Comparative Analysis of Adherence and Effectiveness Outcomes Between Rheumatoid Arthritis (RA) Patients Treated With Tofacitinib Modified Release (MR) Formulation 11mg Once Daily (QD) and Tofacitinib Immediate Release (IR) Formulation 5 mg Twice Daily (BID) Within a United States (US) Healthcare Claims Database
Conditions: Rheumatoid Arthritis
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Title
Comparative Analysis of Adherence and 
Effectiveness Outcomes Between 
Rheumatoid Arthritis (RA) Patients Treated 
with Tofacitinib Modified Release (MR) 
Formulation 11mg Once Daily (QD) and
Tofacitinib Immediate Release (IR) 
Formulation 5 mg Twice Daily (BID) within 
a United States (US) Healthcare Claims
Database
Protocol number
A3921349
Protocol version identifier
Version 1
Date 
27 March 2019
Active substance
L04AA29 (tofacitinib)
Medicinal product
Xeljanz (tofacitinib)
Research question and objectives
Primary Objectives:
To compare two proxies of medication
effectiveness (a validated criteria-based 
algorithm and a persistence-based measure) 
over 12 months of follow-up among RA 
patients treated with tofacitinib MR 11 mg 
once daily and tofacitinib IR 5 mg twice 
daily.
Compare 12-month proportion of RA 
patients who are persistent and adherent with
tofacitinib MR 11 mg once daily and 
tofacitinib IR 5 mg twice daily.
Secondary Objectives:
To compare a persistence-based measure of 
effectiveness over 6 months of follow-up 
among RA patients treated with tofacitinib
MR 11 mg once daily and tofacitinib IR 
5 mg twice daily.
Compare 6-month proportion of RA patients 

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who are persistent and adherent with
tofacitinib MR 11 mg once daily and 
tofacitinib IR 5 mg twice daily.
 
 
 
Author
, Ph.D.
, PhD
PPD
PPD
PPD
CCI

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TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS................................................................................................5
2. RESPONSIBLE PARTIES....................................................................................................7
3. ABSTRACT...........................................................................................................................7
4. AMENDMENTS AND UPDATES.......................................................................................7
5. MILESTONES.......................................................................................................................7
6. RATIONALE AND BACKGROUND..................................................................................8
7. RESEARCH QUESTION AND OBJECTIVES ...................................................................9
8. RESEARCH METHODS ......................................................................................................9
8.1. Study Design .............................................................................................................9
8.2. Setting........................................................................................................................9
8.2.1. Inclusion Criteria ........................................................................................10
8.2.2. Exclusion Criteria.......................................................................................10
8.3. Cohort Assignment..................................................................................................11
8.4. Period of Observation..............................................................................................11
8.5. Variables..................................................................................................................11
19
8.7. Study Size................................................................................................................21
8.8. Data Management ...................................................................................................21
8.9. Data Analysis ..........................................................................................................21
8.9.1. Primary and Secondary Analyses................................................................21
8.9.2. Descriptive Analysis...................................................................................22
8.9.3. Multivariate Analysis..................................................................................22
23
23
23
23
8.10. Quality Control......................................................................................................23
8.11. Limitations of the Research Methods....................................................................23
8.12. Other Aspects ........................................................................................................24
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................24
9.1. Patient Information..................................................................................................24
CCI
CCI
CCI
CCI
CCI

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9.2. Patient Consent........................................................................................................24
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............24
9.4. Ethical Conduct of the Study ..................................................................................24
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................24
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........25
12. REFERENCES ..................................................................................................................26
13. LIST OF TABLES.............................................................................................................27
14. LIST OF FIGURES ...........................................................................................................27
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................28
ANNEX 2. DRUG AND DIAGNOSIS CODE LISTS ...........................................................29
ANNEX 3. CCI CODE LIST...................................................................................................29
ANNEX 4.  CLAIMS-BASED INDEX OF RA SEVERITY (CIRAS)...................................31

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1. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse Event
bDMARD
Biologic disease-modifying antirheumatic drug
BID
Twice daily (bis in die)
CIRAS
Claims-based index for RA severity
COB
Coordination of Benefits
COPD
Chronic obstructive pulmonary disease
CPI
Consumer price index
CPT
Current Procedural Terminology
csDMARD
Conventional synthetic disease-modifying antirheumatic drug
DAS
Disease Activity Score
ED
Emergency department
ER
Emergency room
FDA
Food and Drug Administration
GLM
Generalized linear model
HCPCS
Healthcare Common Procedure Coding System
HIPAA
Health Insurance Portability and Accountability Act
ICD-9 CM
International Classification of Diseases, 9th Revision, Clinical Modification
ICD-10 CM
International Classification of Diseases, 10th Revision, Clinical Modification
ISPOR
International Society for Pharmacoeconomics and Outcomes Research
IEC
Independent Ethics Committee
IR
Immediate release
IRB
Institutional review board
IV
Intravenous
JAK
Janus Kinase inhibitor
MPR
Medication Possession Ratio
MR
Modified release
MTX
Methotrexate
nbDMARD
Non-biologic disease-modifying antirheumatic drug
NDC
National Drug Code
NIS
Non-interventional study
NSAID
Non-steroidal anti-inflammatory drug
PDC
Proportion of Days Covered
PMDA
Pharmaceutical and Medical Devices Agency

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Abbreviation
Definition
QD
Once daily (quaque die)
RA
Rheumatoid Arthritis
RCT
Randomized controlled trial
RX
Outpatient pharmacy prescription
TNFi
Tumor-Necrosis Factor-alpha inhibitor
US
United States

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2. RESPONSIBLE PARTIES
Principle Investigator(s) of the Protocol
Name, degree(s)
Job Title
Affiliation
Address
 
, PhD
 
, MS
 
, PhD
 
, PhD
 
 
3. ABSTRACT
Not applicable.
4. AMENDMENTS AND UPDATES
None
5. MILESTONES
Milestone
Planned date
Start of data collection (programming start)
27 March 2019
End of data collection (draft tables)
16 April 2019 
Interim study report
1 May 2019
Final study report
31 Jan 2020
PP
D
PPD
PPD
PPD
PP
D
PPD
PPD
PPD
PP
D

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6. RATIONALE AND BACKGROUND
Tofacitinib 5 mg immediate release formulation (IR) was approved for twice daily (BID) 
dosing schedule by the Food and Drug Administration (FDA) in November 2012 for the 
treatment of adult patients with moderately to severely active rheumatoid arthritis who have 
had an inadequate response or intolerance to methotrexate. In February 2016, an 11 mg once 
a day (QD) modified release (MR) tablet for treatment of rheumatoid arthritis was approved 
in the United States.  It may be used as monotherapy or in combination with methotrexate
(MTX) or other conventional synthetic disease-modifying antirheumatic drugs 
(csDMARDs). Biologic disease-modifying antirheumatic drugs s (bDMARDs) have been 
used for many years to treat RA with varying levels of success; however, no study has 
compared the effectiveness and treatment patterns of tofacitinib to bDMARDs in a real-world
setting.
In study A3921215, a randomised controlled direct comparative clinical study conducted in 
Japan, the MR formulation did not meet the non-inferiority criteria based on the stringent 
criteria requested by the Pharmaceutical and Medical Devices Agency (PMDA), the 
Regulatory Agency in Japan. However, the point estimate of the difference in efficacy 
between the MR and IR formulations, based on the primary endpoint of Disease Activity 
Score (DAS)28, was within the pre-specified margin. Nonetheless, the data from this study 
are not sufficient to conclude statistical similarity between the clinical efficacy of MR and IR 
formulations. While randomised controlled trials (RCT) are considered high in the hierarchy 
of medical evidence for a conventional treatment comparison, the A3921215 results may not 
be applicable to clinical practice due to many factors including reduced adherence. Patients 
tend to demonstrate worse adherence when they know their medication is being monitored. 
For example, in a metanalysis of RCTs that used electronic pill count monitors, patients had 
lower adherence in studies where they were blinded to the fact of monitoring than in studies 
where they were aware of the monitoring.2  Since once daily dosing is associated with 
significantly improved adherence,2 the double-dummy nature of A3921215 and high levels of 
patient monitoring may have masked the benefit of the MR 11 mg QD formulation relative to 
IR 5 mg BID by minimizing the variation in adherence across the two study arms. 
Increasingly, there is a recognition that patients’ use of medicines in regular clinical practice 
or in settings better reflecting the reality of healthcare delivery can explain differences 
between expected efficacy based on RCT outcomes and actual effectiveness in real world.1  
Evidence from medication use in the real-world setting can help to extrapolate and/or 
augment data obtained in randomised controlled trials and establishes a broad picture of a 
medication’s place in everyday clinical practice.6
A study comparing MR 11 mg QD and IR 5 mg BID within the Corrona RA registry 
demonstrated that 6 months post initiation, tofacitinib MR 11 mg QD is effective in 
managing signs and symptoms of RA in real world clinical use; and that it does so to a 
similar degree as tofacitinib IR 5 mg BID formulation (Pfizer, data on file).  However, 
adherence information is not collected in the register and could not be evaluated.

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This study is designed to compare the RA patient adherence between patients initiating 
tofacitinib MR 11 mg QD to those starting IR 5 mg BID, and to compare two proxy measures 
of effectiveness in an insurance claims-based real-world data setting.  
7. RESEARCH QUESTION AND OBJECTIVES
Primary Objectives:
To compare, through multivariate regression analyses:
•
Two proxies of medication effectiveness (a validated criteria-based algorithm and a 
persistence-based measure)3 over 12 months of follow-up among RA patients treated 
with tofacitinib MR 11 mg once daily and tofacitinib IR 5 mg twice daily.
•
12-month proportion of RA patients who are persistent and adherent with tofacitinib
MR 11 mg once daily and tofacitinib IR 5 mg twice daily.
Secondary Objectives:
To compare, through multivariate regression analyses:
•
A persistence-based measure of effectiveness over 6 months of follow-up among RA 
patients treated with tofacitinib MR 11 mg once daily and tofacitinib IR 5 mg twice 
daily.
•
A 6-month proportion of RA patients who are persistent and adherent with tofacitinib
MR 11 mg once daily and tofacitinib IR 5 mg twice daily.
 
 
8. RESEARCH METHODS 
8.1. Study Design
To address the objectives, a retrospective cohort design will be employed to evaluate patient
characteristics, proportion persistent and adherent, and effectiveness proxies in RA patients 
newly initiating tofacitinib within the Truven Health MarketScan Research Databases,
 
8.2. Setting
This study will utilize the de-identified claims data in the Truven Health MarketScan
Research Databases.
CCI
CC
I

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8.2.1. Inclusion Criteria
This study will include individuals with RA who are commercially insured (commercial 
claims and encounters database) or Medicare-eligible retirees with employer sponsored 
Medicare Supplemental coverage (Medicare database) who are treated with tofacitinib.
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. First pharmacy claim for tofacitinib is a 30-day supply (index event).
2. Index prescription is for labelled dosing for tofacitinib MR 11 mg QD or IR 5 mg 
BID between 01 March 2016 and 31 October 2018 (the identification period) (See 
Annex 2 for operationalization). Since the specific dose frequency, ie, twice daily or 
once daily is not available, for those initiating a 30 days supply of tofacitinib MR 11 
mg, a quantity of 30 pills is required (ie, 1x11 mg per day) and for those starting a 
30 days supply of tofacitinib 5 mg, 60 pills (2x5 mg per day) will be required. 
Patients from the overall cohort will be further assigned into MR 11 mg QD and IR 5 
mg BID subcohorts based on their assignment at index.
3. Continuously enrolled in a commercial or Medicare Supplemental insurance plan for 
at least one year before the index date through at least 1 year after the index date.
Note: Patients will have a variable length baseline of at least a year long. The
baseline period will be censored at January 1, 2013 based on licensed data 
availability.  The majority of baseline measures will use data from the 12 months 
immediately prior to the index date. Select measures will use data during the entire 
variable length baseline.
4. Presence of The International Classification of Diseases, 9th Revision or 10th
Revision, Clinical Modification (ICD-9 CM or ICD-10 CM) code for RA (in any
position) during the one-year pre-index period or on the index date.  
ICD-9 = 714.0x-714.4x & 714.81 or ICD10 = M05.* & M06.0*-M06.3* or 
M06.8*-M06.9*.
5. At least 18 years old as of the index date.
6. At least one claim for methotrexate anytime pre-index.
8.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in any study cohort:
1. Patients with claims for other conditions for which advanced therapies (bDMARD or 
Janus Kinase inhibitor (JAK)) are used during the one-year pre-index period or on the 
index date: ankylosing spondylitis, Crohn’s disease, psoriasis, psoriatic arthritis,
juvenile idiopathic arthritis or ulcerative colitis will be excluded from the study.

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Table 1.
Exclusionary Diagnosis
Disease
ICD-9 diagnosis code
ICD10 diagnosis code
Ankylosing Spondylitis
720.0x
M45.*
Crohn's Disease
555.xx
K50.*
Psoriasis
696.1x
L40.0*-L40.4*, L40.8*- L40.9*
Psoriatic Arthritis
696.0x
L40.5*
Ulcerative Colitis
556.xx
K51.*
Juvenile RA
714.3*
M08.*
ICD: International classification of diseases; RA = rheumatoid arthritis
2. Patients with evidence of the index medication during the one-year pre-index period.  
Patients will be allowed to have been treated with other advanced therapies defined 
as other bDMARDs or other JAK inhibitors (not tofacitinib) during the one-year 
pre-index period.
3. Patients with more than one advanced therapy prescription fill on the index date will 
be removed from the study, ie, a bDMARD and JAK inhibitor or more than one JAK 
inhibitor or two different tofacitinib formulations (ie, IR and MR), filled on the index 
date will be removed from the study.
8.3. Cohort Assignment
Patients will be assigned to a tofacitinib study cohort based on the first tofacitinib claim and 
formulation observed and for which the patient meets the other inclusion/exclusion criteria
While patients may have multiple eligible treatment episodes, only the first will be evaluated. 
Patients whose first tofacitinib prescription reflects a 11 mg formulation and day supply 
consistent with daily dose equal to 11 mg will be assigned to MR 11 mg QD.  Patients whose 
first tofacitinib prescription reflects 5 mg formulation with a daily dose equal to 10 mg will 
be assigned to IR 5 mg BID.  Patients are only eligible for inclusion in one cohort.
8.4. Period of Observation
All patients will be required to have been continuously enrolled in the health plan for at least 
24 months (12 months prior to index, and 12 months post index, at minimum).  Patients will 
have a variable length pre-index baseline period of at least 12 months. The 12 months prior 
to the index date will be used to assess the majority of pre-index characteristics. However, 
for select measures, eg, use of methotrexate, number of prior advanced therapies, and years
since first RA diagnosis, the entire variable length baseline period will be utilized. The 
twelve months following the index date will be used to assess outcomes including adherence, 
persistence, and medication effectiveness.
8.5. Variables
Adherence is defined as percentage of time with medication on hand and will be assessed 
with the Medication Possession Ratio (MPR) and Proportion of Days Covered (PDC).  Both 
measures have been evaluated in numerous publications for rheumatoid arthritis and other 
conditions and will be reported in current study for 6 and 12-month follow-up periods.  Both 

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adherence measures will leverage tofacitinib medication days supply in the numerator, for 
which PDC adjusts for overlap in prescriptions while MPR does not. Further, the PDC is a 
more conservation measure of adherence as the denominator includes all pre-defined 
follow-up (360 days for the 12-month period; 180 days for the 6-month period), which may 
include time after stopping a medication in the calculation, while MPR only includes time 
between first and last prescription (plus last prescription days supply) in the denominator.  
Patients with an MPR or PDC ≥0.8 are typically characterized as adherent. The Pharmacy 
Quality Alliance recommends use of PDCs for adherence measurements.8
The proportion of patients who are persistent with treatment is also commonly evaluated in
similar published studies and will be reported for 6 and 12-month follow-up periods.  Prior 
studies have indicated at least 1/3rd of  patients are not persistent with TNFi therapy, which is 
consistent with proportion of patients with inadequate response in clinical trials.5  This
measure takes into account patients who have not discontinued (gap of 60 days between 
refills) or switched medications; however, it may underestimate the proportion who are 
persistent depending on the duration of gap (ie, 60 vs. 90 days) for patients that may appear to 
discontinue and resume treatment for multiple reasons including hospitalization, drug samples
not recorded in claims, use of stockpile, etc. Hence sensitivity analyses with different gaps 
are often employed. 
Two measures of effectiveness will be used in this study: 1) a validated algorithm-based, 
dichotomous measure (over the 12 month follow up period) and 2) a duration of therapy 
based continuous measure of medication persistence (over 6 and 12 month follow up 
periods). 
Among patients with at least one year of follow up, medication effectiveness at one year after
the index date will be determined using an algorithm-based proxy measure of effectiveness 
based on the following six criteria.3,7  This measure was shown to have good sensitivity, 
specificity, positive and negative predictive values ranging from 75% to 90% using a gold 
standard of low disease activity (DAS28 ≤3.2) or improvement in DAS28 by >1.2 units, 
which the authors suggested was consistent with but not identical to European League 
Against Rheumatoid Arthritis (EULAR) responder definition.3
The second effectiveness proxy is length of treatment duration which captures both the 
sustained positive treatment effect as well as inefficacy, loss of efficacy and adverse events 
as well as any discontinuations unrelated to treatment effect, such as costs and adherence.11  
Note that the MR and IR tofacitinib formulations have same costs. Duration of therapy has 
been used as an endpoint to demonstrate the improved effectiveness of methotrexate relative 
to other csDMARDs despite similar efficacy in RCT.11  In this study, treatment duration was 
defined as the number of days between index date to the first of the following: the date of last 
prescription that is followed by a gap of 60 days without evidence of another advanced 
therapy prior to expiration of gap; the day before receipt of another advanced therapy; or the 
end of follow up period.  

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Table 2.
Variables Used in Analyses
Variable
Role
Operational definition
Index date
Baseline Patient 
Characteristics
Month and year of the patient’s treatment index date 
(see Section 8.2.1, 8.2.2).
Age
Baseline Patient 
Characteristics
Patient age as of the index date.
Age group
Baseline Patient 
Characteristics
Age categorized into: 18–44, 45–64, and 65+.
Sex
Baseline Patient 
Characteristics
Male or female. 
Geographic region
Baseline Patient 
Characteristics
Region in which the study patient is enrolled in a 
health plan will be categorized into five geographic 
regions: Northeast, North Central, South, West, and 
Unknown.
Insurance type
Baseline Patient 
Characteristics
Insurance type (commercial or Medicare) of index 
claim.
bDMARD use, 12 month 
pre-index, categorical
Baseline Clinical 
Characteristics
The count of unique bDMARDs with at least one 
prescription (Annex 2) received during the 12 month 
pre-index period. Will characterize use of 0, 1, 2 or 
more bDMARDs.
bDMARD use, 12 month 
pre-index, continuous
Baseline Clinical 
Characteristics
Number of unique bDMARD medications and 
claims during 12 months pre-index.  
bDMARD use, variable 
pre-index, categorical
Baseline Clinical 
Characteristics
The count of unique bDMARDs with at least one 
prescription (Annex 2) received during the entire 
variable length pre-index period. No use will be 
classified as bDMARD naïve. Use of 1, 2 or more 
will be classified as bDMARD experienced.
TNFi  use, 12 month pre-
index, categorical
Baseline Clinical 
Characteristics
The count of unique TNFi with at least one 
prescription (Annex 2) received during the 12 month 
pre-index period. Will characterize use of 0, 1, 2 or 
more TNFi’s.
TNFi  use, 12 month pre-
index, continuous
Baseline Clinical 
Characteristics
Number of unique TNFi claims during 12 months 
pre-index.  
TNFi use, variable pre-
index, categorical
Baseline Clinical
Characteristics
The count of unique TNFi with at least one 
prescription (Annex 2) received during the entire 
variable length pre-index period. No use will be 
classified as TNFi naïve. Use of 1, 2 or more will be 
classified as TNFI experienced.

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Table 2.
Variables Used in Analyses
Variable
Role
Operational definition
Advanced therapy use 12 
month pre-index, 
categorical
Baseline Clinical 
Characteristics
Use of bDMARDs or JAK inhibitors (Annex 2) 
during 12 months pre-index.  Will characterize use 
of 0,1, 2 or more advanced therapies.
Advanced therapy use 12 
month pre-index, 
continuous
Baseline Clinical 
Characteristics
Number of unique medications and claims during 
12 months pre-index.  
Advanced therapy use, 
variable length pre-index, 
categorical
Baseline Clinical 
Characteristics
Use of any bDMARDs or JAK inhibitors (Annex 2) 
during variable length pre-index period. No use will 
be classified as advanced therapy naïve. Use of 1, 2 
or more will be classified as advanced therapy 
experienced.
csDMARD use, 12 month 
pre-index, categorical
Baseline Clinical 
Characteristics
The count of unique csDMARDs with at least one 
prescription (see Annex 2) during the 12 month 
pre-index period as 0,1,2 or more. 
csDMARD use, 12-month 
pre-index, continuous
Baseline Clinical 
Characteristics
The count of unique csDMARD medications and
claims (see Annex 2) during 12-month pre-index 
period.
csDMARD use, 90 days 
pre-index, dichotomous
Baseline Clinical 
Characteristics
Presence of csDMARD in 90 days pre-index.  
Combination therapy, 90 
days post-index (including 
index)
Baseline Clinical 
Characteristics
Combination therapy defined as first comedication 
with any csDMARD (Annex 2) within 90 days on or 
after the index date.  Classify first csDMARD as 
methotrexate, leflunomide, hydroxychloroquine, 
sulfasalazine or other.  If more than 1 csDMARD on 
same day, note methotrexate plus other or if not with 
methotrexate, just classify as >1 csDMARD other 
than methotrexate.
Monotherapy defined as the complement to 
combination therapy.
Quan-Charlson comorbidity 
score, continuous, 12-
month pre-index
Baseline Clinical 
Characteristics
A weighted scale of 17 co-morbidities (based on 
associated diagnosis codes on medical claims in the 
12-months pre-index) presented as a summative 
score to evaluate co-morbid chronic illness burden.
Quan-Charlson comorbidity 
score, categorical 12-month 
pre-index
Baseline Clinical 
Characteristics
The continuous Quan-Charlson comorbidity score 
categorized into:  0, 1-2, 3-4, 5+ QCCI comorbidities
(Annex 3).4,9
Opioid, non-steroidal anti-
inflammatory drug 
(NSAID) use, dichotomous, 
12-month pre-index 
Baseline Clinical 
Characteristics
The use of weak and/or strong opioids and/or non-
steroidal anti-inflammatory drug (NSAID) 
(Annex 2) during the 12-month pre-index periods.
Opioid, non-steroidal anti-
inflammatory drug 
(NSAID) use, continuous 
12 month pre-index
Baseline Clinical 
Characteristics
The number of pharmacy claims for weak and/or 
strong opioids and/or non-steroidal 
anti-inflammatory drug (NSAID) (Annex 2) during 
the 12-month pre-index periods.

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Table 2.
Variables Used in Analyses
Variable
Role
Operational definition
Pre-index corticosteroids, 
dichotomous
Baseline Clinical 
Characteristics
The use of oral corticosteroids (Annex 2) during the 
12-month pre-index.
Pre-index corticosteroid 
total exposure/dose, 
continuous, 12-month pre-
index
Baseline Clinical 
Characteristics
The total prednisone-equivalent dose of oral 
corticosteroids in the 12 months prior to index, 
defined as: the  sum of prednisone equivalent dose 
(Strength*quantity/equivalence factor) of a filled 
corticosteroid. (Dose equivalent factors: 
Betamethasone=0.6, Dexamethasone=0.75; 
Methylprednisolone, Triamcinolone=4, Prednisone, 
Prednisolone=5; Hydrocortisone=20, Cortisone=25; 
Fludrocortisone=n/a).
Visit with a rheumatologist 
in 90 days prior to index, 
dichotomous
Baseline Clinical 
Characteristics
At least one ambulatory visits (office visit or 
outpatient visit) in which the physician was a 
rheumatologist in the 90 days before or on the index 
date. 
Visit with a rheumatologist 
in 12 months prior to index, 
dichotomous
Baseline Clinical 
Characteristics
At least one ambulatory visits (office visit or 
outpatient visit) in which the physician was a 
rheumatologist in the 12 months before or on the 
index date. 
Visit with a rheumatologist 
in 12 months prior to index, 
continuous 
Baseline Clinical 
Characteristics
Count of Ambulatory visits (office visit or outpatient 
visit) in which the physician was a rheumatologist in 
the 12 months before or on the index date. 
Disease duration
Baseline Clinical 
Characteristics
The number of days from the earliest claim with a 
diagnosis of RA in the variable length baseline until 
the index date.
Total all-cause costs, 12-
month pre-index, 
continuous
Baseline Clinical 
Characteristics
Sum of patient and plan paid costs for all healthcare 
resource use in 12 month pre-index period.  CPI 
adjusted to 2018 dollars (http://data.bls.gov/cgi-
bin/surveymost?cu U.S. Medical Care, 1982-
84=100 - CUUR0000SAM). 
Comorbidities, 12 month 
pre-index, dichotomous
Cardiovascular diseases
Chronic obstructive 
pulmonary disease (COPD)
Asthma
Kidney disease
Diabetes
Depression
Anxiety
Liver disease
Sleep disorders
Hypertension
Hyperlipidemia
Baseline clinical 
characteristics
Presence or absence of codes for the comorbidities 
of interest during the 12-months prior to index
(Annex 2).

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Table 2.
Variables Used in Analyses
Variable
Role
Operational definition
Pre-index Claims-based 
index for RA severity 
(CIRAS), 12 month pre-
index, continuous
Baseline clinical 
characteristic
The Claims-based Index for RA Severity will be 
implemented. CIRAS provides a single value of 
severity using the following 9 measures: age, 
gender, inflammatory marker tests, rehabilitation 
visits, Felty Syndrome, platelet orders, rheumatoid 
factor tests, chemistry panels, and rheumatologist 
visits.  Scores range from 0 (low) to 
10 (high)(Annex 4).10
Length of variable length 
pre-index period, 
continuous
Baseline characteristic
The period from start of continuous enrollment 
through index without gaps in coverage.  
Length of variable length 
pre-index period, 
categorical
Baseline characteristic
Continuous variable length duration categorized into 
<13, 13-18, 19-24, 25-30,31-36 and >36 months.
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2.
Variables Used in Analyses
Variable
Role
Operational definition
 
 
 
Treatment Persistent, 6 and 
12 months post-index, 
dichotomous 
Outcome (persistence)
Patients who do not have a switch to another 
advanced therapy or discontinue tofacitinib (ie, 
60-day gap between the run out of prior tofacitinib 
prescription and subsequent fill) over 6 and 
12 month follow-up periods are characterized as 
persistent.  The run out date is the prescription fill 
date + day supply – 1.  For retail outpatient 
pharmacy prescription (RX) claims, the day supply 
will be utilized.  There are no null tofacitinib days 
supply in dataset; however, claims with negative 
days supply or zero days supply will be excluded.  
Most tofacitinib prescriptions are for 30 days supply 
(86%) followed by 90 (12%) and 60 (~1%) days. 
Patients with early refills will be allowed to 
accumulate a stockpile of the index medication of up 
to 14 days for later use. 
A change in the formulation of active ingredient 
prescribed, eg, 5 mg BID vs 11 mg QD is not 
considered a switch for persistence endpoints in 
primary analyses.
Medication Possession 
Ratio (MPR), 6 and 12 
months post-index, 
continuous
Outcome (adherence)
The total days supply between the first and including 
the last tofacitinib prescription divided by the time 
between the first through and including last index 
therapy prescription days supply. Multiple 
prescriptions for the same treatment with the same 
fill date will be treated as one prescription with 
longest days supply; and for all prescriptions days 
supply will be capped at end of follow-up. MPR 
will be capped at 1.0 and will be reported at 
6 months and 12 months.
Medication Possession 
Ratio (MPR), 6 and 12 
months post-index, 
dichotomous  
Outcome (adherence)
High adherence (MPR≥0.8) vs. Low Adherence 
(MPR <0.8).
Proportion of Days Covered 
(PDC), 6 and 12 months 
post-index, continuous
Outcome (adherence)
The PDC was defined as number of days covered by 
arrays for each fill or administration during the 
denominator periods of 180 and 360 days post-index. 
Patients with early refills will be allowed to stockpile 
medications up to a maximum of 14 days total for 
later use. PDC is capped at 1.0.
Proportion of Days Covered 
(PDC), 6 and 12 months 
post-index, dichotomous
Outcome (adherence)
High adherence (PDC≥0.8) vs. Low Adherence (PDC 
<0.8).
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Table 2.
Variables Used in Analyses
Variable
Role
Operational definition
Medication Effectiveness, 
algorithm defined, 12 
months post-index, 
dichotomous
Outcome (effectiveness)
Patients who meet all 6 effectiveness criteria will be 
considered effectively treated. Patients who fail any 
one of the 6 criteria are considered not effectively 
treated.
High adherence criterion
Effectiveness criterion 1
High adherence criterion met if PDC >=0.8 during 
the 12 month follow-up period.
Dose escalation criterion
Effectiveness criterion 2
No dose escalation criterion is met if no increases in 
index medication dose between index and 12 months 
after index. Dose increase threshold defined per 
Table 3.
No treatment switch 
criterion
Effectiveness criterion 3
No treatment switch criterion is met if there is no use 
of an advanced therapy (Annex 2) other than index 
therapy during the 12 month follow-up period.
Addition of csDMARD 
criterion
Effectiveness criterion 4
No addition of csDMARD criterion is met if there 
are no claims for any csDMARD during the 1-year 
post-index for which there was not a claim during 
1-year pre-index and/or 90 days post-index.
Oral glucocorticoids 
criterion
Effectiveness criterion 5
The oral glucocorticoids criterion is met if  a) For 
patients with no oral glucocorticoid prescriptions in 
the 6 months prior to index date, there is not more 
than 30 total days supply of oral glucocorticoids 
between 3-12 months post index; b) For patients 
with at least one claim for oral glucocorticoids 
during 6 months pre-index, oral glucocorticoid dose 
does not increase during months 6-12 post-index 
compared to the 6 months before the index date. 
Dose increase is defined as ≥20% increase in 
prednisone equivalent dose (per above) for all 
glucocorticoid claims filled during the respective 
time periods.
Note:  Patients with more than one glucocorticoid 
injection during months 3-12 after index will be 
evaluated per the injection glucocorticoid criterion.
Injection glucocorticoid 
criterion
Effectiveness criterion 6
The injectable glucocorticoids criterion is met if 
patients have one or fewer glucocorticoid injections 
during months 3-12 after index date.  Patients having 
one or more glucocorticoid injections on a single day 
are not considered to have failed the criterion. 
Medication effectiveness, 
Duration of therapy 
(persistence), continuous, 
12 month post-index 
Outcome (effectiveness 
proxy)
The number of days between index date to the first 
of the following: the date of last prescription that is 
followed by a gap of 60 days without evidence of 
another advanced therapy prior to expiration of gap; 
the day before receipt of another advanced therapy; 
or the end of follow up period.
A sensitivity analysis will be conducted for the 
Tofacitinib MR and IR comparison to include a 
switch in formulation as a criterion for 
discontinuation.

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Table 3.
Dose Escalation Criteria
Generic Name
Standard dosing schedule
Criteria for dose escalation for medication
effectiveness
Tofacitinib
(tofacitinib IR)
5 mg twice daily
At least 1 claim in the follow-up period with an
average daily dose of at least 20 mg/day.
tofacitinib
(tofacitinib MR)
11 mg once daily
At least 1 claim in the follow-up period with an
average daily dose of at least 22 mg/day.
 
 
 
 
 
 
 
 
 
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8.7. Study Size
The sample size for this study is fixed by the number of people meeting the inclusion criteria 
during the observation period. No formal sample size computation was performed.  All 
patients who meet inclusion/exclusion criteria will be included in the analyses.
8.8. Data Management 
The MarketScan Research Databases comply with both the spirit and the letter of the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  The MarketScan Databases
meet the criteria for a limited-use dataset and contain none of the data elements prohibited by
HIPAA for limited-use datasets.
8.9. Data Analysis 
8.9.1. Primary and Secondary Analyses 
Descriptive and multivariate regression analyses will be performed to satisfy the primary and 
secondary analyses as described in Table 4.  Details on the descriptive and multivariate 
methods follow in Section 8.9.2 and Section 8.9.3 respectively.
Table 4.
Primary and Secondary Objectives for Comparison Between MR 11 mg QD 
and IR 5 mg BID. 
Endpoint
Objective
Type
Post Index 
Duration
Analysisa
Effectivenessb
(algorithm defined)
Primary
Dichotomous
12 months
Generalized 
linear model
Effectivenessc
(duration of persistence)
Primary
Continuous
12 months
Cox regression
Adherence 
(MPR)
Primary
Continuous
12 months
Generalized 
linear model
Adherence 
(MPR ≥80%) 
Primary
Dichotomous
12 months
Logistic 
regression
Adherence 
(PDC)
Primary
Continuous
12 months
Generalized 
linear model
Adherence 
(PDC ≥80%)
Primary
Dichotomous
12 months
Logistic 
regression
Effectiveness 
(duration of persistence)
Secondary
Continuous
6 months
Cox regression
Adherence 
(MPR)
Secondary
Continuous
6 months
Generalized 
linear model
Adherence 
(MPR ≥80%) 
Secondary
Dichotomous
6 months
Logistic 
regression
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Table 4.
Primary and Secondary Objectives for Comparison Between MR 11 mg QD 
and IR 5 mg BID. 
Endpoint
Objective
Type
Post Index 
Duration
Analysisa
Adherence 
(PDC)
Secondary
Continuous
6 months
Generalized 
linear model
Adherence 
(PDC ≥80%)
Secondary
Dichotomous
6 months
Logistic 
regression
a.
Analyses will be repeated stratifying by number of previous advanced treatments (0, 1, and 2+ prior) if 
feasible.
b.
The proportions of patients not meeting each of the 6 criteria separately will be described.
8.9.2. Descriptive Analysis
All study variables, including pre- and post-index measures, will initially summarized 
descriptively.  In general, numbers and percentages will be provided for dichotomous and 
polytomous variables, while means, medians, and standard deviations will be provided for 
continuous variables. Missing or unavailable data will not be imputed. 
Results will be stratified by treatment cohort, bivariate comparisons of pre- and post-index 
measures will be provided, and appropriate tests (eg, t-test, Mann Whitney-U test, chi-square 
test) will be used based on the distribution of the measure. The analysis that is performed (ie, 
the methods that are used and the patients who are included) will be specific the objective 
being examined.  Descriptive techniques will be implemented for each objective. 
8.9.3. Multivariate Analysis
To control for possible confounding of the relationship between the outcomes and 
independent variable of interest multivariable (logistic, generalized linear, and Cox) 
regression models will be evaluated as described in Table 4. 
The models will include insurance type, region, age, sex, prior advance therapies in variable 
length period (None, 1 and 2+) as covariates.  The following variables will be evaluated for 
inclusion as a covariate and be included if differences between MR 11 mg QD and IR 5 mg 
BID at baseline with p <0.10: 12-month pre-index use (% and means) of csDMARD, opioids, 
corticosteroids and presence of comorbidities including, cardiovascular disease, chronic 
obstructive pulmonary disease (COPD), asthma, kidney disease, depression, anxiety, liver 
disease, sleep disorders, hypertension, hyperlipidemia, Quan-Charlson comorbidity index and 
CIRAS scores, rheumatologist visit count during 1-year pre-index, disease duration, 
pre-index total costs, length of pre-index period, use of advanced therapy in 12 month 
pre-index and presence of csDMARD in 90 days post-index.  
Generalized linear models (GLM) will be fit, using appropriate distributions and links for the 
nature of the data (eg, normally-distributed data with identity link, binary data and logit link).  
Point estimates, 95 percent confidence intervals, and p-values will be presented for contrasts; 
analysis of variance table will be presented to display the strength of the independent 
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variables, including point estimates and p-values. If there are problems with model fit, for 
example, failure to converge, transformation of data may be used in order to try a different 
distribution and link.
 
 
 
 
 
 
  
 
 
 
8.10. Quality Control
This is a retrospective study, so issues of quality control at study sites, eg, data queries, do
not apply.  Analyses are programmed according to the specifications in the protocol, and if
applicable, the statistical analysis plan, and documented in a programming plan. Final
deliverables are reviewed and verified by a second, independent programmer who may also
perform double programming.  All quality checks are documented in the programming plan.
8.11. Limitations of the Research Methods
Limitations that are general to claims database analyses and specific to this study should be
noted. First, diagnosis of autoimmune conditions will be identified using ICD-10-CM
diagnosis codes, which are subject to potential miscoding, though presumably without 
respect to the treatment or outcomes. Second, the baseline period for this study will 
generally be 12 months long.  Therefore, patients treated with a bDMARD or tofacitinib in
the baseline can be considered to be prior users of therapy; however, patients with no
bDMARD or tofacitinib use in the baseline may have just been off therapy for the 12 months 
prior. Lastly, this study will include an examination of medication effectiveness at 1 year
among all bDMARD and tofacitinib users. Effectiveness (yes/no) will be measured using a 
validated algorithm; however, the algorithm was not validated for all medications being
included. Specifically, tofacitinib was approved for treatment of RA after the algorithm was
developed. This study will include consultation with physicians to determine if the algorithm 
is valid for all study medications or if modifications need to be implemented.
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8.12. Other Aspects
Not applicable.
9. PROTECTION OF HUMAN SUBJECTS
9.1. Patient Information 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, any patient names will be removed and will be replaced by a single, specific, 
numerical code.  All other identifiable data transferred to Pfizer or other authorized parties 
will be identified by this single, patient-specific code.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with the vendor contract and applicable privacy laws.
9.2. Patient Consent
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required. 
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
IRB is not required for this study as it uses commercially available de-identified secondary
data sources and is considered exempt from the requirements for “human subjects research”
in the US.
9.4. 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 CT24-WI-GL02-RF04 and the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR).
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study involves data that exist as structured data by the time of study start or a 
combination of existing structured data and unstructured data, which will be converted to 
structured form during the implementation of the protocol solely by a computer using 
automated/algorithmic methods, such as natural language processing.

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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.
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
For all publications relating to the Study, Pfizer 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.
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 the party responsible for collecting data 
from the participant is aware of any new information which might influence the evaluation of 
the benefits and risks of a Pfizer product, Pfizer should be informed immediately.

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12. REFERENCES
1.
Association of British Pharmaceutical Industry (ABPI) Securing a Future for Innovative 
Medicines: a discussion paper. 2014 Available at: 
http://www.abpi.org.uk/media/1432/securingafuture_final.pdf  Accessed 23 March 
2019.
2.
Coleman CI, Limone B, Sobieraj DM, Lee S, Roberts MS, Kaur R, Alam T. Dosing 
frequency and medication adherence in chronic disease. J Manag Care  
Pharm. 2012 Sep;18(7):527-39.
3.
Curtis JR, Baddley JW, Yang S, et al. Derivation and preliminary validation of an 
administrative claims-based algorithm for the effectiveness of medications for 
rheumatoid arthritis. Arthritis Res Ther 2011;13(5):R155.
4.
Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with 
ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45:613– 619.
5.
Harnett J, Wiederkehr D, Gerber R, et al.  Real-world evaluation of TNF-inhibitor 
utilization in rheumatoid arthritis, J Med Econ 2016;2(19):101-12.
6.
Katkade VB, Sanders KN, Zou KH. Real world data: an opportunity to supplement 
existing evidence for the use of long-established medicines in health care decision 
making. J Multidiscip Healthc 2018;2(11):295-304. 
7.
Oladapo, et. al. Medication Effectiveness with the Use of Tumor Necrosis Factor 
Inhibitors Among Texas Medicaid Patients Diagnosed with Rheumatoid Arthritis.
J Manag Care Pharm 2014;7(20):657-67.
8.
Pharmacy Quality Alliance (PQA), Adherence 2018.  Available at: 
https://www.pqaalliance.org/adherence-measures, Accessed 23 March 2019.
9.
Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, Saunders LD, Beck 
CA, Feasby TE, Ghali WA. Coding algorithms for defining comorbidities in ICD-9-
CM and ICD-10 administrative data. Med Care. 2005 Nov;43(11):1130-9.
10.
Ting G, Schneeweiss S, Scranton R, et al. Development of a health care utilisation 
data-based index for rheumatoid arthritis severity: a preliminary study.  Arthritis Res 
Ther. 2008;10(4):R95. 
11.
Wolfe, F. The epidemiology of drug treatment failure in rheumatoid arthritis, Baillieres 
Clin Rheumatol 1995;9:619-632.

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13. LIST OF TABLES
Table 1.
Exclusionary Diagnosis ............................................................................11
Table 2.
Variables Used in Analyses......................................................................13
Table 3.
Dose Escalation Criteria ...........................................................................19
Table 4.
Primary and Secondary Objectives for Comparison Between MR 11 
mg QD and IR 5 mg BID..........................................................................21
14. LIST OF FIGURES
None.

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ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.

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ANNEX 2. DRUG AND DIAGNOSIS CODE LISTS
The drug and diagnosis codes corresponding to the variables in this protocol will be found in 
the study folder.  
ANNEX 3. CCI CODE LIST
The CCI Code list will be maintained in the study folder.  QCCI is a weighted sum of 
0/1 indicator variables for 17 disease categories.  The weights are: 
1*(cci01+cci02+cci03+cci04+cci05+ cci06+cci07+cci08+cci09+cci10)
2*(cci11+cci12+cci13+cci14)
3*(cci15)
6*(cci16+cci17) 
cci01 = 'Myocardial infarction (MI)'
cci02 = 'Congestive heart failure (CHF)'
cci03 = 'Peripheral vascular disease 
(PVD)'
cci04 = 'Cerebrovascular disease 
(CD)'
cci05 = 'Dementia'
cci06 = 'Chronic pulmonary disease 
(CPD)'
cci07 = 'Rheumatologic disease (RD)'
cci08 = 'Peptic ulcer disease (PUD)'
cci09 = 'Mild liver disease (MLD)'
cci10 = 'Diabetes without chronic 
complication'
cci11 = 'Diabetes with chronic 
complications'
cci12 = 'Hemiplegia or paraplegia'
cci13 = 'Renal disease'

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cci14 = 'Any malignancy, including 
leukemia and lymphoma'
cci15 = 'Moderate or severe liver disease'
cci16 = 'Metastatic solid tumor'
cci17 = 'AIDS/HIV'

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ANNEX 4.  CLAIMS-BASED INDEX OF RA SEVERITY (CIRAS)
Measure10
Score
Age (continuous)
-0.066
Gender
0: male
1: female
-0.092
Inflammatory marker test ordered
0: no
1: yes
0.60
Rehabilitation visit
0: no
1: yes
0.69
Rheumatoid factor test
0: no
1: yes
2.1
Felty’s syndrome
0: no
1: yes
2.3
Number of platelet counts ordered
0 = 0 visits
1 = 1 visit
2 = 2 visits
3 = 3 visits
4 = 4+ visits
0.42
Number of chemistry panels ordered
0 = 0 panels
1 = 1 panel
2 = 2 panels
3 = 3 panels
4 = 4 panels
5 = 5+ panels
-0.14
Rheumatologist visit count
1 = 0 visits
2 = 1-4 visits
3 = 5+ visits
0.52
Intercept
6.5
Number of platelet counts, chemistry panels, and rheumatologist visits are counted 1 per person per day.

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Codes for CIRAS Calculation 
Codes
Visits/Tests 
Inflammatory 
Markers
85651, 85652 
86140, 86141
ESR
CRP
Rehabilitation 
OT/PT Codes: G0151,G0152,G0157,G0158, 
G0159,G0160,S9129,S9131,97001,97002,970
03,97004
Occupational therapy/physical 
therapy visits
Rheumatoid 
Factor
CPT 86430,86431
Rheumatoid Factor Test Qual, 
Rheumatoid Factor Test Quant
Felty’s 
syndrome
ICD-9/10: 714.1, M05.0x
Platelet counts 
CPT: 85049
Automated platelet count
Chemistry 
panels
CPT: 80053, 82248, 82465, 82977, 83540,
83615, 84100, 84478, 84550
A/G Ratio, Albumin, Alkaline 
Phosphatase, Alanine 
Aminotransferase, Asparate 
Aminotransferase, Direct and 
Total Bilirubin, 
BUN/Creatinine Ratio, 
Calcium, Carbon Dioxide, 
Chloride, Cholesterol, 
Creatinine, Gamma 
Glutamyltransferase, Globulin, 
Glucose, Iron, Lactate 
Dehydrogenase, Phosphate, 
Potassium, Total Protein, 
Sodium, Triglycerides, Urea 
Nitrogen (BUN), Uric Acid

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