseline) and baseline 
values; 
• Increased lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) should be monitored and treated according to local guidance (eg, diet 
and behavior modification, statin therapy).  
If the abnormality is confirmed after re-test, follow-up should be discussed with the sponsor 
and frequency of monitoring increased.   
Country specific amendment for EU sites (including UK sites): Study drug will be 
discontinued temporarily for confirmed absolute neutrophil counts (ANC) levels of 
500 - 1000 neutrophils/mm3.  The subject will be monitored closely through unscheduled 
visits and laboratory retesting until ANC is >1000 neutrophils/mm3.  Dosing may be resumed 
when ANC returns to >1000 neutrophils/mm3. 
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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 9.7.1: Potential Cases of 
Drug-Induced Liver Injury. 
8.3.2. Discontinuation of Study Drug Criteria 
Study drug will be discontinued in the event of any of the following: 
• Serious infections defined as any infection (viral, bacterial, or fungal) requiring 
parenteral antimicrobial therapy or hospitalization for treatment, or meeting other 
criteria that require the infection to be classified as a serious adverse event (see 
Section 9.5.1); 
• Opportunistic infection judged significant by investigator;  
• Two sequential absolute neutrophil counts <0.5 x 109/L (<500/mm3); 
• Two sequential hemoglobin values <8.0 g/dL (80 g/L) or decreases of >30% from 
baseline value; 
• Two sequential absolute lymphocyte counts <0.5 x 109/L (<500/mm3) by repeat 
testing; 
• Two sequential platelet counts <75 x 109/L (<75,000/mm3); 
• Two sequential AST or ALT elevations >3 times ULN with a total bilirubin value 
≥2 times the upper limit of normal;a 
• Two sequential AST or ALT elevations >3 times ULN with an elevated INR;a 
• Two sequential AST or ALT elevations >3 times ULN accompanied by signs or 
symptoms consistent with hepatic injury;a  
• Two sequential AST or ALT elevations >5 times ULN, regardless of total bilirubin or 
accompanying symptoms;  
• The subject must return to the study site for prompt retesting and include the 
following: albumin, creatine kinase (CK), total bilirubin, direct and indirect 
bilirubin, GGT, PT/INR, and alkaline phosphatase.  Additional investigations 
include a detailed history, occupational exposure, sexual history, travel history, 
history of contact with a jaundiced subject, surgery, blood transfusion, history of 
liver or allergic disease, work exposure, history of ethanol, recreational drug and 
dietary supplement consumption.  Testing for acute hepatitis A, B or C 
infection and biliary tract imaging may be considered. 
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• Two sequential increases in serum creatinine >50% over the average of screening and 
baseline values OR an absolute increase in serum creatinine ≥0.5 mg/dL 
(≥44.2 umol/L) over the average of screening and baseline values AND a confirmed 
(two sequential) CrCl decrease of >30% over the average of screening and baseline 
CrCl values.  If the serum creatinine increase and the CrCl decrease have an 
identifiable and reversable reason (eg, concomitant medication), then an additional 
retest may be considered after discussion with the Sponsor study clinician or medical 
monitor.  After retest, a decision for the subject to continue in the study will be made 
after discussion with the Sponsor study clinician or medical monitor. 
• 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 Pfizer study 
team before discontinuation of the subject; 
• Malignancies, excluding adequately treated or excised basal cell or squamous cell 
carcinoma of the skin and cervical carcinoma in situ.  
• If venous thromboembolism is confirmed, discontinue treatment with tofacitinib. 
8.4. Pharmacokinetic Assessment 
Plasma samples for population pharmacokinetic (PK) analysis of tofacitinib will be collected 
over a 3-hour to 4-hour time period from all subjects enrolled in the study, at baseline (Day 1 
of tofacitinib administration) and after 8 weeks of study treatment.  
In general, every effort should be made to collect blood samples for PK analysis within the 
specified time windows.  At all times, it is essential to accurately record the date and time 
study treatment is administered and PK samples are collected.  This includes the date and time 
of the dose taken on the evening prior to the specified PK visit.  
On days where a pre-dose PK sample is collected, the subject and parent/legal guardian will 
be instructed that the subject should not take the morning dose until after the pre-dose PK 
sample is collected. 
Blood samples for PK analysis at additional time points and/or in additional subjects may be 
collected, as determined by the Sponsor. 
8.4.1. PK Blood Sample Collection Time 
In all subjects in Cohorts 1-2: in Part 1 of the study (N=7 in each cohort), 4 blood samples 
of 1.2 mL for PK will be collected at the Day 1 visit (first day of tofacitinib administration) 
and 3 blood samples of 1.2 mL will be collected after 8 weeks of tofacitinib treatment at the 
time points indicated below: 
Day 1 - PK Collection Time Points: 
• 0.25 hours [5 – 30 minutes] = 15 minutes post dose; 
• 0.75 hours [35 – 55 minutes] = 45 minutes post dose; 
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• 1.5 hours [1.25 – 2h] post dose; 
• 4 hours [3 – 6h] post dose.  If feasible for the subject, this blood sample should be 
drawn between 4 to 6 hours post dose, however any time between 3 to 6 hours post 
dose is allowed. 
Week 8 PK Collection Time Points: 
Note, the subject and parent/legal guardian will be instructed that the subject should not take 
the morning dose until after the pre-dose PK sample is collected. 
• Pre-dose (approximately 12 hours post the previous evening dose); 
• 1 hour [0.5 – 1.5h] post dose; 
• 3 hours [2 – 4h] post dose.  If feasible for the subject, this blood sample should be 
drawn between 3 to 4 hours post dose, however any time between 2 to 4 hours post 
dose is allowed. 
In all subjects after initial cohorts of the study who consented to provide PK samples, only 
3 blood samples of 1.2 mL for PK will be collected at the Day 1 visit (first day of tofacitinib 
administration) and 3 blood samples of 1.2 mL will be collected after 8 weeks of tofacitinib 
treatment at the time points indicated below: 
Day 1 - PK Collection Time Points: 
• 0.25 hours [5 - 30 minutes] = 15 minutes post dose; 
• 0.75 hours [35 – 55 minutes] = 45 minutes post dose; 
• 4 hours [3 – 6h] post dose.  If feasible for the subject, this blood sample should be 
drawn between 4 to 6 hours post dose, however any time between 3 to 6 hours post 
dose is allowed. 
Week 8 PK Collection Time Points: 
Note, the subject and parent/legal guardian will be instructed that the subject should not take 
the morning dose until after the pre-dose PK sample is collected. 
• Pre-dose (approximately 12 hours post the previous evening dose); 
• 1 hours [0.5-1.5h] post dose; 
• 3 hours [2– 4h] post dose.  If feasible for the subject, this blood sample should be 
drawn between 3 to 4 hours post dose, however any time between 2 to 4 hours post 
dose is allowed. 
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8.4.2. Blood Sample Processing 
Blood samples (1.2 mL) to provide a minimum of 0.4 mL of plasma for PK analysis will be 
collected into appropriately labeled tubes containing lithium heparin.  
Samples will be centrifuged at approximately 1700 g for about 10 minutes at 4° C.  The 
plasma will be stored in appropriately labeled screw-capped polypropylene tubes at 
approximately -20° C within 1 hour of collection.  
8.4.3. PK Sample Shipment 
The shipment address and assay laboratory contact information will be provided to 
investigator sites prior to initiation of the study. 
At the assay laboratory, samples will be analyzed using a validated analytical method in 
compliance with Pfizer standard operating procedures. 
• The PK samples must be processed and shipped as indicated to maintain sample 
integrity.  Any deviations from the PK processing steps, including any actions taken, 
must be documented and reported to the sponsor.  On a case-by-case basis, the sponsor 
may make a determination as to whether sample integrity has been compromised.  Any 
sample deemed outside of established stability, or of questionable integrity, will be 
considered a protocol deviation. 
As part of understanding the pharmacokinetics of the study drug, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method, as well as for other 
internal exploratory purposes.  These data will not be included in the clinical report.  Samples 
collected for this purpose will be retained in accordance with local regulations and, if not used 
within this timeframe, will be destroyed. 
8.5. Banked Biospecimens 
Banked biospecimens will be collected to provide an opportunity for exploratory retrospective 
analyses associated with study- and program-related endpoints (eg, safety, efficacy), the 
subjects’ disease (sJIA), the drug’s mechanism of action, and/or to potentially support future 
personalized medicine approaches.  Collection of banked biospecimens is optional for all 
subjects.  
8.5.1. Markers of Drug Response 
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who respond 
well and those who respond poorly to treatment may help to better define the most appropriate 
group of subjects in which to target a given treatment.  Collecting biospecimens for 
exploratory pharmacogenomic/biomarker analyses and retaining them in the Pfizer BioBank 
makes it possible to better understand the drug’s mechanism of action and to seek 
explanations for differences in, for example, exposure, efficacy, tolerability, or safety not 
anticipated prior to the beginning of the study.  Providing these biospecimens is an optional 
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study activity for study sites and subjects, unless prohibited as such by local regulations or 
ethics committee decision.  
To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s study identification (ID) number.  Samples will be kept in a 
facility accessible only by swiping a badge.  Data will be stored on password-protected 
computer systems.  The key between the code and the subject’s personal identifiers will be 
held at the study site; the researchers using the biospecimens and data generated from them 
will not have access to the key nor any personally identifying information.  Biospecimens will 
be used only for the purposes described here and in the informed consent document/subject 
information sheet; any other uses require additional ethical approval.  Unless a time limitation 
is required by local regulations or ethical requirements, biospecimens will be stored 
indefinitely to allow for future research on the topics described here, including research 
conducted during the lengthy drug development process and also post marketing research.  
Subjects can withdraw their consent for the use of their biospecimens at any time by making a 
request to the investigator, in which event any remaining biospecimen will be destroyed; data 
already generated from the biospecimens will continue to be stored to protect the integrity of 
existing analyses.  It is very unlikely that results generated from the biospecimens will have 
any clinical, diagnostic, or therapeutic implications for the individual study participants.  
Subjects are notified in the informed consent document/subject information sheet that their 
results will not be given to them, unless required by local laws or regulations, in which case 
results will be returned via the investigator.  Results will not be provided to family members 
or other physicians, nor will they be recorded in the subject’s medical record.  There is no 
intention to contact subjects after completion of the clinical study. 
A single 2 mL blood biospecimen Prep D1.5 (K2 edetic acid [ethylenediaminetetraacetic 
acid] [EDTA] whole blood collection optimized for DNA analysis) will be collected at the 
Week 8 visit to be retained for potential pharmacogenomic/biomarker analyses related to drug 
response, unless prohibited by local regulations or ethics committee decision.  For example, 
putative safety biomarkers, drug-metabolizing enzyme genes, drug-transport protein genes, or 
genes thought to be related to the mechanism of drug action may be examined.  
Additional biospecimens to be retained for exploratory analyses in this study include the 
following: 
Prep B2.5 (serum collection optimized for biomarker/proteomics/metabonomic 
analysis): A 2 mL blood biospecimen will be collected at Day 1 (pre-dose), at randomization, 
when the subject flares (at the Early Termination or End of Study visit), and if applicable 
when a subject reaches inactive disease status.  
Prep R1 (PAXGene whole blood collection optimized for RNA analysis): A 2.5 mL blood 
biospecimen will be collected at Day 1 (pre-dose), at randomization, when the subject flares 
(at the Early Termination or End of Study visit), and if applicable when a subject reaches 
inactive disease status for the first time.  
The banked biospecimens will be collected from all subjects unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage, and 
shipment instructions are provided in the Central Laboratory Manual.  
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It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document/subject information sheet that they 
will not be compensated in this event. 
8.5.2. Additional Research 
Unless prohibited by local regulations or ethics committee decision, subjects will be asked to 
indicate on the consent form whether they will allow the banked biospecimens to also be used 
for the following research: 
• Investigations of the disease under study in the clinical study, and related conditions; 
• Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation among people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics/biomarkers.  
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimen specified in the Section 9.5.1 will be used.  Subjects may still participate in the 
clinical study if they elect not to allow their bank banked biospecimens to be used for the 
additional purposes described in this section. 
9. ADVERSE EVENT REPORTING 
9.1. Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.  
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a serious 
adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  Follow-up 
by the investigator may be required until the event or its sequelae resolve or stabilize at a level 
acceptable to the investigator, and Pfizer concurs with that assessment. 
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.  
9.2. Time Period and Frequency for collecting AE and SAE Information   
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving study intervention), through and including a 
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minimum of 28 calendar days after the last administration of the study intervention or until 
study completion or withdrawal, whichever is longer.  
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator 
and Pfizer concurs with that assessment. 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE reported 
using the CT SAE Report Form. 
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation.  However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and they consider the event to 
be reasonably related to the study intervention, the investigator must promptly report the SAE 
to Pfizer using the CT SAE Report Form. 
9.3. Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  
• Abnormal test findings; 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• Progression/worsening of underlying disease; 
• Drug abuse; 
• Drug dependency. 
Additionally, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 
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• Drug misuse;  
• Drug interactions; 
• Extravasation; 
• Exposure during pregnancy (EDP); 
• Exposure via breastfeeding; 
• Medication error; 
• Occupational exposure. 
9.4. Medication Errors 
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error case report form (CRF) which is a specific version of the adverse event (AE) page, and 
on the SAE form when appropriate.  In the event of medication dosing error, the sponsor 
should be notified immediately. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
• Medication errors involving subject exposure to the investigational product; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the adverse 
event (AE) page and, if applicable, any associated AE(s) are captured on an AE CRF page.   
9.4.1. Tofacitinib Overdose 
There is no experience with overdose of tofacitinib (CP-690,550).  Pharmacokinetic data up to 
and including a single dose of 100 mg in healthy adult volunteers indicates that more than 
95% of the administered dose is expected to be eliminated within 24 hours.  There is no 
specific antidote for overdose with tofacitinib.  In case of an overdose, it is recommended that 
the subject be monitored for signs and symptoms of adverse reactions.  Subjects who develop 
adverse reactions should receive appropriate medical treatment.  
Concomitant treatment with prohibited potent CYP3A inhibitors (Appendix 5) is assumed to 
result in a doubling of tofacitinib exposure.  For further details, please refer to the SRSD 
(eg, the Investigator Brochure). 
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9.5. Infections 
All treated infections occurring during the study, including, but not limited to, respiratory 
infections, cutaneous infections, urinary tract infections and episodes of suspicious or febrile 
diarrhea should be cultured and any identified organisms noted in the case report form. 
Infections should be classified as either serious infections and/or treated infections, as defined 
below.  
9.5.1. Serious Infections 
A serious infection is any infection that requires hospitalization for treatment or requires 
parenteral antimicrobial therapy or meets other criteria that require it to be classified as a 
serious adverse event.  A subject who experiences a serious infection must be discontinued 
from Investigational Product.   This infection must be reported as a serious adverse event and 
should be listed as the reason for discontinuation of study drug 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, must be reported as described in Section 9.1 on Adverse Event Reporting. 
9.5.2. Treated Infections 
A treated infection is any infection that requires antimicrobial therapy by any route of 
administration or any surgical intervention (eg, incision and drainage).  A subject who 
experiences a serious infection must be discontinued from the study.  This information must 
be noted in the eCRF. 
9.6. Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:  
• Test result is associated with accompanying symptoms; and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
• Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or 
• Test result is considered to be an AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
9.7. Serious Adverse Events 
A serious adverse event is any untoward medical occurrence at any dose that: 
• Results in death; 
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• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
9.7.1. Protocol-Specified Serious Adverse Events  
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see Section 0 SAE Reporting Requirements).  
9.7.2. Potential Cases of Drug-Induced Liver Injury  
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to definitively 
determine the etiology of the abnormal laboratory values: 
• Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values ≥3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin value ≥2 X ULN with no evidence of 
hemolysis and an alkaline phosphatase value ≤2 X ULN or not available; 
• For subjects with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above: 
• For subjects with preexisting AST or ALT baseline values above the normal range: 
AST or ALT values ≥2 times the baseline values and ≥3 X ULN, or ≥8 X ULN 
(whichever is smaller). 
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Concurrent with: 
• For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 X ULN or 
if the value reaches ≥3 X ULN (whichever is smaller). 
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may 
be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria defined 
above, with no other cause for liver function test (LFT) abnormalities identified at the time, 
should be considered potential Hy’s law cases irrespective of availability of all the results of 
the investigations performed to determine etiology of the abnormal LFTs.  Such potential 
Hy’s law cases should be reported as SAEs. 
9.8. Hospitalization 
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance. 
Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (eg, caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Same-day surgeries (as outpatient/same-day/ambulatory procedures). 
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Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE 
is not in itself an SAE.  Examples include:  
• Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality); 
• Social admission (eg, subject has no place to sleep); 
• Administrative admission (eg, for yearly physical examination); 
• Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol); 
• Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery); 
• Hospitalization for observation without a medical AE; 
• Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject. 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE. 
9.9. Severity Assessment 
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, or 
SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, these 
intensity grades are defined as follows: 
MILD 
Does not interfere with subject's usual function. 
MODERATE 
Interferes to some extent with subject's usual function. 
SEVERE 
Interferes significantly with subject's usual function. 
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with the 
subject's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above.  
9.10. Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
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applicable.  An investigator’s causality assessment is the determination of whether there exists 
a reasonable possibility that the investigational product caused or contributed to an AE; 
generally, the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see section on Reporting Requirements).  If the 
investigator's causality assessment is “unknown but not related to investigational product,” 
this should be clearly documented on study records.  
In addition, if the investigator determines that an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable. 
9.11. Exposure During Pregnancy 
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;  
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products). 
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.  
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on a Serious Adverse Event (SAE) Report Form and 
Exposure During Pregnancy (EDP) supplemental form, regardless of whether an SAE has 
occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a subject reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred and within 
24 hours of awareness of the exposure.  The information submitted should include the 
anticipated date of delivery (see below for information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for all 
EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up to 
the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
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termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedural 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 as SAEs follows:  
• Spontaneous abortion includes miscarriage and missed abortion; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.  
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The investigator must document in the source 
documents that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner. 
9.12. Occupational Exposure 
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event. 
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a Case Report Form (CRF), however a copy of the 
completed SAE report form is maintained in the investigator site file. 
9.13. Withdrawal Due to Adverse Events  
Withdrawal from Investigational Product due to AEs should be distinguished from withdrawal 
due to other causes, according to the definition of AE noted earlier, and recorded on the 
appropriate AE CRF page.  
When a subject withdraws from Investigational Product because of an SAE, the SAE must be 
reported in accordance with the reporting requirements defined below. 
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9.14. Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject and/or their parent/legal guardian.  In addition, each study subject and/or 
their parent/legal guardian will be questioned about AEs. 
9.15. Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for SAEs. If an SAE 
occurs, expedited reporting will follow local and international regulations, as 
appropriate.  
9.15.1. Serious Adverse Event Reporting Requirements 
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his or her first awareness of the AE. 
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an expedited 
fashion.  This information collected for SAEs is more detailed than that captured on the AE 
CRF.  In general, this will include a description of the AE in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of possible causality.  
Information on other possible causes of the event, such as concomitant medications, vaccines, 
and/or illnesses, must be provided.  In the case of a subject death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer or its designated 
representative.  
9.15.2. Nonserious Adverse Event Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information. 
9.15.3. Sponsor’s Reporting Requirements to Regulatory Authorities 
AE reporting, including suspected unexpected serious adverse reactions, will be carried out in 
accordance with applicable local regulations. 
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10. DATA ANALYSIS/STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan, which will be maintained by the sponsor.  
This document may modify the plans outlined in the protocol: however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment. 
Note: All references in Section 10 to the nominal 5 mg BID dose include the respective 
equivalent weight-based lower doses.  
10.1. Sample Size Determination 
Approximately 100 subjects will be enrolled in the open-label run-in phase of the study.  The 
study will target to enroll at least 12 subjects in each of the following age groups: from 2 to 
<6 years, from 6 <12 years, and from 12 to <18 years.  Based on results from a similarly 
designed sJIA clinical trial,14 it is estimated that approximately 55% of the subjects enrolled in 
the open-label run-in phase will enter the randomized withdrawal double-blind phase of the 
study.14  It is reasonable to assume that tofacitinib can achieve this target rate by the end of the 
open-label phase. 
At the start of the double-blind phase, qualifying subjects receiving tofacitinib 5 mg BID in 
the open-label active treatment phase will be randomized into a tofacitinib sequence 
(continuation of tofacitinib treatment) or a placebo sequence (withdrawal of the tofacitinib 
treatment) with a 1:1 allocation ratio, stratified by age group. 
Subjects who discontinue Investigational Product in the double-blind phase of the study due to 
any reason will be counted as having an sJIA flare in the primary analysis for the primary 
endpoint of the study and will contribute to the requisite number of subjects with flare for the 
study to be considered complete.  Subjects who achieve clinical remission during the double 
blind withdrawal phase are completers of the study and will not be counted as having an sJIA 
flare in the primary analysis.   
10.1.1. Power Analysis 
At the start of the double-blind randomized withdrawal phase, qualified subjects who are 
Adapted JIA ACR 30 responders (and maintained response for at least 4 weeks), will be 
randomized to receive tofacitinib 5 mg BID or a placebo (withdrawal of the tofacitinib dose) 
with a 1:1 allocation ratio.   
The primary objective in the double-blinded phase of the study is to test the superiority of 
tofacitinib (5 mg BID) over placebo as measured by the time to flare.  There will be 
potentially 2 planned analyses.  The First Analysis will be performed after at least 20 subjects 
have reported flare in the double-blind phase (approximately 50% of the total flares expected).  
The purpose of the First Analysis is to allow early stopping of the study for efficacy or 
futility, and to assess safety of tofacitinib. Depending on the number of flares in the First 
Analysis, up to 40 subjects with flares may be required for the Final Analysis to yield an 
overall power of 80% using a log-rank test to detect the treatment difference, assuming a 
1-sided type-I error rate of 2.5%  (or equivalently two-sided type-I error rate of 5%), and a 
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64% improvement in median time to flare (ie, a hazard ratio of 0.36 and a median time to flare 
of 236 days for placebo; assumptions based on a similar sJIA randomized withdrawal trial).14  
The investigators, subjects and sponsor study team will remain blinded to treatment 
assignment in the double-blind phase through the entire duration of the trial until final 
database release. A limited duration unblinded study team will be constructed to perform the 
First Analysis. 
To protect the integrity of the study and to preserve the type I error rate at 0.025 (1-sided test) 
and overall study power at 80% (type II error rate β=0.2), a fraction of α for efficacy and a 
fraction of β for futility will be spent at the First Analysis and accounted for in the overall 
type I error rate and type II error rate, respectively.  A formal efficacy boundary for rejecting 
the null hypothesis is constructed by using the spending function methodology of the gamma 
family design with γ= 4.  Similarly, a formal futility boundary for not rejecting the null 
hypothesis is constructed by using the spending function methodology of the gamma family 
design with γ= -4. 
• If the value of the test-statistic at the First Analysis crosses the efficacy boundary (z≤  
-2.014, 1-sided p≤ 0.022), the trial may be stopped for efficacy. 
• If the value of the test-statistic at the First Analysis crosses the futility boundary (z≥ - 
0.286, 1-sided p≥ 0.387), the trial may be stopped for futility. 
• Otherwise, the trial will continue as planned. The Final Analysis will be performed 
after flares have been reported in approximately 40 subjects. 
The efficacy and futility boundaries will depend on the number of flares.  For logistical and 
administrative reasons, the actual number of flares at the First Analysis and the Final Analysis 
might differ slightly from those that have been pre-specified here.  In that case appropriate 
adjustments will be made to the efficacy and futility boundaries based on the gamma family 
spending functions.  The actual boundary used for the First or the Final Analysis will be re-
calculated from the specified spending function based on the actual number of flares achieved 
at the time of First or Final analysis.  These boundaries will be calculated and finalized prior 
to the evaluation of comparative data.  More details regarding the calculation of futility and 
efficacy boundaries will be provided in the SAP. 
Applying a 1:1 allocation ratio to treatment groups and an Adapted JIA ACR response rate of 
approximately 55% at the end of the open-label phase, it is estimated that approximately 
100 subjects would need to be enrolled in the open-label phase to randomize 54 subjects in the 
double-blind phase.  As of November 2022, 23 subjects have been randomized during the 
accrual period of 225 weeks.  Assuming a future accrual rate of 0.315 subjects per week, it is 
anticipated that it will take a total of 262 and 358 weeks to achieve the requisite number of 
flares for the First and Final Analyses, respectively. 
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10.2. Efficacy Analysis 
10.2.1. Analysis of Primary Endpoint 
The primary objective of the study is to determine if tofacitinib 5 mg BID is superior to 
placebo as measured by time to flare in the double-blind phase.  
Time to flare will be assessed using Kaplan-Meier methods and displayed graphically.  The 
median time to flare and corresponding 2-sided 95% confidence interval (CI) will be 
provided.  Difference in time to flare between the two treatment groups (tofacitinib vs. 
placebo) will be assessed using an unstratified log-rank test.  
In the primary analysis, subjects who complete study treatment due to inactive disease for at 
least 24 weeks in the double-blind phase without flare will be censored at the last available 
flare assessment while on investigational product.  Treatment discontinuations for any other 
reasons will be considered as flares in the primary analysis.  
A supportive analysis will be performed in support of the primary analysis whereby subjects 
discontinued investigational product from double-blind treatment for any reason other than 
flare, including inactive disease for at least 24 weeks in the double-blind phase, will be 
censored at the last available flare assessment while on investigational product.  
Moreover, per Sections 6.9 Pfizer will make every effort to collect flare data for subjects 
discontinuing from investigational product early, before reaching 52 weeks of double-blind 
treatment, for reasons other than flare.  Such subjects rolling over into study A3921145 will 
continue to be followed for sJIA exacerbation (flares) in the long-term extension (LTE).  
Subjects who discontinue from investigational product in the double-blind phase and who do 
not enter A3921145 will continue in A3921165 for follow up of efficacy and safety endpoints. 
Subjects will be required to perform all scheduled visits until Week 52 after randomization or 
until the study concludes, whichever comes first.  
In an additional supportive analysis, all the flare data collected both on- and off-study 
treatment in the double-blind phase of this study, A3921165, will be used.  For subjects who 
discontinue study early, before reaching 52 weeks of double-blind treatment in this study and 
enrolled in the LTE study (Study A3921145), the flare data collected through Week 52 post 
randomization from both studies A3921165 and A3921145 will be included. Investigational 
product discontinuation will not be considered as disease flares in this analysis. 
Additional details regarding the analysis of the primary endpoint will be provided in the SAP.  
10.2.2. Analysis of Secondary Endpoints 
As this is a time-to-event trial, patients will have varying follow-up times during the double-
blind phase.  For efficacy endpoints analyzed by visit, only the data through 52 weeks in the 
double-blind phase will be analyzed statistically.  The data after week 52 will not be analyzed 
statistically but summarized descriptively.  The reason for choosing 52 weeks is that majority 
of the patients are expected to complete 52 weeks of the study in the double-blind phase and 
52 weeks are deemed adequate to evaluate secondary efficacy by visit. 
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For the double-blind phase, the majority of the analyses will be performed by treatment group.  
Secondary binary endpoints such as: occurrence of disease flare or inactive disease status, 
achieving a response of adapted JIA 30/50/70/90/100, absence of fever, etc., will be analyzed 
using statistical methods for binary variables; eg, normal approximation to binomial 
proportions.  For the continuous endpoints, a linear mixed-model will be applied.  Treatment 
differences along with the associated 2-sided 95% CIs and p-values, will also be calculated.  
In the double-blind phase analyses, descriptive/summary statistics by treatment group for the 
effect on the primary and secondary endpoints will be provided at each time point.  
Secondary endpoints in the open-label run-in phase will be summarized descriptively by visit. 
In the open-label phase, the study will target enrollment of at least 12 subjects in each of the 
following age groups: from 2 to <6 years, from 6 <12 years, and from 12 to <18 years.  
Consistency across all age groups with the overall results will be evaluated by informally 
comparing confidence intervals graphically with the use of forest plots.  In addition, 
descriptive statistics of baseline demographic characteristics and all endpoints, broken down 
by age group will be provided. 
Baseline definitions: This study will have a separate type of baseline for each of its two 
phases.  The open-label baseline will be defined as the last value collected prior to tofacitinib 
administration in this phase.  For the analyses in the double-blind phase, baseline will refer to 
the values collected at the randomization visit – before the start of the double-blind phase- for 
all endpoints, with the exception of Adapted ACR responses.  For Adapted JIA ACR 
responses the open-label baseline will be utilized as the reference point.  Selected analyses in 
the double-blind phase, such as changes in laboratory parameters and changes in the JIA core 
set variables , may also refer back to the open-label baseline as a separate analysis, in addition 
to using the double-blind baseline.  
10.3. Guidance to Open Enrollment following Cohort Review 
In Part 1 of the open-label phase, dosing decisions will be made based on the evaluation of 
cohorts of 7 subjects treated with tofacitinib.  Enrollment will be conducted in a staggered 
fashion.  The Sponsor, under the guidance of a Steering Committee, will assess safety, 
efficacy, and pharmacokinetics of the 5 mg BID dose and advise on further enrollment and 
dosing with 5 mg BID in the study.  
For efficacy, the upper limit of a 95% confidence interval (shown below) for an Adapted JIA 
ACR 30 response will serve as guidance to evaluate the initial cohorts of 7 subjects dosed 
with tofacitinib 5 mg BID.  
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Table 6. 
95% Confidence Intervals for Adapted JIA ACR 30 Response in Open Label 
Cohorts 
 
 
 
95% CI for p 
N (Total) 
n (Responder) 
p (Response Rate) 
Lower Limit 
Upper Limit 
7 
0 
0 
0 
0.410 
7 
1 
0.143 
0.004 
0.579 
7 
2 
0.285 
0.037 
0.710 
7 
3 
0.429 
0.099 
0.816 
7 
4 
0.571 
0.184 
0.901 
A 95% confidence interval can be interpreted as: There is a 95% probability that the 
calculated confidence interval from sampling encompasses the true response rate for the 
population.  Thus, if 1 out of 7 responders were observed in a cohort, a response rate of 
approximately 58% or higher could be ruled out with 95% confidence.  Using the confidence 
interval, a given cohort will be deemed to have sufficient efficacy for further study if at least 
2 responders out of 7 subjects are observed.  The following will serve as guidance for making 
decisions about the cohorts: 
• If ≤1 out of 7 responders is observed in 2 consecutive cohorts, the dose level will be 
discontinued. 
• If ≥2 out of 7 responders are observed in each of 2 consecutive cohorts at the 5 mg 
BID dose level, efficacy at this dose level will be considered sufficient to allow further 
evaluated in additional subjects.  
• In the event that intermediate response rates are observed (for example, 1 out of 7 in 
the first cohort and 2 out of 7 in the second), the decision on whether or not to evaluate 
the dose level in additional subjects would be based on review of the totality of the 
data by the Sponsor and Steering Committee and further cohort(s) may be needed to 
evaluate this dose. 
In general, the safety and efficacy data in each cohort will be reviewed by the Steering 
Committee and Sponsor in order to make decisions concerning a given dose level.  Further 
details about guidelines for evaluation and management of initial dose cohorts will be 
provided in a Steering Committee Charter.  
Other details of the statistical analyses for all endpoints in both phases will be described in the 
SAP. 
10.4. Population Pharmacokinetics and Exposure-Response Analyses 
Plasma concentration-time data for tofacitinib will be analyzed using a nonlinear mixed 
effects modeling approach to characterize PK in sJIA subject population.  Effects of 
demographic and disease covariates (age, weight, CRP etc.) on PK may be explored if 
appropriate.  PK data (on Day 1 in the run-in open-label phase) from the two cohorts 
(5 mg BID dose) will be analyzed and utilized along with efficacy and safety data to advance 
to open enrollment at the 5 mg BID dose.  Concentrations from the two cohorts 
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(approximately 14 subjects) will be analyzed to confirm the current dosing scheme for the 
remaining subjects based on the results of this analysis. 
Relationships between various measures of systemic exposure of tofacitinib and efficacy and 
safety outcomes may be explored, using similar methodology, if considered necessary or 
useful upon review of the available data.  The details of the analysis plan will be provided in a 
separate document (population PK modeling plan or PMAP) and the results may be reported 
separately (population PK modeling report or PMAR) from the clinical study report. 
10.5. Safety Analysis 
Safety analysis will be performed on all subjects who received at least one dose of study drug.  
The Sponsor has standard algorithms for reporting adverse events and clinical laboratory test 
results, and these will be employed in the analysis of the data from this trial.  Safety data will 
be subject to clinical review and summarized by appropriate descriptive statistics.  Details will 
be presented in the SAP. 
10.6. Interim Analysis 
The planned analysis is as outlined in Section 10.1.  The analysis will be performed after 
approximately 20 subjects have reported flare in the double-blind phase (approximately 50% 
of the total flares expected).  
10.7. Data Safety Monitoring Board (DSMB)  
An independent Data Safety Monitoring Board (DSMB), a group of experts external to Pfizer, 
will review accumulating safety data from this study on an ongoing basis within the context of 
the Phase 3 pediatric program as well as adult program.  Based on these reviews, the DSMB 
will have the capacity to make recommendations to Pfizer that might impact the future 
conduct of the trial.  The recommendations made by the DSMB to alter the conduct of the 
study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, which 
may include summaries of aggregate analyses of endpoint events and of safety data which are 
not endpoints, to regulatory authorities, as appropriate.  The DSMB will have access to 
unblinded treatment information from concurrently ongoing double-blind studies during the 
clinical trial.  The management and process of this committee will be in accordance with 
Pfizer’s Standard Operating Procedures and will be documented in the DSMB Charter.  The 
DSMB members will all be individuals who are independent of Pfizer.  A DSMB Liaison will 
be appointed; this is an individual who represents Pfizer to coordinate communications and 
facilitates access to Pfizer’s resources, but is not involved in the study design, study 
management, site management, data accrual, or study analysis.  Records of DSMB meetings, 
interactions with Pfizer contacts, assessments and recommendations and materials reviewed 
will be maintained and kept proprietary and confidential by the DSMB.  Further information 
about the DSMB can be found in the DSMB 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. 
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10.8. Steering Committee 
The Sponsor will use a Steering Committee to provide guidance regarding evaluation of the 
5 mg BID dose level of tofacitinib in the initial cohorts of this study.  In the open-label phase 
the Steering Committee will assess preliminary efficacy and safety of the 5 mg BID dose level 
based on a review of 2 cohorts, each receiving tofacitinib 5 mg BID.  The Steering Committee 
will provide recommendations regarding further enrollment at the 5 mg BID dose level and 
open-enrollment in the study.  
Refer to Section 10.3 for details regarding the evaluation of cohorts.  Additional details will 
be provided in a separate Steering Committee Charter. 
10.9. Safety Endpoint Adjudication Committee 
To help assess specific safety events in this and other studies in the tofacitinib program, 
adjudication committees have been established to harmonize and standardize selected safety 
event assessment.  Members of these safety event adjudication committees will be blinded to 
treatment assignment in order to allow for unbiased assessments.  These committees include a 
Cardiovascular Endpoint Adjudication Committee (CV EAC), Malignancy Adjudication 
Committee (MAC), Opportunistic Infection Review Committee (OIRC), Hepatic Event 
Review Committee (HERC), Gastrointestinal Perforation Review Committee (GIPRC), and 
Macrophage Activation Syndrome (MAS) Review Committee.  Further information about 
these committees can be found in the respective charters, including specific descriptions of the 
scope of their responsibilities and the processes and definitions used to review and assess 
specific safety events.  
In addition to these external committees, an internal committee of medically qualified Pfizer 
personnel with expertise in the assessment and diagnosis of respiratory disease will review 
and categorize potential events of interstitial lung disease (Interstitial Lung Disease 
Committee, ILDRC). 
Additional safety event adjudication or review committees may be established to harmonize 
and standardize selected safety event assessments.  As described above, individual committee 
charters will provide specific descriptions of the scope of responsibilities and the processes 
and definitions used to review and assess specific safety events. 
In addition to the event adjudication or review committees described above, all biopsies of 
potentially malignant tumors, suspicious lymphadenopathy, or possible extranodal 
lymphoproliferative disorder should be submitted to the central laboratory for review by 
central laboratory pathologists.  In some instances, additional expert pathology review of 
submitted samples may be performed.  Description of the scope of review and the processes 
used to obtain and assess biopsies is described in the Histopathology Review (HPR) for 
Potential Malignancy charter. 
11. 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 
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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 study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities. 
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly provide 
copies of the inspection findings to Pfizer or its agent.  Before response submission to the 
regulatory authorities, the investigator will provide Pfizer or its agents with an opportunity to 
review and comment on responses to any such findings. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
12. DATA HANDLING AND RECORD KEEPING 
12.1. Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.  
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases, data collected on the CRFs must match the data in those charts.  
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document. 
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When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems 
12.2. Record Retention 
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent/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 ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The study 
records must be transferred to a designee acceptable to Pfizer, such as another investigator, 
another institution, or an independent third party arranged by Pfizer.  Investigator records 
must be kept for a minimum of 15 years after completion or discontinuation of the study or for 
longer if required by applicable local regulations.  
The investigator must obtain Pfizer's written permission before disposing of any records, even 
if retention requirements have been met. 
12.3. Data Protection  
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
Participants’ 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 will 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 participants with regard to the processing of personal 
data, participants will be assigned a single, participant specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant specific code. The study site will maintain 
a confidential list of participants who participated in the study, linking each participant’s 
numerical code to their actual identity and medical record ID. In case of data transfer, the 
sponsor will protect the confidentiality of participants’ personal data consistent with the 
clinical study agreement and applicable privacy laws. 
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Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems. 
13. ETHICS 
13.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines; 
• Applicable ICH GCP Guidelines; 
• Applicable laws and regulations, including applicable privacy laws. 
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by 
the investigator, and reviewed and approved by the IRB/EC before the study is initiated. 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC; 
• Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures; 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations. 
13.2. 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 
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information that might influence the evaluation of the benefits and risks of the study 
intervention, 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 participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of. 
Netherlands country-specific amendment requires that in the Netherlands, patients will be 
evaluated for enrollment in this study if previous treatments recommended by the JVN 
Medicamenteuze behandeling van kinderen met jeugdreuma (Dutch Guidelines: JVN Drug 
Treatment of Children with Juvenile Rheumatism) have failed to control their systemic JIA 
disease. 
13.3. Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.  
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study subjects.  The study site 
will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws. 
The informed consent/assent documents must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws. 
The informed consent/assent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.  
The investigator must ensure that each study subject, or his or her legally acceptable 
representative, or parent(s) or legal guardian if a minor, is fully informed about the nature and 
objectives of the study and possible risks associated with participation.  
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s) or 
legal guardian, the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a subject’s decisional capacity is so limited they cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the subject’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study subject does not provide his 
or her own consent, the source documents must record why the subject did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the subject’s legally acceptable representative, the consent 
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signer’s relationship to the study subject (eg, parent/legal guardian, spouse) and that the 
subject’s assent was obtained, or waived.  If assent is obtained verbally it must be documented 
in the source documents. 
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must re-consent as adults to remain in the study.  If the 
enrollment of ‘emancipated minors’ is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative, parent(s) or legal 
guardian and the subject’s assent, when applicable, before any study-specific activity is 
performed, unless a waiver of informed consent has been granted by an IRB/EC. The 
investigator will retain the original of each subject's signed consent/assent document. 
13.4 Subject Recruitment 
Advertisements approved by IRBs/ECs and investigator databases may be used as recruitment 
procedures.  Use of IRB/EC committee approved, generic, prescreening questionnaire to 
assess basic subject characteristics to determine general eligibility for this study is allowed.  
This generic questionnaire may be used by sites as a phone script and/or to review internal 
databases to identify subjects. 
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used. 
13.5 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
14. DEFINITION OF END OF TRIAL 
14.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State. 
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14.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as Last Subject Last Visit (LSLV). 
Last subject last visit (LSLV) is defined as the date the investigator reviews the last subject’s 
final safety data and determines that no further evaluation is required for the subject to 
complete the trial. 
15. SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, 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 or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and the 
hospital pharmacy (if applicable) within 7 days.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible. 
16. PUBLICATION OF STUDY RESULTS 
16.1. Communication of Results by Pfizer 
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
www.clinicaltrials.gov 
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in subjects that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations. 
Primary completion date is defined as the date that the final subject was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the prespecified protocol or was terminated. 
EudraCT 
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year of 
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the primary completion date for studies in adult populations or within 6 months of the primary 
completion date for studies in pediatric populations. 
www.pfizer.com 
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data that 
could be used to identify individual subjects has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov. 
16.2. Publications by Investigators 
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.  The investigator will provide any publication to 
Pfizer at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, the investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days. 
The investigator will, on request, remove any previously undisclosed confidential information 
before disclosure, except for any study- or Pfizer product-related information necessary to the 
appropriate scientific presentation or understanding of the study results. 
If the study is part of a multicenter study, the investigator agrees that the first publication is to 
be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section. 
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 Clinical Study Agreement (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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17. REFERENCES 
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JAKs, STATs, and relationship to immunodeficiency. J Leukocyte Biol 1996; 
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2. 
Conklyn M, Andresen C, Changelian P et al. The JAK3 inhibitor CP-690550 selectively 
reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic 
oral dosing. J Leukoc Biol. 2004; 76(6):1248-55. 
3. 
Changelian PS, Moshinsky D, Kuhn CF et al. The specificity of JAK3 kinase inhibitors. 
Blood. 2008 Feb 15; 111(4):2155-7. 
4. 
Petty RE et al. International League of Associations for rheumatology classification of 
juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 
2004;31:390–2. 
5. 
Martini A. Systemic juvenile idiopathic arthritis. Autoimmune Reviews 12 (2012) 56-59. 
6. 
Correll C K, Binstadt B A. Advances in the pathogenesis and treatment of systemic 
juvenile idiopathic arthritis. Pediatric Research Volume 75, Number 1, Jan 2014. 
7. 
Ravelli et al. 2016 Classification Criteria for Macrophage Activation Syndrome 
Complicating Systemic Juvenile Idiopathic Arthritis. Arthritis and Rheumatology, 
Vol 68, Nr. 3, March 2016. Pg 566 – 576. 
8. 
Prescribing Information Actemra® (tocilizumab) 2010.   
9. 
Hodge et al. The mechanism of action of tofacitinib. Clin. Exp. Rheumatology 2016. 
10. Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium 
tuberculosis Infection, United States. Online. Available: 
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm. 16 December 2005. 
11. Singh G, Athreya BH, Fries JF, Goldsmith DP. Measurement of health status in children 
with juvenile rheumatoid arthritis. Arthritis Rheum 1994; 37:1761–1769. 
12. Ruperto N, Ravelli A, Pistorio A, et al. Cross-cultural adaptation and psychometric 
evaluation of the Childhood Health Assessment Questionnaire (CHAQ) and the Child 
Health Questionnaire (CHQ) in 32 countries. Review of the general methodology. Clin 
Exp Rheumatol 2001; 19 (4 Suppl. 23): S1-9. 
13. Land Landgraf, J. M., L. Abetz, and J. E. Ware. "The CHQ user’s manual." Boston: The 
Health Institute, New England Medical Center (1996): 235-9. 
14. Ruperto N, Brunner H, Lovell D, Martini At et al. Two randomized trials of 
Canakinumab in Systemic Juvenile Idiopathic Arthritis. New England Journal of 
Medicine, Dec 2012, 367, 25. 
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15. Brunner HI, Lovell DJ, Finck BK, Giannini EH. Preliminary definition of disease flare in 
juvenile rheumatoid arthritis. J Rheumatol 2002; 29(5):1058-64. 
16. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N for the Childhood Arthritis and 
Rheumatology Research Alliance (CARRA), the Pediatric Rheumatology Collaborative 
Study Group (PRCSG), and the Pediatric Rheumatology InterNational Trials 
Organisation (PRINTO). American College of Rheumatology provisional criteria for 
defining clinically inactive disease in select categories of juvenile idiopathic arthritis. 
Arthritis Care Res 2011;63;929-936. 
17. Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, Aricò M, Avcin T, Behrens 
EM, De Benedetti F, Filipovich L, Grom AA, Henter J, Ilowite NT, Jordan MB, 
Khubchandani R, Kitoh T, Lehmberg K, Lovell DJ, Miettunen P, Nichols KE, Ozen S, 
Pachlopnick-Schmid J, Ramanan AV, Russo R, Schneider R, Sterba G, Uziel Y, Wallace 
C, Wouters C, Wulffraat N, Demirkaya E, Brunner HI, Martini A, Ruperto N, Cron RQ 
on behalf of the Pediatric Rheumatology International Trials Organization (PRINTO); 
the Childhood Arthritis & Rheumatology Research Alliance (CARRA); the Pediatric 
Rheumatology Collaborative Study Group (PRCSG); the Histiocyte Society. 2016 
Classification criteria for macrophage activation syndrome complicating systemic 
juvenile idiopathic arthritis. A European League Against Rheumatism/American College 
of Rheumatology/Paediatric Rheumatology International Trials Organisation 
Collaborative Initiative. Ann Rheum Dis 2016;75:481–489. 
18. Consolaro A, Bracciolini G, et al.  Remission, minimal disease activity and acceptable 
symptom state in juvenile idiopathic arthritis, 2012;64:2366-74. 
19. Dorn, LD. Perceptions of puberty: Adolescent, parent, and health care personnel. 
Developmental Psychology 1990; 26(2): 322. 
20. Bazso A, Consolaro A, et al.  Development and testing of reduced joint counts in 
juvenile idiopathic arthritis.  J Rheumatol, 2009; 36:183-90. 
21. Nordal EB, Zak M, et al.  Validity and predictive ability of the juvenile arthritis disease 
activity score based on CRP versus ESR in a Nordic population-based setting.  Ann 
Rheum Dis, 2012;71:1122-7. 
22. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for 
reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 
2005;140:509–16. 
23. Schwartz GJ, Munoz A, Schneider MF, et al. New equations to estimate GFR in children 
with CKD. J Am Soc Nephrol 2009;20(3):629-37. 
24. Brunner HI, Lovell DJ, Finck BK, Giannini EH. Preliminary definition of disease flare in 
juvenile rheumatoid arthritis. The Journal of Rheumatology. 2002 May 1;29(5):1058-64. 
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25. De Benetti F, Brunner HI, et al. Randomized Trial of Tocilizumab in Systemic Juvenile 
Idiopathic Arthritis. The New England Journal of Medicine. 2012 December 2 ; 
367:2385-95. 
26. Taylor S JC; Whincup PH et al. Performance of a new pubertal self-assessment 
questionnaire a preliminary study. Blackwell Science Ltd. Paeditric and Perinatal 
Epidemiology 2001, 15; 88-94. 
27. 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. 
28. Innovative study design for paediatric clinical trials. Baiardi et al, European Journal of 
Clinical Pharmacology, Springer Verlag, 2011, 67 (S1), pp.109-115. 
10.1007/s00228-011-0990-y. hal-00667593. 
29. Varicella Vaccine Recommendations. Centers for Disease Control and Prevention. 
Online. Available: 
https://www.cdc.gov/vaccines/vpd/varicella/hcp/recommendations.html. 
07 August 2019. 
30. Food and Drug Administration, Center for Drug Evaluation and Research. General 
clinical pharmacology considerations for pediatric studies for drugs and biological 
products. 2014 December; 1-25. 
31. Martini A, Ravelli A, et al. Toward new classification criteria for juvenile idiopathic 
arthritis: First steps, pediatric rheumatology international trials organization international 
consensus. The Journal of Rheumatology. 2019; 46(2):190-197 
32. Schoenfeld, D. A., & Tsiatis, A. A. (1987). A modified log rank test for highly stratified 
data. Biometrika, 74(1), 167-175.  
33. Shih, J. H. (1999). A class of permutation tests for stratified survival data. Biometrics, 
55(4), 1156-1161. 
34. Yang 2012 (2012). The effects of overstratification on the stratified log rank test for 
survival analysis; http://d-scholarship.pitt.edu/11951/1/SY_ETD_04202012.pdf 
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Appendix 1. Allowed and Disallowed DMARDs 
Allowed DMARDs: 
The following DMARDs are allowed in doses:  
• Methotrexate: stable dose ≤25 mg/week or 20 mg/m2/week for at least 4 weeks before 
the first dose of tofacitinib (Day 1 Visit). 
• If treated with MTX, treatment must be for ≥3 months before the first study drug dose. 
Disallowed Biologic and Non-Biologic DMARDs: 
The following biologic agents and DMARDs are disallowed at any time during this study.  If 
a subject requires (in the opinion of the investigator) treatment with one of these agents, the 
subject should be discontinued from the study: 
• Leflunomide (Arava®) must have been discontinued 8 weeks prior to the first dose of 
study drug if no elimination procedure is followed;   
• Cyclosporine, tacrolimus, sulfasalazine and azathioprine: Discontinued for 7 days 
prior to the first dose of study drug; 
• Anakinra (Kineret®): Discontinued for 3 days prior to the first dose of study drug; 
• Baricitinib (Olumiant®) and Upadacitinib (Rinvoq®): Discontinued for 4 weeks prior 
to the first dose of study drug; 
• Etanercept (Enbrel®): Discontinued for 2 weeks prior to the first dose of study drug; 
• Canakinumab (Ilaris®): Discontinued for 7 weeks prior to the first dose of study drug; 
• Adalimumab (Humira®): Discontinued for 2 weeks prior to first dose of study drug; 
• Infliximab (Remicade®): Discontinued for 3 weeks prior to the first dose of study 
drug; 
• Golimumab (Simponi TM): Discontinued for 4 weeks prior to the first dose of study 
drug; 
• Abatacept (Orencia®), Tocilizumab (Actemra®), Certolizumab pegol (Cimzia®): 
Discontinued for 4 weeks prior to first dose of study drug; 
• Rituximab (Rituxan®) or other selective B lymphocyte depleting agents (either 
marketed or investigational): Discontinued for 1 year prior to the first dose of study 
drug and if CD19/20+ counts are normal by FACS analysis. 
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• Immunoglobulin G (IgG): Discontinued for 8 weeks  prior to the first dose of study 
drug. 
Other Disallowed Agents: 
• Thalidomide (Thalidomid®), bucillamine, mizoribine, d-penicillamine, chloroquine, 
hydroxychloroquine, and staphylococcal protein A immuno-absorbant pheresis 
columns (eg, PROSORBA® device/column) must be discontinued for 4 weeks prior to 
first dose of study drug; 
• Auranofin (oral gold), aurothioglucose (injectable gold), aurothiomalate (injectable 
gold) must be discontinued for 8 weeks prior to first dose of study drug. 
Disallowed Investigational Drugs: 
• Investigational NSAIDs: Any experimental non-steroidal anti-inflammatory drug 
(NSAID), including selective COX-2 inhibitors, must be discontinued for 4 weeks 
prior to the first dose of study drug; 
Other Investigational Drugs: Any other experimental therapy must be discontinued for 
4 weeks or 5 half-lives (whichever is longer) prior to the first dose of study drug.  
Note: The above prohibited agents are permitted during the study only for subjects 
permanently withdrawn from Investigational Product and continuing in the study on 
standard-of-care in accordance with local treatment policies. 
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Appendix 2. Approximate Equivalent Morphine Doses of Opioid Analgesics 
Common opioid analgesics 
Drug 
Maximum Allowed Total 
Daily Dose 
Relative potency to 
oral morphine 
Half-Life 
Morphine  
0.2-0.5 mg/kg/dose, up to 
15 mg/dose.  No more than 
5 doses/day. 
1 
1.5-4 hrs 
Hydromorphone 
(Dilaudid) 
0.03-0.08 mg/kg/dose, up 
to 2 mg/dose.  No more 
than 5 doses/day. 
4 
2.5 hrs 
Codeine (Paveral, 
Tylenol #2 and #3) 
0.5-1.0 mg/kg/dose, up to 
60 mg/dose.  No more than 
5 doses a day. 
0.15 
2.5-3.5 hrs 
Oxycodone 
[Roxicodone; 
Percocet, Tylox] 
0.05-0.15 mg/kg/dose, up 
to 5 mg/dose.  No more 
than 5 doses a day. 
~2 
3.2 hrs 
Sites should contact project team for acceptable alternative preparations and related data.  
Lexi Comp Pediatric Dosage Handbook 15th Edition  
Sick Kids Drug Handbook & Formulary 2008-2009  
Rx Files Pediatric Pain: Treatment Considerations, Q & A’s. Oct. 08. 
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Appendix 3. Permitted Adjustments in sJIA Therapies  
The following adjustments of background medications are allowed for reasons of inadequate 
efficacy of current treatment, or may be tapered or discontinued due to disease improvement.  
Adjustments for safety reasons may be done at any time, but if this leads to changes in excess 
of those allowed below, the investigator must receive approval from the Pfizer project team to 
allow the subject to continue in the trial. 
1. NSAIDs/COX-2 inhibitors: dose adjustments may be made, or background 
NSAID/COX-2 inhibitors may be switched, but should be no more frequently than 
every 3 months, and should be more than 14 days prior to a study visit.  
2. Oral Corticosteroid (CS) dose should be stable for the duration of Part 1 of the 
open-label phase and not exceed 1.0 mg/kg/day up to 30 mg/day oral prednisone or 
equivalent daily.  In Part 2 at each study visit if the subject continues to meet an 
adapted ACR 50 level of response, then the daily prednisone dose can be tapered in 
accordance with the tapering criteria of Section 3.2.  During the double-blind phase of 
the study the oral CS dose must remain stable unless the subject meets the flare 
criteria.  At that time the subject will be discontinued from the study and the oral CS 
dose can be adjusted as necessary in the physician’s judgment. 
3. Methotrexate (MTX) may be administered either orally or parenterally MTX at doses 
not to exceed 25 mg/wk or 20 mg/m2/week (whichever is lower).  The dose should be 
stable for at least 4 weeks before the first dose of investigational drug and remain 
stable for the duration of the study (open-label and double-blind phases).  
4. Intra-articular steroids should be administered in a total dosage of no more than 
2 mg/kg (up to 80 mg) of methylprednisolone or equivalent every 6 months.  No more 
than two joints should be injected in any given 6-month period and individual joints 
should not be injected any more frequently than once in a 6-month period.  Injected 
joints will be considered active joints for the following 3 months.  
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Appendix 4. Estimated Glomerular Filtration Rate Calculation and Creatinine 
Clearance Calculation 
The Bedside Schwartz23 GFR equation will be used to estimate glomerular filtration rate 
(eGFR) from serum creatinine (creatinine method with calibration traceable to IDMS).  eGFR 
will be evaluated at screening to determine if a subject is eligible.  
eGFR (mL/min/1.73 m2) = 0.413 × (Ht/Scr) 
Height (Ht) in cm;  
Serum creatinine (Scr) in mg/dL. 
In addition, at every study visit a subject’s creatinine clearance (CrCl) will be evaluated.  
The Modified Schwartz equation will be used to estimate creatinine clearance in participants 
<12 yrs old.30  
CrCl (mL/min/1.73 m2) = (K x Ht)/ Scr 
K (proportionality constant):  
Female Child <12 years: K = 0.55 
Male Child<12 years: K = 0.70 
The Cockcroft-Gault equation will be used to estimate the creatinine clearance for the 
participants ≥12 years of age.30 
CrCl (ml/min) = [ (140 - age) x weight in kg] / [ Scr x 72] (x 0.85 if female) 
 
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Appendix 5. Prohibited Concomitant Medications 
All prohibited drugs require a 4-week (or ≥5 half-lives, whichever is longer) washout, except: 
* Amiodarone half-life averages about 58 days and requires a 290-day washout (5 half-lives). 
All herbal supplements are prohibited during the study and require a 28-day washout. 
** Biologic and Non-Biologic DMARDs which have specific washout periods listed in 
Appendix 1. 
NOTE: Topical administration (eg, cutaneous, 
ophthalmic, or intravaginal) of listed concomitant 
medications, which are prohibited if administered 
systemically, is allowed in the study. 
Moderate or Potent CYP3A Inhibitors  
 
 
 
 
Moderate or Potent CYP3A Inducers 
HIV antivirals: 
efavirenz (Sustiva) 
-delavirdine (Rescriptor) 
nevirapine (Viramune) 
-indinavir (Crixivan) 
Barbiturates 
-nelfinavir (Viracept) 
carbamazepine (Carbatrol, Tegretol) 
-ritonavir (Kaletra, Norvir) 
modafinil (Provigil) 
-saquinavir (Fortovase) 
phenobarbital 
-atazanavir 
phenytoin (Dilantin, Phenytek) 
amiodarone (Cordarone, Pacerone)* 
rifabutin (Mycobutin)  
cimetidine (Tagamet) 
rifampin (Rifadin, Rifamate, Rifater) 
clarithromycin (Biaxin, Prevpac) 
rifapentine (Priftin) 
telithromycin (Ketek) 
St. John's Wort 
clotrimazole 
troglitazone (Rezulin) 
chloramphenicol 
All Investigational Drugs 
diethyl-dithiocarbamate   
DMARDs 
diltiazem (Cardizem, Tiazac) 
All Biologics**, such as: 
anakinra (Kineret), etanercept (Enbrel), 
adalimumab (Humira), infliximab 
(Remicade), abatacept (Orencia), 
canakinumab (Ilaris), tocilizumab 
(Actemra), golimumab (Simponi), 
rituximab (Rituxan), Immunoglobulin G 
(IgG) 
erythromycin  
fluconazole (Diflucan) 
fluvoxamine (Luvox) 
Grapefruit juice and marmalade 
itraconazole (Sporanox) 
ketoconazole (Nizoral) 
Other DMARDs**: 
leflunomide, sulfasalazine, d-penicillamine, 
bucillamine, mizoribin, azathioprine, 
cyclosporine, tacrolimus, auranofin, 
aurothioglucose, aurothiomalate, 
staphylococcal protein A 
immuno-absorbant pheresis columns 
mifepristone (Mifeprex, RU486) 
nefazodone (Serzone) 
norfloxacin (Shibroxin, Noroxin) 
mibefradil   
verapamil (Calan SR,Covera HS, Isoptin SR, Tarka, Verelan) 
voriconazole 
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Appendix 6. Rescue Therapy 
Acetaminophen/paracetamol is allowable as rescue medication if dosed no more than 
10-15 mg/kg/dose orally or 15-20 mg/kg/dose rectally (not exceeding 5 doses in 24 hours) for 
no more than 10 consecutive days.  If a subject is already taking stable background doses of 
acetaminophen/paracetamol, (s)he may increase the dose up to the maximum dose stated 
above for up to 10 consecutive days for rescue purposes. 
The following paradigm should be used to determine appropriate opioid rescue 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: 
Morphine  
0.2-0.5 mg/kg/dose, up to 15 mg/dose.  No more 
than 5 doses/day. 
Hydromorphone (Dilaudid) 
0.03-0.08 mg/kg/dose, up to 2 mg/dose.  No more 
than 5 doses/day. 
Codeine (Paveral, Tylenol #2 and #3) 
0.5-1.0 mg/kg/dose, up to 60 mg/dose.  No more 
than 5 doses a day. 
Oxycodone [Roxicodone; Percocet, 
Tylox] 
0.05-0.15 mg/kg/dose, up to 5 mg/dose.  No more 
than 5 doses a day. 
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 or increased for rescue purposes. 
Intravenous or intramuscular CSs, biologic response modifiers and DMARDs other than those 
specified as allowed DMARDs (Appendix 1) are not allowed during this study.  Intra-articular 
CSs be given in no more than two joints, in a cumulative dose of no more than 80 mg 
methylprednisolone or its equivalent in any 6-month study period.  Injected joints will also be 
considered as having their pre-injection status (tender/painful and swollen) for the remainder 
of the trial.  
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 for more than 
10 consecutive days should be considered for allowed JIA medication adjustments or 
discontinued from the trial.  In addition, subjects should not be dosed with rescue 
acetaminophen/paracetamol or opioids during the 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. Guidelines For Safety Monitoring And Discontinuations 
The following laboratory abnormalities require prompt re-testing, ideally within 3-5 days: 
• Lymphocyte counts <500 lymphocytes/mm3. 
• Neutrophil counts <1000 neutrophils/mm3. 
• Platelet counts <100,000 platelets/mm3. 
• Any single hemoglobin value <8.0 g/dL.  
• Any single hemoglobin value that is ≥2 gm/dL below the baseline. 
• Any single AST and/or ALT elevation >3 times the upper limit of normal, regardless 
of the total Bilirubin (repeat laboratory testing must include CK, Total Bilirubin, 
Direct and Indirect Bilirubin, GGT, INR and alkaline phosphatase). 
• Any single serum creatinine increase >50% over the average of screening (most recent 
value prior to baseline) and baseline values OR an absolute increase in serum 
creatinine ≥0.5 mg/dL (≥44.2 umol/L) AND any single CrCl decrease of >30% over 
the average of screening (most recent value prior to baseline) and baseline values. 
• Increased lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) should be monitored and treated according to local guidance (eg, diet 
and behavior modification, statin therapy).  
Temporary Withholding and discontinuation of Investigational Product related to Venous 
Thromboembolism:  
• Per Amendment 3, for subjects with suspected venous thromboembolism, 
investigational product treatment should be temporarily withheld while the subject is 
evaluated.  If venous thromboembolism is confirmed, discontinue investigational 
product.  Refer to Section 8.2.14. 
Investigational Product will be discontinued  for: 
• Serious infections (those requiring parenteral antimicrobial therapy or hospitalization), 
and opportunistic infections; 
• Malignancies, excluding adequately treated or excised basal cell or squamous cell 
carcinoma of the skin and cervical carcinoma in situ;  
• Confirmed venous thromboembolism; 
• Two sequential lymphocyte counts <500 lymphocytes/mm3; 
• Two sequential neutrophil counts <500 neutrophils/mm3; 
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• Two sequential platelet counts <75,000 platelets/mm3; 
• Two sequential hemoglobins <8.0 g/dL or a decrease of more than 30% from baseline 
value; 
• 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;  
• Two sequential AST or ALT elevations >3 times the upper limit of normal with an 
abnormal INR;  
• Two sequential AST or ALT elevations >3 times the upper limit of normal 
accompanied by symptoms consistent with hepatic injury; 
• Two sequential AST or ALT elevations >5 times the upper limit of normal, regardless 
of Total Bilirubin or accompanying symptoms;  
• Two sequential increases in serum creatinine >50% over the average of screening and 
baseline values OR an absolute increase in serum creatinine ≥0.5 mg/dL 
(≥44.2 umol/L) over the average of screening and baseline values AND a confirmed 
(two sequential) CrCl decrease of >30% over the average of screening and baseline 
CrCl values.  If the serum creatinine increase and the CrCl decrease have an 
identifiable and reversable reason (eg, concomitant medication), then an additional 
retest may be considered after discussion with the Sponsor study clinician or medical 
monitor.  After retest, a decision for the subject to continue in the study will be made 
after discussion with the Sponsor study clinician or medical monitor; 
• Single positive HBc Ab and a negative HBs Ab;  
• Other serious or severe AEs, after consultation with the Pfizer Medical Monitor. 
 
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Appendix 8. List of Abbreviations 
Abbreviation 
Term 
Ab 
Antibody 
ACR 
American College of Rheumatology 
AE 
adverse event 
ANC 
Absolute neutrophil counts 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
Twice daily 
BMI 
Body Mass Index 
CDC 
Centers for Disease Control and Prevention 
CDER 
Center for Drug Evaluation and Research 
CDS 
core data sheet 
CHAQ 
Childhood Health Assessment Questionnaire 
CHQ 
Child Health Questionnaire 
COVID-19 
coronavirus disease 2019 
CrCl 
Creatinine clearance 
CRF 
case report form 
CRP 
C-reactive protein 
CS 
Corticosteroids 
CSA 
clinical study agreement 
CSF 
cerebrospinal fluid 
CTA 
clinical trial application 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAI 
dosage and administration instructions 
DB 
Double-blind 
DMARD 
Disease Modifying Antirheumatoid Drugs 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DU 
dispensable unit 
EC 
ethics committee 
ECG 
Electrocardiogram 
EDMC 
external data monitoring committee  
EDP 
exposure during pregnancy 
EDTA 
edetic acid (ethylenediaminetetraacetic acid) 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunosorbent assay 
ESR 
Erythrocyte Sedimentation Rate 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration (United States) 
FDAAA 
Food and Drug Administration Amendments Act (United States) 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
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Abbreviation 
Term 
HBV 
Hepatitis B Virus 
HCG 
Human Chorionic Gonadotropin 
HIV 
human immunodeficiency virus 
HCV 
Hepatitis C Virus 
HRQL 
health-related quality of life 
IB 
investigator’s brochure 
ICH 
 International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ID 
Identification 
IgG 
Immunoglobulin G 
ILAR 
International League Against Rheumatism 
IND 
investigational new drug application 
INR 
international normalized ratio 
IOBU-SDMC 
Internal Oncology Business Unit-Safety Data Monitoring Committee 
IRB 
institutional review board 
IRC 
internal review committee 
IRT 
interactive response technology 
IUD 
intrauterine device 
IUS 
intrauterine system 
IVR 
interactive voice response 
IWR 
interactive web response 
JADAS 
Juvenile Arthritis Disease Activity 
JAK 
Janus Kinase 
JIA 
Juvenile Idiopathic Arthritis 
LTE 
Long Term Extension (Study A3921145) 
LFT 
liver function test 
LPD 
local product document 
LSLV 
last subject last visit  
MACE 
lymphomas, major adverse cardiovascular events 
MAS 
Macrophage Activation Syndrome 
N/A 
not applicable 
NMSC 
non-melanoma skin cancer  
OBU 
Oncology Business Unit 
PCD 
primary completion date 
PFS 
pre-filled syringe 
pJIA 
Polyarticular Juvenile Idiopathic Arthritis 
PK 
Pharmacokinetics 
PRCSG/PRINTO 
Pediatric Rheumatology Clinical Study Group/Pediatric 
Rheumatology International Trials Organization 
PsA 
psoriatic arthritis 
PT 
prothrombin time 
QTF-Gold 
QuantiFERON®-TB Gold test 
QTF-TB 
QuantiFERON®-TB In-Tube test  
RA 
rheumatoid arthritis 
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Abbreviation 
Term 
RF+ 
Rheumatoid Factor positive 
RF- 
Rheumatoid Factor negative 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
Subcutaneous 
SCL 
Supply Chain Lead 
Scr 
Serum creatinine 
SIB 
suicidal ideation and behavior 
sJIA 
Systemic JIA 
SOA 
Schedule of Activities 
SOC 
Standard of Care 
SOP 
standard operating procedure 
SPC 
summary of product characteristics 
SRSD 
single reference safety document 
SUN 
Standard Uveitis Nomenclature 
TB 
Tuberculosis 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States package insert 
VTE 
Venous thromboembolism  
VZV 
Varicella Zoster Virus 
 
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Appendix 9. The Degree of Burden and the Risk Threshold Assessment required at each 
visit. [article 40 (4) No. 4 of the German Medicines Act] 
As written in the protocol under the Schedule of Activities, in Study Procedures and 
Assessments sections, and here summarized, at each visit, the physician will complete the 
following (including, but not limited to):  
1. A medical history which includes at least one conversation regarding the child’s 
wellbeing, generally at the beginning of the study and at each visit.  
2. A physical examination including vital signs, growth, and maturation. 
3. Laboratory testing, eg, haematology and liver enzymes, etc.  
4. Various functional and global assessments depending on the child’s specific 
rheumatologic diagnosis such as the JIA joint assessment, CHAQ, CHQ, and the 
PRCSG/PRINTO Disease Flare Assessment; the Physician’s Global Evaluation of 
Overall Disease Activity. 
5. The investigator also will assess for flare and ACR responses as determined by 
PRINTO/PRCSG. 
6. Adverse events such as and including blood cell numbers, liver enzyme test, renal 
function tests, lipid panel, evaluating for the presence of, for example, as in protocol 
Section 10.7, serious infections, opportunistic infections, tuberculosis, herpes zoster, 
malignancies (excluding NMSC), non-melanoma skin cancer (NMSC), lymphomas, 
major adverse cardiovascular events (MACEs), interstitial lung disease, 
macrophage-activation syndrome (MAS), and GI perforations. 
Subjects who experience a single episode of disease flare based on the JIA disease flare 
criteria24 at any time during the study, (including the open-label run-in and double-blind 
phase) will be discontinued from study, and offered the possibility to continue receiving drug 
in the long term extension study, based on fulfilling certain safety criteria and judgement of 
the treating physician.  Additionally, the investigator refers to Appendix 7 “Guidelines for 
Safety Monitoring and Discontinuations”.  At each visit, the investigator considers all of this 
and any additional information, assesses the burden of disease and the risks of continued 
participation, and confirms whether continued participation by the minor subject is 
permissible. 
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Appendix 10. Temporary Measures for Study Visits Occurring During Public 
Emergencies  
In response to public emergencies, including the ongoing global pandemic COVID-19, and 
increasing restrictions and concerns on public health, the following changes are incorporated 
into this A3921165 protocol to clarify alternative solutions to accommodate study procedures.  
These alternate solutions should only be implemented after discussion with the Sponsor. If 
public emergencies other than the COVID-19 global pandemic occur, there may be additional 
or different alternate solutions provided to the sites at that time. 
For subjects unable to return to the investigational site for study visits due to local restrictions 
put in place the following temporary options may be implemented and must be documented in 
the medical record:  
• Section 6: STUDY PROCEDURES: Study visits, except the baseline (Day 1) and 
randomization visit: In-home visits or Telephone Calls (may include video) for 
safety assessment by the study staff: may replace a site visit only in case a subject 
has controlled sJIA disease, and is quarantined, or self-isolating.  Follow the protocol 
schedule of activities when possible.  
In-home visits: Assessment of Adapted JIA ACR response and review of the results 
from the Coordinating Center may occur after the in-home visit after faxing/emailing 
the sJIA Disease Assessment worksheets and JIA ACR core component CRF to the 
Coordinating Center.  Instructions to the study participants regarding background 
treatment, ie, corticosteroid tapering in Part 2 may be provided after the visit via a 
telephone call.  Likewise, blood samples can be sent to the central laboratory after the 
in-home visit. 
Telephone Calls: It is expected that all subjects should at least have a safety 
assessment via phone call at the time of their scheduled visit. 
During telephone calls at a minimum the following must be assessed and documented:  
• Absence of fever via remote review of the fever diary; 
• Adverse events; 
• Compliance of dosing of investigational product; 
• Use of concomitant medication; 
• Partial assessment of disease status by asking how the subject is feeling. 
If a subject is due for a site visit but has uncontrolled sJIA the subject should be 
evaluated on site.  Please notify the clinical team if this happens. 
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Refer to protocol mandated discontinuation criteria (Section 3.2.1, 4.2.2.2, 4.3, 6.3, 
Section 8.3.2, Appendix 7).  Any subject for whom in the opinion of the investigator 
the benefit/risk of continuing investigational product is no longer favorable should be 
discontinued.  
• Section 6: STUDY PROCEDURES and Section 8.2.9 Laboratory Testing: 
Protocol-specified safety laboratory tests: must be performed per protocol, but may 
be performed at a local laboratory, where allowable by law or local guidance, if the 
study participant is unable to visit the study site.  In this case, local laboratory 
reference ranges and accreditation need to be documented.  Local laboratory results 
should include all assays as required by the protocol.  If laboratory testing is not 
performed, this must be documented as a Protocol Deviation related to the public 
emergency, including COVID-19. 
• Section 6: STUDY PROCEDURES and Section 5.4.2 Preparation and Dispensing: 
Investigational Product Dispensing: In situations where participants are quarantined 
or self-isolating, temporary arrangements to send medicinal product via courier may 
be implemented where allowable by law or by local guidance and with the 
participant’s verbal consent.  Sites may ship Investigational Product only if there is no 
safety concern and only to participants known to have controlled sJIA disease with 
recent laboratory testing indicating no relevant laboratory abnormalities for 
haematology, serum chemistry and lipids that would require retesting, or 
discontinuation per protocol Section 8.3 and confirmed negative pregnancy test (if 
required per protocol Section 4.4.1 Contraception). 
• Section 3.3 Randomized Withdrawal Phase and Section 6.6 Randomization Visit: Start 
Double-blind Withdrawal Phase: Open-label Part 2 and randomization: Subjects 
with controlled sJIA who meet the criteria to proceed to randomization, but are at risk 
of restricted access to care by the study staff will be allowed to remain in open-label 
Part 2, provided that the overall duration does not exceed 24 weeks. 
• Compliance with protocol and data entry: Investigators should continue to follow 
the protocol and data entry timeliness.  Any deviations to the protocol related to the 
public emergency, including COVID-19 pandemic, should be documented and 
recorded as deviation as requested by Health Authorities. 
• If the sponsor determines that the impact of the public emergency, including 
COVID-19, on protocol visits and procedures and associated timeframe needs to be 
reported on a case report form (CRF), this will be requested.  For participant 
discontinuation reporting in the CRF: select the most appropriate status for 
discontinuation; if the discontinuation is associated with the current COVID-19 
pandemic, check the “OTHER” box and enter “COVID-19” in the “Specify” field. 
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• Adapted JIA ACR response: If a telephone call replaces a site visit this response 
cannot be assessed and a Protocol Deviation related to the public emergency, including 
COVID-19 will be recorded.  The overall duration of the Open-label (OL) phase may 
not be extended to more than 16 weeks for Part 1 and 24 weeks for Part 2, even if site 
visits are missed.  
The following rules will apply to assess maintenance of a stable Adapted JIA ACR 30 
response for 4 weeks in the Open-Label phase:   
• If site visits are missed between Day 3 and Week 4: any Adapted JIA ACR 30 
response that a subject achieved within the first month will not count towards 
the 4 weeks of stable Adapted JIA ACR 30 response.  The subject will be 
required to achieve and maintain the Adapted JIA ACR 30 after Week 4 to 
proceed to OL Part 2 or randomization.  
• If only 1 monthly site visit is missed after Week 4: The Adapted JIA ACR 30 
response at the visit immediately before the missed visit will count towards the 
4 weeks of stable response if the subject continues to demonstrate an Adapted 
JIA ACR 30 response at the next site visit, even if more than 4 weeks have 
passed between the site visits.  
• If 2 consecutive monthly site visits are missed after Week 4: any Adapted JIA 
ACR 30 response that a subject achieved before the missed visits will not count 
towards the 4 weeks of stable Adapted JIA ACR 30 response.  
• If 3 consecutive monthly site visits are missed after Week 4: the subject will 
have to be discontinued. 
Use of these temporary measures are expected to cease upon the return of business as usual 
circumstances (including lifting of any pertinent quarantines and travel bans/advisories).  
For German sites only: The alternative measures outlined above will only apply to the 
COVID-19 pandemic and not other public emergencies.   
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Appendix 11. Summary of Changes from Original Protocol through Amendment 7 
Document 
Version Date 
Summary of Changes and Rationale 
Amendment 7 
22 Aug 2022 
3. Study Design 
The following update to the study design is 
made throughout the protocol: 
Subjects who discontinue Investigational 
Product (IP) in the double-blind phase and who 
do not enter A3921145 will continue in 
A3921165 for follow up of efficacy and safety 
endpoints. Subjects will be required to perform 
all scheduled visits until Week 52 after 
randomization or until the study concludes, 
whichever comes first. Subjects should receive 
standard-of-care treatment in accordance with 
local treatment guidelines. 
The telephone contact visit at 24 weeks post 
randomization (for subjects not entered in 
A3921145 LTE study) is no longer applicable 
and removed. 
No study design change is made to the follow-
up of subjects discontinuing in the Open Label 
phase; however, the following wording is added 
for clarification throughout the protocol: 
Subjects who discontinue the study in the Open-
Label Phase and do not enter A3921145, will be 
required to perform a follow-up visit 28 days 
after the last dose of study treatment.  
3.  Study Design Figure 1 / Figure 2 
Clarification that subjects in randomized 
withdrawal phase will receive Investigational 
Product up to 1st sJIA flare, 24 consecutive 
weeks inactive disease or ET/EOS visit.  
Added footnote that subjects who discontinue 
IP in randomized phase will continue in the 
study. 
Schedule of Activities 
Footnote #25 added: 
Subjects who discontinue Investigational 
Product in the double-blind phase and who do 
not enter A3921145 will continue in A3921165 
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Document 
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Summary of Changes and Rationale 
for follow up of efficacy and safety endpoints. 
Subjects will be required to perform all 
scheduled visits until Week 52 after 
randomization, or until the study concludes, 
whichever comes first. Subjects should receive 
standard-of-care treatment in accordance with 
local treatment guidelines. All visit activities 
should be performed with the exception of 
Investigational Product dispensing, dosing and 
compliance.  
5.8.1.2. Disease Modifying Anti Rheumatic 
Drugs (DMARDs) 
Appendix 1. Allowed and Disallowed 
DMARDs 
Shortened washout periods of tacrolimus, 
sulfasalazine and azathioprine from 4 weeks to 
7 days. 
6.7.1 Discontinuation from Investigational 
Product during Randomized Withdrawal 
Phase 
New sub-section added: Subjects who 
discontinue Investigational Product in the 
double-blind phase, for reasons other than sJIA 
flare or clinical remission, and who do not 
rollover to A3921145 Long Term Extension 
(LTE) study, should continue with the regular 
scheduled visits every 4 weeks. All required 
procedures and assessments should be 
performed with the exception of IP dispensing 
and compliance. Subjects should receive 
standard-of-care treatment as per local 
guidelines. There are no protocol restrictions on 
the use of DMARDs and other disallowed 
agents, detailed in Appendix 1, for subjects 
receiving standard-of care treatment. 
6.10. Follow Up Telephone Contact 
This section is removed. 
6.12 Subject Withdrawal  
7. Discontinuation of Study Intervention and 
Subject Withdrawal 
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Subject Withdrawal Section is removed and 
replaced with Section 7. Discontinuation of 
Study Intervention and Subject Withdrawal  
The following sub-sections are added: 
• Discontinuation of Study Intervention 
• Subject Withdrawal from Study 
• Lost to Follow-Up 
• Withdrawal of Consent 
8.2.14 Temporary Withholding of Study 
Drug 
8.3.2 Discontinuation of Study Drug Criteria  
9.13 Withdrawal due to Adverse Events 
Appendix 7: Guidelines for Safety 
Monitoring and Discontinuation 
Updated language to clarify that subjects are not 
withdrawn from the study if study drug is 
discontinued. 
8.2.12 Blood Volume Table 5 
Clarified that samples are collected every 4 
weeks until ET/EOS not just until a subject 
flares. 
Statistical Analysis  
10.2 Efficacy analysis 
The log-rank test is updated from stratified to 
unstratified. 
Appendix 1 : Allowed and Disallowed 
DMARDS 
Added clarification that protocol prohibited 
agents can be used for subjects discontinued 
from Investigational Product and continuing in 
study on standard-of-care. 
Protocol Summary: Study design 
Duration of study updated from approximately 
5 years to approximately 7 years. 
Schedule of Activities 
Footnote #26 added: 
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Document 
Version Date 
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At the ET/EOS visit, for subjects considering 
entering A3921145 LTE study, an Informed 
Consent/Assent Document for A3921145 
should be provided to the subject prior to the 
visit, if possible. 
Schedule of Activities Footnote #3  
The wording of “flare evaluations will only be 
done if the subject discontinued due to other 
reasons than flare before Week 24 of the 
double-blind phase” is removed. 
Schedule of Activities Footnote #10 
8.1.6.2 Erythrocyte Sedimentation Rate 
A local lab ESR testing kit (Westergren 
method) can be substituted for a Sponsor kit 
only if supply issues have resulted in a Sponsor 
kit not being available at the time of the visit.  
3.3 Randomized Withdrawal Phase 
Clarification that participation in the study ends 
for subjects who experience 24 consecutive 
weeks of inactive disease, as well as subjects 
who flare. An EOS visit should be performed 
for these subjects who complete the study. 
6.7 Double-blind withdrawal phase 
6.8 End of Study or Early Termination Visit 
Clarification that participation in the study ends 
for subjects who experience 24 consecutive 
weeks of inactive disease, as well as subjects 
who flare. 
Schedule of Activities 
A banked biospecimen is collected at the Open 
Label Part 1 Phase Week 8 visit. This was 
previously omitted in the table. 
8.1.2 Fever and Absence of Fever Assessment 
Each subject to receive a temperature diary at 
the screening visit instead of day 1. 
8.1.9.  JIA ACR Clinical Inactive Disease and 
Clinical Remission Criteria 
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Clinical Inactive disease will be defined only 
using ESR and not CRP. 
8.1.11. JADAS 27 Minimal Disease Activity 
and Inactive Disease 
Clarified polyarthritis is more than 4 active 
joints, and oligoarthritis is 4 or less. 
12.1 Case Report Forms/Electronic Data 
Record 
Added language: 
When participant data are to be deleted, the 
investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from 
all systems. 
12.3 Data Protection 
New section added to describe the requirements 
for storage of personal data. 
13 Ethics 
New language added on regulatory and ethical 
considerations. 
Appendix 5: Prohibited Concomitant 
Medications 
Clarified that required washout is 4 weeks or ≥5 
half-lives, whichever is longer. 
Appendix 10: 
Temporary Measures for Study Visits 
Occurring During Public Emergencies  
For German sites only: The alternative 
measures will only apply to the COVID-19 
pandemic and not other public emergencies. 
Amendment 6 
09 Feb 2022 
Protocol Summary 
Secondary Efficacy Endpoints:  
• Occurrence of inactive disease status at 
every visit from Day 7 onward (JIA 
ACR) in the open label phase and the 
double-blind phase and assessment of 
clinical remission in the double-blind 
phase as clinical remission is not 
evaluated in the open-label phase. 
 
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Statistical Analysis: 
• Difference in time to flare between the 
two treatment groups (tofacitinib 5 mg 
BID vs. placebo) will be assessed using 
a stratified log rank test if enough events 
are observed in each stratum.  
Otherwise, the unstratified log-rank test 
will be used. 
 
Schedule of Activities 
Footnote 1: 
• Clarified that if more than 40 days in 
screening elapsed, subjects should be 
screen failed and rescreened if eligible. 
Footnote 6: 
• Added skin examinations 
Footnote 8: 
• Added India to countries where annual 
TB testing is required as the incidence of 
TB is >50 cases per 100,000 people. 
Footnote 18: 
• Removed the requirement that only 
subjects with positive VZV serology 
tests can be enrolled in the study. 
Footnote 20: 
• Clarified that subjects in India would not 
participate in PK testing. 
Footnote 24: 
• Added skin examinations for rash 
related to varicella (chickenpox) and 
herpes zoster are required. 
 
Section 1.1 Indication 
• Updated the text regarding the approved 
indications for tofacitinib as of 03 
December 2021, tofacitinib 5 mg BID is 
also approved for the treatment of 
psoriatic arthritis, ulcerative colitis, and 
polyarticular course juvenile idiopathic 
arthritis who have had an inadequate 
response or intolerance to one or more 
TNF blockers. 
 
Section 2.3 Benefit/Risk Assessment 
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• Discussion of the risks and benefits of 
using tofacitinib in the pediatric 
population added to the body of the 
protocol at the request of an ethics 
committee. 
  
Section 3.2.1 Open label Phase, Part 1: 
Treatment with Tofacitinib while on Stable 
Background Therapy 
• Clarified the text relating to Part 1 of the 
Open-label Phase 
 
Section 3.2.2 Open label Phase, Part 2: 
Treatment with Tofacitinib while on Stable 
Background Therapy 
Clarified the text relating to Part 2 of the 
Open-label Phase 
 
Section 3.3 Randomized Withdrawal Phase  
• Clarified the definition of ‘flare’ and 
how it will contribute to the primary 
endpoint. 
 
Section 3.4.1 Evaluation of 5 mg BID or 
Equivalent Weight based Lower Dose  
• Informed that Cohorts 1 and 2 had 
completed and the study is now in open 
enrollment. 
 
Section 4.1 Inclusion Criteria 
• Criteria #4 removed 3rd bullet as it was 
redundant with the first sentence of the 
criteria. 
 
Section 4.2 Exclusion Criteria 
• Criteria #14 revised exclusion regarding 
household contacts to align with IDSA 
Clinical Practice Guidelines for 
Vaccination of the 
Immunocompromised Host. 
• Criteria #15 removed the requirement 
for evidence of 2 doses of varicella 
(chickenpox) vaccination or positive 
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VZV serology testing to qualify for 
enrollment in the study. 
 
Section 4.5 Vaccine and Exposure to 
Infections Guidelines 
• Section 4.5.1 Subject Specific 
Recommendations was revised to 
clarify what vaccines can and cannot be 
administered to study participants and 
stated requirement for skin examinations 
for varicella vaccinated (inspect for 
herpes zoster rash) and varicella 
unvaccinated (inspect for chickenpox 
rash). 
• Section 4.5.2 Guidance Regarding 
Household Contact Vaccine Related 
Exposure was revised to align with 
IDSA Clinical Practice Guidelines for 
Vaccination of the 
Immunocompromised Host. 
 
Section 4.7 Elective Surgery 
• This section was modified to allow 
investigator discretion for withholding 
study treatment if surgery is required. 
 
Section 5.1 Allocation to Treatment 
• Section 5.1.1.1 Enrollment in 5 mg BID 
Cohort was revised to clarify the cohort 
was complete and the study could 
continue to the next phase. 
• Section 5.1.1.2 Open Enrollment at the 5 
mg BID Dose Level was revised to 
clarify that the previous cohort 
requirements were satisfied and the 
study was now in open enrollment. 
 
Section 5.8 Concomitant Treatment(s) 
• Section 5.8.1.1 Corticosteroids (CS) was 
revised to clarify the transition and 
timing of pre-study IV corticosteroid use 
(IV pulse). 
 
Section 6 Study Procedures 
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• Section 6.1 Screening Visit text was 
clarified to inform that the screening 
visit window is no more than 40 days 
and that if it extends beyond that time, 
the subject must be screen failed and 
rescreened with all assessments 
repeated. 
• Section 6.3 through Section 6.9 added at 
all regularly scheduled visits that all 
examinations should include skin 
examination for chickenpox or shingles. 
• Section 6.10 Follow Up Telephone 
Contact added an assessment for adverse 
events, including skin rash that could 
potentially indicate the presence of 
chickenpox or shingles, sJIA flare, and 
other manifestations of sJIA 
exacerbations. 
• Section 6.11 Unscheduled Study Visit or 
Telephone Contact added an assessment 
for skin rash that could indicate the 
presence of chickenpox or shingles. 
 
Section 7.2.6 Varicella (chickenpox) and 
Herpes zoster (shingles) Assessment and 
Guidance 
• This section was added to describe the 
rash and other symptoms that may 
accompany these events and how they 
differ from the typical sJIA rash. This 
section also added the requirement that 
parent/guardian/subject perform at least 
weekly skin checks between visits and 
any concern for potential chickenpox or 
shingles be reported to the investigator 
immediately.  
 
Section 7.2.9 Laboratory Testing 
• VZV-specific ELISA testing was 
modified to remove the requirement of 
VZV seropositivity for subject to enroll 
if they do not have a history of having 
received 2 doses of varicella vaccine. 
 
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Table 5. Maximum Blood Volume Collection 
at Each Study Visit 
• Footnote 6 noted that India will not 
participate in PK sampling. 
• Footnote 9 updated to include India in 
annual TB testing. 
 
Section 7.2.14 Temporary Withholding of 
Study Drug 
• Section Title was changed from citing 
tofacitinib rather than study drug as 
during the double-blind phase of the 
study, subjects could be receiving 
placebo. 
• Text of section was revised to identify 
study drug instead of tofacitinib, 
identifies when study drug does not 
require withholding, and informs that 
when drug is withheld for protocol-
related reasons (e.g., adverse events, 
laboratory abnormalities) missed doses 
would not contribute to non-compliance. 
 
Section 9.1 Sample Size Determination 
• Further clarified that subjects 
discontinuing study drug in the double-
blind phase of the study for reasons 
other than clinical remission will be 
counted as having an sJIA flare in the 
primary analysis for the primary 
endpoint of the study. 
Section 9.2.1 Analysis of Primary Endpoint 
• Clarified the text regarding the planned 
supportive analyses.  
 
Section 9.2.2 Analysis of Secondary 
Endpoints 
• Clarified that secondary endpoints 
would not be statistically analyzed 
beyond 52 weeks but will be 
summarized descriptively. 
 
Section 12.2 
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• Add country-specific requirement for 
the Netherlands that in the Netherlands, 
patients will be evaluated for enrollment 
in this study if previous treatments 
recommended by the JVN 
Medicamenteuze behandeling van 
kinderen met jeugdreuma (Dutch 
Guidelines: JVN Drug Treatment of 
Children with Juvenile Rheumatism) 
have failed to control their systemic JIA 
disease. 
 
Appendix 10 Temporary Measures for Study 
Visits Occurring During Public Emergencies 
• Clarified that these temporary measures 
should not be implemented by the study 
sites without conversation with the 
Sponsor and that if other public 
emergencies other than the COVID 
pandemic occur additional or different 
alternate solutions may be provided. 
• Removed the restriction that CRP cannot 
be performed locally, as CRP is not 
blinded in this study. 
 
Appendix 11 Summary of Changes from 
Original Protocol through Amendment 5 
• Updated the title to include Amendment 
5 and added the summary of changes 
and rationale from Amendment 5 to the 
table. 
Amendment 5 
21 July 2021 
This global amendment incorporates updates to 
facilitate enrollment of sJIA patients who were 
previously treated with biological DMARDs or 
JAK-inhibitors:  
• Section 5.8.1.2 (Table 4), Appendix 1: 
The washout period for biological 
DMARDs has been shortened from 
5 half-lives to 2 half-lives.  This change 
is made to minimize the length of time 
that sJIA patients with active disease 
must go without adequate treatment.  
This update is supported by previous 
analyses with tofacitinib in rheumatoid 
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arthritis (RA) and psoriatic arthritis 
(PsA) patients who were switched from 
adalimumab to tofacitinib without a 
washout period; no increase in adverse 
events after the switch was noted in 
these analyses.  
• Section 4.2 (Excl Criterion #4) and 
Section 5.8.1.2: Removed the restriction 
that only 40% of subjects are allowed to 
have previously failed two biologic 
DMARDs.  All subjects are allowed to 
have previously failed two or more 
biologic DMARDs, provided washout 
periods are respected.  
• Section 4.2, Section 5.8.1.2 and 
Appendix 1: Updated Exclusion 
Criterion #1: Previous treatment with 
baricitinib or JAK-inhibitors, other than 
tofacitinib, is allowed provided washout 
periods are respected.  Baricitinib 
(Olumiant®) and Upadacitinib 
(Rinvoq®) are added to list of DMARDs 
requiring a washout.  These changes are 
made to address the changed landscape 
with more sJIA patients being treated 
with JAK-inhibitors. 
In addition, this amendment reflects: 
• Section 4.1: Inclusion Criterion #2: 
Clarified that subjects diagnosed with 
sJIA who have first-degree relatives 
with history of psoriasis, ankylosing 
spondylitis, enthesitis-related arthritis, 
sacroiliitis with inflammatory bowel 
disease, Reiter’s syndrome, or acute 
anterior uveitis may be allowed for 
enrollment after consultation with the 
sponsor.  These excluding conditions for 
siblings no longer apply to the definition 
of sJIA according to the revised ILAR 
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criteria agreed during the Printo 1st 
consensus meeting in 2019. 
• Section 3.2.2: Clarified the 
Corticosteroid tapering in Open-label 
Part 2.  A subject must be on the final 
tapered CS dose on or before the day 
after the open-label Part 2 Week 20 
visit. 
• Schedule of Activities, Figure 1, 
Figure 2, Section 6.1, Section 6.2, 
Section 7.2.11: Updated the screening 
period with 10 additional days for 
additional flexibility.  
• Section 6.1: Clarified the circumstances 
in which re-screening is allowed. 
• Section 6.1, Section 7.2.8, & 
Section 7.2.11: Clarification that a 
one-time repeat testing of screening 
hematology and serum chemistry 
laboratory abnormalities is allowed if the 
abnormal laboratory result was 
uncharacteristic for the participant.  This 
change is made to avoid screen failures 
as a result of laboratory errors. 
• Section 6.6: Correction of error: once a 
subject is able to maintain the Adapted 
JIA ACR 30 response for 4 weeks on a 
stable tapered CS dose in the open-label 
phase he/she can start the double-blind 
phase (not open-label Part 2). 
• Section 9.9: Clarified that from study 
start, the Sponsor is using an 
independent Macrophage Activation 
Syndrome (MAS) Review Committee to 
adjudicate events of MAS reported 
during the study. 
• Section 5.3: Updated to state that 
subjects who exhibit non-compliance 
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may be discontinued from the study 
after discussion with the Sponsor.  
• Schedule of Activities, Section 7.1.4, 
Section 7.1.5: Updated to include that an 
adult caregiver interacting daily with the 
subject can complete the CHAQ and 
CHQ assessments during the course of 
the study.  This change is made to 
accommodate study participants who are 
accompanied by caregivers during study 
visits. 
• Section 1.1: Updated to include the 
current number of countries in which 
tofacitinib is approved for RA. 
• Schedule of Activities, Appendix 10: 
Updated to expand the Temporary 
Measures for Study Visits for any public 
emergency, including COVID-19.  This 
change is made to cover all public 
emergencies that may require 
alternatives to clinic visits.  
Minor updates made for general clarity and 
consistency throughout the document. 
Amendment 4  
17 March 2021 
This global amendment incorporates updates to 
address enrollment challenges:  
• Section 4.1 (Inclusion Criterion #2): 
Subjects must have active disease at the 
time of screening and enrollment.  
Six (6) weeks of active disease before 
screening are no longer required 
(previous minimum).  This change is 
made to minimize the length of time that 
sJIA patients with active disease must 
go without adequate treatment.  
• Section 4.1 (Inclusion Criterion #3); 
Appendix 1; Appendix 3; 
Section 5.8.1.2 Allowed DMARDs: A 
stable dose of methotrexate in the last 
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4 (instead of 6) weeks before Dose 1 is 
required in subjects who receive 
background methotrexate.  This change 
is justified by the half-life of 
methotrexate.  
• Section 4.2 (Exclusion Criterion #1): 
Subjects who received previous JIA 
treatment with tofacitinib, baricitinib or 
any other JAK-inhibitor will be 
excluded.  This exclusion criterion was 
broadened to include any JAK-inhibitor.  
• Section 4.2 (Exclusion Criterion #5b): 
Any infection requiring hospitalization, 
parenteral antimicrobial therapy or 
judged to be opportunistic by the 
investigator within the 3 months (instead 
of 6 months) prior to the first dose of 
study drug will exclude a subject.  This 
change reflects the current safety profile 
of tofacitinib.  
In addition, this amendment reflects:  
• Background, Section 1.2.1: Added a 
sentence that Study A3921104 in pJIA 
patients is completed and results 
demonstrated that tofacitinib was safe 
and efficacious.  Section 1.2.2: Added 
further justification for the randomized 
withdrawal study design.   
• Section 4.2 (Exclusion Criterion #15), 
Section 4.5.1, Section 6.1, Section 7.2.8, 
Section 7.2.11, Schedule of Activities: 
Subjects who have documented 
evidence from a health professional of 
receiving 2 vaccinations for varicella 
zoster virus (VZV) are eligible for 
inclusion and do not require a positive 
VZV IgG serology test at screening.  
This change is consistent with CDC 
guidelines that do not recommend 
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testing for VZV immunity after 
receiving 2 doses of varicella vaccine.29 
• Monitoring and Discontinuation 
Criteria, Section 7.3.1 and 7.3.2; 
Appendix 4, Appendix 7: the creatinine 
monitoring and discontinuation criteria 
were updated: in addition to a single 
increase or 2 sequential increases in 
serum creatinine >50% over the average 
of screening and baseline values OR an 
absolute increase in serum creatinine 
≥0.5 mg/dL (≥44.2 umol/L), a single or 
2 sequential Creatinine Clearance (CrCl) 
decreases of >30% over the average of 
screening and baseline CrCl values are 
required to monitor (retest creatinine) or 
discontinue a subject from the study, 
respectively.  Appendix 4: Clarified that 
estimated glomerular filtration rate will 
be calculated at screening to determine 
subject eligibility and Creatinine 
Clearance will be calculated at all visits 
(via Modified Schwartz equation for 
subjects <12 years old and 
Cockcroft-Gault equation for subjects 
≥12 years old).  These updates were 
made to account for potential increases 
in creatinine due to physical activity, age 
and growth and to align with 
FDA/CDER 2014 guidelines regarding 
monitoring of kidney function in 
pediatric studies.30  
• Section 4.2: Exclusion Criterion #28: 
This country-specific exclusion criterion 
is made global to ensure consistent 
eligibility criteria for the study 
population, and is broadened to exclude 
subjects with a history of allergies, 
intolerance or hypersensitivity to any 
other excipients of the investigational 
product, including placebos, at the 
request of the German regulatory 
agency: subjects will be excluded if they 
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have a history of allergies, intolerance or 
hypersensitivity to lactose or 
CP-690,550 (tofacitinib), or any other 
excipients of the investigational 
medicinal products, including placebos.  
As the oral solution does not include 
lactose, subjects with hereditary or 
acquired lactose intolerance may be 
treated with the tofacitinib oral solution, 
instead of the tablet, at the investigators 
request. 
• Section 4.5.1: Clarification that 
administration of non-live COVID-19 
vaccines that are fully approved or 
approved for emergency use is permitted 
during the study, provided that the 
vaccination is not part of another clinical 
study.  
• Schedule of Activities, Section 6.4, 
Section 6.5, Section 7.2.11: Clarification 
of PK sample collection in accordance 
with Section 7.4.1: the PK sample after 
8 weeks of tofacitinib treatment may be 
obtained at Week 8 Part 1, or at Week 4 
Part 2 in case a subject moves from 
Part 1 to Part 2 after 4 weeks of 
tofacitinib treatment.   
• Appendix 1: Correction of the washout 
period for investigational drugs to be 
4 weeks in accordance with 
exclusion criterion #24. 
• Appendix 3: Correction of 
administrative error.  The maximum 
dose of corticosteroids is 30 mg/day of 
oral prednisone, not 30 mg/kg. 
• Section 4.2: Exclusion Criterion #16, 
Appendix 7, and Section 7.3.2: 
Consistent nomenclature in accordance 
with other tofacitinib protocols to state 
“basal cell or squamous cell carcinoma 
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of the skin” instead of “NMSC (non 
melanoma skin cancer)” and “cervical 
carcinoma” instead of “cervical cancer.”  
Amendment 3 
4 May 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.  In 
addition, it includes temporary measures for 
visits occurring during the COVID-19 
pandemic, updates in accordance with recent 
PACLs and some clarifications of text.  
The following sections have been updated to 
reflect these changes: 
• Schedule of Activities, Section 4.2 
(Exclusion Criteria), Section 6 (Study 
Procedures), Section 7.2.12 (Risk Factor 
Check for Venous Thromboembolism), 
Section 7.2.13 (Tofacitinib Temporary 
Withholding), Section 7.3.2 
(Discontinuation Criteria) and 
Appendix 7. 
• Temporary measures for visits occurring 
during COVID-19 are added in 
Appendix 10.  
• Update in accordance with JIA protocol 
A3921145: Clarified under what 
conditions temporary withholding of 
tofacitinib up to 28 days is allowed in 
Section 7.2.13 (Tofacitinib Temporary 
Withholding). 
• Update in accordance with PACL#9: In 
countries with an incidence rate of 
Tuberculosis (TB) of >50 cases per 
100,000 persons, eg, China, Russian 
Federation; South Africa and Ukraine 
(World Health Organization): yearly TB 
testing is required after screening.  The 
Schedule of Activities, Section 6.7 
(Visits every 4 weeks in Double-blind 
Withdrawal phase), Section 7.2.7 
(Tuberculosis Testing), and 
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Section 7.2.11 (Blood Volume) have 
been updated accordingly. 
• Table 4: Correction in accordance with 
PACL#9: the incorrect statement that the 
washout of Anakinra is 4 weeks before 
Day 1 is removed. 
• Childhood Health Questionnaire (CHQ) 
and Childhood Health Assessment 
Questionnaire (CHAQ): Parents/legal 
guardians are required to complete the 
CHQ and CHAQ throughout the study. 
Subjects >18 yrs will not complete the 
CHQ and CHAQ.  Sections 7.1.4 and 
7.1.5 (Efficacy assessments) have been 
updated accordingly. 
• Correction in accordance with PACL#9: 
the CHQ is required every 6 months (not 
every 3 months) after randomization.  
The protocol summary and Section 2.2 
(Secondary Endpoints) have been 
updated accordingly.   
• Update in accordance with Amendment 
2: an additional PK blood sample must 
be obtained 1.5 hours (1.25-2h) post 
tofacitinib administration in the first 
14 subjects enrolled in Cohorts 1 and 2.  
Footnote 20 of the SOA, Section 6.2 
(Day 1 Visit) and Section 7.2.11 (Blood 
Volume) have been updated 
accordingly.  
• Section 8.2 (Time Period and Frequency 
for collecting AE and SAE Information) 
was updated according to the new 
standard text.  
• Update for consistency with LTE 
protocol A3921145: in Section 7.2.11 
(Blood Volume) is added that in case of 
insufficient blood sample or poor sample 
quality a subject must return within 
1 week for a new sample collection.  A 
reference to Section 7.2.11 is added to 
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the SOA and Section 6 (Study 
Procedures).  
• Section 3.4: Clarified the sentence 
regarding open enrollment, which will 
occur after completion of initial cohorts 
of subjects ≥40 kg and aged ≥12 years.  
Amendment 2 
16 May 2019 
• Tofacitinib 10 mg BID dose will no longer 
be evaluated.  References to the 10mg BID 
group and 10 mg BID dose increase at Day 
14 are removed throughout the protocol. 
At the time of this amendment (Amendment 
2) only Cohort 1 (5 mg BID dose 
evaluation) has been completed and Cohort 
2 (5 mg BID dose evaluation) is ongoing.  
There were 2 subjects that required a dose 
escalation to 10 mg BID after 14 days of 
dosing due to uncontrolled fever.  One 
subject discontinued 4 days after the dose 
increase due to sJIA exacerbation and one 
subject has decreased their dose to 5 mg 
BID. 
• Reference to the Section 7.1.2 added in the 
schedule of activities. 
• Minor editorial corrections throughout the 
document. 
Amendment 1 
14 December 
2018 
• EudraCT number corrected (front page); 
PACL issued 09-May-2017. 
• Schedule of activities updated to clarify that 
the End of Study (EOS)/Early Termination 
(ET) visit is required for all subjects who 
discontinue from the study outside of a 
regular scheduled visit regardless of the 
phases; PACL issued 29-Jun-2017. 
• Background section updated to reflect the 
start of the A3921104 study (Refer to 
Section 1.2.1 Tofacitinib). 
• Inclusion criterion #4 and protocol section 
7.2.7 Tuberculosis Testing updated to clarify 
which treatment is considered “adequate” 
prior to enrollment of a subject with latent 
tuberculosis; the Sponsor considers ongoing 
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treatment with isoniazid or equivalent for at 
least 4 weeks before the first dose of 
tofacitinib (Day 1) adequate, provided that 
local rates of primary multi-drug resistant 
TB infection are <5%; PACL issued 02-Jan-
2018. 
• Exclusion criterion #4 updated to clarify that 
only discontinuation of a biologic DMARD 
due to safety concerns, or lack of efficacy 
would be considered a treatment failure.  A 
switch from the IL-1 inhibitor Anakinra 
(Kineret®) to the IL-1 inhibitor 
Canakinumab (Ilaris®) for convenience 
would not count as a biologic DMARD 
failure; PACL issued 23-Oct-2017. 
• Exclusion Criterion #15 changed to exclude 
any subjects without documented evidence 
of prior exposure to varicella zoster virus 
based on positive serological testing at 
screening.  Schedule of activities, protocol 
Section 4.2 Exclusion criteria, 4.5.1 Subject 
Specific Recommendations, 6.1 Screening 
Visit, 7.2.8 Laboratory Testing and 
7.2.11 Blood Volume have been updated 
accordingly.  
• Washout period for Anakinra and 
Cyclosporine corrected to 7 days in 
Section 5.8.1.2 Disease Modifying 
AntiRheumatic Drugs and Appendix 1; 
PACL issued 23-Oct-2017/PACL 
issued 15-Oct-2018. 
• Immunoglobulin IV added to list of 
prohibited medication, a washout period of 
20 weeks or 5 half-lives (whichever is 
longer) is required prior to the first dose of 
study drug (Section 5.8.1.2 Disease 
Modifying AntiRheumatic Drugs and 
Appendix 1); PACL issued 31-May-2018. 
• Child Health Questionnaire added in 
Section 6.1 Screening Visit; PACL issued 
29-Jun-2017. 
• Duplicated procedures “ sJIA disease 
activity status” removed in Section 6.1 
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Screening Visit; PACL issued  
29-Jun-2017.  
• Protocol section 6.3 Open-Label Phase /Part 
1: Day 3, Day 7 and Day 14 visit updated to 
clarify that the assessment of the Adapted 
JIA ACR response based on ESR is Only 
required at the Day 7 and Day 14 visit; 
PACL 15-Oct-2018. 
• Telephone contact at 11 Weeks for subject 
who had a dose increase at Day 14 added to 
the list of visits in the Section 6.5.1 
Telephone Contact 1,3,5,7,9 and 11 weeks 
after Dose Increase, PACL issued 
29-Jun-2017. 
• List of analysis required at the biweekly 
visit after dose increase corrected to include 
Hematology, Chemistry, Lipid panel, CRP 
and urinalysis in Section 6.5.2 Extra Visits 
at 4, 8, and 12 weeks after Tofacitinib Dose 
Increase from 5mg to 10 mg BID; PACL 
issued 15-Oct-2018. 
• Child Health Questionnaire added in Section 
6.10 Follow-up Visit (only for subject not 
entering study A3921145); PACL issued 
29-Jun-2017. 
• List of analysis required at the Follow-up 
visit corrected to include Hematology, 
Chemistry, Lipid panel, CRP and urinalysis 
Section 6.10 Follow-up Visit (only for 
subject not entering study A3921145); 
PACL issued 14-Aug-2018. 
• Tanner stage assessment required at 
screening visit instead of Day 1 in 
Section 7.2.6 Pubertal Development 
Assessment (Tanner Stage); PACL 
29-Jun-2017. 
• Guidelines about blood volume collection in 
pediatric study added to Section 7.2.11 
Blood Volume.  (PACL issued 
15-Oct-2018). 
• Reference to“QuantiFERON®-TB Gold 
Plus” In-tube Test added, 
QuantiFERON®-TB Gold or 
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QuantiFERON®-TB Gold Plus will be 
available according to the 
country.“QuantiFERON®-TB Gold or Gold 
Plus” added throughout the protocol and the 
required volume of blood updated to 3 mL 
or 4 mL (Section 7.2.7 Tuberculosis Testing, 
Section 7.2.11 Blood Volume and Schedule 
of Activities), PACL issued 11-Sep-2018. 
• Correction in Table 5 Maximun Blood 
Volume Collection at Each Study Visit: 
• Minimum volume of blood required at 
Day1 visit corrected to 9.4 mL instead 
of 9.3 mL. 
• Volume of blood required for banked 
biospecimen at Week 8 corrected to 
2mL in line with protocol Section 7.5 
Banked Biospecimens.  
• Volume of blood required at screening 
updated to include QuantiFERON®-TB 
Gold Plus and the varicella zoster virus 
testing (Refer to Section 6.1 Screening 
Visit and Section 7.2.11 Blood Volume. 
• Pharmacokinetic (PK) samples to be 
collected at baseline (day of tofacitinib 
administration) and after 8 weeks of study 
treatment, instead of at baseline (day of 
tofacitinib administration) and after 8 or 
12 weeks of study treatment.  Schedule of 
activities, protocol Section 6.4 Open-Label 
Phase/Part 1: Visits Every 4 Weeks from 
Week 8 up to Week 16, Table 5 Maximum 
Blood Volume Collection at Each Study 
Visit, and 7.4 Pharmacokinetic Assessment 
have been updated accordingly.   
• PK samples timing updated in order to more 
accurately characterize the tofacitinib 
exposure profile, the last PK sampling time 
point was revised.  (Refer to Section 7.4 
Pharmacokinetic Assessment). 
Country Specific Amendment for European 
Union (EU), (including United Kingdom 
[UK]):  
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Protocol amended in line with the European 
Union Regulatory Authority requirements for 
the protocol A3921104 which is part of the 
same program.  These changes are applicable to 
sites within the EU (including UK).  
• Added clarification on the contraception 
requirements specific to subjects included 
by EU sites, including UK sites.  (Refer to 
Section 4.1 Inclusion Criteria and 4.4.1 
Contraception). 
• Added guidance for breaking the blind for 
study treatment.  (Refer to Section 5.2 
Breaking the Blind). 
• Added a full skin cancer examination to the 
complete physical examination.  (Refer to 
the Schedule of Activity, Section 6, and 
Section 7.2.2 Physical Examination). 
• Added guidance regarding participants who 
have resided or travelled in areas of endemic 
tuberculosis or endemic mycoses; or have 
underlying conditions that may predispose 
them to infection.  (Refer to Section 7.2.7 
Tuberculosis Testing). 
• Added guidance regarding limiting the 
number of attempts for blood collection.  
(Refer to Section 7.2.11 Blood Volume). 
• Added guidance regarding the blood volume 
limit recommended in pediatric studies.  
(Refer to Section 7.2.11 Blood Volume). 
• Provided guidance for monitoring confirmed 
absolute neutrophils count levels of 500 – 
1000 neutrophils/mm3.  (Refer to 
Section 7.3.1 Monitoring Criteria). 
• Dose increase restriction: dose increase at 
Day 14 from tofacitinib 5 mg BID to 10 mg 
BID in the case that sJIA fever is not 
controlled within the first 2 weeks of 
treatment, will be allowed following 
confirmation of the safety and efficacy of 
the 10 mg BID dose for at least 12 weeks 
from subjects in cohorts 3 and 4.  (Refer to 
the Section 5.1.1.3 Dose Increase from 5 to 
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10 mg BID Dose Level for Individual 
Subjects, and the Schedule of Activities). 
Country specific amendment for Germany:  
• The Degree of Burden and the Risk 
Threshold Assessment required at each 
visit to be in compliance with the article 
40 (4) No. 4 of the German Medicines 
Act] (Refer to the Schedule of 
Activities, Section 6 Study Procedures 
and Appendix 9). 
• Added new exclusion criterion: History 
of allergies, intolerance or 
hypersensitivity to lactose or 
CP-690,550 (tofacitinib).  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. 
Country specific amendment for South 
Africa:  
• Due to the high incidence rate of 
Tuberculosis (TB) in South Africa; 
additional TB testing is required every 
year.  (Refer to Schedule of Activities 
and protocol Section 7.2.7 Tuberculosis 
Testing).  Protocol Section 7.2.11.  
Blood Volume has been updated 
accordingly. 
Original protocol 
15 March 2017 
Not Applicable (N/A) 
 
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