NON-INTERVENTIONAL STUDY TO REVIEW THE CHANGES OF DEPRESSION AFTER FIRST-YEAR OF TOFACITINIB TREATMENT IN RHEUMATOID ARTHRITIS (XELJANZ (Registered))
Conditions: Rheumatoid Arthritis
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
PASS Information
Title
NON-INTERVENTIONAL STUDY TO 
REVIEW THE CHANGES OF 
DEPRESSION AFTER FIRST-YEAR OF 
TOFACITINIB TREATMENT IN 
RHEUMATOID ARTHRITIS (XELJANZ®)
Protocol number
A3921330
Protocol version identifier
Version 2.0
Date 
18 June 2021 
EU Post Authorization Study (PAS) 
register number
EUPAS40263
Active substance
L04AA29 tofacitinib
Medicinal product
Xeljanz®
Product reference
EU/1/17/1178/003
SUKL code 0222098 
Procedure number
N/A
Marketing Authorization Holder(s) 
(MAH)
Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium
Joint PASS
No
Research question and objectives
The primary objective of this study is to 
describe and evaluate the changes of 
depression level within 12 months from the 
start of tofacitinib therapy in patients with 
RA and at least minimal level of depression.
The secondary objectives of this study are to 
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describe and evaluate the level and changes 
of pain, anxiety, and insomnia in patients 
with rheumatoid arthritis (RA) and at least 
minimal level of depression. Additionally, it 
will describe the safety and effectiveness of 
tofacitinib for the treatment of RA.
Country of study
Czech Republic
Author
, PharmD.
, M.D., Ph.D.
Marketing Authorization Holder(s)
Marketing Authorization Holder(s)
Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium
MAH contact person
, PharmD
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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PPD
PPD
PPD

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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................3
2. LIST OF ABBREVIATIONS................................................................................................5
3. RESPONSIBLE PARTIES....................................................................................................7
4. ABSTRACT...........................................................................................................................8
5. AMENDMENTS AND UPDATES.......................................................................................9
6. MILESTONES.....................................................................................................................12
7. RATIONALE AND BACKGROUND................................................................................12
8. RESEARCH QUESTION AND OBJECTIVES .................................................................15
8.1. Endpoints.................................................................................................................15
8.1.1. Primary Endpoint........................................................................................15
8.1.2. Secondary Endpoints ..................................................................................15
9. RESEARCH METHODS ....................................................................................................16
9.1. Study Design ...........................................................................................................16
9.2. Setting......................................................................................................................17
9.2.1. Inclusion Criteria ........................................................................................19
9.2.2. Exclusion Criteria.......................................................................................19
9.3. Variables..................................................................................................................19
9.4. Data Sources............................................................................................................21
9.4.1. Study Procedures ........................................................................................21
9.4.2. Assessments – Treatment/Medication........................................................24
9.4.3. Assessments – Efficacy ..............................................................................25
9.4.4. Assessments – Safety..................................................................................26
9.5. Study Size................................................................................................................26
9.6. Data Management ...................................................................................................27
9.6.1. Electronic Case Report Forms (eCRFs) .....................................................28
9.6.2. Record Retention ........................................................................................28
9.7. Data Analysis ..........................................................................................................29
9.7.1. Analysis Populations ..................................................................................29
9.7.2. Efficacy Analysis........................................................................................29
9.7.3. Safety Analysis ...........................................................................................31
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9.7.4. Interim Analysis..........................................................................................31
9.8. Quality Control........................................................................................................31
9.9. Limitations of the Research Methods......................................................................31
9.10. Other Aspects ........................................................................................................32
10. PROTECTION OF HUMAN SUBJECTS ........................................................................33
10.1. Patient Information................................................................................................33
10.2. Patient Consent......................................................................................................33
10.3. Patient Withdrawal................................................................................................34
10.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............34
10.5. Ethical Conduct of the Study ................................................................................34
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................35
11.1. Requirements.........................................................................................................35
11.1.1. Reporting Period.......................................................................................36
11.1.2. Causality Assessment ...............................................................................37
11.1.3. Definition of Safety Events ......................................................................37
11.1.4. Scenarios Necessitating Reporting to Pfizer Safety Within 24 Hours .....40
11.2. Single Reference Safety Document.......................................................................43
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........43
13. REFERENCES ..................................................................................................................44
14. LIST OF TABLES.............................................................................................................48
15. LIST OF FIGURES ...........................................................................................................48
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................48
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................48
ANNEX 3. ADDITIONAL INFORMATION.........................................................................48
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2. LIST OF ABBREVIATIONS
Table 1. List of Abbreviations
Abbreviation
Definition
ACR
American Colleague of Rheumatology
AE
Adverse Event
AEM
Adverse event monitoring
ALT
Alanine transaminase
AST
Aspartate transaminase
bDMARD
Biologic Disease Modifying Anti Rheumatic Drug
csDMARD
Conventional Synthetic Disease Modifying Anti 
Rheumatic Drug
CIOMS
Council for International Organizations of Medical 
Sciences
CRO
Contract Research Organization
CRP
C-reactive Protein
CUDOS
Clinically Useful Depression Outcome Scale
CUXOS
Clinically Useful Anxiety Outcome Scale
CYP
Cytochrome P450
DAS
Disease Activity Score
DCT
Data Collection Tools
DMARD
Disease Modifying Antirheumatic Drug
eCRF
electronic Case Report Form
EDP
Exposure during pregnancy
EMA
European Medicines Agency
ENCePP
European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance
EQ-5D-3L
EuroQol five dimensions three level
ESR
Erythrocyte sedimentation rate
EULAR
European League Against Rheumatism
GPP
Good Pharmacoepidemiology Practices
IEC
Independent Ethics Committee
IFN
Interferon
IL
Interleukin
INR
International normalized ratio
IRB
Institutional Review Board
ISPE
International Society for Pharmacoepidemiology
JAK
Janus kinase
JSEQ
Jenkins Sleep Evaluation Questionnaire 
LDA
Low Disease Activity
LFT
Liver function test
LSLV
Last subject, last visit
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Abbreviation
Definition
MAH
Marketing Authorization Holder
MAPK
Mitogen-activated protein kinase
MTX
Methotrexate
NI
Non-interventional
NIS
Non-Interventional Study
NSAID
Nonsteroidal Anti-Inflammatory Drugs
PASS
Post-authorization safety study
PRO
Patient reported outcome
PsA
Psoriatic arthritis
PT
Prothrombin time
PtGA
Patient’s Global Assessment of Health
PY
Patient years
RA
Rheumatoid arthritis
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SAPK
Stress-activated protein kinases
SJC
Swollen joint count
SmPC
Summary of Product Characteristics
STAT
Signal Transducer and Activator of Transcription 
proteins
SUKL
State Institute for Drug Control
TB
Tuberculosis
TJC
Tender joint count
TNF
Tumor necrosis factor
tsDMARD
Targeted synthetic disease-modifying anti-rheumatic 
drug
ULN
Upper limit of normal
USA
United States of America
VAS
Visual Analogue Scale
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4. ABSTRACT
In Annex 1 as a standalone document.
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5. AMENDMENTS AND UPDATES
Table 4. Amendments and Updates
Amendment 
number
Date
Protocol section(s) 
changed 
Summary of amendment(s)
Reason
1 substantial
18
June
2021
6 Milestones
Milestones were updated.
The milestones were adjusted to 
reflect the current recruitment rate. 
7 Rational and background Updated details of previous 
studies to align with current 
knowledge. 
Updated information. 
8.1.2 Secondary endpoint
Added safety endpoints.
To align with PASS requirements.
9.2 Setting
Changed the definition of loss to 
follow-up.
Enrollment months increased 
from 24 to 48
Clarified CUDOS score
Updated study visit attendance 
and added further criteria for 
clarity
The definition was previously 
wrong and was now corrected. 
9.2.2 Exclusion criteria
Deleted criteria.
Patients will be prescribed study 
drug according to standard of care;
therefore, some exclusion criteria 
were not required. 
9.3 Variables
Safety variables added.
The study meets criteria for being 
considered a PASS.
9.3 Variables
9.4.1 Study procedures 
9.4.1.2 Schedule of 
activities
Assessment of satisfaction with 
treatment will not be collected.
Removed variable ‘current RA 
treatment with tofacitinib’ and 
eCRF where it was no longer 
applicable
Will not be relevant to the final 
data analysis.
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Amendment 
number
Date
Protocol section(s) 
changed 
Summary of amendment(s)
Reason
9.3 Variables
9.4.1 Study procedures 
9.4.1.2 Schedule of 
activities
Physician global assessment will 
not be collected.
Will not be relevant to the final 
data analysis.
9.4 Data source
Added details about data flow in 
CRF. 
For clarification. 
9.4.3 Assessments –
Efficacy
Updated patient assessments. 
Clarification that CRP and ESR 
are not required per protocol and 
that disease activity indicator
(DAS 28) is evaluated as standard 
of care assessment. 
For clarification. 
9.4.4.1 Safety Criteria
Section was updated to contain 
more clarity. 
For clarification. 
9.6 Data Management 
Process of Patient reported 
outcome (PRO) completion and 
processing updated. 
For clarification. 
9.7.2 Efficacy analysis
Deleted details about EQ-5D-3L 
PRO.
These details will be documented in 
the SAP and are not required in the 
protocol. 
9.7.4 Interim analysis
Details regarding Statistical 
Analysis Plan were added.
Clarification where methodology of 
statistical analysis can be found. 
9.8 Quality control
Data review and data cleaning 
processes were added. 
Details on how data will be 
reviewed and cleaned were missing 
and were added. 
10.5 Ethical conduct of the 
study
Not applicable requirements were 
deleted and only local and study 
specific requirements were kept. 
This section was adapted to the 
study type and the location. Only 
applicable requirements were kept 
in this paragraph. 
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Amendment 
number
Date
Protocol section(s) 
changed 
Summary of amendment(s)
Reason
11.1 Safety requirements
(Table 9)
Added the list of AEs which have 
to be reported to the sponsor. 
These changes were made to align 
with the processes of the sponsor. 
Section 12
Updated submission timeline to 
SUKL from 150 days to 
12 months.
To align with internal timelines. 
Throughout the protocol
Change the time window for the 
12 months visit from ±30 days to 
±45 days for V3. 
Minor editorial updates
throughout
This change was decided to allow 
more flexibility. 
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6. MILESTONES
Table 5. Milestones
Milestone
Planned date
Start of data collection 
01 June 2019
End of data collection
22 Jan 2024
Registration in the EU PAS register
30 April 2021
Final study report
21 December 2024
7. RATIONALE AND BACKGROUND
Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by joint 
inflammation and destruction, progressive disability and adverse psychological effects.1
Apart from the risk of suffering from musculoskeletal complications directly related to their 
rheumatic disease, RA patients are also at risk of suffering from other diseases called 
co-morbidities. Such risk seems to be higher in RA than in the general population in 
particular with regard to some particular diseases (eg, cardiovascular and infectious diseases,
osteoporosis, and some cancers).2
Such increased risk in comparison to the general population can be explained by both the 
treatment of RA (eg, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs)) and 
also by the systemic inflammation observed in RA.
RA represents significant health and socioeconomic burdens for the individual patient and 
society. There is currently no cure for RA. The purpose of treatment is to control disease 
activity, alleviate signs and symptoms, maintain physical function, optimize quality of life, 
reduce the rate of joint damage, and, if possible, induce complete remission.
Tofacitinib is an oral Janus kinase (JAK) inhibitor that targets inflammation by reducing 
pro-inflammatory cytokine signaling and production.3 Tofacitinib acts inside the cell by 
preferentially inhibiting signaling by cytokine receptors associated with JAK1 or JAK3.4
Inhibition of JAK1 and JAK3 by tofacitinib blocks signaling through the common gamma 
chain containing receptors for several cytokines, including interleukin (IL) -2, -4, -7, -9, -15, 
and -21. These cytokines are integral to lymphocyte activation, development, homeostasis, 
proliferation, and function; therefore, inhibition of their signaling may result in modulation of 
multiple aspects of the immune response. In addition, inhibition of JAK1 will result in 
attenuation of signaling by additional pro-inflammatory cytokines, such as IL-6 and 
interferon (IFN) γ.5,6 At higher exposures, inhibition of erythropoietin, prolactin, and other 
hormones can occur via inhibition of JAK2 signaling.
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The efficacy and safety evaluation of tofacitinib for the treatment of RA is based on a 
comprehensive clinical development program including six randomized, double-blind, 
multi-center Phase III studies in adult subjects with active in rheumatoid arthritis (RA). In 
these trials tofacitinib consistently reduces signs and symptoms of RA, improves physical 
function and other patient-reported outcomes such as fatigue, pain, and health-related aspects 
of quality of life in patients with moderate to severe RA. Combined with its inhibition of the 
progression of structural damage, the clinical development program has demonstrated 
tofacitinib as an effective targeted synthetic disease-modifying anti-rheumatic drug 
(tsDMARD) in treating RA.7-12 Long-term extension studies demonstrated sustained efficacy 
and a consistent safety profile as seen in the Phase 2 and 3 controlled clinical trials.13,14
The post hoc analysis of SF-36 Mental Component Summary score in tofacitinib Phase 3 and 
3b/4 clinical trials showed a significantly greater improvement in "probable major depressive 
disorder” and in “probable generalized anxiety disorder" in RA patients treated with 
tofacitinib versus placebo or adalimumab.15
The safety database currently includes data from more than 7000 RA clinical trial subjects 
with over 22875 patient-years (PYs) of exposure and more than 9.5 years of observation.16,17
However, these trials may have limitations reflecting real world situations. It has been 
estimated that only 21-33% of patients documented in registries, reflecting more accurately 
routine care, would have met eligibility criteria of major trials as they often exclude patients 
with co-morbidities.18 It is furthermore well known that RA is a systemic inflammatory 
disease, and that it is associated with increased cardiovascular risks and respiratory 
problems.19 Compared with controls, people with RA have increased rates of lung disease, 
are twice as likely to suffer from diabetes mellitus, eight-times as often from hypertension 
and almost four-times as often from osteoporosis.20 Also treatment of patients in daily 
clinical practice may vary from strict regulations in clinical trials.
By targeting intracellular JAK tofacitinib represents a new class of oral DMARDs. All other 
available therapy options given after failure of methotrexate (MTX) and other csDMARDs 
are administered parenterally. It has been shown that up to 22% of patients have difficulties
injecting to themselves 21 and that around 40% of patients discontinuing bDMARD 
treatment, reported the need for self-injection as one reason for discontinuation.22
Additionally data from different surveys confirmed a patient preference for an oral 
application.23,24 However data on influence of the route of administration on drug survival, 
patient satisfaction and quality of live are still limited. 
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The prevalence of psychological and psychiatric comorbidities (depression, anxiety, sleep 
disturbances) is increased in patients with rheumatoid arthritis (RA) similarly to other 
progressive rheumatologic diseases. These conditions substantially influence the patient´s 
quality of life and therefore merit further investigation and better understanding. Several 
studies have investigated the prevalence of psychological comorbidities in RA patients, but 
the literature data revealing the influence of the novel biologic therapy on the occurrence or 
severity of these comorbidities are inadequate.25
Patients with chronic pain often suffer from pain-related anxiety, overall affecting physical, 
social and emotional functioning of the patients.26,27 The retrospective study from Taiwan 
with 3657 RA patients and 14628 controls with 10 year follow-up showed 2.06 higher risk of 
developing the depressive disorders in RA patients compared to the general population 
(p <0.001).28 These results are supported by study comparing two commonly used anxiety 
and depression scales in 169 RA patients.29 Interestingly, there might be also increased 
prevalence of bipolar disorder in RA patients.30
The high influence of psychological factors on quality of life in RA and psoriatic arthritis 
patients was revealed in study with 282 patients. The prevalence of moderate to severe levels 
of depressive symptoms was found in 25.1% RA patients.31
These psychological conditions can be attributable to the psychological stressors and 
physical impairment in medically ill patients. Recently, data were published suggesting that 
the activation of the immune system that results in the higher activity of cytokines such as 
TNF-α, IFN-α, IL-1 and IL-6 can be involved in pathogenesis of psychological 
comorbidities. A possible common thread linking inflammation in RA to cytokine responses 
that are strongly implicated in the pathogenesis and progression of clinical depression 
probably involves activation of stress-activated protein kinases/mitogen-activated protein 
kinases (SAPK/MAPK) and Janus kinases/signal transducer and activator of transcription 
proteins (JAK/STAT) pathways by pro-inflammatory cytokines.32 Animal model was used to 
investigate the role of Janus kinase in major depressive disorder. The data show that stress 
reduces neurogenesis, which is restored by application of Jak-3 inhibitors. Inhibition of 
neurogenesis correlated with an anxious-depressive behavior that was also normalized upon 
application of Jak-3 inhibitor.33
Overall, the occurrence of depression, pain, anxiety, and sleep disturbances can be connected 
to RA. As expected, these comorbidities lead to the prescription of the analgesics (opioid, 
non-opioid, adjuvants), anxiolytics, antidepressants and/or hypnotics. Whether the use of 
JAK inhibitor in the treatment of the primary disease is associated with change in the 
prevalence or severity of these comorbidities is not well known. This prospective, 
observational, non-interventional study aims to assess the changes in the level of depression 
in RA patients. This study will enroll patients with at least a minimal level of depression (by 
CUDOS scale) which is a sub-population of RA patients which has not been sufficiently 
described in the previous trials and the information is thus limited.
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This non-interventional study is designated as a post-authorization safety study (PASS) and 
is conducted voluntarily by Pfizer.
8. RESEARCH QUESTION AND OBJECTIVES
The primary objective of this study is to describe and evaluate the changes of depression 
level within 12 months from the start of tofacitinib therapy in patients with RA and at least 
minimal level of depression. The primary goal is to find out if treatment by tofacitinib 
reduces the depression by at least 10% during 12 months, based on the Clinically Useful 
Depression Outcome Scale (CUDOS) score.
The secondary objectives of this study are to describe and evaluate the level and changes of 
pain, anxiety, and insomnia in patients with RA and at least minimal level of depression.
Additionally, it will describe the safety and effectiveness of tofacitinib for the treatment of 
RA.
8.1. Endpoints
8.1.1. Primary Endpoint
The primary endpoint of the study is:

Relative change between visit 3 and baseline of Clinically Useful Depression 
Outcome Scale (CUDOS) score.
8.1.2. Secondary Endpoints
The secondary endpoints of this study are:

Baseline value and relative change between visit 2 and baseline of CUDOS score.

Baseline value and relative change between visit 2 and baseline and between 
visit 3 and baseline of Clinically Useful Anxiety Outcome Scale (CUXOS), Jenkins 
Sleep Evaluation Questionnaire (JSEQ) and Visual Analog Scale (VAS) score for 
evaluation of anxiety, insomnia, and arthritis assessment.

Baseline counts of concomitant medication (antidepressants, analgesics, anxiolytics,
and hypnotics) together with doses for each and the change in number of used 
medications and in their dosage between visit 3 and baseline.

Baseline value and absolute change between visit 2 and baseline and between 
visit 3 and baseline of DAS28-4 (Erythrocyte sedimentation rate (ESR)), 
DAS28-4 (C-reactive protein (CRP)).

Remission as assessed by: DAS28-4 (ESR) <2.6 or DAS28-4 (CRP) <2.6.

LDA as assessed by: DAS28-4 (ESR) <3.2 or DAS28-4 (CRP) <3.2.
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
Change from Baseline in EuroQol Three Dimension – 3L (EQ-5D-3L) Health State 
Profile.

Incidence of any adverse event (AE) reported by the patient or investigator
9. RESEARCH METHODS 
9.1. Study Design
This is a 12-month, single arm, prospective cohort, non-interventional, multi-center study 
according to Czech legal definitions (Law 378/2007 Sb.).
Data for the study will be obtained from clinical practice records and patients printed 
questionnaires and transcribed to an anonymous electronic case report form (eCRF).
The primary aim of the study is to review the changes of depression after first year of 
tofacitinib (XELJANZ®) treatment in rheumatoid arthritis patients. For the description and
evaluation of depression in RA patients the prospective data from a 12-month follow-up will 
be used. The depression assessment will be performed by using the CUDOS questionnaire34
in form of a printed patient questionnaire presented to patients on each study visit. 
For the description and evaluation of arthritis, anxiety, and insomnia in RA patients with at 
least minimal depression (as per CUDOS questionnaire) the prospective data from 
a 12-month follow-up will be used. The patient assessment of arthritis, anxiety and insomnia 
will be performed by using the 100mm VAS scale, CUXOS35 and JSEQ36 questionnaire, 
respectively, in form of a printed patient questionnaire presented to patients on each study 
visit. 
The study follows one cohort of patients who were newly prescribed tofacitinib at baseline
and who scored at least 11 points on CUDOS scale (equivalent of minimal depression). 
There are 3 visits planned for each patient:

Visit 1 (start of tofacitinib treatment).

Visit 2 (6 months after start of tofacitinib treatment).

Visit 3 (12 months after start of tofacitinib treatment).
Observation period: Eligible patients will be followed from the date of first tofacitinib 
prescription until study end, death, or loss to follow-up (whichever comes first) for the 
occurrence of the endpoints of interest.
In this study, tofacitinib is prescribed in the usual manner in accordance with the terms of the 
marketing authorization. 
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The assignment of the patient to a particular therapeutic strategy is not decided in advance by 
this protocol but falls within current practice and the prescription of the medicine should be 
clearly separated from the decision to include the patient in the study. 
No additional diagnostic or monitoring procedures will be applied to the patients and 
follow-up visits are captured as part of normal medical practice. Investigators will be actively 
asking patients about the occurrence of any AEs. Epidemiological methods will be used for 
the analysis of collected data.
All patients are required to sign a written consent form with their participation in this study. 
All assessments except CUDOS, CUXOS and JSEQ described in this protocol are performed 
only when directed by the treating physician as part of normal clinical practice or standard 
practice guidelines for the patient population and healthcare provider specialty in the Czech 
Republic where this non-interventional study is being conducted.
9.2. Setting
This non-interventional study follows the population of 154 patients with moderate to severe 
rheumatoid arthritis, which were currently prescribed tofacitinib treatment for the first time 
and who scored at least 11 points on CUDOS scale (equivalent of minimal depression).
Patients will be followed for the period of 12 months and are likely to have a total of 3 visits 
per patient as per common medical care. 
The data will be collected by physicians allowed (according to indication restriction 
of reimbursement) to prescribe tofacitinib and, in the same time are specialized in the 
treatment of rheumatoid arthritis – rheumatologists. The total number of 10 to 20 out-patient 
physicians will be involved. 
Requirements for the physician´s eligibility are as followed: out-patient setting of the clinical 
practice, satisfactory experience in the care of patients with rheumatological diseases, and 
sufficient number of patients with diagnosis of rheumatoid arthritis.
It is expected (based on the clinic experience) that the patients will be enrolled within 
48 months from the start of the study – the enrollment of new subjects will be closed as soon 
as there are 154 patients enrolled. If there are not 154 patients enrolled within 48 months, the 
enrollment period can be prolonged as required. The aim of the study is to provide additional 
information on the population of RA patients with depression. Only patients with at least 
minimal level of depression score ≥11 (as per CUDOS questionnaire score ranging 0 to 72) 
may be included, as per the inclusion criteria.  This setting will ensure the ability of this 
study to assess changes of depression and changes of arthritis, anxiety, and insomnia 
outcomes in correlation to depression level of enrolled patients. 
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Subjects may be discontinued for the following reasons: 

The switch to a different treatment (for any reason – eg, new contraindication as per 
Summary of Product Characteristics (SmPC), tofacitinib interaction with other 
medicine, adverse reactions).

Non-compliance with the study schedule – the patient not coming for the planned 
study visit (which by the non-interventional setting of the study has to be planned for 
the same date as the visit planned within normal clinical practice). The period for 
study visit attendance is ±30 days for V2 and ±45 days for V3. 
Study flow:

Patient signed informed consent.

Evaluation of inclusion/exclusion criteria.

Patient enrollment.

Visit 1 (Baseline visit) (start of tofacitinib treatment).

eCRF completion.

Completion of printed patient questionnaires.

Visit 2 (6 months ±30 days after start of tofacitinib treatment):

AE detection, processing, and reporting, if applicable.

eCRF completion.

Completion of printed patient questionnaires.

Visit 3 (12 months ±45 days after start of tofacitinib treatment):

AE detection, processing, and reporting, if applicable.

eCRF completion.

Completion of printed patient questionnaires.
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9.2.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before patients are included in the study. 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. Patients aged ≥18 years.
2. Moderate to severe activity of rheumatoid arthritis (DAS28 ≥3.2). 
3. Patient for whom the physician decision has been made to initiate a treatment with 
tofacitinib.
4. Patient with at least minimal level of depression (CUDOS questionnaire ≥11 points).
5. Capable of understanding and signing a written informed consent form.
6. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study is a requirement for inclusion into this study.
9.2.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Patients unwilling/unable to fill in printed patient questionnaires. 
9.3. Variables
Table 6. Study Variables
Variable
Role
Data Source(s)
Operational Definition
RA treatment with 
tofacitinib – date of 
initiation
Exposure, Potential 
confounder, subgroup 
identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan
RA treatment with 
tofacitinib – dose
Exposure, Potential 
confounder, subgroup 
identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan
RA treatment with 
tofacitinib - tolerability
Potential confounder, 
subgroup identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan
Age
Baseline characteristic, 
potential confounder, 
sub-group identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan 
Gender
Baseline characteristic, 
potential confounder, 
sub-group identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan 
Height
Baseline characteristic, 
Case records 
Details will be provided 
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Variable
Role
Data Source(s)
Operational Definition
potential confounder, 
sub-group identifier
in Statistical Analysis 
Plan 
Weight
Baseline characteristic, 
potential confounder, 
sub-group identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan 
Smoking history and 
current smoking status
Baseline characteristic, 
potential confounder, 
sub-group identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan 
Alcohol intake
Baseline characteristic, 
potential confounder, 
sub-group identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan 
Date of first diagnosis of 
RA
Baseline characteristic, 
potential confounder, 
sub-group identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan 
Co-morbidities
Baseline characteristic, 
potential confounder, 
sub-group identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan 
Prior pharmacotherapy 
for RA
Potential confounder, 
sub-group identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan 
Co-medication relevant 
to RA and mental health 
Potential confounder, 
sub-group identifier
Case records 
Details will be provided 
in Statistical Analysis 
Plan 
Patient Assessment of 
Depression (CUDOS)
Baseline and Outcome
Printed questionnaire
Details will be provided 
in Statistical Analysis 
Plan 
Patient Assessment of 
Arthritis
Baseline and Outcome
Printed questionnaire
Details will be provided 
in Statistical Analysis 
Plan 
Patient Assessment of 
Anxiety (CUXOS)
Baseline and Outcome
Printed questionnaire
Details will be provided 
in Statistical Analysis 
Plan 
Patient Assessment of 
Insomnia (JSEQ)
Baseline and Outcome
Printed questionnaire
Details will be provided 
in Statistical Analysis 
Plan 
Erythrocyte 
Sedimentation Rate 
(ESR) or C-Reactive 
Protein (CRP)
Baseline and Outcome
Case records 
Details will be provided 
in Statistical Analysis 
Plan 
DAS28-4 (CRP) or 
DAS28-4 (ESR)
Baseline and Outcome
Case records 
Details will be provided 
in Statistical Analysis 
Plan 
EuroQol EQ-5D-3L
Health State Profile
Baseline and Outcome
Printed questionnaire
Details will be provided 
in Statistical Analysis 
Plan 
Occurrence of adverse 
events
Outcome
Case records and eCRF
Details will be provided 
in Statistical Analysis 
Plan
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9.4. Data Sources 
This is a multisite study and includes private outpatient clinics and hospitals. The data will be 
recorded using an electronic case report form (eCRF) and printed patient questionnaires for 
each patient included. The completed original eCRFs and printed questionnaires are the sole 
property of Pfizer and must not be provided to third parties in any format without the written 
approval of Pfizer, with the exception of authorized representatives of Pfizer or the 
appropriate competent authorities.
The treating physician is ultimately responsible for the collection and reporting of all clinical 
data, safety and laboratory data entered on the eCRFs and other forms for data collection 
(source documents) and must guarantee that they are accurate, authentic/original, traceable, 
complete, consistent, legible, timely (contemporaneous), permanent, and available as 
required. The eCRFs must be sent by the treating physician or authorized personnel. Once 
sent through the web interface (browser), the data is backed-up on the encrypted and secured 
server. Once sent, the data cannot be modified. Incomplete forms can be also saved by the 
physician and the session can be completed upon the next login. 
The treating physician is ultimately responsible for the distribution and re-collection of 
printed questionnaires from enrolled patients and must guarantee that they are correctly 
identified and available as required (once completed by a patient). 
All corrections of entries on the eCRFs must be explained (reason for change) and properly 
described. Corrections of entries are recorded by the physician via email to the responsible 
Contract Research Organization (CRO) (incl. date of correction, old and new value, reason 
for change).
In most cases, the source documents are patient records in the hospital or at the doctor’s 
office. In these cases, the data collected on the eCRFs must match the data in these records.
The clinical parameters recorded, especially those used to assess efficacy, are usual known,
and recognized variables within each respective indication. All questionnaires used in the 
study (CUDOS, CUXOS, JSEQ) have been validated.
9.4.1. Study Procedures
Consecutive patients attending will be included if they fulfil all selection criteria for the study
and are started on treatment with tofacitinib for moderate to severely active rheumatoid 
arthritis and (as per CUDOS evaluation criteria) have at least minimal level of depression.
All visits shall be scheduled according to clinical practice. Within this study 3 visits may be 
documented. At each visit patients will undergo procedures in compliance with the country 
label and as per standard of care. In order to collect comparable study data, visits occurring 
±30 days for V2 and ±45 days for V3 of the scheduled visit date can be documented. 
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After a training session the sites will get access to the eCRF, where the data and findings of 
the patient are documented. Additionally, a folder with printed patient questionnaires will be 
provided. The collection of all data is prospective.
Dose and duration of treatment should be based on clinical and individual needs and are 
determined by the treating physician. To provide accurate information of the treatment, the 
initial tofacitinib dose and all changes and the reasons for changes are documented during the 
course of the evaluation. The concomitant medication is determined by the treating physician 
and is registered in the documentation sheet. 
9.4.1.1. Study Period
The planned observation period of each patient is 12 months.  In this time period up to 
3 visits will be documented.
9.4.1.1.1. Baseline Visit
Following parameters will be documented at baseline visit:

Informed Consent.

Inclusion/Exclusion criteria according to protocol and SmPC.

Duration since diagnosis.

Demography.

Prior drug treatment of RA.

Treatment of RA with tofacitinib.

Concomitant drug treatment relevant to RA or mental health.

Comorbidities.

CUDOS questionnaire.

CUXOS questionnaire.

JSEQ questionnaire.

Patients Assessment of Arthritis.

Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP).

DAS28-4 (CRP) and/or DAS28-4 (ESR).

EuroQol EQ-5D-3L Health State Profile.
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9.4.1.1.2. Scheduled Visit 2 – Visit 3/Month 6 – Month 12
Following parameters will be documented at each visit:

Treatment of RA with tofacitinib.

Concomitant drug treatment relevant to RA or mental health.

CUDOS questionnaire.

CUXOS questionnaire.

JSEQ questionnaire.

Patients Assessment of Arthritis.

Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP).

DAS28-4 (CRP) and/or DAS28-4 (ESR).

EuroQol EQ-5D-3L Health State Profile.

Adverse event monitoring.
9.4.1.2. Schedule of Activities
The Schedule of Activities table provides an overview of the visits that may be documented. 
According to his/her clinical practice the investigator may schedule visits (unplanned visits) 
in addition to those listed on the schedule of activities (see the table below); in order to 
conduct evaluations or assessments required to protect the well-being of the patient. As this 
is a non-interventional study the study visits should be scheduled according to clinical 
practice.
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Other relevant concomitant drug treatment (active substance and dosing of antidepressants, 
anxiolytics, hypnotics, and analgesics) will be recorded at the Baseline Visit (Visit 1). At 
each subsequent visit such concomitant treatment will be documented.
9.4.3. Assessments – Efficacy
9.4.3.1. Patient Assessment of Depression
The CUDOS questionnaire assesses the level of depression in the past week. It consists of 
18 statements.  For each statement of the questionnaire the patient indicates how well it 
describes his feelings during past week: 0 – not at all true, 1 – rarely true, 2- sometimes true, 
3 – often true, 4-almost always true. The score ranges from 0 to 72, the higher the score, the 
more severe the depression. Further details will be included in the SAP. The form should 
then be checked by the site staff for completeness.
9.4.3.2. Patient Assessment of Anxiety
The CUXOS questionnaire assesses the level of anxiety in the past week. It consists of 
20 statements. For each statement of the questionnaire the patient indicates how well it 
describes his feelings during past week: 0 – not at all true, 1 – rarely true, 2- sometimes true, 
3 – often true, 4-almost always true. The score ranges from 0 to 80, the higher the score, the 
higher the anxiety level. Further details will be included in the SAP. The form should then be 
checked by the site staff for completeness.
9.4.3.3. Patient Assessment of Insomnia
The JSEQ questionnaire (Jenkins Sleep Evaluation Questionnaire) assesses the level of 
insomnia, sleep disturbance in the past month. It consists of 4 questions related to 1) trouble 
falling asleep, 2) trouble staying asleep, 3) waking up several times per night, and 4) waking 
up feeling tired and worn out after a usual amount of sleep. The response alternatives are not 
at all (0), 1-3 days (1), 4–7 days (2), 8–14 days (3), 15–21 days (4), and 22–30 days (5). The 
score ranges from 0 to 20, the higher the score, the lower the sleep quality. Further details 
will be included in the SAP. The form should then be checked by the site staff for 
completeness.
9.4.3.4. Patient Assessment of Arthritis 
Patients will assess how much arthritis impacting their life using a 100 mm visual analogue 
scale (VAS) by placing a mark on the scale between 0 (not affecting) and 100 (maximal 
impact), which corresponds to the level arthritis affects their life. Further details will be 
included in the SAP. The form should then be checked by the site staff for completeness.
9.4.3.5. C-reactive Protein (CRP) and/or Erythrocyte Sedimentation Rate (ESR)
CRP and ESR measurements are not required by the protocol and will be recorded in the 
eCRF if they were assessed as standard of care. 
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9.4.3.6. DAS28
The DAS28 is evaluated as standard of care and will be recorded in the eCRF if available. 
The effectiveness of the treatment with tofacitinib will be documented using, one of the 
following tools for the evaluation of the course of the disease:
Table 8. Disease Activity Indicators
Indicator
Definition
DAS28-4 (CRP)
0.56 × √(TJC28) + 0.28 × √(SJC28) + 0.36 × ln 
(CRP in mg/l +1) + 0.014 × PtGA in mm + 0.96
DAS28-4 (ESR)
0.56 × √(TJC28) + 0.28 × √(SJC28) + 0.70 × In 
(ESR in mm/ hour) + 0.014 × PtGA in mm
TJC = tender joint count; SJC = swollen joint count; CRP = C-reactive protein in mg/L; ESR = erythrocyte 
sedimentation rate in mm/first hour, PtGA = Patient’s global assessment of health.
9.4.3.7. EuroQol EQ-5D-3L Health State Profile
The EuroQol EQ-5D-3L Health State Profiles a copyrighted, patient completed instrument 
designed to assess impact on health-related quality of life in five domains: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. Additionally, scores from 
the five domains may be used to calculate a single index value, also known as a utility score. 
Further details will be included in the SAP. The validity and reliability of the EuroQol 
EQ-5D-3L has been established in a number of disease states, including rheumatoid arthritis. 
The form should then be checked by site staff for completeness.
9.4.4. Assessments – Safety
9.4.4.1. Safety Criteria
In contrast to the usual procedure for clinical trials in observational studies the treatment 
decision is independent of the protocol. Additionally, selection criteria of patients at baseline 
are not as strict as for clinical trials. Thus, this study can provide new insights into the safety 
of tofacitinib in routine care. At each visit after initiation of tofacitinib, the patient will be 
asked for the occurrence of adverse events. All adverse events (AEs) will be documented in 
the eCRF and if applicable reported to the sponsor’s safety unit, as indicated in Table 9. 
9.5. Study Size
The goal of the study is to describe the change of the CUDOS score after 12 months of 
treatment – to assess the change in depression after the treatment. Since the hypothesis lies in 
the relative decrease, t-test is used to test the null hypothesis that the ratio between the score 
after and before the therapy equals to 1 against the alternative that there is percentage 
difference in score after and before the treatment. The sample size is computed to detect the 
reduction of score by 10%, which is expected by current research articles. 
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The sample size is calculated for paired t-test of logarithm of CUDOS score with 5% alpha 
level, power 90% and two-sided alternative. For the calculation, it is assumed that the score 
is reduced by 10% after the therapy. Standard deviation is based on assumption that mean 
baseline score is 27.9 with standard deviation 9.91 and decreases by 10% to mean value score 
25.1 keeping the same standard deviation 9.9 after the therapy. Correlation between the 
second and first measurement is expected to be 0.5, which is based on expert opinion.
To have the sufficient 90% power at least 123 patients need to be analyzed. When include a 
20% drop-out rate, 154 patients need to be recruited in total.
9.6. Data Management 
Patients’ personal data will be collected, stored, and processed exclusively in anonymized 
form in accordance with the national data protection laws. All data will remain in 
anonymized form. The data will not be used for any other purposes other than for the 
research which is described in the patient information and the declaration of consent. During 
the conduct of the study, Value Outcomes undertakes responsibility to guarantee data 
protection and will adhere to all applicable laws and regulations on data protection.
All study data will be recorded by the study sites in the electronic case report form system. 
Access to the system takes place via a secure website. Access is only given to registered 
users who log in with a unique username and password. Access rights to the eCRF system 
are monitored by authorized employees of Value Outcomes.
Patients complete paper patient reported outcomes (PROs) at visit, the results are manually 
entered in the eCRF by site personnel. A copy of the anonymous patient questionnaires will 
be provided in paper form to Value Outcomes for verification (eCRF versus source paper 
form). Automatic checks of the data for plausibility and completeness using programmed 
so-called edit checks will take place already during electronic data entry by the study site. 
Other discrepancies will be clarified additionally with the study site using manual queries.
Due to the non-interventional nature of the study, the extent of data cleansing is limited and 
missing and/or implausible values are to be anticipated at the end of the study. In the 
Statistical Analysis Plan, handling of these values will be described in detail.
Confirmation of the data collected is required by final submission of the eCRF by the 
physician.
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9.6.1. Electronic Case Report Forms (eCRFs)
As used in this protocol, the term eCRF should be understood to refer to an electronic data 
record.
An eCRF is required and should be completed for each included patient. The completed 
original eCRFs are the sole property of Pfizer and should not be made available in any form 
to third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the 
eCRFs are securely stored at the study site in encrypted electronic and/or paper form and will 
be password protected or secured in a locked room to prevent access by unauthorized third 
parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the eCRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The
eCRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the eCRFs are true. Any corrections to entries made in the eCRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases the source documents are the hospital or the physician's chart. In these cases, 
data collected on the eCRFs must match those charts. In some cases, the CRF may also serve 
as the source document. In these cases, a document should be available at the investigator 
site and at Pfizer that clearly identifies those data that will be recorded on the CRF, and for 
which the CRF will stand as the source document.
9.6.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, eCRFs and hospital records), all original signed 
informed consent documents, copies of all eCRFs, 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 the investigator according to local regulations or as specified in the clinical 
study agreement (CSA), whichever is longer. The investigator must ensure that the records 
continue to be stored securely for so long as they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
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Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
9.7. Data Analysis 
This section gives an overview of the key methods and derivations required for the study. 
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. STATA (StataCorp LP, USA Version 13.1 or above) will be used for 
all analyses.
Unless specified otherwise, continuous variables will be summarized using descriptive 
statistics (n, mean, SD, median, min, max) and discrete variables will be summarized using 
counts and percentages.  To access drop-out, study flow-chart (patient disposition) between 
visits will be preset.
All adverse events will be presented as absolute numbers, frequency, and line-listings.
9.7.1. Analysis Populations
The Full Analysis Set is defined as patients who receive at least one dose of tofacitinib and 
have the data for evaluation of primary hypothesis, which means CUDOS score reported both 
at baseline and visit 3. This population will be used for all efficacy analysis. Details of any 
methods employed to deal with missing data will be outlined in the SAP.
The Safety Analysis Set is defined as all patients who receive at least one dose of tofacitinib. 
This population will be used for all safety analysis.
9.7.2. Efficacy Analysis
9.7.2.1. Primary Analysis
The ratio of CUDOS at visit 3 and baseline CUDOS score will be described as continuous
variable, together with geometric mean. The primary hypothesis about relative decrease in 
CUDOS score will be tested by ratio t-test with hypothesis that the ratio of CUDOS at 
visit 3 and baseline CUDOS equals 1 against two-sided alternative with alpha level 0.05.
Furthermore, the primary endpoint will also be assessed in the original metric of measure 
using a paired t-test, details will be specified in the SAP.
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9.7.2.2. Secondary Analysis
The baseline CUDOS score and the ratio of CUDOS at visit 2 and baseline CUDOS will be 
described as continuous variables. For the ratio geometric mean will be presented too. When 
the primary hypothesis test reaches significance and primary hypothesis is rejected, the same 
test will be performed for ratio of CUDOS at visit 2 and baseline to examine if the effect of 
the treatment was already present after 6 months to describe the effect in more detail. 
Because of the fixed sequence of testing, no adjustment of alpha value is needed. 
9.7.2.2.1. Anxiety, Insomnia and Arthritis 
Anxiety, insomnia, and arthritis assessment will be accessed via particular questionnaire 
scores (CUXOS, JSEQ, VAS scale). Each score will be summarized at baseline, as ratio of 
value at visit 3 and baseline value and as ratio of value at visit 2 and baseline value. For 
ratios geometric means will be presented too. The efficacy in secondary endpoints will be 
accessed via hierarchical testing separately, eg, the ratio of value at visit 3 and baseline will 
be tested by ratio t-test and only if this test reaches significance, the same test of ratio of 
value at visit 2 and baseline will be performed with the same alpha level. 
9.7.2.2.2. Antidepressants, Analgesics, Anxiolytics and Hypnotics
The number and percentage of patients who dropped/started concomitant treatment between 
baseline, visit 2 and visit 3 will be reported, as well as the summary of changes in dosing in 
concomitant treatment between baseline and visit 2 and between baseline and visit 3 if 
relevant data will be available. These descriptive statistics will be presented for each group of 
treatment (antidepressants, analgesics, anxiolytics, and hypnotics) separately. 
9.7.2.2.3. DAS28-4 (ESR), DAS28-4 (CRP)
For DAS28-4 (ESR), DAS28-4 (CRP) physicians will be asked to provide a final value 
(depends on which scale do they use in their common clinical practice). The summary 
statistics of the baseline value and the absolute change from baseline at each visit will be 
reported.
9.7.2.2.4. Rate of Remission, LDA
The rate of Remission and LDA will be presented as frequency and proportion of the patients 
achieving the relevant criteria at each time point. 
Where:

Remission is defined as DAS28-4 (ESR) <2.6 or DAS28-4 (CRP) <2.6.

LDA is defined as DAS28-4 (ESR) <3.2 or DAS28-4 (CRP) <3.2.
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9.7.2.2.5. EQ-5D-3L
The EQ-5D-3L is a standardized instrument used to measure quality of life. It is based on 
five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
Each dimension has 5 responses and the patient is asked to select the response that best 
describes them.
9.7.3. Safety Analysis
Adverse events will be reviewed and summarized on ongoing basis during the study to 
evaluate the safety of patients. Safety data will be presented in tabular and/or graphical 
format showing absolute numbers, frequency and summarized descriptively.
9.7.4. Interim Analysis
An interim analysis will not be performed in this study. 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
The Sponsor delegates the conduct of this non-interventional study (NIS) to the Contract 
Research Organization named Value Outcomes. Study Coordination has been assigned to 
Project Manager and central as well as remote monitoring is conducted by Data Manager.
Completeness and quality of data recorded in the eCRF will be regularly monitored by Data 
Manager. The schedule is detailed in the Monitoring plan. If in doubt a query will be raised 
to the investigator via Email. Data Manager creates an Error report based on the email 
(including date of correction, old and new value, reason for change). The dataset is backed-
up in regular periods so that an audit trail is available. 
If there is missing, unused, or inconsistent data, Data Manager will query the site to complete 
missing data. The formal-logic control of data will be done at the beginning of statistical 
analysis for detection of missing numbers, unused or inconsistent data via automated quality 
checks and by manual reviews, as well. Missing data handling is specified in the Statistical 
Analysis Plan.
9.9. Limitations of the Research Methods
Randomized controlled trials are important and powerful tools in assessing efficacy and 
safety but have their limitations in terms of generalizability. In order to assess clinical 
effectiveness and safety of tofacitinib in a usual care setting, parameters need to be 
determined by performing observational studies.
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Inherent limitations of non-interventional, observational, non-controlled, non-randomized 
studies in general are the risk of selection/ascertainment bias and lack of a parallel control 
group, which complicate the interpretation of the causality between treatment and outcomes. 
Furthermore, as with any “as observed” analysis, there is a potential risk of bias due to 
missing outcome data; the risk increases with increasing number of missing outcome data.
As data captured will be limited to information available from the physician participating in 
the study under a usual care setting, there is a greater possibility that there will be individual 
items of missing data (eg, CRP not measured). If the different factors being considered in the 
primary statistical model to look at impact of treatment change are highly correlated it may 
not be clear which of the factors is in fact driving the rate of treatment escalation. Other 
sensitivity analyses may be explored to assess the impact of any confounding. Further details 
will be included in the SAP.
Patients selected for study inclusion represent a population who are initiated on tofacitinib as 
part of a usual care setting. The sample of patients will be obtained from physicians who are 
willing to participate in the study and there is a possibility that certain types of patients will 
be selected to be prescribed tofacitinib (selection bias) and join the study and this could 
potentially have an impact on findings of the primary analysis (if the ‘type’ is expected to 
impact the rate of treatment escalation). Therefore, study findings may not be generalizable 
to all RA patients.
9.10. Other Aspects
Not applicable.
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10. PROTECTION OF HUMAN SUBJECTS
10.1. 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. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
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, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer. All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, patient-specific code. 
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity. In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the Clinical Study Agreement and applicable privacy laws.
10.2. Patient Consent
The informed consent documents and any patient recruitment materials must be in 
compliance with local regulatory requirements and legal requirements, including applicable 
privacy laws.
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the institutional 
review board (IRB)/independent ethics committee (IEC) before use, and available for 
inspection.
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study, the sharing of data relating to the study and possible risks associated 
with participation, including the risks associated with the processing of the patient’s personal 
data. The investigator further must ensure that each study patient is fully informed about his 
or her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed. The investigator 
will retain the original of each patient's signed consent document.
10.3. Patient Withdrawal
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons. In any circumstance, every effort should be made to document 
patient outcome, if possible. The investigator should inquire about the reason for withdrawal 
and follow-up with the patient regarding any unresolved adverse events. 
If the patient withdraws from the study, and also withdraws consent for disclosure of future
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
If the patient voluntarily withdraws from the study or he/she is discontinued at the discretion 
of the investigator, the investigator shall inform the CRO within next 10 working days.
10.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents, 
(eg, recruitment advertisements), if applicable, from the IRB/IEC. All correspondence with 
the IRB/IEC should be retained in the Investigator File. Copies of IRB/IEC approvals should 
be forwarded to Pfizer. 
10.5. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE), European Medicines Agency 
(EMA) European Network of Centers for Pharmacoepidemiology and Pharmacovigilance 
(ENCePP) 
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patient was administered a drug under study on the last day of the observation period, then 
the reporting period should be extended for 28 calendar days following the end of 
observation.  
Most often, the date of informed consent is the same as the date of enrollment. In some 
situations, there may be a lag between the dates of informed consent and enrollment. In these 
instances, if a patient provides informed consent but is never enrolled in the study (eg, patient 
changes his/her mind about participation), the reporting period ends on the date of the 
decision to not enroll the patient. 
If the investigator becomes aware of a SAE occurring at any time after completion of the 
study and s/he considers the SAE to be related to tofacitinib, the SAE also must be reported 
to Pfizer Safety. 
11.1.2. Causality Assessment
The investigator is required to assess and record the causal relationship. For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of 
each AE. For AEs with a causal relationship to tofacitinib, follow-up by the investigator is 
required until the event and/or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment. 
An investigator’s tofacitinib causality assessment is the determination of whether there exists 
a reasonable possibility that tofacitinib caused or contributed to an AE. If the investigator’s 
final determination of causality is “unknown” and s/he cannot determine whether tofacitinib 
caused the event, the safety event must be reported within 24 hours. 
If the investigator cannot determine the etiology of the event but s/he determines that 
tofacitinib did not cause the event, this should be clearly documented on the eCRF and the 
NIS AEM Report Form. 
11.1.3. Definition of Safety Events
11.1.3.1. Adverse Events
An AE is any untoward medical occurrence in a patient administered a medicinal product. 
The event need not necessarily have a causal relationship with the product treatment or 
usage. Examples of adverse events include but are not limited to: 

Abnormal test findings (see below for circumstances in which an abnormal test 
finding constitutes an adverse event).

Clinically significant symptoms and signs.

Changes in physical examination findings.

Hypersensitivity.
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
Progression/worsening of underlying disease.

Lack of efficacy.

Drug abuse.

Drug dependency.
Additionally, for medicinal products, they may include the signs or symptoms resulting from:

Drug overdose.

Drug withdrawal.

Drug misuse.

Off-label use.

Drug interactions.

Extravasation.

Exposure during pregnancy.

Exposure during breast feeding.

Medication error.

Occupational exposure.
Abnormal test findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or

Test result is considered to be an adverse event by the investigator or sponsor.
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Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
11.1.3.2. Serious Adverse Events
A serious adverse event is any untoward medical occurrence in a patient administered a 
medicinal or nutritional product (including pediatric formulas) at any dose that:

Results in death.

Is life-threatening.

Requires inpatient hospitalization or prolongation of hospitalization (see below for 
circumstances that do not constitute AEs).

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions).

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization. However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above, the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Additionally, any suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious. The event may be suspected from 
clinical symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product. The terms “suspected transmission” and “transmission” are considered 
synonymous. These cases are considered unexpected and handled as serious expedited cases 
by PV personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
Hospitalization
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
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however, an event leading to an emergency room visit should be assessed for medical 
importance. 
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. 
For example, the following reports of hospitalization without a medical AE are not to be 
reported. 

Social admission (eg, patient has no place to sleep).

Administrative admission (eg, for yearly exam).

Optional admission not associated with a precipitating medical AE (eg, for elective 
cosmetic surgery).

Hospitalization for observation without a medical AE.

Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with a worsening of the pre-existing condition (eg, for 
work-up of persistent pre-treatment lab abnormality).

Protocol-specified admission during clinical study (eg, for a procedure required by 
the study protocol).
11.1.4. Scenarios Necessitating Reporting to Pfizer Safety Within 24 Hours 
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication 
error, overdose, misuse, extravasation, lack of efficacy, and occupational exposure are 
described below.
Exposure during pregnancy
An exposure during pregnancy (EDP) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed to (eg, environmental) tofacitinib or the female becomes, or is found to be, 
pregnant after discontinuing and/or being exposed to tofacitinib (maternal exposure).
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed, either due to treatment or environmental exposure to 
tofacitinib prior to or around the time of conception and/or is exposed during the 
partner pregnancy (paternal exposure).
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As a general rule, prospective and retrospective exposures during pregnancy reports from any 
source are reportable irrespective of the presence of an associated AE and the procedures for 
SAE reporting should be followed.
If a study participant or study participant’s partner becomes, or is found to be, pregnant 
during the study participant’s treatment with tofacitinib this information must be submitted to 
Pfizer Safety, irrespective of whether an adverse event has occurred using the NIS AEM 
Report Form and the EDP Supplemental Form. 
In addition, the information regarding environmental exposure tofacitinib in a pregnant 
woman (eg, a patient reports that she is pregnant and has been exposed to a cytotoxic product 
by inhalation or spillage) must be submitted using the NIS AEM Report Form and the EDP 
supplemental form. This must be done irrespective of whether an AE has occurred. 
Information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy; in addition, 
follow-up is conducted to obtain information on EDP outcome for all EDP reports with 
pregnancy outcome unknown. A pregnancy is followed until completion or until pregnancy 
termination (eg, induced abortion) and Pfizer is notified of the outcome. This information is 
provided as a follow up to the initial EDP report. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-
procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (eg, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
procedures for reporting SAEs should be followed.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion.

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to investigational product.
Additional information regarding the exposure during pregnancy may be requested. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). 
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In the case of paternal exposure, the study participant will be provided with the Pregnant 
Partner Release of Information Form to deliver to his partner. It must be documented that the 
study participant was given this letter to provide to his partner.
Exposure during breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated AE. An exposure during breastfeeding report is not created when a Pfizer drug 
specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use. However, if the infant experiences an AE associated with such a 
drug’s administration, the AE is reported together with the exposure during breastfeeding.
Medication error
A medication error is any unintentional error in the prescribing, dispensing or administration 
of a medicinal product that may cause or lead to inappropriate medication use or patient harm 
while in the control of the health care professional, patient, or consumer. Such events may be 
related to professional practice, health care products, procedures, and systems including: 
prescribing; order communication; product labelling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; monitoring; and use. 
Medication errors include:

Near misses, involving or not involving a patient directly (eg, inadvertent/erroneous 
administration, which is the accidental use of a product outside of labelling or 
prescription on the part of the healthcare provider or the patient/consumer).

Confusion with regard to invented name (eg, trade name, brand name).
The investigator must submit the following medication errors to Pfizer Safety, irrespective of 
the presence of an associated AE/SAE:

Medication errors involving patient exposure to the product, whether or not the 
medication error is accompanied by an AE.

Medication errors that do not involve a patient directly (eg, potential medication 
errors or near misses). When a medication error does not involve patient exposure to 
the product the following minimum criteria constitute a medication error report:

An identifiable reporter.

A suspect product.

The event medication error.
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Overdose, Misuse, Extravasation
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reported to Pfizer Safety by the investigator, irrespective of the presence of an associated 
AE/SAE. 
Lack of Efficacy
Reports of lack of efficacy to a Pfizer product are reported to Pfizer Safety by the 
investigator, irrespective of the presence of an associated AE/SAE or the indication for use of 
the Pfizer product.
Occupational Exposure
Reports of occupational exposure to a Pfizer product are reported to Pfizer Safety by the 
investigator, irrespective of the presence of an associated AE/SAE.
11.2. Single Reference Safety Document
The Xeljanz SmPC will serve as the single reference safety document during the course of 
the study, which will be used by Pfizer safety to assess any safety events reported to Pfizer 
Safety by the investigator during the course of this study. 
The single reference safety document should be used by the investigator for prescribing 
purposes and guidance.
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
The final report of this study will be submitted to SUKL within 12 months after the end of 
data collection.
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 NI study protocol that the investigator becomes aware of.
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Meyer DM, Jesson MI, Li X, Elrick MM, Funckes-Shippy CL, Warner JD, et al. Anti-
inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, 
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Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol 
Baltim Md 1950. 2007 Mar 1;178(5):2623–9. 
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O’Sullivan LA, Liongue C, Lewis RS, Stephenson SEM, Ward AC. Cytokine receptor 
signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol. 2007 
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30]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/art.33383
8.
Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. 
Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J 
Med. 2012 Aug 9;367(6):495–507. 
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A3921330 NON-INTERVENTIONAL STUDY PROTOCOL
Amendment 1, 18 June 2021
PFIZER CONFIDENTIAL 
CT24-WI-GL02-RF01 3.0 Non-Interventional Study Protocol Template For Primary Data Collection Study
02-Nov-2020 
Page 45 of 48
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A3921330 NON-INTERVENTIONAL STUDY PROTOCOL
Amendment 1, 18 June 2021
PFIZER CONFIDENTIAL 
CT24-WI-GL02-RF01 3.0 Non-Interventional Study Protocol Template For Primary Data Collection Study
02-Nov-2020 
Page 46 of 48
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Tofacitinib citrate
A3921330 NON-INTERVENTIONAL STUDY PROTOCOL
Amendment 1, 18 June 2021
PFIZER CONFIDENTIAL 
CT24-WI-GL02-RF01 3.0 Non-Interventional Study Protocol Template For Primary Data Collection Study
02-Nov-2020 
Page 47 of 48
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Tofacitinib citrate
A3921330 NON-INTERVENTIONAL STUDY PROTOCOL
Amendment 1, 18 June 2021
PFIZER CONFIDENTIAL 
CT24-WI-GL02-RF01 3.0 Non-Interventional Study Protocol Template For Primary Data Collection Study
02-Nov-2020 
Page 48 of 48
14. LIST OF TABLES 
Table 1. List of Abbreviations ...................................................................................................5
Table 2. Responsible Parties Accountable for the Design and Implementation of the 
Protocol.......................................................................................................7
Table 3. Country Coordinating Investigator and Principal investigator of the protocol ...........7
Table 4. Amendments and Updates ...........................................................................................9
Table 5. Milestones..................................................................................................................12
Table 6. Study Variables..........................................................................................................19
Table 7. Schedule of Activities................................................................................................24
Table 8. Disease Activity Indicators........................................................................................26
Table 9. Safety Requirements..................................................................................................35
15. LIST OF FIGURES
Not applicable.
ANNEX 1. LIST OF STANDALONE DOCUMENTS
Number
Document reference 
number
Date
Title
1
Section 4
18 June 2021
Abstract: A3921330 Non-interventional 
study to review the changes of depression 
after first-year of tofacitinib (XELJANZ®) 
treatment in rheumatoid arthritis patients
2
ANNEX 2
08 June 2021
A3921330 ENCePP checklist
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
In Annex 1 as a standalone document.
ANNEX 3. ADDITIONAL INFORMATION 
Not applicable.
090177e1975b2d82\Approved\Approved On: 23-Jun-2021 15:25 (GMT)

Document Approval Record
Document Name:
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