IDentification of Predictive Factors of Continuation of Treatment With Tofacitinib in Patients With Rheumatoid Arthritis in Common Practice and the Impact of the Patient's Behavioural Strategies on Clinical Parameters: The DeFacTo Study.
Conditions: Arthritis, Rheumatoid
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
Information on the study   
Title 
IDentification of Factors predictive of Tofacitinib’s 
survival in patient with rheumatoid arthritis in routine 
practice and impact of patients’ behavioural strategies on 
clinical parameters: the DeFacTo study. 
Protocol number 
A3921313 
Protocol version 
2.0 
Date of last version of protocol 
21 december 2020 
Active substance  
Tofacitinib (a selective immunosuppressant, JAK 
inhibitor, and a targeted synthetic DMARD) 
Medicinal product 
XELJANZ®, Tofacitinib citrate 
Question and objectives of the study  
The primary objective of this study is to identify factors 
predictive of drug survival with Tofacitinib in RA patient.  
In addition to evaluation of effectiveness and tolerability, 
one of the secondary objectives is to evaluate the impact 
of patients’ behavioural strategies on Tofacitinib drug 
survival and other clinical parameters in routine practice. 
Author 
  
Responsable Médical et Scientifique Inflammation & 
Immunologie PFIZER  
 
 
 
 
 
 
This document contains confidential information that is the property of Pfizer. Unless otherwise indicated in 
writing, by accepting or revising this document, you agree to keep this information confidential and to not 
copy or disclose it to other persons (except when applicable law so requires) or to not use it for unauthorised 
purposes. In the eventuality of a real or suspected violation of this obligation, Pfizer should be immediately 
notified.  
PPD
PPD

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1. TABLE OF CONTENTS 
 
1. TABLE OF CONTENTS ...................................................................................................... 2 
2. LIST OF ABBREVIATIONS ............................................................................................... 5 
3. RESPONSIBLE PARTIES ................................................................................................... 7 
4. SUMMARY .......................................................................................................................... 9 
5. AMENDMENT(S) .............................................................................................................. 14 
6. STUDY MILESTONES ...................................................................................................... 14 
7. JUSTIFICATION AND CONTEXT .................................................................................. 15 
8. STUDY OBJECTIVES ....................................................................................................... 17 
9. METHODS .......................................................................................................................... 17 
9.1. Study design............................................................................................................ 17 
9.1.1. Study Schema ............................................................................................. 17 
9.1.2. Set up of centres ......................................................................................... 19 
9.1.3. Visit for inclusion: Establishment of the cohort and collection of data ..... 20 
9.1.4. Follow-up visits of patients ........................................................................ 20 
9.1.5. Withdrawal of a patient from the study...................................................... 21 
9.1.6. Endpoints ................................................................................................... 21 
9.1.6.1. Primary endpoint ...................................................................... 21 
9.1.6.2. Secondary endpoints ................................................................. 21 
9.2. Context .................................................................................................................... 22 
9.2.1. Criteria for inclusion .................................................................................. 23 
9.2.2. Criteria for non-inclusion ........................................................................... 23 
9.3. Variables ................................................................................................................. 23 
9.3.1. Data collected by sites ................................................................................ 23 
9.3.2. Patient Reported Outcomes ........................................................................ 26 
9.3.2.1. PCS questionnaire PCS – Pain Catastrophizing Scale 
(Annexe 3.1): .................................................................................... 26 
9.3.2.2. CSQ questionnaire– Coping Strategies Questionnaire 
(Annex 3.2): ...................................................................................... 26 
9.3.2.3. GIRERD questionnaire (Annex 3.3): ....................................... 26 
9.3.2.4. FiRST questionnaire -Fibromyalgia Rapid Screening Tool 
(Annex 3.4): ...................................................................................... 26 
9.3.2.5. Euro QoL EQ-5D -3L questionnaire (Annex 3.5): ................... 26 

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9.3.2.6. SF-12 questionnaire – Short Form Survey (Annex 3.6): .......... 27 
9.3.2.7. FACIT-F questionnaire - Functional Assessment of 
Chronic Illness Therapy-Fatigue (Annex 3.7): ................................. 27 
9.4. Sources of data ........................................................................................................ 27 
9.5. Sample size ............................................................................................................. 28 
9.6. Data management ................................................................................................... 28 
9.7. Data analysis ........................................................................................................... 32 
9.8. Quality control ........................................................................................................ 34 
9.8.1. Data entry in centres................................................................................... 34 
9.8.2. Quality control ........................................................................................... 34 
9.9. Limits of the methods of research .......................................................................... 35 
9.10. Other aspects ......................................................................................................... 35 
9.10.1. Logistical follow-up ................................................................................. 36 
9.10.2. Data collection ......................................................................................... 36 
9.10.3. Archiving ................................................................................................. 37 
10. PROTECTION OF PATIENTS ........................................................................................ 37 
10.1. Information and protection of patients ................................................................. 37 
10.2. Patient Information Leaflet ................................................................................... 37 
10.3. Withdrawal of the patient ..................................................................................... 38 
10.4. Ethics Committee (CPP) ....................................................................................... 38 
10.5. National Medical Council (CNOM) ..................................................................... 38 
10.6. Protection of data: National Data Processing Commission “CNIL” .................... 39 
10.7. Ethical conduct of the study ................................................................................. 39 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS ................................... 40 
11.1. Single reference document on safety of use ......................................................... 40 
11.2. Requirements in terms of pharmacovigilance ...................................................... 40 
12. PLANS FOR COMMUNICATION OF STUDY RESULTS ........................................... 48 
12.1. Scientific Committee ............................................................................................ 48 
12.2. Access to source data ............................................................................................ 48 
12.3. Confidentiality ...................................................................................................... 48 
12.4. Data ownership ..................................................................................................... 49 
12.5. Communication and publication ........................................................................... 49 
12.6. Communication of problems ................................................................................ 49 
13. REFERENCES .................................................................................................................. 49 
14. LIST OF TABLES ............................................................................................................ 53 

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15. LIST OF FIGURES ........................................................................................................... 53 
ANNEX 1. LIST OF INDEPENDENT DOCUMENTS ......................................................... 53 
ANNEX 2. ADDITIONNAL INFORMATION ..................................................................... 53 
 

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2. LIST OF ABBREVIATIONS 
Abbreviation 
Definition  
ACPA 
Anti-citrullinated protein antibody  
(e)CRF 
electronic Case Report Form  
ACR 
American College of Rheumatology 
AE(S)s 
Adverse Events (Serious) 
AEM 
Adverse Event Monitoring 
JIA 
Juvenile Idiopathic Arthritis 
ANSM 
French National Agency for the Safety of Medicines and Health 
Products Safety 
BMI 
Body Mass Index  
CDAI 
Clinical Disease Activity Index 
CENGEPS 
French National Centre for Management of Healthcare Product Trials  
CNIL 
National Commission on Data processing and Freedoms  
CNOM 
National Medical Council 
CPP 
Committee for the Protection of persons (Ethics Committee) 
CRA 
Clinical Research Associate  
CRP 
C Reactive Protein  
CSQ 
Coping Strategies Questionnaire 
CYP 
Cytochrome P450 
DAS 
Disease Activity Score 
DMARD 
Disease-Modifying Anti-Rheumatic Drug 
EMA 
European Medicines Agency 
ESR 
Erythrocyte sedimentation rate 
EULAR 
EUropean League Against Rheumatism 
EuroQoL 
EQ-5D-3L 
EuroQoL EQ-5D-3L:  5-dimensions of health status questionnaire 
FACIT-
Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FiRST 
Fibromyalgia Rapid Screening Tool 
FPFV 
First Patient First Visit 
GVP 
Guidelines on good pharmacovigilance practice 
IL 
Information Leaflet 
LPLV 
Last Patient Last Visit 
MA 
Market Authorisation 
TJC 
Tender Joint Count 
SJC 
Swollen Joint Count 
PCS 
Pain Catastrophising Scale 
PhGA 
Physician Global Assessesment 
PtGA 
Patient Global Assessesment 
PV 
Pharmacovigilance 
QC 
Quality Control 
RA 
Rheumatoid Arthritis  
RF 
Rheumatoid Factors  
RMP 
Risk Management Plan 
SDAI 
Simplified Disease Activity Index 

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SF-12 
Short Form-12 Health Survey – 12-item quality of life questionnaire  
SmPC 
Summary of Product Characteristics 
VAS 
Visual Analogue Scale 
WHO 
World Health Organisation  
WMA 
World Medical Association 

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3. RESPONSIBLE PARTIES 
Principal investigator(s) of the protocol 
Name(s), diploma(s) 
Position title 
Institution 
Address 
Separated document 
 
 
 
 
Pfizer project team 
Nom 
Titre 
Fonction 
Adresse 
 
Docteur 
 
  
 
 
 
 
Docteur 
 
 
  
 
 
 
 
Madame 
 
 
  
 
 
 
 
Madame 
 
  
 
 
 
 
Monsieur 
 
  
 
 
 
 
Scientific Committee Experts
Name 
Title 
Firm 
Address  
 
Professor 
 
 
 
 
 
 
 
Doctor 
 
 
 
 
 
 
 
Coordinator of the Scientific Committee 
 
1 CHR: Regional Hospital Centre 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Name 
Title 
Firm 
Address  
 
Professor 
 
 
 
 
 
 
 
PPD
PPD
PPD

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5. AMENDMENT(S) 
A substantial amendment is a change that is likely to have an impact on the safety or physical 
or mental integrity of study participants or that may affect the results of the study and their 
interpretation, e.g. changes in the primary or secondary objectives of the study, study 
population, study design, data sources, data collection method, sample size, definitions of 
primary exposure, results and confounding factors as well as the analytical design as 
described in the protocol. 
Amendment 
number 
Date 
 
Modified 
section(s) of 
protocol 
Summary of amendment(s) 
Reason 
Version 2.0 
21- DEC -2020 
Version 1.2 
modified by 
version 2.0 
Cover page 
Summary 
Section 6 
Sections 9.2 et 
9.5 
Section 9.3.2.1 
Section 9.6.3 
Section 12 
Section 13 
Updated the protocol template used, 
in accordance with Pfizer Inc 
Standard Operating Procedures 
Modification of the Medical and 
Scientific Responsible 
Introduction of new tofacitinib 
dosage as per SmPC 
Adding study planned schedules 
(Section 6) 
Change in recruitment target 
Update the PCS Self Questionnaire 
Score Threshold – Pain 
Catastrophizing Scale  
Clarification on the secure-cover 
self-questionnaires transmission 
circuit 
Clarification on the publication of 
the study results 
Added a bibliographic reference 
following the update of the PCS 
questionnaire score 
The target of 500 patients could not be 
achieved given the decline in visits this 
year due to the COVID-19 pandemic. 
The number of patients to be included 
was reduced, and the resulting 
hypotheses and sample calculation were 
adjusted accordingly. 
 
6. STUDY MILESTONES 
Table 2: Planned Study Schedule 
Study milestone 
Expected date 
Selection of investigator sites 
July 2018 – July 2019 
Start of data collection 
January 2019 
End of data collection 
January 2023 

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Final study report 
January 2024 
 
7. JUSTIFICATION AND CONTEXT 
Rheumatoid arthritis (RA) is a chronic auto-immune disease characterised by inflammation 
and joint destruction which is at the origin of progressive incapacity and negative 
psychological effects (1, 2). RA is a problem of public health, whether at the level of the 
individual or of society, in particular, regarding incapacity for work and resultant loss of 
productivity (3, 4). 
Earlier diagnosis leading to earlier therapeutic intervention with the goal of disease activity 
control, maintenance of physical function, optimization of quality of life and improvement of 
patient mindset, is a universally recognized principle (1, 5). 
The recent European League Against Rheumatism (EULAR) recommendations (5) and the 
current recommendations of the French Society of Rheumatology (SFR) (1) define treat-to-
target as the basic therapeutic principle in order to reach a target of sustained remission or low 
disease activity in every patient. Conventional synthetic DMARDs, mainly methotrexate 
(MTX), in the absence of contraindication, constitute the first-line treatment approach of 
symptomatic RA patients (1, 5). In case of inadequate or insufficient response to csDMARDs 
with persistent disease activity, treatment with biologic agents, like Tumor Necrosis Factor α 
(TNFα) blockers therapy or biologic agents with other mechanism of action should be offered. 
Biologic DMARDs have proven their efficacy on symptoms and signs of rheumatoid arthritis, 
quality of life, productivity and on reducing joint destruction (1, 5). 
As recently, two orally targeted synthetic DMARDs (ts-DMARDs) of the new class called 
Janus kinase inhibitors (JAK-inhibitors) has been brought into the market in the European 
Union (6), the EULAR recommendations were expanded to include tsDMARDs : “If the 
treatment target is not achieved with the first csDMARD strategy, when poor prognostic 
factors are present, addition of a bDMARD or a tsDMARD should be considered” (5). 
XELJANZ® is one of these two ts-DMARDs (7, 8). It is a selective and reversible inhibitor of 
Janus kinases JAK 1 and JAK 3, enzymes involved in the pathophysiology of RA through 
signal transduction of many cytokines (7, 8). 
It has the specificity of being administered orally while the biological background treatments 
currently available are all administered by parenteral route. The recommended dosage is one 
Tofacitinib 5 mg tablet (immediate release tablets) twice daily or Tofacitinib 11 mg (extended 
release tablets) once a day, the transition from one formulation to another is possible 
according to the recommendations mentioned in the SmPC (7, 8). 
Xeljanz® (Tofacitinib), in combination with methotrexate (MTX), obtained on 22 March 2017 
Market Authorisation (MA) in the treatment of moderate-to-severe active RA in adult patients 
who have responded inadequately to, or who are intolerant to one or more disease modifying 
anti-Rheumatic drugs (DMARDs). Furthermore, Xeljanz® can also be administered as 
monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate (7, 
8). The recommended dosage is 5 mg of Tofacitinib bid (7, 8). 
In its opinion of 27 September 2017, the French Transparency Commission issued a 
favourable opinion to registration of XELJANZ® on the list of medicinal products 
reimbursable to social security beneficiaries and on the list medicinal products certified for 
use by communities in the indication and dosage of the Market Authorisation (7). 

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Evaluation of the efficacy and safety of Tofacitinib in the treatment of rheumatoid arthritis is 
based on a wide clinical development plan including 7 phase III studies and 2 long-term 
extension studies (7, 9-15, 16) which to date amount to a total of over 22,800 patient-years 
exposure to treatment (17). 
In 2012, following market launch of XELJANZ® in the USA, post-marketing monitoring of 
patients exposed to Tofacitinib since November 2012 (FDA Market Authorisation), using the 
CORRONA US registry, was set up. To date, apart from Herpes Zoster, no specific safety 
signal has been demonstrated compared to other DMARDs (7). 
Currently marketed in over 80 countries worldwide (6) with over 110,000 patients who have 
been or are under treatment with Tofacitinib (17), XELJANZ® has a clinical experience and 
post-marketing follow-up of over 9 years (16, 17). 
Although the efficacy and safety profile of Tofacitinib is currently well-documented in the 
clinical setting (7, 9-15, 16), many fields of research remain to be investigated regarding this drug 
of a novel therapeutic class, including outcomes in the real world setting.  
Nowadays it is recognized that treatment retention is an overall marker of treatment success 
depending on multiple factor including efficacy, safety, patients’ and disease characteristics at 
baseline, patients’ and physicians’ confidence with the treatment (1, 5). Survival rate is a 
standardized method for identifying predictive factors of drug survival. Existing data with 
biologic DMARDs in rheumatoid arthritis have identified a number of independent predictors 
for treatment continuation (18-23). 
Regarding Tofacitinib, few data on drug retention in patients with rheumatoid are available 
(24). Based on the data of the Swiss Clinical Quality Management Registry (SCQM), recent 
findings of Finckh A et al. (24) have shown that Tofacitinib drug retention is at least 
comparable to other available biologic DMARDs. Even more, after adjustment for potential 
confounders including age, gender, disease duration, seropositivity,  BMI, smoking status, 
DAS28-CRP and the total number of previous biologic DMARDs, the adjusted analysis 
demonstrated a slightly higher hazard of drug discontinuation with TNF inhibitors compared 
to Tofacitinib (HR 1.27, 95%CI [1.02-1.57], p=0.04), while no difference was observed for 
biologic DMARDs with other mechanism of action and Tofacitinib (HR 1.03, 95%CI [0.83-
1.28], p=0.76) (24). 
And to date, no data exists on the factors predictive of Tofacitinib drug survival in the 
management of RA patients. 
The DeFacTo observational study will therefore has as primary objective to identify the 
factors predictive of Tofacitinib drug survival in patients with RA. 
Moreover, rheumatoid arthritis substantially affects quality of life. Different factors such as 
pain, disability or fatigue, which are directly or indirectly the result of inflammation, can have 
a negative influence on such quality of life (1, 25). Nevertheless, this quality of life is not 
governed solely by symptoms of the disease, but also by the behaviour of the patient, as well 
as the behavioural strategies which he/she evidences with regard to his/her disease. We often 
refer to the term catastrophisation (26-28) or coping (29-32) to evaluate such behavioural 
strategies. 
Catastrophisation is described as a distortion of the perception of pain involving a component 
that is both emotional and cognitive that pushes the patient to see only the worst (26-28). It is 
often the translation of a persistent or transient pessimism, separate from depression. 

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On the contrary, coping corresponds to all processes by which a patient strives to “do the 
best” with his/her disease. Coping implies adaptive strategies where the patient tries to find 
solutions in order to deal successfully with his/her disease (29-32). It has been demonstrated that 
such behavioural strategies can influence directly or indirectly the intensity of symptoms (33). 
Both catastrophisation and coping can be evaluated and rated by a specific validated patient 
questionnaire, Catastrophizing Pain Scale (34, 35) and Coping Strategies Questionnaire (29-32) 
respectively. 
To date, no data exists in the literature regarding the impact of behavioural strategies, whether 
catastrophisation or coping, on DMARDs drug survival and other clinical parameters in 
patients suffering from rheumatoid arthritis. Therefore it will be evaluated in this study as 
secondary objectives.  
The DeFacTo study will also make it possible to collect data on effectiveness and tolerability 
of Tofacitinib under real-life conditions of use in French patients with rheumatoid arthritis. 
8. STUDY OBJECTIVES 
Primary objective of the study   
• To identify factors predictive of drug survival with Tofacitinib 
Secondary objectives 
• To evaluate the impact of behavioural strategies in patient with rheumatoid arthritis on 
Tofacitinib drug survival  
• To study the correlation between behavioural strategies and effectiveness 
• To evaluate the effectiveness of Tofacitinib 
• To evaluate the tolerability of Tofacitinib 
 
9. METHODS  
9.1. Study design  
9.1.1. Study Schema 
This is an observational, open-label, prospective, multi-centre, national study designed to 
identify factors predictive of Tofacitinib’s survival in patients with RA. Additionally it will 
provide real world patient outcome in France. Furthermore, data from France will be 
compared and also pooled with data from other countries. Details will be included in a 
separate analysis plan for a pooled analysis. 

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Figure 1: Study schema 
  
 
Patients can be enrolled in the study by their rheumatologist if they satisfy all of the following 
criteria for inclusion. All visits must be scheduled according to usual clinical practice. 
Medical follow-up of patients is independent of enrolment of patients in the study.  
In the setting of this study, 6 visits can be documented.  Data will be collected from the 
patient’s medical dossier at V0 and at time of the 6 follow-up visits: at 1 month (V1), at 3 
months (V2), at 6 months (V3), at 12 months (V4), at 18 months (V5) and at 24 months (V6). 
No sample will be collected specifically for this study. At each visit, patients will be subjected 
to management in compliance with healthcare standards. In order to collect comparable study 
data, visits 2 to 6 performed within ±14 days after planned date of the visit will be used for 
analysis of data. 
In case of discontinuation of treatment with Tofacitinib, for whatever reason, clinical data will 
be collected as close as possible to the date of such a discontinuation. 

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Likewise, in case of Tofacitinib discontinuation outside the 6 scheduled visits, an additional 
visit to collect clinical data as close as possible to the date of this discontinuation should be 
organised.  
Eligible patients will be followed starting from the date of the first prescription of 
Tofacitinib during 24 months, whether they continue treatment with Tofacitinib or not. 
The dose and duration of treatment, as well as the frequency of follow-up of the patient must 
be based on clinical and individual needs and will be determined by the rheumatologist. To 
provide precise information on treatment, the initial dose of Tofacitinib and all changes and 
reasons for changes will be documented in the evaluation.  
All AE spontaneously reported by the patient or observed by the participating physician 
during the study will be recorded on the AE page of the electronic case report form (eCRF). 
9.1.2. Set up of centres 
In order to ensure expected recruitment, the study will be conducted by about 100 
rheumatologists. Participating physicians will be selected from among those all over France 
out of the total number of French health institutions which manage patients with rheumatoid 
arthritis. 
In order to reach an objective of participation of 100 centres desired, the study will be offered 
to about 550 centres. 
In a first phase, all centres which have the potential to participate in the study will be 
contacted by Pfizer to submit to them a questionnaire on feasibility which will be sent to them 
by email.   
Physicians who accept to participate must return the “Participating physician” form to the 
centre for management of the study, attached to the email for proposal of the study. This will 
also enable them to choose the type of agreement to participate in this study. 
Following receipt by Pfizer of this form, physicians who accepted to participate will receive 
their agreements for signature and final validation of their participation. 
Physicians who do not respond after receipt of the invitation for participation will be 
contacted again in order to ensure that they do not wish to participate. 
Physicians who did not return their signed agreement within two weeks after its dispatch will 
also be reminded up until obtainment of the expected number of participating doctors. 
Once the agreement has been validated by Pfizer, the physician will be contacted by Pfizer in 
order to organise the set up of the centre. The latter will take place by Teleconference (TC) 
for each of the participating physicians involved in the study. During this TC, the study 
protocol, the logistics and pharmacovigilance will be presented. 
Each set up will result in distribution of access codes to the study eCRF. 
The study eCRF will include all documents necessary for perfect knowledge of the project 
and of its conduct: 
- 
opinion of the CPP, 
- 
authorisation of the CNIL (if applicable), 

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opinion from the CNOM2, 
- 
the study protocol, 
- 
the information leaflet, 
- 
the physician questionnaires (CRF), 
- 
the patient questionnaires. 
In order to enable constant contact between participating physicians and Pfizer, a green phone 
number (free phone) will be available. 
9.1.3. Visit for inclusion: Establishment of the cohort and collection of data  
Each physician will include consecutively all adult patients with rheumatoid arthritis and 
initiating treatment with Tofacinitib, seen in a consultation in a centre participating in the 
study. 
Each patient then must be informed about the principle of the study with the information 
leaflet, and if the patient accepts to participate in the study, the physician then must do the 
following: 
- 
provide the patient with the signed information leaflet,  
- 
complete the questionnaire corresponding to the visit for inclusion, 
- 
give his or her patient the PCS, CSQ, FiRST, GIRERD, EuroQoL EQ-5D-3L, 
- 
SF-12, FACIT-Fatigue questionnaires that the patient must complete and give 
back to his/her physician for return to the logistics centre of the study. 
Patient paper questionnaires will be recovered by a carrier who will deliver them to Pfizer and 
will be transferred by Pfizer electronically via a secure website to the firm in charge of data 
management for data entry. 
Starting with the first inclusion and up to the date of end of inclusions, participating 
physicians make a commitment for comprehensive collection of data from all adult patients 
with rheumatoid arthritis and initiating treatment with Tofacinitib. 
Constitution of the cohort will take about 24 months. 
9.1.4. Follow-up visits of patients  
Patients will be followed in the setting of the study over a maximum 24-month duration or up 
to their early withdrawal from the study for whatever reason. 
At each follow-up visit (1 month (V1), 3 months (V2), 6 months (V3), 12 months (V4), 18 
months (V5), 24 months (V6) and at time of withdrawal from the study), the physician must 
do the following: 
- 
complete the questionnaire corresponding to the follow-up visit,  
- 
give the patient the PCS, CSQ, FiRST, GIRERD, EuroQoL EQ-5D-3L, SF-12, 
                FACIT-Fatigue questionnaires. 
 
 

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The patient must complete these questionnaires and give them back to his/her physician at the 
end of each visit. 
The patient paper questionnaires will be recovered by a carrier who will deliver them to Pfizer 
and they will be transferred by Pfizer electronically via a secure website to the firm in charge 
of data management for data entry. During this period, physicians make a commitment for 
comprehensive and regular collection of follow-up data for each patient enrolled.   
Total duration of follow-up for a patient will be a maximum of 24 months. 
Total duration of the study will be 48 months. 
9.1.5. Withdrawal of a patient from the study  
Withdrawals from the study before the planned end of follow-up will be classified according 
to the following categories: 
- 
Patient lost to follow-up (if yes, specify measures taken to find patient) 
- 
Non compliance with study procedure (if yes, specify the cause) 
- 
Withdrawal from study desired by patient/doctor (if yes, specify the reason given)  
- 
Withdrawal from study because of an adverse event (if yes, specify the type)  
- 
Serious adverse event (if yes, specify the type)  
- 
Death (cause and date)  
- 
Other reason (if yes, specify) 
9.1.6. Endpoints 
9.1.6.1. Primary endpoint 
• Duration of Tofacitinib survival 
9.1.6.2. Secondary endpoints 
• Change from baseline in catastrophising behaviour adopted by the patient (PCS-Pain 
Catastrophising Scale) (34, 35) 
• Change from baseline in coping adaptive strategy adopted by the patient (CSQ-Coping 
Strategies Questionnaire) (29-32) 
• Percentage of patients with low disease activity (LDA) as assessed by DAS28-4 
ESR/CRP < 3.2, SDAI ≤ 11, CDAI ≤ 10 (36), 
• Percentage of patients in remission as assessed by DAS28-4 ESR/CRP < 2.6, SDAI ≤ 
3.3, CDAI ≤ 2.8, ACR-EULAR 2011 Boolean criteria (TJC ≤ 1 + SJC ≤ 1 + CRP ≤ 1 
mg/dL + VAS patient ≤ 1) (36, 37) 
Change from baseline in score DAS28 ESR/CRP and in its components over time 
• Evaluation of response to treatment considering outcome of the DAS28 (EULAR 
criteria) (38) 

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Table 1: Evaluation of response to treatment considering outcome of DAS28 (EULAR 
criteria) 
 
• Change from baseline in the number of painful joints (TJC) over time 
• Change from baseline in the number of swollen joints (SJC) over time 
• Evaluation of the possible existence of fibromyalgia (FiRST questionnaire) (39, 40)  
• Change from baseline in the duration of morning stiffness over time 
• Change from baseline in patient compliance over time (GIRERD Questionnaire) (41) 
• Change from baseline in overall health status over time (EuroQoL EQ-5D-3L 
questionnaire) (42-44) 
• Change from baseline in quality of life over time (SF-12 questionnaire) (45) 
• Change from baseline in fatigue over time (FACIT-Fatigue questionnaire) (46, 47) 
• Evaluation of tolerability 
9.2. Context 
The duration of this study will be approximately 48 months including a 24-month recruitment 
period and a 24-month patient follow-up period. 
Patients will be followed prospectively and follow-up visits will follow up on regular visits. 
No additional visits or examinations are required by the protocol, as the study is 
observational: follow-up and treatment arrangements will be at the sole discretion of the 
participating physician. 
Population of physicians 
Physicians participating in this study will be hospital rheumatologists and rheumatologists 
with a combined activity (private practice and hospital practice), representative of French 
hospital rheumatologists managing patients treated with biologic medicinal products or 
targeted synthetic DMARD for RA. 
A list of 550 hospital centres geographically divided over all of France has been pre-
established in order to recruit 300 patients in approximatively 100 centres (about 5 patients 
per centre).  
Population of patients 
Patients eligible for this study can be included by the physician if they are starting a treatment 
with Tofacitinib for RA according to usual clinical practice and satisfy all of the following 
criteria for inclusion. Patient treatment is independent from patient enrolment into the study. 
Patients who are eligible but not enrolled in the study will be recorded in a non-inclusion 
registry with minimum collection of information. 
 

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9.3.2. Patient Reported Outcomes 
9.3.2.1. PCS questionnaire PCS – Pain Catastrophizing Scale (Annexe 3.1): 
Catastrophisation of pain affects the manner in which patients perceive pain. In this 
questionnaire, patients will be asked to describe the type of thoughts and of emotions that they 
experience when faced with pain (34, 35). 
The PCS is a 13-item questionnaire (13 thoughts or feelings at time of pain onset) which 
provides an overall score resulting from the sum of three subscale scores evaluating 
rumination, exaggeration and helplessness. 
The scores for each item are calculated on a 5-point rating scale (0 point for “not at all”, up to 
4 points for “all the time”).  
PCS total scores range from 0 to 52. 
An overall score greater than or equal 20 indicates a clinically relevant level of 
catastrophisation (34, 35,53). 
9.3.2.2. CSQ questionnaire– Coping Strategies Questionnaire (Annex 3.2): 
The Coping Strategies Questionnaire (CSQ) evaluates use by the patient of this coping 
strategy to best deal with and best live with disease/pain (29-32). In its French version, five 
factors of cognitive coping are evaluated in it: “Distraction”, “Dramatisation”, “Unawareness 
of painful sensation”, “Reinterpretation” and “Prayer” (32). 
9.3.2.3. GIRERD questionnaire (Annex 3.3): 
The GIRERD questionnaire (41), consisting of 6 questions, is used to evaluate compliance with 
a medical treatment. The patient is invited to reply “yes” or “no” to each of 6 questions 
relating to compliance with a prescribed treatment.   
- 
If the patient responds “no” to all questions, he is considered as a good complier. 
- 
If the patient responds “yes” once or twice, he is considered as a minor complier. 
- 
If the patient responds “yes” three times or more, he is considered as a non-complier. 
9.3.2.4. FiRST questionnaire -Fibromyalgia Rapid Screening Tool (Annex 3.4): 
The FiRST questionnaire (Fibromyalgia Rapid Screening Tool) is a tool for detecting 
fibromyalgia in patients with diffuse rheumatic pain. 
Six items are evaluated: (1) diffuse pain, (2) painful symptoms, (3) fatigue, (4) sleep and 
cognitive disorders, (5) nonpainful abnormal sensations, (6) functional somatic symptoms. A 
score of 5 positive items out of 6 items in the questionnaire (Yes/No responses) makes it 
possible to detect fibromyalgia with a sensitivity of 90.5% and a specificity of 85.7% (39-40). 
9.3.2.5. Euro QoL EQ-5D -3L questionnaire (Annex 3.5): 
The EuroQol EQ-5D Health State Profile (42-44) 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 
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validity and reliability of the EuroQol EQ-5D has been established in a number of disease 
states, including rheumatoid arthritis. 
9.3.2.6. SF-12 questionnaire – Short Form Survey (Annex 3.6): 
The short form version of the “Medical Outcomes Study Short-Form General Health Survey” 
(SF-36) contains only 12 questions out of 36. The SF-12 makes it possible to measure the 
physical and mental quality of the life score. It evaluates eight aspects of quality of life using 
the WHO definition of quality of life: overall and mental health status, physical and social 
functioning, physical and emotional health, pain and vitality (45). 
Physical and mental scores, between 0 and 100, are calculated by means of an algorithm: 
- 
A score greater than 50 corresponds to average quality of life, 
- 
A score of between 40 and 49 translates mild incapacity, 
- 
A score of between 30 and 39, moderate incapacity, 
- 
A score of less than 30, to severe incapacity. 
9.3.2.7. FACIT-F questionnaire - Functional Assessment of Chronic Illness Therapy-
Fatigue (Annex 3.7): 
The FACIT-Fatigue questionnaire (Functional Assessment of Chronic Illness Therapy Fatigue 
scale) measures the impact of fatigue on quality of life of patients who have cancer or a 
chronic disease (46). It is a score validated in RA (47). In consists of 4 dimensions: physical, 
social, family, emotional, functional (47). The self-evaluation is performed with a 13-item 
questionnaire. Each response is scored from 0 to 4. 
The FACIT-Fatigue score is derived by taking the sum of the scores for the 13 questions in 
the instrument, resulting in a score between 0 and 52, with higher scores representing better 
patient status (less fatigue) (47). 
9.4. Sources of dataEach patient with RA in whom the rheumatologist decides to initiate 
treatment with Tofacitinib, seen in a consultation or in a centre participating in the study, will 
be informed orally and in writing of the study modalities, its objectives and its duration. 
Patients who volunteer to participate in the study will provide their oral consent prior to their 
enrolment in the study and to completion by the participating doctor of at least one of the 
items in the eCRF. 
The doctor will indicate this agreement in the patient’s source dossier (hospital medical 
dossier) in compliance with rules of good practice. 
A case report form will be used for recording of data. In the setting of this protocol, the term 
“case report form” refers to the collection of medical data in electronic format or on paper 
medium.  
Data will be collected using two methods: 
- By physicians in an electronic case report form (eCRF) 
- By patients in questionnaires on paper format 
The data of interest will be reported in an electronic observation book (eCRF) by the 
investigating site, based on the data available in the patient’s medical record if available. A 
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patient data into the eCRF. For each patient included, it is suggested that the investigator 
collect the data in the eCRF during the inclusion visit and throughout the treatment with 
Xeljanz®. 
Pfizer in charge of the study data management is responsible for the creation and maintenance 
of the eCRFs. 
No directly nominative data will be collected. When setting up the investigation centre 
individually, Pfizer will assign a 4-digit code to each centre: this code corresponds to the 
centre number. 
The patient number will consist of the centre number (out of 4 digits) followed by a 3-digit 
code assigned in ascending order of inclusions: for example, patient number 0009-002 
corresponds to the second patient of the center 9. The data collected will be confidential and 
covered by medical confidentiality. 
In addition, quality of life and compliance questionnaires will be completed by patients on 
paper forms before being returned by secure T-envelopes to the service provider in charge of 
data processing. 
9.5. Sample size 
The primary objective of this study is to identify factors predictive of drug survival. This will 
be investigated using a multivariate Cox regression model. A review of the literature suggests 
that such an analysis requires at least 10 events (discontinuation of treatment) per variable 
proposed in a multivariate regression model (48). The minimum number of subjects to include 
in the study can then be estimated using the following formula: 
N = 10 k / p 
Where p is the smallest of the proportion of positive cases (cases that reached the endpoint) 
and negative cases (cases that did not reach the endpoint) in the population and k the number 
of predictor variables. 
Assuming a drug survival of 50% at 24 months (24) and also that 30% of the potential 
predictive factors will pass the univariate selection, it will be necessary to observe 150 events 
(i.e. 50 x0,3 variables x10 events) in approximately 300 patients (i.e. 150 events/0.50).  
9.6. Data management 
All information in the study will be collected by the participating doctor directly in an eCRF. 
The databases and eCRFs will be created by the clinical research organisation under contract 
(CRO) in charge of Data Management of the study. 
The eCRF will be the tool usually used by the CRO for this type of study. All Data 
Management operations will be carried out in agreement with requirements of Pfizer and 
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The data management plan will be designed and will describe in a detailed manner the 
specifications of the eCRF and the controls which will be executed for each variable, as well 
as a list of obvious authorised corrections 
The eCRF and the database specific for the study will be created, tested and validated before 
start of data entry of information by the scientific committee. All study participants will be 
trained in knowledge of the study and in the tools (eCRF) before their account is activated. 
E-CRFs allow the use of pretests (on-line consistency tests which allow the investigators to 
immediately correct any discrepancies) in order to reduce the number of correction requests.  
Once the pages are entered and monitored, the Data Manager will start the programmed 
consistency tests and any discrepancies will be resolved online by the participating 
investigator sites.  
Once any corrections are made on the database, the Data Management report drafted by the 
Data Manager and a database lock authorization request will be sent to the Sponsor. Once the 
database has been locked, the final version of the Data Management Report and the database 
lock certificate will be sent to the Sponsor. 
The frozen database will be transferred to Pfizer and the firm in charge of conduct of 
statistical analysis by Pfizer.  
AEs reported during the study will be coded using the latest version of the “Medical 
Dictionary for Regulatory Activities” (MedDRA) available at time of the first coding. The 
codes and decodes associated with the “lower lowest term” (LLT), “preferred term” (PT) and 
“system organ class” (SOC) will be entered into the database. Ongoing treatments at V0 and 
received during the study will be coded with the latest available version of the “World Health 
Organization Drug Reference List” dictionary (WHODRL) available at time of the first 
coding. The codes and decodes associated with “anatomic therapeutic class” (ATC) and WHO 
code will be entered into the database.  
9.6.1. Electronic Case Report Forms (e-CRF) 
As it is used in this protocol, the term Electronic Case Report Form (e-CRF) must be 
understood as referring to an electronic record of data, based on the method of collection of 
the data used in this study. 
The eCRF will be completed by the investigator site. 
Data of interest will be reported in an electronic Case Report Form (eCRF).  
A e-CRF is required and must be filled in for each included patient. The completed original e-
CRFs are the sole property of Pfizer and must not be disclosed to any third party, whatever 
their form, except for the authorized representatives of Pfizer or the appropriate regulatory 
authorities, without the written authorization of Pfizer. The investigator must make sure that 
the e-CRFs are kept in a secure manner on the study site in encrypted electronic or paper form 
and are protected by a password or securely kept in a locked room to prevent any access by 
unauthorized third parties.  
The investigator is ultimately responsible for the collection and notification of all the clinical, 
safety and laboratory data recorded in the e-CRFs and on any other data collection medium 
(source documents) and for ensuring that they are accurate, authentic/original, traceable, 
complete, consistent, readable and available if necessary. The e-CRFs must be signed by the 
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authenticity of the data captured in them. Any correction made to the entries in the e-CRF or 
source documents must be dated, accompanied by the author’s initials and an explanation (if 
necessary), and must not mask the original data.  
In most cases, the source documents comprise the hospital or doctor’s records. In this case, 
the data collected in the e-CRF must correspond to these records.  
In certain cases, the e-CRF can also be used as source document. In this case, a document, 
available at the investigator site or at Pfizer, must clearly identify the data that were recorded 
in the e-CRF, and for which the e-CRF constitutes the source document.  
9.6.2. Record Keeping 
To allow for evaluations and/or inspections/audits from regulatory authorities or Pfizer, 
participating doctors accept to keep the files, including the identity of all of the participating 
patient (sufficient information to make a link between the files, for example CRFs and 
hospital files), all of the original signed information documents, the copies of all of the CRFs, 
the notification forms for tolerance of use, the source documents, the detailed documents for 
distribution of treatments and appropriate documentation of any pertinent correspondence (for 
example, letters, minutes from meetings and reports from phone calls).  
The files must be kept by the participating doctors in compliance with the local regulations or 
according to the specifications of the Study Convention (SE), depending on which has the 
longest duration. Participating doctors must ensure that the files continue to be stocked 
securely for as long as they must be kept. 
If the participating doctor is no longer able to keep the study files for the required period for 
whatever reason (for example, retirement, transfer), Pfizer must be notified in advance. The 
study files must be transferred to a third person, designated by Pfizer, for example another 
participating doctor, another institution or an independent third party named by Pfizer. 
The files of the participating doctor must be kept for a minimal duration of 15 years after the 
end or the interruption of the study or longer if required by the local regulations in force. 
The participating doctor must obtain written authorization from Pfizer before divulging any 
files, even if the record keeping requirements have been satisfied. 
9.6.3. Circuit des CRF  
The data collected by the investigator from the inclusion of patients and throughout the study 
will be directly recorded by the investigator site on the study eCRF.  
Adverse events will be collected using the eCRF by the investigator sites during the usual 
follow-up visits, for all the study patients. Where applicable, requests for additional 
information from the Pfizer pharmacovigilance department will be sent to the person who 
reported the event (investigator or another member of the investigator team). All the reports 
(initial and follow-up reports) will be collected using a site number and the patient number. 
Patient self-questionnaires may be directly completed in electronic format by the patients on 
the study ePRO. 
Hard copies of the completed patient self-questionnaires will be sent to Pfizer by the 
investigator site using secure follow-up envelopes. They will then be sent electronically by 
Pfizer via a secure site to the data management for entry. 

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9.6.4. Database construction  
The database and eCRFs will be created by the clinical research organisation under contract 
(CRO) in charge of Data Management of the study. 
The eCRF will be the tool usually used by the CRO for this type of study. All Data 
Management operations will be carried out in agreement with requirements of Pfizer and 
according to the standard operating procedures (SOP) of the CRO. 
An annotated questionnaire will be drawn up by Pfizer giving the name of the tables and 
name of the variables. Each variable will be associated with its type, length and where 
applicable, its format. The annotated questionnaire will be submitted to Pfizer for validation.  
Pfizer will then construct a database using its own software. The structure of the database will 
be documented and verified on listings by comparing the attributes of the database variables 
with the specifications noted on the annotated questionnaire.  
Before any entry of real data, the structure of the database and data entry screens will be 
tested and validated according to the Standard Operating Procedures of Pfizer. Fictitious 
questionnaires will be filled in and entered for these tests. Validation will be performed by 
printing out the data in listings and comparing them with the data noted in the questionnaires. 
A validation report will be drafted by Pfizer. The final structure of the database must be 
submitted for validation to Pfizer before the entry of any real data.  
An audit file will be created to record all the modifications made to the database. The original 
data, modified data, date and time of the change, the person who made the change and the 
reason for the change will be recorded in the audit file. The functioning of the audit file will 
be tested by changing the fictitious data. A report will be drafted by the CRO. 
9.6.5. Data control  
A list of consistency tests used to detect discrepancies and aberrant responses in the 
questionnaires will be published by the CRO in charge of datamanagement. These tests will 
be programmed with CRO’s own software and then tested with fictitious data. This fictitious 
data and documents about the tests will be kept in the study file by Pfizer and available for 
review.  
After entry, the data will be continuously controlled and a specific request for each 
discrepancy will be electronically generated by the data control system. In order to reduce the 
number of requests submitted to investigators, a guide of self-evident corrections may be 
prepared by the CRO.  
The CRO will make the data control documents available to Pfizer on simple request. Periodic 
data monitoring progress reports will be published by the CRO.  
9.6.6. Access to data  
The databases and servers on which the data are saved will be located in locked rooms. Only 
personnel dedicated to the study will have access to the databases.  
9.6.7. Database lock  

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The database will only be locked once data entry, monitoring and, where applicable, coding 
have been completed by Pfizer. The database will be locked using the Pfizer procedure and 
the CRO’s Standard Operating Procedures. After validation by Pfizer, the database will be 
locked and ready for statistical analysis.  
9.6.8. Data management report  
A data management report will be drafted by Pfizer after database lock. 
 
9.7. Data analysis  
Detailed methodology for summary and statistical analysis of data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be dated, recorded and 
maintained by the sponsor. The Statistical Analysis Plan (SAP) may modify the plans outlined 
in the protocol; any major modifications of the primary end point definition or their analyses 
would be reflected in a protocol amendment. 
A descriptive statistical analysis will be carried out including the number of cases, missing 
data, and the mean, standard deviation, median, first and third quartiles, minimum and 
maximum, or frequency tables according to the nature of the parameter. 
All tests will be two-sided and the type I error (α) will be set at 5% for the entire study, except 
for the screening of predictive factors of drug survival using an univariate analysis (see the 
following) where a type I error will be set at 10%. No adjustment for multiplicity will be used. 
Two-sided 95% confidence intervals will be provided whenever this is relevant. 
A 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. The population for analysis of tolerability will be comprised of all patients 
enrolled, who received at least one dose of Tofacitinib.  
Tofacitinib maintenance will be estimated by considering the date of initiation of treatment 
with Tofacitinib and the date of permanent discontinuation of this same treatment. The 
follow-up time of patients not presenting with an event of interest (permanent discontinuation 
of a patient) will be censored at the date of the last visit. Drug survival with Tofacitinib will 
be described with the Kaplan-Meier method. Survival function S(t) (probability that an event 
of interest does not occur before the date (t) will be depicted graphically by a survival curve 
with 95% confidence intervals estimated with the Klein and Moeschberger method (49). An 
estimate of drug survival with Tofacitinib at 12 and 24 months will be provided. 
Principal analysis 
Factors predictive of drug survival will be investigated using a Cox model. 
The potential predictive factors of drug survival are as follows: 
 
 
 

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Figure 2 : Potential predictive factors of drug survival 
 
First, the effect of each factor on drug survival will be tested with a univariate Cox model. 
Thus, the hazard-ratios calculated are called “raw”. They will be presented with their 95% 
confidence interval and their associated p-value. Then, all potential factors for which the p-
value resulting from univariate analysis is strictly less than 10% will be included in a 
multivariate Cox model. Predictive factors and their interactions will be chosen using a 
backward (step-down) selection. Predictive factors chosen will be those which have a p-value 
< 5%. In the case of a significant interaction, all individual components of the interaction will 
be “forced” in the model, whether they are statistically significant or not. The adjusted 
hazards-ratios thus obtained will be presented with their 95% confidence interval and their 
associated p-value. 
Missing data will be managed using a method based on missing data indicators (50, 51). This 
method is not a method of imputation of missing data. A fixed value will be assigned to 
missing observations, and a dummy variable (1/0) will be added to the multivariate model in 
order to indicate if the value of this variable is missing or not.  If more than 10% of the 
patients have missing baseline covariates, a complete case analysis will also be performed as a 
sensitivity analysis. Additional methods for handling missing data may also be used.  Further 
details will be provided in the statistical analysis plan as appropriate. 
Secondary analyses 
The impact of behavioural strategies (catastrophisation and coping) on Tofacitinib drug 
survival will be evaluated in patients suffering from RA. A Cox proportional hazards model 
will be used with the 5 dimensions in the coping questionnaire and the catastrophisation score 
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In a second phase and in a similar manner, a Cox model will be used to estimate the impact of 
the adaptive strategies under treatment. Therefore, the last evaluation available before 
discontinuation of treatment (or the last visit if a patient does not permanently discontinue 
treatment) and the change between this latter evaluation and the baseline value will be taken 
into account in separate models. 
The correlation between behavioural strategies and effectiveness will be studied with 
Pearson’s or Spearman’s coefficient according to the nature of variables compared. 
Interim analysis 
Interim descriptive analyses will be conducted annually. 
In general, additional analyses, in relation to the objectives of the study, may be carried out in 
agreement with the Scientific Committee of the study, for publication purposes. 
Pooled analysis within a programme of studies conducted by Pfizer 
This study falls within a programme of studies conducted by Pfizer across different countries 
(Germany, Turkey, Greece, Spain, Czech Republic, Israel, etc.) in order to create a database 
of patients treated under real-life conditions with Tofacitinib in rheumatoid arthritis. This 
database is based on EULAR 2017 recommendations for a core data set to support 
observational research in RA (52). 
Data collected from this French study will be compared to and pool-analysed with data from 
other countries in order to evaluate the long-term effectiveness and tolerability of Tofacitinib 
in a broader population of RA patients. 
9.8. Quality control 
9.8.1. Data entry in centres 
The physician has the responsibility of collecting and of recording data in the eCRF. He/she 
must ensure that data are entered completely and accurately, and that they are consistent with 
source data. 
Centres may request the aid of a TEC (study technician) in the setting of the study in order to 
help them for data entry in the eCRF. During these data entry visits, the TEC will be in charge 
of reporting in the case report forms data on patients enrolled by the centre and to report AEs 
to the Pfizer pharmacovigilance department.  
9.8.2. Quality control 
Follow-up, quality control, data entry and analysis of data will be carried out by the CRO 
specialising in follow-up, management and processing of data from observational studies 
according to good practice in force under contract with Pfizer S.A.S.  
Requests for additional information and/or requests for corrections may be sent (by dispatch 
in electronic format) to participating physicians, requesting missing or inconsistent 
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Throughout this study, doctors will be contacted by staff especially trained under contract 
with Pfizer to ensure comprehension of the protocol and of the electronic questionnaire by the 
physician, and compliance with the protocol. All these contacts will be documented. 
The quality of the data collected during the study will be ensured by: 
• 
The training of investigator teams during study set-up (objectives and conduct of the 
study, protocol and eCRF, logistics, pharmacovigilance procedures etc.) 
• 
Regular follow-up of investigators during the study (by telephone calls and emails) 
• 
Online control of data captured in the eCRF (automated on-line control for key data 
and additional correction requests). All of these controls will be described in the Data 
Management Plan. 
Key indicators of the good conduct of the study (number of active sites, number of included 
patients, number of follow-ups performed etc.) will be generated from the study database. 
This database can be used to edit study progress reports in order in order to manage site 
reminders. 
Data quality control will be performed on site on a sample of 10% of active centres. Screening 
of active centres for quality control will be performed by randomisation at the end of the 
enrolment period. 
9.9. Limits of the methods of research 
This protocol was designed in such a way as to best meet the objectives defined for this 
observational study. However it has certain limitations which must be discussed and which 
must be taken into account during the implementation of the study and processing of the 
results.  
The study has methodological limitations that are inherent to its non-interventional design. 
To minimise potential selection bias, patients enrolled in the study will be so enrolled 
according to a consecutive method (study proposed systematically to all patients who satisfy 
eligibility criteria seen in a consultation during the period of enrolment). In addition, in order 
to verify the absence of a selection bias, characteristic of patients enrolled in the study will be 
compared to those of patients who have refused to participate in the study; characteristics of 
these patients will be collected in a non-inclusion registry with a minimum collection of 
information. 
9.10. Other aspects 
Pfizer will ensure, by its study assistants, regular administrative follow-up of participating 
sites. 
Pfizer may make available to sites, a TEC in order to assist doctors with data entry in the 
eCRF. 

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The CRO responsible for data management will ensure the parameterisation of the eCRF, and 
printing of requests for correction. 
The firm responsible for statistical analyses will ensure drafting of the statistical analysis plan, 
the statistical report and the clinical report of this study. 
 
9.10.1. Logistical follow-up 
Follow-up of participating physicians will be carried out by a team of Pfizer study assistants 
especially trained for the study. This follow-up may be performed in different manners: phone 
calls, email, a specific letter and newsletter. This follow-up consists of dispatch via mailing to 
participators in the study, collection of regulatory documents and fee payments. 
The quality of these contacts will be preferred in light of the fact that it will promote 
involvement and work quality performed by participating physicians. Each one will be 
followed insofar as possible by the same study assistant, from the time of his/her recruitment 
up to closure of the study. 
The research assistants will perform follow-up of incomplete or inconsistent data (control of 
inconsistencies, non-responses and omissions) and will be in constant contact with 
participating physicians. During the patient screening process and depending on number of 
inactive participating doctors (no patient selected), the research assistants may decide to send 
reminders to the latter. 
Furthermore, a free phone number (green phone number) specific for the study will be set up 
targeting participating physicians in order to respond immediately to their questions 
throughout the study. 
In terms of traceability, all “entering” calls via the green phone number and “outgoing” calls 
(call for screening, reminders, etc.) will be the subject of a written report (date, purpose of 
call, measures to be taken, etc.) and will be recorded in the panel of operating indicators. 
9.10.2. Data collection 
After signing the contract and the set-up visit, the investigators and each person participating 
at the site must send the Pfizer Post-MA Study department: the protocol acknowledgement 
form, the eCRF training certificate and the pharmacovigilance training certificate. 
Participating doctors will then receive the link with their identifier and their access code to the 
e-CRF.  
These codes are personal, and all the persons trained and involved in the study at the site will 
receive their identifier and code.  
The investigator sites will complete the questionnaire for each included patient during the 
scheduled regular visits. 
If a patient drops out of the study during follow-up, the investigator site will fill in the end-of-
study questionnaire and give the reason for withdrawal. 
The investigators undertake to exhaustively collect the data for each patient. 

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9.10.3. Archiving  
The investigators will keep the questionnaires for up to 15 years after the last visit of the last 
patient. All the documents will then be returned to the study sponsor. 
The study management center will keep all study-related documentation until 15 years after 
the last patient’s visit. 
10. PROTECTION OF PATIENTS 
10.1. Information and protection of patients 
All the parties shall comply with current legislation and in particular the laws concerning the 
implementation of technical and organizational measures for ensuring the protection of the 
patients’ personal data. These measures comprise the omission of the patients’ names or other 
data making it possible to identify them directly in all reports, publications and other 
communications, except where required by current legislation. 
Personal data will be kept at the study site in encrypted electronic/or paper form and will be 
protected by a password or secured in a locked room in order to ensure that only approved 
study personnel has access to it. The study site will set up the appropriate technical and 
organizational measures to ensure that personal data can be recovered in the event of loss or 
damage. In the event of a potential personal data breach, the study site will assume 
responsibility for determining whether the breach has actually occurred and, if so, for making 
the notifications required by law. 
To protect the rights and freedoms of individuals with regard to the processing of personal 
data, when the study data are compiled for transfer to Pfizer and the other approved parties, 
patients’ names will be removed and replaced by a specific unique numeric code, on the basis 
of the numbering system defined by Pfizer. All the other data allowing the identification of 
patients and transferred to Pfizer or other approved parties will be identified using this 
specific unique code for each patient. The investigator site will keep a confidential list of the 
patients taking part in the study, with the link between the numeric codes of each patient and 
the real identity of each of them. When data are transferred, Pfizer will maintain high 
standards of confidentiality and protection of the patients’ personal data, in accordance with 
the provisions of the study agreement and applicable privacy protection laws. 
10.2. Patient Information Leaflet  
The information documents and all the materials intended for the recruitment of patients must 
comply with local regulatory and legislative requirements and in particular the current laws 
concerning the respect of privacy. 
The documents used during the consent process for data collection and all the materials 
allowing patient recruitment must be examined and approved by Pfizer and approved by the 
Committee for the Protection of Persons (CPP) before their use, and must be available for 
inspection. 
The investigator must make sure that all the study patients or their legal representatives are 
fully informed about the nature and objectives of the study, the disclosure of study-related 
data and any risks associated with their participation, in particular the risks associated with the 
processing of patients’ personal data. The investigator must also make sure that all the study 
patients or their legal representatives are fully informed about their rights to access and 
correct their personal data and withdraw their consent for the processing of their personal 
data. 

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The investigator will provide exhaustive information and hand over the information sheet to 
each patient or admissible legal representative before the conduct of any study-specific 
activity, in particular with regard to the collection of data about the patient.  
Investigators will keep in the medical records the information sheets that they signed 
certifying that they adequately informed and gave the patients and/or their legal 
representatives the information sheet before inclusion in the study. 
Note that only the principal investigator or co-investigators trained in the study can sign the 
information sheet. 
10.3. Withdrawal of the patient 
Patients can withdraw from the study at any time at their own request, or can be withdrawn at 
any time at the investigator’s or sponsor’s discretion for pharmacovigilance, behavioral or 
administrative reasons. In all circumstances and where applicable, every effort should be 
made to document patient outcomes. Investigators will obtain information about the reason 
for withdrawal and the follow-up of the patient after all unresolved adverse events. 
If the patient withdraws from the study, and opposes the disclosure of future information, no 
other evaluation may be carried out, and no other data must be collected. The sponsor can 
keep and continue to use all the data collected before his/her voluntary withdrawal from the 
study. 
10.4. Ethics Committee (CPP) 
This is a non-interventional study that does not modify in any way the usual medical 
management of the persons entering the study, or compromise their physical or mental 
integrity or require any particular follow-up visit for the persons entering the study. All 
procedures are performed and all products used in a usual way, without any additional or 
unusual diagnostic or monitoring procedure.  
Under these conditions, this study comes within the scope of application of Ordinance No. 
2016-800 of 16 June 2016 for research, article L1121-1, and the project must therefore be 
declared to the French National Agency for Medicines and Health Products Safety (ANSM), 
and a submission made to the Committee for the Protection of Persons (CPP).  
The sponsor must obtain prior authorization for the study protocol, protocol amendments and 
patient information sheets, and all other significant documents (for example, advert to obtain 
recruits), where necessary, from the CPP.  
All correspondence with the CPP must be kept by the investigator.  
10.5. National Medical Council (CNOM) 
In application of article L4113-6 of the Public Health Code and articles R4113-104 and 
R4113-105 of the Public Health Code, the following documents have been sent by the sponsor 
of the study to the CNOM: 
• Final study protocol   
• Questionnaire for collection of data  
• List of physicians participating in the study and members of the scientific committee  

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• Financial agreement proposed to doctors participating and to members of the scientific 
committee  
• Information letter for patients 
The sponsor of the study must inform the CNOM by registered letter of all financial aspects 
between the sponsor, members of the scientific committee and doctors participating in the 
study. 
Non-response 2 months after receipt of the dossier by the CNOM signifies a favourable 
opinion. A copy of the opinion of receipt will be sent to each participating physician by the 
Sponsor. It is the responsibility of each participating physician then to send a copy of this 
opinion of receipt and the financial agreement signed by the Departmental Medical Council 
(CDO) to which he is attached by articles L4113-9, L4113-10 and L4163-10 of the Public 
Health Code. 
In the setting of this study, CENGEPPS contracts are not applicable and may be used only for 
payment of hospital extra costs paid directly to the institution to which the participating 
doctor is attached. 
10.6. Protection of data: National Data Processing Commission “CNIL” 
In accordance with law No. 78-17 of 6 January 1978 on Data Processing, Data Files and 
Civil Liberties, amended by law 2004-801 of 6 August 2004 concerning the protection of 
individuals with regard to the processing of personal data, this protocol will be subject to a 
declaration of compliance with a reference method to the French Data Protection Agency 
(CNIL).  
Taking into account the fact that the study comes within the scope of MR003, the compliance 
commitment of Pfizer allows us to start without the opinion of the French Data Protection 
Agency (CNIL). 
10.7. Ethical conduct of the study  
The study will be conducted in conformity with legal and juridical requirements, as well as 
the objective, value and scientific rigor and in compliance with generally accepted practices 
of research described in recommendations on pharmacoepidemiologic good practice (GPP) 
published by the International Society for Pharmacoepidemiology (ISPE), recommendations 
of good epidemiological practice (GEP) published by the International Epidemiological 
Association (IEA), good practice of research on results published by the International Society 
for Pharmacoeconomics and Outcomes Research (ISPOR), the international ethical 
recommendations for epidemiological research published by the Council for International 
Organizations 
of 
Medical 
Sciences 
(CIOMS), 
the 
European 
network 
of 
pharmacoepidemiology and pharmacovigilance centres (ENCePP) of the European Medicines 
Agency (EMA), the guide of methodological standards in pharmacoepidemiology and FDA 
guidelines for industry: Good Pharmacovigilance and Pharmacoepidemiologic Assessment, 
FDA guidelines for industry and for FDA staff: Good Practice of Conduct and Reporting of 
Pharmacoepidemiologic Safety Studies using all electronic medical data, and guide lines for 
industry: measures of change noted by the patient; use in development of medicinal products 
in support of labelling and/or equivalent. 

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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS 
  
11.1. Single reference document on safety of use 
The current French Summary of Product Characteristics (SmPC) will be the single reference 
safety document during the study. It will be used by Pfizer pharmacovigilance department to 
evaluate any safety event reported to the Pfizer pharmacovigilance department by the 
investigator during this study. 
This single safety reference document should be used by the investigator for prescribing 
information and recommendations. 
11.2. Requirements in terms of pharmacovigilance 
The following table summarises the requirements for recording of adverse events in the 
electronic case report and for reporting adverse events via the Adverse Event Reporting Form 
for noninterventional studies to Pfizer pharmacovigilance (NIS AEM Report Form). These 
requirements are defined by three types of events:  
(1) 
serious adverse events (SAE) 
(2) 
non-serious adverse events (AE) (if applicable), and 
(3) 
situations involving exposure to a medicinal product including exposure in 
pregnancy, exposure in a breastfeeding mother, medicinal product errors, 
overdoses, misuse, extravasation and occupational-related exposure. 
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For each AE, the participating physician must look for and obtain sufficient information, both 
in order to determine the outcome of the adverse event and to evaluate if it satisfies criteria for 
classification as an SAE (see section entitled “serious adverse events” below). 
Adverse events must be reported to Pfizer within 24 hours following awareness of the event 
by the participating physician, whether the event has been considered as related to the study 
medicinal product or not by the participating physician. 
In particular, if a serious adverse event is fatal or life-threatening, reporting to Pfizer must be 
done immediately, whatever the information available on the adverse event. This time period 
also applies to all new information (follow-up) relating to reporting of adverse events 
forwarded previously. In rare cases where the participating physician is not immediately 
informed of occurrence of an adverse event, the participating physician must report the event 
within 24 hours after he becomes aware of it and complete the information at time when he 
became aware of this adverse event for the first time. 
For adverse events considered as serious or identified in the right-hand column of the 
abovementioned table which are to be reported to Pfizer within 24 hours following awareness 
of them, the participating physician is required to look for and to provide all further 
information to Pfizer in conformity with this 24h time period. Furthermore, Pfizer can request 
that a participating physician obtain in an urgent manner specific further information on 
follow-up. This information can be more detailed than that recorded in the study case report 
form. Generally, this information will include a sufficiently detailed description of the adverse 
event in order to enable complete medical evaluation of the case and the independent 
determination of a possible causal relationship. All relevant information regarding the event, 
such as concomitant treatments or disorders, must be provided. If a patient dies, a summary of 
available results of an autopsy must be forwarded as soon as possible to Pfizer or to its 
certified representative. 
Period of reporting 
For each patient, the period of reporting of adverse events starts from the time the patient 
received the first dose of the study medicinal product or from the date on which the patient 
provided his/her informed consent if he/she has previously been exposed to the study 
medicinal products, and ends at end of the study period of observation which should include 
at least a period of 28 calendar days after the last administration of the study medicinal 
product; a report must be sent to the PFIZER Pharmacovigilance department or to its certified 
representative for all types of adverse events listed in the abovementioned table and occurring 
during this period. If the patient receives the study medicinal product on last day of the 
observational period, the reporting period will be extended by 28 calendar days after the end 
of the observational period. 
In the event that the patient provides his/her consent but was never enrolled in the study (for 
example, the patient changed his/her mind on participation; failure in terms of screening 
criteria), the period of reporting ends on date of decision for non-inclusion of the patient. 
If the participating physician becomes aware of a serious adverse event which occurred at any 
time after the end of the observational period, and he/she considers it related to a study 
medicinal product, this serious adverse event must also be reported to the Pfizer 
Pharmacovigilance department. 
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The participating physician must evaluate and record the causal relationship. For all adverse 
events, sufficient information must be obtained by the participating physician in order to 
determine the causal relation of each adverse event. For AE considered as related to a study 
medicinal product, the participating physician is required to perform follow-up up until 
resolution or stabilisation of the event and/or of its sequelae at a level considered acceptable 
by the participating doctor and that Pfizer is in agreement with this evaluation. 
Evaluation of the causal relationship by the participating physician is the determination of the 
fact that a reasonable possibility exists that a study medicinal product has caused or has 
contributed to an adverse event. If the final determination of a causal relation is “unknown” 
and that the participating physician cannot determine if a study medicinal product has caused 
an event, then the event must be reported within 24 hours. 
If the participating physician cannot determine the aetiology of the event but that he/she has 
determined that no study medicinal product was the cause of the event, information on this 
must be clearly provided in the case report form and in the adverse event reporting form for 
noninterventional studies. 
Definition of an adverse event 
 
Adverse events  
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. It is not necessary that the event have a causal relationship 
with the treatment or use. Examples of adverse events include, without this list being 
exhaustive, the following:  
a. Abnormal test results (see the following for circumstances in which an abnormal test 
result constitutes an AE); 
b. Clinically significant symptoms and signs; 
c. Changes to results of the clinical examination; 
d. Hypersensitivity; lack of efficacy; abuse of a medicinal product;  
e. Pharmacodependence. 
Furthermore, for medicinal products, they can include resultant signs or symptoms: 
a. Of an overdose; 
b. Of withdrawal; 
c. Of misuse;  
d. Of off-label use (Off-Label of MA);  
e. Of medicinal product interactions; 
f. Of extravasation; 
g. Of exposure during pregnancy; 
h. Of exposure during breastfeeding; 
i. Of a medicinal product error; 
j. Of occupational exposure. 

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Abnormal test results 
Criteria enabling to determine if an abnormal result of an objective test must be 
reported as an adverse event are as follows: 
• The test result is associated with symptoms, and/or  
• The test result requires further diagnostic investigations or a medical/surgical 
intervention, and/or  
• The test result leads to a change in dosage or to withdrawal of a patient from the study, 
to administration of a significant additional concomitant treatment, or to another 
treatment, and/or  
• The test result is considered as an adverse event by the participating doctor or the 
sponsor. 
The simple repetition of an abnormal test result, in the absence of one of the aforementioned 
conditions, does not constitute an adverse event. All abnormal test results which prove to 
result from an error do not need to be reported as adverse events. 
Serious adverse events  
A serious adverse event is defined as any untoward medical occurrence in a patient receiving 
a medicinal product or a nutritional product, whatever the dose, or using a medical device, 
and that: 
• Causes death;  
• Is life-threatening; 
• Requires hospitalisation of the patient or results in prolongation of hospitalisation (see 
below for circumstances in which this does not constitute an adverse event); 
• Results in permanent or important disability or incapacity (important deterioration of 
ability to accomplish actions of daily living); 
• Results in a congenital anomaly or a malformation. 
Progression of a malignancy during the study (including signs and symptoms of progression) 
must not be reported as a serious adverse event unless its outcome is fatal during the study or 
during the period of reporting of adverse events. Hospitalisation due to signs and symptoms of 
progression of the disease must not be reported as a serious adverse event. If a malignancy has 
a fatal outcome during the study or during the period of reporting of adverse events, then the 
event leading to death must be recorded as an adverse event, and as a grade 5 serious adverse 
event. 
An event will be defined as medically important based on medical and scientific judgement. A 
medically important event may not be immediately life-threatening and/or result in death or 
hospitalisation. However, if it is established that the event can be life-threatening for the 
patient and/or require an intervention in order to prevent one of the outcomes stated in the 
above, the medically important event must be reported as serious. 
Events, for example, that enter into this category of medically important events are allergic 
bronchospasm requiring intensive care in the emergency room (ER) or at home, coagulation 
disorders, seizures which have not resulted in hospitalisation, or development of 
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Furthermore, all suspected transmission of an infectious agent, pathogenic or not, by a Pfizer 
product is considered as a serious adverse event. Such event can be suspected by clinical 
symptoms or test results indicating an infection in a patient exposed to a Pfizer product. The 
terms “suspicion of transmission” and “transmission” are considered synonymous. 
These cases are considered as unexpected and must be managed as serious cases by the Pfizer 
Pharmacovigilance Department. These cases can also be reported as product defect, if 
applicable. 
Hospitalisation 
Hospitalisation is defined as any initial admission to hospital (even for a duration less than 24 
hours) into a health institution or any prolongation of an admission. 
The admission also includes transfer within the hospital to an intensive care unit ICU (for 
example, from a psychiatric ward to a medical ward, from a medical ward to a coronary 
intensive care unit, from a neurology ward to a unit for treatment of tuberculosis). 
A visit to the ER is not necessarily a hospitalisation; however, an event which leads to a visit 
to the ER must be evaluated as medically important. 
Hospitalisation in the absence of an adverse event is not an adverse event in itself and does 
not require reporting. For example, the following reasons for hospitalisation without an AE 
are not to be reported: 
• A social admission (for example, patient does not have a place to sleep) 
• Administrative admission (for example, for an annual check-up) 
• An optional admission not associated with a triggering AE (for example, for a 
scheduled cosmetic surgery procedure) 
• Hospitalisation for observation in the absence of an AE 
• Admission for treatment of a pre-existing condition not associated with development 
of another AE nor with worsening of a pre-existing disorder (for example, for an 
assessment following persistence of abnormal laboratory test data existing prior to the 
treatment) 
• Planned admission by the protocol during the clinical study (for example, for a 
procedure required by the study protocol). 
Situations requiring reporting to Pfizer Pharmacovigilance within 24 hours: 
Situations involving exposure in pregnancy, exposure during breastfeeding, a medicinal 
product error, an overdose, misuse, extravasation, lack of efficacy, occupational exposure are 
described in the following. 
Exposure in pregnancy (or exposure in utero)  
An exposure during pregnancy occurs if: 
A woman becomes pregnant or it turns out that she is pregnant while she is receiving or is 
exposed to a study medicinal product (for example, environmental exposure) or a woman 
becomes pregnant or it turns out that she is pregnant after having discontinued or having been 
exposed to a study medicinal product (maternal exposure); 

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An example of environmental exposure would be a case involving direct contact with a Pfizer 
product in a pregnant woman (for example, a nurse reports that she is pregnant and has been 
exposed to a chemotherapy product). 
A man has been exposed, in the setting of treatment or of environmental exposure, to a study 
medicinal product before or around the period of conception and/or has been exposed during 
pregnancy of his partner (paternal exposure). 
Generally, cases of prospective and retrospective exposure in pregnancy, whatever the source, 
are to be reported, whether an adverse event is present or not, according to the procedure for 
reporting serious adverse events. 
If a female patient in the study or the partner of a study patient becomes pregnant or it turns 
out that she is pregnant during treatment of a male patient in the study with the study 
medicinal product, the participating doctor must report this information to Pfizer, whether an 
adverse event has occurred or not, by completing the adverse event reporting form for 
noninterventional studies, as well as the additional form entitled “Exposure during 
pregnancy”.  
Furthermore, information relating to environmental exposure to a medicinal product by a 
pregnant woman (for example, a female patient reports that she is pregnant and reports that 
she has been exposed to a cytotoxic product by inhalation or after having accidentally spilled 
it) must be reported to Pfizer, whether an adverse event has occurred or not, by completing 
the adverse event report form for noninterventional studies, as well as the additional form 
“Exposure during pregnancy”. 
The information forwarded must include the planned date of term of the pregnancy (see the 
following for information on term of pregnancy). 
Follow-up must be implemented to obtain general information on the pregnancy. 
Furthermore, follow-up must be implemented to obtain information on the outcome of the 
pregnancy for all cases which are the subject of reporting of exposure in pregnancy whose 
outcome is unknown. 
A pregnancy must be followed up to its end or up to termination of the pregnancy (for 
example, voluntary termination of pregnancy) and Pfizer must be informed of its outcome. 
This information will be provided in the setting of follow-up of the initial report of exposure 
during pregnancy. In case of a birth, the structural integrity of the neonate can be evaluated at 
time of birth.  
In case of a termination of pregnancy, the reason must be specified and, if possible clinically, 
the structural integrity of the foetus must be evaluated by a visual inspection (at least that the 
results of tests performed before the procedure have concluded in a congenital anomaly and 
that these results have been reported). 
If the outcome of the pregnancy corresponds to criteria of an SAE (for example, an ectopic 
pregnancy, a spontaneous abortion, a foetal death in utero, a neonatal death or a congenital 
anomaly [for a viable baby, an aborted foetus, foetal death in utero or neonatal death]), 
procedures for reporting of SAE must be followed. 
Further information on the outcome of pregnancy which are reported as an SAE are as 
follows:  
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Neonatal deaths which occur during the month following the childbirth must be reported, 
whatever the causal relationship, as SAEs. Furthermore, death of a baby after one month of 
age must be reported as an SAE whenever the participating doctor evaluates the death of the 
child of a young age as related or possibly related to exposure to the study product. 
Further information on exposure in pregnancy can be requested. Follow-up on outcome at 
time of childbirth will be treated on a case-by-case basis (for example, follow-up in children 
born before full term, of a young age, in order to identify developmental retardation). 
In case of paternal exposure, a form for communication of information intended for pregnant 
partners will be given to the male patient participating in the study for his partner. It must be 
documented that this document has been given to the patient participating in the study for 
transmission to his partner. 
Exposure during breastfeeding 
Situations of exposure during breastfeeding must be reported independently of existence of a 
concomitant AE. 
A report of exposure during breastfeeding must not be filed with a Pfizer product specifically 
indicated for use in a pregnant woman (for example, vitamins) administered in agreement 
with the MA. 
However, if a toddler presents an AE associated with administration of such a medicinal 
product, the AE must be reported as with exposure during breastfeeding. 
A medicinal product error 
A medicinal product error means any unintentional error in prescribing, dispensing or 
administration of a medicinal product, which can cause or lead to inappropriate use of a 
medicinal product or to harm for the patient, even though it is under the control of a health 
professional, the patient or of a consumer. Such events can be related to professional practice, 
products,  procedure, and to systems in particular; prescribing; transmission of an order; 
product information, packaging and nomenclature of a product; composition; dispensing; 
distribution; administration; training in use of the product; monitoring and use. 
Medicinal product errors include the following: 
Near-accidents involving or not a patient directly (for example, administration by 
inadvertence or error, which is an accidental use of a product outside of indication of 
prescription by a healthcare professional or a patient/consumer); 
Confusion concerning the name of a product (for example, marketing name and trade name). 
The participating doctor must report the following medicinal product errors to Pfizer, 
independently of existence of an associate AE/SAE: 
Medicinal product errors involving exposure of a patient to a product, whether the medicinal 
product error is accompanied by an adverse event or not. 
Medicinal product errors not involving a patient directly (for example, potential medicinal 
product errors or near-accidents). Whenever a medicinal product error does not involve 
exposure of a patient to a product, the following minimal criteria constitute a case of 
medicinal product error: 
The notifier is identifiable; 
A suspect product; 

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Medicinal product error. 
Overdose, Misuse, Extravasation 
Cases of an overdose, misuse and extravasation associated with use of a Pfizer product must 
be reported to Pfizer by the participating doctor, independently of existence of a concomitant 
AE/SAE. 
Lack of efficacy 
Cases of lack of efficacy of a Pfizer product must be reported to Pfizer by the participating 
physician independently of existence of a concomitant AE/SAE; or indication of a Pfizer 
product. 
Occupational exposure 
Cases of occupational exposure to a Pfizer product must be reported to Pfizer by the 
participating physician, independently of existence of a concomitant AE/SAE. 
12. PLANS FOR COMMUNICATION OF STUDY RESULTS  
Pfizer and the scientific committee undertake to send the study results to all the doctors 
participating in the study.  
At least one communication and one publication are planned at the end of the study. 
12.1. Scientific Committee 
A qualified scientific committee was set up for this study. It is composed of 2 doctors 
specialized in gastroenterology, who participated in drafting the protocol and its validation, 
and who will take part in the validation of the statistical analysis plan and drafting the clinical 
report. The scientific committee is also responsible for proposing and/or validating changes to 
the protocol once the study is underway. 
12.2. Access to source data 
A source document is any original document or object that proves the existence or accuracy of 
a data or fact recorded during the research and in particular the medical records of included 
patients. 
The investigators will make available the documents and individual data strictly necessary for 
data collection during the study, study monitoring, quality control and auditing of the study, to 
the persons with access to these documents in accordance with legislative and regulatory 
provisions (Articles L.1121-3 and R.5121-13 of the Code of Public Health). 
12.3. Confidentiality 
Pursuant to current legislation (Articles L.1121-3 and R.5121-13 of the Code of Public 
Health), persons with direct access to source data must take all the necessary precautions to 
ensure the confidentiality of information about the experimental drugs, the research and 
participating subjects, in particular as regards their identity and the results obtained. These 
persons and the investigators themselves are subject to professional secrecy. 
During the study or after its completion, the data collected on the participants and sent to the 
sponsor by the investigators (or any other specialized persons involved) will be made 
anonymous. They should in no case show the names of the persons concerned or their 
address. 

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No nominative data about the patient will be collected. 
The sponsor (or its representative) must ensure that each person participating in the research 
gives his/her agreement for access to his/her personal data which are strictly necessary for the 
quality control of the research. 
12.4. Data ownership 
PFIZER will retain ownership of all the case report forms, data analysis, and reports resulting 
from this study. 
12.5. Communication and publication  
All the information obtained from this study will be considered confidential, until Pfizer and 
the members of the scientific committee have carried out its analysis and final review. 
The study results may be published or presented by the members of the scientific committee 
after revision and approval by Pfizer, who will ensure that confidential information or 
industrial property are not disclosed. Before publication or presentation, a copy of the final 
text should be sent by the member(s) of the scientific committee to Pfizer, for comment. Such 
comments aim to ensure the scientific content of the proposed publications and/or 
presentations and make sure that the data and the material referring to Pfizer products and 
activities receive a fair, accurate, and reasonable presentation. 
12.6. Communication of problems 
If a prohibition or restriction is imposed (for example, the suspension of the study) by a 
responsible competent authority in any region of the world, or if the investigator becomes 
aware of any new information that could affect the evaluation of the benefits and risks of a 
Pfizer product, Pfizer must be immediately informed.  
Moreover, the investigator shall immediately inform Pfizer about all the urgent safety 
measures taken by the investigator to protect study patients from any immediate danger, and 
from all the serious breaches of this non-interventional study protocol about which the 
investigator is aware.  
 
13. REFERENCES 
(1) Gaujoux-Viala C et al. Recommandations de la Société française de rhumatologie pour 
la prise en charge de la rheumatoid arthritis. Revue du rhumatisme 2014;81:303–312. 
(2) Michel B et al. Facteurs psychologiques et intensité de la fatigue perçue auprès de 
patients souffrant d’une rheumatoid arthritis: une recherche préliminaire. Annales 
Médico-Psychologiques 2016; 174:344-51. 
(3) Boonen A, Severens JL. The burden of illness of rheumatoid arthritis. Clin Rheumatol 
2011;30:S3-S8. 
(4) Fautrel B et al. Economic consequences and potential benefits. Best Practice & 
Research Clinical Rheumatology 2011;25:607-624. 
(5) Smolen JS et al. EULAR recommendations for the management of rheumatoid 
arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 
update. Ann Rheum Dis 2017;76:960-77. 
(6) www.ema.com 
(7) HAS. Transparency Commission Opinion XELJANZ®. 27 September 2017. 

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(8) Summary of product characteristics on XELJANZ®. 
(9) Lee EB et al. Tofacitinib versus Methotrexate in Rheumatoid Arthritis. N Engl J Med 
2014;370:2377-86. 
(10) van der Heidje D et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis 
receiving methotrexate. Twelve-month data from a twenty-four–month phase III 
randomized radiographic study. Arthritis Rheum 2013;65(3):559-570. 
(11) van Vollenhoven RF et al. Tofacitinib or adalimumab versus placebo in rheumatoid 
arthritis. N Engl J Med. 2012;367(6):508-519. 
(12) Fleischmann R et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with 
methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis 
(ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. 
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14. LIST OF TABLES  
Table 1: Evaluation of response to treatment considering outcome of DAS28 (EULAR 
criteria)  
Table 2: Planned Study Schedule 
Table 3: Patients data collected 
Table of adverse events 
15. LIST OF FIGURES 
Figure 1: Study schema 
Figure 3 : Potential predictive factors of drug survival 
ANNEX 1. LIST OF INDEPENDENT DOCUMENTS  
Numéro 
Numéro de 
référence du 
document 
Date 
Titre 
1 
1.2 
09-NOV-
2018 
Patient Information Leaflet 
2 
2.0 
21-DEC-2020 
Case Report Form including non-inclusion log 
and adverse event reporting form 
3.1 
PCS 
 
PCS – Pain Catastrophizing Scale 
3.2 
CSQ 
 
CSQ – Coping Strategies Questionnaire 
3.3 
GIRERD 
 
GIRERD 
3.4 
FIRST 
 
FiRST-Fibromyalgia Rapid Screening Tool 
3.5 
Euro QoL 
 
Euro QoL EQ-5D -3L 
3.6 
SF-12 (Version 2) 
 
SF-12 (Version 2) 
3.7 
FACIT-F 
 
FACIT-F - Functional Assessment of Chronic 
Illness Therapy-Fatigue 
4 
NA 
08-DEC-2020 Sites list 
ANNEX 2. ADDITIONNAL INFORMATION 
Not Applicable