Comparative Analysis of Outcomes Among Patients Initiating Xeljanz in Combination With Oral MTX Who Withdraw MTX Versus Continue MTX Using a United States Healthcare Claims Database
Conditions: Rheumatoid Arthritis
Sponsor: Pfizer

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Study information
Title
Comparative Analysis of Outcomes among Patients
Initiating Xeljanz in Combination with Oral MTX Who 
Withdraw MTX Versus Continue MTX Using a United
States Healthcare Claims Database
Protocol number
A3921336
Protocol version 
identifier
Version 1
Date of last
version of 
protocol
01 May 2018
Active substance
L04AA29 (tofacitinib)
Medicinal product
Xeljanz (tofacitinib)
Research 
question and 
objectives
Primary Objective:
Compare treatment patterns including dosing, concomitant 
medication use, adherence, persistence, and switching among 
tofacitinb+MTX patients who withdraw MTX vs. persist with 
MTX or experience interrupted MTX.
Secondary Objectives:
Explore the differences in demographic and clinical 
characteristics among tofacitinb+MTX patients who withdraw 
MTX vs. persist with MTX or experience interrupted MTX.
Compare rheumatoid arthritis (RA)-related costs among 
tofacitinb+MTX patients who withdraw MTX vs. persist with 
MTX or experience interrupted MTX.
Compare medication effectiveness among tofacitinb+MTX 
patients who withdraw MTX vs. persist with MTX or experience 
interrupted MTX.
Compare all-cause and RA-related health care utilization among 
tofacitinb+MTX patients who withdraw MTX vs. persist with 
MTX or experience interrupted MTX.
Compare all-cause healthcare costs among tofacitinb+MTX 
patients who withdraw MTX vs. persist with MTX or experience 
interrupted MTX.

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Author(s)
, Ph.D
PPD
PPD

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TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS................................................................................................5
2. RESPONSIBLE PARTIES....................................................................................................6
3. ABSTRACT...........................................................................................................................6
4. AMENDMENTS AND UPDATES.......................................................................................6
5. MILESTONES.......................................................................................................................6
6. RATIONALE AND BACKGROUND..................................................................................6
7. RESEARCH OBJECTIVES..................................................................................................7
8. RESEARCH METHODS ......................................................................................................7
8.1. Study Design .............................................................................................................7
8.2. Setting........................................................................................................................7
8.2.1. Inclusion Criteria ..........................................................................................8
8.2.2. Exclusion Criteria .........................................................................................8
8.3. Cohort Assignment....................................................................................................9
8.4. Sample Subsets..........................................................................................................9
8.5. Period of Observation..............................................................................................10
8.6. Variables..................................................................................................................10
8.6.1. Patient Characteristics ................................................................................10
8.6.2. Clinical Characteristics...............................................................................10
8.6.3. Treatment Patterns......................................................................................14
8.6.4. Medication Effectiveness............................................................................15
8.6.5. Health Care Cost and Utilization................................................................16
8.7. Data Sources............................................................................................................17
8.7.1. Truven.........................................................................................................17
8.8. Study Size................................................................................................................19
8.9. Data Management ...................................................................................................19
8.10. Data Analysis ........................................................................................................19
8.10.1. Descriptive Analysis.................................................................................21
8.10.2. Multivariate Analysis................................................................................21
8.10.3. Cost Data ..................................................................................................22
8.10.4. Dichotomous Data ....................................................................................22
8.10.5. Other Continous Data ...............................................................................23

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8.10.6. Decomposition..........................................................................................23
8.11. Quality Control......................................................................................................23
8.12. Limitations of the Research Methods....................................................................23
8.12.1. Claims.......................................................................................................23
8.13. Other Aspects ........................................................................................................23
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................24
9.1. Patient Information and Consent.............................................................................24
9.2. Patient Withdrawal..................................................................................................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........24
12. REFERENCES ..................................................................................................................25
13. LIST OF TABLES.............................................................................................................25
14. LIST OF FIGURES ...........................................................................................................25
15. ANNEX 1. LIST OF STAND ALONE DOCUMENTS ...................................................26
16. ANNEX 2. LIST OF RA TREATMENTS........................................................................27
17. ANNEX 3. LIST OF OTHER MEDICATIONS ...............................................................29

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1. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse Event
AHRQ
Agency for Healthcare Research and Quality
ARRA
American Recovery and Reinvestment Act
CIRAS
Claims-based index for RA severity
CMS
Centers for Medicare & Medicaid Services
COB
Coordination of benefits
COPD
Chronic obstructive pulmonary disease
CPI
Consumer price index
CPT
Current Procedural Terminology
ED
Emergency department
ER
Emergency room
FDA
Food and Drug Administration
GLM
Generalized linear model
HCFA
Care Financing Administration
HCPCS
Healthcare Common Procedure Coding System
HIPAA
Health Insurance Portability and Accountability Act
ICD-9 CM
The International Classification of Diseases, 9th Revision, Clinical
Modification
IEC
Independent Ethics Committee
IRB
Institutional review board
ISPOR
International society for pharmacoeconomics and outcomes research
IV
Intravenous
MTX
Methotrexate
NB-DMARD
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
RA
Rheumatoid Arthritis
RAPID3
Routine assessment of patient index data
RX
Outpatient pharmacy
TNFi
Tumor-Necrosis Factor-alpha inhibitor
UB
Uniform Bill
US
United States

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2. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Title
Affiliation
Address
PharmD,
MS
, 
PhD
, PhD
 
, MD, 
PhD
3. ABSTRACT
Not applicable.
4. AMENDMENTS AND UPDATES
None.
5. MILESTONES
Milestone
Planned date
Start of data collection
1 May 2018
End of data collection
31 May 2018
Final study report
30 September 2018
6. RATIONALE AND BACKGROUND
Tofacitinib was approved 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. It may be used as
monotherapy or in combination with methotrexate (MTX) or other nonbiologic
disease-modifying antirheumatic drugs (NB-DMARDs).
Pfizer is currently conducting a phase 3b/4 study (A3921192) which was designed to 
evaluate the sustained efficacy and safety of tofacitinib modified release formulation 
(11 mg QD) after withdrawal of MTX versus tofacitinib modified release formulation plus 
continued MTX treatment in subjects with moderate to severe rheumatoid arthritis who are 
insufficiently responding to their stable dose of methotrexate treatment.  This retrospective 
claims analysis is designed to compare the effectiveness and treatment patterns among 
tofacitinb+MTX patients who withdraw MTX vs. continue MTX in a real world setting.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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7. RESEARCH OBJECTIVES
The primary and secondary objectives will be conducted among patients who are identified 
from the Truven Health MarketScan Research Database.
Primary Objective

Compare treatment patterns including dosing, concomitant medication use,
adherence, persistence, and switching among tofacitinb+MTX patients who withdraw 
MTX vs. persist with MTX or experience interrupted MTX.
Secondary Objectives
1. Explore the differences in demographic and clinical characteristics among 
tofacitinb+MTX patients who withdraw MTX vs. persist with MTX or experience 
interrupted MTX.
2. To compare RA-related costs among tofacitinb+MTX patients who withdraw MTX 
vs. persist with MTX or experience interrupted MTX.
3. Compare medication effectiveness among tofacitinb+MTX patients who withdraw 
MTX vs. persist with MTX or experience interrupted MTX.
4. Compare all-cause and RA-related health care utilization among tofacitinib+MTX 
patients who withdraw MTX vs. persist with MTX or experience interrupted MTX.
5. Compare all-cause healthcare costs among tofacitinb+MTX patients who withdraw 
MTX vs. persist with MTX or experience interrupted MTX.
8. RESEARCH METHODS
8.1. Study Design
To address the objectives, a retrospective cohort design will be employed to evaluate patient
characteristics, treatment patterns, medication effectiveness, and health care cost and
utilization in RA patients newly initiating tofacitinib in combination with oral MTX between 
January of 2014 and January 2017 utilizing the Truven Health MarketScan Research
Database, see Section 8.7 below.
8.2. Setting
This study will utilize the de-identified claims data in the Truven Health MarketScan
Research Database.

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8.2.1. Inclusion Criteria
This study will include individuals who are privately insured and with Medicare
Supplemental insurance paid for by their employers and initiating tofacitinib in combination 
with MTX for RA between 01 January 2014 and 31 January 2017. To be included in the 
final study sample, patients must meet the following inclusion criteria:
1. At least one claim for tofacitinib between 01 January 2014 and 31 January 2017 (the 
identification period).
a.
Medication index date. The index date will be the date of the first claim for 
tofacitinib during the identification period.
Note: Patients will have a variable length baseline of at least a year long. The
baseline period will be censored at January 1, 2012 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.
b. Tofacitinb initiation.  Patients must have a 2nd claim for tofacitinib within 60 days 
of the end of the days supplied from their index claim (at least two claims with no 
60 day gap).
c.
Oral MTX initiation.  Patients must have an initial prescription for oral MTX in 
the period between 30 days prior to index date and 30 days following index date 
followed by a 2nd prescription for oral MTX within 60 days of the end of the days 
supplied from their initial MTX claim (at least two claims/administrations with no 
60 day gap).
2. Presence of The International Classification of Diseases, 9th Revision, Clinical
Modification (ICD-9 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*.
3. At least 18 years old as of the index date.
8.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study:
1. Patients with claims for other conditions for which biologics are used during the 
one-year pre-index period or on the index date: ankylosing spondylitis, Crohn’s
disease, psoriasis, psoriatic arthritis, or ulcerative colitis will be excluded from the
study.

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Table 1.
Exclusionary Diagnoses
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 Rheumatoid 
Arthritis
714.3*
M08.*
2. Patients with evidence of the index medication during the one-year pre-index period
will be removed from the analysis.  Patients will be allowed to have been treated with
other biologics approved for RA (Tumor-Necrosis Factor-alpha inhibitors (TNFi) 
[adalimumab (Humira), etanercept (Enbrel), certolizumab pegol (Cimzia), golimumab 
(Simponi), infliximab (Remicade)] and non-TNFi’s with alternative mechanisms of 
action [abatacept (Orencia), and rituximab (Rituxan), anakinra (Kineret), tocilizumab 
(Actemra)]) during the one-year pre-index period.
3. Patients with 1 or more biologics on the index date will be removed from the study.
4. Patients with tofacitinib therapy prior to index.
5. Patients with 1 or more claims for injectable MTX (see Jcodes in Annex 2.B.) in 
combination with tofacitinib.
8.3. Cohort Assignment
Patients will be assigned to a study cohort based on MTX status following initiation of 
combination therapy with tofacitinib and MTX.  The “MTX discontinued” cohort will 
contain patients who experience a gap in MTX therapy of >60 days within 12 months 
post-index.  The “MTX interrupted” cohort will contain patients who experience a gap in 
MTX therapy of >60 days with 1 or more subsequent fills within 12 months post-index.  The 
“MTX persistent” cohort will contain patients with no gap >60 days within 12 months 
post-index.  If sample size is insufficient, the MTX “discontinued” and “MTX interrupted” 
cohorts may be combined.
8.4. Sample Subsets
The following sample subsets will be identified and included in the analysis of select
outcomes.

Commercial vs. Medicare Supplemental- Patients who meet all selection criteria
and have Medicare Supplemental insurance at index will be classified as such.

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
Number of prior Biologics: 0, 1, 2, 3+ at any time prior to index.

Pre-index MTX therapy: Treatment with MTX prior to index medication.
8.5. Period of Observation
All patients will be required to be continuously enrolled in the health plan for at least
24 months.  Patients will have a variable length 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, number of prior biologic therapies, and
years since first RA diagnosis, the entire variable length baseline period will be utilized.
Measures utilizing the variable length baseline are noted. All baseline periods will be
censored at January 1, 2012.  The twelve months following the index date will be used to
assess outcomes including treatment patterns, and health care costs, utilization and
medication effectiveness.
8.6. Variables
8.6.1. Patient Characteristics

Index month/year-The month and year of the patient’s index date will be identified.

Age-Age will be defined as of the index year.

Age groups-Patients will be assigned to one of the following age groups: 18–44,
45-64, and 65+.

Sex-sex will be captured from enrollment data; patients with undefined gender will be 
removed from the study sample.

Insurance type-Whether the patient was covered under a commercial or Medicare
Supplemental insurance plan will be captured.

Geographic region-The United States (U.S.) region in which the study patient is
enrolled in a health plan will be determined and reported and states will be 
categorized into five geographic regions: Northeast, North Central, South, West, 
Unknown.
8.6.2. Clinical Characteristics

Pre-index biologic use-The use of biologics during the pre-index period will be
identified. In addition, indicator variables will identify the specific biologic(s) used
during the pre-index period.  A count will be created to identify the number of
different biologics received during the baseline. These measures will be created
during the 12 month baseline and during the entire variable length baseline period.

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
Pre-index NB-DMARD use: The use of the 4 main NB- DMARDS (methotrexate,
sulfasalazine, hydroxychloroquine, and leflunomide), and the other NB-DMARDS
will be identified during the pre-index period. In addition, indicator variables will
identify the specific medications used during the pre-index period.  A count will be
created to identify the number of different NB-DMARDS received during the 
baseline. These measures will be created during the 12 month baseline and during the
entire variable length baseline period.

Pre-index Quan-Charlson comorbidity score-A comorbidity score will be
calculated based on the presence of diagnosis codes on medical claims in the
12-months pre-index period.1,2  The Quan-Charlson comorbidity score will also be
categorized into the following groups: zero, one to two, three to four, and five or 
more.

Comorbid conditions—General comorbid conditions will be defined using the
Clinical Classifications Software managed by the Agency for Healthcare Research
and Quality (AHRQ).3  This measure generates indicator variables for specific disease
conditions based on ICD-9-CM diagnoses.  The top 25 comorbid conditions identified
during the pre- and post-index period will be presented.

Pre-index claims based index of RA severity (CIRAS): The claims-based index for
RA severity will be implemented. CIRAS provides a single value of severity using the 
following 9 measures.
                                                
1 Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, Januel JM, Sundararajan V. Updating and
validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using
data from 6 countries. Am J Epidemiol. 2011;173(6):676-82.
2 Bayliss EA, Ellis JL, Shoup JA, Zeng C, McQuillan DB, Steiner JF. Association of patient-centered
outcomes with patient-reported and ICD-9-based morbidity measures. Ann Fam Med 2012;10(2):126-33.
3 Clinical Classification Software (CCS) for ICD-9-CM. Agency for Healthcare Research and Quality,
Rockville,MD.http://www.hcup-us.ahrq.gov/toolssoftware/ccs/ccs.jsp

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Measure4
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

Pre-index medications-The most common medications used during the 12-month
pre- and post-index periods will be identified. The most common 25 medications
received will be identified.

Opioid, non-steroidal anti-inflammatory drug (NSAID) use-The use of weak
and/or strong opioids and/or non-steroidal anti-inflammatory drug (NSAID) during
the 12-month pre- and 12-month post-index periods will be identified. The number of
pharmacy claims for opioids and/or NSAIDs and the number of days from the index
date to the first opioid and/or NSAIDs claim will be identified.
                                                
4 Number of platelet counts, chemistry panels, and rheumatologist visits are counted 1 per person per day.

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
Opioid, NSAID use while persistent. In addition to opioid/NSAID use during the
follow-up, use of opioids/NSAIDs while persistent and after persistence will be
identified in the 12-month follow-up period.

Corticosteroid use.  The use of oral corticosteroids during the 12-month pre- and
12-month post-index periods will be identified. In addition, the total
prednisone-equivalent dose of oral corticosteroids will be calculated.

Pre-index visit with a rheumatologist.  A 0/1 flag will be created to determine if the
patient had an ambulatory visits (office visit or outpatient visit) in which the physician
was a rheumatologist in the 90 days before or on the index date. A separate variable
will be created identifying the number of visits with a rheumatologist during the 
entire 12-month baseline.  A flag will also be created identifying the presence of a
rheumatologist visit in the entire variable length baseline and the number of visits in 
the variable length baseline.

Disease duration.  The number of days from the earliest claim with a diagnosis of
RA in the variable length baseline until the index date will be identified.
Disease
duration will only be created during the variable length baseline.

Pre-index Out-of-pocket expenses. The patient’s total all-cause and RA-related out
of pocket healthcare cost for healthcare services in the one year before the index date
and during the entire variable length baseline period will be calculated.

Comorbidities of interest. 0/1 flags will be created to identify the presence of the
following comorbidities during the 12-month baseline period.

Cardiovascular diseases;

Chronic obstructive pulmonary disease (COPD);

Asthma;

Kidney disease;

Diabetes;

Depression;

Anxiety;

Liver disease;

Sleep disorders;

Hypertension;

Hyperlipidemia.

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8.6.3. Treatment Patterns

Non-persistence. A 0/1 flag will be created to identify if the patient is not persistent
with tofacitinib before the end of the 12 month follow-up period.
Non-persistence will be identified based on a gap in treatment with the index
medication or switching to another biologic.
Among patients with 1 year of follow-up, persistence through the end of the 1 year
follow-up will be identified. Persistence will be identified based on the day supply
(or presumed day supply) and fill dates of claims for the index medication (see
Table 2 for a listing of presumed day supplies). Persistence with the index 
medication will be defined as not having a gap in therapy of at least 60 days between
fills/infusions.  For retail pharmacy (RX) claims the day supply will be utilized. For
Healthcare Common Procedure Coding System (HCPCS) claims a presumed day
supply derived from the product label will be utilized. A gap of at least 60 days
between the run-out date (service date + day supply-1) and the next service date will
be considered non-persistence. Patients with early refills will be allowed to
accumulate a stockpile of the index medication of up to 14 days for later use.

Post persistence treatment patterns. Patients who are not persistent for the entire
follow-up period will be classified into the following mutually exclusive categories
based on the first occurrence of non-persistence: switch immediately, discontinue
then restart, discontinue then switch, discontinue and never switch or restart.

Switch immediately. Patients will be classified as switching immediately if they
initiate a non-index biologic before a 60-day gap in treatment is observed for the
index medication.

Discontinue then restart.  Patients will be classified as discontinuing and then
restarting if there is a gap in the index therapy of at least 60 days and the first
medication observed after the gap is the index medication.

Discontinue then switch.  Patients will be classified as discontinuing and then
switching if there is a gap in the index therapy of at least 60 days and the first
medication observed after the gap is a biologic (including Tofacitinib) different 
from index medication.

Discontinue without switch or restart. Patients will be classified as
discontinuing without switch or restart if they have a gap in therapy of at least
60 days and there are no claims for either the index med or a different biologic for
the remainder of the follow-up period.

Switch any time. In addition to the 4 mutually exclusive treatment patterns, patients
with a switch medication any time during the 12-month follow-up period will be
identified.

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
Restart any time. In addition to the 4 mutually exclusive treatment patterns, patients
who have a claim for the index medication any time after they are considered
non-persistent with the index treatment (ie, including after switching) during the
12-month follow-up, will be identified.

Medication Possession Ratio (MPR): In addition to the adherence measure in the
medication effectiveness assessment (see Section 8.6.4), the MPR will be evaluated
for persistent patients as the total days supply between the first and including the last
prescription/administration divided by the time between the first through and
including last biologic prescription/administration days supply. Adherent patients
will be considered those with MPR ≥0.8. For MPR calculations, multiple 
prescriptions having 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. 
Also, the MPR will be capped at 1.0.

NB-DMARD adherence/addition. Adherence with MTX and addition of a
non-biologic DMARD other than MTX (sulfasalazine, hydroxychloroquine, 
leflunomide) during the 12 month follow-up will be identified.

MTX adherence.  A single measure of adherence (PDC) will be created using all 
claims for MTX during the 12-month follow-up period. Adherence will be
calculated as the total day supply divided by the number of days from the first
claim during the follow-up until the end of the follow-up.

NB-DMARD addition. Addition of a NB-DMARD will be evaluated.
8.6.4. Medication Effectiveness
Among patients with at least one year of follow up, medication effectiveness at one year after
the index date will be determined using the following six criteria.5,,6  For each of the
6 criteria, a 0/1 flag will be created. Patients who are effectively treated for each of the
6 criteria will be considered effectively treated. Patients who fail any of the 6 criteria are
therefore not effectively treated.
1. High adherence to index agent: a proportion of days covered (PDC) will be calculated
based on total days supply over the 1 year follow-up. The PDC will be calculated by
using the date of service and the day supply for each fill of the index medication. For 
patients that receive both 5mg and 11mg tofacitinb, both configurations will be treated 
interchangeably.  Patients with early refills will be allowed to stockpile medications up to
a maximum of 14 days total for later use.
                                                
5 Curtis, J.R., 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): p. R155.
6 Oladapo, et. al. Medication Effectiveness with the Use of Tumor Necrosis Factor Inhibitors Among Texas
Medicaid Patients Diagnosed with Rheumatoid Arthritis. Journal of Managed Care Pharmacy. 657 – 67. Vol. 20,
No. 7. July 2014

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2. No increase in dose for index medication compared to the starting dose. Dose escalation 
will be identified per the criteria listed in Table 2.
3. No switching from the index medication to a (different) biologic agent or tofacitinib. A 
switch will be defined as use of a different biologic or tofacitinib any time during the 
follow-up period.
4. No adding of a new non-biologic DMARD to the index therapy. Adding a new non-
biologic will be considered as having at least 1 claim for one of the 3 main:
1. NB-DMARDs during follow-up and not having a claim for the same NB-DMARD
during the baseline. Changing from 1 NB-DMARD at baseline to a different.
2. NB-DMARD at follow-up will be considered as adding a new NB-DMARD, ie, 
failing the algorithm.
5. Oral glucocorticoids.  Only National Drug Code (NDC) codes for oral glucocorticoids
will be included:
a.
For patients with no claims for oral glucocorticoid prescriptions in the six months
prior to the index date: cannot receive more than 30 days of oral glucocorticoids
between (index date +91) to (index date + 359).  30 days of oral glucocorticoids will 
be determined by summing up the day supply of all glucocorticoids claims with a fill
date between (index date +91) to (index date +359).
b. For patients with claims for oral glucocorticoids during the six months prior to the 
index date: No increase in oral glucocorticoid dose during months 6-12 after:
a.
Index compared to the 6 months before the index date. Increase in oral
glucocorticoids will be determined from the prednisone equivalent dose for all 
glucocorticoid claims filled during the respective time periods.
6. At most one parenteral or intra-articular glucocorticoid joint injection on unique days
after the patient had been on biologic treatment for more than three months between
(index date +91) to (index date +359).

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Table 2.
Adherence and Dose Escalation Criteria
Generic Name
Standard dosing schedule
(Presumed) day supply
Criteria for dose escalation for 
medication effectiveness
SC/oral only
tofacitinib
5 mg twice daily or 11 mg 
once daily
Day supply rounded to the
nearest 30 day period. 
Day supplies less than 
15 days will be rounded to 
30 days.
At least 1 claim in the follow-up period
with an average daily dose of at least 
15 mg/day for both 5 mg and 11 mg doses.

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8.6.5. Health Care Cost and Utilization
All cost and utilization measures will be identified in the 12-month pre-index period and the
12-month post-index period.  Claims occurring on the index date will be considered part of
the post-index period.  Baseline and follow-up costs and the change in 12-month costs from
baseline to follow-up will then be examined.  Cost measures will comprise the total amount
paid by the health plan and patient.

Health care resource utilization-Health care resource utilization will be calculated
for ambulatory visits (office and outpatient), emergency department (ED) visits, and 
inpatient admissions.

RA-related resource health care utilization-Health care resource utilization related
to RA will be calculated for ambulatory visits, emergency room (ER) visits, and
inpatient admissions Utilization will be defined as RA-related if the claim had a
diagnosis for RA in any position and/or is for the administration of a biologic or
NB-DMARD.

Health care costs-Health care costs will be computed as the combined health plan
and patient paid amounts. Costs will be calculated as total costs, pharmacy costs, and
medical costs, Medical costs will be further broken down into ambulatory costs,
emergency services costs, inpatient costs, and other costs. Costs will be adjusted
using the annual medical care component of the Consumer Price Index (CPI) to
reflect inflation between 2013 (the earliest start of the pre-index period) and 2015 (the
cost of claims occurring in 2016 will not be adjusted).7
Costs from other payers are of importance for older patients dually eligible for
commercial and Medicare coverage. Payments from Medicare (and other payers) will
be estimated based on coordination of benefits information obtained by the health
plan in its usual course of business. This study will incorporate the amounts 
estimated to be paid by other payers for a total paid or allowable amount.8

RA-related health care costs-CPI- and coordination of benefits (COB)-adjusted
RA-related health care costs will be calculated as total costs related to RA (treatment
and other medical claims with a diagnosis of RA). RA-related treatment costs will
include the cost of tofacitinib, biologic DMARDs, non-biologic DMARDs, and
administration of intravenous (IV) biologics (CPT = 96413 or 96415). Medical costs
will include all utilization with a diagnosis of RA and are also not treatment claims. 
Medical costs will comprise: inpatient costs, ambulatory costs, emergency services
costs, administration, and other costs.
                                                
7 US Department of Labor, Bureau of Labor Statistics. Consumer Price Index. Medical Care. Series ID:
CUUR0000SAM. Washington, DC: U.S. Dept. of Labor, Bureau of Labor Statistics. http://data.bls.gov/cgi-
bin/surveymost?cu
8 Frytak JF, Henk JH, et al. Health Services Utilization Among Alzheimer’s Patients: Evidence from
Managed Care. Alzheimer’s and Dementia. 2008; 4(5):361-67.

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
Monthly costs-Total all-cause and RA-related health care cost will be identified
during each month (30-day period) of the patient’s 12-month baseline and the
12-month follow-up period.
8.7. Data Sources
8.7.1. Truven
The Truven Health MarketScan Research Databases reflects the combined healthcare service 
use of individuals covered by Truven Health clients (including employers, health plans, and 
hospitals) nationwide in the US. Truven Health builds databases comprise the healthcare 
experience of the clients’ covered populations, as well as information about the populations 
themselves and the providers that serve them.  MarketScan Research Databases provide 
detailed cost, utilization, and outcomes data for healthcare services performed in both 
inpatient and outpatient settings.  In the claims databases, the medical services are linked to 
outpatient prescription drug claims and person-level enrollment data using unique enrollee 
identifiers.
The MarketScan Commercial Database contains the healthcare experience of privately 
insured individuals.  Coverage is provided under a variety of fee-for-service, fully capitated, 
and partially capitated health plans, including preferred provider organizations, point of 
service plans, indemnity plans, and health maintenance organizations.
Total Health
care cost
Medical cost
+
Pharmacy cost
Inpatient
ER
Outpatient hospital
Office visits
Home health care
Urgent care
Other medical services
Treatment cost
Total RA-related
Health care cost
Tofacitinib
biologic DMARDs
non-biologic DMARD
administration of IV biologics
+
Medical cost
Inpatient
ER
Outpatient hospital
Office visits
Home health care
Urgent care
Other medical services

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The data that make up the Commercial Database are stored in the following tables:

The Inpatient Admissions Table contains records that summarize information about a
hospital admission. Truven Health constructs this table after identifying all of the
service records associated with an admission (eg, the hospital claims, physician
claims, surgeon claims, and claims from independent labs). Similar information 
(such as payments for professional services) is then summed across the claims. The
admission record includes the principal procedure and diagnosis, Major Diagnostic 
Category, and Diagnosis-Related Group. It also includes all diagnoses and procedures 
(up to 14 each) found on the service records.

The Inpatient Services Table contains the individual claims that are summed to create 
the inpatient admission records. An admission identifier on both the Inpatient
Admissions and the Inpatient Services Tables identifies the claims that make up each
admission record.

The Outpatient Services Table comprises services that were rendered in a doctor’s
office, hospital outpatient facility, or other outpatient facility.

The Facility Header Table contains the header records from facility claims for
inpatient and outpatient services, including full diagnosis information.

The Outpatient Pharmaceutical Claims Table contains outpatient prescription drug
data from multiple sources, including mail-order data. Each record includes National
Drug Code (NDC), therapeutic class, ingredient cost, dispensing fee, copayment,
deductible, total gross payment, and other data elements.

The RED BOOKSupplement Table contains RED BOOK variables that enhance
prescription drug analyses.  These variables are linked to the Outpatient
Pharmaceutical Claims Table by NDC.

The Annual Enrollment Summary Table provides a single record per year for each
enrollee, showing enrollment start and end dates and, for some demographic 
variables, the most prevalent demographic and plan information; for other variables,
monthly values are included.

The Enrollment Detail Table provides a single record per month of enrollment for 
each enrollee, with detailed demographic information.

The Population Aggregate Table provides average counts of the covered (insured)
population to use for rate-supported analysis.  The counts are recorded by several
demographic variables (eg, age group, gender, region, etc.).
The MarketScan Medicare Supplemental Database contains the healthcare experience of 
individuals with Medicare supplemental insurance paid for by employers. Both the
Medicare-covered portion of payment (represented as Coordination of Benefits Amount, or

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COB) and the employer-paid portion are included in this database. The tables that make up
the Medicare Supplemental Database are the same as those that make up the Commercial
Database.
Claims are not included in the database until they have been adjudicated; there is a lag of 
approximately six months after the close of a calendar year or a quarter between services
provided and their inclusion in the Research Databases. However, the Early View Database 
has a 90-day lag that includes paid amounts for 100 percent of prescription drugs,
approximately 85 percent of physician office visits, and approximately 70 percent of hospital
claims. The MarketScan Early View Database includes all of the components found in the
standard MarketScan Commercial and Medicare Supplemental Databases. It includes
standardized inpatient, outpatient, pharmaceutical, and health-plan enrollment data. The
MarketScan Early View Database captures healthcare services incurred up to 90 days before
data release and includes only adjudicated claims. However, the medical component of care 
for some patients will not be complete, since some claims (particularly inpatient claims) take
longer to be adjudicated. Because this study is examining only comorbidities prior to and
treatments during or prior to tofacitinib initiation fully adjudicated claims are not required 
and all available data will be used including Commercial, Medicare Supplemental, and Early
View Databases.
8.8. Study Size
The sample size for this study is fixed by the duration of the observation window. No formal
sample size computation was performed.  All patients who meet inclusion/exclusion criteria
will be included in the analyses.
8.9. 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.
8.10. Data Analysis
Primary Objective

To compare treatment patterns including dosing, concomitant medication use, 
adherence, persistence and switching among tofacitinb+MTX patients who 
discontinue MTX vs. persist with MTX or experience interrupted MTX.
For this objective, treatment patterns will be summarized across the cohorts of interest.
Specific treatment patterns include non-persistence with the index medication, receipt of an
opioid, receipt of an NSAID, adherence with the index medication, adherence with MTX.

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Secondary Objectives

Explore the differences in demographic and clinical characteristics among 
tofacitinb+MTX patients who discontinue MTX vs. persist with MTX or
experience interrupted MTX.
For this objective descriptive analysis will be conducted.  The goal of this objective will be to
describe the respective populations and explore the presence of demographic differences
between the cohorts. Known demographic characteristics (eg, age, gender geographic
location, pre-index cost and utilization) will be summarized. In addition, other patient
characteristics (eg, most common comorbid diagnoses and most common medications
received) will be summarized.

To compare RA-related costs among tofacitinb+MTX patients who discontinue
MTX vs. persist with MTX or experience interrupted MTX.
For this objective both descriptive and multivariable analysis will be conducted. For the
descriptive analysis, 12-month RA-related cost measures will be presented per patient during
the baseline and follow-up periods.  The change in health care cost from baseline to follow-
up will be identified. In addition, total RA-related health care cost will be presented in each
of the months of the baseline and follow-up.  The mean cost in each month will be included 
on a figure demonstrating the trend in costs over time.  Multivariable analysis of cost will 
also be conducted using generalized linear models (see Section 8.10.3).

Compare medication effectiveness using a validated claims-based algorithm 
among tofacitinb+MTX patients who discontinue MTX vs. persist with MTX or 
experience interrupted MTX.
Medication effectiveness at one year will be examined by the medication cohorts of interest
using patients who have at least 1 year of follow-up. For this objective both descriptive
analysis and multivariable analysis will be used. Descriptive analysis will focus on
quantifying the percentage of patients who are effectively treated at one year.  Analysis of
this objective may also include multivariable analysis (eg, logistic regression).  Specifically,
the dependent variable will be effectively treated at one year (yes/no) and the independent 
variables will be study cohort, demographic characteristics, characteristics of interest, and
other characteristics identified from previous objectives (see Section 8.10.4).

Compare all-cause and RA-related health care utilization among 
tofacitinb+MTX patients who discontinue MTX vs. persist with MTX or
experience interrupted MTX.
For this objective descriptive analysis will be conducted. Utilization measures (flags and
12-month counts) will be presented per patient during the baseline and follow-up periods. In
addition, for counts the change from baseline to follow-up will be calculated.

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
Compare all-cause healthcare costs among tofacitinb+MTX patients who 
discontinue MTX vs. persist with MTX or experience interrupted MTX.
For this objective descriptive and multivariable analysis will be conducted. For the
descriptive analysis, 12-month cost measures will be presented per patient during the baseline 
and follow-up. The change in 12-month costs from the baseline to the follow-up will also be 
calculated. In addition, total all-cause cost will be presented in each of the months of the 
baseline and follow-up.
The mean cost in each month will be included on a figure 
demonstrating the trend in costs over time. Multivariable analysis of follow-up health care
cost will also be conducted using generalized linear models (see Section 8.10.3).

Evaluate the primary and secondary objectives in cohorts of interest.
All objectives will be evaluated for Commercial and Medicare Supplemental lives separately
as well as by Monotherapy vs. Combination regimens as identified in Section 8.10.2 and by
prior biologic experience (0, 1, 2, 3+ at any time prior to index).
8.10.1. Descriptive Analysis
All study variables, including pre- and post-index measures, will initially be analyzed
descriptively.  In general, numbers and percents 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.
Multivariable techniques (including effect decomposition) will be used when comparing 
outcomes and controlling for differences in patient characteristics between study cohorts.
8.10.2. Multivariate Analysis
To control for possible confounding of the relationship between the outcomes and
independent variable of interest, select objectives will be conducted utilizing multivariable 
methods as described above.
Final outcomes for multivariate analysis will be selected after review of descriptive results. 
Possible outcomes of interest include: total all-cause health care cost, total RA-related health 
care cost, cost of biologics/tofacitinib/administration/nb-DMARDS, medication effectiveness 
(yes vs. no).
For each model, specific predictors to be included will be determined based upon clinical 
rationale and statistical significance.  Variables listed in Section 8.6.1 and 8.6.2 will be 
considered for inclusion in the multivariable models. Additional variables identified 
throughout the course of the study will also be considered.  Following standard procedure, 

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regression diagnostics will be performed for each model to assess goodness of fit and 
violations of model assumptions (eg, multicollinearity, heteroskedasticity).  When there are 
violations of the model, programmers will note them and make appropriate corrections to the 
data (ie, typically through transformation of either the independent or dependent variables) or 
in the method of estimation.
8.10.3. Cost Data
Because health care costs are often skewed, estimated cost measures will be modeled using 
Manning and Mullahy's formulation.9  This method avoids potential difficulties introduced 
by transformation and retransformation of the dependent variable.10  Coefficients from a 
generalized linear model (GLM) are estimated cost ratios. Cost ratios, 95 percent confidence 
intervals, and p-values will be presented for each categorical covariate included in the model.  
For ease of interpretation and comparison with the bivariate results, the average cost will be 
predicted for each cohort and may also be predicted for pre-determined levels of other patient 
characteristics (eg, combination vs. monotherapy, gender).
If a significant number of patients have zero values for costs (eg, more than 5% in one of 
tofacitinb+MTX patients who withdraw MTX or continue MTX groups), estimated cost 
measures will be compared using Blough et al.’s formulation of the traditional two-part 
model (ie, one equation estimating the probability of any cost and a GLM with a gamma 
distribution and log link estimating the level of cost).11  This method avoids potential 
difficulties introduced by transformation and retransformation of the dependent variable.
Odds ratios, 95 percent confidence intervals, and p-values will be presented for each 
categorical covariate included in the logistic model estimating the probability of non-zero 
costs, if any. Cost ratios, 95 percent confidence intervals, and p-values will be presented for 
each categorical covariate included in the GLM model estimating the level on costs.  For 
continuous covariables of both models, estimates and their 95 percent confidence intervals, 
and p-values will be presented.
8.10.4. Dichotomous Data
For binary variables, the probability of achievement (eg, being effectively treated at one year)
will be modeled using logistic regression. For ease of interpretation, the results of logistic 
regression will be presented as odds ratios, 95 percent confidence intervals, and p-values for 
each categorical covariate included in the model, and for continuous covariables, estimates 
and their 95 percent confidence intervals, and p-values will be presented.
                                                
9 Manning WG, Mullahy J. Estimating log models: to transform or not to transform. J Health Econ. 2001
10 Manning WG. The logged dependent variable, heteroskedasticity, and the retransformation problem. J
Health Econ.1998;17(3):283-295.
11 Blough DK, Madden CW, Hornbrook MC. Modeling risk using generalized linear models. J Health
Econ. 1999;18(2):153–171.

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8.10.5. Other Continous Data
For continuous variables, mean values will be modeled using a normal model.  The results 
will be presented as mean differences, 95 percent confidence intervals, and p-values for each 
categorical covariate included in the model, and for continuous covariables, estimates and 
their 95 percent confidence intervals, and p-values will be presented.
8.10.6. Decomposition
Given that the sample size for this study will be relatively small and the comparator
populations will be noticeably different, implementing propensity score matching may
reduce the available sample below what is needed for a meaningful study. One possible
solution would be to implement a method known as decomposition [Blinder (1973), Oaxaca 
(1973)] Decomposition splits out the treatment effect into two parts, the effect of the actual 
treatment and the effect of the other differences between the treatment groups.
Presumably,
if the treatment groups were randomly assigned, then the effect of the treatment would be the 
entire effect and the effect of all other differences would be negligible.  However, since 
biologic treatment choice is not randomly assigned, the decomposition method would
determine how much of the treatment effect is due to the medication and how much is due to 
the difference in characteristics between the two tofacitinib cohorts (tofacitinb+MTX patients 
who withdraw MTX or continue MTX).
8.11. 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 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.
8.12. Limitations of the Research Methods
8.12.1. Claims
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. Second, the baseline period for
this study will be 12 months long.  Therefore, patients treated with a biologic in the baseline
can be considered to be continuing users of biologic therapy; however, patients with no
biologic 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
biologic users.
Effectiveness 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.
8.13. Other Aspects
Not applicable

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9. PROTECTION OF HUMAN SUBJECTS
9.1. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of patient personal data.
As this is a retrospective non-interventional study using fully anonymized secondary data, no 
additional informed consent is required.
9.2. Patient Withdrawal
Not applicable.
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 Good Practices for Outcomes Research issued by the International Society for
Pharmacoeconomics and Outcomes Research (ISPOR).
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE
REACTIONS
This study includes unstructured data (eg, narrative fields in the database) that will be
converted to structured (ie, coded) data solely by a computer using automated/algorithmic
methods and/or data that already exist as structured data in an electronic database. In these
data sources, 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 (ie, identifiable patient, identifiable reporter, a suspect product,
and event) are not available and adverse events are not reportable as individual Adverse
Event (AE) reports.
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.

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COMMUNICATION OF ISSUES
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 investigator 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.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures
taken by the investigator to protect the study patients against any immediate hazard, and of
any serious breaches of this non-interventional (NI) study protocol that the investigator
becomes aware of.
12. REFERENCES
None.
13. LIST OF TABLES
Table 1.
Exclusionary Diagnoses..............................................................................9
Table 2.
Adherence and Dose Escalation Criteria ..................................................15
14. LIST OF FIGURES
None.

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15. ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.

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16. ANNEX 2. LIST OF RA TREATMENTS
a. Biologics/JAK inhibitor
NDC codes will be refreshed based on latest data.
Generic
Name
Brand
Name
Route of
Administration
TNF or Non-
TNF
NDC
HCPCS
tofacitinib
Xeljanz
Oral
Non-TNF
00069100103
00069100101
00069100102
adalimumab
Humira
SC
TNF
00074937402
00074379902
00074433902
00074433906
00074433907
54569552400
54868482200
anakinra
Kineret
SC
Non-TNF
55513017701
55513017707
55513017728
66658023401
66658023407
66658023428
certolizumab
pegol
Cimzia
SC
TNF
50474070062
50474071079
50474071081
etanercept
Enbrel
SC
TNF
54868478200
58406044501
58406044504
54868544400
58406043501
58406043504
58406044501
58406044504
58406045501
58406045504
58406042534
58406042541
abatacept
Orencia
IV
Non-TNF
C9230
J0129
abatacept
Orencia
SC
Non-TNF
00003218811
00003218831
golimumab
Simponi
SC
TNF
57894007001
57894007002
57894007101
57894007102
golimumab
Aria
IV
TNF
J1602
tocilizumab
Actemra
IV
Non-TNF
C9264
J3262
tocilizumab
Actemra
SC
Non-TNF
50242013801
Infliximab
Infliximab-dyyb
Infliximab-abda
Remicade
Inflectra
Renflexis
IV
TNF
J1745
Q5102
rituximab
Rituxan
IV
Non-TNF
J9310

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b. Non-Biologic (Traditional) DMARDs
Generic Names
J-codes
NDC
Hydroxychloroquine
n/a
See attached Excel Sheet
Methotrexate
J8610, J9250, J9260
Leflunomide
n/a
Sulfasalazine
n/a
Other Medications:
Chloroquine
J0390
Proprietary codes (based on groupings 
of NDC codes by generic name) will
be used to identify these drugs from
pharmacy claims
Combos
n/a
Cyclosporine
J7502, J7515, J7516,
C9438, J7503, K0121,
K0122, K0418
Thalidomide
n/a
Azathioprine
J7500, J7501, C9436, 
K0119, K0120
Cyclophosphamide
J8530, J9070, J9080,
J9090, J9091, J9092,
J9093, J9094, J9095,
J9096, J9097, C9420,
C9421
Auranofin
n/a
Aurothioglucose
J2910
Gold Sodium Thiomalate
J1600
Penicillamine
n/a
Tacrolimus
J7507, J7525, C9006, 
J7508
Minocycline
J2265

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17. ANNEX 3. LIST OF OTHER MEDICATIONS
GLUCOCORTICOIDS^
betamethasone
J7624
Budesonide
cortisone
J0810
dexamethasone
J1094, J1095,
J1100, J8540,
Q0137,
Q0138,
S0173
Fludrocortisone
hydrocortisone
methylprednisolone
J1020, J1030,
J1040, J2920,
J2930, J7509
prednisolone
J1680, 
J2640,
J2650, 
prednisone
J1690, J7506,
K0125
triamcinolone
J3300, 
J3301,
J3302, 
NSAID
J1885
Opioids
^Proprietary codes (based on groupings of NDC codes by generic name) will
also be used to identify these drugs from pharmacy claims