A LONG-TERM, OPEN-LABEL FOLLOW-UP STUDY OF TOFACITINIB FOR TREATMENT OF JUVENILE IDIOPATHIC ARTHRITIS (JIA)
Phase: PHASE2
Conditions: Juvenile Idiopathic Arthritis
Sponsor: Pfizer

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A LONG-TERM, OPEN-LABEL FOLLOW-UP STUDY OF TOFACITINIB FOR 
TREATMENT OF JUVENILE IDIOPATHIC ARTHRITIS (JIA)
Compound:
CP-690,550
Compound Name:
Tofacitinib
United States IND Number:
117400
European Clinical Trial Database 
(EudraCT) Number:
2011-004915-22
Protocol Number:
A3921145
Phase:
2/3
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 12
06 May 2022
Amendment 11
26 May 2021
Amendment 10
04 May 2020
Amendment 9
23 May 2019
Amendment 8 
07 February 2018
Amendment 7
10 August 2017
Amendment 6
07 April 2016
Amendment 5 
17 August 2015
Amendment 4 
03 April 2015
Amendment 3
27 August 2014
Amendment 2 
22 August 2013
Amendment 1
18 September 2012
Original protocol
16 November 2011
This amendment incorporates all revisions to date including amendments made at the request 
of country health authorities, Institutional Review Board (IRB)/Ethics Review Board (ERB), 
and any protocol administrative change letter(s). 
Protocol Amendment Summary of Changes Table
Amendment 12 (06 May 2022)
Overall rationale for the amendment: This global amendment incorporates updates made 
to Qualifying Study A3921165 GPA#5 and GPA#6 and makes additional modifications to 
text for clarification purposes.
Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Schedule of 
Activities
Footnote #17
6.0 Study 
Procedures
Added requirement for skin 
examination for chicken pox or 
shingles at all visits, applicable 
for subjects enrolled from 
A3921165 only.
Requirement added 
to A3921165 
GPA#6
Substantial
2.3 Benefit/Risk 
Assessment
New section added on 
risk/benefits of tofacitinib.
Included to align 
with information 
added in A3921165 
GPA#6.
Substantial 
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Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
4.2 Exclusion 
Criteria
#25 
Removed to allow previous 
treatment with baricitinib or 
JAK-inhibitors. 
Updated to align 
with A3921165 
GPA#6.
Substantial
4.3.3 Vaccine 
and Exposure to 
Infections 
Clarification on allowed 
vaccines, including guidance 
on COVID-19 vaccines. 
Section added on varicella 
vaccination for participants 
enrolled from A3921165. 
Guidance Regarding 
Household Contact Vaccine-
Related Exposure is revised.
Guidelines updated 
to align with 
A3921165 GPA#6
Substantial
7.2.7 Physical 
Examination
Appendix 16
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 is added
Requirement for 
skin examinations 
added to A3921165 
GPA#6
Substantial
Appendix 1: 
Allowed and 
Disallowed 
Treatments for 
JIA
The washout periods for 
biological DMARDs are 
shortened from 5 half-lives to 
2 half-lives.
Updated to align 
with the updates to 
washout periods 
made in A3921165 
GPA#5
Substantial
Appendix 16: 
Varicella 
(chickenpox) 
and Herpes 
zoster (shingles) 
Assessment and 
Guidance
New appendix applicable to 
subjects enrolled from 
A3921165 added to describe 
the rash and other symptoms 
that may accompany 
chickenpox and shingles 
events and how they differ 
from the typical sJIA rash.
Requirement added 
to A3921165 
GPA#6
Substantial
1.1 Indication
Updated number of countries 
in which tofacitinib is 
approved and included 
additional indication approvals
To provide updated 
information
Non-substantial
4.1 Inclusion 
Criteria #6
5.5.2  Permitted 
Medications 
Removed need for Medical 
Monitor agreement for use of 
higher prednisone-equivalent 
doses for subjects enrolled 
from A3921165
Medical Monitor 
agreement is not 
considered 
necessary as 
allowed doses are 
Non-
Substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
And/Or 
Treatments
Appendix 3
well-defined in the 
protocol
4.3.4 Elective 
Surgery
Modification to allow 
investigator discretion for 
withholding study treatment if 
surgery is required.
Added for 
clarification 
Non-substantial
5.2.1 Tofacitinib 
Temporary
Withholding
Clarification that withholding 
study drug is not necessary 
when administering non-live 
vaccines.
Added for 
clarification 
Non-substantial
5.3.4 
Compliance
Clarification that protocol 
allowed temporary 
discontinuation of study drug 
for SAEs/AEs, surgical 
procedures and other allowed 
reasons is not considered as 
noncompliance and a PD will 
not be recorded
Added for 
clarification 
Non-substantial
7.1.4 CHAQ
Clarification that an adult 
caregiver interacting daily with 
the subject can complete the 
CHAQ.
Added for 
clarification 
Non-substantial
7.1.9 JADAS 
27 Minimal 
Disease Activity 
and Inactive 
Disease
Polyarthritis corrected to more 
than 4 joints, and oligoarthritis 
to 4 or less
Correction to > and 
≤ symbols
Non-substantial 
Section 7.2.2. 
QuantiFERON®-
TB Gold Plus 
In-Tube Test
Schedule of 
Activities 
Footnote#3
Added India to countries 
where annual TB testing is 
required as the incidence of TB 
is >50 cases per 100,000 
people.
Added for 
clarification
Non-substantial
7.2.5 Uveitis 
exam
Clarified that uveitis exam by 
ophthalmologist at the EOS/ET 
Visit is not required if an exam 
To reduce patient 
burden
Non-substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
has been performed within the 
past 6 months of the EOS/ET 
visit.
Section 7.2.9
Laboratory Tests
Schedule of 
Activities 
footnote #5
Clarified that lipid panel is 
required at the EOS/ET visit.
Added for 
clarification 
Non-substantial
7.3 Pregnancy 
testing 
Clarification that a positive 
urine pregnancy test will be 
confirmed by a serum 
pregnancy test performed 
either locally or by the central 
laboratory.
Added for 
clarification 
Non-substantial
7.4.1 PK 
Sampling 
Timepoints for 
All Subjects
Schedule of 
Activities 
footnote #6
Clarified that participants in 
India will not participate in PK 
testing.
Incorporates 
country-specific 
requirement (India 
PACL 14Jan22)
Non-substantial
8.5.2 Treated 
Infections
Removed need to obtain 
Medical Monitor approval for 
temporary discontinuation of 
study drug in subjects who 
experience infections 
Medical Monitor 
agreement is not 
considered 
necessary as 
requirements for 
discontinuation of 
study drug are 
well-defined in the 
protocol
Non-substantial
9.5 Interim 
Analysis
Added that IA may be 
performed for purposes of 
planned publications.
Clarifies that IA is 
allowed for 
planned 
publications
Non-substantial
9.7 Safety 
Endpoint 
Adjudication 
Committees
Clarification that the Sponsor 
is using an independent 
Macrophage Activation 
Syndrome (MAS) Review 
Committee to adjudicate 
events of MAS.
Added for 
clarification
Non-substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Appendix 4: 
Permitted 
Adjustments 
(Tapering) of 
JIA Medications 
Removed requirement to notify 
Pfizer Clinical or Medical 
Monitor of medication 
adjustments
Notification is not 
considered 
necessary as the 
permitted 
adjustments are 
well-defined in the 
protocol
Non-substantial
Appendix 17: 
Summary of 
Changes
Summary of changes from 
original protocol through to 
Amendment 11 moved to end 
of protocol document.
To align with 
protocol template
Non-substantial
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PROTOCOL SUMMARY
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, 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.  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) .  At higher exposures, inhibition of 
erythropoietin signaling could occur via inhibition of JAK2 signaling.
Tofacitinib pediatric development program is designed to demonstrate both efficacy, as 
demonstrated by a reduction in signs and symptoms of Juvenile Idiopathic Arthritis (JIA) in 
subjects 2 years of age and older, and safety supporting the use of tofacitinib for the 
treatment of pediatric subjects with JIA.
The rationale of this study is to enable subjects potentially benefitting from treatment in a 
previous qualifying/index study to continue to receive tofacitinib at the same dose as the 
qualifying/index study (unless further analysis of the qualifying/index study data indicate 
otherwise), and to characterize long-term safety and tolerability of tofacitinib for the
treatment of JIA.
It is anticipated that benefit of continued treatment with tofacitinib for individual subjects in 
this study will have been established in the qualifying/index study as per the Investigator’s 
assessment.  Potential risks of continued treatment are expected to be consistent with those 
described in the Single Reference Safety Document (current version of the tofacitinib 
Investigator Brochure).
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 Investigator’s Brochure.
STUDY OBJECTIVES AND ENDPOINTS:
Objectives
Primary

The primary objective of this study is to determine the long term safety and 
tolerability of tofacitinib for treatment of the signs and symptoms of JIA.
Secondary

The secondary objective of this study is to evaluate the persistence of efficacy of 
tofacitinib for treatment of the signs and symptoms of JIA.
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Exploratory 
The exploratory objectives of this study are:

To assess tofacitinib pharmacokinetics (PK) in pediatric subjects on a stable dose of 
tofacitinib in the setting of a long-term, open label study.

To assess changes in PK parameters (within subject) with increase in weight in this 
pediatric population and to explore exposure-response relationships of tofacitinib for 
various efficacy and safety endpoints after long-term exposure of tofacitinib in this 
pediatric population.
Endpoints
Primary

Standard laboratory safety data and adverse event (AE) reports.  Body weight, height
and Tanner Stages will be collected to assess growth and physical development.
Secondary 
The following efficacy parameters will be assessed:

Physician global evaluation of disease activity at each visit.

Number of joints with active arthritis at each visit.

Number of joints with limitation of motion at each visit.

Index of inflammation (C-reactive protein [CRP] and Erythrocyte Sedimentation Rate 
[ESR]) at each visit.

Childhood Health Assessment Questionnaire (CHAQ) at each visit.

Parent’s Assessment of Physical Function (CHAQ Disability Index).

Parent’s Assessment of Child’s Arthritis Pain (CHAQ Discomfort Index, Visual 
Analog Scale [VAS]). 

Parent’s Global Assessment of Overall Wellbeing (CHAQ subsection, Visual 
Analog Scale [VAS]).

JIA American College of Rheumatology (ACR) response at each visit and occurrence 
of JIA ACR disease flare after Month 3. 

JIA ACR Clinical Inactive Disease status and Clinical Remission on Medication at 
each visit.
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
Change from baseline in Juvenile Arthritis Disease Activity Score (JADAS) 27- CRP 
and JADAS 27-ESR, and occurrence of JADAS minimum disease activity and 
inactive disease at each visit. 

Eligibility of tapering defined per protocol for corticosteroids, MTX/leflunomide, and 
tofacitinib.

In subjects with sJIA: “Absence of Fever”, defined as absence of fever due to sJIA in 
the week preceding the assessment at each visit.

In subjects with Enthesitis Related Arthritis (ERA): Change from baseline in the 
Tender Entheseal Assessment, Modified Schober’s Test, Overall Back Pain and 
Nocturnal Back Pain responses at various visits.

In subjects with psoriatic arthritis (PsA): Change from baseline in body surface area 
(BSA) affected by psoriasis and Physician’s Global Assessment (PGA) of psoriasis) 
at various visits.
Exploratory

Plasma concentration time data for tofacitinib will be analyzed to characterize the PK 
in this subject population.  Exposure-response relationships will be explored for 
various efficacy and safety endpoints after long-term exposure of tofacitinib.
Statistical Analysis
Statistical analyses will be focused on descriptions of long term safety and tolerability of 
tofacitinib for the treatment of signs and symptoms of JIA.  Safety endpoints will be 
measured by scheduled physical examinations and safety laboratory tests, and described over 
time.  In addition, spontaneous reporting of AEs and serious adverse events (SAE) 
throughout the trial will be evaluated in all subjects.  Measurements of efficacy will be 
summarized using descriptive statistics, such as number and percent, mean, standard 
deviation and quartiles at each visit where measured.  Displays of results will be performed 
combining and stratifying by qualifying studies.  Details will be specified in a statistical 
analyses plan.
STUDY DESIGN:
This is a Phase 2/3, long term, open-label, follow-up study.  Subjects will have previously 
participated in qualifying/index JIA studies of tofacitinib.  Those who have already 
completed such participation and enroll outside the 14 day window following completion of 
the End of Study (EOS) Visit of the qualifying/index study will participate in a screening 
Visit to determine eligibility.  A Baseline Visit will then occur within 28 days after the 
Screening Visit.  For subjects who are completing participation in a qualifying study of 
tofacitinib and enrolling on the same day of the EOS Visit of the qualifying/index study, the 
EOS Visit of the qualifying/index study can be combined with the Screening and Baseline 
Visits for this study.  The subjects who enroll within the 14 day window following 
completion of the EOS Visit of the qualifying/index study will participate in a combined 
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Screening and Baseline Visit for this study.  After the Baseline Visit, visits will occur at 
1 month (1 month=30 days) and 3 months, then every 3 months thereafter as long as the 
subject remains in the study.
Approximately 340 participants are projected to enroll into this open label extension study 
after completing a qualifying/index study (ie, A3921103, A3921104 or A3921165) in the JIA 
program.
For subjects who entered this study from the A3921103 and A3921104 qualifying/index 
studies, their participation in this study ends after the first marketing approval of tofacitinib 
for the treatment of polyarticular course Juvenile Idiopathic Arthritis (pJIA) in any country. 
This study will end once the last subject, and all other subjects, who entered from study 
A3921165 have completed  approximately 1 year in this study, or after the first marketing 
approval of tofacitinib for the treatment of systemic JIA, whichever comes first.
The total duration of an individual subject’s participation may vary depending upon when 
they enter the trial. 
Applicable to Canadian Investigator Sites Only: The duration of subject participation will 
be restricted to a maximum of 3 years, unless, in the Investigator’s opinion, it is in the 
subject’s best interest to continue receiving tofacitinib (to be determined on a case-by-case 
basis and in consultation with the Sponsor).
Depending on local regulatory requirements, and as per the EU Voluntary Harmonisation 
Procedure (EU VHP), access to tofacitinib may be made available to patients after the 
conclusion of this study via, but not limited to, an expanded access/compassionate use 
program until either 1) commercially available for JIA; 2) no longer beneficial to a patient as 
determined by the treating investigator; 3) the benefit-risk for JIA is determined to be 
unfavorable; or 4) the sponsor’s application for marketing authorization is 
denied/disapproved for any reason by both US Food And Drug Administration (FDA) and 
European Medicines Agency (EMA).  
The Sponsor may continue to provide tofacitinib to patients benefitting from this treatment in 
situations where the patient cannot access treatment through typical post-approval channels.  
Availability of the oral solution formulation may be limited or discontinued when patients 
taking the oral solution have either discontinued treatment or have transitioned to use of the 
oral tablet formulation consistent with applicable weight based dosing guidance.
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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to Study Procedures (Section 6) 
and Assessments (Section 7) for detailed information on each procedure and assessment required for compliance with the protocol.
The Investigator may schedule visits (unplanned visits) in addition to those listed on the Schedule of Activities, in order to conduct 
evaluations or assessments required to protect the well-being of the subject. 
For Investigative Sites in Belgium Only: The degree of burden and the risk threshold should be assessed at each scheduled visit as 
outlined in Appendix 13.
For any visits impacted by public emergencies, including the COVID-19 pandemic, refer to Appendix 14 for additional guidance and 
instructions. 
Protocol Activity
Subjects 
>14 days after
EOS7 Visit
Combined
with EOS7
Visit
Separate
Visit within
14 days
after EOS7
Visit
Year 1
Months 1, 3, 
6, 9, 128
Years 2-5
Every 
3 Months8
Years 6-10
Every 3 months 
(except at 
Months 72, 84, 
96, 108, 120)8
Years 6-10
Months 72, 84, 
96, 108, 1208
End of Study 
/Early 
Termination
ScreeningBaseline
Screening 
/Baseline
Screening 
/Baseline
Informed Consent/Assent 
X
X
X
Medical History
X
Adverse Events (AE) assessment
Xd
Xd
Xd
Xd
X
X
X
X
X
Risk Factor Check for Venous 
Thromboembolism16
Xd
Xd
Xd
Xd
X
X
X
X
X
Prior/Concomitant Medications
X
X
X
X
X
X
X
X
Childhood Health Assessment 
Questionnaire (CHAQ)
X
X
X
X
X
X
Vital signs: Blood pressure (BP), Pulse 
Rate (PR), Temperature1
X
X
X
X
X
X
X
X
Complete Physical Exam15, 17
X
Xa
Xa
Xa
Xa
Targeted Physical Exam2, 17
X
X
X
X
X
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Protocol Activity
Subjects 
>14 days after
EOS7 Visit
Combined
with EOS7
Visit
Separate
Visit within
14 days
after EOS7
Visit
Year 1
Months 1, 3, 
6, 9, 128
Years 2-5
Every 
3 Months8
Years 6-10
Every 3 months 
(except at 
Months 72, 84, 
96, 108, 120)8
Years 6-10
Months 72, 84, 
96, 108, 1208
End of Study 
/Early 
Termination
ScreeningBaseline
Screening 
/Baseline
Screening 
/Baseline
Tanner Stage Assessment
Xb
(annually)b
(annually)b
(annually)b
Xb
Physician Global Evaluation of Disease 
Activity
X
X
X
X
X
X
X
X
Joint Assessment of Active Arthritis 
(Swelling, Pain/Tenderness) and 
Limitation of Motion
X
X
X
X
X
X
X
X
Duration of Morning Stiffness 
Assessment
X
X
X
X
X
X
X
X
Signs and symptoms of Systemic 
Disease (sJIA ONLY)
X
X
X
X
X
X
X
X
Assessment of JIA-associated Fever 
(sJIA ONLY)14
X
X
X
X
X
X
X
X
Tender Entheseal Assessment (ERA 
ONLY)11
X
X11
X11
X11
X
X
Modified Schober’s Test (ERA 
ONLY)11
X
X11
X11
X11
X
X
Overall Back Pain and Nocturnal Back 
Pain Assessment (ERA ONLY)11
X
X11
X11
X11
X
X
PGA of Psoriasis (PsA ONLY)12
X
X12
X12
X12
X
X
BSA affected by psoriasis (PsA 
ONLY)12
X
X12
X12
X12
X
X
Investigator ACR30 Response 
Assessment (Applicable to Canadian 
Investigator Sites Only)10
X10
X10
X10
X10
QuantiFERON or Mantoux PPD/Chest 
Radiograph, if Applicable3
X3
(annually)3
(annually)3
(annually)3
Safety Laboratory Testing4
X
X
X
X
X
X
X
X
Contraception checke
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Lipid Panel5
X
X5
X5
X
X
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Protocol Activity
Subjects 
>14 days after
EOS7 Visit
Combined
with EOS7
Visit
Separate
Visit within
14 days
after EOS7
Visit
Year 1
Months 1, 3, 
6, 9, 128
Years 2-5
Every 
3 Months8
Years 6-10
Every 3 months 
(except at 
Months 72, 84, 
96, 108, 120)8
Years 6-10
Months 72, 84, 
96, 108, 1208
End of Study 
/Early 
Termination
ScreeningBaseline
Screening 
/Baseline
Screening 
/Baseline
Human Immunodeficiency Virus (HIV) 
Serology, Hepatitis B, Hepatitis C9
X
C-Reactive Protein (CRP)
X
X
X
X
X
X
X
X
Erythrocyte Sedimentation Rate 
(ESR)-Westergren method13
X
X
X
X
X
X
X
X
Pharmacokinetic Sampling6
X
X
X
Uveitis Exam 
Xc
(annually)c
(annually)c
(annually)c
Xc
Investigation Product Dosing 
Compliance
X
X
X
X
X
Dispense/Collect Drug
X
X
X
X
X
X
X
X
1.
Temperature for all subjects, excluding those with sJIA: oral, tympanic or temporal methods preferred.  For subject with sJIA: temperature must be measured orally using a 
digital thermometer, with the exception of very young children or others who cannot tolerate an oral thermometer.  In these cases temperature may be measured rectally using 
a digital thermometer.  The definition of fever with a rectal thermometer is one degree Fahrenheit higher.  (Example >101.4F/38.6C rectally compared to >100.4F/38C 
orally).  See Section 7.1.10.1 for addition detail on the presence of absence of JIA-associated fever. 
2.
Targeted physical exam consists of weight, height, examination of heart, lungs, extremities for peripheral edema, abdomen and lymph nodes.  For children under 40 kg body 
weight obtained at study visits will be used to adjust dosing as the child grows.
3.
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; South Africa, India and Ukraine. (World Health Organization).  Subjects who enroll more than 14 days after their EOS Visit in their qualifying/index study must 
have a QuantiFERON-TB Gold or Gold Plus In-Tube test administered at screening and reported as negative in order to be eligible for enrollment in the study, unless one 
was performed and documented within the last 3 months.  Subjects having a Purified Protein Derivative (PPD) test must return within 48-72 hour for evaluation.  Annual TB 
screening will be conducted using QuantiFERON®-TB Gold or Gold Plus In-Tube test.  QuantiFERON® -TB Gold or Gold Plus In-Tube test is not performed in subjects who 
had positive result during prior testing (screening visit or prior annual visits) and/or who previously received adequate treatment for TB.  Sites must perform chest radiograph 
for TB status determination when subjects have a positive annual QFT-TB test for the first time.  For more information, including chest x-rays, refer to Section 7.2.2.
4.
Laboratory testing includes hematology (Complete Blood Count [CBC] with differential); Chemistry Panel includes urea nitrogen, creatinine, glucose, calcium, sodium, 
potassium, bicarbonate, chloride, total protein, total bilirubin, direct bilirubin, indirect bilirubin, alanine transferase (ALT), aspartate transferase (AST), alkaline phosphatase, 
gamma-glutamyl transferase (GGT), albumin, and creatine kinase (CK); urinalysis (U/A), and urine pregnancy test (βhCG) for females of childbearing potential.  Safety 
laboratory testing as appropriate for standard of care for subjects receiving background Disease-Modifying Antirheumatic Drugs (DMARDs.  In case of insufficient sample or 
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Protocol Activity
Subjects 
>14 days after
EOS7 Visit
Combined
with EOS7
Visit
Separate
Visit within
14 days
after EOS7
Visit
Year 1
Months 1, 3, 
6, 9, 128
Years 2-5
Every 
3 Months8
Years 6-10
Every 3 months 
(except at 
Months 72, 84, 
96, 108, 120)8
Years 6-10
Months 72, 84, 
96, 108, 1208
End of Study 
/Early 
Termination
ScreeningBaseline
Screening 
/Baseline
Screening 
/Baseline
issue on the sample quality (eg, hemolysis or clotting) the subject should return within 1 week for a new sample collection. Creatinine Clearance will be calculated at all study 
visits (see Appendix 5)
5.
Lipid panel (total cholesterol, direct Low Density Lipoprotein [LDL], indirect High Density Lipoprotein [HDL], apolipoprotein A-1 and B, and triglycerides) will be collected 
at the baseline visit for subjects who roll over more than 14 days after their End of Study (EOS) Visit for their qualifying/index study, every 6 months through year 5 and then 
every 12 months after year 5 for all subjects, and at the End of Study/Early Termination Visit.  Subjects should be instructed to fast for approximately 9 to 12 hours, if 
possible, prior to lipid panel testing.
6.
Pharmacokinetic (PK) blood samples will be collected at Month 12 and at approximately yearly intervals thereafter up to Month 36 (ie, Month 12, Month 24, Month 36).  
Samples will be collected at pre-dose and 0.5 hr (time window: 0.25-0.75 hr) and 2 hr (time window: 1.75-2.5 hr) post-dose.  PK samples will be collected at the End of 
study/Early Termination Visit up to Month 36; this collection may not be possible or feasible if drug has been discontinued prior to this visit; a comment should be included 
in the applicable PK CRF page.  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.  See Section 7.4 for details regarding PK sampling. PK blood samples will not be collected from participants in India.
7.
End of Study (EOS) Visit for the qualifying/index study.
8.
Visits will occur every 3 months after the Month 1 visit and throughout the study.  Visit windows: Months 1 and 3 Visits (5 days); Months 6 and subsequent visits 
(10 days). 
9.
Collected in all subjects who enroll more than 14 days after their EOS Visit for their qualifying/index study.  Hepatitis B: HBs Ag and HBc Ab are tested in all subjects who 
undergo a Screening visit.  HBs Ab is analyzed in subjects who test negative for HBsAg but positive for HBcAb.  If when tested, the HBsAb test is negative (surface antibody 
negative), the subject will be excluded from the study.  Hepatitis B testing will not be performed in subjects determined to be HBs Ab positive in their qualifying study.  
Hepatitis C: HCV RNA tested in case a positive HCV Ab result is obtained.  To conserve blood volume at screening, HCV RNA sample collection may be deferred and 
collected only if required to confirm eligibility based on the HCV Ab results.  See Section 7.2.9.
10. Applicable to Canadian Investigator Sites Only: Excluding the Month 1 visit, calculate the subject’s ACR30 response (see Section 7.1.6.1) at each visit.  Subjects with less 
than an ACR30 response at 2 consecutive visits, beginning with the Month 3 visit and anytime thereafter, should be discontinued from study treatment, unless in the opinion 
of the Investigator, it is in the subject’s best interest to continue receiving tofacitinib (to be determined on a case-by-case basis and in consultation with the Sponsor). 
11. Tender Entheseal Assessment, Modified Schober’s Test, and Overall Back Pain and Nocturnal Back Pain Assessment will be performed in subjects with Enthesitis Related 
Arthritis (ERA) ONLY at baseline visit for subjects who roll over more than 14 days after the EOS Visit for their qualifying/index study, at Month 3 Visit, Month 6 Visit, 
then every 6 months and at the End of study/Early Termination Visit for all subjects.
12. Physician’s Global Assessment (PGA) of Psoriasis, Body Surface Area (BSA) affected by psoriasis will be performed in subjects with Psoriatic Arthritis (PsA) ONLY at 
baseline visit for subjects who roll over more than 14 days after the EOS Visit for their qualifying/index study, at Month 3 Visit, Month 6 Visit, then every 6 months and at 
the End of study/Early Termination Visit for all subjects.
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Protocol Activity
Subjects 
>14 days after
EOS7 Visit
Combined
with EOS7
Visit
Separate
Visit within
14 days
after EOS7
Visit
Year 1
Months 1, 3, 
6, 9, 128
Years 2-5
Every 
3 Months8
Years 6-10
Every 3 months 
(except at 
Months 72, 84, 
96, 108, 120)8
Years 6-10
Months 72, 84, 
96, 108, 1208
End of Study 
/Early 
Termination
ScreeningBaseline
Screening 
/Baseline
Screening 
/Baseline
13. The Erythrocyte Sedimentation Rate (ESR) will be determined locally utilizing the Westergren method ESR which will be provided by the Sponsor or their local laboratory 
ESR Testing Kit (Westergren method). The ESR Testing Kit provided by the sponsor should be the preferred choice for ESR testing.  Every effort should be made to use the 
same ESR Testing Kit (whether provided by the sponsor or local) throughout the course of the study.  
14. For the definition of JIA-associated fever refer to Section 7.1.10.1.
15. Applicable to Investigative Sites in the United Kingdom (UK) and Belgium: a full skin cancer examination must be performed as part of the complete physical examination.
16. Per Amendment 10, all subjects will be asked at every study visit if they have any newly-developed risk factors for venous thromboembolism as described in Section 7.2.10).
17. Applicable only to participants enrolled from Study A3921165. A skin examination for the presence of varicella (chicken pox) and herpes zoster should be 
performed (see Appendix 16).
Frequency of assessments:  
a.
Complete physical exam is performed at Month 12 and every 12 months after Month 12 (ie, on yearly basis) in place of Targeted Physical Exam and at the End of 
Study/Early Termination Visit.
b.
Tanner stage is performed at Baseline Visit and annually thereafter.  No need to be repeated after the subject has reached Tanner Stage 5.
c.
Uveitis Exam by an ophthalmologist (or qualified equivalent per local practice) is performed at Screening (if no exam is done within past 6 months), then annually thereafter, 
and at End of study/Early Termination Visit.  If the exam was performed within the past 6 months the next uveitis exam should occur 1 year after the previous exam and 
annually thereafter.  The window for this particular examination is ±30 days relative to the visits where uveitis exam is performed (see Section 6.2 and Section 6.2.5 for 
additional details).  At all other visits the investigator should assess if there are potential changes in uveitis status and refer for formal evaluation if deemed clinically 
necessary.  For JIA subtypes that may require more frequent uveitis examination, investigators should manage this type of examination according to local standard of care.  
For subjects with sJIA, this exam is not required but if available, documentation of previous uveitis assessment(s) by an ophthalmologist (or qualified equivalent per local 
practice) should be reviewed, the date of the prior examination recorded, and the presence/absence of active uveitis documented.  
d.
Serious adverse events (SAEs) are captured from the time of informed consent at Screening.  For more information see Section 7.2.5.  Adverse events (AEs) are captured 
following the first dose of investigational product.
e.
The contraception check is an opportunity to confirm that contraception is used consistently and correctly.  Also, it is the opportunity to assess changing potential to
father/bear children and allows for implementing contraception and pregnancy testing as children mature physically and behaviorally during conduct of the study.
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TABLE OF CONTENTS
PROTOCOL SUMMARY.........................................................................................................7
SCHEDULE OF ACTIVITIES................................................................................................11
LIST OF TABLES...................................................................................................................21
LIST OF FIGURES .................................................................................................................21
APPENDICES .........................................................................................................................22
1. INTRODUCTION ...............................................................................................................23
1.1. Indication.................................................................................................................23
1.2. Background .............................................................................................................23
1.2.1. Study Rationale...........................................................................................23
1.2.2. Dose Rationale............................................................................................24
1.2.3. Single Reference Safety Document............................................................26
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................26
2.1. Objectives................................................................................................................26
2.1.1. Primary .......................................................................................................26
2.1.2. Secondary ...................................................................................................26
2.1.3. Exploratory .................................................................................................26
2.2. Endpoints.................................................................................................................27
2.2.1. Primary .......................................................................................................27
2.2.2. Secondary ...................................................................................................27
2.2.3. Exploratory .................................................................................................28
2.3. Benefit/Risk Assessment.........................................................................................28
2.3.1. Risk Assessment.........................................................................................28
2.3.2. Benefit Assessment.....................................................................................29
2.3.3. Overall Benefit/Risk Conclusion................................................................30
3. STUDY DESIGN.................................................................................................................31
4. SUBJECT SELECTION......................................................................................................32
4.1. Inclusion Criteria.....................................................................................................32
4.2. Exclusion Criteria....................................................................................................34
4.3. Life Style Guidelines...............................................................................................37
4.3.1. Contraception..............................................................................................37
4.3.2. Non-Pharmacologic Interventions..............................................................38
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4.3.3. Vaccine and Exposure to Infections Guidelines.........................................38
4.3.4. Elective Surgery..........................................................................................39
4.3.5. Dietary Supplements...................................................................................40
4.4. Sponsor Qualified Medical Personnel.....................................................................40
5. STUDY TREATMENTS.....................................................................................................40
5.1. Dosing Scheme........................................................................................................40
5.2. Allocation to Treatment ..........................................................................................41
5.2.1. Tofacitinib Temporary Withholding...........................................................41
5.3. Drug Supplies..........................................................................................................42
5.3.1. Formulation and Packaging........................................................................42
5.3.2. Preparation and Dispensing........................................................................42
5.3.3. Administration............................................................................................42
5.3.4. Compliance.................................................................................................42
5.4. Drug Storage and Drug Accountability...................................................................42
5.5. Concomitant Medication(s).....................................................................................43
5.5.1. Prohibited Medications And/Or Treatments...............................................44
5.5.2. Permitted Medications And/Or Treatments................................................44
5.5.2.1. Permitted Dose Adjustments in Background JIA 
Therapies (Worsening Disease).........................................................45
5.5.2.2. Permitted Dose Adjustments (Tapering) in Background 
JIA Therapies (Inactive Disease).......................................................45
5.5.2.3. Rescue Therapy.........................................................................45
6. STUDY PROCEDURES .....................................................................................................45
6.1. Screening and Baseline Visits.................................................................................45
6.1.1. Subjects Requiring Separate Screening and Baseline Visits......................45
6.1.1.1. Screening Visit ..........................................................................46
6.1.1.2. Baseline Visit ............................................................................47
6.1.2. Subjects with Combined End of Qualifying/Index Study Visit/LTE 
Screening/Baseline Visit..................................................................................49
6.1.3. Subjects with Separate End of Qualifying/Index Study Visit and 
Combined LTE Screening/Baseline Visit........................................................49
6.2. Study Period ............................................................................................................51
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6.2.1. Year 1: Months 1 and 3 Visits (Visit Window 5 Days); Months 6, 
9 and 12 Visits (Visit Window 10 Days).......................................................51
6.2.2. Years 2-5: Months 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 
54, 57, 60 Visits (Visit Window 10 Days).....................................................53
6.2.3. Years 6-10: Month 63, 66, 69, 75, 78, 81, 87, 90, 93, 99, 102, 105, 
111, 114, 117 Visits (Visit Window 10 Days)...............................................55
6.2.4. Years 6-10: Month 72, 84, 96, 108, 120 Visits (Visit Window 
10 Days).........................................................................................................57
6.2.5. End of Study Visit/Early Termination Visit ...............................................60
6.2.6. Subject Withdrawal ....................................................................................61
7. ASSESSMENTS..................................................................................................................62
7.1. Efficacy ...................................................................................................................62
7.1.1. Continued Disease Activity Assessment ....................................................63
7.1.2. Physician Global Evaluation of Disease Activity.......................................63
7.1.3. Joint Assessment.........................................................................................63
7.1.4. Childhood Health Assessment Questionnaire (CHAQ) .............................64
7.1.4.1. Parent’s Assessment of Physical Function (CHAQ 
Disability Index)................................................................................65
7.1.4.2. Parent’s Assessment of Child’s Arthritis Pain (CHAQ 
Discomfort Index) .............................................................................65
7.1.4.3. Parent’s Global Assessment of Overall Well-Being 
(CHAQ Subsection)...........................................................................65
7.1.5. Inflammatory Markers................................................................................66
7.1.5.1. C-Reactive Protein (CRP).........................................................66
7.1.5.2. Erythrocyte Sedimentation Rate (ESR).....................................66
7.1.6. JIA ACR Response and Flare Criteria........................................................66
7.1.6.1. JIA ACR Response Criteria ......................................................66
7.1.6.2. JIA ACR Flare Criteria .............................................................67
7.1.7. JIA ACR Clinical Inactive Disease Status Determination and 
Clinical Remission Criteria..............................................................................67
7.1.8. Juvenile Arthritis Disease Activity (JADAS 27- CRP and JADAS 
27- ESR) Score ................................................................................................68
7.1.9. JADAS 27 Minimal Disease Activity and Inactive Disease ......................68
7.1.10. Additional Assessments in Subjects with Systemic JIA...........................69
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7.1.10.1. Presence or Absence of JIA-associated Fever.........................69
7.1.11. Additional Assessments in Subjects with Enthesitis-Related 
Arthritis............................................................................................................69
7.1.11.1. Tender Entheseal Assessment .................................................69
7.1.11.2. Modified Schober’s Test .........................................................70
7.1.11.3. Overall Back Pain and Nocturnal Back Pain Assessment.......71
7.1.12. Additional Assessments in Subjects with Psoriatic Arthritis (PsA).........71
7.1.12.1. Body Surface Area (BSA).......................................................71
7.1.12.2. Physician’s Global Assessment (PGA) of Psoriasis ...............72
7.2. Safety.......................................................................................................................72
7.2.1. Blood Pressure, Pulse Rate and Temperature.............................................72
7.2.2. QuantiFERON-TB Gold or Gold-Plus In-Tube Test ...............................72
7.2.3. Tuberculin Test (PPD)................................................................................73
7.2.4. Radiograph of Chest ...................................................................................74
7.2.5. Uveitis Exam ..............................................................................................74
7.2.6. Macrophage Activation Syndrome (MAS) Markers (sJIA Only) ..............75
7.2.7. Physical Examination .................................................................................76
7.2.8. Assessment of Pubertal Development ........................................................76
7.2.9. Laboratory Tests .........................................................................................77
7.2.9.1. Blood Volume ...........................................................................79
7.2.10. Risk Factor Check for Venous Thromboembolism..................................79
7.3. Pregnancy Testing...................................................................................................80
7.4. Pharmacokinetic Sampling......................................................................................81
7.4.1. PK Sampling Time Points for All Subjects................................................81
7.4.2. Plasma for Analysis of Tofacitinib.............................................................81
7.4.3. Shipment of Pharmacokinetic Samples ......................................................81
8. ADVERSE EVENT REPORTING......................................................................................82
8.1. Adverse Events........................................................................................................82
8.2. Time Period and Frequency for collecting AE and SAE Information ....................82
8.3. Definition of an Adverse Event...............................................................................83
8.4. Medication Errors....................................................................................................83
8.4.1. Tofacitinib Overdosage ..............................................................................84
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8.5. Infections.................................................................................................................84
8.5.1. Serious Infections .......................................................................................84
8.5.2. Treated Infections.......................................................................................85
8.6. Abnormal Test Findings..........................................................................................85
8.7. Serious Adverse Events...........................................................................................85
8.7.1. Protocol-Specified Serious Adverse Events...............................................86
8.7.2. Potential Cases of Drug-Induced Liver Injury............................................86
8.8. Hospitalization ........................................................................................................87
8.9. Severity Assessment................................................................................................89
8.10. Causality Assessment............................................................................................89
8.11. Exposure During Pregnancy..................................................................................89
8.12. Occupational Exposure .........................................................................................91
8.13. Withdrawal Due to Adverse Events (See Also the Section 6.2.6  Subject 
Withdrawal)...............................................................................................................91
8.14. Eliciting Adverse Event Information ....................................................................91
8.15. Reporting Requirements........................................................................................91
8.15.1. Serious Adverse Event Reporting Requirements .....................................91
8.15.2. Non-Serious Adverse Event Reporting Requirements .............................92
8.15.3. Sponsor Reporting Requirements to Regulatory Authorities ...................92
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................92
9.1. Sample Size Determination.....................................................................................92
9.2. Efficacy Analysis ....................................................................................................93
9.2.1. Analysis of Primary Endpoint ....................................................................93
9.2.2. Analysis of Secondary Endpoints...............................................................93
9.3. Safety Analysis........................................................................................................93
9.4. PK Analysis.............................................................................................................94
9.5. Interim Analysis ......................................................................................................94
9.6. Data Safety Monitoring Board ................................................................................94
9.7. Safety Endpoint Adjudication Committees.............................................................94
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................95
11. DATA HANDLING AND RECORD KEEPING .............................................................96
11.1. Case Report Forms/Electronic Data Record .........................................................96
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11.2. Record Retention...................................................................................................96
12. ETHICS..............................................................................................................................97
12.1. Institutional Review Board (IRB)/ Ethics Committee (EC)..................................97
12.2. Ethical Conduct of the Study ................................................................................97
12.3. Subject Information and Consent/Assent..............................................................97
12.4. Subject Recruitment ..............................................................................................98
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................98
13. DEFINITION OF END OF TRIAL...................................................................................98
13.1. End of Trial in a Member State.............................................................................98
13.2. End of Trial in all Participating Countries ............................................................99
14. SPONSOR DISCONTINUATION CRITERIA ................................................................99
15. PUBLICATION OF STUDY RESULTS..........................................................................99
15.1. Communication of Results by Pfizer ....................................................................99
15.2. Publications by Investigators ..............................................................................100
16. REFERENCES ................................................................................................................101
LIST OF TABLES
Table 1.
Summary of Tofacitinib Pharmacokinetic Parameter Values (CV%) 
in JIA Subjects from Study A3921103.....................................................25
Table 2.
Study Treatment Dosing and Administration...........................................41
Table 3.
Laboratory Testing....................................................................................78
LIST OF FIGURES
Figure 1.
Modified Schober’s Test...........................................................................70
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APPENDICES
Appendix 1. Allowed And Disallowed Treatments for JIA ..................................................104
Appendix 2. Approximate Equivalent Morphine Doses of Opioid Analgesics.....................107
Appendix 3. Permitted Adjustments In JIA Therapies for Worsening Disease ....................108
Appendix 4. Permitted Adjustments (Tapering) of JIA Medications for Subjects with 
Inactive Disease for at Least 24 Weeks..................................................109
Appendix 5. Estimated Glomerular Filtration Rate (GFR) and Creatinine Clearance 
(CrCl) Calculations.................................................................................111
Appendix 6. Prohibited Concomitant Medications................................................................112
Appendix 7. Rescue Therapy.................................................................................................114
Appendix 8. Guidelines For Safety Monitoring And Discontinuations ................................116
Appendix 9. Evaluation Of Potentially Malignant Tumors, Suspicious 
Lymphadenopathy, Possible Extra-Nodal Lymphoproliferative 
Disorder (LPD) .......................................................................................119
Appendix 10. Body Surface Area ..........................................................................................120
Appendix 11. Physician’s Global Assessment Of Psoriasis..................................................121
Appendix 12. Dosing Scheme For Subjects Rolling Over From Study A3921103 Under 
Protocol Amendment 5...........................................................................123
Appendix 13. By Visit Assessment of the Degree of Burden and Risk Threshold 
During the Trial (Investigative Sites in Belgium Only) .........................124
Appendix 14. Alternative Measures During Public Emergencies .........................................125
Appendix 15. End of Study....................................................................................................128
Appendix 16. Varicella (chickenpox) and Herpes Zoster (shingles) Assessment and 
Guidance. (Applicable for subjects enrolled from A3921165 only) .......129
Appendix 17. Summary of Changes from Original Protocol through Amendment 11 .........130
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1. INTRODUCTION
1.1. Indication
Tofacitinib (also known as CP-690,550) is currently approved in the United States and more 
than 98 countries for the treatment of adult patients with moderately to severely active 
rheumatoid arthritis (RA) who have had an inadequate response or intolerance to 
methotrexate.  In adults, it is also approved for the treatment of psoriatic arthritis (PsA), 
ulcerative colitis and ankylosing spondylitis. It may be used in combination with 
methotrexate or other non biologic disease modifying antirheumatic drugs (DMARDs).  In 
the pediatric population, from 2 to less than 18 years of age, tofacitinib is approved for active 
polyarticular course JIA in the United States and polyarticular JIA and juvenile PsA in the 
EU.
1.2. Background
Tofacitinib is a potent, selective inhibitor of the 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, to a lesser extent TyK2.  In cellular settings where JAK kinases signal 
in pairs, tofacitinib preferentially inhibits signaling by heterodimeric receptors associated 
with JAK3 and/or JAK1 with functional selectivity over receptors that signal via pairs of 
JAK2.  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 -21.1,2,3 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 IFN .  
At higher exposures, inhibition of erythropoietin signaling could occur via inhibition of 
JAK2 signaling.
1.2.1. Study Rationale
The tofacitinib pediatric development program is designed to demonstrate both efficacy, as 
demonstrated by a reduction in signs and symptoms of JIA in subjects 2 years of age and 
older, and safety supporting the use of tofacitinib for the treatment of pediatric subjects with 
JIA.
The rationale of this study is to enable subjects potentially benefitting from treatment in a 
previous qualifying/index study to continue to receive tofacitinib at the same dose as the 
qualifying/index study (unless further analysis of the qualifying/index study data indicate 
otherwise), and to characterize long-term safety and tolerability of tofacitinib for the 
treatment of JIA.
It is anticipated that benefit of continued treatment with tofacitinib for individual subjects in 
this study will have been established in the qualifying/index study as per the Investigator’s 
assessment.  Potential risks of continued treatment are expected to be consistent with those 
described in the Single Reference Safety Document (current version of the tofacitinib 
Investigator Brochure).
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1.2.2. Dose Rationale
Selection of the 5 mg BID dose of tofacitinib for this long term extension (LTE) study of 
tofacitinib in JIA subjects is supported by pharmacokinetic (PK) data from the completed 
Phase 1 PK study of tofacitinib in JIA subjects (A3921103) and the benefit/risk profile of 
tofacitinib in adult RA subjects.
Tofacitinib clearance is not dependent on body weight for weights >40 kg based on 
tofacitinib PK in the adult RA population [body weight range of the population studied was 
40 kg-140 kg].  Thus the dose of tofacitinib in adolescents with body weight ≥40 kg was set 
to 5 mg twice a day (BID), the only approved dose of tofacitinib in adult RA subjects in most 
countries.  The doses for JIA subjects with lighter weight were selected to match the 
predicted steady state concentrations (Cavg,ss) in JIA subjects with body weight ≥40 kg after 
administration of a 5 mg BID dose.
Generally, for approved DMARDs in the treatment of JIA, partial extrapolation of efficacy 
from the adults to pediatrics is well accepted (Dunne et al, Pediatrics 2011).11 Thus, the dose 
range selected for JIA subjects across the weight-group is predicted to achieve Cavg,ss values 
equivalent to efficacious doses in adult RA population (between 3 to 5 mg BID dose). 
Due to lack of prior PK data for tofacitinib in the pediatric population, initial doses for the 
PK study (A3921103) were selected using allometric (weight-based) scaling of the adult 
PK parameters with an exponent of 0.75 (θ in Eq. 1 and 2).  For most small molecules, the 
relationship between clearance (CL) and body weight (BWT) is best described by a 
non-linear relationship; whereby clearance is commonly scaled to the 0.75 power of 
BWT and volume of distribution (V) is linearly correlated with BWT.  Following these 
principles, with Cavg,ss as the target, CL and dose were allometrically scaled and the exponent 
estimated (Eq. 1 and Eq. 2, respectively), assuming bioavailability (F) to be similar between 
adults and children.  These relationships were used to obtain pediatric doses that were 
expected to provide similar Cavg,ss to adult RA tofacitinib 5 mg BID dosing (assuming 70 kg 
BWT for an adults).
ܥܮሺ݌݁݀ሻ/ܨൌܥܮሺܽ݀ݑ݈ݐሻ/ܨൈቀ
஻ௐ்
଻଴ቁ
௾
Eq. 1
ܦ݋ݏ݁ሺ݌݁݀ሻൌܦ݋ݏ݁ሺܽ݀ݑ݈ݐሻൈቀ
஻ௐ்
଻଴ቁ
௾
Eq. 2
The PK study of tofacitinib in subjects with JIA has completed.  A total of 26 subjects 
between 2 and 17 years of age and weighing between 13.9 and 70.9 kg were dosed with 2 to 
5 mg BID doses of tofacitinib for 5 days in Study A3921103.  Pharmacokinetic evaluations 
were performed on Day 5 at pre-dose, 0.5, 1, 2, 4 and 8 hours.  Non-compartmental analysis 
(NCA) was performed on the PK profiles, and a summary of PK parameters is presented in
Table 1.
HDFF?$SSURYHG?$SSURYHG2Q0D\*07

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Table 1.
Summary of Tofacitinib Pharmacokinetic Parameter Values (CV%) in 
JIA Subjects from Study A3921103
Cohort
No. 
Subjects
Weight 
(Kg)
AUCtau
(ng·hr/mL)
Cmax
(ng/mL)
Tmax
(hr)
T1/2
(hr)
CL/F 
(L/hr)
Cohort 1
12 to 
<18 yrs
8
38.3-70.9
156.6 (25)
46.97 (40)
0.75 [0.5-6.9]
2.616 ± 
0.454
28.09 (22)
Cohort 2
6 to 
<12 yrs
9
20.3-48.9
118.8 (27)
41.67 (29)
1.0 [0.50-2.05]
1.949 ± 
0.294
25.48 (40)
Cohort 3
2 to 
<6 yrs
9
13.9-19.8
142.5 (32)
66.15 (28)
0.50 (0.50-1.92)
1.771 ± 
0.406
20.53 (33)
*Geometric Mean (CV%) for Area under the effect curve (AUCtau), Cmax, apparent clearance (CL/F) and arithmetic mean 
(±SD) for terminal half-life (T1/2); Median [range] for Time to Cmax (Tmax); Source: Table 14.1.2.1.1, date of table 
generation: 18 January 2016 (08:42) and Table 14.4.3.1.1, date of table generation: 02 February 2016 (05:22). 
The exposures from the first 16 subjects in Cohort 1 and Cohort 2 in Study A3921103 (as 
shown above) indicated higher CL/F values than predicted from Eq. 1 using an allometric 
component of 0.75 and thus resulting AUCtau,ss and Cmax,ss values 38-53% and 19-28% lower, 
respectively, as compared to adult RA subjects (252 ng·hr/mL and 58 ng/mL respectively; 
data on file).  However, due to higher doses administered in Cohort 3 (protocol was amended 
based on interim analysis of PK data from Cohorts 1 and 2 to target systemic exposure 
equivalent to 5 mg BID in adult rheumatoid arthritis [RA] subjects), AUCtau in Cohort 3 was 
comparable to Cohort 1 and higher than Cohort 2, and Cmax value was higher than both 
preceding cohorts. 
A population PK model was developed, and concentrations from the 26 JIA subjects enrolled 
in study A3921103 were fitted adequately using an one compartment model with first-order 
absorption (Ka) and linear elimination.  In this model, body weight was used as an allometric 
covariate to describe changes in CL/F and V/F with changes in weight and the exponents 
being estimated.  The estimated power exponents were 0.292 (%RSE: 40.1%) for CL/F and 
0.843 (%RSE: 12.3%) for V/F.  Similar to adult RA subjects, age, gender and race were not 
found to be significant covariates to describe inter-subject variability in tofacitinib CL/F or 
V/F.  Formulation (solution or tablets) was tested as a covariate for first order absorption 
constant, Ka , and was found to be not statistically significant.  Thus it was not included in 
the final model.
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Following model fitting, Monte Carlo simulations using the estimated population 
PK parameters and their inter individual variability were conducted to evaluate doses 
expected to provide Cavg,ss and Cmax,ss concentrations comparable to efficacious 
concentrations in adult RA subjects with maximum nominal dose capped at 5 mg BID.  With 
the current proposed dosing regimen (Section 5.1), the predicted Cavg,ss is similar to that of 
3-5 mg BID in adult RA subjects across the expected weight range, with Cmax,ss not 
exceeding that of 10 mg BID in most subjects.  Based on the results of the modeling using 
allometric scaling and the PK data from Study A3921103, it is expected that doses of 2 to 
5 mg BID (depending on body weight of the subjects), administered approximately 12 hours 
apart will provide safe and efficacious exposures of tofacitinib in this study (see Section 5.1
for the planned doses and regimens).
PK collection time points (see Section 7.4.1) in this study were decided based on optimal PK 
sampling design utilizing the population PK (POPPK) model built on data from A3921103. 
1.2.3. 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 Investigator’s 
Brochure.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary

The primary objective of this study is to determine the long term safety and 
tolerability of tofacitinib for treatment of the signs and symptoms of JIA.
2.1.2. Secondary

The secondary objective of this study is to evaluate the persistence of efficacy of 
tofacitinib for treatment of the signs and symptoms of JIA.
2.1.3. Exploratory
The exploratory objectives of this study are:

To assess tofacitinib pharmacokinetics (PK) in pediatric subjects on a stable dose of 
tofacitinib in the setting of a long-term, open label study.

To assess changes in PK parameters (within subject) with increase in weight in this 
pediatric population and to explore exposure-response relationships of tofacitinib for 
various efficacy and safety endpoints after long-term exposure of tofacitinib in this 
pediatric population.
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2.2. Endpoints
2.2.1. Primary

Standard laboratory safety data and adverse event (AE) reports.  Body weight, height 
and Tanner stages will be collected to assess growth and physical development.
2.2.2. Secondary 
The following efficacy parameters will be assessed:

Physician global evaluation of disease activity at each visit.

Number of joints with active arthritis at each visit.

Number of joints with limitation of motion at each visit.

Index of inflammation (C-reactive protein [CRP] and Erythrocyte Sedimentation Rate 
[ESR]) at each visit.

Childhood Health Assessment Questionnaire (CHAQ) at each visit.

Parent’s Assessment of Physical Function (CHAQ Disability Index).

Parent’s Assessment of Child’s Arthritis Pain (CHAQ Discomfort Index, Visual 
Analog Scale [VAS]). 

Parent’s Global Assessment of Overall Wellbeing (CHAQ subsection, Visual 
Analog Scale [VAS]).

JIA American College of Rheumatology (ACR) response at each visit and occurrence 
of JIA ACR disease flare after Month 3.

JIA ACR Clinical Inactive Disease status and Clinical Remission on Medication at 
each visit.

Change from baseline in Juvenile Arthritis Disease Activity Score (JADAS) 27- CRP 
and JADAS 27-ESR, and occurrence of JADAS minimum disease activity and 
inactive disease at each visit. 

Eligibility of tapering defined per protocol for corticosteroids, MTX/leflunomide, and 
tofacitinib.

In subjects with sJIA: “Absence of Fever”, defined as absence of fever due to sJIA in 
the week preceding the assessment at each visit.
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
In subjects with Enthesitis Related Arthritis (ERA): Change from baseline in the 
Tender Entheseal Assessment, Modified Schober’s Test, Overall Back Pain and 
Nocturnal Back Pain responses at various visits.

In subjects with psoriatic arthritis (PsA): Change from baseline in body surface area 
(BSA) affected by psoriasis and Physician’s Global Assessment (PGA) of psoriasis) 
at various visits.
2.2.3. Exploratory

Plasma concentration time data for tofacitinib will be analyzed to characterize the PK 
in this subject population.  Exposure-response relationship will be explored for 
various efficacy and safety endpoints after long-term exposure of tofacitinib.
2.3. Benefit/Risk Assessment
2.3.1. Risk Assessment
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, 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 
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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 7.8.1.2 (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 
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 
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(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, a Phase 3 study of tofacitinib in polyarticular JIA 
subjects (A3921104) was completed in 2019, and a Phase 3 efficacy, safety, tolerability and 
PK study of tofacitinib in sJIA subjects (A3921165) is on-going. 
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 
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. 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 (data cutoff 04 Jun 2019, data snapshot 03 Jul 2019) was conducted for 
Study A3921145. At the time of the 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 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 A3921145 provides an 
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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
This is a Phase 2/3, long term, open-label, follow-up study.  Subjects will have previously 
participated in qualifying/index study in the tofacitinib JIA program.  Those who have 
already completed such participation and enroll outside the 14 day window following 
completion of the End of Study (EOS) Visit of the qualifying/index study will participate in a 
Screening Visit to determine eligibility.  A Baseline Visit will then occur within 28 days after 
the Screening Visit.  For subjects who are completing participation in a qualifying study of 
tofacitinib and enrolling on the same day of the EOS Visit of the qualifying/index study, the 
EOS Visit of the qualifying/index study can be combined with the Screening and Baseline 
Visits for this study.  The subjects who enroll within the 14 day window following 
completion of the EOS Visit of the qualifying/index study will participate in a combined 
Screening and Baseline Visit for this study.  After the Baseline Visit, visits will occur at 
1 month (1 month=30 days) and 3 months, then every 3 months thereafter as long as the 
subject remains in the study.
Approximately 340 participants are projected to enroll into this open label extension study 
after completing a qualifying/index study (ie, A3921103, A3921104 or A3921165) in the JIA 
program.
For subjects who entered this study from the A3921103 and A3921104 qualifying/index 
studies, their participation in this study ends after the first marketing approval of tofacitinib 
for the treatment of polyarticular course Juvenile Idiopathic Arthritis (pJIA) in any country. 
This study will end once the last subject and all other subjects, who entered from study 
A3921165 have completed approximately 1 year in this study, or after the first marketing 
approval of tofacitinib for the treatment of systemic JIA, whichever comes first.
The total duration of an individual subject’s participation may vary depending upon when 
they entered the trial. 
Applicable to Canadian Investigator Sites Only: The duration of subject participation will 
be restricted to 3 years, unless, in the Investigator’s opinion, it is in the subject’s best interest 
to continue receiving tofacitinib (to be determined on a case-by-case basis and in 
consultation with the Sponsor).
Depending on local regulatory requirements, and as per the EU Voluntary Harmonisation 
Procedure (EU VHP), access to tofacitinib may be made available to patients after the 
conclusion of this study via, but not limited to, an expanded access/compassionate use 
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program until either 1) commercially available for JIA; 2) no longer beneficial to a patient as 
determined by the treating investigator; 3) the benefit-risk for JIA is determined to be 
unfavorable; or 4) the sponsor’s application for marketing authorization is 
denied/disapproved for any reason by both US FDA and EMA.  The Sponsor may continue 
to provide tofacitinib to patients benefitting from this treatment in situations where the 
patient cannot access treatment through typical post-approval channels. Availability of the 
oral solution formulation may be limited or discontinued when patients taking the oral 
solution have either discontinued treatment or have transitioned to use of the oral tablet 
formulation consistent with applicable weight based dosing guidance.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before subjects are included in the study.
All subjects must meet Inclusion Criteria 1-11 to be eligible for enrollment into the study:
1. Pediatric subjects with JIA aged from 2 to less than 18 years who met entry criteria 
for the qualifying/index study and in the opinion of the investigator have sufficient 
evidence of JIA disease activity to warrant use of tofacitinib as a DMARD.  Subjects 
turning 18 years of age during participation in the qualifying/index study or 
subsequently will be eligible for participation in this study.
2. The subject has discontinued disallowed concomitant medications for the required 
time prior to the first dose of study drug, as defined in Appendix 1 (Allowed and 
Disallowed Treatments for JIA), and is taking only those concomitant medications in 
doses and frequencies allowed by the protocol.
3. 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 be using a highly effective method of contraception as outlined in this 
protocol throughout the study and for at least 28 days after the last dose of study 
medication.
4. Subjects must have previously completed participation in a qualifying study of 
tofacitinib for the treatment of JIA.  Subjects who have required earlier 
discontinuation of treatment in a qualifying study for reasons other than tofacitinib 
related serious adverse events may be eligible.
5. For subjects receiving methotrexate (MTX) treatment, MTX may be administered 
either orally or parenterally at doses not to exceed 25 mg/week or 20 mg/m2/week, 
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whichever is lower.  Subjects taking methotrexate must be taking folic acid or folinic 
acid in accordance with local standards.
6. For subjects receiving an oral glucocorticoid, glucocorticoids may be administered at 
a maximum dose of 0.20 mg/kg/day or 10 mg/day, prednisone or equivalent, 
whichever is lower (intramuscular and intravenous corticosteroids are not permitted 
in the 4 weeks preceding the first dose of study medication and throughout the study).  
For subjects coming from the systemic JIA study A3921165, a higher prednisone-
equivalent dose may be continued or started (doses must be ≤1.0 mg/kg/day up to 
30 mg/day oral prednisone [or equivalent]). 
7. For subjects receiving leflunomide treatment, leflunomide may be administered 
according to the following dosing scheme: 

10 mg every other day for subjects weighing less than 20 kg;

10 mg every day for subjects weighing between 20 and 40 kg;

20 mg every day for subjects weighing over 40 kg;

Or as according to local standards.
8. For subjects receiving sulfasalazine, chloroquine, or hydroxychloroquine treatment, 
these medications may be administered according to local standards.
9. Evidence of a personally signed and dated informed consent document with assent as 
appropriate indicating that the subject (or a legally acceptable 
representative/parent(s)/legal guardian) has been informed of all pertinent aspects of 
the study.
10. Subjects who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
11. Subjects for whom, in the Investigator’s opinion, treatment with tofacitinib is 
considered clinically appropriate while also taking into consideration currently 
available therapies and prior response to these therapies. 
Subjects who enroll outside the 14 day window of the EOS Visit of their qualifying/index 
study must also meet Inclusion Criterion 12 to be eligible for enrollment into the study:
12. No evidence of active tuberculosis (TB) or inadequately treated tuberculosis 
(TB) infection (active or latent) as evidenced by all of the following: 
a.
A negative QuantiFERON-TB Gold or Gold Plus In-Tube test4 performed within 
the 3 months prior to screening.  A negative purified protein derivative (PPD) test 
with a result of <5 mm induration can be substituted for the QuantiFERON-TB 
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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. 
b. 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 (see 
Section 7.2.4).
c.
No history of either untreated or inadequately treated latent or active 
TB infection.
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®- Gold 
or Gold Plus test need be obtained.  A chest radiograph should be obtained if not 
done within the 3 months prior to screening (see Section 7.2.4).  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 (<5%) and documentation of an adequate treatment regimen. 
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
For subjects who enroll outside the 14 day window of the EOS Visit of their qualifying/index 
study (Exclusion 13-15):
1. Blood dyscrasias, including:
a.
Hgb <10 g/dL or Hct <33%; 
b. WBC <3.0 x 109/L;
c.
Neutrophil count <1.2 x 109/L;
d. Platelet count <100 x 109/L;
e.
Lymphocyte count of <0.75 x 109/L.
2. Estimated glomerular filtration rate [GFR] <40 mL/min/1.73 m2 calculated using 
Bedside Schwartz formula (Appendix 5) at the Screening Visit.
3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 1.5 times the 
upper limit of normal or any other clinically significant laboratory abnormality.
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For all subjects:
4. Persistent oligoarthritis and undifferentiated JIA.
5. Current or recent history of uncontrolled clinically significant renal, hepatic, 
hematological, gastrointestinal, endocrine, pulmonary, cardiac, or neurological 
disease.
6. History of any other rheumatic autoimmune disease, other than Sjogren’s syndrome.
7. History or current symptoms suggestive of any lymphoproliferative disorder, such as 
Epstein Barr Virus (EBV) related lymphoproliferative disorder, history of lymphoma, 
leukemia, or signs and symptoms suggestive of current lymphatic disease.
8. 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 visit. (excluding those treated 
with topicals only).
d. A subject known to be infected with human immunodeficiency virus (HIV), 
hepatitis B or hepatitis C virus.
e.
History of infected joint prosthesis with prosthesis still in situ.
9. History of recurrent (more than one episode) herpes zoster or a single episode of 
disseminated herpes zoster or a single episode of disseminated (both oral and genital 
lesions simultaneously, or widespread lesions not contained to oral or genital regions 
alone) herpes simplex.
10. Subjects taking potent and moderate cytochrome P450 3A4 (CYP3A4) inhibitors 
(Appendix 6).
11. Subjects taking potent and moderate CYP3A4 inducers (Appendix 6).
12. Participation in studies of investigational compounds (excluding qualifying/index 
study with tofacitinib) within 4 weeks or 5 half-lives (whichever is longer) prior to 
the first dose of study drug.  Subjects cannot participate in studies of other 
investigational compounds at any time during their participation in this study.  
Exposure to investigational biologics should be discussed with the Pfizer Medical 
Monitor.
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13. Any 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.
14. Pregnant or nursing females are excluded.
15. Intramuscular or intravenous corticosteroids in the 4 weeks preceding first dose of 
study medication (oral corticosteroids permitted as per inclusion criterion).
16. Subjects who have been vaccinated with live or attenuated vaccines within the 
6 weeks prior to the first dose of study medication.  All study participants should be 
up-to-date with respect to standard of care vaccinations (as defined by their country 
health ministry).  (See Life Style Guidelines for further information regarding 
avoidance of household contacts who may be vaccinated).
17. Use of prohibited prescription or nonprescription drugs and dietary supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
medication.
18. Herbal supplements must be discontinued at least 4 weeks prior to the first dose of 
study medication.
19. Subjects with a first degree relative with a hereditary immunodeficiency; IgA 
deficiency not exclusionary.
20. Subjects with a malignancy or with a history of malignancy with the exception of 
adequately treated or excised non-metastatic basal cell or squamous cell cancer of the 
skin or cervical carcinoma in situ.
21. Recent (within 28 days prior to first dose of study drug) significant trauma or major 
surgery.
22. Unwilling or unable to comply with the Life Style Guidelines described in this 
protocol.
23. 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. 
24. 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.
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25. Any factors or clinical characteristics potentially related to the risk of venous 
thromboembolism (see Section 7.2.10, 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.
26. History of allergies, intolerance or hypersensitivity to lactose or CP-690,550 
(tofacitinib), or any other excipients of the Investigational Medicinal Product.  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 investigator’s request.
4.3. Life Style Guidelines 
4.3.1. 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/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 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/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 partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following: 
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal) provided the subject 
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 (eg, EU), this option is 
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not appropriate.  (Note: In the UK and Belgium, a condom plus spermicide is not 
accepted as highly effective contraception).
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. 
Also, 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.
4.3.2. 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.  For 
subjects with psoriatic arthritis, refer to Section 5.5.2.
4.3.3. Vaccine and Exposure to Infections Guidelines
It is recommended that all study participants should be up-to-date with respect to standard of 
care vaccinations (as defined by their country health ministry) or JIA guidelines.  
Vaccination with live components (e.g. live attenuated influenza vaccine, MMR (measles, 
mumps, and rubella) vaccine, or MMR-V (measles, mumps, rubella and varicella) vaccine) is 
prohibited within the 6 weeks prior to first dose of study drug.  At the discretion of the 
investigator, subjects may be vaccinated with a live or live-attenuated vaccine at any time 
during the study only if tofacitinib is discontinued for a minimum of 6 weeks prior to 
vaccination and a minimum of 6 weeks after vaccination. 
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.
4.3.3.1 Varicella vaccination for participants enrolled from A3921165
Varicella vaccination is encouraged when appropriate, and if the participant is vaccinated, the 
first dose of study drug may not be administered until at least 4 weeks after vaccination. 
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For subjects who have not been vaccinated for varicella and did not have a positive VZV IgG 
Ab serology test at the A3921165 screening visit, 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 
Appendix 16 regarding the diagnosis and treatment of varicella and herpes zoster in study 
subjects.
4.3.3.2 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.
i.
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. 
ii.
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. 
iii.
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. 
iv.
Oral polio vaccine (OPV) should not be administered to individuals who live in a 
household with a study subject. 
v.
Study subjects should avoid handling diapers of infants who have been vaccinated 
with rotavirus vaccine for 4 week after vaccination. 
vi.
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 vaccinated or infected persons and contact the Investigator 
promptly should they develop signs and symptoms of infections.
4.3.4. 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 at least 
one week prior to the surgical procedure and remain off study medication after the surgical 
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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.
4.3.5. Dietary Supplements
For the purposes of this protocol, dietary supplements are defined as vitamins, minerals, 
purified food substances, and herbals with pharmaceutical properties.
Vitamins, minerals and purified food substances are allowed in amounts not known to be 
associated with adverse effects (such as hypervitaminosis).  Herbals must be discontinued for 
at least 4 weeks prior to first dose of study drug.
4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the study manual.
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, subjects are provided with an emergency contact card.  The card 
contains, at a minimum, protocol and investigational compound identifiers, subject study 
number, contact information for the investigational site and contact details for a help desk in 
the event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subjects participation in the study.  The help desk number can also be used by investigational 
staff if they are seeking advice on medical questions or problems, however it should only be 
used in the event that the established communication pathways between the investigational 
site and the study team are not available.  It is therefore intended to augment, but not replace 
the established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study.  The help desk 
number is not intended for use by the subject directly and if a subject calls that number they 
will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Dosing Scheme 
Oral solution (1 mg/mL concentration) will be used for subjects weighing <40 kg.  Oral 
tablets (5 mg) will be used for subjects weighing 40 kg; subjects who are unable to swallow 
tablets will have the option of taking oral solution.
Subjects will swallow study tablets whole and will not manipulate or chew tablets prior to 
swallowing.
Dosing cards with clear written instructions on how to properly take study medication will be 
provided to the parent/legal guardian/subject at the time study medication is dispensed.
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Tofacitinib will be administered orally BID (twice daily) approximately 12 hours (2 hours) 
apart, once in the morning and once in the evening, based on body weight as provided in the
Table 2 below.  Body weight will be assessed at each visit and entered into Interactive 
Response Technology (IRT) system; study drug dose will be dispensed based on the subject 
body weight.
Table 2.
Study Treatment Dosing and Administration
Body Weight (kg)
Dosage Regimen
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 
Important Note: For subjects rolling over from study A3921103 and actively participating in 
this study at the time of Protocol Amendment 6 and receiving a dosage of tofacitinib in 
accordance with the dosing scheme specified in Protocol Amendment 5 (see Appendix 12), 
investigators will have the option of maintaining the subject’s current dosage regimen from 
index study A3921103(if the desired clinical response has been attained with no safety 
concern) or adjusting the dosage regimen in accordance with the dosing scheme specified in 
this section.
5.2. Allocation to Treatment
Subjects will have previously participated in tofacitinib studies within the JIA program and 
will participate in a Screening Visit to determine eligibility. 
Eligible subjects will continue their dose regimen from the qualifying/index study until PK or 
efficacy/safety assessments are made based on the data from the qualifying/index study that 
may warrant dose modification.
5.2.1. Tofacitinib Temporary Withholding 
Dosage of tofacitinib may be temporarily discontinued for up to 28 consecutive days, for 
more severe cytopenias, 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.  Additionally, tofacitinib must be temporarily discontinued for a 
minimum of 6 weeks prior to giving live or live-attenuated vaccines.  Tofacitinib would then 
be restarted a minimum of 6 weeks after receiving the vaccine. Withholding of study drug is 
not necessary when administering non-live vaccines, including inactivated influenza vaccine 
and non-live COVID-19 vaccines.
Per Amendment 10, for subjects with suspected venous thromboembolism, treatment with 
tofacitinib should be temporarily withheld while the subject is evaluated.  If venous 
thromboembolism is confirmed, discontinue treatment with tofacitinib and withdraw the 
subject from the study (see Section 6.2.6: Subject Withdrawal).
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5.3. Drug Supplies 
5.3.1. Formulation and Packaging
CP-690,550-10, compound name for Tofacitinib Citrate, will be provided as tablets and as an 
oral solution by the Sponsor.  Tablets and solution will be supplied in bottles to the sites. 
5.3.2. Preparation and Dispensing
The study medication will be supplied in bottles.  The study medication will be packaged and 
labeled in such a manner that the subject and study staff will be able to determine the 
assigned treatment.  Study medication along with written dosing instructions will be
dispensed by a qualified study site staff member.
5.3.3. Administration
Tofacitinib should be administered orally, twice daily, approximately 12 hours apart, once in 
the morning and once in the evening.  Tofacitinib may be administered with or without food.  
If a tofacitinib dose is missed and the interval to the next scheduled dose is less than 6 hours, 
the missed dose of tofacitinib should not be administered; if a tofacitinib dose is missed and 
the interval to the next scheduled dose is more than 6 hours, the missed dose of tofacitinib 
should be administered as soon as possible.  Subjects should be instructed to document any 
missed doses.
5.3.4. Compliance
Subject compliance with dosing administration will be verified by accounting of returned 
containers and trial medication and will be captured in the source document at each visit.  
The subject dosing compliance should be within the range of 80% and 110% between two 
regularly scheduled study visits.  Subjects with noncompliance will be retrained to follow 
dosing instruction.  PLEASE NOTE: the protocol-allowed temporary discontinuation of 
study drug for SAEs/AEs, surgical procedures and other allowed reasons (see Section 5.2.1)
is not considered as noncompliance and a PD will not be recorded.
Subjects who demonstrate significant noncompliance, ie, 30% noncompliance between two 
regularly scheduled visits, both the subject and parent/legal guardian should be counseled by 
study staff to address reasons for noncompliance.  If after counseling the subject continues to 
exhibit significant noncompliance (ie, 30% noncompliance over two consecutive visits or 
over two nonconsecutive visits in 12-month time frame), then the subject should be 
withdrawn from the study. 
5.4. Drug Storage and Drug Accountability 
The investigator, or an approved representative (eg, Pharmacist), will ensure that study drug 
is stored in a secured (locked) area with restricted access under recommended storage 
conditions and in accordance with applicable regulatory requirements.
Storage conditions stated in the single reference safety document (SRSD) (ie, Investigator 
Brochure [IB], United States Package Insert [USPI], Summary of Product Characteristics 
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[SPC], or Local Product Document [LPD] will be superseded by the storage conditions stated 
on the investigational product label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure which 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 labeled storage 
conditions, as soon as possible.  Deviations from the storage requirements, including any 
actions taken, must be documented and reported to the sponsor.
Once an excursion is identified, the investigation 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 and parent/legal guardian on the storage requirements for take 
home medications including how to report temperature excursions. 
The investigator’s site must maintain adequate records documenting receipt, use, loss, or 
disposition of study drug supply.  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 study medication returned by the subjects.  At the end 
of the study, Pfizer will provide instructions as to disposition of any unused investigational 
product.  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.
All bottles must be returned to the investigator by the parent/legal guardian /subject, and the 
investigator will return the bottles to Pfizer.
5.5. Concomitant Medication(s)
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 that are 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.  All concomitant medication taken during the study must be recorded with 
indication, daily dose, and start and stop dates of administration. 
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5.5.1. Prohibited Medications And/Or Treatments
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 6, 
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.  Disallowed DMARDS and biologics are listed in 
Appendix 1. 
Herbal supplements must be discontinued for at least 4 weeks prior to first dose of study 
drug.
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.
Additional prohibited medications and/or treatment for subjects with PsA:

Ultraviolet B (UVB) (narrowband or broadband) phototherapy must be discontinued 
at least 2 weeks prior to first dose of study drug.  Psoralens + ultraviolet A (UVA) 
phototherapy (PUVA) must be discontinued at least 4 weeks prior to first dose of 
study drug. 

Oral and topical retinoids must be discontinued at least 2 weeks prior to first dose of 
study drug. 
5.5.2. Permitted Medications And/Or Treatments
Subjects will continue on their stable background arthritis therapy, which can include 
nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, 
allowed DMARDs (MTX, leflunomide, sulfasalazine, chloroquine, and hydroxychloroquine) 
(see Appendix 1), opioids (Appendix 2) and oral corticosteroids (0.20 mg/kg/day or 
10 mg/day, prednisone or equivalent, whichever is lower).  For subjects entering from the 
sJIA study, a higher prednisone-equivalent dose may be continued or started (doses must be 
≤1.0 mg/kg/day up to 30 mg/day oral prednisone [or equivalent]).  Subjects taking MTX 
during this trial must be taking folic acid or folinic acid according to local standards. 
Additional permitted medications for subjects with PsA:
The dose and type of the following may be adjusted at the discretion of the investigator:

Topical steroids and tar based shampoos on all regions;

Topical vitamin A or D analog preparations;

Anthralin.
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5.5.2.1. Permitted Dose Adjustments in Background JIA Therapies (Worsening 
Disease)
For subjects who experience worsening JIA symptoms refer to Appendix 3 for permitted 
adjustments in background JIA therapies. 
5.5.2.2. Permitted Dose Adjustments (Tapering) in Background JIA Therapies (Inactive 
Disease)
For subjects who experience improvement in JIA symptoms refer to Appendix 4 for 
permitted tapering of background JIA therapies.  See Section 7.1.7 for definition of inactive 
disease.
5.5.2.3. Rescue Therapy
Permitted rescue therapy can be found in Appendix 7.
6. STUDY PROCEDURES
For Investigative Sites in Belgium Only: The degree of burden and the risk threshold should 
be assessed at each scheduled visit as outlined in Appendix 13.
6.1. Screening and Baseline Visits
Subjects from qualifying/index tofacitinib studies who elect to participate should complete a 
combined Screening/Baseline Visit on the same day they end participation in the previous 
randomized tofacitinib study (EOS) or within 14 days to be eligible for rollover into 
A3921145.  Subjects enrolling outside the 14 day window will be required to participate in 
the full Screening Visit and Baseline Visit.
6.1.1. Subjects Requiring Separate Screening and Baseline Visits 
Subjects who do not roll over into this study from their qualifying/index study within the 
14-day window after their EOS in the qualifying/index study must participate in separate 
Screening and Baseline Visits to determine eligibility for enrollment in this study.
The study investigator or a sub-investigator will discuss, with each subject, the nature of the 
study, its requirements, and its restrictions.  Written informed consent must be obtained prior 
to performance of any protocol specific procedures. 
Subjects who are on prohibited medications and are deriving a beneficial response from them 
should not be entered into this study.  However, there may be subjects taking a prohibited 
medication who have experienced an ineffectual/suboptimal response or side effects and 
would consider entering the study.  These subjects may require a washout period that extends 
beyond the screening duration (See Section 5.5 Concomitant Medication(s)).  For these 
subjects written informed consent and a Study Subject Identification (SSID) number must be 
obtained prior to initiation of the washout period or, if washout has already begun for other 
reasons, upon decision that the study is an appropriate medical option.  In no instance should 
the informed consent be signed more than 3 months prior to the conduct of the screening 
procedures.
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6.1.1.1. Screening Visit
The following procedures and assessments will be performed for all subjects: 

Informed consent/Assent obtained.

Medical history: The medical history should include previous vaccination history (eg, 
varicella, influenza, and etc.), smoking status; average weekly alcohol consumption 
(if applicable) and family history of premature coronary heart disease (CHD).  
Premature coronary heart disease is defined as CHD in a male first-degree relative 
first observed at <55 years or CHD in female first-degree relative first observed at 
<65 years. 

Risk factor check for venous thromboembolism (see Section 7.2.10).

Document Prior medication ongoing or started since last visit in the qualifying/index 
study not exceeding the last 12 months.

Vital signs: temperature (oral, tympanic or temporal preferred), blood pressure (BP) 
and pulse rate (PR).  For subjects with sJIA: temperature must be measured orally 
using a digital thermometer, with the exception of very young children or others who 
cannot tolerate an oral thermometer.  In these cases temperature may be measured 
rectally using a digital thermometer.  The definition of fever with a rectal 
thermometer is one degree Fahrenheit higher.  (Example >101.4F/38.6C rectally 
compared to >100.4F/38C orally).

Complete physical examination, including height and weight measurements. 
(Applicable to Investigative Sites in the UK and Belgium: a full skin cancer 
examination must be performed as part of the complete physical examination.
Applicable to subjects enrolled from Study A3921165: a skin examination for 
chicken pox or shingles must be performed).

Physician global evaluation of disease activity.

Joint assessment of active arthritis (swelling, pain/tenderness), and limitation of 
motion.

Duration of morning stiffness.

QuantiFERON- TB Gold or Gold Plus In-Tube test or Mantoux Purified Protein 
Derivative (PPD) skin test where applicable and/or chest radiograph where applicable 
(unless done in the prior 3 months).  If the Mantoux PPD tuberculin skin test is done, 
the subject must return 48-72 hours post test for evaluation.

Safety laboratory testing: this includes hematology, urinalysis, chemistry panel, 
estimated GFR (Appendix 5), urine pregnancy test (-hCG, female of childbearing 
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potential only), HIV Serology, Hepatitis B (HBsAg, HBc Ab and if needed, HBs Ab), 
Hepatitis C (HCVAb and if needed, HCV RNA). 

C-reactive protein (CRP).

Erythrocyte sedimentation rate (ESR) determination (Westergren method).

Confirm highly effective contraception is being used. 

Referred for uveitis exam by an ophthalmologist (or qualified equivalent per local 
practice) if not done within previous 6 months.  For subjects with sJIA, this exam is 
not required, but if available documentation of previous uveitis assessment(s) by an 
ophthalmologist (or qualified equivalent per local practice) should be reviewed, the 
date of the prior exam recorded, and the presence/absence of active uveitis 
documented.

Serious Adverse Event reporting.

To prepare for study participation, subjects and their legally acceptable 
representative/parent(s)/legal guardians will be instructed on the use of the Life Style 
Guidelines and Concomitant Medication(s) sections of the protocol.
sJIA subjects ONLY: 

Assessment of JIA-associated fever: Fever is defined as temperature >38C/100.4F).  
Refer to Section 7.1.10.1 for details.

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 7.2.9 for details regarding 
these blood sample collections.

Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA.
6.1.1.2. Baseline Visit
Baseline visit will take place 2-28 days after Screening.  The following procedures and 
assessments will be performed for all subjects unless otherwise indicated:

AE assessment. 

Risk factor check for venous thromboembolism (see Section 7.2.10).

Document concomitant medications taken since Screening Visit.

Childhood Health Assessment Questionnaire (CHAQ).
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
Vital signs: temperature (oral, tympanic or temporal preferred), BP and PR.  For 
subjects with sJIA: temperature must be measured orally using a digital thermometer, 
with the exception of very young children or others who cannot tolerate an oral 
thermometer.  In these cases temperature may be measured rectally using a digital 
thermometer.  The definition of fever with a rectal thermometer is one degree 
Fahrenheit higher.  (Example >101.4F/38.6C rectally compared to >100.4F/38C 
orally).

Targeted physical examination, including height and weight measurements.
(Applicable to subjects enrolled from Study A3921165: a skin examination for 
chicken pox or shingles must be performed)

Tanner stage assessment.

Physician global evaluation of disease activity.

Joint assessment of active arthritis (swelling, pain/tenderness), and limitation of 
motion.

Duration of morning stiffness.

Safety laboratory testing (chemistry, hematology, urinalysis), including urine 
pregnancy testing (-hCG) for females of child-bearing potential. 

Confirm highly effective contraception is being used. 

Lipid panel (total cholesterol, indirect LDL (low-density lipoprotein), direct HDL 
(high-density lipoprotein), apolipoprotein A-1 and B, triglycerides).
** Important Note ** Subjects should be instructed to fast (for 9 to 12 hours prior 
the scheduled visit), if possible, for lipid panel testing.

CRP.

ESR determination (Westergren method).

Dispense study medication and provide dosing instructions/schedule next visit.
sJIA subjects ONLY:

Assessment of JIA-associated fever: Fever is defined as temperature >38C/100.4F).  
Refer to Section 7.1.10.1 for details.

MAS diagnosis: Only if subject has fever and Macrophage Activation Syndrome 
(MAS) is suspected: obtain blood samples to evaluate ferritin, platelets, 
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triglycerides and fibrinogen levels.  Refer to Section 7.2.9 for details regarding 
these blood sample collections.

Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA.
ERA subjects ONLY:

Tender Entheseal Assessment.

Modified Schober’s Test.

Overall Back Pain.

Nocturnal Back Pain Assessment. 
PsA subjects ONLY:

Body surface area (BSA) with psoriasis rash.

Physician’s Global Assessment (PGA) for psoriasis.
6.1.2. Subjects with Combined End of Qualifying/Index Study Visit/LTE 
Screening/Baseline Visit
Subjects who complete their combined Screening/Baseline Visit on the same day as EOS in 
the qualifying/index tofacitinib study must also complete the following procedures:

Informed consent/Assent obtained.

AE assessment.

Risk factor check for venous thromboembolism (see Section 7.2.10).

Confirm highly effective contraception is being used. 

Dispense study medication and provide dosing instructions/schedule next visit.
6.1.3. Subjects with Separate End of Qualifying/Index Study Visit and Combined LTE 
Screening/Baseline Visit 
Subjects who complete their combined Screening/Baseline Visit within 14 days of EOS in 
the qualifying/index tofacitinib study but not on the same day as EOS must complete the 
following procedures at the combined Screening/Baseline Visit:

Informed consent/Assent obtained.

AE assessment. 
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
Risk factor check for venous thromboembolism (see Section 7.2.10).

Concomitant medications (ongoing or started since last visit in qualifying/index 
study).

Vital signs: temperature (oral, tympanic or temporal preferred), BP and PR.  For 
subjects with sJIA: temperature must be measured orally using a digital thermometer, 
with the exception of very young children or others who cannot tolerate an oral 
thermometer.  In these cases temperature may be measured rectally using a digital 
thermometer.  The definition of fever with a rectal thermometer is one degree 
Fahrenheit higher.  (Example >101.4F/38.6C rectally compared to >100.4F/38C 
orally). 

Targeted physical exam, including weight and height.
(Applicable to subjects enrolled from Study A3921165: a skin examination for 
chicken pox or shingles must be performed). 

Physician global evaluation of disease activity.

Joint assessment of active arthritis (swelling, pain/tenderness), and limitation of 
motion.

Duration of morning stiffness.

Safety laboratory testing (chemistry, hematology, urinalysis), including urine 
pregnancy testing (-hCG) for females of child-bearing potential.

Confirm highly effective contraception is being used. 

CRP.

ESR determination (Westergren Method).

Dispense study medication and provide dosing instructions/schedule next visit.
sJIA subjects ONLY:

Assessment of JIA-associated fever: Fever is defined as temperature >38C/100.4F).  
Refer to Section 7.1.10.1 for details.

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 7.2.9 for details regarding 
these blood sample collections.
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
Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA.Assess Flare: 
Refer to Flare Criteria in Section 7.1.6.2.
6.2. Study Period
6.2.1. Year 1: Months 1 and 3 Visits (Visit Window 5 Days); Months 6, 9 and 12 Visits 
(Visit Window 10 Days)
The following procedures and assessments will be performed for all subjects unless 
otherwise indicated:

AE assessment. 

Risk factor check for venous thromboembolism (see Section 7.2.10).

Document concomitant medications (ongoing or started since previous visit).

Childhood Health Assessment Questionnaire (CHAQ).

Vital signs: temperature (oral, tympanic or temporal preferred), BP and PR.  For 
subjects with sJIA: temperature must be measured orally using a digital thermometer, 
with the exception of very young children or others who cannot tolerate an oral 
thermometer.  In these cases temperature may be measured rectally using a digital 
thermometer.  The definition of fever with a rectal thermometer is one degree 
Fahrenheit higher.  (Example >101.4F/38.6C rectally compared to >100.4F/38C 
orally).

Physical examination: Targeted physical examination is done at Months 1-9.  
Complete physical examination is done at Month 12.  (Applicable to Investigative 
Sites in the UK and Belgium: a full skin cancer examination must be performed as 
part of the complete physical examination. Applicable to subjects enrolled from 
Study A3921165: a skin examination for chicken pox or shingles must be performed
as part of the complete or targeted physical examination).

Tanner stage assessment (Month 12 only).

Physician global evaluation of disease activity.

Joint assessment of active arthritis (swelling, pain/tenderness), and limitation of 
motion.

Duration of morning stiffness.

QuantiFERON® Gold or Gold Plus In-Tube Test (QFT) is performed annually ONLY 
for subject enrolled in countries where TB incidence has been reported at a rate of 
>50 cases per 100,000 persons, eg, China, Russian Federation; South Africa, India
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and Ukraine. (World Health Organization).  Sites must perform chest radiograph for 
TB status determination when subjects have a positive annual QFT-TB test for the 
first time.  Refer to Section 7.2.2 for further guidance.

Safety laboratory testing (chemistry, hematology, urinalysis), including urine 
pregnancy testing (-hCG) for females of child-bearing potential.

Confirm highly effective contraception is being used.

Lipid panel (total cholesterol, indirect LDL, direct HDL, apolipoprotein A-1 and B, 
triglycerides) done at Months 6 and 12.
** Important Note ** Subjects should be instructed to fast (for 9 to 12 hours prior 
the scheduled visit), if possible, for lipid panel testing at Month 6 and Month 
12 visits.

CRP.

ESR determination (Westergren method).

PK blood samples (pre-dose, and post dose at 0.5 hr [time window: 0.25-0.75 hr] and 
2 hr [time window: 1.75-2. 5 hr]) obtained at Month 12.
** Important Note ** Subject and parent/legal guardian should be instructed 
that the subject should NOT take the morning dose at home.  The subject’s 
morning dose will be taken at the study site after pre-dose PK sampling.

Uveitis exam performed by an ophthalmologist (or qualified equivalent per local 
practice) annually beginning 1 year after the previous exam (the window for this 
particular examination is ±30 days).  Refer to Section 7.2.5 for further guidance.

Assess investigational product dosing compliance.

Dispense/collect study medication/schedule next visit.
sJIA subjects ONLY: 

Assessment of JIA-associated fever: Fever is defined as temperature >38C/100.4F).  
Refer to Section 7.1.10.1 for details.

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 7.2.9 for details regarding 
these blood sample collections.

Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA.
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ERA subjects ONLY (Months 3, 6, and 12): 

Tender Entheseal Assessment.

Modified Schober’s Test.

Overall Back Pain.

Nocturnal Back Pain Assessment. 
PsA subjects ONLY (Months 3, 6, and 12): 

Body surface area (BSA) with psoriasis rash.

Physician’s Global Assessment (PGA) for psoriasis.
Applicable to Canadian Investigator Sites Only: Excluding the Month 1 visit, calculate the 
subject’s ACR30 response (see Section 7.1.6.1) at each visit.  Subjects with less than an 
ACR30 response at 2 consecutive visits, beginning with the Month 3 visit and anytime 
thereafter, should be discontinued from study treatment, unless, in the opinion of the 
Investigator, it is in the subject’s best interest to continue receiving tofacitinib (to be 
determined on a case-by-case basis and in consultation with the Sponsor). 
6.2.2. Years 2-5: Months 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 Visits 
(Visit Window 10 Days)
The following procedures and assessments will be performed: 

AE assessment. 

Risk factor check for venous thromboembolism (see Section 7.2.10).

Document concomitant medications (ongoing or started since previous visit).

Childhood Health Assessment Questionnaire (CHAQ).

Vital signs: temperature (oral, tympanic or temporal preferred), BP and PR.  For 
subjects with sJIA: temperature must be measured orally using a digital thermometer, 
with the exception of very young children or others who cannot tolerate an oral 
thermometer.  In these cases temperature may be measured rectally using a digital 
thermometer.  The definition of fever with a rectal thermometer is one degree 
Fahrenheit higher.  (Example >101.4F/38.6C rectally compared to >100.4F/38C 
orally).

Physical examination: Complete physical examination is done annually (ie, 
Months 24, 36, 48, and 60).  Targeted physical examination is done at all other visits 
(ie, Months 15, 18, 21, 27, 30, and etc.).  (Applicable to Investigative Sites in the 
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UK and Belgium: a full skin cancer examination must be performed as part of the 
complete physical examination. Applicable to subjects enrolled from Study 
A3921165: a skin examination for chicken pox or shingles must be performed as part 
of the complete or physical examination).

Tanner stage assessment (Months 24, 36, 48 and 60).

Physician global evaluation of disease activity.

Joint assessment of active arthritis (swelling, pain/tenderness), and limitation of 
motion.

Duration of morning stiffness.

QuantiFERON® Gold or Gold Plus In-Tube test (QFT) performed annually: ONLY 
for subjects enrolled in countries where TB incidence has been reported at a rate of 
>50 cases per 100,000 persons, eg, China, Russian Federation; South Africa, India 
and Ukraine. (World Health Organization).  Sites must perform chest radiograph for 
TB status determination when subjects have a positive annual QFT-TB test for the 
first time.  Refer to Section 7.2.2 for further guidance.

Safety laboratory testing (chemistry, hematology, urinalysis), including urine 
pregnancy testing (-hCG) for females of child-bearing potential.

Confirm highly effective contraception is being used.

Lipid panel (total cholesterol, indirect LDL, direct HDL, apolipoprotein A-1 and B, 
triglycerides) done at Months 18, 24, 30, 36, 42, 48, 54, and 60.
** Important Note ** Subjects should be instructed to fast (for 9 to 12 hours prior 
the scheduled visit), if possible, for lipid panel testing.

CRP.

ESR determination (Westergren method).

PK blood samples (pre-dose, and post dose at 0.5 hr [time window: 0.25-0.75 hr] and 
2 hr [time window: 1.75-2. 5 hr]) obtained at Months 24 and 36. 
** Important Note ** Subject and parent/legal guardian should be instructed that 
the subject should NOT take the morning dose at home.  The subject’s morning 
dose will be taken at the study site after pre-dose PK sampling.

Uveitis exam performed by an ophthalmologist (or qualified equivalent per local 
practice) annually (the window for this particular examination is ±30 days).  Refer to 
Section 7.2.5 for further guidance.
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
Assess investigational product dosing compliance.

Dispense/collect study medication/schedule next visit.
sJIA subjects ONLY: 

Assessment of JIA-associated fever: Fever is defined as temperature >38C/100.4F).  
Refer to Section 7.1.10.1 for details:

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 7.2.9.1 for details regarding 
these blood sample collections.

Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA.
ERA subjects ONLY (Months 18, 24, 30, 36, 42, 48, 54, and 60):

Tender Entheseal Assessment.

Modified Schober’s Test.

Overall Back Pain.

Nocturnal Back Pain Assessment. 
PsA subjects ONLY (Months 18, 24, 30, 36, 42, 48, 54, and 60): 

Body surface area (BSA) with psoriasis rash.

Physician’s Global Assessment (PGA) for psoriasis.
Applicable to Canadian Investigator Sites Only: Calculate the subject’s ACR30 response 
(see Section 7.1.6.1) at each visit.  Subjects with less than an ACR30 response for 
2 consecutive visits, beginning with the Month 3 visit and anytime thereafter, should be 
discontinued from study treatment, unless, in the opinion of the Investigator, it is in the 
subject’s best interest to continue receiving tofacitinib (to be determined on a case-by-case 
basis and in consultation with the Sponsor).
6.2.3. Years 6-10: Month 63, 66, 69, 75, 78, 81, 87, 90, 93, 99, 102, 105, 111, 114, 
117 Visits (Visit Window 10 Days)
The following procedures and assessments will be performed:

AE assessment. 

Risk factor check for venous thromboembolism (see Section 7.2.10).
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
Document concomitant medications (ongoing or started since previous visit).

Childhood Health Assessment Questionnaire (CHAQ).

Vital signs: temperature (oral, tympanic or temporal preferred), BP and PR.  For 
subjects with sJIA: temperature must be measured orally using a digital thermometer, 
with the exception of very young children or others who cannot tolerate an oral 
thermometer.  In these cases temperature may be measured rectally using a digital 
thermometer.  The definition of fever with a rectal thermometer is one degree 
Fahrenheit higher.  (Example >101.4F/38.6C rectally compared to >100.4F/38C 
orally).

Targeted physical examination. 
(Applicable to subjects enrolled from Study A3921165: a skin examination for 
chicken pox or shingles must be performed).

Physician global evaluation of disease activity.

Joint assessment of active arthritis (swelling, pain/tenderness), and limitation of 
motion.

Duration of morning stiffness.

QuantiFERON® Gold or Gold Plus In-Tube test (QFT) performed annually: ONLY 
for subjects enrolled in countries where TB incidence has been reported at a rate of 
>50 cases per 100,000 persons, eg, China, Russian Federation; South Africa, India
and Ukraine. (World Health Organization).  For subjects who have a positive annual 
QFT-TB for the first time, sites must perform chest radiograph for TB status 
determination.  Refer to Section 7.2.2 for further guidance.

Safety laboratory testing (chemistry, hematology, urinalysis), including urine 
pregnancy testing (-hCG) for females of child-bearing potential.

Confirm highly effective contraception is being used.

CRP.

ESR determination (Westergren method).

Assess investigational product dosing compliance.

Dispense/collect study medication.
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sJIA subjects ONLY: 

Assessment of JIA-associated fever: Fever is defined as temperature >38C/100.4F 
Refer to Section 7.1.10.1 for details.

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 7.2.9 for details regarding 
these blood sample collections.

Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA.
ERA subjects ONLY (Months 66, 78, 90, 102, and 114):

Tender Entheseal Assessment.

Modified Schober’s Test.

Overall Back Pain.

Nocturnal Back Pain Assessment. 
PsA subjects ONLY (Months 66, 78, 90, 102, and 114): 

Body surface area (BSA) with psoriasis rash.

Physician’s Global Assessment (PGA) for psoriasis.
Applicable to Canadian Investigator Sites Only: Calculate the subject’s ACR30 response 
(see Section 7.1.6.1) at each visit.  Subjects with less than an ACR30 response for 
2 consecutive visits, beginning with the Month 3 visit and anytime thereafter, should be 
discontinued from study treatment, unless, in the opinion of the Investigator, it is in the 
subject’s best interest to continue receiving tofacitinib (to be determined on a case-by-case 
basis and in consultation with the Sponsor).
6.2.4. Years 6-10: Month 72, 84, 96, 108, 120 Visits (Visit Window 10 Days)
The following procedures and assessments will be performed: 

AE assessment.

Risk factor check for venous thromboembolism (see Section 7.2.10).

Document concomitant medications (ongoing or started since previous visit).

Childhood Health Assessment Questionnaire (CHAQ).
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
Vital signs: temperature (oral, tympanic or temporal preferred), BP and PR.  For 
subjects with sJIA: temperature must be measured orally using a digital thermometer, 
with the exception of very young children or others who cannot tolerate an oral 
thermometer.  In these cases temperature may be measured rectally using a digital 
thermometer.  The definition of fever with a rectal thermometer is one degree 
Fahrenheit higher.  (Example >101.4F/38.6C rectally compared to >100.4F/38C 
orally).

Complete physical examination.  (Applicable to Investigative Sites in the UK and 
Belgium: a full skin cancer examination must be performed as part of the complete 
physical examination. Applicable to subjects enrolled from Study A3921165: a 
skin examination for chicken pox or shingles must be performed). 

Tanner stage assessment.

Physician global evaluation of disease activity.

Joint assessment of active arthritis (swelling, pain/tenderness), and limitation of 
motion.

Duration of morning stiffness.

QuantiFERON® Gold or Gold Plus In-Tube test (QFT) performed annually: ONLY 
for subjects enrolled in countries where TB incidence has been reported at a rate of 
>50 cases per 100,000 persons, eg, China, Russian Federation; South Africa, India
and Ukraine. (World Health Organization).  Sites must perform chest radiograph for 
TB status determination when subjects have a positive annual QFT-TB test for the 
first time.  Refer to Section 7.2.2 for further guidance.

Safety laboratory testing (chemistry, hematology, urinalysis), including urine 
pregnancy testing (-hCG) for females of child-bearing potential.

Confirm highly effective contraception is being used.

Lipid panel (cholesterol, indirect LDL, direct HDL, apolipoprotein A-1 and B, 
triglycerides). 
** Important Note ** Subjects should be instructed to fast (for 9 to 12 hours prior 
the scheduled visit), if possible, for lipid panel testing.

CRP. 

ESR determination (Westergren method).
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
Uveitis exam performed by an ophthalmologist (or qualified equivalent per local 
practice) annually (the window for this particular examination is ±30 days).  Refer to 
Section 7.2.5 for further guidance.

Assess investigational product dosing compliance.

Dispense/collect study medication/schedule next visit.
sJIA subjects ONLY:

Assessment of JIA-associated fever: Fever is defined as temperature >38C/100.4F).  
Refer to Section 7.1.10.1 for details.

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 7.2.9 for details regarding 
these blood sample collections.

Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA.
ERA subjects ONLY:

Tender Entheseal Assessment.

Modified Schober’s Test.

Overall Back Pain.

Nocturnal Back Pain Assessment. 
PsA subjects ONLY: 

Body surface area (BSA) with psoriasis rash.

Physician’s Global Assessment (PGA) for psoriasis.
Applicable to Canadian Investigator Sites Only: Calculate the subject’s ACR30 response 
(see Section 7.1.6.1) at each visit.  Subjects with less than an ACR30 response for 
2 consecutive visits, beginning with the Month 3 visit and anytime thereafter, should be 
discontinued from study treatment, unless, in the opinion of the Investigator, it is in the 
subject’s best interest to continue receiving tofacitinib (to be determined on a case-by-case 
basis and in consultation with the Sponsor).
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6.2.5. End of Study Visit/Early Termination Visit
The following procedures and assessments will be performed:

AE assessment. 

Risk factor check for venous thromboembolism (see Section 7.2.10).

Document concomitant medications (ongoing or started since previous visit).

Childhood Health Assessment Questionnaire (CHAQ).

Vital signs: temperature (oral, tympanic or temporal preferred), BP and PR.  For 
subjects with sJIA: temperature must be measured orally using a digital thermometer, 
with the exception of very young children or others who cannot tolerate an oral 
thermometer.  In these cases temperature may be measured rectally using a digital 
thermometer.  The definition of fever with a rectal thermometer is one degree 
Fahrenheit higher.  (Example >101.4F/38.6C rectally compared to >100.4F/38C 
orally).
Complete physical examination.  (Applicable to Investigative Sites in the UK and 
Belgium: a full skin cancer examination must be performed as part of the complete 
physical examination. Applicable to subjects enrolled from Study A3921165: a 
skin examination for chicken pox or shingles must be performed). 

Tanner stage assessment.

Physician global evaluation of disease activity.

Joint assessment of active arthritis (swelling, pain/tenderness), and limitation of 
motion.

Duration of morning stiffness.

Safety laboratory testing (chemistry, hematology, urinalysis), including urine 
pregnancy testing (-hCG) for females of child-bearing potential.

Confirm highly effective contraception is being used.

Please note: Subjects must use contraception consistently and correctly for at least 
28 days after the last dose of investigational product.

Lipid panel (cholesterol, indirect LDL, direct HDL, apolipoprotein A-1 and B, 
triglycerides).
** Important Note ** Subjects should be instructed to fast (for 9 to 12 hours prior 
the scheduled visit), if possible, for lipid panel testing.
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
CRP.

Erythrocyte sedimentation rate (ESR) determination (Westergren method).

PK blood samples (pre-dose, and post-dose at 0.5 hr [time window: 0.25-0.75 hr] and 
2 hr [time window: 1.75-2. 5 hr] if early termination occurs within 36 months.
** Important Note ** Subject and parent/legal guardian should be instructed that 
the subject should NOT take the morning dose at home.  The subject’s morning 
dose will be taken at the study site after pre-dose PK sampling.

Uveitis exam performed by an ophthalmologist (or qualified equivalent per local 
practice) (the window for this particular examination is ±30 days).

Collect study medication.
Assess investigational product dosing compliance sJIA subjects ONLY: 

Assessment of JIA-associated fever: Fever is defined as temperature >38C/100.4F).  
Refer to Section 7.1.10.1 for details.

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 7.2.9 for details regarding these blood sample 
collections.

Assess extra-articular sJIA manifestations: rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to sJIA.
ERA subjects ONLY: Tender Entheseal Assessment, Modified Schober’s Test, Overall 
Back Pain and Nocturnal Back Pain Assessment. 
PsA subjects ONLY: Body surface area (BSA) with psoriasis rash and Physician’s Global 
Assessment (PGA) for psoriasis.
6.2.6. Subject Withdrawal
Guidelines for monitoring and discontinuing subjects from this study are listed in 
Appendix 8.  If a subject is discontinued for safety reasons an Early Termination Visit should 
be conducted whenever possible.
If venous thromboembolism is confirmed, discontinue treatment with tofacitinib and 
withdraw the subject from the study (Appendix 8, Guidelines for Monitoring and 
Discontinuation).
All abnormal laboratory events of clinical significance should be followed until the 
laboratory values have returned to normal or baseline level or are deemed clinically stable.  
In addition, any subject with a confirmed increase in serum creatinine >33% above the 
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average of screening and baseline values, will be followed up with retesting every one to two 
weeks until the creatinine elevation has fully reversed to within 10% of the average of 
screening and baseline values or has stabilized.
Subjects may withdraw from the trial at any time at their own request/or request of their 
parent or legal guardian, or they may be withdrawn at any time at the discretion of the 
investigator or sponsor for safety or behavioral reasons, or the inability of the subject to 
comply with the protocol-required schedule of study visits or procedures at a given study 
site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject and parent/legal guardian.  In any circumstance, every effort should be made to 
document subject outcome, if possible.  The investigator should inquire about the reason for 
withdrawal, request the subject to return all unused investigational product(s), request the 
subject to return for a final visit, if applicable, and follow-up with the subject regarding any 
unresolved adverse events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Applicable to Canadian Investigator Sites Only: Subjects with less than an 
ACR30 response (see Section 7.1.6.1) for 2 consecutive visits, beginning with the 
Month 3 visit and anytime thereafter, should be discontinued from study treatment, unless, in 
the opinion of the Investigator, it is in the subject’s best interest to continue receiving 
tofacitinib.  If continuation of treatment is warranted, the Investigator must contact the 
Sponsor to discuss the case and obtain prior approval.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well being of the subject.  When a protocol required test can not be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/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.
7.1. Efficacy
Measures of arthritis efficacy that will be collected throughout the study are described in 
this section.
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7.1.1. Continued Disease Activity Assessment
Subjects who enroll >14 days after their EOS Visit in their qualifying/index study must, in 
the opinion of the investigator, have sufficient evidence of JIA disease activity to warrant use 
of tofacitinib as a DMARD.
7.1.2. Physician Global Evaluation of Disease Activity
The investigator will assess how the overall arthritis appears at the time of the visit.  This is 
an evaluation based on the subject’s disease signs, functional capacity and physical 
examination. 
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 the 
21- numbered circle visual analog scale (VAS), as shown below.
7.1.3. Joint Assessment 
At each study visit,  joints with swelling, pain on motion and tenderness, and limitation of 
motion will be assessed and recorded on the appropriate CRF.  The duration of morning 
stiffness will also be assessed.
The ACR defines a joint with active arthritis as a joint with swelling due to inflammation or, 
in the absence of swelling, limitation of motion accompanied by pain on motion, and/or 
tenderness.
Swelling will be assessed in the following joints:

Temporomandibular, Sternoclavicular, Acromioclavicular, Shoulder, Elbow, Wrist, 
Metocarpophalangeal (MCP I-V), Proximal Interphalangeal (PIP I-V), Distal 
Interphalangeal (II-V), Knee, Ankle, Subtalar joints, Intertarsal joints, 
Metotarsophalangeal (MTP I-V), Toe Interphalangeal (I-V).
Pain/Tenderness will be assessed in the following joints:

Temporomandibular, Sternoclavicular, Acromioclavicular, Shoulder, Elbow, Wrist, 
Metocarpophalangeal (MCP I-V), Proximal Interphalangeal (PIP I-V), Distal 
Interphalangeal (II-V), Hip, Knee, Ankle, Subtalar joints, Intertarsal joints, 
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Metotarsophalangeal (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, Metocarpophalangeal (MCP I-V), 
Proximal Interphalangeal (PIP I-V), Distal Interphalangeal (II-V), Hip, Knee, Ankle, 
Subtalar joints, Intertarsal joints, Metotarsophalangeal (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.
7.1.4. Childhood Health Assessment Questionnaire (CHAQ)
The CHAQ,5 derived from the adult Health Assessment Questionnaire, comprises two 
indices, Disability and Discomfort, and parent global assessment of Overall Well Being.  The 
CHAQ has been cross-culturally adapted and validated in more than 30 languages by the 
PRINTO group (Ruperto 2001).20

The Disability Index assesses function in 8 areas - dressing and grooming, arising, 
eating, walking, hygiene, reach, grip, and activities-distributed among a total of 
30 items.  In each functional area, at least one question is relevant to children of all 
ages.  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.  The Disability Index is calculated as the mean of the 8 functional 
areas. 

Discomfort Index is determined by the presence of pain measured by a 21-numbered 
circle VAS. 

Parent Assessment of Global Well-Being is measured on a 21- numbered circle VAS 
scale.
The CHAQ will be obtained at Baseline Visit for subjects entering the study more than 
14 days after the EOS Visit for their qualifying/index study, then at all study visits and at the 
End of Study/Early Termination visit for all subjects. 
Note: The parent/legal guardian (or an adult caregiver interacting daily with the subject) will 
complete the CHAQ.  Every effort should be made to have the same individual complete the 
CHAQ throughout the course of the study.
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7.1.4.1. Parent’s Assessment of Physical Function (CHAQ Disability Index)
The parent/legal guardian (or an adult caregiver interacting daily with the subject) will 
answer the CHAQ subsection questions concerning eight areas of daily function.  The 
parent/legal guardian will indicate their child’s ability to perform these activities as: without 
any difficulty, with some difficulty, with much difficulty, or unable to do (Grades 0-3, 
respectively); and whether or not help from another person or use of an assistive device is 
required to perform these activities.  The parent/legal guardian is required to answer all 
questions.  The Parent’s Assessment of Physical Function is to be completed before 
performing any other arthritis assessments at the visit. 
7.1.4.2. Parent’s Assessment of Child’s Arthritis Pain (CHAQ Discomfort Index)
For the assessment of arthritis pain, the parent/legal guardian (or an 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 an adult caregiver interacting daily with the subject) will rate 
the subject’s arthritis 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-numbered circle visual analog scale (VAS), 
as shown below.
7.1.4.3. Parent’s Global Assessment of Overall Well-Being (CHAQ Subsection)
For the assessment of overall well-being, the parent/legal guardian (or an 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/legal guardian (or an adult caregiver interacting daily with the subject) will rate 
the subject’s 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-numbered circle visual analog scale 
(VAS), as shown below.
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7.1.5. Inflammatory Markers
In this study, testing for both Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein 
(CRP) will be performed in all subjects at each study visit except Screening/Baseline Visit 
for subjects who roll over on the same day of EOS from their Index Studies (see Schedule Of 
Activities).
7.1.5.1. C-Reactive Protein (CRP)
At the study visits as specified in Schedule Of Activities, a blood sample for CRP testing will 
be collected and sent to the central laboratory for determination. 
7.1.5.2. Erythrocyte Sedimentation Rate (ESR)
At the study visit as specified in Schedule Of Activities, ESR (Westergren method) will be 
collected and determined locally, utilizing an ESR Testing Kit which will be provided by the 
sponsor or their local laboratory ESR Testing Kit (Westergren method). The ESR Testing Kit 
provided by the sponsor should be the preferred choice for ESR testing. Every effort should 
be made to use the same ESR Testing Kit (whether provided by the sponsor or local) 
throughout the course of the study.  Please refer to the ESR Testing Kit manual for detailed 
instructions on how to perform this test appropriately. 
7.1.6. JIA ACR Response and Flare Criteria
The JIA ACR Response and Flare Criteria assessment6,7 is a derived measurement of the 
6 components of the JIA core set variables, which includes:

Physician global evaluation of disease activity.

Number of joints with active arthritis.

Number of joints with limited range of motion.

Parent/legal guardian/subject evaluation of overall well-being (from the CHAQ).

Functional ability (Disability Index from the CHAQ).

ESR or CRP.
Additional details regarding JIA ACR response criteria in Section 7.1.6.1 and additional 
details regarding disease flare in all subtypes are provided in Section 7.1.6.2.
7.1.6.1. JIA ACR Response Criteria 
The assessments using JIA ACR 30, 50, 70, 90 and 100 will be performed.  Other responder 
criteria may be assessed if appropriate.  The JIA ACR 30, 50, 70, 90, 100 response criteria 
are as follows: 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%. 
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In subjects with systemic JIA, absence of fever due to sJIA in the preceding 7 days is also 
required (Ruperto et al. 2012).22  (see Section 7.1.10.1).
Applicable to Canadian Investigator Sites Only: The Investigator will calculate and record 
the subject’s ACR30 response using ESR as the acute phase reactant at the Month 3 Visit and 
each subsequent visit thereafter.  Subjects with less than an ACR30 response at 2 consecutive 
visits, beginning with the Month 3 visit and anytime thereafter, should be discontinued from 
study treatment, unless, in the opinion of the Investigator, it is in the subject’s best interest to 
continue receiving tofacitinib (to be determined on a case-by-case basis and in consultation 
with the Sponsor).  If continuation of treatment is warranted, the Investigator must contact 
the Sponsor to discuss the case and obtain prior approval.
7.1.6.2. JIA ACR Flare Criteria
JIA ACR flare is defined as a worsening of 30% or more in 3 or more of the 6 variables of 
the JIA core set listed above, with no more than one variable improving by 30% or more. In 
addition, the following minimum worsening contingencies apply: if either the number of 
active joints or the number of joints with limited range of motion are included in the 
calculation of "flare" then there must be a worsening of at least two joints. If the Physician’s 
or parent/legal guardian global rating scores are used in the definition of "flare" then there 
must be a worsening of at least 2 units on the 10 unit scales. If the ESR is used in the 
definition of "flare" then the second value for the ESR used in the calculation must be above 
the upper limit of normal for the ESR.
In addition, for subjects with sJIA, a disease flare may also constitute a recurrence of fever 
due to sJIA of >38C/100.4F (oral) or >101.4F/38.6C (rectal) on 2 or more consecutive 
days. 
7.1.7. JIA ACR Clinical Inactive Disease Status Determination and Clinical Remission 
Criteria
The American College of Rheumatology (ACR) JIA Clinical Inactive Disease and Clinical 
Remission (Wallace 2011)8 criteria is defined as follows:
The Clinical Inactive Disease:
The Clinical Inactive Disease Status Determination assessment8 is a derived measurement 
and defined as follows: which includes:

No joints with active arthritis.

No fever, rash, serositis, splenomegaly, hepatomegaly, or generalized 
lymphadenopathy attributable to JIA.

No active uveitis (as defined by the SUN Working Group). 

ESR or CRP levels within normal limits in the laboratory where tested or, if elevated, 
not attributable to JIA. 
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
Physician global evaluation of disease activity score of ‘best possible’ on the scale 
used.

Duration of morning stiffness of 15 minutes.
Clinical Remission on Medications:

Inactive disease for 6 months continuously while on medications.
Clinical inactive disease and clinical remission status will be based on the investigator’s 
assessment of the above components.
7.1.8. Juvenile Arthritis Disease Activity (JADAS 27- CRP and JADAS 27- ESR) Score
The Juvenile Arthritis Disease Activity score is a validated composite disease activity 
measure for JIA (Consolaro 2009).13 Recently, the scoring system was adapted to use the 
27 joint count (Bazso 2009),15 and C- reactive protein in place of Erythrocyte Sedimentation 
Rate (ESR) for the inflammatory marker component (Nordal 2012).16
JADAS 27- CRP and JADAS 27-ESR score consists of four components: 

Physician global assessment of disease activity; 

Parent/legal guardian/subject global assessment of Child well being (from the 
CHAQ);

Number of joints with active disease (27 joint assessment); 

CRP or ESR.
The JADAS 27- CRP and JADAS 27- ESR score will be determined based on the 
investigator and parent/legal guardian assessment of the above components.
7.1.9. 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)14 are defined as follows:
Polyarthritis ( >4 active joints):

Inactive Disease: 1.

Minimal Disease Activity: 3.8.
Oligoarthritis ( ≤4 active joints):

Inactive Disease: 1.
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
Minimal Disease Activity: 2.
The JADAS 27- CRP and JADAS 27- ESR score will be determined based on the 
investigator and parent/legal guardian/subject assessment of the above components.
7.1.10. Additional Assessments in Subjects with Systemic JIA
7.1.10.1. Presence or Absence of JIA-associated Fever
At each study visit, the subject’s oral temperature will be taken.  The subject will also be 
asked if he/she had fever, defined as temperature ˃38C (100.4F) if taken orally or 
>101.4F/38.6C if taken rectally, 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, as a key component of the Adapted JIA ACR 
response. 
Subjects will be provided with a digital thermometer to measure their oral temperature on 
days that they have fever symptoms.  Each subject will receive a diary 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.
7.1.11. Additional Assessments in Subjects with Enthesitis-Related Arthritis
In addition to all other efficacy assessments specified in Section 7.1, subjects with 
enthesitis-related arthritis (ERA) will undergo additional efficacy assessments, including 
Tender Entheseal Assessment, Modified Schober’s Test, and Overall Back Pain and 
Nocturnal Back Pain Assessment as specified in the following subsections.  These 
assessments will be performed at baseline visit for subjects who roll over more than 14 days 
after the EOS Visit from index study, at Month 3 Visit, Month 6 Visit, then every 6 months 
and at the End of Study/Early Termination Visit for all subjects (see Schedule Of Activities).
7.1.11.1. Tender Entheseal Assessment
The Tender Entheseal Assessment will be performed at the study visits as specified in 
Schedule Of Activities only in subjects with enthesitis-related arthritis.
Following anterior/posterior and left/right joint assessment, the investigator will enter one of 
the following codes for each enthesis on the appropriate CRF.  Palpation should be 
performed per standard practice (eg, using fingertips) for this assessment.
Y = Any tenderness upon firm palpation over the indicated enthesis
N = No tenderness upon firm palpation over the indicated enthesis
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7.1.11.2. Modified Schober’s Test
The Modified Schober’s Test (Macrae 1969, Moll 1971)17,18 will be performed at the study 
visits as specified in Schedule Of Activities only in subjects with enthesitis-related arthritis.
With the subject standing erect and with feet together, a line joining the posterior superior 
iliac spines (the dimples of Venus) is used as a landmark for the lumbosacral junction.  A 
mark is made 5 cm below and 10 cm above the lumbosacral junction.  With the subject in 
maximum forward flexion with the knees straight, the investigator will measure the distance 
between the two marks in centimeters.  The full measurement between the two lines will be 
recorded to the nearest tenth of a centimeter (eg, 15.2 cm) on the appropriate CRF.
Figure 1.
Modified Schober’s Test
A.  Measurement 10 cm above and 5 cm below the lumbosacral junction (the dimples of Venus) in the upright 
position. 
B.  Measurement of the distance between the upper and the lower marks when the child is bending forward. 
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7.1.11.3. Overall Back Pain and Nocturnal Back Pain Assessment
The Overall Back Pain and Nocturnal Back Pain assessment will be performed at the study 
visits as specified in Schedule Of Activities only in subjects with enthesitis-related arthritis.
Overall back pain (at any time) and nocturnal back pain will be measured on a 21-numbered 
circle visual analog scale (VAS).
The parent/legal guardian (subject may complete if at least 14 years of age and able to 
complete correctly and consistently for duration of study) will be asked to fill a circle on the 
scale shown below in response to the following questions:
Overall Back Pain (Please fill a circle) 
What is the amount of back pain at any time that your child experienced in the past week?

0
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
5.5 6
6.5 7
7.5 8
8.5 9
9.5 10
No Pain
Most Severe Pain
Nocturnal Back Pain (Please fill a circle)
What is the amount of back pain at night that your child experienced in the past week?

0
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
5.5 6
6.5 7
7.5 8
8.5 9
9.5 10
No Pain
Most Severe Pain
7.1.12. Additional Assessments in Subjects with Psoriatic Arthritis (PsA)
In addition to all other efficacy assessments specified in Section 7.1, subjects with psoriatic 
arthritis (PsA) will undergo additional efficacy assessments, including assessment of body 
surface area (BSA) affected by Psoriasis and Physician’s Global Assessment (PGA) of 
psoriasis (Horneff 2014).19 These assessments will be performed at baseline visit for subjects 
who roll over more than 14 days after EOS Visit from index study, at Month 3 Visit, Month 
6 Visit, then every 6 months and at the End of Study/Early Termination Visit for all subjects 
with PsA.
7.1.12.1. Body Surface Area (BSA)
BSA will be measured as the percentage of BSA affected by psoriasis using the palm 
method; the subject’s palm will be used for the calculation with 1 of the subject’s palms to 
PIP and thumb equal to 1% of BSA (see Appendix 10).
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7.1.12.2. Physician’s Global Assessment (PGA) of Psoriasis
PGA of Psoriasis will assess the amount of induration, erythema, and scaling averaged over 
all psoriatic lesions on a scale of 0 to 5 (see Appendix 11).
7.2. Safety
Safety will be assessed by the spontaneous reporting of 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.
7.2.1. Blood Pressure, Pulse Rate and Temperature
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 be collected in the sitting position, supine position is allowed.  
Position should be documented in the CRF and should be consistent for the subject 
throughout the study. 
Pulse Rate
Pulse rate should be obtained after resting for at least 5 minutes.
Temperature
For subjects with all JIA subtypes, other than sJIA, it is preferred that body temperature be 
collected using tympanic, oral or temporal methods and that the same method should be used 
consistently throughout the study.
For subjects with sJIA, body temperature must be collected orally using a digital 
thermometer, with the exception of very young children or others who cannot tolerate an oral 
thermometer.  In these cases temperature may be measured rectally using a digital 
thermometer.  The same method should be used consistently throughout the study. 
Refer to Section 7.1.10.1 for guidance on the presence and absence of JIA-associated fever.
7.2.2. QuantiFERON-TB Gold or Gold-Plus In-Tube Test 
Quantiferon®-TB (QTF-TB) Gold or Gold Plus test will be available according to local 
regulations and approvals.
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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; 
South Africa, India and Ukraine. (World Health Organization).
Subjects who enroll within 14 days after their EOS visit in their qualifying/index study must 
have a QuantiFERON-TB Gold or Gold Plus In-Tube test administered 1 year ±30 days 
from the date of the last examination in the qualifying study.
Subjects who enroll more than 14 days after their EOS Visit in their qualifying/index study 
must have a QuantiFERON-TB Gold or Gold Plus In-Tube test administered at screening 
and reported as negative in order to be eligible for enrollment in the study, unless one was 
performed and documented within the last 3 months. 
A negative PPD 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.  Annual TB testing will be performed using 
Quantiferon®-TB Gold or Gold Plus In-Tube test (PPD test may be substituted only as 
outlined above).  For subjects with positive results, sites must perform chest radiograph for
TB status determination; the radiograph must be negative for active TB infection for the 
subject to continue study participation.  Note: Quantiferon®-TB Gold or Gold Plus In-Tube 
test is not be performed in subjects who had a positive result during prior testing (screening 
visit or prior annual visits) and/or who previously received adequate treatment for TB.  
However, sites are recommended to perform a chest radiograph for TB status determination 
or as per local standards of care or country-specific guidelines.
Applicable to Investigative Sites in the UK and Belgium: 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.
QuantiFERON-TB Gold or Gold Plus In-Tube test is an in vitro diagnostic test using a 
peptide cocktail simulating ESAT-6, CFP-10 and TB7.7 proteins 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 or Gold Plus In-Tube test 
is an indirect test for M. tuberculosis infection (including disease) and is intended for use in 
conjunction with risk assessment, radiography and other medical and diagnostic evaluations.
The procedure for using this test and interpreting the results is described fully in the 
laboratory manual, which will be provided to investigators.
7.2.3. Tuberculin Test (PPD)
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, subjects can be screened using the 
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PPD Tuberculin Test.  Subjects must have a Mantoux tuberculin 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.  A negative PPD Tuberculin Test is one that is 
<5 mm induration.
7.2.4. Radiograph of Chest
For subjects who enroll more than 14 days after their EOS Visit from their qualifying study, 
a chest radiograph without changes suggestive of active tuberculosis (TB) infection within 
3 months prior to screening is recommended and should be considered in accordance with 
local standards of care or country-specific guidelines.  To be considered eligible for the 
study, the radiograph, if performed, must be negative for active tuberculosis infection.
During the course of this study, annual screening for latent and/or active TB will be 
conducted using the QuantiFERON®-TB Gold or Gold Plus In-Tube test.  All subjects with a 
positive result must have a chest radiograph performed and the radiograph must be negative 
for active tuberculosis infection for the subject to continue study participation.  Subjects 
identified as having latent TB (ie, positive tuberculosis test, chest radiograph negative for 
active tuberculosis, and no evidence of active disease) should be treated appropriately 
(Section 8.5.2).
7.2.5. Uveitis Exam
Uveitis exam must be performed by an ophthalmologist (or qualified equivalent per local 
practice) and will be done at Screening if no documented history of uveitis exam within past 
6 months is available) then annually thereafter, and at the End of Study/Early Termination 
Visit if required
If there is documented history of uveitis exam within the past 6 months, the next exam will 
be done one year from the date of the previous exam, then annually thereafter, and at the End 
of Study/Early Termination Visit if required.
A uveitis exam at the End of Study/Early Termination Visit is not required if an exam has 
been performed within the past 6 months of the EOS/ET visit.
The window for this particular examination is ±30 days relative to the visits where uveitis 
exam is to be performed.  At all other visits the investigator should assess if there are 
potential changes in uveitis status and refer for formal evaluation if deemed clinically 
necessary.  For JIA subtypes that may require more frequent uveitis examination, 
investigators should manage this type of examination according to local standard of care.
For subjects with sJIA, this exam is not required but if available, documentation of previous 
uveitis assessment(s) by an ophthalmologist (or qualified equivalent per local practice) 
should be reviewed, the date of the prior examination recorded, and the presence/absence of 
active uveitis documented.  For subject with sJIA, the investigator should assess at all visits 
if there are potential changes in uveitis status and refer for formal evaluation if deemed 
clinically necessary.
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Uveitis exam should be performed according to standard of care and the results (ie, a report) 
recorded in the source document.  Development of new uveitis or worsening of existing 
uveitis according to Standardization of Uveitis Nomenclature (SUN) criteria should be 
reported as adverse events in the CRF.
The activity of the anterior chamber (AC) inflammation will be evaluated according to the 
SUN criteria, where the activity of AC inflammation is graded from 0 to 4 (grade/cells in 
field: 0/<1, 0.5+/1–5, 1+/6–15, 2+/16–25, 3+/26–50, 4+/>50) (Jabs 2005).12
7.2.6. Macrophage Activation Syndrome (MAS) Markers (sJIA Only)
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 (Ravelli et al. 2016).23
Subjects with sJIA 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/European Union League Against Rheumatology 
(EULAR)/Paediatric Rheumatology International Trials Organisation (PRINTO) Criteria, 
(Ravelli A. et al. 2016)24 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.
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7.2.7. 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.  For children under 40 kg, body weight obtained at study 
visits will be used to adjust dosing as the child grows.  
Applicable to Investigative Sites in the UK and Belgium: 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, heart, lungs, lower extremities for peripheral edema, abdomen and lymph nodes, 
weight and height.  Any clinically significant changes from the baseline examination should 
be recorded as AEs. 
Applicable for subjects enrolled from A3921165: 
If rash is present, the type of rash should be noted (e.g., typical sJIA rash, varicella rash, 
herpes zoster lesions, or other types of rash). The parent/guardian/subject should perform at 
least weekly skin checks between visits and any concern for potential chickenpox or shingles 
be reported to the investigator immediately. Please refer to Appendix 16.
7.2.8. Assessment of Pubertal Development
Determination of physical and sexual maturation will be performed annually at study visits 
using the Tanner stages by a trained physician/clinician in the presence of a parent/legal 
guardian or clinic staff member, until the subject has reached Tanner Stage 5. 
In the event the parent/legal guardian or child 9 years or older 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.
Based on a multi-informant investigation, Dorn et al. (1990)9 and Taylor et al. (2001)10 found 
that when boys and girls were shown schematic drawings (5 ordinally-scaled 
drawings/photographs corresponding to the Tanner stages), their self-ratings correlated quite 
well with health-care-provider examination Tanner staging. 
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 
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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 U.S. begins as early as age 8 and completes as late as 
age 17.  Once a subject has reached the highest stage of development (Stage 5) then that 
score may be carried forward for the remainder of the study.
7.2.9. Laboratory Tests
Blood and urine samples will be collected at the time points identified in Schedule of 
Activities and Section 6 the protocol.  Unscheduled clinical labs may be obtained at any time 
during the study to assess any perceived safety concerns.
Protocol required testing includes hematology (CBC with differential), urinalysis, chemistry 
panel (sodium, potassium, chloride, bicarbonate, calcium, glucose, urea nitrogen, creatinine, 
creatine kinase, total protein, total bilirubin, direct and indirect bilirubin, alkaline 
phosphatase, gamma-glutamyl transferase, albumin, aspartate aminotransferase, alanine 
aminotransferase, and urine pregnancy testing (females of childbearing potential only). 
Lipid Panel (cholesterol, indirect LDL, direct HDL, apolipoproteins A-1 and B, triglycerides) 
will be collected under fasting conditions, if possible, at the baseline visit for subjects who 
roll over more than 14 days after their EOS Visit from their qualifying/index study, every 
6 months through year 5 and then every 12 months after year 5, and at the End of 
Study/Early Termination Visit for all subjects who enroll in this study. 
Hepatitis B, Hepatitis C virus antibody (HCV Ab), and HIV-1/HIV-2 antibody screen will be 
obtained at the screening visit for subjects who enroll more than 14 days after their EOS Visit 
from their qualifying/index study. 
In case of insufficient sample or issue on the sample quality (eg, hemolysis or clotting) the 
subject should return within 1 week to collect a new sample.
Creatinine clearance will be evaluated at every study visit using the Modified Schwartz 
equation or Cockcroft-Gault equation. (Appendix 5)
Hepatitis B testing:
The blood sample will first be analyzed for HBsAg and HBcAb.  If HBsAg is positive, the 
subject is excluded from the study.  If the sample is HBsAg negative but HBcAb positive, the 
subject will be tested for HBsAb.  If when tested, the HBsAb test is negative, the subject will 
be excluded from the study.  Hepatitis B testing will not be performed in subjects determined 
to be HBs Ab positive in their qualifying study.
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Hepatitis C testing:
HCV RNA is tested in case a positive HCV Ab result is obtained.  Only subjects with 
negative HCV Ab or HCV RNA will be allowed to enroll in the study.  To conserve blood 
volume at screening, HCV RNA sample collection may be deferred and collected only if 
required to confirm eligibility based on the HCV Ab results.
Subjects who are receiving concomitant MTX, leflunomide, sulfasalazine, chloroquine, or 
hydroxychloroquine should have Hematology (CBC with differential) and chemistry 
laboratory tests (eg, electrolytes, BUN, creatinine, liver function tests, etc.) obtained as 
appropriate for standard of care.
Tuberculosis testing
QuantiFERON-TB Gold or Gold Plus In-Tube will be obtained at the screening visit for 
subjects who enroll more than 14 days after their EOS Visit from their qualifying/index 
study.  Annual TB testing will be performed using the QuantiFERON®-TB Gold or Gold 
Plus In-Tube test.  Subjects should withhold study medication on the day of the visit to limit 
the number of potential false positive results.
The following Table 3 lists the components of all laboratory testing (mandatory and optional) 
that will be conducted during the course of this study.
Table 3.
Laboratory Testing
Laboratory Testing Profile
Tests Included
Infections 
QuantiFERON-TB Gold or Gold Plus In-Tube test, 
hepatitis C virus antibody (and hepatitis C virus RNA if 
needed), hepatitis B surface antigen and hepatitis B core 
antibody (and hepatitis B surface antibody if needed), 
HIV-1/HIV-2 antibody screen.
Hematology
Hemoglobin, hematocrit, RBC, WBC, neutrophils (%, abs), 
lymphocytes (%, abs), Monocytes (%, abs), eosinophils 
(%, abs), basophils (%, abs), platelets.
Chemistry Panel
Urea nitrogen, creatinine, glucose, calcium, sodium, 
potassium, bicarbonate, chloride, total protein, total 
bilirubin, direct bilirubin, indirect bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase, gamma-glutamyl transferase (GGT), 
albumin, creatine kinase (CK).
Lipid Panel (fasting, if possible)
Total cholesterol, direct HDL, indirect LDL, apolipoprotein 
A-1 and B, triglycerides. 
Urine
Specific gravity, pH, protein, glucose, ketones, blood and 
leukocyte esterase, urine microscopy.a  Urine HCG 
pregnancy testing for women of childbearing potential.
Acute Phase Reactants
C-reactive protein (CRP), erythrocyte sedimentation rate 
(ESR).
Macrophage activation syndrome (MAS)b
Ferritin, fibrinogen, platelets, triglycerides.
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Table 3.
Laboratory Testing
Laboratory Testing Profile
Tests Included
a.
Only if dipstick positive for blood or protein or clinically indicated.
b.
MAS diagnostic laboratory testing (sJIA subjects only): 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.
Clinically significant abnormal findings should be recorded as AEs if they meet any of the 
following criteria:

Test result is associated with accompanying symptom; 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 adverse event by the Investigator or sponsor.
Abnormal test results determined to be caused from laboratory error should not be reported 
as AEs.  Clinically significant laboratory findings at the final assessment should be followed 
to resolution or until determined by the Investigator to be stabilized.  Repeat tests may be 
indicated to establish this.  Refer to Appendix 8 for laboratory discontinuation criteria.
7.2.9.1. 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.  Maximum blood volume during 
the first year of the study will be approximately 90 mL.  After the first year of participation, 
annual blood volume will be approximately 30 mL.  The total volume taken during the study 
does not exceed 2.4 mL/kg during any period of 30 consecutive days.
7.2.10. 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.26  This information is to be captured in the 
subject’s source file and on the relevant case report form.
A subject may be at high risk for venous thromboembolism if he/she:

has heart failure or prior myocardial infarction within the past 3 months;

has inherited coagulation disorders;
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
has had venous thromboembolism, either deep venous thrombosis or pulmonary 
embolism;

is taking combined hormonal contraceptives or hormone replacement therapy;

has malignancy (association is strongest with cancers other than non melanoma skin 
cancers);

is undergoing major surgery 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 1 or more of the risk factors for venous thromboembolism listed above, 
investigator judgement based on Exclusion Criterion 25 will apply to determine whether the 
subject is appropriate for entry into this study.
If a subject has 1 or more of the risk factors for venous thromboembolism listed above under 
Amendment 10 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 10, he/she will remain on their assigned tofacitinib dose. 
7.3. Pregnancy Testing
For female subjects of childbearing potential, a serum or urine pregnancy test, with a 
sensitivity of at least 25 mIU/mL for hCG, will be performed locally at Screening and 
Baseline Visits for subjects who roll over within 14 days or more than 14 days after their 
EOS Visit from their qualifying/index study, at all study visits and at the End of Study/Early 
Termination for all subjects.  If preferred, urine and/or serum pregnancy test may be 
performed at any time using the local laboratory.
A negative pregnancy result is required before the subject may receive the tofacitinib.  
Pregnancy tests will also be done whenever one menstrual cycle is missed during the 
treatment period (or when potential pregnancy is otherwise suspected) and at the end of the 
study to confirm the subject has not become pregnant during the study.  Pregnancy tests may 
also be repeated if requested by institutional review boards (IRBs)/ethics committees (ECs) 
or if required by local regulations.
A positive urine pregnancy test will be confirmed by a blood (serum) pregnancy test 
performed either locally or by the central laboratory. 
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In the case of a positive confirmed pregnancy, the subject will be withdrawn from study 
medication and from the study.
7.4. Pharmacokinetic Sampling
7.4.1. PK Sampling Time Points for All Subjects
Blood samples for PK analyses of tofacitinib will be collected from all subjects at Month 12, 
Month 24, Month 36 visits, and/or at the End of Study/Early Termination (if feasible) up to 
Month 36.  While PK sampling is desired at the End of Study/Early Termination visit (up to 
Month 36), it is recognized that this collection may not be possible or feasible if drug has 
been discontinued prior to this visit; a comment should be included in the applicable PK CRF 
page.
PK samples should be obtained pre-dose and post-dose at 0.5 hr (time window: 0.25-0.75 hr), 
and 2hr (time window: 1.75-2.5 hr) after the dose is given at the study site.
Before the visits 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 of study 
medication on the visit day until after the pre-dose PK sample is collected.
Note: PK samples will not be collected from subjects participating at India sites.
7.4.2. Plasma for Analysis of Tofacitinib
Blood samples (1.2 mL) to provide a minimum of 0.6 mL of plasma for PK will be collected 
into appropriately labeled tubes containing lithium heparin. 
The actual times may change but the number of samples will remain the same.  All efforts 
will be made to obtain the PK samples at the exact nominal time relative to dosing.  
However, samples obtained within the specified time window will not be captured as a 
protocol deviation, as long as the exact time of the sample collection is noted on the source 
document and data collection tool (eg, CRF).
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. 
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures.
7.4.3. Shipment of Pharmacokinetic Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
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 non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. 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 
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 he/she considers the event 
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to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
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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. 
In addition, all overdoses are medication errors.  For the purpose of this study, medication 
errors will be reported as protocol deviations if the subject reported taking 2-fold or more of 
their prescribed dose for one or more days or were identified as consuming more than 
110% of their prescribed dose over the visit interval.
8.4.1. Tofacitinib Overdosage
There is no experience with overdose of tofacitinib.  Pharmacokinetic data up to and 
including a single dose of 100 mg in healthy adult volunteers indicate that more than 95% of 
the administered dose is expected to be eliminated within 24 hours.  There is no specific 
antidote for overdose with tofacitinib.  In case of an overdose, it is recommended that the 
subject be monitored for signs and symptoms of adverse reactions.  Subjects who develop 
adverse reactions should receive appropriate treatment.
Please note, that concomitant treatment with a prohibited potent CYP3A4 inhibitor 
(Appendix 6) is assumed to result in a doubling of exposure.  For further details, please refer 
to the tofacitinib Investigator Brochure.
8.5. Infections
All treated infections occurring during the study, including, but not limited to, respiratory 
infections, cutaneous infections, urinary tract infections and episodes of suspicious or febrile 
diarrhea, should be cultured and any identified organisms noted in the case report form.
Infections should be classified as either serious infections or treated infections, as defined 
below. 
8.5.1. 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 the study.  This infection must be reported as a serious adverse event and should be 
listed as the reason for discontinuation in the eCRF.  Appropriate laboratory investigations, 
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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 8.1 on ADVERSE EVENT REPORTING.
8.5.2. 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).  Subjects who 
experience infections that require treatment can have their study drug temporarily 
discontinued during antimicrobial therapy. A subject who experiences a serious infection 
should be discontinued from the study.  This information should be noted in the eCRF. 
A subject who experiences a latent TB infection (ie, positive tuberculosis test, chest 
radiograph negative for active tuberculosis, and no evidence of active disease) may remain in 
the study, provided that current local incidence rate of multi-drug resistant TB infection is 
<5% and the subject is willing to have an adequate treatment regimen (9 months of isoniazid 
or an acceptable alternative regimen) which is documented.  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,  
rifabutin and rifapentine are prohibited concomitant medications in this study.
8.6. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event 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 trial dosing or discontinuation from the trial, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.
8.7. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;
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
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.
8.7.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see the Section 8.15.1 Serious Adverse Event Reporting Requirements).
8.7.2. 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 
upper limit of normal, the following threshold values should be used in the definition 
mentioned above:

For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 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 pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of at least one time the 
upper limit of normal or if the value reaches 3 times the upper limit of normal 
(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 serious adverse events. 
8.8. Hospitalization
Hospitalization is defined as any initial admission (even if 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, 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.
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Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting condition 
(eg, for work-up 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 adverse event (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned 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 non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event.
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8.9. Severity Assessment
If required on the AE case report forms (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 
subject’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.10. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an AE, 
generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see the Section 8.15  Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product", 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.11. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
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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 termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported 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 
serious adverse events 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 Subject Partner Release of Information Form to 
provide to his partner.
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8.12. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
Investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a Case Report Form (CRF), however, a copy of the 
completed SAE Report form is maintained in the investigator site file.
8.13. Withdrawal Due to Adverse Events (See Also the Section 6.2.6 Subject 
Withdrawal)
Withdrawal 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 because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.14. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/ parent/legal guardian.  In addition, each study subject/parent/legal guardian 
will be questioned about AEs.
8.15. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.15.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This timeframe 
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/her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
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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. 
8.15.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.15.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Methodology for summary and statistical analyses of the data collected in this trial are given 
here and further detailed in a statistical analysis plan, which will be dated and maintained by 
Pfizer.  This analysis plan may modify what is outlined in the protocol; however, any major 
modifications of the endpoint definitions or their analyses will also be reflected in a protocol 
amendment.
For  purpose of analysis, for all safety and efficacy endpoints except for JIA ACR disease 
flare, the baseline values will come from the baseline of the qualifying/index study for 
subjects who enroll in this study within 14 days of the last visit of the qualifying/index study;  
for the subjects whose enrollment are out of 14-day window, their baseline values will come 
from the baseline visit of this study.  For JIA ACR disease flare, baseline values will come 
from  Month 3 visit of this study. Details will be specified in the Statistical Analysis Plan.
9.1. Sample Size Determination
Sample size will be determined by the number of subjects who enroll from the 
qualifying/index studies.  Feedback from literature and Investigators indicates about 90% of 
subjects from qualifying/index studies would enter into this study.  Therefore, approximately 
340 subjects are expected to join from currently planned studies (ie, A3921103, A3921104 
and A3921165).  Enrollment will depend on the timing of the initiation of on-going and 
planned studies.  Analyses performed, including interim analyses, if any, will primarily be 
for safety though some measures of efficacy may be analyzed, and no adjustment of sample 
size due to interim analyses is needed (No hypothesis testing is planned in this study).
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9.2. Efficacy Analysis
9.2.1. Analysis of Primary Endpoint
The primary focus of this study is the long term safety and tolerability of tofacitinib for 
treatment of the signs and symptoms of JIA.  Safety endpoints will include standard 
laboratory safety data (as listed in Section 7.2.9) and AE reports (including SAE).  Body 
weight, height and Tanner stages will be collected to assess growth and physical 
development.
Analyses for safety will be based on Pfizer reporting standards unless otherwise specified or 
noted (as described in Section 9.3 below).
9.2.2. Analysis of Secondary Endpoints
The measures of efficacy (as listed in Section 7.1) will be summarized using descriptive 
statistics, such as number and percent for binary endpoints, mean, standard deviation and 
quartiles for continuous endpoints at each visit where measured.  Displays combining and 
stratifying by qualifying studies will also be included.  Exploratory analyses may also be 
performed.
Complete details will be specified in the statistical analysis plan.
9.3. Safety Analysis
All the safety data, including the following, will be summarized descriptively through 
appropriate data tabulations, descriptive statistics, and graphical presentations:

Adverse events will be summarized according to Pfizer standards.

Safety laboratory tests will be summarized according to Pfizer standards. 

Special attention will be given to the following safety criteria: neutrophil counts, 
lymphocyte counts, serum creatinine levels, liver tests, hyperlipidemia, diabetes, 
anemia and hypertension.

Serious infections, defined as any infection (viral, bacterial, and fungal) requiring 
hospitalization or parenteral antimicrobials or meets other criteria that require it to be 
classified as a serious adverse event, will be summarized.

Special attention will be given to the following safety endpoints: MAS, uveitis, 
cytopenias, malignancies, cardiovascular diseases, gastrointestinal perforations and 
validated assessments of growth and pubertal development.
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9.4. PK Analysis
Plasma concentration-time data for tofacitinib will be analyzed using a nonlinear mixed 
effects modeling approach to characterize PK in this subject population if data is collected 
from 40% of the subjects.  Subjects’ current weight will be used as one of the primary 
covariates for CL/F and V/F in the model to characterize body weight mediated changes in 
CL/F within a subject.  Relationship between various measures of systemic exposure of 
tofacitinib (eg, observed or model predicted trough or 2 hour post-dose concentrations) and 
efficacy/long-term safety outcomes may be explored using appropriate methodology.  Details 
will be captured in a separate Population Modeling Analysis Plan (PMAP).
9.5. Interim Analysis
There are no planned formal interim analyses.  Interim analyses may be performed for study 
monitoring for internal decision making, regulatory purposes or for planned publications.  
As this is an open-label long term follow-up study with no control group and no hypothesis 
testing.  There are no issues of protecting the Type I error rate.
9.6. Data Safety Monitoring Board
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.
9.7. Safety Endpoint Adjudication Committees
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 
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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 for Potential 
Malignancy charter.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and 
appropriate regulatory authorities direct access to source documents to perform this 
verification.
The study site may be subject to review by the Institutional Review Board (IRB)/ Ethics 
Committee (EC), and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true.  Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
according to local regulations, or as specified in the Clinical Study Agreement (CSA), 
whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (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 to 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. 
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12. ETHICS
12.1. Institutional Review Board (IRB)/ Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the Investigator File.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 and 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent/Assent
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 laws. 
When study data is compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify the study subject.  The 
study site will maintain a confidential list of subjects who participated in the study linking 
their numerical code to the subject’s actual identity.  In case of data transfer, Pfizer will
maintain high standards of confidentiality and protection of subject personal data consistent 
with applicable privacy laws.
The informed consent and assent documents must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent and assent documents used during the informed consent process must 
be reviewed by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study subject, or his/her legally acceptable 
representative or parent or legal guardian, is fully informed about the nature and objectives of 
the study and possible risks associated with participation.
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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 he/she cannot 
reasonable be consulted, as permitted by the IRB/EC and consistent with local regulatory and 
legal requirements, then the subject’s assent may be waived with source documentation of 
the reason assent was not obtained.  If the study subject does not provide his/her own 
consent, the source documents must record why the subject did not provide consent 
(eg, minor, decisionally impaired adult), how the investigator determined that the person 
signing the consent was the subject’s legally acceptable representative, the consent signer’s 
relationship to the study subject (eg, parent/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 be re-consented 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, the must provide documentation of legal status to give consent without the 
permission of the 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 before any study-specific activity is performed.  The investigator will retain the 
original of each subject’s signed consent document.
12.4. Subject Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
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13.2. End of Trial in all Participating Countries 
End of Trial in all participating countries is defined as Last Subject Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of tofacitinib at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within one week.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of this study 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.ClincialTrials.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 pre-specified protocol or was 
terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
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www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual subjects has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer has no objection to publication by an investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, the investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed Confidential 
Information (other than the study results themselves) before disclosure.
If the study is part of a multi-centre study, the investigator agrees that the first publication is 
to be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, the investigator is free to publish separately, subject to the other 
requirements of this Section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.
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16. REFERENCES
1.
Johnston JA, Bacon CM, Riedy MC, et al.  Signaling by IL-2 and related cytokines: 
JAKs, STATs, and relationship to immunodeficiency.  J Leukocyte Biol 1996; 
60(4):441-52.
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.
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.
5.
Singh G, Athreya BH, Fries JF, Goldsmith DP. Measurement of health status in 
children with juvenile rheumatoid arthritis. Arthritis Rheum 1994; 37:1761–1769.
6.
Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary 
definition of improvement in juvenile arthritis. Arthritis Rheum 1997; 40: 1202-1209.
7.
Brunner HI, Lovell DJ, Finck BK, Giannini EH. Preliminary definition of disease flare 
in juvenile rheumatoid arthritis. J Rheumatol 2002; 29(5):1058-64.
8.
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.
9.
Dorn, LD, et al. Perceptions of puberty: Adolescent, parent, and health care personnel. 
Developmental Psychology 1990; 26(2): 322-329.
10.
Taylor, SJ. et al. Performance of a new pubertal self-assessment questionnaire: a 
preliminary study. Paediatr Perinat Epidemiol 2001; 15(1):88-94.
11.
Dunne J, et al. Extrapolation of Adult Data and Other Data in Pediatric Drug-
Development. Pediatrics 2011;128; e1242.
12.
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.
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13.
Consolaro A, Ruperto N, et al.  Development and validation of a composite disease 
activity score for juvenile idiopathic arthritis.  Arthritis Care and Research, 2009; 
61(5):658-666.
14.
Consolaro A, Bracciolini G, et al.  Remission, minimal disease activity and acceptable 
symptom state in juvenile idiopathic arthritis, 2012;64:2366 -74.
15.
Bazso A, Consolaro A, et al.  Development and testing of reduced joint counts in 
juvenile idiopathic arthritis.  J Rheumatol, 2009; 36:183 -90.
16.
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.
17.
Macrae IF, Wright V. Measurement of back movement. Ann Rheum Dis, 
1969;28:584-589.
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Moll JM, Wright V. Normal range of spinal mobility: an objective clinical study. Ann 
Rheum Dis, 1971;30:381-386.
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Horneff G, Burgos-Vargas R, Constantin T, Foeldvari I, Vojinovic J, Chasnyk VG, 
Dehoorne J, Panaviene V, Susic G, Stanevica V, Kobusinska K, Zuber Z, Mouy R, 
Rumba-Rozenfelde I, Breda L, Dolezalova D, Job-Deslandre C, Wulffraat N, Alvarez 
D, Zang C, Wajdula J, Woodworth D, Vlahos B, Martini A, Ruperto N, for the 
Paediatric Rheumatology International Trials Organisation (PRINTO). Efficacy and 
safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, 
enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the CLIPPER 
study. Ann Rheum Dis, 2014;73:1114–1122.
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Ruperto N, Ravelli A, Pistorio A, Malattia C, Cavuto S, Gado-West L, Tortorelli A, 
Landgraf JM, Singh G, Martini A, for the Paediatric Rheumatology International Trials 
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Childhood Health Assessment Questionnaire (CHAQ) and the Child Health 
Questionnaire (CHQ) in 32 countries. Review of the general methodology. Clin Exp 
Rheumatol. 2001; 19 (Suppl. 23): S1-9.
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Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, and Furth SL. 
New Equations to Estimate GFR in Children with CKD.J Am Soc Nephrol 2009; 20: 
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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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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.
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24.
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. 
25.
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.
26.
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.
27.
US Food and Drug Administration, Center for Drug evaluation and Research. Draft 
Guidance for Industry: General Clinical Pharmacology Considerations for Pediatric 
Studies for Drugs and Biological Products. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/general-
clinical-pharmacology-considerations-pediatric-studies-drugs-and-biological-products. 
Published: Dec 2014. Accessed: 06 Apr 2021
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Appendix 1. Allowed And Disallowed Treatments for JIA
Allowed DMARDs
Subjects <18 years of age may take no more than 1 of the 5 following permitted non-biologic 
DMARDs at the same time.  Subjects ≥18 years of age may take no more than 2 of the 
5 following permitted non-biologic DMARDs at the same time (hydroxychloroquine and 
chloroquine must not be taken at the same time).  Subjects may either start a permitted 
non-biologic DMARD, continue at same dose, reduce the dose, stop taking the permitted 
non-biologic DMARD, or switch to a different permitted non-biologic DMARD; subjects 
≥18 years may also add 1 of the permitted DMARDs to the existing DMARD.

Methotrexate (20 mg/m2/week or 25 mg/week, whichever is lower);

Leflunomide (Arava) (10 mg every other day for body weight of <20 kg; 10 mg 
every day for body weight of 20 to 40 kg; 20 mg every day for body weight 
>40 kg; or as according to local standards);

Hydroxychloroquine (maximum recommended dose per local product 
information).  Subjects may not start treatment with hydroxychloroquine while 
participating in A3921145.  Continued treatment with hydroxychloroquine is 
permitted for those taking this concomitant medication prior to enrollment.

Chloroquine (maximum recommended dose per local product information). 
Subjects may not start treatment with chloroquine while participating in 
A3921145.  Continued treatment with chloroquine is permitted for those taking 
this concomitant medication prior to enrollment.

Sulphasalazine (maximum recommended dose per local product information).  
Subjects may not start treatment with sulphasalazine while participating in 
A3921145.  Continued treatment with sulphasalazine is permitted for those taking 
this concomitant medication prior to enrollment.
Allowed Treatments for Psoriatic Arthritis:
The dose and type of the following may be adjusted at the discretion of the investigator:

Topical steroids and tar based shampoos on all regions;

Topical vitamin A or D analog preparations;

Anthralin.
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Disallowed DMARDs and Biologic Agents:
The following DMARDS and biologic agents are disallowed at any time during this study.  If 
a subject needs to be treated with one of these agents, the subject should be discontinued 
from the study.

Anakinra (Kineret) must be discontinued for 3 days prior to the first dose of study 
drug.

Cyclosporine must be discontinued for 7 days prior to the first dose of study drug.

Etanercept (Enbrel) must be discontinued for 2 weeks prior to the first dose of study 
drug.

Adalimumab (Humira): Discontinued for 2 weeks prior to first dose of study drug.

Canakinumab (Ilaris): Discontinued for 7 weeks prior to the first dose of study 
drug.

Golimumab (Simponi TM): Discontinued for 4 weeks prior to the first dose of study 
drug.

Infliximab (Remicade) must be discontinued for 3 weeks prior to the first dose of 
study drug.

Abatacept (Orencia), Certolizumab pegol (Cimzia), secukinumab (Cosentyx), and 
tocilizumab (Actemra) must be discontinued for 4 weeks prior to the first dose of 
study drug.

Bucillamine, mizoribine, d-penicillamine, azathioprine, tacrolimus, 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.

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 fluorescence-activated cell sorting 
(FACS) analysis.

Baricitinib (Olumiant®), Upadacitinib (Rinvoq®) or other JAK inhibitors must be 
discontinued 4 weeks prior to the first dose of study drug.

Immunoglobulin intravenous (IV) must be discontinued  8 weeks or  2 half-lives 
(whichever is longer) prior to the first dose of study drug.
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Disallowed Treatments for PsA:

Ultraviolet B (UVB) (narrowband or broadband) phototherapy must be discontinued 
at least 2 weeks prior to first dose of study drug.  Psoralens + ultraviolet A (UVA) 
phototherapy (PUVA) must be discontinued at least 4 weeks prior to first dose of 
study drug. 

Oral and topical retinoids must be discontinued at least 2 weeks prior to first dose of 
study drug. 
Disallowed Investigational Drugs

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. 
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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 JIA Therapies for Worsening Disease
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.  Adjustment in background meds due to disease 
improvement can begin upon enrollment in this study.
1. NSAIDs/COX-2 inhibitors: dose adjustments may be made, or background 
NSAID/COX-2 inhibitors may be switched but should be more than 14 days prior to a 
study visit. 
2. Oral corticosteroid dose should not exceed 0.20 mg/kg/day or 10 mg/day, prednisone 
or equivalent daily, whichever is lower. For subjects coming from the systemic JIA 
study A3921165, a higher prednisone-equivalent dose may be continued or started 
(doses must be ≤1.0 mg/kg/day up to 30 mg/day oral prednisone [or equivalent]).
3. Methotrexate (20 mg/m2/week or 25 mg/week, whichever is lower), leflunomide 
(10 mg every other day for body weight of <20 kg; 10 mg every day for body weight 
of 20 to 40 kg; 20 mg every day for body weight of >40 kg; or as according to local 
standards) may be added and/or adjusted.  Increases should be no more frequently 
than every month.  Adjustments should be made more than 4 weeks prior to a study 
visit. 
4. Sulfasalazine (maximum recommended dose per local product information) may be 
adjusted.  Increases should be no more frequently than every month.  Adjustments 
should be made more than 4 weeks prior to a study visit.  (Note: this only applies to 
subjects who enter the study on concomitant sulphasalazine since subjects may not 
start treatment with sulphasalazine while participating in A3921145).
5. Chloroquine (maximum recommended dose per local product information) and 
hydroxychloroquine (maximum recommended dose per local product information) 
should be adjusted no more frequently than every month.  Adjustments should be 
made more than 8 weeks prior to a study visit.  (Note: this only applies to subjects 
who enter the study on concomitant cholorquine or hydroxychloroquine since 
subjects may not start treatment with cholorquine or hydroxychloroquine while 
participating in A3921145).
6. Intra-articular steroid (eg, triamcinolone (KENALOG®, Aristospan®)) should be 
administered to no more than four joints 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 as not assessed during the remainder of the study.  
Intra-articular injections should be avoided during the 6 weeks prior to a study visit.
A UNIFORM TAPERING OF A MEDICATION OR TITRATING UP ON A DOSAGE OF 
MEDICATION TOWARD A SPECIFIC PRE-DETERMINED GOAL DOSAGE 
(INCLUDING DISCONTINUATION) WILL BE CONSIDERED A SINGLE CHANGE IF 
ACCOMPLISHED WITHIN 1 MONTH.
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Appendix 4. Permitted Adjustments (Tapering) of JIA Medications for Subjects with 
Inactive Disease for at Least 24 Weeks
Subjects who have inactive disease for at least 24 consecutive weeks may begin to taper off 
of concomitant JIA therapies and tofacitinib.  Tapering of therapies is to be completed in the 
following order: oral corticosteroids, MTX/leflunomide, tofacitinib. 

For subjects who are not taking concomitant oral corticosteroids, tapering will start 
with MTX/leflunomide, followed by tofacitinib.

For subjects who are not taking concomitant MTX/leflunomide, tapering will start 
with oral corticosteroids, followed by tofacitinib. 

For subjects not taking concomitant oral corticosteroids or MTX/leflunomide, 
tapering will start with tofacitinib.
The rate at which each drug is tapered is described below. 
Oral Corticosteriods: The dose of oral corticosteroids may be reduced or discontinued for 
subjects who have inactive disease for at least 24 consecutive weeks (time in parent study 
and A3921145 inclusive).  The dose can be reduced by 0.1mg/kg each week.  Once the dose 
of corticosteroids is at 5 mg/day then an absolute decrease by 1 mg/day each week can be 
implemented.
Methotrexate/leflunomide: The dose of MTX/leflunomide may be decreased or 
discontinued for subjects who continue to have inactive disease for at least 24 consecutive 
weeks after receiving the last dose of oral corticosteroids.  MTX/leflunomide may be 
discontinued with or without tapering based on local practice; it is acceptable to stop the drug 
abruptly or by tapering the dose.
Tofacitinib: The dose of tofacitinib may be decreased or discontinued for subjects who 
continue to have inactive disease for at least 24 consecutive weeks after receiving the last 
dose of MTX/leflunomide.  The dose is to be reduced by 5 mg every 12 weeks as long as the 
subject’s disease remains inactive.  The evening dose should always be reduced before the 
morning dose.  For example, a subject receiving a total daily dose (TDD) of 10 mg (5 mg 
BID) prior to tapering will step down to a TDD of 5 mg by taking 5 mg in the morning and 
0 mg in the evening.  If they continue to have inactive disease for a least 12 consecutive 
weeks while receiving a TDD of 5 mg, the 5 mg morning dose may also be discontinued. 
Subjects will be followed for 6 months (24 weeks) after tofacitinib is discontinued by 
returning to the site for schedule visits and completing all visit assessments.
If at any time during the tapering process or after discontinuation of tofacitinib, the subject is 
not able to maintain the inactive disease status (as defined in the protocol Section 7.1.7), 
concomitant JIA therapies (eg, oral corticosteroid, methotrexate/leflunomide) and tofacitinib 
can resume if appropriate according to investigator judgment.
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Tofacitinib will restart at 5 mg BID. Concomitant JIA therapies and doses should be adjusted 
at the discretion of the investigator. 
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Appendix 5. Estimated Glomerular Filtration Rate (GFR) and Creatinine Clearance 
(CrCl) Calculations
1. eGFR will be evaluated at screening to determine if a subject is eligible.
The Bedside Schwartz GFR equation21 will be used to estimate glomerular filtration 
rate (eGFR) from serum creatinine (creatinine methods with calibration traceable to 
IDMS). 
eGFR (mL/min/1.73 m2) = 0.413 × (Ht / Scr)
Height (Ht) in cm; 
Serum creatinine (Scr) in mg/dL  
2. Creatinine clearance (CrCl) will be evaluated at every study visit.
(i)   Participants <12 years of age
The Modified Schwartz equation27 will be used to estimate creatinine clearance in 
participants < 12 years of age
CrCl (mL/min/1.73 m2) = (K x Ht)/ Scr
K (proportionality constant):  
Female Child < 12 years of age: K = 0.55
Male Child< 12 years of age: K = 0.70
(ii)   Participants ≥12 years of age
The Cockcroft-Gault equation27 will be used to estimate the creatinine clearance for  
participants ≥ 12 years of age.
                                (140 - age) x Body Weight (kg) 
                                Serum Creatinine (mg/dL) x 72 
(x 0.85 if female)
CrCl (ml/min) =
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Appendix 6. Prohibited Concomitant Medications
All prohibited drugs require a 4 week (5 half-lives) washout, except:
* Amiodarone half-life averages about 58 days and requires a 290 day washout (5 half-lives);
** 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 
erythromycin 
fluconazole (Diflucan)
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fluvoxamine (Luvox)
(Actemra), golimumab (Simponi), rituximab 
(Rituxan), baricitinib (Olumiant), 
certolizumab (Cimzia), secukinumab 
(Cosentyx).
Grapefruit juice and marmalade
itraconazole (Sporanox)
ketoconazole (Nizoral)
Other DMARDs**:
d-penicillamine, bucillamine, mizoribin, 
azathioprine, cyclosporine, tacrolimus, 
auranofin, aurothioglucose, aurothiomalate, 
staphylococcal protein A immuno-absorbant 
pheresis columns and Immunoglobulin IV.
mifepristone (Mifeprex, RU486)
nefazodone (Serzone)
norfloxacin (Shibroxin, Noroxin)
mibefradil  
verapamil (Calan SR,Covera HS, Isoptin SR, Tarka, Verelan)
Voriconazole
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Appendix 7. 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:
For patients who are NOT on stable, background opioid therapy: any of the following 
single opioid agents may be given as rescue medication (with or without acetaminophen/ 
paracetamol) for no more than 10 consecutive days in the following total daily doses:
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.
For patients who ARE on stable, background opioid therapy:

They may NOT add a second opioid agent for rescue.

If their background medication is 1 of the 4 listed above, they may, within the above 
maximum total dosage limits, increase the dosage for up to 10 consecutive days for 
rescue purposes.

If their background medication is a short-acting (half-life <5 hrs, Appendix 2) opioid 
that is not one of those listed above, they may increase the dosage for up to 
10 consecutive days (up to a total daily dose which must not exceed the potency 
equivalent of 30 mg of orally-administered morphine Appendix 2) for rescue 
purposes.

Sustained release opioid formulations (eg, OxyContin, MS Contin) and opioids 
with half lives greater than 5 hours (eg, methadone, propoxyphene) may NOT be 
USED for rescue medication or increased for rescue purposes.
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Intravenous or intramuscular corticosteroids, biologic response modifiers and DMARDs 
other than those specified as allowed DMARDs (Appendix 1) are not allowed during this 
study.  Intra-articular corticosteroids (eg, triamcinolone (KENALOG®, Aristospan®)) may be 
given in no more than four joints in a six month period.  Injections should be avoided for 
6 weeks before any study visit.  Injected joints will also be considered as not assessed 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 unless indicated for subject safety and individual case management at the 
discretion of the investigator.
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Appendix 8. Guidelines For Safety Monitoring And Discontinuations
For the purpose of safety monitoring for serum creatinine, creatinine clearance (CrCl) and 
hemoglobin levels in Study A3921145, baseline values are defined as:

For subjects who enroll in study A3921145 on the same day and within 14 days
following previous participation in there tofacitinib qualifying/index study. 

For serum creatinine, the average of qualifying/index study screening and 
baseline visit values will be used.

For creatinine clearance, the average of qualifying/index study screening and 
baseline visit values will be used. 

For hemoglobin, the qualifying/index study baseline visit value will be used. 

For subjects who enroll in study A3921145 greater than 14 days after participating in 
the tofacitinib qualifying/index study.

For serum creatinine, the average of A3921145 screening and baseline visit values 
will be used.

For creatinine clearance, the average of A3921145 screening and baseline visit 
values will be used.

For hemoglobin, the A3921145 baseline visit values will be used. 
The following laboratory abnormality requires monitoring:

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).
The following laboratory abnormalities require prompt retesting, ideally within 3-5 days:

Lymphocyte counts <500 lymphocytes/mm3.

Neutrophil counts <1000 neutrophils/mm3.

Applicable to Investigative Sites in the UK and Belgium: 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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
Platelet counts <100,000 platelets/mm3.

Any single AST and/or ALT elevation >3 times the upper limit of normal (repeat 
laboratory testing must include CK, Total Bilirubin, Direct and Indirect Bilirubin, 
GGT, INR and alkaline phosphatase), regardless of the total Bilirubin.

Any single hemoglobin value <8.0 g/dL. 

Any single hemoglobin value that is 2 gm/dL below the baseline (defined above) 
within the first 12 months of participation in A3921145.  For the decreased 
hemoglobin (2 gm/dL below baseline) still within the reference range, retesting 
hemoglobin can be performed once prior to the next scheduled study visit.

After the first 12 months of participation in A3921145, any hemoglobin value that is 
2 gm/dL below the highest hemoglobin level reported within the previous 12 month 
period.

Any single increase in serum creatinine >50% over the average of screening and 
baseline values (as defined above) OR an absolute increase in serum creatinine ≥
0.5mg/dL (≥44.2 µmol/L) over the average of screening and baseline values (as 
defined above)
AND
Any single CrCl decrease of >30% over the average of screening and baseline values
(as defined above)
(N.B. Screening and baseline values to be used for this monitoring criteria are defined 
at the beginning of Appendix 8)
Tofacitinib Temporary Withholding or Discontinuation for Venous Thromboembolism: 

Per Amendment 10, for subjects with suspected venous thromboembolism, treatment 
with tofacitinib should be temporarily withheld while the subject is evaluated.  If 
venous thromboembolism is confirmed, discontinue treatment with tofacitinib and 
withdraw the subject from the study.
Treatment with tofacitinib will be discontinued and the subject withdrawn from this study 
for:

Serious infections (those requiring parenteral antimicrobial therapy or 
hospitalization).

Two sequential lymphocyte counts <500 lymphocytes/mm3;

Two sequential neutrophil counts <500 neutrophils/mm3.

Two sequential platelet counts <75,000 platelets/mm3.
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
Two sequential AST or ALT elevations >3 times the upper limit of normal with at 
least one Total Bilirubin value >2 times the upper limit of normal.1

Two sequential AST or ALT elevations >3 times the upper limit of normal with an 
abnormal INR.1

Two sequential AST or ALT elevations >3 times the upper limit of normal 
accompanied by symptoms consistent with hepatic injury.1

Two sequential AST or ALT elevations >5 times the upper limit of normal, regardless 
of Total Bilirubin or accompanying symptoms.1

Single positive HBc Ab and a negative HBs Ab (refer to Section 7.2.9 for additional 
testing required).

Two sequential hemoglobins <8.0 g/dL or a decrease of more than 30% from baseline 
value (defined above).

Two sequential increases in serum creatinine >50% over the average of screening and 
baseline values (as defined above) OR an absolute increase in serum creatinine ≥ 
0.5mg/dL (≥44.2 µmol/L) over the average of screening and baseline values (as 
defined above)
AND
A confirmed (two sequential) CrCl decrease of >30% over the average of screening 
and baseline values (as defined above).  
(N.B. Screening and baseline values to be used for this discontinuation criteria are 
defined at the beginning of Appendix 8)
If the serum creatinine increase and the CrCl decrease have an identifiable and 
reversable cause (e.g. concomitant medication), then an additional retest may be 
considered after discussion with Sponsor study clinician or medical monitor. After 
retest, a decision for the subject to continue in the study will be made with the 
Sponsor study clinician or medical monitor. 

Other serious or severe AEs, after consultation with the Pfizer Medical Monitor.  For 
example, subjects with a malignancy (exception of adequately treated or excised 
non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in 
situ) must be discontinued from the study.  All malignancy events should be reported 
as serious AEs.
                                                
1 In each case, there is a need for additional investigations, such as review of ethanol, recreational drug 
and dietary supplement consumption; testing for acute hepatitis A, B or C infection and biliary tract imaging 
should be promptly discussed with the Pfizer Medical Monitor.
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Appendix 9. Evaluation Of Potentially Malignant Tumors, Suspicious 
Lymphadenopathy, Possible Extra-Nodal Lymphoproliferative Disorder (LPD)
The following steps should be taken in the event of potentially malignant tumors, suspicious 
lymphadenopathy or possible extra-nodal lymphoproliferative disorder (LPD) which might 
arise in the course of this study. 
When there is a decision to biopsy a potentially malignant tumor, lymph node, or other 
tissue, the investigator and/or consultants should contact the Pfizer study team to discuss the 
issue and any decisions as soon as possible.  It is recommended that specialists with 
experience in the evaluation of immunosuppressed subjects be consulted.
If a biopsy for lymphadenopathy or lymphoma is to be performed, the investigator or 
consultant should refer to the instructional slide deck in the Lymph Node Biopsy kit and 
review the following points with the surgeon and pathologist:

Fine needle aspiration and core needle biopsy are strongly discouraged; excisional 
biopsy is required for accurate diagnosis.

Tissue must be sent fresh to the pathology laboratory; the pathologist must be 
consulted before the procedure.

Archive multiple frozen tissue samples, if possible.

Include flow cytometry and cytogenetics as part of the pathologic evaluation.

Culture for mycobacterium and fungi, if indicated.

Collect and snap freeze peripheral blood lymphocytes for germ line evaluation 
(DNA).

Archive multiple aliquots of serum samples.
For all biopsies, please request the pathologist to send the original slides used to make the 
definitive diagnosis, ancillary study reports, and the pathologist’s report to the central 
laboratory for blinded review by central pathologists, to be paid for by Pfizer.  Should the 
central pathologists make a diagnosis that is not essentially similar to the local pathologist’s 
diagnosis, the local pathologist will be notified and provided with an opportunity to consult 
with the central pathologists (paid for by Pfizer).  Translation during this consultation, if 
needed, will be provided by the staff of the Pfizer Country Office (PCO).
Both the local pathologist’s diagnosis and the central pathologist’s diagnosis will be reported 
in the study database. 
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Appendix 10. Body Surface Area
The percentage of body surface area affected by psoriasis will be estimated using the palm 
method:
One (1) of the subject’s palm to PIP and thumb equals 1% of BSA.

Head and Neck = 10%  (10 palms)

Upper extremities = 20% (20 palms)

Trunk (axillae and groin) = 30%  (30 palms)

Lower extremities (buttocks) = 40% (40 palms)

Total BSA = 100% (100 palms)
Based on the above, the Physician’s Assessment of Total BSA affected by psoriasis will be 
estimated using the following formula:
Region of the Body
Number of Palms 
Within the Region 
Affected by Psoriasis
Head and Neck
Upper extremities
Trunk (including the axillae and groin)
Lower extremities (including the buttocks)
Physician’s Assessment of Total BSA Affected by Psoriasis 
(addition of the individual regions):
%
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Appendix 11. Physician’s Global Assessment Of Psoriasis
Physician’s static global assessment (PGA) of psoriasis (averaged over all lesions):
The PGA of psoriasis is used to determine the subject’s psoriasis lesions overall at a given 
time point.  Overall lesions are graded for induration, erythema, and scaling based on the 
scales below.  The sum of the 3 scales is then divided by 3 to obtain the final PGA of 
psoriasis score.
Please circle one response each for induration, erythema, and scaling:
Induration (I) (averaged over all lesions):
0 = no evidence of plaque elevation
1 = minimal plaque elevation - 0.5 mm
2 = mild plaque elevation - 1 mm
3 = moderate plaque elevation - 1.5 mm
4 = marked plaque elevation - 2 mm
5 = severe plaque elevation - 2.5 mm or 
more
Erythema (E) (averaged over all lesions):
0 = no evidence of erythema, hyper 
pigmentation may be present
1 = faint erythema
2 = light red coloration
3 = moderate red coloration
4 = bright red coloration
5 = dusky to deep red coloration
Scaling (S) (averaged over all lesions):
0 = no evidence of scaling
1 = minimal; occasional fine scale over 
less than 5% of the lesion
2 = mild; fine scale predominates
3 = moderate; course scale predominates
4 = marked; thick, non-tenacious scale 
predominates
5 = severe; very thick tenacious scale 
predominates
Add I + E + S = ____________ / 3 = ____________ (Total Average)
(0)
Clear, except for residual discoloration
(1)
Majority of lesions have individual scores for [(I + E + S) / 3] that averages 1
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(2)
Majority of lesions have individual scores for [(I + E + S)/3] that averages 2
(3)
Majority of lesions have individual scores for [(I + E + S)/3] that averages 3
(4)
Majority of lesions have individual scores for [(I + E + S)/3] that averages 4
(5)
Majority of lesions have individual scores for [(I + E + S)/3] that averages 5
Note: Scores should be rounded to the nearest whole number:
If total average ≤1.49, score = 1
If total average ≥1.50, score = 2
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Appendix 12. Dosing Scheme For Subjects Rolling Over From Study A3921103 Under 
Protocol Amendment 5
Subjects Completing Index Study A3921103 (Age 2 to <6 years)
Body Weight (kg)
Dosage Regimen
5-6
1 mg (1 mL oral solution) BID
7-9
1.5 mg (1.5 mL oral solution) BID
10-12
2 mg (2 mL oral solution) BID
13-15
2.5 mg (2.5 mL oral solution) BID
16-19
3 mg (3 mL oral solution) BID
20-22
3.5 mg (3.5 mL oral solution) BID
23-26
4mg (4 mL oral solution) BID
27-29
4.5mg (4 mL oral solution) BID
30
5 mg (one 5 mg tablet or 5 mL oral solution) BID
Subjects Completing Index Study A3921103 (Age 6 to <18 years)
Body Weight (kg)
Dosage Regimen
5-11
1 mg (1 mL oral solution) BID
12-18
1.5 mg (1.5 mL oral solution) BID
19-24
2 mg (2 mL oral solution) BID
25-31
2.5 mg (2.5 mL oral solution) BID
32-39
3 mg (3 mL oral solution) BID
40
5 mg (one 5 mg tablet or 5 mL oral solution) BID
Note: Investigators will have the option of maintaining the A3921103 subject’s current 
dosage regimen (if the desired clinical response has been attained with no safety concern) or 
adjusting the dosage regimen in accordance with dosing scheme specified in Section 5.1.
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Appendix 13. By Visit Assessment of the Degree of Burden and Risk Threshold During 
the Trial (Investigative Sites in Belgium Only)
As written in the protocol under the Schedule of Activities and Section 6 and here 
summarised, at each visit (initially at 1 month, 3 months, and every 3 months thereafter), the 
investigator 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., and uveitis examination;
4. Various functional and global assessments depending on the child’s specific 
rheumatologic diagnosis such as the JIA joint assessment, flare assessment CHAQ, 
and the CHQ; the Physician’s Global Evaluation of Overall Disease Activity, the 
Tender Entheseal Assessment, Modified Schober’s Test, Overall Back Pain and 
Nocturnal Back Pain Assessment for enthesitis related arthritis, psoriatic body surface 
area assessment; the Physician’s Global Assessment (PGA) for psoriatic arthritis;
5. The investigator also will assess for flare and ACR responses using the JIA ACR 
Response and Flare Criteria provided in Section 7.1.6 of this protocol;
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 9.7, serious infections, opportunistic infections, tuberculosis, herpes zoster, 
malignancies (excluding non-melanoma skin cancer [NMSC]), 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 
criteria25 at any time during the study will be evaluation for discontinuation from study.  
Additionally, the investigator refers to Appendix 8 “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 14. Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic.  This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer.
Use of these alternative study measures are expected to cease upon the return of business as
usual circumstances (including the lifting of any quarantines and travel bans/advisories).
1. Eligibility
Subjects from the A3921165 study will be able to enter this study if eligible (See Section 4
SUBJECT SELECTION).
While SARSCoV2 testing is not mandated for this study, local clinical practice standards for 
testing should be followed. A patient should be excluded if he/she has a positive test result 
for SARS-CoV2 infection, is known to have asymptomatic infection, or is suspected of 
having SARS-CoV2. Patients with active infections are excluded from study participation as 
per Section 4.2 Exclusion Criteria.
2. Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study participants at scheduled visits per the Schedule of Activities 
or unscheduled visits.
Telehealth visits may be used to continue to assess participant safety and collect data points. 
Telehealth includes the exchange of healthcare information and services via 
telecommunication technologies (eg, audio, video, video-conferencing software) remotely, 
allowing the participant and the investigator to communicate on aspects of clinical care, 
including reminders, education, and safety monitoring. 
Follow the protocol schedule of activities when possible, except for the patient reported 
outcomes which cannot be completed over the phone. The following assessments must be 
performed during a telehealth visit :

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. (See Section 8
ADVERSE EVENT REPORTING).

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.
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
Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. See Section 4.3.1 Contraception.
3. Home Health Visits
A home health care service may be utilized to facilitate scheduled visits per the Schedule 
of Activities. Home health visits include a healthcare provider condiucting an in-person study 
visit at the participants location, rather than an in-person visit at the site. Refer to protocol 
Section 6 Study procedures, for the list of assessment which may be performed during a 
home health visit. 
4. Laboratory Testing. 
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local regulations. 
The local laboratory may be a standalone institution or within a hospital. The following 
safety laboratory evaluations may be performed at a local laboratory:

Haematology, urinalysis, chemistry panel, lipid panel, pregnancy testing
If a local laboratory is used, qualified study site personnel must order, receive, and review
results. Site staff must collect the local laboratory reference ranges and 
certifications/accreditations for filing at the site. Laboratory test results are to be provided to 
the site staff as soon as possible.  The local laboratory reports should be filed in the 
participant’s source documents/medical records.  Relevant data from the local laboratory 
report should be recorded on the CRF.
If a participant requiring pregnancy testing cannot visit a local laboratory for pregnancy 
testing, a home urine pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be 
used by the participant to perform the test at home, if compliant with local regulatory 
requirements. The pregnancy test outcome should be documented in the participant’s source 
documents/medical records and relevant data recorded on the CRF.  Confirm that the 
participant is adhering to the contraception method(s) required in the protocol.
5. Study Intervention
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered.
Investigational product may be shipped by courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for the 
Investigational product. Pfizer does not permit the shipment of Investigational product by 
mail. The tracking record of shipments and the chain of custody of investigational product 
must be kept in the participant’s source documents/medical records.
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Investigational product may be shipped only if there is no safety concern and negative 
pregnancy test is confirmed (if required per protocol Section 7.3 Pregnancy Testing and 
Section 4.3.1 Contraception). Participants must consent verbally to providing contact details 
for shipping purposes, and consent is to be documented in the medical record.
6. Adverse Events and Serious Adverse Events.
If a participant has COVID-19 during the study, this should be reported as an adverse event 
(AE) or serious adverse events (SAE) and appropriate medical intervention provided. 
Temporary discontinuation of the study intervention may be medically appropriate until the 
participant has recovered from COVID-19. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor.
Per protocol Section 8.5.1 Serious Infections a subject who experiences a serious infection 
must be discontinued from the study.  
In such case, if the discontinuation is associated with the current COVID-19 pandemic, enter 
“COVID-19” in the CRF “Specify” field.
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Appendix 15. End of Study 
Subjects participation in this study will end in 2 phases : 

For subjects who entered this study from the A3921103 and A3921104 
qualifying/index studies, their participation in the study will end, after the first 
marketing approval of tofacitinib for the treatment of polyarticular course JIA in any 
country.

This study will end once the last subject, and all other subjects, who entered from 
study A3921165 have completed approximately 1 year in this study, or after the first 
marketing approval of tofacitinib for the treatment of systemic JIA, whichever comes 
first.
In advance of each phase, sites will receive a communication letter to schedule an End of 
Study visit for the applicable subjects. 
Please refer to the Schedule of Activities and Section 6.2.5 End of Study Visit/Early 
Termination Visit for the list of procedures and assessments to be completed at this visit. 
Depending on local regulatory requirements, and as per the EU Voluntary Harmonisation 
Procedure (EU VHP), access to tofacitinib may be made available in situations where the 
subject cannot access treatment through typical post-approval channels after the subjects last 
visit in this study. 
Availability of the oral solution formulation may be limited or discontinued when patients 
taking the oral solution have either discontinued treatment or have transitioned to use of the 
oral tablet formulation consistent with applicable weight based dosing guidance.
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Appendix 16. Varicella (chickenpox) and Herpes Zoster (shingles) Assessment and 
Guidance. (Applicable for subjects enrolled from A3921165 only)
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 the A3921165 screening visit. 
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 (e.g., 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 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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Appendix 17. Summary of Changes from Original Protocol through Amendment 11
Document
Version Date
Summary of Change
Protocol Amendment 11
26 May2021
Global Amendment 
Protocol is amended as follows: 

Protocol summary Section 3 study 
design: end of study text updated to 
clarify that subjects participation to 
the A3921145 study will end in 
2 phases.

Schedule of Activities and Study 
Procedures Section 6.2.5 updated to 
clarify which procedures are required 
at the End of Study/Early Termination 
visit.

Addition of monitoring criteria related 
to Creatinine and Lipids increase for 
continuous assessment of subject’s 
safety in the Appendix 8.

Creatinine discontinuation criteria 
wording updated in Appendix 8 to 
require two sequential increases in 
serum creatinine >50% over the 
average of screening/baseline and a 
confirmed creatinine clearance (CrCl) 
decrease of >30%. These updates are 
made to account for potential 
increases in creatinine due to physical 
activity, age and growth. CrCl added 
to the schedule of activities footnote 
and Section 7.2.9 laboratory tests. 

Exclusion criterion #27 related to 
history of allergies, intolerance or 
hypersensitivity to lactose or 
CP-690,550 (tofacitinib): This 
country-specific exclusion criterion is 
made global to ensure consistent 
eligibility criteria for the study 
population.

Exclusion #8 is updated such that any 
infection requiring hospitalization, 
parenteral antimicrobial therapy or 
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judged to be opportunistic by the 
investigator within the 3 months 
(updated from 6 months) prior to the 
first dose of study drug will exclude a 
subject.  

Appendix #5: Updated to include 
CrCl equations to be used for the new 
monitoring and discontinuation 
criteria related to CrCl.

Reference to “QuantiFERON®-TB 
Gold” added throughout the protocol. 
QuantiFERON®-TB Gold or 
QuantiFERON®-TB Gold Plus will be 
available according to local 
regulations and approvals.

Protocol wording updated to clarify 
that a chest x-ray is required when 
subjects have a positive annual 
QFT-TB test for the first time.

Clarification made to JIA ACR 
disease flare assessment timing for 
analysis in Protocol Summary and 
Section 2.2.2. Secondary endpoints.

Clarification made to baseline 
definition in Section 9 Data 
Analysis/Statistical Methods.

Requirement of Pfizer medical 
monitor approval removed from 
Section 4.1 inclusion criterion 12, 
Section 7.2.2 QFT test, Section 7.2.3 
Tuberculin Test: Protocol includes all 
information required for the 
monitoring of subject’s safety.

Protocol Section 7.1.5.2 Erythrocyte 
Sedimentation Rate (ESR) updated to 
clarify that sites can use the ESR 
testing kit provided by the Sponsor or 
use their local laboratory ESR Kit. 
Reference to Covance lab kit removed 
throughout the protocol.
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
Appendix 1: Correction of the 
washout period for investigational 
drugs to be 4 weeks, in accordance 
with exclusion #12

Appendix 14: Updated to include 
alternative measures during public 
emergencies in addition to COVID-19 
pandemic

Editorial changes to correct 
typographical errors throughout the 
protocol.
Protocol Amendment 10
04 May 2020
Global Amendment 
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.

Instructions for the assessment and 
monitoring of Venous 
Thromboembolism have been added 
to Schedule of activities, Section 5.2 
Allocation to Treatment; 6 Study 
Procedures, 6.2.6 Subject 
Withdrawal, 7.2.10 Risk Factor 
Check for Venous 
Thromboembolism, Reference 26 and 
Appendix 8 Guidelines for Safety 
Monitoring and Discontinuations.

Protocol updated to clarify that annual 
TB testing is required for subjects 
included in countries where TB 
incidence rate is >50 cases per 
100,000 persons.  Schedule of 
Activities, Section 6. Study 
Procedures and 7.2.2 Quantiferon 
Gold Plus In-Tube Test updated 
accordingly. 

Protocol updated to clarify that in 
case of insufficient sample or issue on 
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the sample quality (eg, hemolysis or 
clotting) the subject should return 
within 1 week for a new sample 
collection. Schedule of Activities and 
7.2.9 laboratory Tests updated 
accordingly.

Removal of the text allowing subjects 
aged 14 and older to complete the 
CHAQ and text added to clarify that 
every effort should be made to have 
the same individual complete the 
CHAQ throughout the course of the 
study, in Section 7.1.4 CHAQ.

Time Period and Frequency for 
collecting AE and SAE Information 
updated according to the new 
standard text, in Section 8.2.

Washout period required for Anakinra 
(Kineret®) and cyclosporine corrected 
to 7 days prior the first dose of study 
drug in Appendix 1 Protocol 
(Administrative Change Letter 
[PACL] issued 11 July 2019).

Washout period required for 
Immunoglobulin IV which is 
20 weeks or 5 half-lives (whichever is 
longer) prior the first dose of study 
drug added in Appendix 1 (PACL 
issued 11 July 2019).

Appendix 3 and Appendix 7. Updated 
to clarify that after intra-articular 
steroid injection, the injected joints 
will be considered “not assessed” 
during the remainder of the study 
(PACL issued 20 November 2019).

Appendix 4 updated to clarify that 
concomitant JIA therapies and 
tofacitinib treatment can resume at 
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any time during or after the tapering if 
the subject is not able to maintain the 
inactive disease status.

Appendix 6 updated to include 
Immunoglobulin IV to the list of 
prohibited concomitant medications.

Temporary measures for study visit 
occurring during the COVID-19 
Pandemic added in Appendix 14 
(PACL issued 27 March 2020 and 
07 April 2020).

Editorial changes to corrected 
typographical errors throughout the 
protocol.
Protocol Amendment 9
23 May 2019
Global Amendment

Removed the tofacitinib 10 mg BID 
dose (Refer to Section 1.2.2.2, 
Section 5.1, and Appendix 4).  Note: 
At the time of this amendment no 
subjects were receiving, or had
received the 10 mg BID dose during 
participation in this study.

Removed baseline PK sample for 
subjects from A3921165 who do not 
enroll in the LTE on the same day 
they complete the qualifying study 
(Refer to Schedule of Activities 
[SOA], Section 6.1.1.2, Section 6.1.3, 
and Section 7.4.1.1).
Per PACL dated 16-November 2017, 
update made to SOA to correct 
formatting issues.
Per PACL dated 18-December-2017, 
updates made to clarify inconsistencies 
between 
Appendix 1, Appendix 3, and Appendix 4 
that occurred with the addition of 
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tapering JIA medications in Amendment 
7.

Per PACL dated 16-November 2018, 
updates made to allow vaccination 
with live or live-attenuated vaccines 
during the study.  (Refer to 
Section 4.3.3 and Section 5.2).

Name of QuantiFERON®-TB Gold 
Plus In-Tube test updated (Refer to 
SOA, Section 4.1, Section 6.1, 
Section 6.2, Section 7.2.2, 
Section 7.2.3, Section 7.2.4, and 
Section 7.2.9).

Timing of QuantiFERON® -TB Gold 
Plus In-Tube test updated for 
consistency within the protocol and 
clarity.  (Refer to Section 6.2, 
Section 7.2.2, and Section 7.2.9).

Timing of Uveitis Examination 
updated for consistency within the 
protocol and clarity.  (Refer to SOC, 
Section 6.2, and Section 7.2.5).
Protocol Amendment 8 
07 February 2018

For Investigative Sites in Belgium 
and the United Kingdom (UK):

Add Exclusion Criterion 26: History 
of allergies, intolerance or 
hypersensitivity to lactose or 
CP-690,550 (tofacitinib).  (Refer to 
Section 4.2).

Added text to clarify that a condom 
plus spermicide is not accepted as 
highly effective contraception.  (Refer 
to Section 4.3.1).

Added guidance regarding 
participants who have resided or 
travelled in areas of endemic 
tuberculosis or endemic mycoses; or 
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have underlying conditions that may 
predispose them to infection.  (Refer
to Section 7.2.2).

Added a full skin cancer examination 
to the complete physical examination.  
(Refer to the Schedule of Activity 
(SOA), Section 6.0, and Section 
7.2.7).

Provide guidance for monitoring 
confirmed absolute neutrophils count 
levels of 500 –
1000 neutrophils/mm3.  (Refer to 
Appendix 8).

For Investigative Sites in Belgium 
only:

Added Appendix 13: By Visit 
Assessment of the Degree of Burden 
and Risk Threshold During the Trial.  
Also added statement in SOA and 
Section 6.0 referencing Appendix 13.
Protocol Amendment 7 
10 August 2017
Changes made to accommodate the 
inclusion of subjects rolling over from 
sJIA Study A3921165.
Updated Dose Rationale to include 10 mg 
BID dose of tofacitinib (see 
Section 1.2.2.2).

Added endpoints for subjects with 
sJIA: “Absence of Fever”, defined as 
absence of fever due to sJIA in the 
week preceding the assessment at 
each visit (see Protocol Summary and 
Section 2.2.2).
Changed number of subjects to be 
enrolled in the study from approximately 
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290 to approximately 340 (see Protocol 
Summary, Sections 3 and 9.1).

Updated Inclusion Criterion 6 to 
allow subjects coming from sJIA 
study to continue or start higher 
prednisone-equivalent doses (doses 
must be ≤1.0 mg/kg/day up to 
30 mg/day oral prednisone [or 
equivalent]) than permitted for 
subjects from other qualifying studies 
(with the agreement of the Pfizer 
medical monitor).  See Section 4.1).
Updated Exclusion # Criterion 4 to only 
exclude subjects with persistent 
oligoarthritis and undifferentiated JIA 
(see Section 4.2).
Updated study treatments to include 
tofacitinib 10 mg BID.  Changes included 
reorganizing section and adding headers 
for clarification (see Section 5.1).

Updated permitted medications and/or 
treatments to allow for the use of 
higher prednisone-equivalent doses in 
subjects from the sJIA study (with 
agreement from Pfizer medical 
monitor).  (see Section 5.5.2).

Updated uveitis exam to provide 
guidance regarding sJIA subjects (see 
Schedule of Activities [SOA] and 
Section 6.1).

Updated vital sign assessment to 
specify that oral or rectal temperature 
must be taken with a digital 
thermometer in subjects with sJIA 
(see Section 6.1).

Added assessments specific to 
subjects with sJIA: Assessment of 
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JIA-associated Fever and assessment 
of extra-articular sJIA manifestations.  
In addition, assessments for 
Macrophage Activation Syndrome 
(MAS) were added for sJIA subjects 
with fever and where MAS is 
suspected. (see Sections 6.1).

Add/Update Assessment Section 7.

Update JIA ACR Flare Criteria to 
provide guidance for assessing 
subjects with sJIA, specifically 
fever assessment (see Section 
7.1.6.2).

Add Presence or Absence of 
JIA-associated Fever to 
Assessment section (see 
Section 7.1.10.1).

Update Temperature to provide 
guidance for assessing oral or 
rectal temperature in subjects with 
sJIA (see Section 7.2.1).

Add Macrophage Activation 
Syndrome (MAS) Markers for 
subjects with sJIA (see Section 
7.2.6).

Update Table 4 Laboratory 
Testing, to include tests for 
assessing MAS.

Add baseline and post-date 
change PK sampling time points 
for subjects from the sJIA study 
A3921165 as preparation for 
potential dose increase to 
tofacitinib 10 mg BID (see SOA 
and Section 7.4.1.1).
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
Added Exclusion Criterion 
25 - Previously failed treatment with 
another JAK inhibitor, such as 
baricitinib.  Prior to Amendment 7 
there were no approved JAK 
inhibitors other than tofacitinib.  
Change made so that subject who fail 
a drug with the same mechanism of 
action as tofacitinib are not enrolled 
in the study.  (see Section 4.2).
Changes made to allow the tapering of 
concomitant JIA medications 
(corticosteroids, methotrexate, and 
tofacitinib) in subjects with improved 
symptoms-All JIA subtypes.
Added endpoint: Eligibility of tapering 
defined per protocol for corticosteroids, 
MTX/ leflunomide, and tofacitinib (see 
Protocol Summary and Section 2.2.2).
Revised Section 5.5.2 Permitted 
Medications and/or Treatments to include 
permitted dose adjustments in 
background JIA therapies for inactive 
disease.  Changes included reorganizing 
and adding headers for clarity.
Appendix 3: Changed title from 
Permitted Adjustments in JIA Therapies
to Permitted Adjustments in JIA 
Therapies for Worsening Disease.
Added new Appendix 4: Tapering of JIA 
Medications for Subjects with Inactive 
Disease.  Within this appendix is 
guidance for tapering doses of oral 
corticosteroids, methotrexate, and 
tofacitinib in subjects who have had 
inactive disease for at least 24 weeks.
Appendix 1 Allowed and Disallowed 
Treatments for JIA was updated to 
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included baricitinib, (Olumiant®) and 
secukinumab (Cosentyx®), which were 
approved since the last protocol 
amendment.
Appendix 6 Prohibited Concomitant 
Medications was updated to included 
baricitinib, (Olumiant), certolizumab 
(Cimzia), secukinumab (Cosentyx), 
which were approved since the last 
protocol amendment.
Lab Assessments:
Lipid Panel: LDL-direct method will be 
changed to an LDL-indirect method.  The 
change was required because one of the 
analysis reagents for LDL direct will no 
longer be produced.  Added “(fasting, if 
possible)” to provide guidance (see 
Sections 6.1, 7.2, and Table 4).
Triglycerides are added as a lab 
assessment since values over 400 mg/dL 
could affect the results of the LDL (see 
Sections 6.1, 7.2 and Table 4).
Per PACL dated 08-December-2016, 
wording to clarify washout and timing of 
consent was added to Section 6.1.1 
Subjects Requiring Separate Screening 
and Baseline Visits.
Administrative changes made to provide 
clarification.
Updated wording for Inclusion Criterion 
6 to clarify corticosteroid use before and 
during the study (see Section 4.1).

Updated wording for Exclusion 
Criterion 8c with following: 
“(excluding those treated with topical 
only)” to provide additional guidance 
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on what is meant by “treated 
infection” (see Section 4.2).
Updated wording for Exclusion Criterion 
9 to provide further guidance regarding 
herpes zoster and herpes simplex (see 
Section 4.2).
Updated wording for Exclusion Criterion 
15 to clarify corticosteroid use before and 
during the study (see Section 4.2).
Order of assessments reorganized by all 
subjects and by subtype to simplify 
operational conduct of the study (see 
Section 6).

Added “with psoriasis rash” to the 
body surface area assessment for 
subjects with psoriatic arthritis (PsA) 
only, to provide further guidance on 
what is being assessed (see Section 
6).
Added “Westergren Method” to ESR 
assessment to provide clarity as to the 
method sites should be using for this 
study (see SOA and Sections 6. and 7.5).
Per PACL dated 13 January 2017, change 
made to correct typographical error, 
“total volume take during the study does 
not exceed 2.7 mL/kg during any period 
of 30 consecutive days” was changed to 
“…does not exceed 2.4 mL/kg…” (see 
Section 7.2.9.1).

The option to send urine and serum 
samples to the central laboratory was 
removed from Section 7.3 Pregnancy 
Testing.  Covance, the central 
laboratory for the study, provides 
urine pregnancy kits with the 
protocol-specified sensitivity to all 
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sites.  Sites continue to have the 
option to have serum and/or urine 
pregnancy test analyzed by their local 
laboratory.
Analysis of Secondary Endpoints were 
clarified as follows: efficacy will be 
summarized using descriptive statistics, 
such as number and percent for binary 
endpoints, mean, standard deviation and 
quartiles for continuous endpoints (see 
Section 9.2.2).
Added to Section 9.3 Safety Analysis for 
clarity: Special attention will be given to 
the following safety endpoints: MAS, 
uveitis, cytopenias, malignancies, 
cardiovascular diseases, gastrointestinal 
perforations and validated assessments of 
growth and pubertal development.
Protocol Amendment 6
07 April 2016
Changed Study Drug Dosing following 
completion of PK study A3921103 and 
available PK for 2 through <18 years of 
age and also based on FDA 
recommendation to cap dosing at 5 mg 
BID for index study A3921104.
Updated Dose Rationale with PK data 
from A3921103 that provides dose 
rationale for this study (see Section 
1.2.2).
Deleted former Appendix 10 Dose 
Rationale as the dosing rationales are 
already established and explained in 
Section 1.2.2.
Changed Dosing Scheme to reflect 
revised dosing regimen and supplied the 
dosing instruction for the active subjects 
under Amendment 5 (see Section 5.1 and 
Appendix 11).
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Added languages to allow Temporary 
Discontinuation of Study Drug for up to 
28 consecutive days under conditions of 
AEs/SAEs and surgical procedures (see 
Section 5.2).
Incorporated Assessment of 
Investigational Product Dosing 
Compliance into Study Procedure (see 
Schedule of Activities, Section 6.1.4.1, 
Section 6.1.4.2, Section 6.1.4.3, 
Section 6.1.4.4, and Section 6.1.5).
Clarified Investigational Product Dosing 
Compliance and Noncompliance (see 
Section 5.3.4). 
Clarified tofacitinib medication errors as 
Protocol Deviations (PDs) and tofacitinib 
overdose for consistency with adult 
rheumatoid arthritis (RA) studies (see 
Section 8.4 and Section 8.4.1).
Updated Introduction paragraph to reflect 
the current global approval status of 
tofacitinib (see Protocol Summary and 
Section 1.1).
Added benefit/risk wording per Protocol 
Review Committee (PRC) feedback (see 
Protocol Summary and Section 1.2.1).
Added language on post-trial access of 
study drug based on KOL’s feedback (see 
Study Design and Section 3). 
Added erythrocyte sedimentation rate 
(ESR) determination for consistency with 
Index Study A3921104 (see Study 
Objectives and Endpoints, Schedule of 
Activities, Section 2.2.2, Section 6.1.1. 
Section 6.1.3, Section 6.1.4, Section 
6.1.5, Section 7.1.5.2, Section 7.1.6, 
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Section 7.1.7, Section 7.1.8, and Section 
7.1.9).
Added a section on inflammatory markers 
(ESR and CRP) for clarity (see Section 
7.1.5).
Added JADAS 27- CRP and JADAS 27-
ESR, JADAS minimum disease activity 
and inactive disease criteria to secondary 
endpoints for consistency with Index 
Study A3921104 (see Study Objectives 
and Endpoints, Section 2.2.2, Section 
7.1.8, Section 7.1.9 and Section 16).
For subjects with Enthesitis Related 
Arthritis (ERA) only: added Tender 
Entheseal Assessment, Modified 
Schober’s Test, Overall Back Pain and 
Nocturnal Back Pain Assessment for 
consistency with Index Study A3921104 
(see Study Objectives and Endpoints, 
Schedule of Activities, Section 6.1.1.2, 
Section 6.1.4, Section 6.1.5, and Section 
7.1.10).
For subjects with Psoriatic Arthritis (PsA) 
only: added body surface area (BSA) 
affected by psoriasis and Physician’s 
Global Assessment (PGA) of psoriasis for 
consistency with Index Study A3921104 
(see Study Objectives and Endpoints, 
Schedule of Activities, Section 6.1.1.2, 
Section 6.1.4, Section 6.1.5, Section 
7.1.11, Appendix 9 and Appendix 10).
Incorporated new contraception template 
languages (see Schedule of Activities, 
Section 4.1., Inclusion Criterion 3, 
Exclusion Criterion 14, Section 4.3.1 and 
Section 7.3).
Added an Inclusion Criterion to further 
clarify the eligibility for the subjects 
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completed participation in a Qualifying 
JIA Study and especially for the subjects 
discontinued in a Qualifying JIA Study 
for reasons other than tofacitinib related 
Serious Adverse Events (see Inclusion 
Criterion 4).
Updated wording for Exclusion Criterion 
24 to adapt for pediatric population (see 
Exclusion Criterion 24).
Added the other required evidences for 
negative Tuberculosis (TB) on Eligibility 
Criteria including the negative outcome 
of chest radiograph per local standards of 
care or country-specific guidelines and no 
history of either untreated or inadequately 
treated latent or active TB infection for 
clarity (see Inclusion Criterion 12).
Added Annual Tuberculosis (TB) 
Screening and chest radiograph for 
Tuberculosis (TB) status determination 
for consistency with tofacitinib adult 
long-term studies (see Schedule of 
Activities, Section 6.1.4.1, Section 
6.1.4.2, Section 6.1.4.4, Section 6.1.5, 
Section 7.2.2, Section 7.2.4, Section 
7.2.8, and Section 8.5.2).
Deleted Reflex Hepatitis B Testing at 
Screening Visit for Subjects who roll 
over on the Same Day or within 14 Days 
after the EOS Visit from Index Studies to 
avoid the duplicated tests with Index 
Studies (see Section 6.1.2, Section 6.1.3, 
and Section 7.2.8).
Changed exclusion cut-off on lymphocyte 
count from <0. 5 x 109/L to <0.75 x 109/L 
for consistency with Index Study 
A3921104 (see Exclusion Criterion 1e).
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Clarified the active systemic features for 
Systemic JIA in Exclusion Criterion 4 by 
adding “other than active joints and 
elevated acute phase reactants” (see 
Exclusion Criterion 4). 
Updated Exclusion Criterion 6 with 
clarifications “other than Sjogren’s 
syndrome.” for consistency with 
tofacitinib adult RA program.
Deleted “latent or active TB or any 
history of previous TB” from Exclusion 
Criterion 8 to avoid the duplicates with
Inclusion Criterion 12 (see Exclusion 
Criterion 8).
Updated Exclusion Criterion 19 with 
clarifications “IgA deficiency not 
exclusionary” based on feedback from 
investigators.
Changed the maximum dose of 
methotrexate (MTX) from “not to exceed 
20 mg/week or 15 mg/m2/week” to “not 
to exceed 25 mg/week or 20 mg/m2/week, 
whichever is lower” based on 
Investigator’s feedback (see Inclusion 
Criterion 5 and Appendix 1).
Added the maximum dose of 
glucocorticoid as an inclusion criterion 
for consistency with Section 
5.5 Concomitant Medication(s) and also 
Index Study A3921104 (see Inclusion 
Criterion 6).
Added sulfasalazine, chloroquine, 
hydroxychloroquine as allowed 
DMARDS for consistency with adult 
tofacitinib long-term safety studies (see 
Inclusion 8, Section 5.5, Appendix 1, and 
Appendix 3).
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Deleted intra-articular hyaluronate 
sodium injections from Permitted 
Adjustments in RA Therapies and Rescue 
Therapy as intra-articular hyaluronate 
sodium injections are not indicated for 
JIA based on Investigators’ feedback (see
Appendix 3 and Appendix 6).
Updated Disallowed DMARDS and 
Prohibited Concomitant Medications 
Lists for consistency with Index Study 
A3921104 (see Appendix 1 and 
Appendix 5).
Changed the maximum dose of 
corticosteroids from 0.15 mg/kg/day 
(prednisone or equivalent) to 
0.20 mg/kg/day or 10 mg/day (prednisone 
or equivalent), whichever is lower, for 
consistency with Index Study 
A3921104 (see Section 5.5 and 
Appendix 3).
Clarified Herbal Supplements in Dietary 
Supplements and Concomitant 
Medication for consistency with 
Exclusion Criterion 18 (see Section 4.3.5 
and Section 5.5).
Added additional prohibited and 
permitted medications and/or treatments 
for subjects with PsA (see Section 5.5 
and Appendix 1).
Incorporated the component of Duration 
of Morning Stiffness assessment for the 
JIA ACR inactive disease into study 
procedures (see Schedule of Activities, 
Sections 6.1.1. Section 6.1.3, 
Section 6.1.4, Section 6.1.5, and 
Section 7.1.3).
Incorporated the component of Signs and 
Symptoms of Systemic Disease (sJIA 
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ONLY) for the JIA ACR inactive disease 
status determination into study 
procedures (see Schedule of Activities, 
Sections 6.1.1. Section 6.1.3, Section 
6.1.4, and Section 6.1.5).
Modified PK time point from 1 h to 2 h 
for better sampling separation from 0.5 h 
(see Schedule of Activities, Section 
6.1.4.1, Section 6.1.4.2, Section 6.1.5, 
and Section 7.4.1).
Added wording for PK sampling at Early 
Termination for clarity (see Schedule of 
Activities and Section 7.4.1).
Modified Years 6-10 assessment 
frequency for Childhood Health 
Assessment Questionnaire CHAQ, 
Physician Global Evaluation of Disease 
Activity, Joint Assessment of Active 
Arthritis and Limitation of Motion, and 
CRP for consistency across all visits (see 
Schedule of Activities, Section 6.1.4.3 
and Section 7.1.5). 
Changed Childhood Health Assessment 
Questionnaire (CHAQ) Overall 
Wellbeing and Arthritis Pain Visual 
Analog Scale (VAS) from 100 mm VAS 
line to 21- numbered circle VAS for 
consistency with Index Study A3921104 
(see Section 7.1.4, Section 7.1.4.2, and 
Section 7.1.4.3).
Added Childhood Health Assessment 
Questionnaire (CHAQ) completion 
instruction on completers for clarity (see 
Section 7.1.4).
Deleted the image for Childhood Health 
Assessment Questionnaire in former 
Appendix 9 to avoid the duplicates with 
Section 7.1.4.
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Included 21- numbered circle VAS in 
Physician Global Evaluation of Disease 
Activity Instruction for consistency with 
Index Study A3921104 (see 
Section 7.1.2).
Added JIA ACR Flare definition for 
consistency with Index Study 
A3921104 (see Section 7.1.6.2).
Added JIA ACR Clinical Remission on 
Medication definition for consistency 
with Index Study A3921104 (see Study 
Objectives and Endpoints, Section 2.2, 
and Section 7.1.7).
Added Language on Fasting Requirement 
for Lipid Panel for consistency with 
Index Study A3921104 (see Section 
6.1.1.2, Section 6.1.4.1, Section 6.1.4.2, 
Section 6.1.4.4, Section 6.1.5, and 
Section 7.2.8). 
Deleted Lipid Panel at Screening/ 
Baseline Visit for subjects who enroll on 
the same day or within 14 days of the 
EOS Visit from Index Studies to avoid 
the repeated measurement in the EOS 
Visit of Index Studies (see Section 6.1.2 
and Section 6.1.3).
Modified Years 2-5 Lipid Panel Time 
Points for consistency with year 1 lipid 
panel time points (see Schedule of 
Activities and Section 6.1.4.2). 
Removed Tanner Stage Assessment at 
Screening/Baseline Visit for subjects who 
enroll within 14 days of the EOS Visit 
from Index Studies to avoid the repeated 
measurement in the EOS Visit of Index 
Studies (see Schedule of Activities and 
Section 6.1.2 and Section 6.1.3).
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Added Uveitis Exam window after 
screening as ± 30 days relative to the 
visits and qualified equivalent for Uveitis 
Exam per local practice, and changed 
Uveitis Exam frequency for the first year 
from every 6 months to annually (see 
Schedule of Activities, Section 6.1.1.1, 
Section 6.1.4.1, Section 6.1.4.2, Section 
6.1.4.4, and Section 6.1.5), and added 
SUN Criteria for Uveitis Exam (see 
Section 7.2.5 and Section 16) for clarity.  
Clarified that at visits when a Uveitis 
Exam is not planned, subjects should be 
assessed for any changes in uveitis status 
and, for JIA subtypes that may require 
frequent uveitis examination, local 
standard of care should be followed (see 
Schedule of Activities and Section 7.2.5). 
Modified visit window for Month 1 and 
Month 3 visits from ±2 days to ±5 days 
and visit window for Month 6, Month 9, 
and Month 12 visits from ±7 days to 
±10 days to enable flexibility in 
scheduling based on Investigator’s 
feedback (see Schedule of Activities and 
Section 6.1.4). 
Added instruction on the morning dose 
for PK sample collection for clarity (see 
Schedule of Activities, Section 6.1.4.1, 
Section 6.1.4.2, Section 6.1.5 and Section 
7.4.1).
Changed the wording of the Baseline 
Visit Window from “within a month” to 
“within 28 days” in Study Design for 
consistency with the Study Procedures 
(see Study Design and Section 3).
Defined a Month (1 Month = 30 Days) 
for the guidance of scheduling on study 
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visits after the baseline visit (see Study 
Design and Section 3).
Clarified Childhood Health Assessment 
Questionnaire (CHAQ) Secondary 
Endpoint by putting the 3 CHAQ 
subsections as the sub-bullet points under 
CHAQ and added specifications for the 
3 CHAQ subsections for accuracy and 
clarification (see Study Objectives and 
Endpoints and Section 2.2.2).
Clarified JIA ACR 30, 50, 70, 90, 
100 Response Criteria (see Section 
7.1.6.1).
Added “Hepatomegaly” Component for 
Active Systemic Features of Systemic 
JIA in Inactive Disease Status 
Determination for consistency with Index 
Study A3921104 (see Section 7.1.7).
Removed German Investigator Sites 
which are no longer participating in study 
for Investigator ACR30 Response 
Assessment (see Schedule of Activities, 
Section 3, Section 6.1.4.1, Section 
6.1.4.2, Section 6.1.4.3, Section 6.1.4.4, 
Section 6.2, and Section 7.1.6.1).
Clarified the starting point for AE/SAE 
reporting in Schedule of Activities (see 
Schedule of Activities).
Clarified malignancy safety reporting and 
malignancy discontinuation criteria for 
consistency with tofacitinib adult long-
term studies (see Appendix 7).
Changed estimated glomerular filtration 
rate (GFR) calculation from “modified 
Schwartz formula or Cockgroft-Gault 
equation depending on age” to “Bedside 
Schwartz formula” based on 
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investigator’s feedback (see Exclusion 
Criterion 2 and Appendix 4).
Clarified the negative purified protein 
derivative (PPD) test as the one with a 
result of <5 mm induration for 
consistency with RA adult studies (see 
Inclusion Criterion 12a and Section 
7.2.3).
Clarified access/compassionate use
program after the conclusion of this study 
(see Study Design and Section 3).
Updated parent to parent/legal guardian 
and patient to subject throughout for 
consistency.
Replaced CP-690,550 with tofacitinib 
throughout for consistency with index 
studies.

Made other administrative edits to 
improve readability and consistency.
Protocol Amendment 5
17 August 2015

Revisions to protocol in response to 
Canadian Regulatory Authority 
request (see Protocol Summary; 
Schedule of Activities; Sections 3, 
6.1.4.1, 6.1.4.2, 6.1.4.3, 6.1.4.4, 6.2, 
7.1.6).  These changes are applicable 
to Canadian sites only.
Protocol Amendment 4
03 April 2015
Included dosing scheme for subjects 
completing index study A3921104 in 
order to permit continuation of dosing 
received in study A3921104 (Section 
5.2).
Updated Safety Endpoint Adjudication 
Committee related language to include 
currently established committees, and to 
update description of committee roles 
(Section 9.7).
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Updated introductory section to clarify 
CP-690, 550 mechanism of action, and to 
include dosing rationale.
Exclusion criteria #3: Changed estimated 
glomerular filtration rate calculation to 
use the modified Schwartz formula for 
subject ≤12 yrs of age and 
Cockcroft-Gault formula for subjects 
>12 yrs age. 
Other minor administration changes.
Protocol Amendment 3
27 August 2014

Revision of dosing scheme (see 
Section 5).

Revisions to protocol in response to 
German Regulatory Authority request 
(see Protocol Summary; Schedule of 
Activities; Sections 3, 4.1, 6.1.4.1, 
6.1.4.2, 6.1.4.3, 6.1.4.4, 6.2, 7.1.6).

Update to standard protocol template 
text in accordance with latest 
Standard Operating 
Procedures/current protocol template 
(see Sections 4.2, 4.3.1, 5.2.3, 5.3, 
6.2, 7.3, 8.4, 8.7.2, 8.8, 8.11, 8.12, 
8.13, 8.14, 8.15.1, 12.3, 15.1).
Protocol Amendment 2
22 August 2013
Lab testing updated: Screening/Baseline 
Hepatitis B testing updated and baseline 
lipid panel added (Schedule of Activities, 
and Section 6 and 7.2.7).
Assessment of Pubertal Development 
description added; Tanner stage 
self-assessment offered as option in case 
of refusal (Section 7.2.6).
JAMAR changed to CHAQ (Protocol 
Summary, Schedule of Activities, and 
Section 2.2.2, 6, 7.1.5 and Appendix 9).
Wording on Endpoint Adjudication 
Committee updated (Section 9.7).
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CT-02 required protocol language 
updates; Section 4.4, 8.2, 8.7.1, 15.1.
Protocol Amendment 1
18 September 
2012
Duration of the study clarified.  Protocol 
Summary and Study Design.
PK sampling times corrected.  Schedule 
of Activities and Section 7.4.1.
Exclusion criteria for lymphocyte levels 
added.  Section 4.2.
New text on medication errors added.  
Section 5.2.3.
Use of topical prohibited medications 
clarified.  Section 5.4 and Appendix 5.
Visit windows added.  Section 6.1.4 and 
Schedule of Activities.
Month 66 Visit added.  Schedule of 
Activities and Section 6.1.4.4.
Vital signs and targeted physical 
examination added to Months 66, 78, 90, 
102, and 104 Visits.  Schedule of 
Activities and Section 6.1.4.4.
New text on AE reporting added.  
Sections 8.1, 8.2, 8.3, 8.5.2, 8.7, 8.7.1, 
8.10.
New text on assessment of drug induced 
liver injury added.  Section 8.7.1.
New text on safety endpoint adjudication 
added.  Section 9.7.
Typos and administrative inconsistencies 
corrected.
Original protocol
16 November 
2011
N/A
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