ESCALATE-RA A NON-INTERVENTIONAL STUDY OF CRITICAL FACTORS FOR ESCALATING DRUG TREATMENT IN PATIENTS TREATED WITH TOFACITINIB FOR MODERATE TO SEVERE ACTIVE RHEUMATOID ARTHRITIS
Conditions: Arthritis, Rheumatoid
Sponsor: Pfizer

Tofacitinib citrate 
A3921302 OBSERVATIONAL PLAN NON-INTERVENTIONAL STUDY 
Final, 23 August 2017  
 
 
OBSERVATIONAL PLAN OF THE NON-INTERVENTIONAL STUDY (NIS) 
ESCALATE-RA 
 
Study information 
 
Title 
ESCALATE-RA 
A NON-INTERVENTIONAL STUDY OF 
CRITICAL FACTORS FOR ESCALATING 
DRUG TREATMENT IN PATIENTS 
TREATED WITH TOFACITINIB FOR 
MODERATE TO SEVERE ACTIVE 
RHEUMATOID ARTHRITIS 
 
Protocol number 
A3921302 
Protocol version identifier 
Final 1.1 
Date of last version of protocol 
23-Aug-2017 
Active substance 
L04AA29   Tofacitinib 
Medicinal product 
Xeljanz® 
Research question and objectives 
The objective of this non-interventional 
study is to identify key factors that are 
driving treatment decisions by 
rheumatologists in the treatment of 
rheumatoid arthritis (RA) patients starting 
treatment with Tofacitinib in a real world 
setting. In addition to disease activity score 
(DAS) 28, the following factors may play an 
important role: difference between DAS28 at 
start of therapy and after 3-6 months, 
physician’s global assessment of disease 
activity, patients' global assessment of 
disease activity, arthritis pain and patient 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................3 
1. LIST OF ABBREVIATIONS ................................................................................................6 
2. RESPONSIBLE PARTIES ....................................................................................................9 
3. AMENDMENTS AND UPDATES .....................................................................................10 
4. MILESTONES .....................................................................................................................11 
5. RATIONALE AND BACKGROUND ................................................................................11 
6. RESEARCH QUESTION AND OBJECTIVES .................................................................12 
6.1. Endpoints .................................................................................................................13 
6.1.1. Primary Endpoint: .......................................................................................13 
6.1.2. Secondary Endpoints: .................................................................................13 
7. RESEARCH METHODS ....................................................................................................14 
7.1. Study design ............................................................................................................14 
7.2. Setting ......................................................................................................................14 
7.2.1. Inclusion criteria .........................................................................................15 
7.2.2. Exclusion criteria ........................................................................................15 
7.3. Variables ..................................................................................................................16 
7.4. Data sources ............................................................................................................18 
7.5. Study procedure .......................................................................................................18 
7.5.1. Study Period................................................................................................19 
7.5.2. Schedule of Activities .................................................................................23 
7.6. Assessments ............................................................................................................25 
7.6.1. Physical Examination .................................................................................25 
7.6.2. Prognostic Factors ......................................................................................25 
7.6.3. Insurance Type ............................................................................................25 
7.6.4. Varicella vaccination status ........................................................................25 
7.6.5. Treatment of Rheumatoid Arthritis (RA-Treatment) with Tofacitinib 
and/or other DMARDs .....................................................................................25 
7.6.6. Concomitant treatment for rheumatoid arthritis with glucocorticoids .......25 
7.6.7. Effectiveness criteria ..................................................................................26 
7.6.8. Joint Counts ................................................................................................26 
7.6.9. Patient Assessment of Arthritis Pain ..........................................................26 
 
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7.6.10. Patient Global Assessment of Arthritis (PtGA) ........................................27 
7.6.11. Physician Global Assessment of Arthritis (PhyGA) ................................27 
7.6.12. Duration of Morning Stiffness ..................................................................27 
7.6.13. Functional Ability Questionnaire Hannover (FFbH) ................................27 
7.6.14. EuroQoL EQ-5D-3L Health State Profile ................................................27 
7.6.15. Functional Assessment of Chronic Illness Therapy (FACIT) - 
Fatigue Scale ....................................................................................................27 
7.6.16. Patient’s satisfaction with drug treatment.................................................27 
7.6.17. C-reactive Protein (CRP) ..........................................................................28 
7.6.18. Erythrocyte Sedimentation Rate (ESR) ....................................................28 
7.6.19. Safety ........................................................................................................28 
7.7. Study size ................................................................................................................28 
7.8. Data management ....................................................................................................30 
7.9. Data analysis ...........................................................................................................30 
7.9.1. Analysis Populations ..................................................................................31 
7.9.2. Efficacy Analysis ........................................................................................31 
7.9.1. Safety Analysis ...........................................................................................34 
7.10. Interim Analysis ....................................................................................................35 
7.11. Quality control .......................................................................................................35 
7.12. Limitations of the research methods .....................................................................36 
7.13. Other aspects .........................................................................................................36 
8. PROTECTION OF PATIENTS ...........................................................................................37 
8.1. Patient Information and Consent .............................................................................37 
8.2. Patient withdrawal ...................................................................................................37 
8.3. Independent Ethics Committee (IEC) .....................................................................37 
8.4. Ethical Conduct of the Study ..................................................................................37 
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................38 
9.1. Requirements ...........................................................................................................38 
9.1.1. Reporting period .........................................................................................39 
9.1.2. Causality assessment ..................................................................................39 
9.1.3. Definitions of safety events ........................................................................40 
 
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9.1.4. Scenarios necessitating reporting to the CRO AMS within 24 hours ........43 
9.2. Single reference safety document............................................................................46 
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........46 
10.1. Communication of study results ............................................................................46 
10.2. Communication of issues ......................................................................................46 
11. REFERENCES ..................................................................................................................46 
12. LIST OF TABLES .............................................................................................................48 
13. LIST OF FIGURES ...........................................................................................................48 
ANNEX 1 LIST OF STAND ALONE DOCUMENTS ..........................................................49 
ANNEX 2 ADDITIONAL INFORMATION ..........................................................................49 
 
 
 
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1. LIST OF ABBREVIATIONS 
 
 
Abbreviation 
Definition 
ACPA 
Anti-citrullinated protein antibodies 
ACR  
American Colleague of Rheumatology 
AE 
Adverse Event 
AEM 
Adverse event monitoring 
AMS 
Advanced Medical Services GmbH 
BfArM 
Bundestinstitut für Arzneitmittel und 
Medizinprodukte (German Federal Institute for 
Drugs and Medical Devices) 
CAPEA 
Course and Prognosis of Early Arthritis 
CDAI 
Clinical Disease Activity Index 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical 
Sciences 
CRA 
Clinical Research Associate 
csDMARD 
Conventional Synthetic Disease Modifying 
Antirheumatic Drug 
eCRF 
Electronic Case Report Form  
CRP 
C-reactive Protein 
DAS 
Disease Activity Score 
DMARD 
Disease Modifying Antirheumatic Drug 
EDC 
Electronic Data Capture 
EDP 
Exposure during pregnancy 
 
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EMA 
European Medicines Agency 
ENCePP 
European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance 
EQ-5D 
 a self-report questionnaire (a quality of life 
instrument) developed by the European Quality of 
Life (EuroQoL) Group 
ESR 
Erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
EuroQoL 
European Quality of Life [Group] 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FFbH 
Functional Ability Questionnaire Hannover 
GEP 
Good Epidemiological Practice 
GPP 
Good Pharmacoepidemiology Practices 
HCP 
Healthcare Professional 
IEA 
International Epidemiological Association 
IEC 
Independent Ethics Committee 
IR 
Incidence Rate 
ISPE 
International Society for Pharmacoepidemiology 
ISPOR 
International Society for Pharmacoeconomics and 
Outcomes Research 
JAK 
Janus-kinase 
LDA 
Low disease activity 
MCP 
Metacarpophalangeal joint 
MTX 
Methotrexate 
NIS 
Non-Interventional Study 
 
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PEI 
Paul-Ehrlich Institut 
PhyGA 
Physician Global Assessment of Arthritis 
PIP 
Proximal interphalangeal joints 
PtGA 
Patient Global Assessment of Arthritis 
PY 
Patient years 
RA 
Rheumatoid arthritis 
RF  
Rheumatoid factor 
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SDAI 
Simplified Disease Activity Index 
SJC 
Swollen Joint Count 
SmPC 
Summary of Product Characteristics 
SSL 
Secure Sockets Layer 
TJC 
Tender Joint Count 
TNF 
Tumor necrosis factor 
VAS 
Visual Analogue Scale 
Vfa 
Verband der forschenden Pharma-Unternehmen 
[German Association of Research-Based 
Pharmaceutical Companies] 
Table 2 List of Abbreviations 
 
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3. AMENDMENTS AND UPDATES 
Amendment 
number 
Date 
Substantial or 
administrative 
amendment 
Protocol 
section(s) 
changed  
Summary of amendment(s) 
Reason 
1 
23 –
Aug-
2017 
Substantial 
4, 7, 9  
 
• 
Start of data collection in 
October 
• 
Add Insurance Type as 
confounder 
• 
Specify patient’s 
satisfaction with drug 
treatment 
• 
Correct number of 
monitoring visits 
• 
Correct safety reporting 
to CRO AMS instead of 
Pfizer 
• 
Clarify that all events 
(both with Xeljanz® and 
DMARDs of other 
manufacturers) have to 
be reported 
Update of timelines, change of 
confounders and 
correction/specification of 
safety reporting process 
Table 4 Amendments and Updates 
 
 
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4. MILESTONES 
 
Milestone 
Planned date 
Completion of feasibility assessment 
 
28-July-2017 
Start of data collection  
 
23-October-2017 
End of data collection  
 
23-October-2022  
Final study report 
 
23-October-2023 
Table 5 Milestones 
 
5. 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 musculoskeletal complications, RA patients suffer from increased frequencies 
and impacts of comorbidities such as cardiovascular and infectious diseases, osteoporosis or 
cancer, leading to higher mortality rates.[2,3,4] In addition, RA represents significant health 
and socioeconomic burdens for the individual patient and society, especially with regard to 
work disability and work productivity loss.[5,6]  
With currently no curative therapy available, treatment strategies aim at controlling disease 
activity, alleviating signs and symptoms, maintaining physical function, improving quality of 
life, reducing the rate of joint damage, and, if possible, inducing complete remission. 
Best treatment outcomes are achieved if RA is treated with disease modifying antirheumatic 
drugs (DMARDs) right from the beginning (‘hit hard and early’, ‘window of 
opportunity’).[7,8,9,10] Furthermore, treatment strategies that aim at a predefined target 
(‘treat-to-target’ concept) have been shown to be superior to former, traditional approaches 
(‘wait and see’).[11] Therefore, current European League Against Rheumatism (EULAR)-
recommendations and the German S1 guideline derived from the EULAR-recommendations 
define treat-to-target as the basic therapeutic principle. The target to aim for is remission, 
especially in DMARD-naïve patients, or low disease activity, primarily in patients who failed 
previous therapies.[12] Although criteria for RA remission vary substantially in studies and 
clinical practice, the 28-joint Disease Activity Score (DAS28) is traditionally being widely 
 
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used where DAS28 < 2,6 defines remission and DAS28 ≤ 3,2 low disease 
activity.[13]According to EULAR recommendations, therapy has to be adjusted until the 
treatment target has been reached.  
How is the treat to target approach applied in everyday care?  
Despite insufficient response after 3 to 6 months therapy, treat-to-target recommendations of 
EULAR were only applied in 50% of the German course and prognosis of early arthritis 
cohort (CAPEA).[14] In an analysis of a cohort from the “Kerndokumentation”, a national 
database of the German Collaborative Arthritis Centres, 45% of patients were not within 
DAS28 low disease activity range and therefore would have needed adaption of therapy 
according to current treatment guidelines. In contrast, rheumatologists’ global assessment of 
disease activity differed, 80% perceived their patients to be in the low disease activity range 
and, hence, as being adequately treated.[15]  
These observations suggest that in a real-world setting, criteria other than calculated DAS28 
remission or low disease activity alone may guide treatment decisions. Among such criteria, 
satisfaction with drug treatment is of particular interest.  On the one hand, a patient who is 
content with his current therapy is less likely to be willing to change a therapy solely to 
achieve a better DAS28 score. On the other hand, patient preference and satisfaction of a 
therapy strongly affects adherence to a prescribed medication, ultimately affecting treatment 
outcome and efficacy. A factor known to impact on patient satisfaction with a prescribed 
treatment is the route of administration. Here, several studies point to a preference for oral 
therapies, also among second-line DMARDs.[16,17]  
Recently, Tofacitinib, an orally applied DMARD of the new class called Janus-Kinase-
Inhibitors (JAK-Inhibitors) has been brought into the market in the European Union. 
Tofacitinib is indicated in combination with methotrexate (MTX) for the treatment of 
moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded 
inadequately to, or who are intolerant to one or more DMARD. Due to oral administration of 
Tofacitinib, the impact of patient’s satisfaction with drug treatment on therapy decisions by 
rheumatologists may be especially pronounced. 
EULAR recommendations have now endorsed individual patient related factors such as 
patient preferences and comorbidities as an overarching principle in the management of RA.  
 
6. RESEARCH QUESTION AND OBJECTIVES 
The objective of this non-interventional study is to identify key factors that are driving treat-
ment decisions by rheumatologists in the treatment of RA patients starting treatment with 
Tofacitinib in a real world setting. In addition to DAS28 score, the following factors may 
play an important role: difference between DAS28 at start of therapy and after 3-6 months, 
physician’s global assessment of disease activity, patient’s global assessment of disease 
activity, arthritis pain and patient’s satisfaction with drug treatment. 
 
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6.1. Endpoints  
6.1.1. Primary Endpoint: 
Impact of the following factors on the number of treatment escalations of Tofacitinib patients 
in 24 months 
a. DAS28-4 with Erythrocyte Sedimentation Rate (ESR) 
b. ΔDAS28-4 (ESR)  
c. Physician Global Assessment of Arthritis 
d. Patient’s Assessment of Arthritis Pain  
e. Patient’s satisfaction with drug treatment 
f. Patient’s Global Assessment of Arthritis 
 
Treatment escalation in this study is defined as a switch to another DMARD or combination 
of DMARDs when compared to the last visit.  
6.1.2. Secondary Endpoints: 
a) Time to first treatment escalation  
b) Rate of Low Disease Activity (LDA) over time of patients on Tofacitinib (in 
combination therapy or monotherapy), as assessed by: Simplified Disease 
Activity Index (SDAI) ≤ 11; Clinical Disease Activity Index (CDAI) ≤10; 
DAS 28-4 (ESR) ≤3.2 and DAS28-4 with C-reactive Protein (CRP) ≤3.2. 
c) Rate of remission over time of patients on Tofacitinib (in combination therapy 
or monotherapy), as assessed by: American College of Rheumatology 
(ACR)-EULAR Boolean remission criteria; SDAI ≤ 3.3; CDAI ≤2.8; DAS 
28-4 (ESR) < 2.6 and DAS28-4 (CRP) < 2.6  
d) Change from baseline over time of patients on Tofacitinib (in combination 
therapy or monotherapy) in DAS 28-4 (ESR) and DAS 28-4 (CRP) 
e) Change from baseline of duration of morning stiffness over time of patients on 
Tofacitinib (in combination therapy or monotherapy) 
 
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f) Change from baseline in the Functional Ability Questionnaire Hannover 
(FFbH) over time of patients on Tofacitinib (in combination therapy or 
monotherapy) 
g) Rate of patients with functional remission in FFbH (FFbH > 83%) over time of 
patients on Tofacitinib (in combination therapy or monotherapy) 
h) Change from baseline in a self-report questionnaire (a quality of life 
instrument) developed by the European Quality of Life (EuroQoL) Group 
(EuroQoL EQ-5D) over time of patients on Tofacitinib (in combination 
therapy or monotherapy) 
i) Change from baseline in Functional Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue scale over time of patients on Tofacitinib (in combination 
therapy or monotherapy) 
j) Drug survival at month 12, 24 of patients on Tofacitinib (in combination 
therapy or monotherapy) 
k) Patient’s satisfaction with Tofacitinib treatment (in combination therapy or 
monotherapy) over time 
 
 
7. RESEARCH METHODS 
7.1. Study design  
This is a 60-month, prospective, non-interventional, multi-centre study to evaluate the impact 
of the following factors on the number of treatment escalations of Tofacitinib patients in 24 
months. 
Eligible patients will be followed up from the date of first Tofacitinib prescription for 24 
months.  Patients who are switched from the initial Tofacitinib therapy to other therapies will 
also be followed up to 24 months. Patient documentation is expected quarterly as per 
standard clinical practice. 
This study observes drug prescription and follow-up visits in daily medical care. Therapeutic 
strategies and frequency of patient follow-up are decided by the treating physician. 
7.2. Setting 
The planned recruitment period is 36 months. With planned observation duration of 24 
months per patient, the entire study would thus last for 60 months. The study is to start in 
October 2017 and will end in October 2022. Overall, about 1500 patients in about 200 
centres in Germany are to be included in this non-interventional study.  
 
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3. Patients who have received any previous treatment with Tofacitinib or other JAK 
inhibitors 
4. Patients who are investigational site staff members or patients who are Pfizer 
employees directly involved in the conduct of the study. 
 
7.3. Variables 
 
Variable 
Role 
Data source(s) 
Operational definition 
RA-treatment with 
Tofacitinib and/or other 
DMARDs - date of 
initiation 
Exposure, Potential 
confounder, subgroup 
identifier 
Case records and electronic 
Case Report Form (eCRF) 
Details will be provided in 
Statistical Analysis Plan  
RA treatment with 
Tofacitinib and/or other 
DMARDs – dose  
Exposure, Potential 
confounder, subgroup 
identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
RA treatment with 
Tofacitinib and/or other 
DMARDs - tolerability 
Potential confounder, 
subgroup identifier 
Case record/eCRF 
Details will be provided in 
Statistical Analysis Plan 
RA treatment with 
Tofacitinib and/or other 
DMARDs – route of 
administration 
Potential confounder, 
subgroup identifier 
Case record/eCRF 
Details will be provided in 
Statistical Analysis Plan 
Age 
Baseline characteristic, 
potential confounder, sub-
group identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Gender 
Baseline characteristic, 
potential confounder, sub-
group identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Height 
Baseline characteristic, 
potential confounder, sub-
group identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Weight 
Baseline characteristic, 
potential confounder, sub-
group identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Insurance Type 
Baseline characteristic, 
Potential confouncer, 
subgroup identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan 
Date of first Diagnosis of 
RA 
Baseline characteristic, 
potential confounder, sub-
group identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
 
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Smoking history and 
current smoking status 
Baseline characteristic, 
potential confounder, sub-
group identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Comorbidities 
Baseline characteristic, 
potential confounder, sub-
group identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Erythrocyte Sedimentation 
Rate (ESR) and C-Reactive 
Protein (CRP) 
Baseline characteristics and 
outcome variable 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Rheumatoid Factor (RF), 
Anti-citrullinated protein 
antibodies (ACPA) 
Baseline characteristic, 
potential confounder, sub-
group identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Prognosis factors 
Baseline characteristic, 
potential confounder, sub-
group identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Prior drug treatment for RA 
Potential confounder, sub-
group identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Concomitant  treatment of 
RA with Glucocorticoids  
Potential confounder, sub-
group identifier 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Patient’s Global 
Assessment of Arthritis 
Baseline and outcome 
variable 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Physician’s Global 
Assessment of Arthritis 
Baseline and outcome 
variable 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Patient’s Assessment of 
Arthritis Pain 
Baseline and Outcome 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Tender and swollen (28) 
joint count 
Baseline and Outcome 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Duration of Morning 
Stiffness 
Baseline and Outcome 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Functional Ability 
Questionnaire Hannover 
(FFbH) 
Baseline and Outcome 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
EuroQoL EQ-5D-3L Health 
State Profile 
Baseline and Outcome 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Functional Assessment of 
Chronic Illness Therapy 
(FACIT) Fatigue Scale 
Baseline and Outcome 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
Patient’s satisfaction with 
drug treatment 
Baseline and Outcome 
Case records/eCRF 
Details will be provided in 
Statistical Analysis Plan  
 
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Table 6 Variables 
7.4. Data sources  
The data will be recorded using an electronic case report form (eCRF) for each patient 
included. The completed eCRFs 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 signed by the treating 
physician or authorized personnel.  
All corrections of entries on the eCRFs must be explained (reason for change) and signed 
off (electronic signatures) if available signature was broken. Corrections of entries are 
automatically recorded by the system (incl. date of change, user changing data, 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.  
In some cases, the eCRF or part of the eCRF can also serve as a source document. In 
these cases, a document must be available at the doctor’s study site and at Pfizer and 
must clearly identify the data recorded in the eCRF and for which the eCRF is considered 
a source document. 
The clinical parameters recorded, especially those used to assess efficacy, are usual, 
known and recognized variables within each respective indication. 
7.5. Study procedure 
Patients attending can be included by the HCP if they fulfil all selection criteria for the 
study and are started on treatment with Tofacitinib for moderate to severely active 
rheumatoid arthritis. 
All visits shall be scheduled according to clinical practice. The treatment of a patient is 
independent from the patient enrolment into the study. Within this study 9 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 
2 to 9 occurring +/- 14 days of the scheduled visit date will be used for data analysis.  
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 questionnaires will be provided. 
The collection of all data is prospective. 
 
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Dose and duration of treatment should be based on clinical and individual needs and are 
determined by the treating physician. To provide accurate information regarding the 
treatment, the initial Tofacitinib dose and all changes and the reasons for changes are 
documented during the course of the evaluation. The concomitant treatment of 
rheumatoid arthritis with Glucocorticoids is determined by the treating physician and is 
registered in the documentation sheet.  
 
7.5.1. Study Period 
The planned observation period of each patient is 24 months. In this time period, up to 9 
visits will be documented. 
7.5.1.1. Baseline visit 
The following parameters will be documented at baseline visit 
• Informed Consent. 
• Prognostic factors (from prior history) 
• Documentation of initial diagnosis of RA 
• Documentation of relevant comorbidities 
• Demographic data 
• Documentation of insurance type 
• Physical Examination (weight, height) 
• Smoking history and current smoking status 
• Inclusion/ Exclusion criteria according to protocol 
• Varicella vaccination status 
• RA-Treatment with Tofacitinib and/or other DMARDs  
• Prior drug treatment of RA 
• Concomitant treatment of RA with Glucocorticoids 
• Inflammatory Markers: 
• Erythrocyte sedimentation rate (ESR) 
 
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• C-reactive protein (CRP) 
• Number of swollen and tender joints 
• Duration of Morning stiffness 
• Patient’s Global Assessment of Arthritis 
• Physician’s Global Assessment of Arthritis 
• Patient’s Assessment of Arthritis Pain 
• Functional Ability Questionnaire Hannover (FFbH) 
• EuroQoL EQ-5D-3L Health State Profile 
• FACIT – Fatigue Scale 
• Patient’s overall satisfaction with prior drug treatment 
 
 
7.5.1.2. Scheduled Visits 2- 8 /month 3 – month 21 
Following parameters will be documented at each interim visit: 
• RA treatment with Tofacitinib and/or other DMARDs  
• Concomitant treatment of RA with Glucocorticoids 
• Inflammatory Markers: 
• Erythrocyte sedimentation rate (ESR) 
• C-reactive protein (CRP) 
• Documentation of Adverse Events (AE) 
• Number of swollen and tender joints 
• Duration of Morning stiffness 
• Patient’s Global Assessment of Arthritis 
• Physician’s Global Assessment of Arthritis 
 
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• Patient’s Assessment of Arthritis Pain  
• Functional Ability Questionnaire Hannover (FFbH) 
• EuroQoL EQ-5D-3L Health State Profile 
• FACIT – Fatigue Scale 
• Patient’s satisfaction with drug treatment 
 
7.5.1.3. Final (or close out) Visit 9 / month 24 
Following parameters will be documented at final visit: 
• RA treatment with Tofacitinib and/or other DMARDs 
• Concomitant treatment of RA with Glucocorticoids 
• Inflammatory Markers: 
• Erythrocyte sedimentation rate (ESR) 
• C-reactive protein (CRP) 
• Documentation of AE 
• Number of swollen and tender joints 
• Duration of Morning stiffness 
• Patient’s Global Assessment of Arthritis 
• Physician’s Global Assessment of Arthritis 
• Patient’s Assessment of Arthritis Pain 
• Functional Ability Questionnaire Hannover (FFbH) 
• EuroQoL EQ-5D-3L Health State Profile 
• FACIT– Fatigue Scale 
• Patient’s satisfaction with drug treatment 
 
 
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7.5.1.4. Treatment Withdrawal 
Patients experiencing adverse drug reactions as listed in the Xeljanz® SmPC or in the 
SmPCs of the other prescribed DMARDs with particular attention paid to Sections 4 
(Contraindications), 5 (Special Warnings and 6 (Precautions)] should be monitored and if 
indicated, treatment should be withdrawn according to provision of the respective SmPC. 
If treatment with Tofacitinib or other DMARDs is withdrawn patients are followed up 
until the end of the observation period unless they withdraw from the study (see section 
8.2).  
 
 
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Inflammatory Markers  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Documentation of AE 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Number of swollen and tender joints 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Duration of Morning stiffness 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient’s Global Assessment of 
Arthritis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physician’s Global Assessment of 
Arthritis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient’s Assessment of Arthritis Pain 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Functional Ability Questionnaire 
Hannover (FFbH) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
EuroQoL EQ-5D-3L  
x 
x 
x 
x 
x 
x 
x 
x 
x 
FACIT – Fatigue Scale  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient’s satisfaction with drug 
treatment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
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7.6. Assessments 
7.6.1. Physical Examination 
At the Baseline Visit (Visit 1) height and weight will be documented. 
7.6.2. Prognostic Factors 
Prognostic factors will be determined at the Baseline Visit (Visit 1) based on prior 
medical history. The EULAR recommendation for the management of rheumatoid 
arthritits with synthetic and biological disease-modifying antirheumatic drugs [12] 
defines the following poor prognostic factors: 
• Moderate (after conventional synthetic DMARD [csDMARD] therapy) to high 
disease activity according to composite measures 
• High acute phase reactant levels 
• High swollen joint counts 
• Presence of RF especially at high levels 
• Presence of ACPA, especially at high levels 
• Combinations of the above 
• Presence of early erosions 
• Failure of two or more csDMARDs 
 
7.6.3. Insurance Type 
Insurance type will be documented at the first visit (baseline visit). Patients can either 
have  statutory health insurance or private insurance. 
7.6.4. Varicella vaccination status 
At the Baseline Visit (Visit 1) current varicella vaccination status of patients will be 
assessed. 
7.6.5. Treatment of Rheumatoid Arthritis (RA-Treatment) with Tofacitinib and/or 
other DMARDs 
At each visit (visits 1-9) dose and route of administration (if applicable) of treatment with 
Tofacitinib and/or other DMARDs will be documented. If an escalation (as defined in 
section 6.1.1) occurred since the last visit, in addition stop date of previous DMARD(s), 
start date of new DMARD(s) and reason for switch (lack of efficacy or intolerability) will 
be documented.  
7.6.6.  Concomitant treatment for rheumatoid arthritis with glucocorticoids 
At each visit (visits 1-9) dose and route of administration of concomitant treatment with 
glucocorticoids will be documented. 
 
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7.6.7. Effectiveness criteria 
The effectiveness of the treatment with Tofacitinib will be documented using the 
following tools for the evaluation of the course of the disease: 
Table 8. Disease Activity Indicators 
Indicator 
Definition/Calculation 
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 
Simplified Disease Activity Index (SDAI) 
(TJC28) + (SJC28) + [PhyGA in cm] + [PtGA in 
cm] + [CRP in mg/dL] 
Clinical Disease Activity Index (CDAI) 
(TJC28) + (SJC28) + [PhyGA in cm] + [PtGA in 
cm] 
ACR/EULAR Boolean-based definition of 
remission 
A patient must satisfy all of the following: tender 
joint count ≤ 1, swollen joint count ≤ 1, CRP ≤ 1 
mg/dL, subject’s global assessment of arthritis ≤ 1 
on a 0-10 scale 
 
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 Arthritis; 
PhyGA = Physician’s Global Assessment of Arthritis 
 
7.6.8. Joint Counts 
7.6.8.1. Tender/Painful Joint Count (TJC28) 
Twenty-eight (28) joints will be assessed to determine the number of joints that are 
considered tender or painful. The 28 joints to be assessed are the shoulders, elbows, 
wrists, metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, 
and knees. Artificial joints will not be assessed. 
The response to pressure/motion on each joint will be assessed.  
7.6.8.2. Swollen Joint Count (SJC28) 
The 28 swollen joint count includes the following joints: shoulders, elbows, wrists, 
metacarpophalangeal joints (MCP), proximal interphalangeal joints (PIP), and knees. 
Artificial joints will not be assessed. 
The swelling of each joint will be assessed. 
7.6.9. Patient Assessment of Arthritis Pain 
Patients will assess the severity of their arthritis pain using a 100 mm visual analog scale 
(VAS) by placing a mark on the scale between 0 (no pain) and 100 (most severe pain), 
which corresponds to the magnitude of their pain. “How severe is your pain today? Place 
a vertical mark on the line below to indicate how bad you feel your pain is today.” 
 
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7.6.10. Patient Global Assessment of Arthritis (PtGA) 
Patients will answer the following question, “Considering all the ways your arthritis 
affects you, how are you feeling today?” The patient’s response will be recorded using a 
100 mm VAS with anchors on 0 = very well and 100 = very poorly. 
7.6.11. Physician Global Assessment of Arthritis (PhyGA) 
The HCP will assess how the patient’s overall arthritis appears at the time of the visit. 
This is an evaluation based on the patient’s disease signs, functional capacity and 
physical examination, and should be independent of the Patient’s Global Assessment of 
Arthritis. The HCP’s response will be recorded using a 100 mm VAS with 0 mm = no 
disease activity and 100 mm = worst disease activity. “Physician’s Global Assessment of 
Rheumatoid Arthritis. Place a vertical mark on the line below to indicate the Disease 
Activity.”  
7.6.12. Duration of Morning Stiffness 
The duration of morning stiffness will be determined by asking the following questions: 
“When you wake up in the morning, do you currently suffer from  morning stiffness?” 
“How long does the morning stiffness last from the time you wake up?”  
7.6.13. Functional Ability Questionnaire Hannover (FFbH) 
The FFbH for RA is a German Short questionnaire for the assessment of patientive 
functional capacity in the context of basic everyday activities (range: 0-100% functional 
capacity)[18]. Functional remission in FFbH is defined as functional capacity > 83 %. 
 
7.6.14. EuroQoL EQ-5D-3L Health State Profile 
The EuroQoL EQ-5D-3L Health State Profile[19] is 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. 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. 
7.6.15. Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale 
The FACIT – Fatigue Scale is a patient completed questionnaire[20]consisting of 13 
items that assess fatigue. Instrument scoring yields a range from 0 to 52, with higher 
scores representing better patient status (less fatigue). This questionnaire should be 
completed by the patient prior to any procedures being performed at the visit, if possible. 
The form should then be checked by site staff for completeness. 
7.6.16. Patient’s satisfaction with drug treatment 
Satisfaction with treatment will be assessed on a 5-point Likert scale (where 0 = 
extremely dissatisfied, 1= dissatisfied, 2 = neither satisfied nor dissatisfied, 3 = satisfied 
 
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and 4 = extremely satisfied) in response to the question “How satisfied are you with the 
drugs that you have received for your arthritis since your last visit?” 
7.6.17. C-reactive Protein (CRP) 
The CRP shall be analysed by a local laboratory according to usual practice. It will be 
used in the calculation of several efficacy parameters. 
7.6.18. Erythrocyte Sedimentation Rate (ESR) 
The ESR shall be analysed by a local laboratory according to usual practice. It will be 
used in the calculation of several efficacy parameters. 
 
7.6.19. Safety 
All adverse events (AEs) that will occur during the observation period will be 
documented. At the final visit or if a patient is switched from Tofacitinib to another 
DMARD, the HCP will be asked to assess the general tolerability of the treatment with 
Tofacitinib and the reasons for discontinuation (intolerability or lack of efficacy) will be 
analysed.. Patient’s satisfaction with drug treatment will be assessed as described in 
section 7.6.16. 
7.7. Study size  
The analysis of the primary endpoint is a time to event analysis, where the event is treatment 
escalation. It is possible for multiple events to occur for each patient within the follow-up 
period. The primary analysis aims to investigate which of the factors listed actually affect the 
rate at which a patient’s treatment is changed. In order to determine an appropriate sample 
size for this study recurrent event data was simulated, using the methods described by Jahn-
Eimermacher et al. (2015), and analysed using cox proportional-hazards models.[21] 
 
The distribution of each of the factors was obtained from the ORAL STANDARD study: 
Achieve DAS28 < 3.2  
 
- 
Binomial(n, 0.2) 
Achieve ΔDAS28 > 1.8 
 
- 
Binomial(n, 0.6) 
ΔPatient Global Assessment  
- 
Normal(-29.31, 38.5792) 
ΔPhysician Global Assessment 
- 
Normal(-27.01, 30.9662) 
ΔPain score 
 
 
 
- 
Normal(-34.99, 24.6722) 
The baseline hazard rate was assumed to be 3.16 events per patient over the follow-up 
period. 
 
The impact of each the factors on the hazard rate, (entered as the regression coefficient), is 
used to simulate the event times for each patient given their values for the simulated factors. 
The regression coefficients were assumed to be (-0.288, -2.303, -0.01, -0.01, -0.01). 
Simulations were carried out for sample sizes ranging from 100 to 4,500.  
Figure 2 shows the power to detect an effect of each factor against sample size for the 5 
different factors. 
 
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7.8. Data management  
 
Patients’ personal data will be collected, stored and processed exclusively in pseudonymised 
form in accordance with the national data protection laws. All data will remain in 
pseudonymised 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. Pfizer 
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 data capture (EDC) system 
Clincase (Quadratek Data Solutions Ltd.). Clincase fulfills all requirements of 21 Code of 
Federal Regulations (CFR) Part 11 and the central server situated in Germany is backed up 
once a day. Access to the system takes place via a secure website (Secure Sockets Layer 
(SSL) encryption). Access is only given to registered users who log in with a unique user 
name and password. Depending on their function in the study, individual users are assigned 
defined access rights. Access rights to the EDC system are monitored by authorised 
Advanced Medical Services GmbH (AMS) employees. 
 
Documentation by physicians will take place using paper questionnaires or eCRF masks. 
Patient questionnaires will be handed out in paper form and entered in the EDC system by 
AMS. Automatic checking 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 the physician’s electronic signature. 
 
Please refer also to previous sections 7.2, 7.3 Variables, and 0 Data sources 
7.9. 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. SAS (Version 9.1, 9.2, 9.3 or 9.4) will be used for all analyses. 
 
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7.9.1. Analysis Populations 
The Full Analysis Set is defined as patients who receive at least one dose of Tofacitinib 
and have at least one set of post-baseline measurements. 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. 
 
7.9.2. Efficacy Analysis 
7.9.2.1. Primary analysis  
The primary analysis will investigate the impact of various factors on the rate of treatment 
escalation. Cox proportional-hazards modelling will be used, with status of each patient 
(whether they experienced a treatment escalation or not) and the times of such treatment 
escalations being used for the baseline model.  
The factors that will be investigated and thus included in the model will be: 
• whether or not a patient achieves LDA, as defined by DAS28-4 (ESR) ≤3.2. 
• whether or not a patient achieves change from baseline in DAS28-4 (ESR) > 1.8 
• Patient’s Global Assessment of Arthritis 
• Physician Global Assessment of Arthritis 
• Patient’s Assessment of Arthritis Pain 
• Patient’s satisfaction with drug treatment 
If patients withdraw or are lost to follow-up they will be censored at the time of the last 
available visit. 
7.9.2.2. Secondary Analysis 
7.9.2.2.1. Time to Event Analysis 
Time to event endpoints will be investigated using Kaplan-Meier methodology and, where 
appropriate, Cox-Proportional Hazards modelling will be used to look at differences in event 
rate between sub-groups. . The time to event will be summarised in terms of medians and 
confidence intervals. Kaplan-Meier plots of the time to event over the study duration will be 
presented. 
 
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7.9.2.2.2. Rate of DAS28 Low Disease Activity (LDA) and Remission 
The rate of DAS28 LDA or remission will be presented as frequency and proportion of the 
patients achieving the relevant criteria at each time point.  See Section 7.9.2.2.4 for all 
definitions of LDA and Remission that will be used in the analysis. 
7.9.2.2.3. Change from Baseline  
The summary statistics of the absolute value and the change from baseline at each visit will 
be reported. Change from baseline will be presented for DAS28-4 (ESR) and DAS28-4 
(CRP) as well as the scores resulting from the PRO questionnaires; FFbH, EQ-5D-3L, 
FACIT-Fatigue and Patients satisfaction with treatment.  
7.9.2.2.4. Definitions and Derivations 
• Remission is assessed by: ACR-EULAR Boolean remission criteria; SDAI ≤ 3.3; CDAI 
≤2.8; DAS 28-4 (ESR) < 2.6 and DAS28-4 (CRP) < 2.6 
• Functional remission is defined as FFbH score > 83% 
• LDA is assessed by: SDAI ≤ 11; CDAI ≤10; DAS 28-4 (ESR) ≤3.2 and DAS28-4 (CRP) 
≤3.2. 
Where  
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. 
 
SDAI = TJC28 + SJC28 + PhyGA in cm + PtGA in cm + CRP in mg/dL 
CDAI = TJC28 + SJC28 + PhyGA in cm + PtGA in cm  
Where TJC is the Tender Joint Count, SJC is the Swollen Joint Count, CRP is the C-reactive protein in mg/L, 
ESR is the Erythrocyte Sedimentation Rate in mm/first hour and PtGA is the Patient’s Global Assessment of 
Health and PhyGA is the Physicians Global Assessment. 
7.9.2.2.5. Functional Ability Questionnaire-FFbH 
The FFbH consists of 18 questions with 3 possible responses (Yes; Yes, but with effort; No 
or only with outside help).  
The total score is the sum of the scores of all 18 questions, where for each question: 
• Yes = 2 points 
• Yes, but with effort = 1 point 
 
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• No or only with outside help = 0 points 
The Functional capacity [%] is then  
(Total score*100)/(2*number of valid responses) 
7.9.2.2.6. EQ-5D-3L 
The EQ-5D-3L is a standardised 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 three responses and the patient is asked to select the response that best 
describes them.  The responses are scored 1-3 as shown in Table 9. 
Table 9: EQ-5D scores 
Dimension 
Response  
Score 
Mobility 
 
I have no problems in walking about 
1 
I have some problems in walking about 
2 
I am confined to bed 
3 
Self-care 
 
I have no problems with self-care 
1 
I have some problems washing or dressing 
myself 
2 
I am unable to wash or dress myself 
3 
Usual 
activities 
(e.g. work, study, 
housework, family 
or leisure activities) 
I have no problems with performing my usual 
activities 
1 
I have some problems with performing my usual 
activities 
2 
I am unable to perform my usual activities 
3 
Pain/discomfort 
 
I have no pain or discomfort 
1 
I have moderate pain or discomfort 
2 
I have extreme pain or discomfort 
3 
Anxiety/depression 
 
I am not anxious or depressed 
1 
I am moderately anxious or depressed 
2 
I am extremely anxious or depressed 
3 
 
The score for each dimension is weighted in accordance with Table 10. 
 
Table 10: EQ-5D weightings 
EQ-5D 
Dimension 
Score = 1 
Score = 2 
Score 
= 3 
Mobility 
0 
0.069 
0.314 
Self-Care 
0 
0.104 
0.214 
Usual Activities 
0 
0.036 
0.094 
Pain/Discomfort 
0 
0.123 
0.386 
Anxiety/Depressio
n 
0 
0.071 
0.236 
 
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The following algorithm is then applied to calculate the EQ-5D Total Score: 
1. If all five EQ-5D dimensions have a score of 1 then the EQ-5D Total Score is 1. 
2. If any of the five EQ-5D dimensions have a score of 3, then the EQ-5D Total Score 
is: 
 
1 −0.081 −൭෍𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
5
1
൱−0.269 
3. If none of the five EQ-5D dimensions has a score of 3, then the EQ-5D Total Score is: 
 
1 −0.081 −൭෍𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
5
1
൱ 
 
Missing weighted dimension scores are replaced by the mean of the non-missing 
weighted dimension scores.  If a weighted score is missing and replaced in this way by a 
mean weighted score of zero, step 3 of the algorithm is applied. 
 
7.9.2.2.7. FACIT-Fatigue Scale 
The FACIT-Fatigue Scale is derived by taking the sum of the scores for the 13 questions in 
the instrument, resulting in a score between 0 and 52. 
 
7.9.1. Safety Analysis 
Adverse events will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of subjects. Safety data will be presented in tabular and/or graphical 
format and summarized descriptively, where appropriate. 
Medical history and physical examination information collected during the course of the 
study will not be captured for inclusion into the study database, unless otherwise noted.  
However, any untoward findings identified on physical examinations conducted after the 
administration of the first dose of study medication will be captured as an adverse event, 
if those findings meet the definition of an adverse event.  Data collected at Screening that 
is used for inclusion/exclusion criteria, such as laboratory data, ECGs and vital signs will 
be considered source data, and will not be captured for inclusion into the study database, 
unless otherwise noted.  Demographic data collected at Screening will be included in the 
study database. 
Adverse events will be reported according to the 3-tier approach as describe in section 
9.1. 
Reasons given for premature discontinuation will also be summarized. 
 
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7.10. Interim Analysis 
It is planned that there will be at least one interim analysis. The details of the timing and 
criteria for any interim analyses will be outlined in the SAP. 
7.11. Quality control 
The Sponsor delegates the conduct of this NIS to the Contract Research Organization 
AMS.  
Study Coordination has been assigned to a Project Manager and monitoring is conducted 
by clinical research associates (CRAs) of the company AMS. 
Upon enrolment of the first patient at the site, the CRA contacts the site to discuss details 
of the study and to clarify any questions. 
A total of 140 monitoring visits will be conducted. During each visit the CRA will check 
whether: 
• 
the patients have been informed and consented to their participation in the NIS, 
• 
all data have been entered into the eCRF and  
• 
all data can be verified in accordance with original patient files.  
A data manager from AMS will perform quality analyses of the data recorded in the 
eCRF in order to reveal any inconsistent or missing responses and a plausibility check 
will be run on the database to reveal any deviant values. 
Coherency tests will be conducted according to predefined criteria. If any inconsistencies 
are discovered in the eCRFs, the relevant data will be checked. 
Before the start of the study, the physician grants the CRA access to all medical records 
of the patients taking part in the NIS and supports the CRA in the performance of their 
tasks. The physicians also consent to the CRAs conducting site visits, if necessary 
repeatedly, for the purpose of monitoring the data collected and agree to ensure sufficient 
time for these visits. 
Additionally remote monitoring calls will be performed quarterly to discuss and solve 
inconsistencies or missing data in the eCRF with a site. 
The accompanying quality assurance measures are based on the Guidelines for Proper 
Conduct in Epidemiological Research (GEP), on the Draft Joint Recommendations of the 
German Federal Institute for Drugs and Medical Devices (Bundesamt für Arzneimittel 
und Medizinprodukte, BfArM), on the recommendations of the Paul Ehrlich Institute 
(PEI) on the planning, conducting and analysing non-interventional studies, as well as on 
the German Association of Research-Based Pharmaceutical Companies (vfa [Verband 
der forschenenden Pharma-Unternehmen]) – Recommendations for the Improvement of 
 
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Quality and Transparency of Non-Interventional StudiesLimitations of the research 
methods. 
 
7.12. Limitations of the research methods  
Randomised controlled trials are important and powerful tools in assessing efficacy and 
safety but have their limitations in terms of generalisability. In order to assess health 
economics, clinical effectiveness and safety of Tofacitinib in a usual care setting, parameters 
need to be determined by performing observational studies.  
 
Inherent limitations of non-interventional, observational, non-controlled, non-randomised 
studies in general are the risk of selection/ascertainment bias and some 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 (e.g. CRP not measured or FFbH questionnaire not completed). . 
Following up patients after treatment escalation, rather than discontinuing patients from the 
study when they switch from Tofacitinib, should result in a higher proportion of the patients 
remaining in the study until the planned completion date. Where data are missing, 
information from the patient at other visits may be used in the primary analysis model to 
assess predictors of treatment decisions.  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. 
7.13. Other aspects 
Not applicable. 
 
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8. PROTECTION OF PATIENTS 
8.1. Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient 
names on any sponsor forms, reports, publications, or in any other disclosures, except 
where required by laws. In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of patient personal data. 
The informed consent form must be in compliance with local regulatory requirements and 
legal requirements. 
The informed consent form used in this study, and any changes made during the course of 
the study, must be prospectively approved by both the independent ethics committee 
(IEC) and Pfizer before use. 
The HCP must ensure that each study patient, or his/her legally acceptable representative, 
is fully informed about the nature and objectives of the study and possible risks 
associated with participation. The HCP, or a person designated by the HCP, will obtain 
written informed consent from each patient or the patient’s legally acceptable 
representative before any study-specific activity is performed. The HCP will retain the 
original of each patient's signed consent form. 
8.2. 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 HCP or sponsor for safety, behavioural, or 
administrative reasons. In any circumstance, every effort should be made to document 
subject outcome, if possible. The HCP should inquire about the reason for withdrawal 
and follow-up with the patient regarding any unresolved adverse events. The further 
treatment of a patient is independent from his/her withdrawal. 
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. 
8.3. Independent Ethics Committee (IEC) 
An IEC will review and approve the protocol before any patients are enrolled. 
8.4. Ethical Conduct of the Study 
The study will be conducted with scientific purpose, value and rigor in accordance with 
legal and regulatory requirements, such as §67 (6) of the German Drug Law (AMG) and 
the 
recommendations 
for 
the 
conduct 
of 
non-interventional 
studies 
(“Anwendungsbeobachtungen”) of the Federal Institute for Drugs and Medical Devices 
(BfArM) and the Paul-Ehrlich-Institut  Furthermore, it will follow generally accepted 
research practices described in Guidelines for Good Pharmacoepidemiology Practices 
 
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determined by the HCP to be related to a drug under study.  In particular, if the SAE is 
fatal or life-threatening, notification to the CRO AMS must be made immediately, 
irrespective of the extent of available event information.  This timeframe also applies to 
additional new (follow-up) information on previously forwarded safety event reports.  In the 
rare situation that the HCP does not become immediately aware of the occurrence of a safety 
event, the HCP must report the event within 24 hours after learning of it and document the 
time of his/her first awareness of the events. 
For safety events that are considered serious or that are identified in the far right column of 
the table above that are reportable to the CRO AMS within 24 hours of awareness, the HCP 
is obligated to pursue and to provide any additional information to the CRO AMS in 
accordance with this 24-hour timeframe.  In addition, an HCP may be requested by the CRO 
AMS to obtain specific follow-up information in an expedited fashion.  This information is 
more detailed than that recorded on the eCRF.  In general, this will include a description of 
the AE in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality.  Any information relevant to the event, such 
as concomitant medications and illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to the CRO 
AMS.  
9.1.1. Reporting period  
For each patient, the safety event reporting period begins at the time of  the patient’s first 
dose of Tofacitinib (Xeljanz®) or the time of the patient’s informed consent if s/he is already 
exposed to Tofacitinib (Xeljanz®), and lasts through the end of the observation period of the 
study, which must include at least 28 calendar days following the last administration of a 
drug under study; a report must be submitted to the CRO AMS   for any of the types of safety 
events listed in the table above occurring during this period.  If a 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 (e.g., patient changes his/her 
mind about participation, failed screening criteria), the reporting period ends on the date of 
the decision to not enroll the patient. 
 
If the HCP 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 (Xeljanz®), the SAE also must be reported 
to the CRO AMS. 
9.1.2. Causality assessment 
The HCP is required to assess and record the causal relationship.  For all AEs, sufficient 
information should be obtained by the HCP to determine the causality of each AE.  For AEs 
with a causal relationship to Tofacitinib (Xeljanz®), follow-up by the HCP is required until 
the event and/or its sequelae resolve or stabilize at a level acceptable to the HCP, and Pfizer 
concurs with that assessment.   
 
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An HCP’s  Tofacitinib (Xeljanz®)or other DMARDs causality assessment is the 
determination of whether there exists a reasonable possibility that Tofacitinib (Xeljanz®) or 
other DMARDs caused or contributed to an AE.  If the HCP’s final determination of causality 
is “unknown” and s/he cannot determine whether Tofacitinib (Xeljanz®) or other DMARD 
caused the event, the safety event must be reported within 24 hours.   
If the HCP cannot determine the etiology of the event but s/he determines that Tofacitinib 
(Xeljanz®) or other DMARD did not cause the event, this should be clearly documented on 
the eCRF and the NIS AEM Report Form.  
9.1.3. Definitions of safety events 
 
9.1.3.1. Adverse events (AE) 
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 AEs include but are not limited to:   
• Abnormal test findings (see below for circumstances in which an abnormal test finding 
constitutes an AE); 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• 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; 
 
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• 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 AE 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 AE by the HCP or sponsor. 
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. 
 
9.1.3.2. Serious adverse events 
A SAE 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. 
 
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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 pharmacovigilance 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 (e.g., 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; 
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 (e.g., patient has no place to sleep) 
• Administrative admission (e.g., for yearly exam) 
• Optional admission not associated with a precipitating medical AE (e.g., 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 (e.g., for work-up of 
persistent pre-treatment lab abnormality) 
 
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• Protocol-specified admission during clinical study (e.g., for a procedure required by the 
study protocol) 
 
9.1.4. Scenarios necessitating reporting to the CRO AMS 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 (e.g., environmental) Tofacitinib (Xeljanz®) or other DMARDs, or the female 
becomes, or is found to be, pregnant after discontinuing and/or being exposed to 
Tofacitinib (Xeljanz®)or other DMARDs  (maternal exposure). 
An example of environmental exposure would be a case involving direct contact with a 
Pfizer product in a pregnant woman (e.g., 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 (Xeljanz®) or other DMARDs prior to or around the time of conception and/or 
is exposed during the partner pregnancy (paternal exposure). 
As a general rule, prospective and retrospective exposure 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 (Xeljanz®) or another DMARD, this 
information must be submitted to the CRO AMS, irrespective of whether an AE has occurred 
using the NIS AEM Report Form and the EDP Supplemental Form.  
In addition, the information regarding environmental exposure to Tofacitinib (Xeljanz®) or 
another DMARD in a pregnant woman (e.g., a subject 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). 
 
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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 
(e.g., induced abortion) and the CRO AMS 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 (e.g., 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 HCP 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 (e.g., follow-up on 
preterm infants to identify developmental delays).   
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 (e.g., 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 
 
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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 labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; monitoring; and use.   
Medication errors include: 
• Near misses, involving or not involving a patient directly (e.g., inadvertent/erroneous 
administration, which is the accidental use of a product outside of labeling or prescription 
on the part of the healthcare provider or the patient/consumer); 
• Confusion with regard to invented name (e.g., trade name, brand name). 
The HCP must submit the following medication errors to the CRO AMS, 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 (e.g., 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. 
Overdose, Misuse, Extravasation 
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reported to the CRO AMS by the HCP, irrespective of the presence of an associated 
AE/SAE.  
Lack of Efficacy 
Reports of lack of efficacy to a Pfizer product are reported to the CRO AMS by the HCP, 
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 the CRO AMS by the 
HCP, irrespective of the presence of an associated AE/SAE. 
 
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9.2. Single reference safety document 
The Summary of product characteristic for Xeljanz® 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 the CRO AMS by the HCP during the course of this study.  
The Product Label should continue to be used by the HCP for prescribing purposes and 
guidance. 
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
10.1. Communication of study results 
It is planned that there will be at least one interim analysis. Results of interim analyses as 
described in the SAP are planned to be presented on national and international congresses. 
Final study results are additionally planned to be published peer-reviewed journals. 
10.2.  Communication of issues 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Competent Authority in any area of the world, or if the HCP is aware of any new information 
which might influence the evaluation of the benefits and risks of a Pfizer product, the CRO 
AMS should be informed immediately.  
In addition, the HCP will inform the CRO AMS immediately of any urgent safety measures 
taken by the HCP to protect the study patients against any immediate hazard, and of any 
serious breaches of this NI study protocol that the HCP becomes aware of. 
11. REFERENCES 
1 Strand V, Singh JA. Improved health-related quality of life with effective disease 
modifying antirheumatic drugs: evidence from randomized controlled trials. The 
American journal of managed care. 2007;13 Suppl 9:S237-51. Epub 2007/01/12. 
2 Gullick NJ, Scott DL. Co-morbidities in established rheumatoid arthritis. Best Pract 
Res Clin Rheumatol. 2011 Aug;25 (4):469-83 
3 Brown K. Rheumatoid Lung Disease. Proc Am Thorac Soc 
2007;4:443–448 
4 Gerhold K, Richter A, Schneider M, Bergerhausen H-J et al. Health-related quality of 
life in patients with long-standing rheumatoid arthritis in the era of biologics: data 
from the German biologics register RABBIT Rheumatology (Oxford) 
2015;54(10):1858–1866 
5 Boonen A, Severens JL. The burden of illness of rheumatoid arthritis. Clin 
Rheumatol. 2011;30 Suppl 1:S3–8 
 
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6 Zhang W, Anis AH. The economic burden of rheumatoid arthritis: beyond  health 
care costs. Clin Rheumatol. 2011;30 Suppl 1:S25–32. 
7 Emery P. Evidence supporting the benefit of early intervention in 
rheumatoid arthritis. J Rheumatol Suppl. 2002 Nov;66:3-8. 
8 Pincus T. Rheumatoid arthritis: a medical emergency? Scand J 
Rheumatol Suppl. 1994;100:21-30. 
9 Nell VP, Machold KP, Eberl G, et al. Benefit of very early referral and very early 
therapy with disease-modifying anti-rheumatic drugs in patients with early 
rheumatoid arthritis. Rheumatology (Oxford) 2004;43:906–14. 
 
10 van Nies JA, Krabben A, Schoones JW, et al. What is the evidence for 
the presence of a therapeutic window of opportunity in rheumatoid 
arthritis? A systematic literature review. Ann Rheum Dis 2014 
May;73(5):861-70. 
11 Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of 
tight control for rheumatoid arthritis (the TICORA study): a single-
blind randomized controlled trial. Lancet 2004;364:263–9. 
12 Smolen, J. S., R. Landewe, J. Bijlsma, G. Burmester, K. 
Chatzidionysiou, M. Dougados, J. Nam, et al. "Eular 
Recommendations for the Management of Rheumatoid Arthritis with 
Synthetic and Biological Disease-Modifying Antirheumatic Drugs: 
2016 Update." [In eng]. Ann Rheum Dis 76, no. 6 (Jun 2017): 960-77 
13 Felson DT, Smolen JS, Wells G, et al. American college of 
rheumatology/European league against rheumatism provisional 
definition of remission in rheumatoid arthritis for clinical trials. Ann 
Rheum Dis 2011;70:404–13. 
14 Albrecht et al. 2016 Klinische Remission bei rheumatoider Arthritis – 
Daten aus der Früharthritiskohortenstudie CAPEA  Z. Rheumatol 
75:90-96).  
15 Albrecht et al. 2017, Versorgung der rheumatoiden Arthritis 2014 –
Aktuelle Daten aus der Kerndokumentation, Z. Rheumatol 76:50-57 
16 Louder MA,Singh A, Saverno K, Cappelleri JC, Aten AJ et al. Patient Preferences 
Regarding Rheumatoid Arthritis Therapies: A Conjoint Analysis. Am Health Drug 
Benefits. 2016;9(2):84-93 
17 Krüger K, Alten R, Schiffner-Rohe  J, Behmer  OS, Schiffhorst G, J. Rellecke J, 
Nolting H.-D. Patient preference in the choice of disease modifying anti-rheumatic 
 
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drugs. Poster presented at the EULAR Annual European Congress of Rheumatology, 
Rome, Italy, June 10-13, 2015 
18 Lautenschläger J, Mau W, Kohlmann T, Raspe HH, Struve F, Brückle W, et al. 
[Comparative evaluation of a German version of the Health Assessment 
Questionnaire and the Hannover Functional Capacity Questionnaire]. [Article in 
German] Z Rheumatol 1997;56:144–55 
19 Hurst NP, Kind P, Ruta D, Hunter M, Stubbings A. Measuring health-related quality 
of life in rheumatoid arthritis: validity, responsiveness and reliability of EuroQol 
(EQ-5D). British journal of rheumatology. 1997;36(5):551-9. Epub 1997/05/01. 
20 Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in cancer patients 
compared with fatigue in the general United States population. Cancer. 
2002;94(2):528-38. Epub 2002/01/15. 
21 A.Jahn-Eimermacher et al. Simulating recurrent event data with hazard functions 
defined on a total time scale. BMC Medical Research Methodology, 15:16, 2015. 
 
 
12. LIST OF TABLES  
Table 1 Study information .........................................................................................................2 
Table 2 List of Abbreviations ....................................................................................................8 
Table 3 Responsible Parties .......................................................................................................9 
Table 4 Amendments and Updates ..........................................................................................10 
Table 5 Milestones ...................................................................................................................11 
Table 6 Variables .....................................................................................................................18 
Table 7. Schedule of Activities ................................................................................................23 
Table 8. Disease Activity Indicators ........................................................................................26 
Table 9: EQ-5D scores ............................................................................................................33 
Table 10: EQ-5D weightings ...................................................................................................33 
Table 11 Requirements for recording safety events ................................................................38 
 
13. LIST OF FIGURES 
Figure 1. Timelines ..................................................................................................................15 
 
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Tofacitinib citrate 
A3921302 OBSERVATIONAL PLAN NON-INTERVENTIONAL STUDY 
Final, 23 August 2017  
 
Figure 2: Plot of Power against Sample Size for simulations of recurrent event data 
analysed using cox-proportional hazards model including all 5 factors 
of interest. ....................................................................................................29 
 
ANNEX 1 LIST OF STAND ALONE DOCUMENTS 
None 
ANNEX 2 ADDITIONAL INFORMATION 
Not applicable 
 
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