Comparative Effectiveness of Tumor Necrosis Factor (TNF) Inhibitors and Tofacitinib, Overall, by Line of Therapy and by Combination Therapy
Conditions: Arthritis Rheumatoid
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study Information
Title
Comparative Effectiveness of Tumor 
Necrosis Factor (TNF) inhibitors and 
Tofacitinib, overall, by line of therapy and 
by combination therapy
Protocol Number
A3921389
Protocol Version Identifier
2.0
Date
18 April 2022
Active Substance
L04AA29
Medicinal Product
Xeljanz (tofacitinib immediate release (IR)
and extended release (XR))
Research Question and Objectives
The objectives of this study are as follows:
1. To compare the effectiveness of 
tofacitinib and TNFs at 6 months and 
12 months, overall and stratified by
mono- and combination therapy.
2. To investigate the association 
between line of tofacitinib therapy 
and response at 6 and 12 months.
Author
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................2
2. LIST OF ABBREVIATIONS................................................................................................4
4. ABSTRACT...........................................................................................................................7
5. AMENDMENTS AND UPDATES.......................................................................................8
6. MILESTONES.......................................................................................................................9
7. RATIONALE AND BACKGROUND..................................................................................9
8. RESEARCH QUESTION AND OBJECTIVES ...................................................................9
9. RESEARCH METHODS ....................................................................................................10
9.1. Study Design ...........................................................................................................10
9.2. Setting......................................................................................................................10
9.2.1. Inclusion Criteria ........................................................................................10
9.2.2. Exclusion Criteria.......................................................................................11
9.3. Variables..................................................................................................................11
9.4. Data Sources............................................................................................................12
9.5. Study Size................................................................................................................13
9.6. Data Management ...................................................................................................13
9.6.1. Record Retention ........................................................................................13
9.7. Data Analysis ..........................................................................................................14
9.8. Quality Control........................................................................................................14
9.9. Limitations of the Research Methods......................................................................15
9.10. Other Aspects ........................................................................................................15
10. PROTECTION OF HUMAN SUBJECTS ........................................................................15
10.1. Patient Information................................................................................................15
10.2. Patient Consent......................................................................................................15
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............15
10.4. Ethical Conduct of the Study ................................................................................15
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................16
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........16
13. REFERENCES ..................................................................................................................17
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14. LIST OF TABLES.............................................................................................................18
15. LIST OF FIGURES ...........................................................................................................18
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................18
ANNEX 2. ADDITIONAL INFORMATION.........................................................................18

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
ACR
American College of Rheumatology
AE
Adverse Event
BMI
Body Mass Index
CABG
Coronary Artery Bypass Grafting
CCP
Cyclic Citrullinated Peptide
CDAI
Clinical Disease Activity Index
CHF
Congestive Heart Failure
COPD
Chronic Obstructive Pulmonary Disease
CRP
C-reactive Protein
csDMARD
Conventional Synthetic Disease Modifying 
Antirheumatic Drug
CV
Cardiovascular
DAS
Disease Activity Score
DMARD
Disease Modifying Antirheumatic Drug
ESR
Erythrocyte Sedimentation Rate
EQ-5D
European Quality of Life-5 Dimensions
FDA
Food and Drug Administration
HAQ
Health Assessment Questionnaire
HEOR
Health Economics and Outcomes Research
ID
Identification
IEC
Independent ethics committee
IL
Interleukin 
ILD
Interstitial Lung Disease
IR
Immediate Release
IRB
Institutional Review Board
JAK
Janus Kinase
mACR
Modified American College of Rheumatology 
MD
Doctor of Medicine
mHAQ
Modified Health Assessment Questionnaire
MI
Myocardial Infarction
MOA
Mechanism of Action
MTX
Methotrexate
NI
Non-interventional 
NSAID
Nonsteroidal Anti-inflammatory Drug
PASS
Post Authorization Safety Study
PCI
Percutaneous Coronary Intervention
RA
Rheumatoid Arthritis
SAP
Statistical Analysis Plan
SD
Standard Deviation
TIA
Transient Ischemic Attack

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Abbreviation
Definition
TNF
Tumor Necrosis Factor
US
United States
VAS
Visual Analogue Scale
XR
Extended Release

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4. ABSTRACT
Not applicable.

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5. AMENDMENTS AND UPDATES
Amendment 
number
Date
Protocol 
section(s) 
changed 
Summary of amendment(s)
Reason
1 administrative
18 April
2022
6 Milestones
Milestones were updated.
The planned milestones were 
adjusted to align with information 
in sponsor’s internal systems. 

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6. MILESTONES
Milestone
Planned date
Start of data collection 
31 January 2021
End of data collection
30 November 2021
Final study report
30 October 2022
7. RATIONALE AND BACKGROUND
Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease with an estimated
prevalence of 0.5-1.0% and a mean annual incidence of 0.02-0.05% within Western
populations.1 RA is characterized by inflammation, joint destruction, and progressive 
disability. Joint destruction is frequently irreversible resulting in significant cumulative 
morbidity. Patients experience a broad range of co-morbidities. These patients are also 
treated with multiple classes of agents, including nonsteroidal anti-inflammatory drugs 
(NSAIDs), glucocorticoids, and disease modifying antirheumatic drugs (csDMARDs)
including biologicals, each of which carry significant risks as well as benefits.
Tofacitinib is the first oral janus kinase (JAK) inhibitor to show clinical efficacy in the 
management of RA. Many of the cytokines that are dysregulated in RA signal through 
JAKs.2,3,4 Tofacitinib reduces the production of proinflammatory mediators5 by inhibiting the 
signaling of multiple cytokines important in the pathogenesis of RA. Unlike biological 
therapies, such as tumor necrosis factor (TNF) inhibitors and anti-interleukin (IL)-6 receptor 
monoclonal antibodies that markedly inhibit one cytokine pathway over an extended period 
of time, JAK inhibition by tofacitinib results in a pattern of partial and reversible inhibition 
of the intracellular effects from several inflammatory cytokines.
This study will help demonstrate if there has been a shift in the treatment landscape between 
2016 (time of the last Corrona registry analysis of this type) and 2020, in regards to 
tofacitinib use in earlier lines of therapy and use as monotherapy. We hope to gain a more 
current understanding of comparative effectiveness of the two mechanisms of action (MOA)
in clinical practice.
8. RESEARCH QUESTION AND OBJECTIVES
There are two primary objectives for this study:
1. To compare the effectiveness of tofacitinib and TNFs at 6 months and 12 months, 
overall and stratified by mono- and combination therapy.
2. To investigate the association between line of tofacitinib therapy and response at 
6 and 12 months.

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9. RESEARCH METHODS 
9.1. Study Design
To meet the study objectives, an observational retrospective cohort study will be conducted 
using patients enrolled in the Corrona RA Registry initiating tofacitinib on or after November 
2012. Patients receiving tofacitinib or TNF after failing a csDMARD (2nd-4th line patients) 
will be included to assess the comparative effectiveness of tofacitinib and TNF (stratified by 
monotherapy and combination therapy) as well as the impact of line of therapy on the 
effectiveness of tofacitinib.  
For further details, please refer to the detailed Statistical Analysis Plan (SAP) included as a 
stand alone document. 
9.2. Setting
The Corrona RA Registry is a prospective, multicenter, observational disease-based registry 
launched in 2001. This registry contains clinical data (eg, disease activity scores, laboratory 
results, comorbidities, imaging results, patient-reported outcomes data, etc.) that is not
available in claims databases. The current Corrona dataset includes 189 private and academic 
active clinical sites with over 817 providers throughout 42 states in the US. This registry 
collects data from both the providers and the patients at the time of a regular office visit. 
Corrona has enrolled over 54,000 patients with RA. The collection of data from Corrona 
represents over 195,750 patient years of data.
To be included in the Corrona RA Registry, patients must be at least 18 years of age and 
have a diagnosis of RA by a rheumatologist. Patients are excluded from the registry if they 
are unable or unwilling to provide informed consent. The inclusion/exclusion criteria for this 
particular analysis are described in Sections 9.2.1 and 9.2.2.
9.2.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. RA patients in Corrona initiating tofacitinib OR a TNF biologic (adalimumab, 
etanercept, infliximab, golimumab, certolizumab pegol) after 06 November 
2012 (market approval of Tofacitinib) during follow-up in Corrona with no prior use 
of tofacitinib. Only the patient’s first initiation after 06 November 2012 will be 
included in the analysis.
2. Have a 6 and/or 12-month follow-up visit (with +/-2 month window).
3. Have Clinical Disease Activity Index (CDAI) measures at baseline and at the 
follow-up visit.

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9.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study:
1. Patients who have not failed methotrexate (MTX) or another csDMARD (ie, 1st line
initiators).
9.3. Variables
Patient characteristics at baseline:

Gender, age, race, and ethnicity.

Duration of RA (Age at onset).

Comorbidity history:

Cardiovascular disease: Myocardial Infarction (MI), stroke, Transient Ischemic 
Attack (TIA), acute coronary syndrome, coronary artery disease, congestive heart 
failure (CHF), revascularization procedure including percutaneous coronary 
intervention (PCI), coronary artery bypass grafting (CABG) or coronary artery 
stents, ventricular arrhythmia, cardiac arrest, unstable angina, other cardiovascular 
(CV) events, carotid artery disease;

Hypertension;

Chronic Obstructive Pulmonary Disease (COPD);

Asthma;

Interstitial Lung Disease (ILD)/Pulmonary Fibrosis;

Diabetes mellitus;

Serious infections;

Cancer: lung cancer, breast cancer, lymphoma, skin cancer (melanoma, basal, 
squamous), and other cancer;

Thromboembolic events: deep vein thrombosis, peripheral arterial 
thromboembolic and pulmonary embolism.

C-reactive Protein (CRP).

Erythrocyte Sedimentation Rate (ESR).

Serum positive (Rheumatoid factor/Cyclic Citrullinated Peptide (CCP)).

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
Smoking status.

Work status.

Height, weight, and body mass index (BMI).

Insurance (patient reported).

Prednisone use.
Disease activity measures:

Physician reported:

CDAI;

MD global assessment;

Tender and swollen joint count (28);

Disease Activity Score (DAS) 28;

Modified American College of Rheumatology (mACR) 20/50/70.

Patient reported:

Health Assessment Questionnaire (HAQ);

mHAQ;

Patient global assessment;

Patient pain VAS;

Patient fatigue VAS;

Morning stiffness.
9.4. Data Sources
Patients are enrolled in the Corrona RA Registry during regularly-scheduled office visits. 
Upon enrollment, providers complete a set of Enrollment Questionnaires, including a 28 joint 
count on RA patients. Patients also complete an Enrollment Questionnaire, which captures 
several data elements, including the Health Assessment Questionnaire (HAQ) and the 
European Quality of Life-5 Dimensions (EQ-5D). Both patient and provider reported disease
activity measures obtained at each visit are captured in Corrona; this includes tender and
swollen joint counts (28 joint counts), patient and physician global disease assessment,

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patient pain assessment and HAQ scores. Providers and patients complete Follow-Up
Questionnaires approximately every six months. During the course of a regularly-scheduled 
office visit, the provider performs assessments as mandated on the Corrona Provider
Questionnaires with recording of pertinent data. Results from certain laboratory tests are 
included, but not mandated. Likewise, during regularly-scheduled office visits, patients are 
asked to complete Questionnaires designed to capture information ranging from their general 
demographics and experience with prescription drug use to an overall global assessment of 
their disease. Early Follow-Up visits occur and questionnaires are completed whenever a 
registry patient is being prescribed or receiving a first dose of a new (different) eligible 
medication at a routine office visit. Eligible medications are biologics, biosimilars, and JAK 
inhibitors Food and Drug Administration (FDA) approved for the treatment of RA. The next 
regularly scheduled visit is calculated from the previous visit. Data are collected on patients 
for as long as they consent to remain in the study.
9.5. Study Size
We used significance level of 0.05 (p=0.05), 80% power (80% rejecting the null hypothesis), 
and two independent sample equal-variance t-test for power calculation. The null hypothesis 
is no difference in mean of CDAI measure between treatment groups. 
Previous study using Corrona RA registry data shown standard deviation (SD) is about 
14 which will be used to estimate the sample size. Using software, it is estimated that 
342 subjects would be needed in each of the treatment groups in order to detect a statistically 
significant difference in mean CDAI of 3 between the two groups. Increasing the mean of 
CDAI difference to 6, would require 87 patients in each group.  
Current feasibility within the registry is 1,383 tofacitinib patients (588 monotherapy patients 
and 795 combination patients) so the necessary sample size has been achieved.
9.6. Data Management 
All statistical analyses will be performed using STATA Version 15.1 (StataCorp, LLC, 
College Station, TX). All analyses will be carried out under the direction of Dr. Ying Shan of 
Corrona.  
9.6.1. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, 
Corrona agrees to keep all study-related records, including safety reporting forms, source
documents, detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports). The records should 
be retained by Corrona according to local regulations or as specified in the vendor contract,
whichever is longer. Corrona must ensure that the records continue to be stored securely for 
so long as they are retained.

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If Corrona becomes unable for any reason to continue to retain study records for the required 
period, Pfizer should be prospectively notified. The study records must be transferred to a 
designee acceptable to Pfizer.
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless Corrona and Pfizer have expressly agreed to a different period of retention 
via a separate written agreement. Records must be retained for longer than 15 years if 
required by applicable local regulations. 
Corrona must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met.
9.7. Data Analysis 
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be dated, filed and maintained 
by the sponsor. The SAP may modify the plans outlined in the protocol; any major 
modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment.
9.8. Quality Control
Corrona or its designee monitors the conduct of the registry at each investigative site. 
Monitoring is primarily conducted remotely. Onsite monitoring visits are conducted once 
every three years, as needed, or as requested. A review of registry records including, but not 
limited to, the informed consent forms, Questionnaires, original source documents such as 
supporting medical records and office notes, subject study files, and any other registry 
documentation is conducted in accordance with applicable regulatory guidelines and the 
protocol. Corrona and its designees are required to maintain the confidentiality of all subjects 
during and after an on-site monitoring visit. 
Quality control checks are built into the on-screen data entry systems in an attempt to reduce 
queries and provide immediate feedback to the investigator regarding inadvertent omissions
and out of range or noncompliant values. Changes made at any time are recorded in an audit 
trail that includes the date, time, and electronic identification (ID) of the person making the 
change.
Corrona will address and resolve discrepancies by requesting clarifications and/or missing 
data from the investigator as needed. Each investigator is expected to designate a point of 
contact to address such inquiries and to promptly address and resolve issues. Representatives 
or designees from Corrona reserve the right to perform random or systematic audits of 
Corrona Questionnaires at an investigator’s site in order to assess the accuracy of the 
reported data compared to the information contained in the original medical records.

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9.9. Limitations of the Research Methods
The Corrona RA Registry includes a sample of adults with RA that are not necessarily 
representative of all adults with RA in the US. In particular, these are RA patients with 
clinical visits with rheumatologists. Patients are recruited by rheumatologists who are
required to indicate diagnosis upon enrollment of the patient into the Corrona RA Registry. 
In addition, history of medication use prior to enrollment is derived from what is reported by 
patients and their current rheumatologist within the registry. Since registry reporting is not 
based on a fixed visit schedule, exact timing of visits to fit 6, 12, 24, or 36 months of post 
index data is not available for all patients so windows of time are used to determine eligible
visits. The “cause” of visits is not captured, although the assumption can likely be made that 
the rheumatologist visit is “RA related.” The registry captures provider reported prescribing; 
there are no measures of patient adherence.
As this is real world study, missing data could be expected for demographic characteristics 
(eg, age, etc.); however, the number of patients with missing data is expected to be very
small. With multiple time points, some visits may have missing CDAI 
9.10. Other Aspects
Not applicable.
10. PROTECTION OF HUMAN SUBJECTS
10.1. Patient Information 
This study involves data that exist in anonymized structured format and contain no patient 
personal information.
10.2. Patient Consent
As this study involves anonymized structured data, which according to applicable legal 
requirements do not contain data subject to privacy laws, obtaining informed consent from 
patients by Pfizer is not required.
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents (eg, informed consent forms if applicable) from the relevant IRBs/IECs. 
All correspondence with the IRB/IEC must be retained. Copies of IRB/IEC approvals must
be forwarded to Pfizer.
10.4. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Good Practices for Outcomes Research issued by the International Society for
Pharmacoeconomics and Outcomes Research (ISPOR).
CCI

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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS
This study involves data that exist as structured data by the time of study start. In these data 
sources, individual patient data are not retrieved or validated, and it is not possible to link 
(ie, identify a potential association between) a particular product and medical event for any 
individual. Thus, the minimum criteria for reporting an adverse event (AE) (ie, identifiable 
patient, identifiable reporter, a suspect product, and event) cannot be met.  
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
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 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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13. REFERENCES
1.
Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev
2005;4(3):130-6.
2.
Walker JG, and Smith MD. The Jak-STAT pathway in rheumatoid arthritis. 
J Rheumatol, 2005;32(9):1650-3.
3.
McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev
Immunol 2007; 7(6):429-42.
4.
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011;
365(23):2205-19.
5.
Meyer DM, Jesson MI, Li XO, et al. Anti-inflammatory activity and neutrophil
reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced
arthritis. J Inflamm 2010; 7:41.

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14. LIST OF TABLES 
None. 
15. LIST OF FIGURES
None. 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
Number
Date
Title
1
09 September
2020
Comparative Effectiveness of TNFs and tofacitinib, overall and by 
combination therapy
2
09 September 
2020
Comparative Effectiveness of Tofacitinib by Line of Therapy
ANNEX 2. ADDITIONAL INFORMATION
Not Applicable.

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