Compare Effectiveness of Tofacitinib 11 mg QD to Tofacitinib 5 mg BID
Conditions: Arthritis Rheumatoid
Sponsor: Pfizer

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Study Information
Title
Compare Effectiveness of Tofacitinib 11 mg 
QD to Tofacitinib 5 mg BID 
Protocol number
A3921359
Protocol version identifier
1.0
Date
10 December 2019
Active substance
Tofacitinib citrate
Medicinal product
Xeljanz (tofacitinib)
Research question and objectives
Main objective is to compare effectiveness
of tofacitinib 11 mg once daily (QD)
initiators to tofacitinib 5 mg twice daily
(BID) initiators
Author
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................2
2. LIST OF ABBREVIATIONS................................................................................................4
3. RESPONSIBLE PARTIES....................................................................................................5
4. ABSTRACT...........................................................................................................................6
5. AMENDMENTS AND UPDATES.......................................................................................7
6. MILESTONES.......................................................................................................................8
7. RATIONALE AND BACKGROUND..................................................................................8
8. RESEARCH QUESTION AND OBJECTIVES ...................................................................9
9. RESEARCH METHODS ......................................................................................................9
9.1. Study Design .............................................................................................................9
9.2. Setting........................................................................................................................9
9.2.1. Inclusion Criteria ..........................................................................................9
9.2.2. Exclusion Criteria.......................................................................................10
9.3. Variables..................................................................................................................10
9.4. Data Sources............................................................................................................11
9.5. Study Size................................................................................................................11
9.6. Data Management ...................................................................................................12
9.7. Data Analysis ..........................................................................................................13
9.8. Quality Control........................................................................................................13
9.9. Limitations of the Research Methods......................................................................13
9.10. Other Aspects ........................................................................................................13
10. PROTECTION OF HUMAN SUBJECTS ........................................................................14
10.1. Patient Information................................................................................................14
10.2. Patient Consent......................................................................................................14
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............14
10.4. Ethical Conduct of the Study ................................................................................14
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................14
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........14
13. REFERENCES ..................................................................................................................15

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14. LIST OF TABLES.............................................................................................................16
15. LIST OF FIGURES ...........................................................................................................16
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................16
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................16
ANNEX 3. ADDITIONAL INFORMATION.........................................................................16

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
ACR
American College of Rheumatology
AE
Adverse Event
BID
Twice daily
CDAI
Clinical Disease activity index
CRP
C- reactive protein
csDMARD
Conventional Disease modifying anti-rheumatic drug
DAS
Disease activity score
mDAS
Modified Disease Activity Score
EMA
European Medicines Agency
ESR
Erythrocyte sedimentation rate
EQ-5D
Euro Qol 5D
FDA
Food and Drug Administration
GPP
Good Pharmacoepidemiology Practices
GEP
Good Epidemiology Practices
mHAQ
modified Health Assessment questionnaire
HAQ
Health Assessment questionnaire
IEA
International Epidemiology Association
IEC
Independent Ethics Committee
IR
Immediate Release
IRB 
Institutional Review Board
ISPE
International Society of Pharmacoepidemiology
JAK
Janus kinase
LDA
Low Disease Activity
LTE
Long Term Extension
MCID
Minimally clinically important difference
MR
Modified release 
MTX
methotrexate
NI 
Non Interventional
PD
Pharmacodynamic
PK
Pharmacokinetic
PS 
Propensity Score
QD
Once daily
RA
Rheumatoid arthritis
SAP
Statistical analysis plan
SAS
Statistical Analysis System 
TyK2
Tyrosine kinase 2
US
United States

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3. RESPONSIBLE PARTIES
Name, degree(s)
Job Title
Affiliation
Address
 MD
Global Medical Affairs
Pfizer, Inc.
Spain
 PhD, 
MPH 
Epidemiologist –
Non-Interventional
Study lead 
Pfizer, Inc.
 
USA
 
MD, MPH
Corrona, LLC
USA
 
PhD
Corrona, LLC
USA
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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4. ABSTRACT
Not Applicable.

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5. AMENDMENTS AND UPDATES
None.

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6. MILESTONES
Milestone
Planned date
Final approved protocol*
December 2019
Start of analysis/data collection
30 September 2018
Approved SAP
20 March 2018 
End of data collection
30 August 2019 
Final study report
11 October 2019 
* This protocol was created retrospective from start of data collection and is part of an Significant Qulaity 
Event (SQE).
7. RATIONALE AND 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. The efficacy and safety of tofacitinib 
5 mg twice daily (BID) administered as monotherapy or in combination with conventional 
disease modifying anti rheumatic drugs (csDMARDs), mainly methotrexate (MTX), in 
patients with moderately to severely active rheumatoid arthritis (RA), have been 
demonstrated in Phase 2,1-5 Phase 3,6-11 and Phase 3b/412 studies of up to 24 months’ 
duration, and in long-term extension (LTE) studies with up to 9.5 years of observation.13-15
The immediate release (IR) formulation of tofacitinib was approved in November 2012 in the 
US for the treatment of moderate to severe rheumatoid arthritis (RA) as a twice daily (BID) 
regimen. It was followed by Food and Drug Administration (FDA) approval of 11 mg 
modified release once daily (QD) dose in February of 2016. 
The modified release (MR) QD regimen has the potential to improve drug compliance of 
patients, patient convenience, and to offer additional dosing options for patients. Data from 
completed pharmacokinetic (PK) studies demonstrated that the desired pharmacokinetic and 
pharmacodynamic (PK-PD) profile was achieved by the MR dose. Overall similarity of PK 
parameters between IR and MR formulations were found Phase 1 PK studies comparing MR 
and IR formulations. Therefore, based on the pharmacokinetic (PK) profile for the 
2 formulations (IR and MR) and from the information obtained from IR BID programs, FDA 
approved MR based on clinical pharmacology studies. 
It is hypothesized that patients prescribed tofacitinib 11 mg MR formulation once daily (QD) 
will achieve similar benefit to those prescribed tofacitinib 5 mg BID dosage in real world 
use. This study will therefore seek to compare the effectiveness of the MR 11 mg QD 
regimen to the IR 5 mg BID regimen for the treatment of RA in a real-world registry of RA 
patients.

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8. RESEARCH QUESTION AND OBJECTIVES
Primary Objective: 
The overall aim of this study is to the compare clinical effectiveness of tofacitinib in patients 
initiating tofacitinib 11 mg QD or 5 mg BID identified from the Corrona US RA Registry.
Secondary Objective: 
The study also aims to descriptively assess effectiveness in patients that switched from 
tofacitinib 5 mg BID to tofacitinib 11 mg QD after February 2016.
9. RESEARCH METHODS 
9.1. Study Design
This is an observational study conducted in a cohort of tofacitinib-exposed patients to 
evaluate effectiveness of tofacitinib MR 11 mg QD tablet compared to IR 5 mg BID tablet. 
In this secondary data collection study of structured data, patient therapeutic strategies are 
not determined by this protocol.
9.2. Setting
Using the United States (US) Corrona RA Registry database,16 patients with RA who have 
been exposed to tofacitinib IR or MR on or after February 2016 will be included in this
study. In order to adequately measure the outcome, the initiators will also be required to 
have a follow-up visit at 6 months (+/- 3 months) after tofacitinib initiation. 
For the primary analysis comparing QD to BID patients, we will consider those patients who 
initiated tofacitinib 5 mg BID on or after February 2016 and those that initiated tofacitinib
11 mg QD after it became available in February 2016. Although the sample size will be 
smaller than if all tofacitinib 5 mg BID patients were considered, the inclusion of those 
patients may introduce noise since there is the possibility that they could differ from the more 
recent initiators. Therefore, we will consider the cleaner cohort of all patients initiating 
tofacitinib on or after February 2016. 
For the secondary aim, patients that switched from tofacitinib 5 mg BID to tofacitinib 11 mg 
QD (“switchers”) will be considered. Patients will be considered to have switched from 5 mg 
BID to 11 mg QD if they initiated 5 mg BID after February 2016 and subsequently changed 
their dose to 11 mg QD. 
9.2.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. All US Corrona RA Registry patients who initiated tofacitinib 5 mg BID or 
tofacitinib 11 mg QD after it became available in February 2016.

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2. Patients must have a follow-up visit at 6 months (+/- 3 months) after tofacitinib 
initiation. These 6 month visits are part of routine practice and is not associated with 
this protocol. 
3. Patients must have a valid clinical disease activity index (CDAI) at initiation and at
6-month follow-up visit.
9.2.2. Exclusion Criteria
There are no exclusion criteria for this study.
9.3. Variables
The US Corrona RA Registry is an efficient data collection system for evaluating a range of 
efficacy outcomes associated with therapies used to treat RA. The endpoints chosen for this 
study will be extracted from patient and physician questionnaires. Demographic data 
collected includes age, gender, race and ethnicity. In addition, baseline disease 
characteristics like disease duration and severity etc. will be captured for both the IR and MR 
cohorts under study to evaluate disease characteristics.
Primary outcome: Minimally clinically important difference (MCID) improvement as 
defined by difference in Clinical Disease activity index (CDAI) from initiation to 6 month 
visit. MCID is dependent on baseline disease activity (at initiation); MCID≥2 if CDAI at 
initiation of Low CDAI ≤10, MCID≥6 if CDAI at initiation Moderate of 10<CDAI≤22 and 
MCID≥11 if CDAI at initiation high of >22.
Secondary Outcomes: 

Change in CDAI from baseline to 6 month follow-up (as a continuous variable).

Achievement of Remission (CDAI≤2.8) at 6 month follow-up (among all).

Achievement of Remission (CDAI≤2.8) at 6 month follow-up (among those that were 
not in remission at initiation).

Achievement of Low Disease Activity (LDA) (CDAI≤10) at 6 month follow-up 
(among all).

Achievement of Low Disease Activity (LDA) (CDAI≤10) at 6 month follow-up 
(among those that were not in remission or LDA at initiation).

Achievement of improvement from baseline to 6 month follow-up in modified Health 
Assessment Questionnaire (mHAQ) of at least 0.25 (as a dichotomous variable).

Achievement of improvement from baseline to 6 month follow-up in Health 
assessment questionnaire (HAQ) of at least 0.22.

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
Change from baseline to 6 month follow-up HAQ (HAQ as a dichotomous variable).

Change from baseline to 6 month follow-up modified HAQ (mHAQ as a continuous 
variable).

Change from baseline to 6 month follow-up HAQ (HAQ as a continuous variable).

Change from baseline to 6 month follow-up modified Disease activity Score
(mDAS as a continuous variable).

Change from baseline to 6 month follow-up Disease activity score- erythrocyte 
sedimentation rate (DAS ESR) (as a continuous variable).

Change from baseline to 6 month follow-up DAS- C- reactive protein (DAS CRP) (as 
a continuous variable).

Change from baseline to 6 month follow-up patient pain (as a continuous variable).

Change from baseline to 6 month follow-up patient fatigue (as a continuous variable).

Change from baseline to 6 month follow-up Euro-Qol (EQ-5D) index (as a 
continuous variable).

Modified American College of Rheumatology (ACR) ACR20, ACR50, ACR70.
Detailed definitions for the original analysis as well as all subsequent analyses will be 
included in respective statistical analysis plans (SAPs).
9.4. Data Sources
The US Corrona RA Registry is the data source for this study. It is an independent, 
prospective, national, observational cohort.  Patients are recruited from 187 private and 
academic sites across 43 states, with 799 providers participating. Providers and subjects
complete study questionnaires approximately every 6 months at routine clinic encounters. 
As of September 2019, the Corrona database included information on 53,438 patients with 
RA.  Data on 403,679 patient visits and 192,141 patient-years of follow-up observation time 
have been collected, with a mean patient follow-up of 4.48 (median 3.24) years. Data are 
collected on subjects for as long as they consent to remain in the study.
9.5. Study Size
Power calculations (below) indicate that to detect a reasonable difference of 15% in the 
percentage meeting MCID in CDAI, about 300-500 patients per group would be needed. 

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With the following assumptions:

Consider the dichotomous outcome of meeting MCID in CDAI.

We would like to have 90% power to detect a difference between the 2 groups in 
percentage meeting MCID in CDAI.

We would like to have a low chance (alpha of 5%) of declaring that there is a 
difference in the outcomes between the 2 groups when in actuality there is not (type I 
error).
The following Table 1, gives the number needed per group and total number needed for 
different scenarios of meeting MCID for CDAI and percent of patients who are available 
under common support (eg, percent of patients in the control group that are similar enough to 
the treatment group so that we are comfortable that the 2 cohorts are similar). If we assume
that the percentage meeting MCID in CDAI is 50%, the following sample sizes are required. 
Table 1.
Sample Size Determination
Difference
between the 2
groups in 
percentage 
meeting MCID
in CDAI that can 
be detected
Analyzable Data 
Set, N per group
% under 
common 
support
N per group 
required to 
recruit
Total N 
required to 
recruit
10%
535
50%
1070
2140
10%
535
75%
713
1426
15%
237
50%
474
948
15%
237
75%
316
632
20%
131
50%
262
524
20%
131
75%
175
350
25%
84
50%
168
336
25%
84
75%
112
224
Under different scenarios for projections of the total number of tofacitinib 11 mg QD 
initiators over time, it was estimated that there would be about 180-220 tofacitinib 11 mg QD 
initiators with 6 month follow-up visits by the end of 2018. 
9.6. Data Management 
Statistical analyses will be performed using Statistical Analysis System (SAS) Version 9.4 
(SAS Institute, Cary, NC) and STATA Version 15 (StataCorp, LP, College Station, TX).  

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9.7. Data Analysis 
Patients initiating tofacitinib during or after February 2016 with a six-month follow-up visit 
(+/- 3 months) will be considered for analysis. Patient and disease characteristics at initiation 
for the two cohorts of 11 mg QD and 5 mg BID will be considered. Propensity score 
matching and adjustment for covariates will be used to identify a balanced, matched subset of 
patients to use in final analyses. 
The primary outcome will be minimum clinically important difference (MCID) improvement 
as defined by difference in CDAI from initiation to 6 month visit (dichotomous variable). 
Secondary outcomes at the 6 month visit (follow-up): change in CDAI from initiation to 
follow-up, achievement of remission (CDAI≤2.8) and achievement of low disease activity 
(LDA) (CDAI≤10), achievement of improvement from baseline to follow-up in HAQ of 
0.22 and change from baseline to 6 month follow-up HAQ, modified DAS, DAS ESR, DAS 
CRP, patient pain, patient fatigue, EQ5D index, modified ACR20/50/70. Sensitivity 
analysis, will be performed if needed. 
Detailed methodology for the original analysis as well as all subsequent analyses is 
documented in respective SAPs, which are dated, filed and maintained by Pfizer. The SAP
may modify the plans outlined in the protocol; any major modifications of primary endpoint 
definitions or their analyses would be reflected in a protocol amendment.
9.8. Quality Control
The Corrona registry has standard operating procedures in place to monitor, perform edit and 
logic checks, and make corrections to the data, as necessary. Specifically, the data for each 
site is reviewed by the Quality Department or other delegated Corrona representative for 
completeness and internal consistency at regular intervals. The Quality Department
generates a list of queries for each site, sends to the clinical site coordinator, and requests 
verification or correction for each query within 14 days. The Quality Department or other 
designated Corrona representative enters corrected data onto the Corrona database. An audit 
trail of all corrections to the data, and the personnel making and date of corrections, is stored 
with the data in the Corrona database. 
9.9. Limitations of the Research Methods
This study has a number of limitations. Patient characteristics and access to medications can
vary substantially between countries, due to payer and regulatory differences, thus these 
results may be less applicable outside of the US. Propensity score (PS) methods are intended 
to adjust for non-random treatment assignment, however, the possibility of bias and endpoint 
misclassification remains for observational studies. Furthermore, while we accounted for the 
most clinically significant variables, unmeasured residual confounding is a possibility.
9.10. Other Aspects
Not applicable.

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10. PROTECTION OF HUMAN SUBJECTS
10.1. Patient Information 
This study involves data that exist in anonymized structured format and contain no patient 
personal information. 
10.2. Patient Consent
As this study involves anonymized structured data, which according to applicable legal 
requirements do not contain data subject to privacy laws, obtaining informed consent from 
patients by Pfizer is not required.
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
IRB/IEC approvals/waivers not required.
10.4. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as
with scientific purpose, value and rigor and follow generally accepted research practices
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the
International Society for Pharmacoepidemiology (ISPE), Good Epidemiological Practices 
(GEP) guidelines issued by the International Epidemiological Association (IEA).
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS
This study involves data that exist as structured data by the time of study start.
In these data sources, individual patient data are not retrieved or validated, and it is not
possible to link (ie, identify a potential association between) a particular product and medical 
event for any individual.  Thus, the minimum criteria for reporting an adverse event (AE) (ie, 
identifiable patient, identifiable reporter, a suspect product, and event) cannot be met.
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
competent authority in any area of the world, or if Corrona becomes aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.  
The protocol will be disclosed at clinical trials.gov website along with the final study results.  
In addition, the study results will be submitted to national and international medical
conferences and a final publication will be developed and submitted to an indexed, 
peer-reviewed medical journal in the area of rheumatology. Results from the interim/full
analysis may also be reported to European Medicines Agency (EMA) to support MR 
submission.

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13. REFERENCES
1.
Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose-ranging study of the oral 
JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in 
patients with active rheumatoid arthritis with an inadequate response to disease-
modifying antirheumatic drugs. Arthritis Rheum 2012;64:617-29.
2.
Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor 
in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled 
phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum
2009;60:1895-905.
3.
Kremer JM, Cohen S, Wilkinson BE, et al. A phase IIb dose-ranging study of the oral
JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background 
methotrexate in patients with active rheumatoid arthritis and an inadequate response to 
methotrexate alone. Arthritis Rheum 2012;64:970-81.
4.
Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofacitinib (CP-690,550) 
combined with methotrexate in patients with rheumatoid arthritis and an inadequate 
response to methotrexate. Arthritis Care Res (Hoboken) 2011;63:1150-8.
5.
Tanaka Y, Takeuchi T, Yamanaka H, et al. Efficacy and safety of tofacitinib as 
monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, 
randomized, phase 2 study. Mod Rheumatol 2015;25:514-21.
6.
Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in 
combination with methotrexate in patients with active rheumatoid arthritis with an 
inadequate response to tumour necrosis factor inhibitors: a randomised Phase 3 trial. 
Lancet 2013;381:451-60.
7.
Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib 
monotherapy in rheumatoid arthritis. N Engl J Med 2012;367:495-507.
8.
Kremer J, Li Z-G, Hall S, et al. Tofacitinib in combination with nonbiologic disease-
modifying antirheumatic drugs in patients with active rheumatoid arthritis: a 
randomized trial. Ann Intern Med 2013;159:253-61.
9.
Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid 
arthritis. N Engl J Med 2014;370:2377-86.
10.
van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients 
with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-
four-month phase III randomized radiographic study. Arthritis Rheum 2013;65:559-70.
11.
van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus 
placebo in rheumatoid arthritis. N Engl J Med 2012;367:508-19.

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12.
Fleischmann R, Mysler E, Hall S, et al. Efficacy and safety of tofacitinib monotherapy, 
tofacitinib with methotrexate, and adalimumab with methotrexate in patients with 
rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, 
randomised controlled trial. Lancet 2017;390:457-68.
13.
Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral 
Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm 
extension studies. J Rheumatol 2014;41:837-52.
14.
Yamanaka H, Tanaka Y, Takeuchi T, et al. Tofacitinib, an oral Janus kinase inhibitor, 
as monotherapy or with background methotrexate, in Japanese patients with rheumatoid 
arthritis: an open-label, long-term extension study. Arthritis Res Ther 2016;18:34.
15.
Wollenhaupt J, Lee EB, Curtis JR, et al. Safety and efficacy of tofacitinib for up to 9.5 
years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-
term extension study. Arthritis Res Ther 2019;21:89.
16.
Kremer JM. The Corrona US registry of rheumatic and autoimmune diseases. Clin Exp 
Rheumatol 2016;34:S96-S9.
14. LIST OF TABLES 
Table 1.
Sample Size Determination ......................................................................12
15. LIST OF FIGURES
Not applicable.
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.
ANNEX 3. ADDITIONAL INFORMATION
Not applicable.