Clinical trial NCT02592434
Conditions: Juvenile Idiopathic Arthritis
Keywords: Arthritis Pediatric Long-term JIA polyarticular CP-690,550 tofacitinib Xeljanz
Sponsor: Pfizer
Start date: 2016-06-10; Completion date: 2019-05-16
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluate efficacy, safety and tolerability of tofacitinib in pediatric JIA patients.

Detailed description:
This is a randomized withdrawal, double blind, placebo controlled study of pediatric subjects (2 to \<18 years of age) with JIA. The primary objective is to compare the efficacy of tofacitinib versus placebo for the treatment of signs and symptoms of JIA at Week 26 of the double blind phase as measured by the percentage of subjects with disease flare (according to PRCSG/PRINTO Disease Flare criteria) after Week 18 of the open label run in phase.All eligible subjects enrolled in the study will initially receive open label tofacitinib for 18 weeks (run in phase). At the end of the 18 week run in phase, only subjects who achieve at least a JIA ACR 30 response will be randomized to the 26 week double blind, placebo controlled phase. Subjects who do not achieve a JIA ACR 30 response at this time point will be discontinued from the study. In addition, subjects who experience a single episode of disease flare at any time during the study (including the open label run in and double blind phase) will also be discontinued from the study. All subjects participating in this study, including those discontinued from the study, will have the option, if eligible (based on inclusion and exclusion criteria), of enrolling in the tofacitinib JIA long term extension study (A3921145).

Subjects who are eligible for the 26 week double blind phase will be randomized (1:1 ratio) to either active tofacitinib or placebo. For subjects with polyarticular course JIA (ie, extended oligoarthritis, polyarthritis RF+, polyarthritis RF , systemic JIA with active arthritis but without active systemic features), randomization will be stratified by JIA category and baseline CRP (normal, above normal). For subjects with psoriatic and enthesitis related arthritis, randomization will be stratified by JIA category.

Approximately 210 subjects will be enrolled in the open label run in phase. Among subjects with polyarticular course JIA, stratification will target at least 50% with a baseline CRP above the upper limit of normal. The first cohort (ie, polyarticular course JIA) will have at least 170 subjects enrolled in the run in phase with the minimum number of JIA categories as follows: 24 with extended oligoarthritis, 20 with polyarthritis RF+, 62 with polyarthritis RF-, and no minimum for subjects with systemic JIA with active arthritis but without active systemic features. Additional cohorts (ie, psoriatic and enthesitis related arthritis) will include a minimum of 20 subjects with psoriatic arthritis, and 20 subjects with enthesitis related arthritis. The overall target minimum number of subjects to be enrolled in the study by age is as follows: 20 subjects 2 to \<6 years, 20 subjects 6 to \<12 years, and 20 subjects 12 to \<18 years. The duration of subject participation among those who complete the study (without discontinuation) is expected to be approximately 44 weeks.

Arms: arm 1: Treatment arm: Tofacitinib tablets or solution, according to subjects' body weights arm 2: Control arm: matching placebo tablets or solution for tofacitinib
Interventions: intervention 1: CP-690,550 (tofacitinib) intervention 2: placebo
Intervention descriptions: intervention 1: During the open label run in phase, all subjects will receive active tofacitinib oral tablets or oral solution twice daily (BID) orally, at a dosage based on the subject's body weight as specified below.

During the double blind, placebo controlled phase, subjects will receive either active tofacitinib oral tablets/oral solution or matching placebo oral tablets/oral solution, twice daily (BID), at a dosage specified below.

Body Weight (Dosage in tablet \[BID\] or solution \[BID\]):

5\<7kg (2mg or 2mL); 7\<10kg(2.5mg or 2. mL); 10 \<15kg (3mg or 3mL); 15\<25kg (3.5mg or 3.5mL); 25\<40kg (4mg or 4mL); 40kg (5 mg or 5 ml).

Oral solution (1 mg/mL) is used for subjects \<40 kg. Oral tablets (5 mg) are used for subjects \>=40 kg. intervention 2: matching placebo tablet or solution for tofacitinib

Protocol documents:
Prot_000.pdf: 
Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 1
EFFICACY, SAFETY AND TOLERABILITY OF TOFACITINIB FOR 
TREATMENT OF POLYARTICULAR COURSE JUVENILE IDIOPATHIC 
ARTHRITIS (JIA) IN CHILDREN AND ADOLESCENT SUBJECTS
Compound:
CP-690,550
Compound Name:
Tofacitinib
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2015-001438-46
Protocol Number:
A3921104
Phase:
3
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 2
Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 6
11 July 2018

Changed the minimum number of subjects 
with systemic JIA with active arthritis to be 
enrolled from 20 to no minimum (see Protocol 
Summary and Section 3 [Study Design]).

Updated Section 9.3 (Population 
Pharmacokinetics and Exposure Response 
Analyses) to account for the potential of not 
enrolling 12 subjects.

Applied clarification and administrative 
changes outlined in PACL dated 21 June 2016 
(see Schedule of Activities [SOA], 
Sections 6.5 [Study Procedures 
Week 8, 12/Day 56, 84 Visit], 9.7 [Safety 
Endpoint Adjudication Committee], and 
Document History).

Applied clarification and administrative 
changes outlined in PACL dated 26 Aug 2016. 
(see Protocol Summary, Section 3 [Study 
Design], Appendix 1 [Allowed and Disallowed 
Treatments for JIA], and Appendix 5 [Rescue 
Therapy]).

Apply clarification and administrative changes 
outlined in PACL dated 08 Dec 2016 (see
Section 6.1 [Study Procedures Screening 
Visit]).
Amendment 5
08 March 2018
For Investigative Sites in Germany Only –

Exclusion Criterion 30 revised to ‘Applicable 
to Investigative Sites in Germany Only: 
History of allergies, intolerance or 
hypersensitivity to lactose or CP-690,550 
(tofacitinib).’ Rationale for change: 
Clarification of the exclusion criterion to focus 
on known allergies, intolerance or 
hypersensitivities to the study treatment (active 
substance or excipients). (Refer to 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 3
Section 4.2).
Amendment 4
21 November 2017

For Investigative Sites in Germany Only –
Appendix 10 added to be in compliance with 
article 40 (4) No. 4 of the German Medicines 
Act. Reference to Appendix 10 added to the 
Schedule of Activities and Section 6 (Study 
Procedures).  A new reference was also added 
to References (Section 16).

Revisions to the protocol made in 
Amendment 3 in response to European Union 
Regulatory Authority request apply to 
Germany.  Therefore Germany has been added 
to the statement Investigative Sites in the 
United Kingdom, Spain, Poland, and Belgium 
Only so that it now reads Investigative Sites in 
the United Kingdom, Spain, Poland, Germany 
and Belgium Only” (Refer to Sections 4.1, 4.2, 
4.4.1, 5.2, Schedule of Activity, Section 6.0, 
and Section 7.2.2, 7.2.6, 7.2.10, and 
Appendix 6.  Further details provided below in 
this Document History for Amendment 3.
Amendment 3
30 October 2017
Revisions to protocol in response to European 
Union Regulatory Authority request.  These 
changes are applicable to sites within the United
Kingdom, Spain, Poland, and Belgium. 

Added new exclusion criterion: History of 
allergies, intolerance or hypersensitivity to 
tofacitinib or any components of the 
formulation.  This includes subjects with rare 
hereditary problems of galactose intolerance,
the Lapp lactase deficenecy 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 (Refer to Section 4.2).

Added modified contraception language (Refer 
to Section 4.4.1).

Added guidance for breaking the blind for 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 4
study treatment (Refer to Section 5.2).
•
Added a full skin cancer examination to the 
complete physical examination (Refer to the 
Schedule of Activity, Section 6.0, and 
Section 7.2.2).
•
Added guidance regarding participants who 
have resided or travelled in areas of endemic 
tuberculosis or endemic mycoses; or have 
underlying conditions that may predispose 
them to infection (Refer to Section 7.2.6).
•
Added guidance regarding limiting the number 
of attempts for blood collection (Refer to 
Section 7.2.10).
•
Update the allowable total volume of blood 
taken during any period of 30 consecutive days 
during the study from 2.7 mL/kg to 2.4 mL/kg
(Refer to Section 7.2.10).
•
Provide guidance for monitoring confirmed 
absolute neutrophils count levels of 
500-1000 neutrophils/mm3 (Refer to 
Appendix 6).
Amendment 2
16 March 2016
•
Removed the text stating that recruitment was 
limited to those ≥6 years of age and weighing 
≥15 kg in Summary and Section 3 Study 
Design, Section 4.1 Inclusion Criteria, and 
Section 5.5 Administration as this group is 
now eligible to participate.
•
Removed Canada-specific language limiting 
recruitment to subjects not <6 years as noted in 
Amendment 1 per Canada Regulatory 
Authority agreement. 
•
Added blood volume to Protocol Summary 
section upon request from country authorities.
•
 
 
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 5
•
Added varicella zoster IgG Antibody testing at 
Screening to confirm varicella zoster virus 
(VZV) exposure in subjects who have not 
received at least one dose of vaccine (KOL 
feedback).
•
For subjects with psoriatic arthritis (PsA) only: 
added body surface area (BSA) and 
Physician’s Global Assessment (PGA) to the 
Schedule of Activities, and in Sections 6, 7, 
and Appendices 8 and 9; updated PsA-related 
allowable/prohibited concomitant medications 
where relevant (KOL feedback).
•
Modified pharmacokinetic (PK) sampling 
times and reduced number of samples 
throughout to reduce blood volume and time 
required in clinic which may facilitate 
recruitment (site feedback).
•
Modified visit window for uveitis assessment 
from ±5 days to ±7 days at visits after 
screening in the Schedule of Activities and 
throughout Section 6 where applicable to 
enable flexibility in scheduling (site feedback).  
Clarified that at visits when an exam is not 
planned, subjects should be assessed for any 
changes in uveitis status.
•
Added Duration of Morning Stiffness 
assessment to Schedule of Activities and 
related sections (administrative).
•
Updated Section 1.2.2 Dose Rationale 
following completion of study A3921103 and 
available PK for ages 2 through <18 years of 
age.  Also updated based on FDA 
recommendation to cap dosing at 5 mg BID; 
weight-based dosing scaled accordingly.
•
Section 3 Study Design updated to reflect 
adjusted number of planned investigator sites 
from 120 to 90 (administrative).
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 6

Section 4.1 Inclusion Criterion #2 and 
Appendix 1 clarified allowable dose of 
methotrexate to align with related A392 
protocols (KOLs/administrative).

Section 4.2 Exclusion Criteria were updated 
with clarifications based on feedback from 
investigators.

Section 4.1, 4.2 and 4.4.1 updated language 
around childbearing potential and allowable 
contraception (administrative).

Updated language in Section 4.4.2 to clarify 
guidelines around vaccines and vaccine-related 
exposure (investigator feedback).

Section 4.8 Dietary Supplements clarified use 
of herbal supplements is not allowed to be 
consistent with the exclusion criterion 
(investigator feedback).

Section 5.2 Breaking the Blind section updated 
to indicate the process is electronic using the 
IRT system (administrative).

Throughout the protocol clarified that 
discontinuation due to a single episode of flare 
was defined as meeting the specified 
PRCSG/PRINTO Disease Flare criteria 
(investigator feedback).

Section 5.3 Subject Compliance was updated 
to clarify definition of non-compliance, 
meaning compliance calculated as <80% or 
>110% for pediatric population 
(administrative).

Table 2 in Section 5.5 Administration updated 
to reflect revised weight-based dosing regimen 
(FDA request).

Updated parent to parent/legal guardian 
throughout for consistency.

Updated Schober’s to Modified Schober’s 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 7
throughout for consistency.

Added emphasis in Section 6.6 Day 
126 (Week 18) Visit around eligibility to 
randomize into the double-blind phase which 
requires confirmation of ACR 30 from the 
Central Coordinating Center.

Section 7.1.2 and 7.1.3, scale images were 
replaced with better quality images.

Section 7.1.4 corrected Childhood to Child 
Health Questionnaire.

Section 7.1, updated language to allow 
flexibility in completion of PROs for subjects 
aged 14 and older (site and KOL feedback).

Section 7.1.4 corrected Childhood to Child 
Health Questionnaire.

Section 7.1.11.3 replaced both overall back 
pain and nocturnal back pain 100 mm visual 
analog scale (VAS) with a 21-circle VAS to 
improve data quality exchange with Central 
Coordinating Center.

Section 7.2.3 Uveitis Assessment clarified 
examination per local guidelines and visit 
window (site feedback).

Section 7.2.9 Pregnancy Testing added 
clarification that females of choildbearing 
potential are those who have passed menarche 
(administrative).

Updated Section 9.6 to reflect use of Data 
Safety Monitoring Board (DSMB) 
(administrative).

Removed Appendix 2 Approximate Equivalent 
Morphine Doses of Opioid Analgesics as not 
applicable in this population (KOL feedback).

Appendix 2 Permitted Adjustments in JIA 
Therapies was updated to clarify when changes 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 8
are allowable and specify the maximum dosing 
limits in alignment with related tofacitinib 
studies.

Updated the glomerular filtration rate formula 
in Appendix 3 to the Bedside Schwartz method 
for all subjects (administrative).

Appendix 7 Dosing Rationale (Abbreviated 
Analysis Report) was updated with PK data 
from A3921103 that provides dose rationale 
for this study.

Added Appendix 8 and 9 for BSA and PGA of 
Psoriasis, respectively (KOL).

Other typographical or administrative edits to 
improve readability and consistency.
Amendment 1
17 August 2015
Revisions to protocol in response to Canadian 
Regulatory Authority request (see Protocol 
Summary and Sections 3, 4.1, and 5.5).  These 
changes are applicable to Canadian sites only.
Final Protocol
03 April 2015
Not Applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 9
PROTOCOL SUMMARY
The safety and effectiveness of tofacitinib for the treatment of rheumatoid arthritis (RA) has 
been demonstrated in adult subjects.  The Sponsor is conducting a pediatric development 
program to determine the safety and efficacy of tofacitinib in subjects 2 to <18 years of age 
for the treatment of Juvenile Idiopathic Arthritis (JIA).
Study Objectives
Primary:

To compare the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA at Week 44/End of Study (Week 26 of the double-blind phase) as 
measured by the percentage of subjects with disease flare (according to Pediatric 
Rheumatology Collaborative Study Group/Pediatric Rheumatology International 
Trials Organization [PRCSG/PRINTO] Disease Flare criteria) after Week 18 of the 
open-label run-in phase.
Secondary:

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by the percentage of subjects with disease flare 
(according to PRCSG/PRINTO Disease Flare criteria) at various time points in the 
open-label run-in and double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by time to disease flare in the double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by achievement of JIA American College of 
Rheumatology (ACR) 30, 50, 70, 90, 100 response at various time points in the 
double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in Juvenile Arthritis Disease 
Activity Score (JADAS) 27 C-Reactive Protein (CRP) and JADAS-27 Erythrocyte 
Sedimentation Rate (ESR), and percentage of subjects achieving JADAS minimal 
disease activity and inactive disease at various time points in the double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for treatment of signs and 
symptoms of JIA as measured by the JIA ACR inactive disease and clinical remission 
rate at various time points in the double-blind phase; 

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in each JIA ACR core set 
variable at various time points in the double-blind phase;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 10
•
To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in Child Health 
Questionnaire (CHQ) responses at various time points in the double-blind phase;
•
To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in Childhood Health 
Assessment Questionnaire (CHAQ) responses at various time points in the 
double-blind phase;
•
To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by the occurrence of active uveitis (according to 
Standardized Uveitis Nomenclature [SUN] criteria) in the double-blind phase;
•
In subjects with enthesitis-related arthritis (ERA): To evaluate the efficacy of 
tofacitinib for the treatment of ERA as measured by changes from baseline in the 
Tender Entheseal Assessment, Modified Schober’s Test, and Overall Back Pain and 
Nocturnal Back Pain responses at various time points in the double-blind phase;
•
In subjects with psoriatic arthritis (PsA): To evaluate the efficacy of tofacitinib for the 
treatment of PsA as measured by changes from baseline in body surface area (BSA) 
affected with psoriasis and Physician’s Global Assessment (PGA) at various time 
points in the double-blind phase;
•
To evaluate the efficacy of tofacitinib in the open-label run-in phase;
•
To evaluate the taste acceptability of tofacitinib oral solution, if applicable, on 
Day 14 of the open-label run-in phase;
•
To evaluate safety and tolerability of tofacitinib in subjects with JIA during the study;
•
To evaluate the pharmacokinetics (PK) of tofacitinib in subjects with JIA during the 
open-label run-in phase.
Study Endpoints
Primary:
•
Occurrence of disease flare (according to PRCSG/PRINTO Disease Flare criteria) at 
Week 44/End of Study (Week 26 of the double-blind phase).
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 11
Secondary:

Occurrence of disease flare (according to PRCSG/PRINTO Disease Flare criteria) at 
various time points in the open-label run-in and double-blind phase;

Time to disease flare in the open-label run-in and double-blind phase;

JIA ACR 30, 50, 70, 90, 100 response at various time points in the open-label run-in 
and double-blind phase;

Change from baseline in JADAS 27-CRP and JADAS-27 ESR, and occurrence of 
JADAS minimum disease activity and inactive disease at various time points in the 
open-label run-in and double-blind phase;

Presence of JIA ACR inactive disease at various time points in the open-label run-in 
and double-blind phase and clinical remission on medication at various time points in 
the double-blind phase;

Change from baseline in each JIA ACR core set variable at various time points in the 
open-label run-in and double-blind phase;

Change from baseline in CHQ responses at various time points in the open-label 
run-in and double-blind phase;

Change from baseline in CHAQ responses at various time points in the open-label 
run-in and double-blind phase;

Occurrence of active uveitis (according to SUN criteria) at various time points in the 
open-label run-in and double-blind phase;

In subjects with ERA: Change from baseline in the Tender Entheseal Assessment, 
Modified Schober’s Test, Overall Back Pain and Nocturnal Back Pain responses at 
various time points in the open-label run-in and double-blind phase;

In subjects with PsA: Change from baseline in BSA affected with psoriasis and PGA
of psoriasis assessments at various time points in the open-label run-in and 
double-blind phase;

Taste acceptability of tofacitinib oral solution, if applicable, on Day 14 of the 
open-label run-in phase;

Safety during the study, with focus on serious infections, cytopenias, malignancies, 
cardiovascular diseases, and validated assessments of growth and pubertal 
development;

Plasma tofacitinib concentrations during the open-label run-in phase.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 12
Statistical Analysis
For the primary endpoint, superiority of tofacitinib to placebo for the percentage of subjects 
with disease flare at Week 44/End of Study (Week 26 of the double-blind phase) in subjects 
with polyarticular course (ie, extended oligoarthritis, polyarthritis rheumatoid factor positive 
[RF+], polyarthritis rheumatoid factor negative [RF-], systemic JIA with active arthritis but
without active systemic features) JIA will be tested using the normal approximation approach 
for the binomial populations.  Subjects who discontinue from the study treatment for any 
reason will be considered as having a disease flare, except subjects who discontinue after 
maintaining JIA ACR inactive disease for at least 24 weeks in the double-blind phase.  These 
discontinuations will be considered as non-disease flare.
All secondary efficacy endpoints that are collected in the double-blind withdrawal phase will 
be analyzed by treatment group. For the binary secondary endpoints, including occurrence of 
disease flare prior to Week 44 (Week 26 of the double-blind phase), JIA ACR responses, 
presence of JIA ACR inactive disease and clinical remission, JADAS minimum disease 
activity and inactive disease status, the normal approximation approach for the binary 
populations, as used for the primary analysis, will be performed.  For the continuous 
secondary endpoints, including change from baseline in JADAS 27-CRP, JADAS 27-ESR, 
CHQ, CHAQ, and JIA ACR core set variables, a mixed-effect model with repeated 
measures, will be applied.  The Kaplan-Meier plot will be generated for the secondary 
endpoint of time to flare.  Descriptive/summary statistics for all endpoints, with 95% 
confidence interval (CI) for treatment difference, will be provided.  Baseline demographic 
characteristics, primary and key secondary endpoints will also be summarized by JIA 
category, baseline CRP, concomitant methotrexate treatment, prior biologic failures, history 
of uveitis and age. 
Safety analysis will be performed on all subjects who received at least one dose of study 
drug.  Safety data will be subject to clinical review and summarized by appropriate 
descriptive statistics.
Details of the statistical analysis will be described in the Statistical Analysis Plan (SAP).
Study Design
This is a randomized withdrawal, double-blind, placebo-controlled study of pediatric subjects 
(2 to <18 years of age) with JIA (see Section 4.1, Inclusion Criteria).
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 13
All eligible subjects enrolled in the study will initially receive open-label tofacitinib for 
18 weeks (run-in phase).  At the end of the 18 week run-in phase, only subjects who achieve 
at least a JIA ACR 30 response will be randomized to the 26 week double-blind, 
placebo-controlled phase.  Subjects who do not achieve a JIA ACR 30 response at this time 
point will be discontinued from the study.  In addition, subjects who experience a single 
episode of disease flare (see Section 7.1.7, PRCSG/PRINTO Disease Flare Criteria) at any 
time during the study (including the open-label run-in and double-blind phase) will also be 
discontinued from the study.
 
 
Subjects who are eligible for the 26 week double-blind phase will be randomized (1:1 ratio) 
to either active tofacitinib or placebo.  For subjects with polyarticular course JIA 
(ie, extended oligoarthritis, polyarthritis RF+, polyarthritis RF-, systemic JIA with active 
arthritis but without active systemic features), randomization will be stratified by JIA 
category and baseline CRP (normal, above normal). Subjects with psoriatic arthritis and 
enthesitis-related arthritis randomization will be stratified by JIA category.
A schematic of the study design is shown below:
Approximately 210 subjects will be enrolled in the open-label run-in phase.  Among subjects 
with polyarticular course JIA, stratification will target enrollment of at least 50% with a 
baseline CRP above the upper limit of normal.
The cohort with polyarticular course JIA will have at least 170 subjects enrolled in the 
open-label run-in phase with the minimum number of JIA categories as follows: 24 with 
extended oligoarthritis, 20 with polyarthritis RF+, and 62 with polyarthritis RF-. There is no 
minimum number for the subjects with systemic JIA with active arthritis but without active 
systemic features. Additional cohorts (ie, psoriatic arthritis and enthesitis-related arthritis) 
will include a minimum of 20 subjects with psoriatic arthritis, and 20 subjects with 
enthesitis-related arthritis.  The overall target minimum number of subjects to be enrolled in 
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 14
the study by age is as follows: 20 subjects 2 to <6 years, 20 subjects 6 to <12 years, and 
20 subjects 12 to <18 years.  The Sponsor will monitor enrollment and periodically notify 
investigator sites regarding the status of enrollment in the various JIA categories and age 
groups.
Initial screening and enrollment of subjects (at least the first 12 subjects) into 
Study A3921104 must be limited to 12 years of age or greater for all eligible JIA subtypes 
(rheumatoid factor negative [RF-] and positive [RF+] polyarthritis, extended oligoarticular, 
psoriatic arthritis, enthesitis related arthritis and systemic arthritis without systemic features 
JIA subtypes).
The duration of subject participation among those who complete the study (without
discontinuation) is expected to be approximately 44 weeks. The estimated blood volume for 
planned assessments over the course of the study (44 weeks) is approximately 99 mL.  
Pediatric blood tubes will be used (reduced volume) for testing to determine eligibility, 
monitor safety, and measure PK.
The study will be conducted over a period of approximately 3 years. 
 
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 15
SCHEDULE OF ACTIVITIES
The schedule of activities (SOA) table provides an overview of the protocol visits and procedures.  Please refer to Section 6 (Study 
Procedures) and Section 7 (Assessments) of the protocol for detailed information on each procedure and assessment required for 
compliance with the protocol. The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of 
activities, in order to conduct evaluations or assessments required to protect the well-being of the subject.
For Investigative Sites in Germany Only: The degree of burden and the risk threshold should be assessed at each scheduled visit as 
outlined in Appendix 10.
Protocol Activity
Screening
Day 11
Week 2
Week 4
Week 8, 12
Week 18
Week 20, 24, 28, 
32, 36, 40
Week 44 
(EOS) or 
Early 
Termination2
Day 14
(3 days)
Day 28
(3 days)
Day 56, 84
(3 days)
Day 126
(3 days)
Day 140, 168, 
196, 224, 252, 
280 (3 days)
Day 308
(3 days)
Informed Consent/Assent 
X
Medical History, Family History
X
Uveitis Assessment3
X
X
(Day 168, 
Week 24 only)
X
Prior/Concomitant Medications
X
X
X
X
X
X
X
X
Complete Physical Examination21
X
X
X
Targeted Physical Examination4
X
X
X
X
X
Vital Signs, Height, Weight5
X
X
X
X
X
X
X
X
Tanner Stage Assessment
X
X
Assessments to be Faxed/Emailed to the Centralized Coordinating Center (CCC):
JIA Disease Status Worksheet Including:
X
X
X
X
X
X
X
X
Uveitis Status Assessment
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
JIA Joint Assessment (Swelling, Pain on Motion and/or 
Tenderness, Limitations of Motion)
X
X
X
X
X
X
X
X
Physician’s Global Evaluation of Overall Disease Activity
X
X
X
X
X
X
X
X
Childhood Health Assessment Questionnaire (CHAQ)  
X
X
X
X
X
X
X
X
Child Health Questionnaire (CHQ) (Not required by the CCC)
X
X
X
X
Disease Flare Assessment (According to the PRINTO/PRCSG 
Criteria and confirmed by the CCC) 
X
X
X
X
X
X
X
X


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 16
Protocol Activity
Screening
Day 11
Week 2
Week 4
Week 8, 12
Week 18
Week 20, 24, 28, 
32, 36, 40
Week 44 
(EOS) or 
Early 
Termination2
Day 14
(3 days)
Day 28
(3 days)
Day 56, 84
(3 days)
Day 126
(3 days)
Day 140, 168, 
196, 224, 252, 
280 (3 days)
Day 308
(3 days)
Subjects with Enthesitis-Related Arthritis (ERA) Only:
Tender Entheseal 
X
X
X
X
X
X
X
X
Modified Schober’s Test, Overall Back Pain and 
Nocturnal Back Pain Assessment 
X
X
X
X
X
X
X
X
Subjects with Psoriatic Arthritis (PsA) Only (Not required by the CCC):
Body Surface Area (BSA)
X
X
X
X
X
X
X
X
Physician’s Global Assessment (PGA) for Psoriasis
X
X
X
X
X
X
X
X
Peripheral Blood Sample Collection for:
QuantiFERON-TB Gold In-Tube Test (or Purified Protein 
Derivative)6
X
Erythrocyte Sedimentation Rate7 (Fax/email result to the CCC)
X
X
X
X
X
X
X
X
C-Reactive Protein
X
X
X
X
X
X
X
X
Hematology8, Chemistry9, Urinalysis10
X
X
X
X
X
X
X
X
Lipid Panel11
X
X
X
X
Blood (serum) or Urine Pregnancy Test, Contraceptive Check12
X
X
X
X
X
X
X
X
Varicella Zoster Virus Serology (VZV IgG Ab) (if applicable)13
X
Rheumatoid Factor (RF)
X
Human Immunodeficiency Virus (HIV-1, HIV-2), Hepatitis B 
Surface Antigen (HBsAg), Hepatitis B Surface Antibody 
(HbsAb), Hepatitis B Core Antibody (HBcAb), Hepatitis C 
Antibody (HCV Ab), Hepatitis C Viral RNA (HCV RNA)14
X
Anti-Cyclic Citrullinated Protein (anti-CCP) Antibodies, 
Antinuclear Antibodies (ANA), Human Leukocyte Antigen B27 
(HLA-B27)
X
Retained Biospecimens
X15
X16
X15
X15
Pharmacokinetic Sampling:
Tofacitinib PK Sampling (first 40 subjects enrolled, excluding 
subjects with Systemic JIA)
X
X(Day 84)17
Tofacitinib PK Sampling (after first 40 subjects enrolled, 
excluding subjects with Systemic JIA)
X18
X
(Day 84)17
Tofacitinib PK Sampling (subjects with Systemic JIA only)
X18
X
(Day 84)17
Randomization to Double-Blind Withdrawal Phase (only 
subjects who achieve JIA ACR 30 response, as confirmed by the
Centralized Coordinating Center)19
X19


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 17
Protocol Activity
Screening
Day 11
Week 2
Week 4
Week 8, 12
Week 18
Week 20, 24, 28, 
32, 36, 40
Week 44 
(EOS) or 
Early 
Termination2
Day 14
(3 days)
Day 28
(3 days)
Day 56, 84
(3 days)
Day 126
(3 days)
Day 140, 168, 
196, 224, 252, 
280 (3 days)
Day 308
(3 days)
Investigational Product Dispensing
X
X
X
X
X
X
Investigational Product Dosing
< ----------Active Tofacitinib ----------- >
<-Active Tofacitinib/Placebo ->
Investigation Product Dosing Compliance
X
X
X
X
X
X
Tofacitinib Oral Solution Taste Acceptability Assessment
X
Adverse Event Assessment
X20
X
X
X
X
X
X
X
Review Entry Criteria for A3921145
X
1.
Day 1 visit (ie, the first day of treatment with investigational product) must occur within 30 days of the first screening visit activity. If more than 30 days has elapsed, all 
screening procedures and assessments must be repeated.  Sponsor approval must be obtained prior to re-screening a subject.
2.
Early termination (ET) procedures should be completed if a subject does not complete all 44 weeks to the end of study.  If a subject discontinues at a regularly scheduled visit, 
this may be considered the ET visit and all required procedures and visit-specific CRFs should be completed, if possible; please use an unplanned Tanner Stage assessment 
CRF if this occurs.
3.
Uveitis exam at Screening is not required if there is documentation of uveitis assessment by an ophthalmologist (or qualified equivalent per local practice) within 3 months of 
the screening visit.  If there is no documentation, a uveitis exam by an ophthalmologist (or qualified equivalent per local practice) must be performed prior to study treatment.  
There is a window of 7 days for the Week 24 and Week 44/ET visits to allow for scheduling this assessment.  At all other visits the investigator should assess and document 
if there are any potential changes in uveitis status; referral for formal evaluation should be done if deemed clinically necessary.  If uveitis is confirmed, please capture as an 
AE and complete an unplanned uveitis CRF.
4.
Targeted physical exam consists of examination of heart, lungs, extremities for peripheral edema, abdomen and lymph nodes.
5.
Vital signs include blood pressure, pulse rate, and temperature assessment.
6.
A negative PPD test can be substituted for the QuantiFERON-TB Gold In-Tube test only if the central laboratory is unable to perform the QuantiFERON-TB Gold In-Tube
test or cannot determine the results to be positive or negative and the Sponsor approves it on a case-by-case basis.  In addition to protocol required TB testing, sites should 
follow their local standards for TB status determination, which may include chest X-ray.  See Section 7.2.6 for additional details.
7.
The Erythrocyte Sedimentation Rate (ESR) will be determined locally utilizing an ESR Testing Kit provided to the investigator site by the Sponsor.  Please refer to the ESR 
Testing Kit for detailed instruction on how to perform this test appropriately.  The ESR result will be recorded on the appropriate CRF.  The ESR result also will be 
faxed/emailed to the Centralized Coordinating Center.
8.
Hematology includes: Hemoglobin, hematocrit, red blood cells, white blood cells, neutrophils (%, absolute), lymphocytes (%, absolute), monocytes (%, absolute), 
eosinophils (%, absolute), basophils (%, absolute), and platelets.
9.
Chemistry includes: Sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, glucose, calcium, total protein, total bilirubin (TB), direct bilirubin, indirect 
bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transferase (GGT), albumin, creatine phosphokinase 
kinase (CPK).


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 18
10. Urinalysis includes specific gravity, pH, protein, glucose, ketones, blood and leukocyte esterase, urine microscopy (only if dipstick positive for blood or protein, or if 
clinically indicated).
11. Lipid profile includes total cholesterol, low density lipoproteins (LDL), high density lipoproteins (HDL), triglycerides, apolipoprotein A1, apolipoprotein B.  Subjects should 
be instructed to fast for approximately 9 to 12 hours, if possible, prior to lipid panel testing. 
12. Blood (serum) or urine pregnancy testing is required only for females who are of childbearing potential (see Section 7.2.9).  Pregnancy testing will be performed locally or by 
the local or central lab at any time.  Pregnancy testing may be repeated more frequently if required by local practices, if a menstrual cycle is missed, or if potential pregnancy 
is otherwise suspected.  A positive urine pregnancy test will be confirmed by a blood (serum) pregnancy test performed either locally or by the central laboratory.  A 
contraceptive check also will be performed to confirm that contraception, if assigned, is being used consistently and correctly.  Childbearing status also will be checked and 
contraception implemented in subjects who mature physically and behaviorally during the conduct of the study.
13. VZV IgG antibody testing is required to confirm eligibility in subjects who have not received at least one dose of a varicella zoster vaccine (see Section 7.2.8).
14. 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 7.2.7 for details regarding viral testing and interpretation of results.
15. Prep B2.5 (2 mL) and Prep R1 (2.5 mL) should be collected pre-dose on Day 1, and at the Week 18 and Week 44/EoS/ET visits.
16. Prep D1.5 (2 mL EDTA) should be collected at Week 8.
17. PK sampling may be obtained at a later visit up to the Week 18/Day 126 visit; 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 7.3 for details regarding PK sampling.
18. PK sampling may be obtained at a later visit up to at the Week 4/Day 28 visit; 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 7.3 for details regarding PK sampling.
19. Only subjects who achieve at least a JIA ACR 30 response, as confirmed by the Centralized Coordinating Center, will be randomized to the double-blind, placebo-controlled 
phase.  See Section 6.6 and Section 7.1.6 for details.
20. Serious adverse events (SAEs) are captured from the time of informed consent at Screening (see Section 8.7); adverse events (AEs) are captured following first dose of 
investigational product (see Section 8.1). 
21. Applicable to Investigative Sites in the United Kingdom (UK), Spain, Poland, Germany and Belgium Only: a full skin cancer examination must be performed as part of 
the complete physical examination.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 19
TABLE OF CONTENTS
PROTOCOL SUMMARY.........................................................................................................9
SCHEDULE OF ACTIVITIES................................................................................................15
LIST OF TABLES...................................................................................................................24
LIST OF FIGURES .................................................................................................................24
APPENDICES .........................................................................................................................24
1. INTRODUCTION ...............................................................................................................27
1.1. Indication.................................................................................................................27
1.2. Background .............................................................................................................27
1.2.1. Study Rationale...........................................................................................27
1.2.2. Dose Rationale............................................................................................27
1.3. Single Reference Safety Document.........................................................................30
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................30
2.1. Objectives................................................................................................................30
2.2. Endpoints.................................................................................................................31
3. STUDY DESIGN.................................................................................................................33
4. SUBJECT SELECTION......................................................................................................34
4.1. Inclusion Criteria.....................................................................................................34
4.2. Exclusion Criteria....................................................................................................37
4.3. Randomization Criteria ...........................................................................................40
4.4. Lifestyle Guidelines ................................................................................................40
4.4.1. Contraception..............................................................................................40
4.4.2. Vaccine and Exposure to Infections Guidelines.........................................42
4.4.2.1. Subject Specific Recommendations..........................................42
4.4.2.2. Guidance Regarding Household Contact Vaccine-Related 
Exposure............................................................................................42
4.4.3. Non-Pharmacologic Interventions..............................................................42
4.4.4. Elective Surgery..........................................................................................42
4.4.5. Dietary Supplements...................................................................................43
4.5. Sponsor’s Qualified Medical Personnel..................................................................43
5. STUDY TREATMENTS.....................................................................................................43
5.1. Allocation to Treatment ..........................................................................................43


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 20
5.2. Breaking the Blind ..................................................................................................44
5.3. Subject Compliance.................................................................................................45
5.4. Investigational Product Supplies.............................................................................45
5.4.1. Dosage Form(s) and Packaging..................................................................45
5.4.2. Preparation and Dispensing........................................................................45
5.5. Administration.........................................................................................................45
5.6. Investigational Product Storage ..............................................................................46
5.7. Investigational Product Accountability...................................................................47
5.7.1. Destruction of Investigational Product Supplies ........................................47
5.8. Concomitant Treatment(s).......................................................................................47
5.9. Rescue Therapy.......................................................................................................48
6. STUDY PROCEDURES .....................................................................................................48
6.1. Screening Visit ........................................................................................................48
6.2. Day 1 Visit ..............................................................................................................50
6.3. Week 2/Day 14 Visit...............................................................................................52
6.4. Week 4/Day 28 Visit...............................................................................................54
6.5. Week 8, 12/Day 56, 84 Visit...................................................................................55
6.6. Week 18/Day 126 Visit...........................................................................................57
6.7. Week 20, 24, 28, 32, 36, 40/Day 140, 168, 196, 224, 252, 280 Visit.....................59
6.8. Week 44, End of Study (EoS)/Day 308 or Early Termination (ET) Visit ..............60
6.9. Subject Withdrawal.................................................................................................62
6.9.1. Subject Withdrawal Due to Failure to Achieve JIA ACR 30 
Response or Disease Flare ...............................................................................62
7. ASSESSMENTS..................................................................................................................63
7.1. Efficacy Assessments..............................................................................................63
7.1.1. Number of Joints with Active Arthritis ......................................................63
7.1.2. Physician’s Global Assessment of Overall Disease Activity .....................64
7.1.3. Childhood Health Assessment Questionnaire (CHAQ) .............................64
7.1.4. Child Health Questionnaire (CHQ) ............................................................66
7.1.5. Inflammatory Markers................................................................................66
7.1.5.1. C-Reactive Protein (CRP).........................................................66
7.1.5.2. Erythrocyte Sedimentation Rate (ESR).....................................67


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 21
7.1.6. JIA Core Set Variables and Response Definition.......................................67
7.1.7. PRCSG/PRINTO Disease Flare Criteria ....................................................68
7.1.8. JIA ACR Clinical Inactive Disease and Clinical Remission Criteria.........68
7.1.9. Juvenile Arthritis Disease Activity (JADAS-27 CRP, JADAS-27 
ESR) Score.......................................................................................................69
7.1.10. JADAS-27 Minimal Disease Activity and Inactive Disease ....................69
7.1.11. Additional Assessments in Subjects with Enthesitis-Related 
Arthritis............................................................................................................70
7.1.11.1. Tender Entheseal Assessment .................................................70
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).........72
7.1.12.1. Body Surface Area (BSA).......................................................72
7.1.12.2. Physician’s Global Assessment (PGA) of Psoriasis ...............72
7.1.13. Centralized Coordinating Center..............................................................72
7.2. Safety Assessments .................................................................................................73
7.2.1. Medical and Family History.......................................................................73
7.2.2. Physical Examination .................................................................................73
7.2.3. Uveitis Assessment.....................................................................................74
7.2.4. Vitals Signs Assessment.............................................................................74
7.2.5. Pubertal Development Assessment (Tanner Stages) ..................................75
7.2.6. Tuberculosis Testing...................................................................................75
7.2.6.1. QuantiFERON-TB Gold In-Tube Test....................................76
7.2.6.2. Purified Protein Derivative (PPD) Test.....................................76
7.2.7. Laboratory Testing......................................................................................76
7.2.8. Varicella Zoster Virus (VZV) IgG Antibody (Ab) Testing........................78
7.2.9. Pregnancy Testing ......................................................................................79
7.2.10. Blood Volume...........................................................................................79
7.3. Pharmacokinetic Assessment ..................................................................................80
7.3.1. PK Blood Sample Collection Time ............................................................81
7.3.1.1. First 40 Subjects Enrolled (Excluding Subjects with 
Systemic JIA) ....................................................................................81


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 22
7.3.1.2. After First 40 Subjects Enrolled (excluding Subjects with 
Systemic JIA) ....................................................................................81
7.3.1.3. Subjects with Systemic JIA.......................................................82
7.3.2. Blood Sample Processing ...........................................................................82
7.3.3. PK Sample Shipment..................................................................................83
7.4. Tofacitinib Oral Solution Taste Acceptability Assessment ....................................83
7.5. Banked Biospecimens .............................................................................................83
7.5.1. Markers of Drug Response.........................................................................83
7.5.2. Additional Research....................................................................................85
8. ADVERSE EVENT REPORTING......................................................................................85
8.1. Adverse Events........................................................................................................85
8.2. Reporting Period .....................................................................................................86
8.3. Definition of an Adverse Event...............................................................................86
8.4. Medication Errors....................................................................................................87
8.4.1. Tofacitinib Overdose ..................................................................................87
8.5. Infections.................................................................................................................87
8.5.1. Serious Infections .......................................................................................88
8.5.2. Treated Infections.......................................................................................88
8.6. Abnormal Test Findings..........................................................................................88
8.7. Serious Adverse Events...........................................................................................88
8.7.1. Protocol-Specified Serious Adverse Events...............................................89
8.7.2. Potential Cases of Drug-Induced Liver Injury............................................89
8.8. Hospitalization ........................................................................................................90
8.9. Severity Assessment................................................................................................91
8.10. Causality Assessment............................................................................................92
8.11. Exposure During Pregnancy..................................................................................92
8.12. Occupational Exposure .........................................................................................93
8.13. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal)...............................................................................................................93
8.14. Eliciting Adverse Event Information ....................................................................94
8.15. Reporting Requirements........................................................................................94
8.15.1. Serious Adverse Event Reporting Requirements .....................................94
8.15.2. Nonserious Adverse Event Reporting Requirements ...............................94


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 23
8.15.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................95
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................95
9.1. Sample Size Determination.....................................................................................95
9.2. Efficacy Analysis ....................................................................................................95
9.2.1. Analysis of Primary Endpoint ....................................................................95
9.2.2. Analysis of Secondary Endpoints...............................................................95
9.3. Population Pharmacokinetics and Exposure-Response Analyses...........................96
9.4. Safety Analysis........................................................................................................97
9.5. Interim Analysis ......................................................................................................97
9.6. Data Safety Monitoring Board (DSMB) .................................................................97
9.7. Safety Endpoint Adjudication Committee ..............................................................97
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................98
11. DATA HANDLING AND RECORD KEEPING .............................................................99
11.1. Case Report Forms/Electronic Data Record .........................................................99
11.2. Record Retention...................................................................................................99
12. ETHICS............................................................................................................................100
12.1. Institutional Review Board/Ethics Committee....................................................100
12.2. Ethical Conduct of the Study ..............................................................................100
12.3. Subject Information and Consent........................................................................100
12.4. Subject Recruitment ............................................................................................101
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................101
13. DEFINITION OF END OF TRIAL.................................................................................102
13.1. End of Trial in the United States.........................................................................102
13.2. End of Trial in a Member State...........................................................................102
13.3. End of Trial in All Other Participating Countries...............................................102
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................102
15. PUBLICATION OF STUDY RESULTS........................................................................102
15.1. Communication of Results by Pfizer ..................................................................102
15.2. Publications by Investigators ..............................................................................103
16. REFERENCES ................................................................................................................105
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 24
LIST OF TABLES
Table 1.
Summary of Tofacitinib Pharmacokinetic Parameter Values (CV%) in JIA 
Subjects from Study A3921103............................................................................29
Table 2.
Study Treatment Dosing and Administration.......................................................46
Table 3.
Blood Volume.......................................................................................................80
LIST OF FIGURES
Figure 1.
Modified Schober’s Test.......................................................................................71
APPENDICES
Appendix 1. Allowed and Disallowed Treatments for JIA....................................................107
Appendix 2. Permitted Adjustments In JIA Therapies ..........................................................109
Appendix 3. Estimated Glomerular Filtration Rate Calculation............................................110
Appendix 4. Prohibited Concomitant Medications................................................................111
Appendix 5. Rescue Therapy.................................................................................................112
Appendix 6. Guidelines For Safety Monitoring And Discontinuations ................................114
Appendix 7. Dosing Rationale (Abbreviated Analysis Report).............................................116
Appendix 8. Body Surface Area (BSA).................................................................................129
Appendix 9. Physician’s Global Assessment of Psoriasis.....................................................130
Appendix 10. By Visit Assessment of the Degree of Burden and Risk Threshold 
During the Trial (Investigative Sites in Germany Only) ....................................131


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 25
List of Abbreviations
Abbreviation
Term
Ab
Antibody
ACR
American College of Rheumatology
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil counts
AST
Aspartate aminotransferase
BID
Twice daily
BQL
Below quantification limit
BSA
Body surface area
CCC
Centralized Coordinating Center
CDS
Core data sheet
CHAQ
Childhood Health Assessment Questionnaire
CHQ
Child Health Questionnaire
CI
Confidence interval
CL
Clearance
CRF
Case report form
CRP
C-reactive protein
CSA
Clinical study agreement
CTA
Clinical trial application
DMARD
Disease Modifying Antirheumatoid Drug
DMC
Data monitoring committee
DU
Dispensable unit
EC
Ethics committee
ECG
Electrocardiogram
EDMC
External data monitoring committee 
EDP
Exposure during pregnancy
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
ERA
Enthesitis-related arthritis
ESR
Erythrocyte sedimentation rate
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GI
Gastrointestinal
HCG
Human Chorionic Gonadotropin
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
ICH
International Conference on Harmonisation
ID
Identification
IgG
Immunoglobulin G
ILAR
International League Against Rheumatism


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 26
Abbreviation
Term
IND
Investigational new drug application
INR
International normalized ratio
IRB
Institutional review board
IRT
Interactive response technology
IUD
Intrauterine device
IUS
Intrauterine system
JADAS
Juvenile Arthritis Disease Activity
JIA
Juvenile Idiopathic Arthritis
LFT
Liver function test
LSLV
Last subject last visit 
MACE
Major adverse cardiovascular events 
MAS
Macrophage-activation syndrome
MTX
Methotrexate
N/A
Not applicable
NMSC
Non-melanoma Skin Cancer
PCD
Primary completion date
PGA
Physician’s Global Assessment
PK
Pharmacokinetics
POPPK
Population PK
PRCSG/PRINTO
Pediatric Rheumatology Clinical Study Group/Pediatric 
Rheumatology International Trials Organization
PsA
Psoriatic arthritis
PT
prothrombin time
RA
Rheumatoid arthritis
RF+
Rheumatoid Factor positive
RF-
Rheumatoid Factor negative
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
sJIA
Systemic JIA
SOA
Schedule of Activities
SOP
Standard operating procedure
SRSD
Single reference safety document
SUN
Standard Uveitis Nomenclature
TB
Tuberculosis
ULN
Upper limit of normal
UK
United Kingdom
US
United States
VAS
Visual analog scale
VZV
Varicella zoster virus
WCC
World Care Clinical


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 27
1. INTRODUCTION
1.1. Indication
Tofacitinib (also known as CP-690,550) is currently approved in the United States and more 
than 45 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.  It may be used in combination with methotrexate or other non-biologic disease 
modifying antirheumatic drugs (DMARDs).
1.2. Background
Tofacitinib is a potent selective inhibitor of the Janus Kinase (JAK) family of kinases with a 
high degree of selectivity against other kinases in the human genome.  In kinase assays, 
tofacitinib inhibits JAK1, JAK2, JAK3 and, to a lesser, extent Tyrosine Kinase 2 (TyK2).  In 
cellular settings where JAK kinases signal in pairs, tofacitinib preferentially inhibits 
signaling by heterodimeric receptors associated with JAK3 and/or JAK1 with functional 
selectivity over receptors that signal via pairs of JAK2.  Inhibition of JAK1 and JAK3 by 
tofacitinib blocks signaling through the common gamma chain containing receptors for 
several cytokines, including interleukins (IL) IL-2, -4,-7,-9, -15 and -21(Johnston 1996, 
Conklyn 2004, Changelian 2008).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 
interferon (IFN)γ.  At higher exposures inhibition of erythropoietin signaling could occur via 
inhibition of JAK2 signaling.
The safety and effectiveness of tofacitinib for the treatment of RA has been demonstrated in 
adult subjects.  The Sponsor is conducting a pediatric development program to determine the
safety and efficacy of tofacitinib in subjects 2 to <18 years of age for the treatment of JIA.
 
 
1.2.1. Study Rationale
This Phase 3 study is intended to provide evidence of efficacy and safety of tofacitinib in 
subjects with JIA.
Due to the availability of effective treatments for subjects with JIA, a randomized withdrawal 
study design was selected to limit exposure to placebo treatment. 
1.2.2. Dose Rationale
Selection of doses for this first efficacy study of tofacitinib in JIA subjects is 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 RA patients.  Based on the tofacitinib PK in the 
adult RA population, clearance (CL) of tofacitinib is not dependent on body weight (range 
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 28
studied in the adult RA program was 40 kg to 140 kg).  Thus, the dose of tofacitinib in 
adolescents with body weight 40 kg was set to 5 mg twice daily (BID), the only approved 
dose of tofacitinib in adult RA patients in most countries.  The tofacitinib doses for the 
younger JIA subjects 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).12 Thus, the dose 
range selected for JIA subjects across the weight-groups is predicted to achieve Cavg,ss values 
equivalent to those from 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 (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).
Eq. 1
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 are presented in 
Table 1. The number of subjects dosed across three cohorts (C1, C2, C3) in this study was
26, with 8, 9, and 9 in each of the following age groups/cohorts: 12 to <18 years (C1), 6 to 
<12 years (C2), and 2 to <6 years (C3), respectively.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 29
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)
12 to <18 yrs
(C1)
8
38.3-70.9
156.6 (25)
46.97 (40)
0.75 [0.5-6.9]
2.616 
0.454
28.09 (22)
6 to <12 yrs
(C2)
9
20.3-48.9
118.8 (27)
41.67 (29)
1.0 [0.50-2.05]
1.949 
0.294
25.48 (40)
2 to <6 yrs
(C3)
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 14.4.3.1.1, date of table 
generation: 28 January 2016 (09:28).
The exposures from the first 16 subjects in Cohorts 1 and 2 (between 8 and 17 years of age) 
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] 
patients), 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 a 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 and the exponents were estimated. The 
estimated power exponents were 0.0.292 (%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 not be statistically significant.  Thus it was not included in the model.
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 patients with maximum nominal dose capped at 5 mg BID for subjects with body weight 
>40 kg. With the current proposed dosing regimen (Section 5.5), the predicted Cavg 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 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 5.5 for the
planned doses and regimens).


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 30
PK collection time points (see Section 7.3.1) in this study were decided based on optimal PK 
sampling design utilizing the population PK (POPPK) model built on data from A3921103.  
Details of the POPPK model and simulation results leading to the proposed current dosing 
regimen for this study are presented in Appendix 7.
1.3. Single Reference Safety Document
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD) which for this study is the current version of the Tofacitinib Investigator 
Brochure.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary:

To compare the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA at Week 44/End of Study (Week 26 of the double-blind phase) as 
measured by the percentage of subjects with disease flare (according to 
PRCSG/PRINTO Disease Flare criteria) after Week 18 of the open-label run-in 
phase.
Secondary:

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by the percentage of subjects with disease flare 
(according to PRCSG/PRINTO Disease Flare criteria) at various time points in the 
double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by time to disease flare in the double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by achievement of JIA ACR 30, 50, 70, 90, 
100 response at various time points in the double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in JADAS 27-CRP and 
JADAS-27 ESR, and percentage of subjects achieving JADAS minimum disease 
activity and inactive disease at various time points in the double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for treatment of signs and 
symptoms of JIA as measured by the JIA ACR inactive disease and clinical remission 
rate at various time points in the double-blind phase;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 31
•
To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in each JIA ACR core set 
variable at various time points in the double-blind phase;
•
To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in CHQ responses at various 
time points in the double-blind phase;
•
To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in CHAQ responses at 
various time points in the double-blind phase;
•
To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by the occurrence of active uveitis (according to SUN 
criteria) in the double-blind phase;
•
In subjects with ERA: To evaluate the efficacy of tofacitinib for the treatment of ERA 
as measured by changes from baseline in the Tender Entheseal Assessment, Modified 
Schober’s Test, and Overall Back Pain and Nocturnal Back Pain responses at various 
time points in the double-blind phase;
•
In subjects with PsA: To evaluate the efficacy of tofacitinib for the treatment of PsA 
as measured by changes from baseline in the BSA affected with psoriasis and PGA of 
psoriasis assessments at various time points in the double-blind phase;
•
To evaluate the efficacy of tofacitinib in the open-label run-in phase;
•
To evaluate the taste acceptability of tofacitinib oral solution, if applicable, on 
Day 14 of the open-label run-in phase;
•
To evaluate safety and tolerability of tofacitinib in subjects with JIA during the study;
•
To evaluate the PK of tofacitinib in subjects with JIA during the open-label run-in 
phase.
2.2. Endpoints
Primary:
•
Occurrence of disease flare (according to PRCSG/PRINTO Disease Flare criteria) at 
Week 44/End of Study (Week 26 of the double-blind phase).
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 32
Secondary:

Occurrence of disease flare (according to PRCSG/PRINTO Disease Flare criteria) at 
various time points in the open-label run-in and double-blind phase;

Time to disease flare in the open-label run-in and double-blind phase;

JIA ACR 30, 50, 70, 90, 100 response at various time points in the open-label run-in 
and double blind-phase;

Change from baseline in JADAS 27-CRP and JADAS-27 ESR, and occurrence of
JADAS minimum disease activity and inactive disease at various time points in the 
open-label run-in and double-blind phase;

Presence of JIA ACR inactive disease and clinical remission at various time points in 
the double-blind phase; 

Change from baseline in each JIA ACR core set variable at various time points in the 
open-label run-in and double-blind phase;

Change from baseline in CHQ responses at various time points in the open-label 
run-in and double-blind phase;

Change from baseline in CHAQ responses at various time points in the open-label 
run-in and double-blind phase;

Occurrence of active uveitis (according to SUN criteria) at various time points in the 
open-label run-in and double-blind phase;

In subjects with ERA: Change from baseline in the Tender Entheseal Assessment,
Modified Schober’s Test, Overall Back Pain and Nocturnal Back Pain responses at 
various time points in the open-label run-in and double-blind phase;

In subjects with PsA: Change from baseline in the BSA affected with psoriasis and 
PGA of psoriasis assessments at various time points in the open-label run-in and 
double-blind phase;

Taste acceptability of tofacitinib oral solution, if applicable, on Day 14 of the 
open-label run-in phase;

Safety during the study, with focus on serious infections, cytopenias, malignancies, 
cardiovascular diseases, and validated assessments of growth and pubertal 
development;

Plasma tofacitinib concentrations during the open-label run-in phase.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 33
3. STUDY DESIGN
This is a randomized withdrawal, double-blind, placebo-controlled study of subjects from 
2 to <18 years of age with JIA (see Section 4.1, Inclusion Criteria).
All eligible subjects enrolled in the study will initially receive open-label tofacitinib for 
18 weeks (run-in phase).  At the end of the 18 week run-in phase, only subjects who achieve 
at least a JIA ACR 30 response will be randomized to the 26 week double-blind, 
placebo-controlled phase.  Subjects who do not achieve a JIA ACR 30 response at this time 
point will be discontinued from the study.  Subjects who experience a single episode of 
disease flare (see Section 7.1.7, PRCSG/PRINTO Disease Flare Criteria) at any time during 
the study (including the open-label run-in and double-blind phase) will also be discontinued 
from the study.
 
 
Subjects who are eligible for the 26 week double-blind phase will be randomized (1:1 ratio) 
to either active tofacitinib or placebo.  For subjects with polyarticular course JIA 
(ie, extended oligoarthritis, polyarthritis RF+, polyarthritis RF-, systemic JIA with active 
arthritis but without active systemic features), randomization will be stratified by JIA 
category and baseline CRP (normal, above normal). For subjects with psoriatic and 
enthesitis-related arthritis, randomization will be stratified by JIA category. 
A schematic of the study design is shown below:
CCI
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 34
Approximately 210 subjects will be enrolled in the open-label run-in phase.  Among subjects 
with polyarticular course JIA, stratification will target enrollment of at least 50% with a 
baseline CRP above the upper limit of normal.
The cohort of subjects with polyarticular course JIA will have at least 170 subjects enrolled
in the run-in phase with the minimum number of JIA categories as follows: 24 with extended 
oligoarthritis, 20 with polyarthritis RF+, and 62 with polyarthritis RF-. There is no minimum 
number of subjects with systemic JIA with active arthritis but without active systemic 
features.  Additional cohorts (ie, psoriatic and enthesitis-related arthritis) will include a 
minimum of 20 subjects with psoriatic arthritis, and 20 subjects with enthesitis-related 
arthritis.  The overall target minimum number of subjects to be enrolled in the study by age is 
as follows: 20 subjects 2 to <6 years, 20 subjects 6 to <12 years, and 20 subjects 12 to 
<18 years.  The Sponsor will monitor enrollment and periodically notify investigator sites 
regarding the status of enrollment in the various JIA categories and age groups.
Initial screening and enrollment of subjects (at least the first 12 subjects) into 
Study A3921104 must be limited to 12 years of age or greater for all eligible JIA subtypes 
(rheumatoid factor negative [RF-] and positive [RF+] polyarthritis, extended oligoarticular, 
psoriatic arthritis, enthesitis related arthritis and systemic arthritis without systemic features 
JIA subtypes).
The duration of subject participation among those who complete the study (without 
discontinuation) is expected to be approximately 44 weeks. Pediatric blood tubes will be 
used (reduced volume) for testing to determine eligibility, monitor safety, and measure PK.
The study will be conducted over a period of approximately 3 years. 
 
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:
1. Male or female aged 2 to <18 years.
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 35
2. Must meet International League Against Rheumatism (ILAR) JIA classification for 
one of the following categories and, in the opinion of the investigator, have active 
disease for at least 6 weeks prior to screening:

Extended oligoarthritis;

Polyarthritis (RF+);

Polyarthritis (RF-);

Systemic JIA with active arthritis but without active systemic features in the prior 
6 months and at the time of enrollment;

Psoriatic arthritis;

Enthesitis-related arthritis.
Subjects with polyarticular course JIA (ie, extended oligoarthritis, polyarthritis RF+, 
polyarthritis RF-, systemic JIA with active arthritis but without active systemic 
features) must have a minimum of 5 active joints (an active joint is defined as a joint 
with swelling or, in the absence of swelling, limited range of motion accompanied by 
either pain on motion or tenderness) at screening and baseline to be eligible for study 
entry.
Subjects with psoriatic or enthesitis-related arthritis must have a minimum of 3 active 
joints (an active joint is defined as a joint with swelling or, in the absence of swelling, 
limited range of motion accompanied by either pain on motion or tenderness) at 
screening and baseline to be eligible for study entry.
Treatment with stable doses of a Non-Steroidal Anti-inflammatory Drug (NSAID)
and/or a stable dose of an oral glucocorticoid, and/or a stable dose of methotrexate is 
permitted.
For subjects receiving an oral glucocorticoid: Glucocorticoids may be administered at 
a maximum dose of 0.2 mg of prednisone equivalent per kilogram per day or 10 mg 
per day for 2 weeks before baseline, whichever is lower. 
For subjects receiving methotrexate (MTX) treatment: MTX may be administered 
either orally or parenterally at doses not to exceed 25 mg/wk or 20 mg/m2/week
(whichever is lower); participants must have taken MTX for 3 months and be at a 
stable dose for at least 6 weeks before baseline.  Subjects taking MTX must be taking 
folic acid or folinic acid in accordance with local standards.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 36
For subjects with psoriatic arthritis, the following topical treatments for psoriasis are 
allowed: non-medicated emollients for use over the whole body; topical steroids 
including hydrocortisone and hydrocortisone acetate 1% for the palms, soles, face, 
and intertriginous areas only; tar, salicylic acid preparations, and shampoos free of 
corticosteroids are permitted only for the scalp.
3. Inadequate response or intolerance to at least one Disease Modifying Anti-Rheumatic 
Drug (DMARD), which may include MTX or biologic agents (see Appendix 1); in 
the case of ERA and psoriatic arthritis, inadequate response to Non-Steroidal 
Anti-Inflammatory Drugs (NSAIDs).
4. No evidence or history of untreated or inadequately treated active or latent 
tuberculosis (TB) infection as evidenced by the following: 
a.
A negative QuantiFERON-TB Gold In-Tube test performed within the 3 months 
prior to screening.  A negative purified protein derivative (PPD) test can be 
substituted for the QuantiFERON-TB Gold In-Tube test only if the central 
laboratory is unable to perform the test or cannot determine the results to be 
positive or negative and the Pfizer medical monitor is informed and agrees on a 
case-by-case basis. 
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. 
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TM
test need be obtained.  A chest radiograph should be obtained if not done within the 
3 months prior to screening (see Section 7.2.6).  To be considered eligible for the 
study, the chest radiograph must be negative for active tuberculosis infection.
A subject who is currently being treated for latent TB infection can only be enrolled 
with confirmation of current incidence rates of multi-drug resistant TB infection, 
documentation of an adequate treatment regimen, and prior approval of the Sponsor. 
5. Fertile males and females who are, in the opinion of the investigator, sexually active 
and at risk for pregnancy with their partner(s) must be willing and able to use a highly 
effective method of contraception as outlined in this protocol during the study and for 
at least 28 days after the last dose of study medication.  Note: Refer to Section 4.4.1
for additional contraception requirements for investigative sites in UK, Spain, Poland, 
Germany and Belgium only.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 37
6. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
7. Evidence of a personally signed and dated Informed Consent document and Assent 
document (as appropriate) indicating that the subject and a legally acceptable 
representative/parent(s)/legal guardian has been informed of all pertinent aspects of 
the study.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Previous JIA treatment with tofacitinib.
2. Systemic JIA (sJIA) with any active systemic features other than active joints and 
elevated acute phase reactants within 6 months of enrollment.
3. Persistent oligoarthritis.
4. Undifferentiated JIA.
5. Infections:
a.
Chronic infections;
b. Any infection requiring hospitalization, parenteral antimicrobial therapy or judged 
to be opportunistic by the investigator within the 6 months prior to the first dose 
of study drug;
c.
Any treated infections within 2 weeks of baseline;
d. A subject known to be infected with Human Immunodeficiency Virus (HIV), 
Hepatitis B, or Hepatitis C (see Section 7.2.7);
e.
History of infected joint prosthesis with prosthesis still in situ.
6. History of recurrent (more than one episode) herpes zoster or disseminated (at least 
one episode) herpes zoster, or disseminated (at least one episode) herpes simplex.
7. Active uveitis (according to SUN criteria) within 3 months of enrollment.
8. Blood dyscrasias, including (see Appendix 6):
a.
Hemoglobin <10 g/dL or Hematocrit <33%;
b. White Blood Cell count <3.0 x 109/L;
c.
Neutrophil count <1.2 x 109/L;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 38
d. Platelet count <100 x 109/L;
e.
Lymphocyte count <0.75 x 109/L.
9. Estimated glomerular filtration rate [GFR] <40 mL/min/1.73 m2 at Screening.  GFR 
will be calculated by the central lab using the bedside Schwartz formula (see 
Appendix 3).
10. Current or recent history of uncontrolled clinically significant renal, hepatic, 
hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurologic 
disease.
11. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 1.5 times the 
upper limit of normal or any other clinically significant laboratory abnormality
(see Appendix 6).
12. History of any other rheumatologic disease, other than Sjogren’s syndrome.
13. History or current symptoms suggestive of lymphoproliferative disorders (eg, Epstein
Barr Virus [EBV] related lymphoproliferative disorder, lymphoma, leukemia, or signs 
and symptoms suggestive of current lymphatic disease).
14. Vaccinated or exposed to a live or attenuated vaccine within the 6 weeks prior to the 
first dose of study drug, or is expected to be vaccinated or to have household 
exposure to these vaccines during treatment or during the 6 weeks following 
discontinuation of study drug.
15. Subjects without documented evidence of having received at least one dose of the 
varicella vaccine in countries where the vaccine is approved and standard of care or 
those who do not have evidence of prior exposure to varicella zoster virus (VZV) 
based on serological testing (ie, VZV IgG Ab).
16. Current malignancy or history of any malignancy with the exception of adequately
treated or excised basal cell or squamous cell or cervical cancer in situ.
17. Subjects who have previously failed more than 3 biologic therapies (with different 
mechanisms of action) for JIA.
18. Subjects with a first degree relative with a hereditary immunodeficiency; IgA 
deficiency not exclusionary.
19. Recent (within 28 days prior to first dose of study drug) significant trauma or major 
surgery.
20. Subjects receiving potent and moderate CYP3A4 inhibitors or inducers (Appendix 4).


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 39
21. Prior treatment with non B cell-specific lymphocyte depleting agents/therapies 
(eg, almetuzumab [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.
22. Use of prohibited prescription or non-prescription drugs and dietary supplements 
listed in Appendix 1 and Appendix 4 within the specified time frame prior to the first 
dose of study medication.
23. Herbal supplements must be discontinued at least 28 days prior to the first dose of 
study medication.
24. Use of certain biologic and non-biologic DMARDs are disallowed at any time during 
this study (Appendix 1).
25. For subjects with PsA, oral and topical medications and alternative treatments that 
could affect psoriasis are prohibited (see Inclusion Criterion 2 for exceptions).  This 
includes topical corticosteroids, tars, keratolytics, anthralin, vitamin D analogs, and 
retinoids which must be discontinued at least 2 weeks prior to first dose of study drug.  
Also prohibited is ultraviolet B (UVB) (narrowband or broadband) phototherapy that 
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.
26. 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.
27. Participation in other studies involving investigational drug(s) within 4 weeks or 
5 half-lives (whichever is longer) prior to study entry and/or during study 
participation.  Exposure to investigational biologics should be discussed with the 
Sponsor.
28. 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.
29. Pregnant or nursing females are excluded.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 40
30. Applicable to Investigative Sites in Germany Only: History of allergies, 
intolerance or hypersensitivity to lactose or CP-690,550 (tofacitinib). This includes 
subjects with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption. The investigators of potential 
subjects with acquired lactose intolerance should consider whether this is sufficiently 
concerning so as to preclude participation.
4.3. Randomization Criteria
All eligible subjects enrolled in the study will initially receive open-label tofacitinib for 
18 weeks (run-in phase).  At the end of the 18 week run-in phase, only subjects who achieve 
at least a JIA ACR 30 response will be randomized to the 26 week double-blind, 
placebo-controlled phase.  Subjects who do not achieve a JIA ACR 30 response at this time 
point will be discontinued from the study.  In addition, subjects who experience a single 
episode of disease flare (per JIA flare criteria as confirmed by the Centralized Coordinating 
Center) at any time during the study (including the open-label run-in and double-blind phase) 
will also be discontinued from the study.
Subjects who enter the 26 week double-blind phase will be randomized (1:1 ratio) to either 
active tofacitinib or placebo.  For subjects with polyarticular course JIA (ie, extended 
oligoarthritis, polyarthritis RF+, polyarthritis RF-, systemic JIA with active arthritis but 
without active systemic features), randomization will be stratified by JIA category and 
baseline CRP (normal, above normal).  For subjects with psoriatic arthritis and ERA
randomization will be stratified by JIA category.
4.4. Lifestyle Guidelines
4.4.1. Contraception
All fertile male subjects and female subjects of childbearing potential who are, in the opinion 
of the investigator, sexually active and at risk for pregnancy with their partner(s) must agree 
to use a highly effective method of contraception consistently and correctly for the duration 
of the active treatment period and for at least 28 days after the last dose of investigational 
product.  The investigator or his or her designee, in consultation with the subject and his/her 
legally acceptable representative/parent(s)/legal guardian, will confirm that the subject has 
selected an appropriate method of contraception from the list of permitted contraception 
methods (see below).  At the time points indicated in the Schedule of Activities (SOA), the 
investigator or designee will instruct the subject of the need to use highly effective 
contraception consistently and correctly and document the conversation and the subject’s 
affirmation in the subject’s chart.  In addition, the investigator or his or her designee will 
instruct the subject to call immediately if the selected contraception method is discontinued 
or if pregnancy is known or suspected in the subject or the subject’s partner. 
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:


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 41
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, or transdermal) is allowed provided 
the subject plans to remain on the same treatment throughout the entire study and has 
been using that hormonal contraceptive for an adequate period of time to ensure 
effectiveness;
2. Correctly placed copper-containing intrauterine device (IUD);
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository). For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
All subjects who are, in the opinion of the investigator, sexually active and at risk for 
pregnancy with their partner(s), and are on background medications (including DMARDs) 
that require contraceptive measures according to the local drug label must meet those 
requirements during the study and after therapy for 3 months or for the duration specified in 
the local drug label.
Applicable to Investigative Sites in the UK, Spain, Poland, Germany and Belgium Only:
Subjects who are, in the opinion of the investigator, sexually active and at risk for pregnancy 
with their partner(s) must agree to use 2 methods of contraception (at least one of which is
considered to be highly effective with low user dependency as defined below) throughout the 
study and for at least 28 days (90 days for male subjects) after the last dose of study drug 
where there is known or suspected teratogenicity.
Highly effective methods of contraception with low user dependency (applies to female
subjects at risk for pregnancy with their male partners):
1. Established use of hormonal methods of contraception associated with inhibition of
ovulation (inserted, injected, and implanted).
2. Correctly placed intrauterine device (IUD) or intrauterine system (IUS).
3. Male sterilization with absence of sperm in the post vasectomy ejaculate.
4. Bilateral tubal ligation/ bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion had been confirmed in accordance with the device’s label).


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 42
4.4.2. Vaccine and Exposure to Infections Guidelines
4.4.2.1. Subject Specific Recommendations
It is recommended that all subjects should be up-to-date with respect to standard of care 
vaccinations (as defined by their country health ministry) or JIA guidelines.  Vaccination of 
subjects with live components is prohibited within the 6 weeks prior to first dose of study 
drug.  Subjects without documented evidence of having received at least one dose of the 
varicella vaccine or those who are without evidence of previous varicella zoster exposure as 
confirmed by VZV IgG Ab serological testing are excluded (Exclusion Criterion 15).
4.4.2.2. Guidance Regarding Household Contact Vaccine-Related Exposure
Current routine household contact with children and others who have been vaccinated with 
live vaccine components may pose a risk during treatment and for 6 weeks following 
completion of the study.  Some of these vaccines include varicella (“chickenpox”) vaccine, 
oral polio vaccine, and the inhaled flu vaccine.  Following vaccination with live component 
vaccines, the virus may be shed in bodily fluids, including stool, and there is a potential risk 
that the virus may be transmitted.  General guidelines for immunosuppressed subjects
suggest that exposure (through routine contact) should be avoided following vaccination (of 
others) with these vaccines for the stated time period:
a.
Varicella or attenuated typhoid fever vaccination for 4 weeks following vaccination.
b. Oral polio vaccination for 6 weeks following vaccination.
c.
Attenuated rotavirus vaccine for 10 days following vaccination.
d. FluMist(inhaled flu vaccine) for 1 week following vaccination.
Subjects should avoid exposure to vaccinated or infected persons and contact the Investigator 
promptly should they develop signs or symptoms of infections.
4.4.3. 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 related 
to JIA.  For subjects with psoriatic arthritis, refer to Inclusion Criterion 2 and 
Exclusion Criterion 25.
4.4.4. 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 
procedure until sutures/staples are removed.  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.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 43
4.4.5. Dietary Supplements
For the purposes of this protocol, dietary supplements are defined as vitamins, minerals, 
purified food substances, and herbals with pharmaceutical properties (see Section 5.8, 
Concomitant Treatments, for additional details).
Vitamins, minerals and purified food substances are allowed in amounts not known to be 
associated with adverse effects (such as hypervitaminosis). 
Herbals supplements are prohibited.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study 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 
numbers, contact information for the investigational site, and contact details for a help desk 
in the event that the investigational site staff cannot be reached to provide advice on a 
medical question or problem originating from another healthcare professional not involved in 
the subject’s participation in the study. The help desk number can also be used by 
investigational staff if they are seeking advice on medical questions or problems; however, it 
should only be used in the event that the established communication pathways between the 
investigational site and the study team are not available. It is therefore intended to augment, 
but not replace, the established communication pathways between the investigational site and 
the study team for advice on medical questions or problems that may arise during the study. 
The help desk number is not intended for use by the subject directly, and if a subject calls 
that number, he or she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference in a clinical trial, including a 
product with a marketing authorization when used or assembled (formulated or packaged) in 
a way different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use (ICH E6 1.33).
5.1. Allocation to Treatment
All eligible subjects enrolled in the study will initially receive open-label tofacitinib for 
18 weeks (run-in phase).  At the end of the 18 week run-in phase, only subjects who achieve 
at least a JIA ACR 30 response will be randomized to the 26 week double-blind, 
placebo-controlled phase.  Subjects who do not achieve a JIA ACR 30 response at this time 
point will be discontinued from the study.  Subjects who experience a single episode of 
disease flare at any time during the study (including the open-label run-in and double-blind 
phase) will also be discontinued from the study.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 44
Subjects who enter the 26 week double-blind phase will be randomized (1:1 ratio) to either 
active tofacitinib tablets/oral solution or matching placebo.  For subjects with polyarticular 
course JIA (ie, extended oligoarthritis, polyarthritis RF+, polyarthritis RF-, systemic JIA with 
active arthritis but without active systemic features), randomization will be stratified by JIA 
category and baseline CRP (normal, above normal).  For subjects with psoriatic arthritis and 
ERA randomization will be stratified by JIA category.
Sites must receive confirmation of subject eligibility from the Centralized Cooridating Center 
indicating JIA ACR 30 response was achieved.  Once confirmed, randomization of subjects 
into the 26 week double-blind placebo-controlled phase will proceed through the use of an 
Interactive Response Technology (IRT) system.  The site personnel (study coordinator or 
specified designee) will be required to enter or select information including but not limited to 
the user’s identification (ID) and password, the protocol number, the subject number and the 
date of birth of the subject. The site personnel will then be provided with a treatment 
assignment and dispensable unit (DU) or container number when drug is being supplied via 
the IRT system.  The IRT system will provide a confirmation report containing the subject 
number and DU or container number assigned. The confirmation report must be stored in the 
site’s files. 
There is a 24 hour a day, 365 days a year IRT helpdesk available for any questions or issues.
The study specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
The IRT system is the source of the subject number. The IRT system will provide the subject 
number at the end of the first IRT subject transaction. 
5.2. Breaking the Blind
During the double-blind phase of the study, the Sponsor, subject and investigator site staff 
will be blinded to the subject’s treatment assignment.  At the initiation of the study, the study 
site will be instructed on the electronic process for breaking the blind using the IRT system. 
Blinding codes should be broken only in emergency situations for reasons of subject safety. 
Whenever possible, the investigator or sub-investigator consults with a member of the study 
team prior to breaking the blind.  When the blinding code is broken, the reason must be fully 
documented in the source documents for that subject.
Applicable to Investigative Sites in the UK, Spain, Poland, Germany and Belgium Only:
Blinding codes should be broken only in exceptional circumstances when knowledge of the 
actual treatment code is absolutely essential for further management of the subject.
Investigators are encouraged to discuss with a member of the study team if they believe that 
unblinding is necessary. When the blinding code is broken, the reason must be fully 
documented and entered on the case report form (CRF).


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 45
5.3. Subject Compliance
Subject compliance will be assessed at each visit during the study and will be verified by 
interviewing subjects and through accounting of returned containers and trial medication at 
each visit. 
Non-compliance (ie, missed or incorrect dosing where compliance is calculated to be 
<80% or >110%) will be documented in the source and the appropriate Case Report Form 
(CRF).  In subjects who demonstrate non-compliance between visit intervals, both the subject 
and parent/legal guardian will be counseled by study staff to address reasons for 
non-compliance.  If after counseling the subject continues to exhibit non-compliance over 
two consecutive study visits, the subject should be withdrawn from the study.  Dosing 
interruptions of 14 days or more should be discussed with the sponsor.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Tofacitinib will be provided as oral tablets (tofacitinib citrate 5 mg) and as an oral solution
(CP-690,550-10 [the compound name for tofacitinib] 1 mg/mL) by the Sponsor.  Tofacitinib 
tablets, oral solution and matching placebo, for oral administration, will be supplied in 
child-resistant bottles to the investigator site.
Open-label bottles of tofacitinib tablets and CP-690,550-10 (compound name for tofacitinib) 
oral solution will be provided for the run-in phase of the study.
Blinded-label bottles of tofacitinib tablets, CP-690,550-10 (compound name for tofacitinib) 
oral solution, and matching placebo, for oral administration, will be provided for the 
double-blind phase of the study.
5.4.2. Preparation and Dispensing
Investigational product will be supplied to subjects in bottles.  Investigational product, along 
with written dosing instructions (dosing cards), will be dispensed by an appropriately 
qualified member of the study staff (eg, physician, nurse, physician’s assistant, practitioner, 
or pharmacist) as allowed by local, state, and institutional guidance.
Oral solution will be administered via oral dosing syringes which will be dispensed along 
with oral solution bottles.
5.5. Administration
During the open-label run-in phase (18 weeks), all subjects will receive active tofacitinib oral 
tablets or oral solution twice daily (BID) orally, approximately 12 hours (2 hours) apart, in 
the morning and evening, at a dosage based on the subject’s body weight as specified in 
Table 2. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 46
During the double-blind, placebo-controlled phase (26 weeks), subjects will receive either 
active tofacitinib oral tablets/oral solution or matching placebo oral tablets/oral solution,
twice daily (BID), approximately 12 hours (2 hours) apart, in the morning and evening, at a 
dosage based on the subject’s body weight as specified in Table 2.
Table 2.
Study Treatment Dosing and Administration
Body Weight (kg)
Dosage Regimen
(Run-In Phase: Tofacitinib, Double-Blind Phase: Tofacitinib/Placebo)
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
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 investigational product tablets whole and will not manipulate or chew 
investigational product 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. 
5.6. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparator and/or marketed products are stored in a 
secured area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
label.
Storage conditions stated in the SRSD will be superseded by the storage conditions stated in 
the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 47
for excursions should be available.  The operation of the temperature monitoring device 
should be regularly inspected to ensure it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion. Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation.  Specific details regarding 
information the site should report for each excursion will be provided to the site. 
Site staff will instruct subjects on the proper storage requirements for take home 
investigational product.
All bottles must be returned to the investigator by the parent/legal guardian/subject.
5.7. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies. To ensure adequate records, all 
drug supplies will be accounted for in the drug accountability inventory forms as instructed 
by Pfizer and will be monitored by the accounting of unused investigational product returned 
by the subjects. 
5.7.1. Destruction of Investigational Product Supplies
The sponsor or designee will provide guidance on the destruction of any unused 
investigational product.  If Pfizer authorizes destruction at the study site, the investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Pfizer.  Destruction 
must be adequately documented. 
5.8. Concomitant Treatment(s)
A subject who is receiving an allowed concomitant medication for any reason must be on a 
locally-approved medication and dose that is considered standard-of-care for the treated 
indication.  Medications taken after informed consent is obtained but before the first dose of 
study medication will be documented as prior medications.  Medications taken after the first 
dose of study drug has been administered will be documented as concomitant medications. 
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 4,
Prohibited Concomitant Medications.  Topical administration (eg, cutaneous, ophthalmic, or 
intravaginal) of these concomitant medications, which are prohibited if administered 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 48
systemically, is allowed in the study.  Disallowed and allowed non-biologic and biologic 
DMARDS are listed in Appendix 1.  If a subject requires (in the opinion of the investigator) 
treatment with one of the disallowed agents, the subject should be discontinued from the 
study.
Subjects will continue on their stable background arthritis therapy (see Inclusion Criterion 2), 
which can include nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 
(COX-2) inhibitors, methotrexate (not to exceed 25 mg/wk or 20 mg/m2/week [whichever is 
lower]) (see Appendix 1), and corticosteroids (at a maximum dose of 0.2 mg of prednisone 
equivalent per kilogram per day or 10 mg per day, whichever is lower).  Subjects taking 
methotrexate must be taking folic acid or folinic acid in accordance with local standards.
For subjects with psoriatic arthritis refer to Inclusion Criterion 2 and Exclusion Criterion 25
for concomitant treatments that are allowed or prohibited (see Appendix 1).  See Appendix 2
for instructions on permitted adjustments in concomitant JIA therapies during the study.
Herbal supplements are not allowed and must be discontinued for at least 4 weeks prior to 
first dose of study drug.
Any experimental or prohibited therapy must be discontinued for at least 4 weeks or 
5 half-lives (whichever is longer) prior to the first dose of study drug (see Appendix 1).  No 
investigational compounds, other than tofacitinib may be taken during participation in this 
study.
All concomitant medication taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.
5.9. Rescue Therapy
Refer to Appendix 2 for permitted JIA rescue therapies. 
6. STUDY PROCEDURES
This section outlines study procedures and tests required to be performed at specified study 
visits.  Please refer to Section 7 for details regarding each procedure/test.
Applicable to Investigative Sites in Germany Only: The degree of burden and the risk 
threshold should be assessed at each scheduled visit as outlined in Appendix 10.
6.1. Screening Visit
Following obtainment of Informed Consent from the parent/legal guardian (and Assent from 
the subject, as appropriate), the procedures and assessments listed below will be performed at 
the screening visit. Serious adverse events (SAEs) are captured starting with the Screening 
visit from the time of informed consent (Section 8.2).
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. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 49
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 5.8 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.
Please note that subjects must be enrolled within 30 days of the screening visit.  If more than 
30 days has elapsed, all screening procedures and assessment listed below must be repeated.  
Sponsor approval must be obtained prior to re-screening a subject.

Medical history and family history.

Prior medications.

Complete physical examination. (Applicable to Investigative Sites in the UK, 
Spain, Poland, Germany and Belgium Only: a full skin cancer examination must 
be performed as part of the complete physical examination).

Vital signs, height and weight.

Obtain blood sample for QuantiFERON-TB Gold In-Tube test and send to central 
laboratory.  Note: If the reference laboratory informs the investigator site that 
QuantiFERON-TB Gold In-Tube testing cannot be performed on the submitted 
sample or if the result is indeterminate, then administer Purified Protein Derivative 
(PPD) skin test (Mantoux method) with Sponsor approval.

Perform the following assessments and fax/email the result to the Centralized 
Coordinating Center:

Joint assessment (joints with active arthritis [swelling, pain on motion/tenderness, 
and limitation of motion]).

JIA Disease Status Worksheet:

Uveitis exam by an ophthalmologist (or qualified equivalent per local 
practice); not required if there is documentation of uveitis assessment by an 
ophthalmologist within the previous 3 months of screening;

Duration of morning stiffness;

Signs and symptoms of systemic disease (sJIA only);


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 50

Physician’s Global Assessment of Overall Disease Activity;

Childhood Health Assessment Questionnaire (CHAQ);

ERA subjects only: Tender Entheseal Assessment, Modified Schober’s Test, 
Overall Back Pain and Nocturnal Back Pain Assessment.

Erythrocyte sedimentation rate (ESR) determination (utilizing ESR test kit provided 
by the Sponsor); record result on appropriate CRF.

PsA subjects only: Body surface area (BSA) and Physician’s Global Assessment 
(PGA) for psoriasis (not needed by the CCC).

Obtain blood or urine sample(s) for the following tests and send to central laboratory:

Hematology;

Chemistry;

C-reactive protein (CRP);

Rheumatoid Factor (RF);

Viral testing: Human Immunodeficiency Virus (HIV), Hepatitis B (Hep B), 
Hepatitis C (Hep C);

Varicella zoster virus (VZV) IgG Ab, if needed;

Urinalysis.

For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.
6.2. Day 1 Visit
The procedures and assessments listed below will be performed at the Day 1 visit.
Please note that the Day 1 visit must occur within 30 days of the screening visit.  If more than 
30 days has elapsed, all screening procedures and assessment must be repeated. Sponsor 
approval must be obtained prior to re-screening a subject.
For the Day 1 Visit, subjects should be instructed to fast (for 9 to 12 hours prior the 
scheduled visit), if possible, for lipid panel testing.

Prior and concomitant medications;

Targeted physical exam;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 51

Vital signs, height and weight;

Tanner stage assessment.

Perform the following assessments and fax/email the result to the Centralized 
Coordinating Center:

Joint assessment (joints with active arthritis [swelling, pain on motion/tenderness, 
and limitation of motion]); 

JIA Disease Status Worksheet:

Uveitis status assessment;

Duration of morning stiffness;

Signs and symptoms of systemic disease (sJIA only).

Physician’s Global Assessment of Overall Disease Activity;

CHAQ;

Child Health Questionnaire (CHQ);

ERA subjects only: Tender Entheseal Assessment, Modified Schober’s Test, Overall 
Back Pain and Nocturnal Back Pain Assessment;

ESR determination (utilizing ESR test kit provided by Sponsor); record result on 
appropriate CRF;

PsA subjects only: BSA and PGA of psoriasis (not needed by the CCC).

Prior to dosing on Day 1, obtain blood or urine sample(s) for the following tests and 
send to central laboratory:

Hematology;

Chemistry;

Lipid panel (under fasting conditions for approximately 9 to 12 hours, if 
possible);

CRP;

Urinalysis;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 52

Inflammatory markers: Anti-Cyclic Citrullinated Protein (anti-CCP) Antibodies, 
Antinuclear Antibodies (ANA), Human Leukocyte Antigen B27 (HLA-B27).

Retained biospecimens:

Prep B2.5 serum collection;

Prep R1 whole blood collection.

For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.

Assess for adverse events.

Dispense investigational product; first dose to be administered at the study site for all 
subjects.

Only for first 40 subjects enrolled (excluding subjects with Systemic JIA):

Obtain blood samples for PK analysis (see Section 7.3.1.1 for details).
Day 1 PK Collection Time Points:

15 [10 – 20] minutes post dose;

45 [35 – 55] minutes post dose;

3 [2.75 – 4.0] hours post dose.
6.3. Week 2/Day 14 Visit
The procedures and assessments listed below will be performed at the Week 2/Day 14 visit.  
The window for this visit is 3 days.

Prior and concomitant medications.

Targeted physical exam.

Vital signs, height and weight.

Perform the following assessments and fax/email the result to the Centralized 
Coordinating Center:

Joint assessment (joints with active arthritis [swelling, pain on motion/tenderness, 
and limitation of motion]); 

JIA Disease Status Worksheet:


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 53

Uveitis status assessment;

Duration of morning stiffness;

Signs and symptoms of systemic disease (sJIA only);

Physician’s Global Assessment of Overall Disease Activity;

CHAQ;

ERA subjects only: Tender Entheseal Assessment, Modified Schober’s Test, 
Overall Back Pain and Nocturnal Back Pain Assessment.

ESR determination (utilizing ESR test kit provided by Sponsor); record the result on 
the appropriate CRF.

PsA subjects only: BSA and PGA of psoriasis (not needed by the CCC).

Prior to dosing, obtain blood or urine sample(s) for the following tests and send to 
central laboratory:

Hematology;

Chemistry;

CRP;

Urinalysis.

For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.

PK sampling after first 40 subjects enrolled and in all subjects with systemic 
JIA:

Obtain blood samples for PK analysis (PK sampling may be deferred to the 
Week 4/Day 28 visit) (see Section 7.3.1.2 for details).
** Important Note ** The subject and parent/legal guardian should be instructed to 
hold the subject’s morning dose to allow for pre-dose PK sampling.
Week 2/Day 14 (or Week 4/Day 28) PK Collection Time Points:

Pre-dose (12 hrs post the previous evening dose).

Assess for adverse events.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 54

Administer tofacitinib oral solution taste acceptability assessment (not applicable for 
subjects taking tablets).

Assess investigational product dosing compliance.

Dispense investigational product.

Administer AM dose at the clinic.

Collect post-dose PK samples:

45 [35 – 55] minutes post dose;

3 [2.75 – 4.0] hours post dose.
6.4. Week 4/Day 28 Visit
The procedures and assessments listed below will be performed at the Week 4/Day 28 visit.  
The window for this visit is 3 days.
For the Week 4/Day 28 Visit, subjects should be instructed to fast (for 9 to 12 hours prior to 
the scheduled visit), if possible, for lipid panel testing.

Prior and concomitant medications.

Targeted physical exam.

Vital signs, height and weight.

Perform the following assessments and fax the result to the Centralized Coordinating 
Center:

Joint assessment (joints with active arthritis [swelling, pain on motion/tenderness, 
and limitation of motion]).

JIA Disease Status Worksheet:

Uveitis status assessment;

Duration of morning stiffness;

Signs and symptoms of systemic disease (sJIA only);

Physician’s Global Assessment of Overall Disease Activity;

CHAQ;

CHQ;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 55

ERA subjects only: Tender Entheseal Assessment, Modified Schober’s Test, 
Overall Back Pain and Nocturnal Back Pain Assessment.

ESR determination (utilizing ESR test kit provided by Sponsor); record the result on 
the appropriate CRF.

PsA subjects only: BSA and PGA of psoriasis (not needed by the CCC).

Prior to dosing, obtain blood or urine sample(s) for the following tests and send to 
central laboratory:

Hematology;

Chemistry;

Lipid panel (under fasting conditions for approximately 9 to 12 hours, if 
possible);

CRP;

Urinalysis.

Obtain pre-dose and post-dose blood sample(s) for PK analysis if deferred from 
Day 14 (see Section 7.3.1 for details).

For females of childbearing potential:  Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.

Assess for adverse events.

Assess investigational product dosing compliance.

Dispense investigational product.
6.5. Week 8, 12/Day 56, 84 Visit
The procedures and assessments listed below will be performed at the Week 8, 12/Day 56, 
84 visit.  The window for these visits is 3 days.

Prior and concomitant medications.

Targeted physical exam.

Vital signs, height and weight.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 56

Perform the following assessments and fax/email the result to the Centralized 
Coordinating Center:

Joint assessment (joints with active arthritis [swelling, pain on motion/tenderness, 
and limitation of motion]).

JIA Disease Status Worksheet:

Uveitis status assessment;

Duration of morning stiffness;

Signs and symptoms of systemic disease (sJIA only).

Physician’s Global Assessment of Overall Disease Activity.

CHAQ.

ERA subjects only: Tender Entheseal Assessment, Modified Schober’s Test, 
Overall Back Pain and Nocturnal Back Pain Assessment.

ESR determination (utilizing ESR test kit provided by Sponsor); record the result on 
the appropriate CRF.

PsA subjects only: BSA and PGA of psoriasis (not needed by the CCC).

Prior to dosing, obtain blood sample(s) for the following tests and send to central 
laboratory:

Hematology;

Chemistry;

CRP.

Week 8 only: Retained biospecimen:

Prep D1.5 (K2 edetic acid [ethylenediaminetetraacetic acid] [EDTA]) whole 
blood;

Urinalysis.

For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 57

Week 12/Day 84 Visit: PK sampling in all subjects:

Obtain blood samples for PK analysis; PK sampling may be deferred to a later 
visit up to Week 18/Day 126; (see Section 7.3.1 for details).
** Important Note ** The subject and parent/legal guardian should be instructed to 
hold the subject’s morning dose to allow for pre-dose PK sampling.
Week 12/Day 84 (or later visit up to Week 18/Day 126 visit) PK Collection Time 
Points:

Pre-dose (12 hrs post the previous evening dose).

Assess for adverse events.

Assess investigation product dosing compliance.

Dispense investigational product.

Administer AM dose at the clinic.

Collect post-dose PK sample:

45 [35 – 55] minutes post dose.
6.6. Week 18/Day 126 Visit
The procedures and assessments listed below will be performed at the Week 18/Day 126
visit.  The window for this visit is 3 days.
For the Week 18/Day 126 Visit, subjects should be instructed to fast, if possible, for lipid 
panel testing.

Prior and concomitant medications.

Complete physical exam. (Applicable to Investigative Sites in the UK, Spain, 
Poland, Germany and Belgium Only: a full skin cancer examination must be 
performed as part of the complete physical examination).

Vital signs, height and weight.

Perform the following assessments and fax/email the result to the Centralized 
Coordinating Center:

Joint assessment (joints with active arthritis [swelling, pain on motion/tenderness, 
and limitation of motion]).


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 58

JIA Disease Status Worksheet:

Uveitis status assessment;

Duration of morning stiffness;

Signs and symptoms of systemic disease (sJIA only).

Physician’s Global Assessment of Overall Disease Activity.

CHAQ.

CHQ.

ERA subjects only: Tender Entheseal Assessment, Modified Schober’s Test, 
Overall Back Pain and Nocturnal Back Pain Assessment.

ESR determination (utilizing ESR test kit provided by Sponsor); record the result on 
the appropriate CRF page.

PsA subjects only: BSA and PGA of psoriasis (not needed by the CCC).

Prior to dosing, obtain blood or urine sample(s) for the following tests and send to 
central laboratory:

Hematology;

Chemistry;

Lipid panel (under fasting conditions for approximately 9 to 12 hours, if 
possible);

CRP.

Retained biospecimens:

Prep B2.5 serum collection;

Prep R1 whole blood collection;

Urinalysis.

For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.

Obtain pre-dose and post-dose blood samples for PK analysis if deferred from 
Week 12/Day 84 (see Section 7.3.1 for details).


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 59

Assess for adverse events.

Assess investigational product dosing compliance.

Randomize to the double-blind phase.
**Important Note** Only subjects who achieve a JIA ACR 30 response in the 
open-label phase based on receipt of confirmation from the Centralized 
Coordinating Center (see Section 7.1.6 for details) are eligible for randomization.

Dispense investigational product.
6.7. Week 20, 24, 28, 32, 36, 40/Day 140, 168, 196, 224, 252, 280 Visit
The procedures and assessments listed below will be performed at the Week 20, 24, 28, 32, 
36, 40/Day 140, 168, 196, 224, 252, 280 visit.  The window for these visits is 3 days.
Week 24/Day 168 Only:
Uveitis assessment by ophthalmologist (or qualified equivalent per local practice) (the 
window for this particular assessment is 7 days).
Week 20, 24, 28, 32, 36, 40/Day 140, 168, 196, 224, 252, 280 Visits:

Prior and concomitant medications;

Targeted physical exam;

Vital signs, height and weight.

Perform the following assessments and fax/eamil the result to the Centralized 
Coordinating Center:

Joint assessment (joints with active arthritis [swelling, pain on motion/tenderness, 
and limitation of motion]).

JIA Disease Status Worksheet:

Uveitis status assessment; a uveitis exam by an ophthalmologist (or qualified 
equivalent per local practice) is required at the Week 24/Day 168 visit as 
noted above; 

Duration of morning stiffness;

Signs and symptoms of systemic disease (sJIA only).

Physician’s Global Assessment of Overall Disease Activity.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 60

CHAQ.

ERA subjects only: Tender Entheseal Assessment, Modified Schober’s Test, 
Overall Back Pain and Nocturnal Back Pain Assessment.

ESR determination (utilizing ESR test kit provided by Sponsor); record the result on 
the appropriate CRF.

PsA subjects only: BSA and PGA of psoriasis (not needed by the CCC).

Prior to dosing, obtain blood sample(s) for the following tests and send to central
laboratory:

Hematology;

Chemistry;

CRP;

Urinalysis.

For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.

Assess for adverse events.

Assess investigational product dosing compliance.

Dispense investigation product.
6.8. Week 44, End of Study (EoS)/Day 308 or Early Termination (ET) Visit 
The procedures and assessments listed below will be performed at the Week 44/Day 308 
visit.  The window for this visit is 3 days.
If a subject discontinues from the study at a regularly scheduled study visit, all assessments 
and procedures for that visit should be completed.  In addition, an unplanned Tanner stage 
assessment CRF should be completed if possible as part of the early termination.  If a subject 
discontinues outside of a regularly scheduled visit, all of the ET visit assessments should be 
completed, if possible.
For the Week 44/Day 308 or Early Termination (ET) Visit, subjects should be instructed to 
fast, if possible, for lipid panel testing.

Prior and concomitant medications.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 61

Complete physical exam.  (Applicable to Investigative Sites in the UK, Spain, 
Poland, Germany and Belgium Only: a full skin cancer examination must be 
performed as part of the complete physical examination).

Vital signs, height and weight.

Tanner stage assessment.

Perform the following assessments and fax/email the result to the Centralized 
Coordinating Center:

Joint assessment (joints with active arthritis [swelling, pain on motion/tenderness, 
and limitation of motion]).

JIA Disease Status Worksheet:

Uveitis exam by an ophthalmologist (or qualified equivalent per local 
practice);

Duration of morning stiffness;

Signs and symptoms of systemic disease (sJIA only).

Physician’s Global Assessment of Overall Disease Activity.

CHAQ.

CHQ.

ERA subjects only: Tender Entheseal Assessment, Modified Schober’s Test, 
Overall Back Pain and Nocturnal Back Pain Assessment.

ESR determination (utilizing ESR test kit provided by Sponsor); record the result on 
the appropriate CRF.

PsA subjects only: BSA and PGA of psoriasis (not needed by the CCC).

Obtain blood sample(s) for the following tests and send to central laboratory:

Hematology;

Chemistry;

Lipid panel (under fasting conditions for approximately 9 to 12 hours, if 
possible);

CRP.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 62
•
Retained biospecimens:
•
Prep B2.5 serum collection;
•
Prep R1 whole blood collection;
•
Urinalysis.
•
For females of childbearing potential: Obtain blood (serum) or urine sample for 
local laboratory pregnancy testing.
•
Assess for adverse events.
•
Assess investigational product dosing compliance.
•
6.9. Subject Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and parent/legal guardian and information 
received during contact attempts must be documented in the subject’s medical record.  In any 
circumstance, every effort should be made to document subject outcome, if possible.  The 
investigator should inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a final visit, if 
applicable, and follow up with the subject regarding any unresolved Adverse Events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
6.9.1. Subject Withdrawal Due to Failure to Achieve JIA ACR 30 Response or Disease 
Flare
All subjects enrolled in the study will initially receive open-label tofacitinib for 18 weeks 
(run-in phase).  At the end of the 18 week run-in phase, only subjects who achieve at least a
JIA ACR 30 response will be randomized to the 26 week double-blind, placebo-controlled 
phase.  Subjects who do not achieve a JIA ACR 30 response at this time point will be 
discontinued from the study.  Achievement of a JIA ACR 30 response at the end of the 
18 week run-in phase will be based on the investigator and parent/legal guardian assessment 
of JIA core set variables and confirmed by the PRCSG/PRINTO Centralized Coordinating 
Center (see Section 7.1.6).
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 63
Subjects who experience a single episode of disease flare based on the PRCSG/PRINTO 
disease flare criteria at any time during the study (including the open-label run-in and 
double-blind phase) will be discontinued from study treatment. 
 
 
 
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
Efficacy evaluators must receive and document protocol specific and efficacy assessment 
scales training prior to performing evaluations.  To assure consistency and reduce variability, 
the same evaluator should assess the clinical evaluations for any individual subject 
throughout the study; a back-up experienced and qualified, protocol-trained evaluator is 
allowed in case of emergency or special situation when the designated evaluator is unable to 
perform the evaluation; this must be documented.  The identity (eg, initials) of the evaluator 
should be captured on the source documentation (eg, worksheet).
7.1. Efficacy Assessments
7.1.1. Number of Joints with Active Arthritis
At each study visit, joints with swelling, pain on motion, tenderness and limitation of motion 
will be assessed and recorded on the appropriate CRF.  The results will be faxed/emailed to 
the Centralized Coordinating Center (see Section 7.1.13).
The ACR defines a joint with active arthritis as a joint with swelling or, in the absence of 
swelling, limitation of motion accompanied by pain on motion 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).
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 64
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, 
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, Metacarpophalangeal (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.
7.1.2. Physician’s Global Assessment of Overall Disease Activity
At each study visit, following an assessment of the number of joints with swelling, 
pain/tenderness and limitation of motion, the investigator will provide an assessment of the 
subject’s overall level of disease activity.  This evaluation is based on the subject’s disease 
signs, functional capacity and physical examination.  The result will be faxed/emailed to the 
Centralized Coordinating Center (see Section 7.1.13).
The investigator will rate the overall level of disease activity by entering a number from 0 to 
10 (in 0.5 increments), with ‘0’ as ‘No Activity’ and ‘10’ as ‘Maximum Activity’ on a 
21-circle visual analog scale (VAS), as shown below.
7.1.3. Childhood Health Assessment Questionnaire (CHAQ)
At each study visit, the Childhood Health Assessment Questionnaire (CHAQ) assessment 
will be administered to the subject’s parent/legal guardian. Subjects aged 14 and older may 
complete this assessment if able to do so correctly and consistently for the duration of the 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 65
study.  The results of the questionnaire will be faxed/emailed to the Centralized Coordinating 
Center (see Section 7.1.13).  Every effort should be made to have the same individual 
complete the CHAQ throughout the course of the study.
The CHAQ (Singh 1994)5 is a validated instrument and comprises two indices, Disability and 
Discomfort, and global assessment of arthritis (overall well-being).  The CHAQ has been 
cross-culturally adapted and validated in more than 30 languages by the PRINTO group 
(Ruperto 2001).6
The CHAQ assessment will be based on the responses, as confirmed by the Centralized 
Coordinating Center.
Disability Index
The parent/legal guardian/subject will be asked to provide responses to questions designed to 
assesses function in 8 areas, including dressing and grooming, arising, eating, walking, 
hygiene, reach, grip, and activities-distributed, among a total of 30 items.  Each question is 
rated on a four-point scale of difficulty in performance, scored from 0-3.  The question with 
the highest score determines the score for the functional area.  If aids or devices are used or 
assistance is required, the minimum score for that functional area is 2. 
Discomfort Index
For the assessment of discomfort, the parent/legal guardian/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/subject will rate the overall pain by entering a number from 0 to 
10 (in 0.5 increments), with ‘0’ as ‘No Pain’ and ‘10’ as ‘Very Severe Pain’ on a 21-circle 
visual analog scale (VAS), as shown below.
Parent/Legal Guardian/Subject Global Assessment of Overall Well-Being
For the assessment of overall well-being, the parent/legal guardian/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.” 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 66
The parent/or legal guardian/subject will rate the overall well-being by entering a number 
from 0 to 10 (in 0.5 increments), with ‘0’ as ‘Very Well’ and ‘10’ as ‘Very Poorly’ on a 
21-circle visual analog scale (VAS), as shown below.
7.1.4. Child Health Questionnaire (CHQ)
The Child Health Questionnaire (CHQ) assessment will be administered at each study visit to 
the parent/legal guardian. Subjects aged 14 and older may complete this assessment if able 
to do so correctly and consistently for the duration of study.  The results of the questionnaire 
will be faxed/emailed to the Centralized Coordinating Center.
The CHQ (Landgraf 1996)20 is a validated general pediatric quality of life instrument.  The 
CHQ assesses for 14 physical and psychosocial domains: general health perceptions, physical 
functioning, role/social physical functioning, bodily pain, role/social emotional functioning, 
role/social behavioral functioning, parent impact-time, parent impact-emotional, self-esteem, 
mental health, behavior, family activities, family cohesion, and change in health.
The response options for the CHQ are ordinal scales that vary by the item.  Each item 
consists of 4–6 response options.  Additionally, each scale consists of varying numbers of 
items.
The CHQ score will be determined based on the questionnaire responses, as confirmed by the 
PRCSG/PRINTO Centralized Coordinating Center.
7.1.5. Inflammatory Markers
In this study, testing for both Erythrocyte Sedimentation Rate and C-Reactive Protein will be 
performed in all subjects at each study visit.
7.1.5.1. C-Reactive Protein (CRP)
At each study visit, a blood sample for CRP testing will be collected and sent to the central 
laboratory for determination. 
Following confirmation from the Centralized Coordinating Center of achievement of at least 
a JIA ACR 30 response at the end of the 18 week open-label, run-in phase, the baseline CRP 
result (obtained at Screening) will be entered into the IRT system by the investigator site for 
the purpose of appropriately stratifying and randomizing the subject to the double-blind, 
placebo controlled phase (see Section 5.1). 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 67
7.1.5.2. Erythrocyte Sedimentation Rate (ESR)
At each study visit, ESR will be determined locally utilizing an ESR Testing Kit which will 
be provided to the investigator site by the Sponsor.  Please refer to the ESR Testing Kit for 
detailed instructions on how to perform this test appropriately.
The ESR result will be recorded on the appropriate CRF.  The ESR result will also be 
faxed/emailed to the Centralized Coordinating Center which, along with other JIA core set 
variables, will be used to perform efficacy assessments at each visit.
7.1.6. JIA Core Set Variables and Response Definition
The JIA ACR response determination is a derived measurement utilizing each component of 
the JIA core set variables (Giannini 1997),7 which include:

Number of joints with active arthritis;

Number of joints with limited range of motion;

Physician global evaluation of disease activity;

Parent/legal guardian/subject evaluation of overall well-being (from the CHAQ);

Functional ability (Disability Index from the CHAQ);

ESR will be used for the real-time assessment of ACR 30 response at Week 18 as 
well as flare and JIA ACR inactive disease status at all visits by the Centralized 
Coordinating Center; CRP may be used for analysis of other related endpoints (details 
will be provided in the Statistical Analysis Plan [SAP]).
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%. In subjects with systemic JIA, the absence of 
spiking fever related to systemic JIA is also required.
The JIA ACR 30, 50, 70, 90, 100 response will be determined based on the investigator’s and 
parent/legal guardian/subject’s assessment of components of the JIA core set variables. 
* Important Note *
At the end of the 18 week open-label run-in phase (Week 18/Day 126 visit), only subjects who 
achieve at least a JIA ACR 30 response, based on the investigator’s and parent/legal 
guardian/subject’s assessment of components of the JIA core set variables (using ESR), will 
be randomized to the 26 week double-blind, placebo-controlled phase.  Subjects who do not 
achieve at least a JIA ACR 30 response at this time point will be discontinued from the study.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 68
Achievement of a JIA ACR 30 response at Week 18 will be confirmed by the Centralized 
Coordinating Center following receipt of assessments of JIA core set variables from the 
investigator site.  Investigators must receive confirmation from the Centralized Coordinating 
Center prior to randomizing the subject to the double-blind phase.
Following confirmation, the investigator site will randomize the subject utilizing the 
Sponsor’s Interactive Response Technology (IRT) system (see Section 5.1).
7.1.7. PRCSG/PRINTO Disease Flare Criteria
The PRCSG/PRINTO Disease Flare (Brunner 2002)8 determination is a derived 
measurement utilizing each component of the JIA core set variables (see Section 7.1.6).
Flare is defined as a worsening of 30% or more in 3 or more of the 6 variables of the JIA 
core set (see Section 7.1.6), 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/subject 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.  For subjects with sJIA, presence of spiking fever due 
to sJIA will be considered sufficient to determine disease flare.
At each visit, the investigator will evaluate the subject for evidence of disease flare, 
according to PRCSG/PRINTO Disease Flare criteria, and confirmed by the Centralized 
Coordinating Center.  Subjects who experience a single episode of disease flare (based on the 
investigator’s and parent/legal guardian/subject’s assessment of components of the JIA core 
set variables, and as confirmed by the Centralized Coordinating Center) will be discontinued 
from the study. 
PRCSG/PRINTO disease flare will be based on the investigator and parent/legal 
guardian/subject assessment of components of the JIA core set variables, as confirmed by the 
Centralized Coordinating Center. 
7.1.8. JIA ACR Clinical Inactive Disease and Clinical Remission Criteria
The American College of Rheumatology (ACR) Clinical Inactive Disease and Clinical 
Remission (Wallace 2011)9 criteria is defined as follows:
Clinical Inactive Disease:

No joints with active arthritis;

No fever, rash, serositis, splenomegaly, hepatomegaly, or generalized 
lymphadenopathy attributable to sJIA;

No active uveitis (as defined by the SUN Working Group);


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 69

Normal ESR (within normal limits of the method used where tested) or, if elevated, 
not attributable to JIA;

Physician global assessment of disease activity score of ‘best possible’ on the scale 
used;

Duration of morning stiffness of 15 minutes.
Clinical Remission on Medication:

Clinical inactive disease for 6 months continuously while on medications for JIA.
Inactive disease and clinical remission status will be based on the investigator’s assessment 
of the above components. 
7.1.9. Juvenile Arthritis Disease Activity (JADAS-27 CRP, JADAS-27 ESR) Score
The Juvenile Arthritis Disease Activity score is a validated composite disease activity 
measure for JIA (Consolaro 2009).16  Recently, the scoring system was adapted to use the 
27-joint count (Bazso 2009),18 and C-reactive protein (CRP) in place of Erythrocyte 
Sedimentation Rate (ESR) for the inflammatory marker component (Nordal 2012).19
JADAS-27 CRP (JADAS-27 ESR) score will be determined based on four components: 

Physician global assessment of disease activity; 

Parent/legal guardian/subject global assessment of well-being (from the CHAQ);

Number of joints with active disease (27 joint assessment); 

CRPor ESR as applicable.
7.1.10. 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)17 are defined as follows:
Polyarthritis:

Inactive Disease: 1;

Minimal Disease Activity: 3.8.
Oligoarthritis (<4 active joints):

Inactive Disease: 1;

Minimal Disease Activity: 2.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 70
The JADAS-27 score will be determined based on the investigator and parent/legal/subject
assessment of the above components.
7.1.11. Additional Assessments in Subjects with Enthesitis-Related Arthritis
In addition to all other efficacy assessments specified in Section 7, 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.
The result of this assessment will be faxed/emailed to the Centralized Coordinating Center.
7.1.11.1. Tender Entheseal Assessment
The Tender Entheseal Assessment will be performed at each study visit 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
7.1.11.2. Modified Schober’s Test
The Modified Schober’s Test (Macrae 1969, Moll 1971)13,14 will be performed at each study 
visit 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 
be recorded to the nearest tenth of a centimeter (eg, 15.2 cm) on the appropriate CRF.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 71
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. 
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 each study 
visit only in subjects with enthesitis-related arthritis.
Overall back pain (at any time) and nocturnal back pain will be measured on a 21-circle 
visual analog scale (VAS).
The parent/legal guardian/subject (if at least 14 years of age and able to complete correctly 
and consistently) will be asked to fill one 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


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 72
7.1.12. Additional Assessments in Subjects with Psoriatic Arthritis (PsA)
In addition to all other efficacy assessments specified in Section 7, subjects with psoriatic
arthritis (PsA) will undergo additional efficacy assessments, including affected body surface 
area (BSA) and Physician’s Global Assessment (PGA) of psoriasis (Horneff 2014).15  The 
PsA assessments are not required to be provided to the Centralized Coordinating Center.
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 (see Appendix 8).
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 9).
7.1.13. Centralized Coordinating Center
This study will utilize the Centralized Coordinating Center of PRCSG/PRINTO whose 
primary purpose is to review and confirm, in real time, a number of efficacy assessments.  
These primarily include verification of the JIA core set variables, JIA ACR 30 response (at 
Week 18), disease flare and inactive disease status at each visit.
To facilitate this evaluation, at each visit the investigator site will fax/email the results of 
each of the following JIA core set variable assessments to the Centralized Coordinating 
Center:

Joint assessment (including number of joints with swelling, pain on 
motion/tenderness, and limited range of motion).

JIA Disease Status Worksheet:

Uveitis status assessment (exam required at certain visits per SOA and 
Section 7.2.3);

Duration of morning stiffness;

Signs and symptoms of systemic disease (sJIA only);

Physician’s Global Assessment of Overall Disease Activity;

Parent/legal guardian/subject’s global assessment of overall well-being (CHAQ);

Functional ability (Disability Index from the CHAQ);

ESR.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 73

In subjects with enthesitis-related arthritis (ERA) only:

Tender entheseal assessment;

Modified Schober’s Test assessment;

Overall Back Pain and Nocturnal Back Pain assessment.
Evaluation of faxed/emailed results will be performed in real time (within approximately 
90 minutes of receipt of clear and complete information) by independent evaluators at the 
Centralized Coordinating Center. The Centralized Coordinating Center will provide the 
investigator site with confirmation of receipt of complete information. 
The Centralized Coordinating Center may contact the investigator site directly to confirm the 
accuracy of information submitted following review and assessment. 
Please refer to the Centralized Coordinating Center manual for details regarding instructions 
relating to submission of required information and other logistical information.
7.2. Safety Assessments
Safety will be assessed by the spontaneous reporting of adverse events (AEs), physical 
examinations and clinical laboratory results in all subjects who received at least 1 dose of 
study medication. 
Investigators and Pfizer clinicians will review individual subject data throughout the conduct 
of the trial to ensure subjects’ well-being.
Please refer to Appendix 6 for guidelines for safety monitoring and discontinuations due to 
laboratory abnormalities, serious infections, opportunistic infections, and malignancies.
Please refer to Section 9.7 for the evaluation of potentially malignant tumors, suspicious 
lymphadenopathy, or possible extra-nodal lymphoproliferative disorder.
7.2.1. Medical and Family History
At the time of screening, a medical and family history will be obtained.  Medical history 
should include information on the subject’s primary arthritis-related diagnosis (including 
duration), any other baseline medical conditions, allergies, and tobacco and alcohol use.  
Family history should include inquiry about family members with immunodeficiency and 
premature coronary heart disease.
7.2.2. Physical Examination
Complete Physical Examination
The following parameters and body systems will be examined and any abnormalities 
described: General appearance, weight and height, skin (presence of rash), HEENT (head, 
eyes, ears, nose and throat), lungs (auscultation), heart (auscultation for presence of 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 74
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. (Applicable to Investigative Sites in the UK, Spain, 
Poland, Germany and Belgium Only: 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 heart, lungs, lower extremities for peripheral edema, abdomen and lymph nodes.  Any 
clinically significant changes from the baseline examination should be recorded as AEs. 
7.2.3. Uveitis Assessment
Uveitis assessment must be performed by an ophthalmologist or qualified equivalent per 
local practice, and will be done at Screening (if no documented history of uveitis assessment 
within past 3 months is available), Week 24/Day 168 and Week 44/Day 308 (EoS) visits 
(7 days), or Early Termination (ET) visit.
Uveitis assessment should be performed according to local standard of care and the results 
(ie, a report) recorded in the source document.  At each visit subjects should be assessed for 
development of new uveitis or worsening of existing uveitis (according to SUN criteria); 
these changes should be reported as an adverse event.  The Centralized Coordinating Center 
worksheet for each visit asks if the subject has active uveitis (yes/no).
The activity of the anterior chamber (AC) inflammation should 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).21
7.2.4. Vitals Signs Assessment
Blood Pressure
Blood pressure will be measured in the subject’s arm and recorded to the nearest mmHg.  
The same arm should be used throughout the study using an appropriate cuff size.  All blood 
pressure readings should be measured after resting for at least 5 minutes.  The same position 
and blood pressure cuff appropriately sized, positioned and properly calibrated should be 
used to measure blood pressure each time.  When the timing of these measurements 
coincides with a blood collection, blood pressure and pulse rate should be obtained first.  It is 
preferred that blood pressure be collected in the sitting position, supine position is allowed.  
Position should be documented in the CRF and should be consistent throughout the study. 
Pulse Rate
Pulse rate should be obtained after resting for at least 5 minutes.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 75
Temperature
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.
Height and Weight
Height and weight should be reported at each visit with height preferentially measured 
utilizing a Harpenden stadiometer.
7.2.5. Pubertal Development Assessment (Tanner Stages)
Determination of physical and sexual maturation will be performed at the Day 1 and 
Week 44 or Early Termination visit using the Tanner stages (Dorn 1990, Taylor 2001)10,11 by 
a trained physician/clinician in the presence of a parent/legal guardian or clinic staff member. 
In the event the parent/legal guardian or subject refuses the examination for sexual maturity, 
or if not possible per site practice or local regulations, subject self-assessment of Tanner 
staging that uses photographs or line drawings corresponding to the Tanner stages will be 
offered to obtain information on pubertal status while avoiding intrusiveness.
The Tanner stage rating will be assigned by the clinician/physician based on the exam or 
based on the subject self-report.  If the clinician believes the subject’s self-report may reflect 
an earlier or later pubertal stage than the clinician believes is correct, the clinician will review 
the self-report form with the subject and/or parent/legal guardian to clarify the subject’s 
responses.  This review will be done in the presence of another person, either the parent/legal 
guardian or a clinic staff member.  At the end of the review, the clinician will then assign a 
best estimate Tanner stage rating. 
Note that pubertal development in the United States begins as early as age 8 and completes as 
late as age 17.
7.2.6. Tuberculosis Testing
At the time of screening, all subjects will undergo tuberculosis (TB) testing.  
QuantiFERON-TB Gold In-Tube Test is the preferred testing method.  If the 
QuantiFERON-TB Gold In-Tube test cannot be performed, or if the results cannot be 
determined by the reference laboratory to be either positive or negative, then subjects may be 
screened using the Purified Protein Derivative (PPD) Tuberculin Skin Test (Mantoux 
method) with Sponsor approval.
In addition to TB testing as specified in this clinical protocol, a chest X-ray may be 
performed to aid in TB status determination, according to local standards of care and/or in 
countries with a high incidence rate of TB.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 76
Applicable to Investigative Sites in the UK, Spain, Poland, Germany and Belgium Only:
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.
7.2.6.1. QuantiFERON-TB Gold In-Tube Test
QuantiFERON-TB Gold In-Tube test (Guidelines 2005)4 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 In-Tube is an indirect test 
for M. tuberculosis infection (including disease) and is intended for use in conjunction with 
risk assessment, radiography and other medical and diagnostic evaluations.
A blood sample (approximately 3 mL) will be collected at screening for QuantiFERON-TB 
Gold In-Tube testing.  Following sample processing, the sample will be shipped to the 
Sponsor’s designated reference laboratory for testing.  The procedure for processing and 
preparing the sample for shipment is described fully in the laboratory manual, which will be 
provided to investigators.
A negative PPD test can be substituted for the QuantiFERON-TB Gold In-Tube test only if 
the central laboratory is unable to perform the test or cannot determine the results to be 
positive or negative and the Pfizer Medical Monitor approves it, on a case-by-case basis.
7.2.6.2. Purified Protein Derivative (PPD) Test
If the QuantiFERON-TB Gold In-Tube test cannot be performed, or if the results cannot be 
determined to be positive or negative, then subjects may be screened using the Purified 
Protein Derivative (PPD) Tuberculin Test (Mantoux method), with the approval of the Pfizer 
Medical Monitor. 
Subjects must have the PPD test administered and evaluated by a health care professional 
48 to 72 hours later in order to be eligible for the study, unless performed and documented 
within the last 3 months.  The test should be performed according to local standards with 
induration of <5 mm required for inclusion.
7.2.7. Laboratory Testing
Blood and/or urine samples for tests specified below will be collected at the time points 
specified in the SOA and sent to the Sponsor’s designated central laboratory for testing.  The 
shipment address of the central laboratory contact information will be provided to 
investigator sites prior to initiation of the study.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 77

Hematology: Hemoglobin, hematocrit, red blood cells, white blood cells, neutrophils 
(%, absolute), lymphocytes (%, absolute), monocytes (%, absolute), eosinophils 
(%, absolute), basophils (%, absolute), platelets.

Chemistry: Sodium, potassium, bicarbonate, chloride, blood urea nitrogen, 
creatinine, glucose, calcium, total protein, total bilirubin (TB), direct bilirubin, 
indirect bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase, gamma-glutamyl transferase (GGT), albumin, creatine 
phosphokinase kinase (CPK).

Lipids (under fasting conditions for approximately 9 to 12 hours): Total 
cholesterol, direct HDL, direct LDL, triglycerides, apolipoprotein A-1 and B.

Urinalysis: Specific gravity, pH, protein, glucose, ketones, blood and leukocyte 
esterase, urine microscopy (only if dipstick positive for blood or protein, or if 
clinically indicated).

Inflammatory markers and other RA related tests: C-reactive protein (CRP), 
Rheumatoid Factor (RF), Anti-Cyclic Citrullinated Protein (anti-CCP) Antibodies, 
Antinuclear Antibodies (ANA), Human Leukocyte Antigen B27 (HLA-B27).
** Please note, ESR will be determined locally utilizing an ESR Testing Kit 
provided to the investigator site by the Sponsor (see Section 7.1.5.2).

Pregnancy testing (all female subjects who have passed menarche): Blood 
(serum) or urine pregnancy testing (for Human Chorionic Gonadotropin [hCG]) will 
be performed locally or by the local or central laboratory.  A positive urine pregnancy 
must be confirmed by a blood (serum) pregnancy test performed either by the local or 
central laboratory. 

Varicella zoster virus IgG Antibody testing (if applicable): Please refer to 
Section 7.2.8.

Hepatitis B testing: HB surface antigen (HBsAg), HB core antibody (HBcAb), HB 
surface antibody (HBsAb).
Interpretation of Hepatitis B Testing Results:

HBsAg negative and HBcAb negative: Subject is eligible for the study;

HBsAg positive and HBcAb negative: Subject is excluded from study 
participation;

HBsAg negative and HBcAb positive and HBsAb positive: Subject is eligible for 
study;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 78

HBsAg negative and HBcAb positive and HBsAb negative: Subject is excluded 
from study participation.

Hepatitis C testing: Hepatitis C Antibody (HCV Ab), Hepatitis C Viral RNA (HCV 
RNA for confirmation of positive HCV Ab result).  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.
Interpretation of Hepatitis C Testing Results:

HCV Ab positive and HCV RNA positive: Subject is excluded from study 
participation. 

Tuberculosis testing: Please refer to Section 7.2.6.

Human Immunodeficiency Virus testing: HIV-1/HIV-2 antibody.
Interpretation of HIV Testing Results:

HIV-1 or HIV-2 antibody positive: Subject is excluded from study participation.
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.
Unscheduled clinical labs may be obtained at any time during the study to assess any 
perceived safety concerns.
7.2.8. Varicella Zoster Virus (VZV) IgG Antibody (Ab) Testing
Subjects without documented evidence of having received at least a single dose of the 
varicella vaccine in countries where the varicella vaccine is approved and standard of care 
will be tested for varicella zoster virus IgG Ab (ELISA method).  Subjects that lack evidence 
of prior exposure to varicella zoster virus based on serological VZV IgG Ab testing are 
excluded. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 79
7.2.9. Pregnancy Testing
For female subjects of childbearing potential (those who have passed menarche), a blood 
(serum) or urine pregnancy test, with sensitivity of at least 25 mIU/mL for hCG, will be 
performed locally at screening, before investigational product administration at the baseline 
visit, at each study visit, and at the Week 44 (End of Study) or Early Termination visit.  If 
preferred, urine and/or serum pregnancy testing may be performed at any time using the local 
or central laboratory.
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period or when potential pregnancy is otherwise suspected.  Pregnancy tests may 
also be repeated as per request of Institutional Review Boards (IRBs)/Ethics Committees 
(ECs) or if required by local regulations. 
A negative pregnancy test is required before the subject may receive the investigational 
product. 
A positive urine pregnancy test will be confirmed by a blood (serum) pregnancy test 
performed either locally or by the central laboratory.  In the case of a positive confirmed 
pregnancy test, the subject will be withdrawn from administration of investigational product 
and from the study.  Please refer to Section 8.11 for additional information regarding 
Exposure During Pregnancy.
7.2.10. 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. 
Applicable to Investigative Sites in the UK, Spain, Poland, Germany and Belgium Only:
If blood collection is difficult for individual subjects, venipuncture will be limited to 
3 attempts, with additional attempts within 3-5 business days unless there is a medical 
emergency.
Total blood sampling volume for the individual subjects is approximately 99 mL over the 
44 week period.
Table 3 reflects approximate sample volumes needed for each measured endpoint.  The 
actual times of blood sampling may change.  In some instances additional blood samples may 
be taken for safety assessments at times specified by Pfizer, provided the total volume taken 
during the study does not exceed 2.7 mL/kg during any period of 30 consecutive days.
Applicable to Investigative Sites in the UK, Spain, Poland, Germany and Belgium Only: 
In some instances additional blood samples may be taken for safety assessments at times 
specified by Pfizer, provided the total volume taken during the study does not exceed 
2.4 mL/kg during any period of 30 consecutive days.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 80
Table 3.
Blood Volume
Laboratory Test
Sample Collection Time (Blood Volume, mL)
Day 1
Week 2 Week 4 Week 8 Week 12 Week 
18
Week 20, 
24, 28, 
32, 36, 40
Week 
44/End of 
Study (EoS)
Screening Day 1
Day 14
Day 28
Day 56
Day 84
Day 126 Days 140, 
168, 196, 
224, 252, 
280
Day 
308/Early 
Termination 
(ET)
Chemistry
x (1.1)
x (1.1)
x (1.1)
x (1.1)
x (1.1)
Chemistry, Lipids
x (1.1)
x (1.1)
x (1.1)
x (1.1)
Apo-A1, Apo-B1, CRP
x (2.5)
x (2.5)
x (2.5)
x (2.5)
Hematology
x (1.2)
x (1.2)
x (1.2)
x (1.2)
x (1.2)
x (1.2)
x (1.2)
x (1.2)
x (1.2)
QuantiFERON TB Gold
x (1.0)
VZV IgG Ab
x (1.1)
Serum pregnancy test1
x (1.1)
CRP
x (1.1)
x (1.1)
x (1.1)
x (1.1)
CRP, RF
x (2.5)
Anti-CCP
x (1.1)
ANA
x (1.1)
HLA-B27
x (2.0)
HIV-1, HIV-2
x (4.0)
HBsAg, HBcAb, 
HCV Ab
x (2.5)
HCV RNA
x (6.0)2
PK
x 
(3.6)3
x (3.6)4
x (2.2)5
Banked Biospecimens
x 
(4.5)6
x (2)7
x (4.5)6
x (4.5)6
Total mL per visit
20.5
(14.52)
17.13 
(13.5)
3.4 (7.0)
4
4.8
5.4
5.6
9.3
(3.4 per 
visit) 20.4
9.3
Total Blood Volume8 = 99.4 mL (86.8 mL minimum)
1.
Alternatively, the investigator site may perform a urine pregnancy test.
2.
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.
3.
PK testing in the first 40 non-sJIA subjects; 3 samples total (each 1.2 mL).
4.
PK testing in all subjects enrolled after the first 40 non-sJIA subjects, and in all sJIA subjects; 4 samples total (each 
1.2 mL).
5.
PK testing in all subjects; 3 samples total (each 1.2 mL).
6.
Prep B2.5 (2 mL) and Prep R1 (2.5 mL) collected pre-dose on Day 1, and at Week 18 and Week 44/EoS/ET.
7.
Prep D1.5 (2 mL EDTA) collected at Week 8.
8.
Total volume does not include unplanned laboratory tests, confirmatory serum pregnancy test (if a positive urine 
pregnancy test is obtained), or discarded blood from pre-draws used to remove fluid from flushed catheters.
7.3. Pharmacokinetic Assessment
Plasma samples for population pharmacokinetic (PK) analysis of tofacitinib will be collected 
from all subjects enrolled in the study at various time points. 
Among the first 40 subjects enrolled (excluding subjects with systemic JIA), the Sponsor will 
attempt to enroll a minimum of 10 subjects from each age group (2 to <6 yrs, 6 to <12 yrs, 
12 to <18 yrs), and approximately 20 subjects each with normal and above normal baseline 
CRP result.  The Sponsor will track enrollment and notify investigators when the target 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 81
number of blood samples for PK analysis in first 40 subjects (excluding subjects with sJIA) 
has been reached. 
In general, every effort should be made to collect blood samples for PK analysis within the 
specified time windows. At all times, it is essential to accurately record the date and time
study treatment is administered and PK samples are collected.  This includes the date and 
time of the dose taken on the evening prior to the specified PK visit. 
On days where a pre-dose PK sample is collected, the subject and parent/legal guardian will 
be instructed that the subject should not take the morning dose until after the pre-dose PK 
sample is collected.
Blood samples for PK analysis at additional time points and/or in additional subjects may be 
collected, as determined by the Sponsor.
7.3.1. PK Blood Sample Collection Time
7.3.1.1. First 40 Subjects Enrolled (Excluding Subjects with Systemic JIA)
In the first 40 subjects (excluding subjects with systemic JIA) enrolled in the study, blood 
samples for PK will be collected on Day 1 and Week 12/Day 84 (or later visit up to 
Week 18/Day 126 visit) at the time points indicated below.
Day 1 PK Collection Time Points:

15 [10 – 20] minutes post dose;

45 [35 – 55] minutes post dose;

3 [2.75 – 4.0] hours post dose.
Week 12/Day 84 (or later visit up to Week 18/Day 126 visit) PK Collection Time Points:
Note, the subject and parent/legal guardian will be instructed that the subject should not take 
the morning dose until after the pre-dose PK sample is collected.

Pre-dose (approximately 12 hrs post the previous evening dose);

45 [35 - 55] minutes post dose.
The Sponsor will track and notify investigators when the target number of blood samples for 
PK analysis in first 40 subjects enrolled (excluding subjects with sJIA) has been reached.
7.3.1.2. After First 40 Subjects Enrolled (excluding Subjects with Systemic JIA)
After the first 40 subjects (excluding subjects with systemic JIA) are enrolled in the study, in 
all subsequent subjects enrolled (excluding subjects with systemic JIA), blood samples for 
PK will be collected on Week 2/Day 14 (or Week 4/Day 28), and Week 12/Day 84 (or later 
visit up to Week 18/Day 126 visit) at the time points indicated below.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 82
Note, the subject and the parent/legal guardian will be instructed that the subject should not 
take the morning dose until after the pre-dose PK sample is collected.
Week 2/Day 14 (or Week 4/Day 28) PK Collection Time Points:

Pre-dose (approximately 12 hrs post the previous evening dose);

45 [35 – 55] minutes post dose;

3 [2.75 – 4.0] hours post dose.
Day 84 (or later visit up to Day 126 visit) PK Collection Time Points:

Pre-dose (approximately 12 hrs post the previous evening dose);

45 [35 - 55] minutes post dose.
7.3.1.3. Subjects with Systemic JIA
In all subjects with systemic JIA, plasma samples for PK will be collected on Week 2/Day 14
(or Week 4/Day 28) and Week 12/Day 84 (or later visit up to Week 18/Day 126 visit) at the 
time points indicated below.
Note, the subject and parent/legal guardian will be instructed that the subject should not take 
the morning dose until after the pre-dose PK sample is collected.
Week 2/Day 14 (or Week 4/Day 28) PK Collection Time Points:

Pre-dose (approximately 12 hrs post the previous evening dose);

45 [35 – 55] minutes post dose;

3 [2.75 – 4.0] hours post dose.
Week 12/Day 84 (or later visit up to the Week 18/Day 126 visit) PK Collection Time Points:

Pre-dose (approximately 12 hrs post the previous evening dose);

45 [35 - 55] minutes post dose.
7.3.2. Blood Sample Processing
Blood samples (1 mL) to provide a minimum of 0.4 mL of plasma for PK analysis will be 
collected into appropriately labeled tubes containing lithium heparin.
Samples will be centrifuged at approximately 1700 g for about 10 minutes at 4C.  The 
plasma will be stored in appropriately labeled screw-capped polypropylene tubes at 
approximately -20C within 1 hour of collection. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 83
7.3.3. PK Sample Shipment
The shipment address and assay laboratory contact information will be provided to
investigator sites prior to initiation of the study.
At the assay laboratory, samples will be analyzed using a validated analytical method in 
compliance with Pfizer standard operating procedures.
The PK samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the PK processing steps, including any actions taken, must be 
documented and reported to the sponsor. On a case-by-case basis, the sponsor may make a 
determination as to whether sample integrity has been compromised.  Any sample deemed 
outside of established stability, or of questionable integrity, will be considered a protocol 
deviation.
 
 
 
7.4. Tofacitinib Oral Solution Taste Acceptability Assessment
Oral solution will be used in subjects weighing <40 kg and in subjects who are unable to 
swallow tablets.
In subjects receiving tofacitinib oral solution, taste acceptability will be assessed at the 
Week 2/Day 14 visit.
Taste acceptability will be assessed by asking the subject to select one of several choices 
which most adequately reflects the subject’s response to taste.  Age appropriate tools (using 
wording and/or graphic facial expressions) will be used to assess taste acceptability.
7.5.1. Markers of Drug Response
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who respond 
well and those who respond poorly to treatment may help to better define the most 
appropriate group of patients in which to target a given treatment
 
 
CCI
CCI
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 84
 
 
 
.
To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s study identification (ID) number.  Samples will be kept in a 
facility accessible only by swiping a badge.  Data will be stored on password-protected 
computer systems.  The key between the code and the subject’s personal identifiers will be 
held at the study site; the researchers using the biospecimens and data generated from them 
will not have access to the key nor any personally identifying information.  Biospecimens 
will be used only for the purposes described here and in the informed consent 
document/subject information sheet; any other uses require additional ethical approval.  
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored indefinitely to allow for future research on the topics described 
here, including research conducted during the lengthy drug development process and also 
postmarketing research.  Subjects can withdraw their consent for the use of their 
biospecimens at any time by making a request to the investigator, in which event any 
remaining biospecimen will be destroyed; data already generated from the biospecimens will 
continue to be stored to protect the integrity of existing analyses.  It is very unlikely that 
results generated from the biospecimens will have any clinical, diagnostic, or therapeutic 
implications for the individual study participants. Subjects are notified in the informed 
consent document/subject information sheet that their results will not be given to them, 
unless required by local laws or regulations, in which case results will be returned via the 
investigator.  Results will not be provided to family members or other physicians, nor will 
they be recorded in the subject’s medical record.  There is no intention to contact subjects 
after completion of the clinical study.
A single 2 mL blood biospecimen Prep D1.5 (K2 edetic acid [ethylenediaminetetraacetic 
acid] [EDTA] whole blood collection optimized for DNA analysis) will be collected at the 
Week 8 visit to be retained for potential pharmacogenomic/biomarker analyses related to 
drug response, unless prohibited by local regulations or ethics committee decision.  For 
example, putative safety biomarkers, drug-metabolizing enzyme genes, drug-transport 
protein genes, or genes thought to be related to the mechanism of drug action may be 
examined. 
 
CCI
CCI
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 85
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 nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
CCI
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 86
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product. 
Serious adverse events occurring to a subject after the active reporting period has ended 
should be reported to the sponsor if the investigator becomes aware of them; at a minimum, 
all SAEs that the investigator believes have at least a reasonable possibility of being related 
to investigational product are to be reported to the sponsor.
All adverse events (serious and nonserious) should be recorded on the Case Report Form 
(CRF) from the time the subject has taken at least 1 dose of investigational product through 
the subject’s last visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 87

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error case report form (CRF) which is a specific version of the adverse event (AE) page, and 
on the SAE form when appropriate.  In the event of medication dosing error, the sponsor 
should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the adverse 
event (AE) page and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.4.1. Tofacitinib Overdose
There is no experience with overdose of tofacitinib (CP-690,550).  Pharmacokinetic data up 
to and including a single dose of 100 mg in healthy adult volunteers indicates that more than 
95% of the administered dose is expected to be eliminated within 24 hours.  There is no 
specific antidote for overdose with tofacitinib.  In case of an overdose, it is recommended 
that the subject be monitored for signs and symptoms of adverse reactions.  Subjects who 
develop adverse reactions should receive appropriate medical treatment. 
Concomitant treatment with prohibited potent CYP3A inhibitors (Appendix 4) is assumed to 
result in a doubling of tofacitinib exposure. For further details, please refer to the SRSD 
(eg, the 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.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 88
Infections should be classified as either serious infections and/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 CRF.  Appropriate laboratory investigations, 
including but not limited to cultures should be performed to establish the etiology of any 
serious infection.  All adverse events, including serious adverse events, must be reported as 
described in Section 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).  A subject who 
experiences a serious infection must be discontinued from the study.  This information must 
be noted in the eCRF.
8.6. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
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;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 89

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 Section 8.15.1 SAE 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 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 90
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 X ULN or
if the value reaches 3 X ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/ international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.
8.8. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 91
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.9. Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, or 
SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, these 
intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 92
8.10. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
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).
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).


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 93
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
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays). In the case of paternal 
exposure, the investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner. The investigator must document in the source 
documents that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner.
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 on 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. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 94
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 and/or their parent/legally acceptable representative.  In addition, each 
study subject and/or their parent/legally acceptable representative will be questioned about 
AEs.
8.15. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.15.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.15.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 95
8.15.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study
will be documented in a Statistical Analysis Plan, which will be maintained by the sponsor.  
This document may modify the plans outlined in the protocol: however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
A sample size of approximately 170 subjects (in the polyarticular cohort) will be enrolled in 
the open-label active treatment run-in phase to provide a power of approximately 90% or 
above to detect a difference in the rate of disease flares between study drug versus placebo in 
the double-blind phase, assuming a 54% to 65% response rate of ACR Pedi 30 from the 
run-in active treatment phase, a 2-sided 5% Type I error,  and a true difference of at least 
31% in flare rates between tofacitinib and placebo, with a placebo flare rate of 57%.  Sample 
sizes for the polyarticular JIA categories were determined from a combination of prevalence 
data and precedents in the literature.
9.2. Efficacy Analysis
9.2.1. Analysis of Primary Endpoint
Superiority of tofacitinib to placebo for the primary endpoint of percentage of subjects with 
disease flare at end of study Week 44 (Week 26 of the double-blind phase) for subjects with 
polyarticular course (polyarthritis RF+/RF-, extended oligoarthritis, and systemic JIA with 
active arthritis but without active systemic features) JIA will be tested using the normal 
approximation approach for the binomial populations.  Subjects who discontinue from the 
study treatment for any reason will be considered as having a disease flare, except subjects 
who discontinue after maintaining JIA ACR inactive disease for at least 24 weeks in the 
double-blind phase.  These discontinuations will be considered as non-disease flare.
Additional details of the analysis of the primary endpoint will be described in the Statistical 
Analysis Plan (SAP).
9.2.2. Analysis of Secondary Endpoints
All secondary efficacy endpoints that are collected in the double-blind withdrawal phase will 
be analyzed by treatment group.  For the binary secondary endpoints, including occurrence of 
disease flare prior to Week 44/EoS (Week 26 of the double-blind phase), JIA ACR 
responses, presence of JIA ACR inactive disease and clinical remission, JADAS minimum 
disease activity and inactive disease status, the normal approximation approach for the binary 
populations, as used for the primary analysis, will be performed. For the continuous 
secondary endpoints, including change from baseline in JADAS 27-CRP, JADAS 27-ESR, 
CHQ, CHAQ, and JIA ACR core set variables, a mixed-effect model will be applied. The 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 96
estimated treatment difference and the associated 95% confidence interval will be presented.  
The Kaplan-Meier plot will be generated for the secondary endpoint of time to flare.  
Descriptive/summary statistics for all endpoints will also be provided.  Baseline demographic 
characteristics, primary and key secondary endpoints will be summarized by JIA category,
baseline CRP, methotrexate background therapy, prior biologic failures, history of uveitis, 
and age. 
Forest plots will be provided for the primary and key secondary endpoints, and will also be 
presented for the subgroup analysis on these endpoints.
For subjects with ERA and subjects with PsA, efficacy endpoints will be assessed separately 
using summary and descriptive statistics by treatement group at each time point in the 
double-blind phase.
For the efficacy endpoints that are collected in the open-label run-in phase, the summary 
statistics or descriptive statistics will be presented at each visit for the binary or continuous 
efficacy endpoints, respectively. 
Taste acceptability assessment questionnaire will be included in the CRF.  Summary 
statistics will be provided for each category of the taste acceptability by treatment and by 
time point.  Data will be listed as well.
Further details of the analysis of secondary endpoints will be described in the Statistical 
Analysis Plan (SAP). 
9.3. Population Pharmacokinetics and Exposure-Response Analyses
Plasma concentration-time data for tofacitinib will be analyzed using a nonlinear mixed 
effects modeling approach to characterize PK in JIA subject population.  Effects of 
demographic and disease covariates (age, weight, CRP etc.) on tofacitinib PK may be 
explored if appropriate.  PK data (on Day 1 in the run-in period) from approximately the first 
20-40 subjects with polyarticular JIA (depending on the enrollment rate) will be analyzed to 
confirm the current dosing scheme for the double-blind phase and doses may be adjusted for 
the remaining subjects based on the results of this analysis.
Relationships between various measures of systemic exposure of tofacitinib and efficacy and 
safety outcomes may be explored, using similar methodology, if considered necessary or 
useful upon review of the available data.  The details of the analysis plan will be provided in 
a separate document (population PK modeling plan or PMAP) and the results may be 
reported separately (population PK modeling report or PMAR) from the clinical study report.
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 97
9.4. Safety Analysis
Safety analysis will be performed on all subjects who received at least one dose of study 
drug.  The Sponsor has standard algorithms for reporting adverse events and clinical 
laboratory test results, and these will be employed in the analysis of the data from this trial.  
Safety data will be subject to clinical review and summarized by appropriate descriptive 
statistics.  Details will be presented in the SAP.
9.5. Interim Analysis
No formal interim analysis is planned.
9.6. Data Safety Monitoring Board (DSMB)
An independent Data Safety Monitoring Board (DSMB), a group of experts external to 
Pfizer, will review accumulating safety data from this study on an ongoing basis within the 
context of the Phase 3 pediatric program as well as adult program.  Based on these reviews, 
the DSMB will have the capacity to make recommendations to Pfizer that might impact the 
future conduct of the trial.  The recommendations made by the DSMB to alter the conduct of 
the study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
which are not endpoints, to regulatory authorities, as appropriate.  The DSMB will have 
access to unblinded treatment information from concurrently ongoing double-blind studies 
during the clinical trial.  The management and process of this committee will be in 
accordance with Pfizer’s Standard Operating Procedures and will be documented in the 
DSMB Charter.  The DSMB members will all be individuals who are independent of Pfizer.  
A DSMB Liaison will be appointed; this is an individual who represents Pfizer to coordinate 
communications and facilitates access to Pfizer’s resources, but is not involved in the study 
design, study management, site management, data accrual, or study analysis.  Records of 
DSMB meetings, interactions with Pfizer contacts, assessments and recommendations and 
materials reviewed will be maintained and kept proprietary and confidential by the DSMB.  
Further information about the DSMB can be found in the DSMB Charter, which outlines the 
operating procedures of the committee, including specific description of the scope of their 
responsibilities, including a plan where communication timelines are defined.
9.7. Safety Endpoint Adjudication Committee
To help assess specific safety events in this and other studies in the tofacitinib program, 
adjudication committees have been established to harmonize and standardize selected safety 
event assessment.  Members of these safety event adjudication committees will be blinded to 
treatment assignment in order to allow for unbiased assessments. These committees include 
a Cardiovascular Endpoint Adjudication Committee (CV EAC), Malignancy Adjudication 
Committee (MAC), Opportunistic Infection Review Committee (OIRC), Hepatic Event 
Review Committee (HERC) and Gastrointestinal Perforation Review Committee (GIPRC).  
Further information about these committees can be found in the respective charters, including 
specific descriptions of the scope of their responsibilities and the processes and definitions 
used to review and assess specific safety events. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 98
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 World Care Clinical (WCC) for review 
by a WCC pathologist. 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
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 99
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator 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/assent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 100
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/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
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The study site 
will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent/assent documents must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent/assent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 101
The investigator must ensure that each study subject, or his or her legally acceptable 
representative, or parent(s) or legal guardian if a minor, is fully informed about the nature 
and objectives of the study and possible risks associated with participation. 
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s) or 
legal guardian, the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a subject’s decisional capacity is so limited he/she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the subject’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study subject does not provide 
his or her own consent, the source documents must record why the subject did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the subject’s legally acceptable representative, the consent 
signer’s relationship to the study subject (eg, parent/legal guardian, spouse) and that the 
subject’s assent was obtained, or waived.  If assent is obtained verbally it must be 
documented in the source documents.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must re-consent as adults to remain in the study.  If the 
enrollment of ‘emancipated minors’ is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative, parent(s) or legal 
guardian and the subject’s assent, when applicable, before any study-specific activity is 
performed, unless a waiver of informed consent has been granted by an IRB/EC. The 
investigator will retain the original of each subject's signed consent/assent document.
12.4. Subject Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.  Use of IRB/EC committee approved, generic, prescreening 
questionnaire to assess basic subject characteristics to determine general eligibility for this 
study is allowed.  This generic questionnaire may be used by sites as a phone script and/or to 
review internal databases to identify subjects.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 102
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 the United States
Last subject last visit (LSLV) is defined as the date the investigator reviews the last subject’s 
final safety data and determines that no further evaluation is required for the subject to 
complete the trial.
13.2. End of Trial in a Member State
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.3. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as Last Subject Last Visit (LSLV).
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 7 days.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), or 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.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 103
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in subjects that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date for 
studies in adult populations or within 6 months of the primary completion date for studies in 
pediatric populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the 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.
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 supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.  The investigator will provide any publication 
to Pfizer at least 30 days before it is submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, the investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 104
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement (CSA)
between Pfizer and the institution.  In this section entitled Publications by Investigators, the 
defined terms shall have the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 105
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, et al. Measurement of health status in children with 
juvenile rheumatoid arthritis. Arthritis Rheum 1994; 37(12):1761–9.
6.
Ruperto N, Ravelli A, Pistorio A, et al. Cross-cultural adaptation and psychometric 
evaluation of the Childhood Health Assessment Questionnaire (CHAQ) and the Child 
Health Questionnaire (CHQ) in 32 countries. Review of the general methodology. Clin 
Exp Rheumatol 2001; 19 (4 Suppl. 23): S1-9.
7.
Giannini EH, Ruperto N, Ravelli A, et al. Preliminary definition of improvement in 
juvenile arthritis. Arthritis Rheum 1997; 40(7): 1202-9.
8.
Brunner HI, Lovell DJ, Finck BK, et al.Preliminary definition of disease flare in
juvenile rheumatoid arthritis. J Rheumatol 2002; 29(5):1058-64.
9.
Wallace CA, Giannini EH, Huang B, et al. American College of Rheumatology 
provisional criteria for defining clinically inactive disease in select categories of 
juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011;63(7);929-36.
10.
Dorn, LD. Perceptions of puberty: Adolescent, parent, and health care personnel. 
Developmental Psychology 1990; 26(2): 322-9.
11.
Taylor SJ, Whincup PH, Hindmarsh PC, et al. Performance of a new pubertal 
self-assessment questionnaire: a preliminary study. Paediatr Perinat Epidemiol 2001; 
15(1):88-94.
12.
Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of Adult Data and Other Data 
in Pediatric Drug-Development. Pediatrics 2011; 128(5); e1242-9.
13.
Macrae IF, Wright V. Measurement of back movement. Ann Rheum Dis, 
1969;28(6):584-9.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 106
14.
Moll JM, Wright V. Normal range of spinal mobility: an objective clinical study. Ann 
Rheum Dis, 1971;30(4):381-6.
15.
Horneff G, Burgos-Vargas R, Constantin T, et al.  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(6):1114–22.
16.
Consolaro A, Ruperto N, Bazso A, et al.  Development and validation of a composite 
disease activity score for juvenile idiopathic arthritis.  Arthritis Care and Research, 
2009; 61(5):658-66.
17.
Consolaro A, Bracciolini G, Ruperto N, et al.  Remission, minimal disease activity and 
acceptable symptom state in juvenile idiopathic arthritis: defining criteria based on the 
juvenile arthritis disease activity score. Arthritis Rheum, 2012;64(7):2366-74.
18.
Bazso A, Consolaro A, Ruperto N, et al.  Development and testing of reduced joint 
counts in juvenile idiopathic arthritis.  J Rheumatol, 2009; 36(1):183-90.
19.
Nordal EB, Zak M, Aalto K, 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(7):1122-7.
20.
Landgraf JM,. Abetz L Ware JE. In:Child-Health Questionnaire(CHQ): a user’s manual. 
Boston, MA: Health Institute, New England Medical Center; 1996: 235-9.
21.
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(3):509–16.
22.
Schwartz GJ, Munoz A, Schneider MF, et al. New equations to estimate GFR in 
children with CKD. J Am Soc Nephrol 2009;20(3):629-37.
23.
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.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 107
Appendix 1. Allowed and Disallowed Treatments for JIA
Allowed DMARDs:
The following DMARDs are allowed in doses consistent with local standards of care:

Methotrexate may be taken orally or parenterally at doses not to exceed 25 mg/wk or 
20 mg/m2/week [whichever is lower]).  Participants must have taken MTX for 
3 months and be at a stable dose for at least 6 weeks before baseline and should be 
on a stable dose for the duration of the study [open-label run-in and double-blind 
phases]).  Subjects taking methotrexate must be taking folic acid or folinic acid in 
accordance with local standards.
Allowed Treatments for Psoriatic Arthritis:
For subjects with PsA, the following topical treatments for psoriasis are allowed: 

Non-medicated emollients for use over the whole body; 

Topical steroids including hydrocortisone and hydrocortisone acetate 1% for the 
palms, soles, face, and intertriginous areas only; 

Tar, salicylic acid preparations, and shampoos free of corticosteroids are permitted 
only for the scalp.
Disallowed Biologic and Non-Biologic DMARDs:
The following biologic agents and DMARDs are disallowed at any time during this study.  If 
a subject requires (in the opinion of the investigator) treatment with one of these agents, the 
subject should be discontinued from the study:

Leflunomide (Arava) must have been discontinued 8 weeks prior to the first dose of 
study drug if no elimination procedure is followed;

Anakinra (Kineret), Enbrel (Etanercept): Discontinued for 4 weeks prior to the first 
dose of study drug;

Canakinumab (Ilaris): Discontinued for 18 weeks prior to the first dose of study 
drug;

Adalimumab (Humira): Discontinued for 6 weeks prior to first dose of study drug;

Infliximab (Remicade): Discontinued for 8 weeks prior to the first dose of study 
drug;

Golimumab (Simponi TM): Discontinued for 10 weeks prior to the first dose of study 
drug;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 108

Abatacept (Orencia), Tocilizumab (Actemra), Certolizumab pegol (Cimzia): 
Discontinued for 12 weeks prior to first dose of study drug;

Rituximab (Rituxan) or other selective B lymphocyte depleting agents (either 
marketed or investigational): Discontinued for 1 year prior to the first dose of study 
drug and if CD19/20+ counts are normal by FACS analysis.
Other Disallowed Agents:

Bucillamine, mizoribine, sulfasalazine, d-penicillamine, azathioprine, chloroquine, 
hydroxychloroquine, cyclosporine, tacrolimus, and staphylococcal protein A 
immuno-absorbant pheresis columns (eg, PROSORBAdevice/column) must be 
discontinued for 4 weeks prior to first dose of study drug;

Auranofin (oral gold), aurothioglucose (injectable gold), aurothiomalate (injectable 
gold) must be discontinued for 8 weeks prior to first dose of study drug.
Disallowed Treatments for PsA:
For subjects with PsA, oral and topical medications and alternative treatments that could 
affect psoriasis are prohibited.  This includes:

Topical corticosteroids (except those described in the “Allowed Treatments for 
Psoriatic Arthritis” section of Appendix 1), tars, keratolytics, anthralin, vitamin D 
analogs, and retinoids which must be discontinued at least 2 weeks prior to first dose 
of study drug;  

Ultraviolet B (UVB) (narrowband or broadband) phototherapy that 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.
Disallowed Investigational Drugs:

Investigational NSAIDs: Any experimental non-steroidal anti-inflammatory drug 
(NSAID), including selective COX-2 inhibitors, must be discontinued for 4 weeks 
prior to the first dose of study drug.

Other Investigational Drugs: Any other experimental therapy must be discontinued 
for 6 months or 5 half-lives (whichever is longer) prior to the first dose of study drug. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 109
Appendix 2. Permitted Adjustments In JIA Therapies 
The following adjustments of background medications are allowed for reasons of inadequate 
efficacy of current treatment.  Adjustments for safety reasons may be done at any time, but if 
this leads to changes in excess of those allowed below, the investigator must receive approval 
from the Pfizer project team to allow the subject to continue in the trial.
1. NSAIDs/COX-2 inhibitors: dose adjustments may be made, or background 
NSAID/COX-2 inhibitors may be switched, but should be no more frequently than 
every 3 months, and should be more than 14 days prior to a study visit. 
2. Oral corticosteroid dose should be stable for the duration of the study (open-label 
run-in and double-blind phases) and not exceed 0.2 mg/kg/day prednisone or 
equivalent or 10 mg per day, whichever is lower. 
3. Methotrexate (MTX) may be administered either orally or parenterally at doses not to 
exceed 25 mg/wk or 20 mg/m2/week (whichever is lower) and should remain stable 
for the duration of the study (open-label run-in and double-blind phases).
4. Intra-articular steroids should be administered in a total dosage of no more than 
2 mg/kg (up to 80 mg) of methylprednisolone equivalent every 6 months.  No more 
than two joints should be injected in any given 6 month period and individual joints 
should not be injected any more frequently than once in a 6-month period.  Injected 
joints will be considered active joints for the remainder of the study and for 
efficacy assessments. 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 110
Appendix 3. Estimated Glomerular Filtration Rate Calculation
Bedside Schwartz (Schwartz, 2009)22 GFR equation will be used to estimate glomerular 
filtration rate (GFR) from serum creatinine (creatinine method with calibration traceable to 
IDMS).
GFR (mL/min/1.73 m2) = 0.413 × (Ht / Scr)
Height (Ht) in cm; 
Serum creatinine (Scr) in mg/dL;  


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 111
Appendix 4. Prohibited Concomitant Medications
All prohibited drugs require a 4 week (or 5 half-lives, whichever is longer) washout, except:
* Amiodarone half-life averages about 58 days and requires a 290 day washout (5 half-lives).
** Biologic and Non-Biologic DMARDs which have specific washout periods are listed in 
Appendix 1.
NOTE: Topical administration (eg, cutaneous, 
ophthalmic, or intravaginal) of listed concomitant 
medications, which are prohibited if administered 
systemically, is allowed in the study.
Moderate or Potent CYP3A Inhibitors 
Moderate or Potent CYP3A Inducers
HIV antivirals:
efavirenz (Sustiva)
-delavirdine (Rescriptor)
nevirapine (Viramune)
-indinavir (Crixivan)
Barbiturates
-nelfinavir (Viracept)
carbamazepine (Carbatrol, Tegretol)
-ritonavir (Kaletra, Norvir)
modafinil (Provigil)
-saquinavir (Fortovase)
phenobarbital
-atazanavir
phenytoin (Dilantin, Phenytek)
amiodarone (Cordarone, Pacerone)*
rifabutin (Mycobutin)
cimetidine (Tagamet)
rifampin (Rifadin, Rifamate, Rifater)
clarithromycin (Biaxin, Prevpac)
rifapentine (Priftin)
telithromycin (Ketek)
St. John's Wort
clotrimazole
troglitazone (Rezulin)
chloramphenicol
All Investigational Drugs
diethyl-dithiocarbamate  
DMARDs
diltiazem (Cardizem, Tiazac)
All Biologics**, such as:
anakinra (Kineret), etanercept (Enbrel), 
adalimumab (Humira), infliximab 
(Remicade), abatacept (Orencia), 
canakinumab (Ilaris), tocilizumab 
(Actemra), golimumab (Simponi), 
rituximab (Rituxan),
erythromycin 
fluconazole (Diflucan)
fluvoxamine (Luvox)
Grapefruit juice and marmalade
itraconazole (Sporanox)
ketoconazole (Nizoral)
Other DMARDs**:
leflunomide, sulfasalazine, d-penicillamine, 
bucillamine, mizoribin, azathioprine, 
cyclosporine, tacrolimus, auranofin, 
aurothioglucose, aurothiomalate, 
staphylococcal protein A immuno-absorbant 
pheresis columns
mifepristone (Mifeprex, RU486)
nefazodone (Serzone)
norfloxacin (Shibroxin, Noroxin)
mibefradil  
verapamil (Calan SR,Covera HS, Isoptin SR, Tarka, Verelan)
voriconazole


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 112
Appendix 5. 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 subjects who are NOT on stable, background opioid therapy: any of the following 
single opioid agents may be given as rescue medication (with or without acetaminophen/ 
paracetamol) for no more than 10 consecutive days in the following total daily doses:
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 subjects who ARE on stable, background opioid therapy:

They may NOT add a second opioid agent for rescue;

If their background medication is 1 of the 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) 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 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. 
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 may be given in no more than two joints, in a 
cumulative dose of no more than 80 mg methylprednisolone or its equivalent in any 6 month 
study period.  Injections should be avoided for 6 weeks before any study visit.  Injected joints 


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 113
will also be considered as having their pre-injection status (tender/painful and swollen) for 
the remainder of the trial.
Acetaminophen/paracetamol is not permitted as a part of combination products such as 
over-the-counter “cold remedies” or in combination with opioids if the acetaminophen/ 
paracetamol dose will exceed 2.6 gm/day.  Subjects who require rescue for more than 
10 consecutive days should be considered for allowed JIA medication adjustments or 
discontinued from the trial.  In addition, subjects should not be dosed with rescue 
acetaminophen/ paracetamol or opioids during the 24 hours prior to a study visit.  Baseline 
stable acetaminophen/ paracetamol or opioids should NOT be discontinued in advance of 
study visits.
Subjects should avoid dosing with 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.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 114
Appendix 6. Guidelines For Safety Monitoring And Discontinuations
The following laboratory abnormalities require prompt re-testing, ideally within 3-5 days:

Lymphocyte counts <500 lymphocytes/mm3;

Neutrophil counts <1000 neutrophils/mm3.
Applicable to Investigative Sites in the UK, Spain, Poland, Germany and 
Belgium Only: Study drug will be discontinued temporarily for confirmed absolute 
neutrophil counts (ANC) levels of 500-1000 neutrophils/mm3. The subject will be 
monitoried closely through unscheduled visits and laboratory retesting until ANC is 
>1000 neutrophils/mm3. Dosing may be resumed when ANC returns to 
>1000 neutrophils/mm3.

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.
Treatment with CP-690,550 will be discontinued and the subject withdrawn from this study 
for:

Serious infections (those requiring parenteral antimicrobial therapy or 
hospitalization), and opportunistic infections;

Malignancies;

Two sequential lymphocyte counts <500 lymphocytes/mm3;

Two sequential neutrophil counts <500 neutrophils/mm3;

Two sequential platelet counts <75,000 platelets/mm3;

Two sequential AST or ALT elevations >3 times the upper limit of normal with at 
least one Total Bilirubin value >2 times the upper limit of normal;

Two sequential AST or ALT elevations >3 times the upper limit of normal with an 
abnormal INR;

Two sequential AST or ALT elevations >3 times the upper limit of normal 
accompanied by symptoms consistent with hepatic injury;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 115

Two sequential AST or ALT elevations >5 times the upper limit of normal, regardless 
of Total Bilirubin or accompanying symptoms;

Single positive HBc Ab and a negative HBs Ab;

Two sequential hemoglobins <8.0 g/dL or a decrease of more than 30% from baseline 
value;

Two sequential increases in serum creatinine >100% over the average of screening 
and baseline values.  For any increase in serum creatinine >50% over the average of 
screening and baseline, protocol-permitted adjustments in concomitant medications 
and/or dose of study drug are permitted within a 90 day period from the initial 
>50% serum creatinine increase.  If the >50% increase in serum creatinine persists for 
90 days, in spite of adjustments in concomitant medications and/or dose of study 
drug, treatment with CP-690,550 must be discontinued and the subject withdrawn 
from the study;

Other serious or severe AEs, after consultation with the Pfizer Medical Monitor.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 116
Appendix 7. Dosing Rationale (Abbreviated Analysis Report)
Population Pharmacokinetics of Tofacitinib in Subjects with Juvenile Idiopathic Arthritis 
(JIA) and Dose Selection for A3921104.
Objectives
The objectives of this analysis were: 

To characterize the population pharmacokinetics (POPPK) of tofacitinib in subjects 
with juvenile idiopathic arthritis (JIA) using available data from the Phase 1 study in 
JIA subjects; 

To select doses for future efficacy/safety study (A3921104) in polyarticular JIA 
subjects based on simulated steady state exposures generated using the POPPK 
analysis parameter values.
Study Design and Assessments
Pharmacokinetic data from 26 subjects in study A3921103 (An Open-Label Multiple Dose 
Study to Evaluate the Pharmacokinetics, Safety and Tolerability of CP-690,550 in Pediatric 
Subjects from 2 to <18 years of age with Juvenile Idiopathic Arthritis (JIA) were available 
for analysis. 
Tofacitinib concentrations were determined using a validated analytical method in 
compliance with Pfizer standard operating procedures by the contract analytical laboratories.  
The minimum quantifiable concentration of the assay is 0.1 ng/ml, and the per-protocol 
(nominal) PK sampling schedules are listed in Table S1.
Table S1.
PK Sampling Schedule in A3921103
Study
PK sampling schedule/Period
Number of 
subjects
planned
Treatment
A3921103
Pre-dose on Day 5 (approximately 
11-13 h post-dose after second 
dose on Day 4) and 0.5, 1, 2, 4 and 
8 hours post first dose on Day 5
26 (At least 
24 with 
n=8 in each 
cohort)a
2-5 mg BID depending 
on body weight of the 
subjects as given below 
in Table S2


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 117
Table S2.
Dosing Scheme in A3921103
Body Weight 
(Kg)
Dose (mg)
Volume (mL)
5-11
1
1
12-18
1.5
1.5
19-24
2
2
25-31
2.5
2.5
32-39
3
3
≥40
5
5
Dosing Scheme for Age 2 to <6 years
5-6
1
1
7-9
1.5
1.5
10-12
2
2
13-15
2.5
2.5
16-19
3
3
20-22
3.5
3.5
23-26
4
4
27-29
4.5
4.5
≥30
5
5
Data for Analysis
The Information Strategy and Analytics function within Clinical Innovation and Informatics 
(CII) generated the PK data files used in this POPPK analysis.  Data files were constructed 
and quality control evaluations completed according to all CII standard operating procedures 
and processes as documented in the programming plan.
PK samples were collected from all specified time points with no missing or below 
quantification limit (BQL) tofacitinib concentrations.  All concentrations were included in 
the analysis.  Actual time points instead of nominal time points of blood sample collection 
were used for the analysis.
Methods
The POPPK analysis was conducted using a nonlinear mixed-effects modeling approach.  
NONMEM version 7.2 (ICON Development Solutions, Hanover, MD) was used for the 
execution of NONMEM. R version 3.0 (R Development Core Team) and R-Studio 0.98.484 
were used for data handling, 
 
  The estimation method was the first-order conditional estimation 
(FOCE).
The analyses were conducted in the following steps: 1) base structural model development; 
2) final model development; 3) assessment of model adequacy; 4) model predictive 
performance (VPC) and 5) simulations to of steady state exposures at various doses of 
Tofacitinib to recommend dosing regimen for the upcoming Phase 3 study.
CCI


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 118
Tofacitinib PK was described by a one-compartment disposition model with first-order 
absorption parameterized in terms of apparent oral clearance (CL/F), apparent volume of 
distribution (V/F), and first-order absorption duration (D) using NONMEM subroutines, 
ADVAN2 and TRANS2.  Inter-individual variability (IIV) on CL/F, V/F and Ka were 
modeled using exponential variance models.  Residual variability was modeled with a 
proportional and additive error models. 
Due to limited number of subjects available for the analysis, a full covariate modeling 
approach was not deemed appropriate.  Instead, based on allometric theory, body weight 
(BWT) was used as a predictor of CL/F and V/F.  Additionally, results from a prior relative 
bioavailability study of Tofacitinib (A3921105) in adult healthy volunteers indicated a 
decrease (~24% decrease at 50 mg dose, N=12) in Cmax (maximum observed concentrations 
post-dose) for tablets compared to OPC (oral powder for constitution) formulation.  
Therefore, formulation (solution or tablet) was explored as a categorical covariate to describe 
the between-subject variability of Ka.  No additional covariate analysis besides these two was 
investigated. 
Goodness of fit of different models to the data was evaluated using the following criteria:  
change in OFV, visual inspection of various diagnostic plots, and precision of the parameter 
estimates.  Visual Predictive Checks (VPCs) were performed for the selected PK models to 
qualify the models with respect to the prediction of the concentration data prior to any 
simulation work.
Results
The Tofacitinib POPPK dataset from A3921103 consisted of 26 subjects (9 males and 
17 females) and 151 plasma concentrations with mean ages of 14.1 years, 9.4 years, and 
4 years for Cohort 1 (12 - <18 years), Cohort 2 (6 - <12 years), and Cohort 3 (2 <6 years), 
respectively.  Median baseline body weights were 54.0 kg, 32.4 kg, and 17.3 kg for Cohort 1,
Cohort 2, and Cohort 3, respectively, and mean CRP values were 3.8 mg/L, 5.7 mg/L, and 
20.2 mg/L for Cohort 1, Cohort 2, and Cohort 3, respectively.  The total number of subjects 
who received 2, 2.5, 3, and 5 mg BID doses was 1, 5, 10, and 8, respectively.
The final PK model was a one compartment model with first order absorption.  Inter subject 
variabilites (IIV) on CL/F and Ka were modeled as exponential error models.  The IIV for 
CL/F and V/F were assumed to be correlated.  Covariance was assumed between CL/F and 
Ka.  Residual random effects were described with a combination of proportional and additive 
error models. 
In the final model, BWT was incorporated as power functions, normalized to standard adult 
weight of 70 Kg on CL/F and V/F.  Although effect of formulation was explored as a 
potential predictor of the difference in absorption rate between tablet and solution 
formulation; the limited data did not support estimating separate Ka for each formulation.  
Individual predicted concentrations from the final model overlaid with population predictions 
and observed concentrations are shown in Figure S1.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 119
Figure S1.
Observed Individual Concentrations overlaid with IPRED and PRED 
from final model vs. Time after Dose
ePharm Artifact ID: 10911469
The POPPK final model parameter estimates (%RSE) for the reference individual (Body 
weight 70 Kg), and the bootstrap generated 95% CI for each are provided in Table S3.  The 
diagnostic plots including visual predictive check (VPC) plots indicate that the final model 
described the tofacitinib concentrations well, adequately describing the concentration-time 
profiles for tofacitinib in subjects with JIA.  The goodness of fit (GOF) plots and the VPC 
plots (comparing predicted AUC and Cmax values from 500 simulations to range of observed 
values) are provided in Figure S2 through Figure S5.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 120
Table S3.
Parameter Estimates of the Final Model
Parameters
Point Estimate 
%RSEa
95% CI (Bootstrap)b
CL/F (L/h)
30.4
11.8
25.0-36.5
IIV on CL/F
20.3 (CV%)
V/F (L)
114
8.9
99.1-131.1
Ka (hr-1)
4.53
18.1
3.02-60490
IIV on Ka
122.9 (%CV)
Inter Individual 
Variance
2
CL/F
0.041
41.1
0.005-0.083
Scalar for IIV on V/F
0.232
103.4
0.001-0.795
2
Ka
1.51
70.2
0.044-50.4
Residual Variance
Prop. Error CV
30.0
32.6
22.7-38.7
Add Error
1.17
62.6
0.0242-2.57
BWT on CL/F
0.292
40.1
0.125-0.525
BWT on V/F
0.843
12.3
0.621-0.993
Objective Function 
Value
679.731
a: ePharm Step ID: 604030; b: ePharm Artifact ID: 10911883


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 121
Figure S2.
Goodness of Fit Plots
ePharm Artifact ID: 10911468


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 122
Figure S3.
Visual Predictive Check Plots Comparing distribution of AUCss values 
(green: 90% PI) at various dose groups from simulations (N=500) to the 
observed (red) exposure metrics
ePharm Artifact ID: 10919998


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 123
Figure S4.
Visual Predictive Check Plots Comparing distribution of Cmax,ss values 
(green: 90% PI) at various dose groups from simulations (N=500) to the 
observed (red) exposure metrics
Epharm Artifact ID: 10919998
Some inferences could be made using the parameters from the final model:

Subjects with 12 kg (median weight for 2 yr old girls), 20 kg (median weight for 6 yr 
old girls) and 40.5 kg (median weight for 12 yr old boys) body weights are estimated 
to have ~40%, ~31% and ~15% lower CL/F, respectively, compared to the CL/F of a 
subject with 70 kg body weight;

Subjects with 12 kg (median weight for 2 yr old girls), 20 kg (median weight for 6 yr 
old girls) and 40.5 kg (median weight for 12 yr old boys) body weights are estimated 
to have ~77%, ~65% and ~37% lower V/F, respectively, compared to the V/F of a 
subject with 70 kg body weight;


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 124

Clearance (CL/F) of a typical 70 kg JIA subject (30.4 L/h) is approximately 
65% higher than in RA subjects (18.4 L/h). 

The reason for this difference in CL/F values could possibly be due to higher 
degree of systemic inflammation in adult RA subjects inhibiting metabolizing 
enzymes for tofacitinib. 
Simulations (N=500) were performed using the parameters from the final model and their
between-subject variability to predict secondary exposure metrics at steady state (area under 
the concentration-time curve at steady state (AUC) and maximum concentration post-dose 
[Cmax]) at the doses used in the A3921103 study.  From the predicted AUC and Cmax values, 
demonstrated in Figure S5, it is evident that over the range of weights examined, higher 
doses were needed to reach an efficacy target Cavg,ss of 21 ng/ml, the 5 mg BID equivalent in 
adult RA patients).  However, concentrations were well within the range of 3 mg BID dose in 
adult RA patients (Figure S5, left panel).  Also, there appears to be discordance between 
Cavg,ss and Cmax,ss, rendering Cmax,ss values that closely approximate median Cmax,ss values in 
adult RA subjects after 5 mg BID dose unlike Cavg,ss.
Figure S5.
Impact of Weight on the Pharmacokinetics of Tofacitinib (The dotted 
lines indicate the median values of relevant exposure metrics at given 
doses)
Q1: 13.9-24.5 kg, Q2: 24.5-38.4 kg, Q3: 38.4-53.3 kg, Q4: 53.3-70.9 kg.
Epharm Artifact ID: 10919997
10 mg 
BID
3 mg 
BID
5 mg 
BID
3 mg 
BID
5 mg 
BID
Weight Quartiles


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 125
Dose Selection for Phase 3 Study of Tofacitinib in Polyarticular JIA subjects
Based on the premise of matching exposures (primarily Cavg,ss) observed in adult RA 
subjects, doses not exceeding the most widely approved dose of 5 mg BID (primarily in 
subjects >40 kg), and conditional on the available A3921103 data and analysis, various 
dosing schemes were simulated using the POPPK final model parameters and inter-subject
parameter variabilities.  Doses were identified that are expected to provide steady state 
exposure metrics similar to those from adult RA subjects following a 3 mg BID dose.  The 
final dosing scheme proposed for Study A3921104 is given in Table S5.  In order to provide 
a practical dosing scheme based on age range and body weight, the body weight categories 
were specified such that the differences between the doses administered, and the doses 
required based on body weight, were not substantial.
Table S5.
Dosing Scheme in A3921104
Body Weight 
(kg)
Dosage Regimen
(Run-In Phase: Tofacitinib, Double-Blind Phase: Tofacitinib/Placebo)
5- <7 
2 mg (2 mL oral solution) BID
7- <10
2.5 mg (2.5 mL oral solution) BID
10- <15
3 mg (3.5 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 oral tablet or 5 mL oral solution) BID
Based on the dosing scheme illustrated in Table S5, steady state Cavg ss and Cmax,ss values 
were simulated.  The predicted steady state Cavg and Cmax (median and 90% PI) values are 
depicted in Figure S6 and Figure S7, overlaid with median and 90% CI of corresponding 
exposure metrics in RA subjects following 3, 5 and 10 mg BID doses as relevant.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 126
Figure S6.
Predicted Average Steady-State Concentrations of Tofacitinib in 
Pediatric Subjects (JIA) with Weights Ranging from 5-80 Kg (Red and 
green solid and broken lines indicate Tofacitinib Cavg,ss in adult RA 
subjects)
ePharm Artifact ID: 10919369
Solid- Median; Broken- 90% PI
95th Percentile at 3 mg BID
Median at 5 mg BID
5th Percentile at 5 mg BID
Median at 3 mg BID
5th Percentile at 3 mg BID


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 127
Figure S7.
Predicted Maximum Steady-State Concentrations of Tofacitinib in 
Pediatric Subjects (JIA) with Weights ranging from 5-80 Kg (Red and 
green solid and broken lines indicate Tofacitinib Cmax,ss in adult RA 
subjects)
ePharm Artifact ID: 10919369
Solid- Median; Broken- 90% PI
95th Percentile at 3 mg BID
Median at 5 mg BID
5th Percentile at 5 mg BID
Median at 3 mg BID
5th Percentile at 3 mg BID


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 128
ePharm Artifact ID: 10919369
Conclusions
The population PK of tofacitinib in subjects with JIA was adequately described by a 
one-compartment model with first order absorption.
The power coefficients relating body weight to CL/F and V/F were lower than 
0.75 and 1, respectively; nevertheless, CL/F and V/F decreased with decreasing body weight 
warranting dose adjustment at lower body weight.
Clearance (CL/F) of a typical 70 kg JIA subject (30.5 L/h) was approximately 65% higher 
than that for a typical adult RA subject (18.4 L/h).  Variability in subjects with JIA was 
higher than the corresponding estimates in RA subjects - possibly due to limited number of
subjects. 
Considering the PK characteristics of tofacitinib in JIA subjects and benefit/risk profile of 
tofacitinib in adult RA patients, the doses for adolescent patients (body weight 40 kg) were 
capped at the maximum dose of 5 mg BID and doses for patients with <40 kg body weight 
were derived to achieve Cavg,ss equivalent to exposures in adolescent subjects. The predicted 
concentrations at the proposed doses for Study A3921104 will be equivalent to adult RA 
subjects receiving doses of 3-5 mg BID.
Median at 10 mg BID
5th Percentile at 10 mg BID
95th Percentile at 5 mg BID
Median at 5 mg BID
5th Percentile at 5 mg BID
95th Percentile at 10 mg BID


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 129
Appendix 8. Body Surface Area (BSA)
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):
%


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 130
Appendix 9. 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
(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.


Tofacitinib
A3921104
Final Protocol Amendment 6, 11 July 2018
Page 131
Appendix 10. By Visit Assessment of the Degree of Burden and Risk Threshold During 
the Trial (Investigative Sites in Germany Only)
As written in the protocol under the Schedule of Activities and Section 6 and here 
summarised, at each visit (initially every two weeks and thereafter at 4 to 6 weekly intervals), 
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., 
4. Various functional and global assessments depending on the child’s specific 
rheumatologic diagnosis such as the JIA joint assessment, CHAQ, CHQ, and the 
PRCSG/PRINTO Disease Flare Assessment; the Physician’s Global Evaluation of 
Overall Disease Activity, 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 as determined by 
PRINTO/PRCSG, 
6. Adverse events such as and including blood cell numbers, liver enzyme test, renal 
function tests, lipid panel, evaluating for the presence of, for example, as in protocol 
Section 9.7, serious infections, opportunistic infections, tuberculosis, herpes zoster, 
malignancies (excluding NMSC), non-melanoma skin cancer (NMSC), lymphomas, 
major adverse cardiovascular events (MACEs), interstitial lung disease, 
macrophage-activation syndrome (MAS), and GI perforations.
Subjects who experience a single episode of disease flare based on the JIA disease flare 
criteria23 at any time during the study, (including the open-label run-in and double-blind 
phase) will be discontinued from study, and offered the possibility to continue receiving drug 
in the long term extension study, based on fulfilling certain safety criteria and judgement of 
the treating physician. Additionally, the investigator refers to Appendix 6 “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.

SAP_001.pdf: 
Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 1
Protocol A3921104
EFFICACY, SAFETY AND TOLERABILITY OF TOFACITINIB FOR 
TREATMENT OF POLYARTICULAR COURSE JUVENILE IDIOPATHIC 
ARTHRITIS (JIA) IN CHILDREN AND ADOLESCENT SUBJECTS
Statistical Analysis Plan
(SAP)
Version:
4.0
Date:
24  April 2019


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION ...............................................................................................................12
2.1. Study Objectives .....................................................................................................12
2.2. Study Design ...........................................................................................................14
2.3. Estimands ................................................................................................................15
2.3.1. The Primary Estimand................................................................................15
2.3.2. The Supportive Estimands for Primary Analysis .......................................15
2.3.2.1. The Supportive Estimand for Per Protocol Analysis ................15
2.3.3. The Key Secondary Estimands...................................................................16
2.3.4. The Secondary Estimands...........................................................................17
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................18
3.1. Primary Endpoint ....................................................................................................18
3.2. Secondary Endpoints...............................................................................................19
3.2.1. Key Secondary Endpoints...........................................................................19
3.2.2. Secondary Endpoints in the Double-Blind Phase.......................................19
3.2.3. Secondary Endpoints in the Open-Label Run-in Phase..............................21
3.2.4. Secondary Endpoints Specific for ERA and PsA in Both Open-Label 
Run-In Phase and Double-Blind Phase............................................................22
3.3. Other Endpoints.......................................................................................................22
3.3.1. PK Endpoints..............................................................................................22
3.4. Baseline Variables...................................................................................................23
3.5. Safety Endpoints .....................................................................................................23
4. ANALYSIS SETS ...............................................................................................................23
4.1. Double-Blind Full Analysis Set (DBFAS)..............................................................25
4.1.1. Double-Blind Polyarticular Course JIA Analysis Set (DBJAS).................25
4.1.2. Double-Blind ERA Analysis Set (DBERA)...............................................25
4.1.3. Double-Blind PsA Analysis Set (DBPsA)..................................................25
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 3
4.2. Double-Blind Polyarticular Course JIA Per Protocol Analysis Set (DBJPP).........25
4.3. Double-Blind Safety Analysis Set (DBSAS)..........................................................26
4.4. Other Analysis Sets .................................................................................................26
4.4.1. Open-Label Run-In Phase Full Analysis Set (OLFAS)..............................26
4.4.2. Open-Label Run-In Polyarticular Course JIA Analysis Set (OLJAS) .......26
4.4.3. Open-Label Run-In ERA Analysis Set (OLERA)......................................26
4.4.4. Open-Label Run-In PsA Analysis Set (OLPsA) ........................................26
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................26
5.1. Hypotheses and Decision Rules ..............................................................................26
5.1.1. Hypotheses..................................................................................................26
5.1.2. Statistical Decision Rules ...........................................................................27
5.2. General Methods .....................................................................................................27
5.2.1. Analyses for Binary Data............................................................................27
5.2.1.1. Normal Approximation Approach ............................................27
5.2.2. Analyses for Continuous Data....................................................................29
5.2.3. Analyses for Time to Event Data................................................................30
5.3. Methods to Manage Missing Data ..........................................................................30
5.3.1. Disease Flare...............................................................................................30
5.3.2. JIA ACR 30-50-70-90-100 Response.........................................................31
5.3.3. JADAS-27 CRP, JADAS-27 ESR, and Occurrence of JADAS 
Minimum Disease Activity and Presence of Inactive Disease ........................31
5.3.4. Presence of JIA ACR Inactive Disease and Clinical Remission................31
5.3.5. JIA ACR Core Set Variable........................................................................32
5.3.6. CHQ and CHAQ Responses.......................................................................32
5.3.7. Occurrence of Active Uveitis .....................................................................32
6. ANALYSES AND SUMMARIES ......................................................................................32
6.1. Primary Endpoint ....................................................................................................32
6.1.1. Primary Analysis ........................................................................................32
6.1.2. Sensitivity/Supplementary Analyses ..........................................................32
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 4
 
 
6.2. Secondary Endpoints...............................................................................................33
6.2.1. Analysis of Key Secondary Endpoints .......................................................33
6.2.2. Analysis of Secondary Endpoints in the Double-Blind Phase....................34
6.2.2.1. Occurrence of Disease Flare and Time to Disease Flare in 
Double-Blind Phase...........................................................................35
6.2.2.2. Achieving JIA ACR 30-50-70-90-100 Response in 
Double-Blind Phase...........................................................................35
6.2.2.3. Change from Double-Blind baseline in JADAS-27 CRP, 
JADAS-27 ESR, and Achieving JADAS Minimum Disease 
Activity and Inactive Disease in Double-Blind Phase ......................35
6.2.2.4. Achieving JIA ACR Inactive Disease and Clinical 
Remission in Double-Blind Phase.....................................................35
6.2.2.5. Change from Double-Blind Baseline and Change from 
Open-Label Run-in Baseline in Each JIA ACR Core Set 
Variable in Double-Blind Phase........................................................35
6.2.2.6. Change from Double-Blind Baseline in CHQ and CHAQ 
Responses in Double-Blind Phase.....................................................36
6.2.3. Analysis of Secondary Endpoints in the Open-Label Run-In Phase ..........36
6.2.4. Analysis of Secondary Endpoints Specific for ERA and PsA in Both 
Open-Label Run-In Phase and Double-Blind Phase........................................36
6.3. Other Endpoint(s)....................................................................................................37
6.3.1. Analysis of PK Endpoints...........................................................................37
6.4. Subset Analyses.......................................................................................................37
6.5. Baseline and Other Summaries and Analyses.........................................................37
6.6. Safety Summaries and Analyses .............................................................................37
6.6.1. Adverse Events...........................................................................................38
7. INTERIM ANALYSES.......................................................................................................39
8. REFERENCES ....................................................................................................................40
CCI
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 5
9. APPENDICES .....................................................................................................................41
9.1. SUMMARY OF EFFICACY ANALYSES............................................................41
9.2. DATA DERIVATION DETAILS ..........................................................................51
9.2.1. The JIA Core Set Variables ........................................................................51
9.2.2. Disease Flare...............................................................................................51
9.2.3. The JIA ACR 30-50-70-90-100 Response .................................................52
9.2.4. JADAS-27 CRP and JADAS-27 ESR........................................................53
9.2.5. JADAS Minimum Disease Activity and Inactive Disease .........................53
9.2.6. Presence of JIA ACR Inactive Disease and Clinical Remission................54
9.2.7. CHQ Responses..........................................................................................55
9.2.8. Childhood Health Assessment Questionnaire (CHAQ) Responses............66
9.2.9. ERA: Tender Entheseal Assessment, Modified Schober’s Test, 
Overall Back Pain and Nocturnal Back Pain Responses .................................68
9.2.10. PsA: Body Surface Area (BSA) and Physician’s Global Assessment 
(PGA) of Psoriasis ...........................................................................................70
9.3. Definition and Use of Visit Windows in Reporting................................................71
9.4. DEFINITION OF PROTOCOL DEVIATIONS THAT RELATE TO
STATISTICAL ANALYSES/POPULATIONS .......................................................73
 
 
9.6.1. Dataset ........................................................................................................79
9.6.2. Baseline.......................................................................................................79
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 6
9.6.3. Supplementary Analysis for the Primary Endpoint (Occurrence of 
Flare at Week 44/EoS (Week26 in Double-Blind Phase))...............................79
9.6.4. Supportive Efficacy Analyses for Key Secondary EndPoints (ACR 
50/30/70 Responses at Week 44/EoS (Week 26 of the Double-Blind 
Phase))..............................................................................................................80
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................7
Table 2.
Summary of Different Analysis Sets ........................................................24
Table 3.
Summary of Efficacy Analyses During Double-Blind (DB) Phase .........41
Table 4.
Summary of Secondary Efficacy Analyses During Open-Label 
Run-in (OL) Phase....................................................................................46
Table 5.
Summary of Endpoints Specific for ERA and PsA..................................49
Table 6.
Visit Windows for Efficacy and Safety Endpoints...................................72


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 7
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 8
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 9
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 10
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 11
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 12
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study A3921104.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
The safety and effectiveness of tofacitinib for the treatment of RA has been demonstrated in 
adult subjects.  The Sponsor is conducting a pediatric development program to determine the 
safety and efficacy of tofacitinib in subjects 2 to <18 years of age for the treatment of JIA. 
As part of this pediatric program, a Phase 1 pharmacokinetic (PK) study of tofacitinib in JIA 
subjects (A3921103) has been completed, and an open-label, non-comparative, long-term 
extension study (A3921145) is currently ongoing. 
This Phase 3 study is intended to provide evidence of efficacy and safety of tofacitinib in 
subjects with JIA. 
Due to the availability of effective treatments for subjects with JIA, a randomized withdrawal 
study design was selected to limit exposure to placebo treatment. 
2.1. Study Objectives
Primary:

To compare the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA at Week 44/End of Study (Week 26 of the double-blind phase) as 
measured by the percentage of subjects with disease flare (according to 
PRCSG/PRINTO Disease Flare criteria) after Week 18 of the open-label run-in 
phase.
Secondary:

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by the percentage of subjects with disease flare 
(according to PRCSG/PRINTO Disease Flare criteria) at various time points in the 
double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by time to disease flare in the double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by achievement of JIA ACR 30, 50, 70, 90, 100 
response at various time points in the double-blind phase;


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 13

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in JADAS 27-CRP and 
JADAS-27 ESR, and percentage of subjects achieving JADAS minimum disease 
activity and inactive disease at various time points in the double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for treatment of signs and 
symptoms of JIA as measured by the JIA ACR inactive disease and clinical remission 
rate at various time points in the double-blind phase; 

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in each JIA ACR core set 
variable at various time points in the double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in CHQ responses at various 
time points in the double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by changes from baseline in the Childhood Health 
Assessment Questionnaire (CHAQ) responses at various time points in the 
double-blind phase;

To evaluate the efficacy of tofacitinib versus placebo for the treatment of signs and 
symptoms of JIA as measured by the occurrence of active uveitis (according to SUN 
criteria) in the double-blind phase;

In subjects with ERA: To evaluate the efficacy of tofacitinib for the treatment of ERA 
as measured by changes from baseline in the Tender Entheseal Assessment, Modified 
Schober’s Test, and Overall Back Pain and Nocturnal Back Pain responses at various 
time points in the double-blind phase;

In subjects with PsA: To evaluate the efficacy of tofacitinib for the treatment of PsA 
as measured by changes from baseline in the BSA affected with psoriasis and PGA of 
psoriasis assessments at various time points in the double-blind phase;

To evaluate the efficacy of tofacitinib in the open-label run-in phase;

To evaluate the taste acceptability of tofacitinib oral solution, if applicable, on Day 14 
of the open-label run-in phase;

To evaluate safety and tolerability of tofacitinib in subjects with JIA during the study;

To evaluate the PK of tofacitinib in subjects with JIA during the open-label run-in 
phase.


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 14
2.2. Study Design
This is a randomized withdrawal, double-blind, placebo-controlled study of subjects from 
2 to <18 years of age with JIA.
All eligible subjects enrolled in the study will initially receive open-label tofacitinib for 
18 weeks (run-in phase).  At the end of the 18 week run-in phase, only subjects who achieve 
at least a JIA ACR 30 response will be randomized to the 26 week double-blind, 
placebo-controlled phase.  Subjects who do not achieve a JIA ACR 30 response at this time 
point will be discontinued from the study.  Subjects who experience a single episode of 
disease flare at any time during the study (including the open-label run-in and double-blind 
phase) will also be discontinued from the study.
 
 
Subjects who are eligible for the 26 week double-blind phase will be randomized (1:1 ratio) 
to either active tofacitinib or placebo.  For subjects with polyarticular course JIA 
(ie, extended oligoarthritis, polyarthritis RF+, polyarthritis RF-, systemic JIA with active 
arthritis but without active systemic features), randomization will be stratified by JIA 
category and baseline CRP (normal
, above normal
).  For subjects with psoriatic and enthesitis-related arthritis, randomization 
will be stratified by JIA category. 
Approximately 210 subjects will be enrolled in the open-label run-in phase.  Among subjects 
with polyarticular course JIA, stratification will target enrollment of at least 50% with a 
baseline CRP above the upper limit of normal.
CCI
CCI
CCI
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 15
The cohort of subjects with polyarticular course JIA will have at least 170 subjects enrolled 
in the run-in phase with the minimum number of JIA categories as follows: 24 with extended 
oligoarthritis, 20 with polyarthritis RF+, 62 with polyarthritis RF-, 20 with systemic JIA with 
active arthritis but without active systemic features.  Additional cohorts (ie, psoriatic and 
enthesitis-related arthritis) will include a minimum of 20 subjects with psoriatic arthritis, and 
20 subjects with enthesitis-related arthritis.  The overall target minimum number of subjects 
to be enrolled in the study by age is as follows: 20 subjects 2 to <6 years, 20 subjects 
6 to <12 years, and 20 subjects 12 to <18 years.  The Sponsor will monitor enrollment and 
periodically notify investigator sites regarding the status of enrollment in the various JIA 
categories and age groups.
The duration of subject participation among those who complete the study (without 
discontinuation) is expected to be approximately 44 weeks.  Pediatric blood tubes will be 
used (reduced volume) for testing to determine eligibility, monitor safety, and measure PK.
The study will be conducted over a period of approximately 3 years. 
 
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 16
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 17
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 18
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint
The primary endpoint of this study is:
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 19
•
Occurrence of disease flare (according to PRCSG/PRINTO Disease Flare criteria) by
Week 44/End of Study (Week 26 of the double-blind phase).
Only disease flare during the double-blind phase will be counted as primary endpoint.
Disease flare (except assigning as flare after discontinuation) will be derived by the 
Centralized Coordinating Center (CCC) using Erythrocyte Sedimentation Rate (ESR) in real-
time, and double-blind baseline will be used to determine disease flare.  
 
 
 
 
 
 
3.2. Secondary Endpoints
3.2.1. Key Secondary Endpoints
•
Achieving JIA ACR 30-50-70 response at Week 44/End of Study (Week 26 of the 
double-blind phase); open-label run-in baseline will be used to determine ACR 
response.
 
 
  
•
Change from double-blind baseline in CHAQ disability index at Week 44/End of 
Study (Week 26 of the double-blind phase).
•
 
3.2.2. Secondary Endpoints in the Double-Blind Phase
•
Disease flare and JIA ACR inactive disease during double-blind phase will be derived 
by the CCC using ESR in real-time, and other secondary endpoints during the double-
blind phase will be derived by Pfizer. 
 
All secondary endpoints with data collected in the double-blind phase (from 
randomization/Week 18 to Week 44/EOS) are:
•
Occurrence of disease flare (according to PRCSG/PRINTO Disease Flare criteria) at 
each scheduled visit up to Week 44 (Week 26 of the double-blind phase) in the 
double-blind phase. 
 
CCI
CCI
CCI
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 20
 
 
 
•
Time to disease flare in the double-blind phase.  Time to disease flare is measured in 
number of days since randomization (day of disease flare – day of randomization +1) 
into the double-blind phase.  
 
 
 
 
 
 
•
Achieving JIA ACR 30-50-70-90-100 response at each scheduled visit up to Week 44 
(Week 26 of the double-blind phase) in the double-blind phase; open-label run-in 
baseline will be used to determine ACR response;
•
Change from double-blind baseline in JADAS-27 CRP, JADAS-27 ESR, and 
achieving JADAS minimum disease activity and inactive disease at each scheduled 
visit up to Week 44 (Week 26 of the double-blind phase) in the double-blind phase;
•
Achieving JIA ACR inactive disease at each scheduled visit up to Week 44 (Week 26 
of the double-blind phase) in the double-blind phase, and achieving clinical remission 
at week 44 (double-blind week 26);
 
 
•
Change from double-blind baseline in each JIA ACR core set variable at each 
scheduled visit up to Week 44 (Week 26 of the double-blind phase) in the 
double-blind phase;
•
Change from open-label run-in baseline in each JIA ACR core set variable at each 
scheduled visit up to Week 44 (Week 26 of the double-blind phase) in the 
double-blind phase;
•
Change from double-blind baseline in CHQ responses at each scheduled visit up to 
Week 44 (Week 26 of the double-blind phase) in the double-blind phase;
•
Change from double-blind baseline in CHAQ responses at each scheduled visit up to 
Week 44 (Week 26 of the double-blind phase) in the double-blind phase.
CCI
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 21
•
The ‘each scheduled visit’ means the visit in the visit window as defined in
Appendix 9.3 throughout the study.
3.2.3. Secondary Endpoints in the Open-Label Run-in Phase
•
Disease flare and JIA ACR inactive disease during open-label run-in phase and DB 
phase, and ACR 30 response at week 18 
 
•
The secondary efficacy endpoints with data collected in open-label run-in phase 
(from Day 1 to randomization/Week 18) are:
•
Occurrence of disease flare at each scheduled visit in the open-label phase. 
 
 
 
•
Time to disease flare in the open-label run-in phase.  Time to disease flare is 
measured in number of days since Day 1 (day of disease flare – Day 1 +1) into the 
open-label run-in phase.  Day 1 is defined as the day of first dose of study drug in 
open-label run-in phase.
 
•
Achieving JIA ACR 30-50-70-90-100 response at each scheduled visit in the open-
label run-in phase; JIA ACR 30-50-70-90-100 response is determined based on the 
open-label run-in baseline.
•
Change from open-label run-in baseline in JADAS-27 CRP, JADAS-27 ESR, and 
achieving JADAS minimum disease activity and inactive disease at each scheduled 
visit in the open-label run-in phase;
•
Achieving JIA ACR inactive disease at each scheduled visit in the open-label run-in 
phase; percentage of subjects experiencing at least one JIA ACR inactive disease 
during open-label phase.  
•
Change from open-label run-in baseline in each JIA ACR core set variable at each 
scheduled visit in the open-label run-in phase.
•
Change from open-label run-in baseline in CHQ responses at each scheduled visit in 
the open-label run-in phase.
•
Change from open-label run-in baseline in CHAQ responses at each scheduled visit in 
the open-label run-in phase.
CCI
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 22
•
Taste acceptability of tofacitinib oral solution (Like very much, Like a little, Not Sure, 
Dislike a little, Dislike very much), if applicable, on Day 14 of the open-label run-in 
phase.
•
 
•
The same secondary endpoints in the open-label run-in phase will also be calculated 
for ERA and PsA subjects.  
3.2.4. Secondary Endpoints Specific for ERA and PsA in Both Open-Label Run-In 
Phase and Double-Blind Phase
•
Secondary endpoints in both open-label run-in phase and double-blind phase are all 
ERA and PsA specific endpoints.  For details of the derivation of these endpoints, see 
Appendix 9.2.9 to 9.2.10.
Open-label phase (Day 1 to randomization/Week 18):
•
In subjects with ERA: Change from open-label run-in baseline in the Tender 
Entheseal Assessment, Modified Schober’s Test, Overall Back Pain and Nocturnal 
Back Pain responses at each scheduled visit in the open-label run-in phase;
•
In subjects with PsA: Change from open-label run-in baseline in the body surface 
area (BSA) affected with psoriasis and PGA of psoriasis assessments at each 
scheduled visit in the open-label run-in phase.
Double-blind phase (randomization/Week 18 to Week 44/EOS):
•
In subjects with ERA: Change from double-blind baseline in the Tender Entheseal 
Assessment, Modified Schober’s Test, Overall Back Pain and Nocturnal Back Pain 
responses at each scheduled visit up to Week 44 (Week 26 of the double-blind phase)
in the double-blind phase;
•
In subjects with PsA: Change from double-blind baseline in the body surface area 
(BSA) affected with psoriasis and PGA of psoriasis assessments at each scheduled 
visit up to Week 44 (Week 26 of the double-blind phase) in the double-blind phase.
•
The ‘each scheduled visit’ means the visit in the visit window as defined in Appendix 
9.2.3 throughout the study.
3.3. Other Endpoints
3.3.1. PK Endpoints
•
Plasma tofacitinib concentrations during the open-label run-in phase.
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 23
3.5. Safety Endpoints
The safety endpoints of this study are:
•
Occurrence of active uveitis (according to SUN criteria) at each scheduled visit in the 
open-label run-in and double-blind phase;
•
Incidence and severity of adverse events, with focus on serious infections, cytopenias, 
malignancies, cardiovascular diseases and gastrointestinal perforations;
•
Incidence of clinical laboratory abnormalities and change from baseline in clinical 
laboratory values;
•
Incidence of abnormalities in physical examination and incidence of significant 
changes from baseline at final visit for physical examination;
•
Incidence of vital sign abnormalities and change from baseline in vital sign measures;
•
Validated assessments of growth and pubertal development (Tanner Stage of 
Development);
The ‘each scheduled visit’ means the visit in the visit window as defined in Appendix 9.2.3
throughout the study.
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per standard operating procedures. Table 2 listed all the analysis sets 
and their corresponding analyses in the study.
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 24
Table 2.
Summary of Different Analysis Sets
Analysis set
Brief description
Efficacy analysis
Safety analysis
DBFAS
Subjects randomized to DB 
phase, received at least one 
dose of study medication in DB 
phase, reported under 
randomized treatment
None
None
DBJAS
pJIA subjects in DBFAS
Primary endpoint, 
key secondary 
endpoints and 
secondary endpoints 
in DB phase for pJIA
None
DBERA
ERA subjects in DBFAS
Secondary endpoints 
in DB phase for 
ERA, ERA specific 
endpoints in DB
phase
None
DBPsA
PsA subjects in DBFAS
Secondary endpoints 
in DB phase for PsA, 
PsA specific 
endpoints in DB
phase
None
DBJPP
Subjects with no major protocol 
violations in the DBJAS
Primary endpoint
None
DBSAS
Subjects received at least one 
dose of study medication in DB
phase, reported under received 
treatment
None
All DB safety 
analyses
OLFAS
Subjects enrolled, received at 
least one dose of study 
medication in OL phase
Taste acceptability
All OL safety 
analyses
OLJAS
pJIA subjects in OLFAS
Secondary endpoints 
in OL phase for pJIA
None


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 25
Analysis set
Brief description
Efficacy analysis
Safety analysis
OLERA
ERA subjects in OLFAS
Secondary endpoints 
in OL phase for ERA, 
ERA specific 
endpoints in OL 
phase
None
OLPsA
PsA subjects in OLFAS
Secondary endpoints
in OL phase for PsA, 
PsA specific 
endpoints in OL 
phase
None
4.1. Double-Blind Full Analysis Set (DBFAS)
The double-blind full analysis set (DBFAS) consists of all subjects randomized to the 
double-blind phase who received at least one dose of study medication in the double-blind 
phase.  Subjects will be reported under the treatment they were randomized to. In this study, 
no efficacy analyses will be performed on the DBFAS, all efficacy analyses will be done on 
the following subsets of the DBFAS.
4.1.1. Double-Blind Polyarticular Course JIA Analysis Set (DBJAS)
The double-blind polyarticular course JIA analysis set (DBJAS) consists of all subjects 
included in the DBFAS with polyarticular course JIA. The double-blind polyarticular course 
JIA analysis set is the primary efficacy analysis set of the study.
4.1.2. Double-Blind ERA Analysis Set (DBERA)
The double-blind ERA analysis set (DBERA) consists of all subjects included in the DBFAS 
with ERA.
4.1.3. Double-Blind PsA Analysis Set (DBPsA)
The double-blind PsA analysis set (DBPsA) consists of all subjects included in the DBFAS 
with PsA.
4.2. Double-Blind Polyarticular Course JIA Per Protocol Analysis Set (DBJPP)
The double-blind polyarticular course JIA per-protocol analysis set (DBJPP) will consist of 
all subjects included in the double-blind polyarticular course JIA analysis set (see 
Section 4.1.1) who have no major protocol violations with regard to inclusion criteria, 
exclusion criteria, or study conduct. 
Inclusion in the DBJPP analysis set will be determined prior to un-blinding of the study.
Efficacy results for the DBJPP analysis set will be produced as part of a sensitivity analysis, 
supporting the analysis of the primary endpoint.


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 26
If there are few major protocol deviations impacting the primary analysis, the study team will 
decide whether to have a DBJPP analysis or not before un-blinding of the study.
See the definition of protocol deviations that relate to statistical analysis/populations in 
Appendix 9.4.
4.3. Double-Blind Safety Analysis Set (DBSAS)
The double-blind safety analysis set (DBSAS) consists of all subjects who have received at 
least one dose of study medication in double-blind phase. Subjects will be reported under the 
treatment which they received.
4.4. Other Analysis Sets
4.4.1. Open-Label Run-In Phase Full Analysis Set (OLFAS)
The open-label run-in phase full analysis set (OLFAS) consists of all subjects who were 
enrolled into the open-label run-in phase of the study and received at least one dose of study 
medication in the open-label run-in phase. This will be the same as the open-label run-in 
safety analysis set.
4.4.2. Open-Label Run-In Polyarticular Course JIA Analysis Set (OLJAS)
The open-label run-in polyarticular course JIA analysis set (OLJAS) consists of all subjects 
included in the OLFAS with polyarticular course JIA.
4.4.3. Open-Label Run-In ERA Analysis Set (OLERA)
The open-label run-in ERA analysis set (OLERA) consists of all subjects included in the 
OLFAS with ERA.
4.4.4. Open-Label Run-In PsA Analysis Set (OLPsA)
The open-label run-in PsA analysis set (OLPsA) consists of all subjects included in the 
OLFAS with PsA.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses
The primary hypothesis is that among subjects who achieve ACR30 response at Week 18, 
those who remain on tofacitinib will have a lower rate of disease flare up to Week 44/EoS
compared to those on placebo. 
From statistical perspective, the primary null hypothesis is 
0
:
0


c
t
p
p
H
,


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 27
and the primary alternative hypothesis is
0
:
0
≠
−
c
t
p
p
H
,
where p refers to the proportion of disease flare by Week 44/End of Study (Week 26 of the 
double-blind phase) for polyarticular course JIA subjects, the subscript c refers to the control 
group (placebo) and the subscript t refers to the treatment group.
Tofacitinib will be considered superior to placebo with respect to occurrence of disease flare 
by Week 44/End of Study (EoS) (Week 26 of the double-blind phase) for polyarticular 
course JIA subjects if the test for difference in the occurrence rate results in a p-value 
(two-sided) less than 0.05.
5.1.2. Statistical Decision Rules
In order to preserve type I error, each endpoint will be assessed sequentially using 
gate-keeping or step-down approach where statistical significance can be claimed for the 
second endpoint only if the first endpoint in the sequence meets the requirements for 
significance.  
Analyses other than primary and key secondary analyses will not be strictly controlled for 
Type I error.
5.2. General Methods 
In addition to the statistical analyses given below, all efficacy endpoints as described in 
Section 3 will be summarized descriptively. In general, number and percent will be 
presented for binary variables; number, mean, median, standard deviation, quartiles, 
minimum, and maximum will be presented for continuous variables; estimates of median 
event-free time and survival probabilities by Kaplan-Meier method will be presented for 
time-to-event endpoints.
5.2.1. Analyses for Binary Data
5.2.1.1. Normal Approximation Approach
Binary endpoints will be analyzed using the normal approximation approach for the binomial 
populations for double-blind polyarticular course JIA analysis set (DBJAS). 
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 28
The normal-approximation to the test statistic for the difference in binomial random variables 
is calculated as
c
c
c
t
t
t
c
t
n
p
p
n
p
p
p
p
Z
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
ˆ
ˆ
−
+
−
−
=
where pˆ refers to the relative frequency, n to sample size, the subscript c refers to the control 
group (placebo) and the subscript t refers to the treatment group.
Two-sided 95% confidence intervals are formed by:
c
c
c
t
t
t
c
t
n
p
p
n
p
p
p
p
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
96
.1
)
ˆ
ˆ
(
−
+
−
±
−
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 29
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
5.2.2. Analyses for Continuous Data
For the continuous secondary endpoints, a mixed-effect model with repeated measures 
(MMRM) will be applied. 
 
 
 
CCI
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 30
5.2.3. Analyses for Time to Event Data
The Kaplan-Meier plot will be generated for the secondary endpoint of time to flare. The log 
rank test will be used to compare the treatment groups.
 
CCI
CCI
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 31
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 32
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 33
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 34
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 35
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 36
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 37
6.3. Other Endpoint(s)
6.3.1. Analysis of PK Endpoints
Please see details in the protocol and PMAP (or population PK modeling plan).
6.3.2. Analysis of Exploratory Endpoints
Exploratory or pooled analyses, if conducted utilizing the biobanked genomic and/or 
biomarker samples from this study, will be documented in a separate analysis plan.
6.4. Subset Analyses 
The primary endpoint, key secondary endpoints and some secondary endpoints (occurrence 
of disease flare, achieving ACR 30/50/70 and JIA ACR inactive disease at each scheduled 
visit in double-blind phase; time to disease flare in double-blind phase) and open-label run-in 
baseline demographic characteristics will be summarized by JIA category, open-label run-in 
baseline C-Reactive Protein (normal and above normal), geographical region (North America
[US and Canada], South and Central America [Brazil, Argentina, Mexico], European Union 
[Poland, Belgium, Great Britain, Spain], All Other [Ukraine, Turkey, Russia, Australia and 
Israel]), baseline body weight (<40 kg, ≥40 kg), and age (2 to <6 years, 6 to <12 years and 12 
to <18 years) by treatment and visit. Inferential statistics and forest plot for treatment 
comparison by the aforementioned subgroups will be performed at week 26 of the 
double-blind phase for the efficacy endpoints if appropriate.  For time to disease flare, 
Kaplan-Meier analysis will be replicated for each JIA category, open-label run-in baseline 
CRP and age group, separately.
As said in Section 6.2.2 to 6.2.4, for ERA subjects and PsA subjects, only descriptive 
statistics will be reported by treatment and visit.
6.5. Baseline and Other Summaries and Analyses
None.
6.6. Safety Summaries and Analyses
Safety analysis will be performed for polyarticular course JIA, ERA and PsA subjects 
combined together. Safety data will be reported separately for the open-label run-in phase
using OLFAS and the double-blind phase using DBSAS. In addition, AE will be reported 
using the entire exposure period (both open-label run-in phase and double-blind phase) while 
the subjects are exposed to tofacitinib.
For occurrence of active uveitis (according to SUN criteria) at each scheduled visit in the 
open-label run-in and double-blind phase, descriptive statistics will be reported. Visit 
window in Appendix 9.3 will be used.
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 38
All the safety data, including the following, will be summarized descriptively through
appropriate data tabulations, descriptive statistics, and graphical presentations:
•
Safety laboratory tests will be summarized according to Pfizer standards.
•
Special attention will be given to the following safety endpoints: serious infections, 
cytopenias, malignancies, cardiovascular diseases, gastrointestinal perforations and 
validated assessments of growth and pubertal development.
6.6.1. Adverse Events
Adverse events will be summarized according to Pfizer data standards for each phase and for 
the entire study period while the subjects are exposed to tofacitinib.  For the AE reported 
over entire study period, subjects randomized to the placebo group will only have their 
events and exposure during the open-label run-in phase counted, and there will be no 
comparisons performed.
For AE reporting for each phase, AEs will not be double counted across phases.  Counting of 
AEs will be based on start date of AE.  If the start date of an AE is in the open label phase, 
the end date of the AE in the double blind phase and severity of AE remained the same or 
became lower in both phases, then the AE will be counted in open lable phase, not in the 
double blind phase.  However, if the same AE started in the open label phase, and get worse 
in severity in the double blind phase, then the AE will be counted in both phases.  In all these 
analyses attention will be restricted to assessments that occurred no more than 28 calendar 
days after the last dose of study drug.
AEs of special interest in double-blind phase and over the entire study period while the 
subjects are exposed to tofacitinib will be analyzed using incidence rates (IR), 
including death, serious infections, opportunistic infections excluding TB, tuberculosis, 
herpes zoster, malignancy excluding NMSC, NMSC (non-melanoma skin cancer), 
lymphoma, MACE (Major Adverse Cardiovascular Events), gastrointestinal perforations, 
and Interstitial Lung Disease (ILD). Adverse events of macrophage activation syndrome
(MAS) will be analyzed using IR. The MAS, Deep vein thrombosis (DVT), and Pulmonary 
embolism (PE) will be listed.
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 39
7. INTERIM ANALYSES
No interim analysis is planned, except for the safety review by DSMB.
Final analyses will be conducted after requirements for final release of the randomization 
codes have been met, and the official database is released.
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.
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 40
8. REFERENCES 
1.
Chan ISF, Zhang Z. (1999). Test-based exact confidence intervals for the difference of 
two binomial proportions. Biometrics, 55:1201–1209.
2.
J. Kalbeisch and R. Prentic. The Statistical Analysis of Failure Time Data. Wiley, New 
York, 1980.
3.
Landgraf JM,. Abetz L Ware JE.. In:Child-Health Questionnaire(CHQ): a  user’s 
manual. Boston, MA: Health Institute, New England Medical Center; 1996: 34-52, 
90-95.
4.
R. Little, J. Wang, X. Sun, T. Hong, E. Suh, M. Lee, T. Sarich, L. Oppenheimer, A. 
Plotnikov, J. Wittes, N. Cook-Bruns, P. Burton, M. Gibson, and S. Mohanty. The 
treatment of missing data in a large cardiovascular clinical outcomes study. Clinical 
Trials, 13(3):344-351, 2016.
5.
6.
Diggle P. J., Liang K.-Y., and Zeger S. L. Analysis of Longitudinal Data. Oxford: 
Clarendon Press, 1994.
7.
McCullagh P., and Nelder J. A. Generalized Linear Models. 2nd ed. London: Chapman 
& Hall, 1989.
8.
9.
Singh G, Athreya BH, Fries JF, et al. Measurement of health status in children with
juvenile rheumatoid arthritis. Arthritis Rheum 1994; 37(12):1761–9
CCI
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 41
9. APPENDICES 
9.1. SUMMARY OF EFFICACY ANALYSES
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 42
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 43
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 44
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 45
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 46
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 47
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 48
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 49
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 50
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 51
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 52
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 53
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 54
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 55
s 
.
al 
 
, 
 
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 56
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 57
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 58
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 59
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 60
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 61
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 62
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 63
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 64
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 65
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 66
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 67
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 68
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 69
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 70
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 71
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 72
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 73
9.4. DEFINITION OF PROTOCOL DEVIATIONS THAT RELATE TO
STATISTICAL ANALYSES/POPULATIONS
The following describes any protocol deviations that relate to the statistical analyses or 
populations:  
It is possible that unexpected deviations will arise, becoming known only after the study has 
been active for a long period of time; hence more deviations may be added.  A full list of 
protocol deviations for the study report will be compiled prior to database closure.  As of this 
writing, the protocol deviations can all be found below.
The list of subjects along with the excluding protocol deviation will be put into the trial 
master file. 
Deviations Assessed Prior to Randomization: 
Granted exceptions to the inclusion or exclusion criteria are not expected to occur.  Any 
subject who enters the study when the inclusion or exclusion criteria would have prevented 
entry will be considered to have had a protocol deviation.
Deviations Assessed Post-Randomization: 
Only protocol deviations that are thought to affect the efficacy of study drug will be 
considered.  Each of the cases will be reviewed by the team and a clinical judgment made in 
each particular circumstance as to whether efficacy would have been affected in the cases of 
these specific classes of protocol deviations assessed post randomization:
•
Subjects who receive excluded concomitant medications;
•
Subjects who interrupt therapy for longer than allowed;
•
Subjects who were randomized but took incorrect treatment;
•
 
 
•
Subjects whose background medications are changed in violation of protocol, 
including subjects who use rescue medication in violation of protocol.
Each subject’s presence on the list of exclusion from the per-protocol analysis means that 
there was at least one deviation for that subject clinically judged to effect efficacy.
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 74
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 75
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 76
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 77
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 78
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 79
CCI


Protocol A3921104 (Tofacitinib) Statistical Analysis Plan
Page 80
 
CCI