Tocilizumab F. Hoffmann-La Roche Ltd. Protocol MA 27950, Version 3.0 1

Transcription

1 Protocol MA 27950, Version 3.0 1

2 Protocol MA 27950, Version 3.0 2

3 TABLE OF CONTENTS PROTOCOL ACCEPTANCE FORM... 8 PROTOCOL SYNOPSIS BACKGROUND Background on Rheumatoid Arthritis Disease Pathogenesis and treatment Background on Tocilizumab Study Rationale and Benefit Risk Assessment OBJECTIVES Primary Objective Secondary Objectives STUDY DESIGN Description of Study Overview End of Study Rationale for Observational Study Rationale for Test Product Dosage Rationale for Patient Population and Analysis Groups Outcome Measures Clinical Effectiveness Measures Safety Outcome Measures Patient Reported Outcome Measures MATERIALS AND METHODS Patients Inclusion Criteria Exclusion Criteria Method of Treatment Assignment Study Treatment Concomitant Therapy Protocol MA 27950, Version 3.0 3

4 4.5 Study OBSERVATIONS Description of Study Observations Medical History and Demographic Data Other Disease-Specific Data to be collected Laboratory Data to be collected Patient-Reported Outcomes Timing of Study Data To Be Collected Enrolment Visit and Eligibility Screening Form Data To Be Collected during Observation Period Data To Be Collected at Study Completion/Early Termination Visit Drug, Patient, Study, and Site Discontinuation Drug and Patient Discontinuation Withdrawal from drug Withdrawal from Study Study and Site Discontinuation ASSESSMENT OF SAFETY Safety Plan Management of Specific Adverse Events Opportunistic Infections and Serious Infections Gastrointestinal Perforations Demyelinating Disorders Haematologic Abnormalities Elevated Liver Enzymes Cardiovascular Events and Elevated Lipids Malignancies Infusion Reactions Safety Parameters and Definitions Adverse Events Serious Adverse Events (Immediately Reportable to Roche) Non-Serious Adverse Events of Special Interest (Immediately Reportable to Roche) Protocol MA 27950, Version 3.0 4

5 5.3 Methods and Timing for Capturing and Assessing Safety Parameters Adverse Event Reporting Period Eliciting Adverse Event Information Assessment of Severity of Adverse Events Assessment of Causality of Adverse Events Procedures for Recording Adverse Events Diagnosis versus Signs and Symptoms Adverse Events Occurring Secondary to Other Events Persistent or Recurrent Adverse Events Abnormal Laboratory Values Abnormal Vital Sign Values Abnormal Liver Function Tests Deaths Preexisting Medical Conditions Lack of Efficacy or Worsening of Rheumatoid Arthritis Hospitalization or Prolonged Hospitalization Overdoses Patient-Reported Outcome Data Immediate Reporting Requirements from Investigator to Sponsor Emergency Medical Contacts Reporting Requirements for Serious Adverse Events and Non-Serious Adverse Events of Special Interest Reporting Requirements for Pregnancies Pregnancies in Female Patients Pregnancies in Female Partners of Male Patients Abortions Congenital Anomalies/Birth Defects Follow-Up of Patients after Adverse Events Investigator Follow-Up Sponsor Follow-Up Protocol MA 27950, Version 3.0 5

6 5.6 Post-Study Adverse Events Expedited Reporting to Health Authorities, Investigators, Institutional Review Boards, and Ethics Committees STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ANALYSIS Populations and SUBGROUPS Analysis Populations Analysis of Subgroups Efficacy Analyses Primary Efficacy Variable Secondary Efficacy Variables Safety Analyses Patient-Reported OutcomeS, Quality of Life and other observations Interim Analysis Determination of Sample Size DATA COLLECTION AND MANAGEMENT Electronic Case Report Forms Source Data Documentation Use of Computerized Systems Retention of Records ETHICAL CONSIDERATIONS Compliance with Laws and Regulations Informed Consent Institutional Review Board or Ethics Committee Confidentiality Financial Disclosure STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION Study Documentation Site Inspections Administrative Structure Protocol MA 27950, Version 3.0 6

7 9.4 Publication of Data and Protection of Trade Secrets Protocol Amendments REFERENCES Appendix 1 Joint Counts (28/28) Appendix 2 Disease Activity Score (DAS28) Appendix 3 Health Assessment Questionnaire (HAQ) Appendix 4 FACIT-Fatigue Scale Table 1 Data Collected During the Observation Period Protocol MA 27950, Version 3.0 7

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9 PROTOCOL SYNOPSIS TITLE: PROTOCOL NUMBER: MA TEST PRODUCT: Tocilizumab (RO ) A GLOBAL COMPARATIVE OBSERVATIONAL STUDY IN RHEUMATOID ARTHRITIS (RA) PATIENTS WHO ARE TREATED WITH A TNF INHIBITOR OR TOCILIZUMAB AS THE FIRST BIOLOGIC THERAPY PHASE: INDICATION: SPONSOR: Not applicable Rheumatoid arthritis F. Hoffmann-La Roche Ltd. Objectives Primary Objective The primary objective for this study is as follows: To observe, in routine clinical practice over the 52-week observation period, clinical effectiveness in patients suffering from rheumatoid arthritis (RA) who have been prescribed a tumor necrosis factor (TNF) inhibitor or tocilizumab after experiencing an insufficient response or intolerance to non-biologic disease-modifying antirheumatic drug (DMARD) therapy. The main assessment time-point is Week 24. Secondary Objectives The secondary objectives for this study are as follows: To describe demographic and RA disease characteristics at the time of initiating the first biologic therapy. To identify predictors of response to treatment that differentiate tocilizumab from TNF inhibitors. To observe efficacy by RA patient types following initiation of first biologic therapy. To observe quality of life (QoL), health economics and safety outcomes with biologic therapy. To observe patterns of treatment, such as use of concomitant medication or persistence with biologic therapy. To observe rates, reasons and timing of biologic treatment discontinuation, and the subsequent biologic choice. To observe and compare treatment safety over time with the biologics of choice, with focus on the following: Incidence of infusion reactions or injection site reactions during the study following the start of first biologic therapy. Incidence of serious and non-serious adverse events (AEs) during the study. Incidence of serious and non-serious AEs of special interest, including infections, during the study. Protocol MA 27950, Version 3.0 9

10 To observe the additional effects of TNF inhibitors and tocilizumab by assessing (where components of the score are available): o Proportion of patients achieving remission at Week 24 according to the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) response criteria definition. o Proportion of patients achieving disease activity score remission and Low Disease Activity state at Week 24. o Proportion of patients achieving remission at Week 24 as defined by Clinical Disease Activity Index (CDAI) score 2.8. o Proportion of patients achieving remission at Week 24 as defined by Simplified Disease Activity Index (SDAI) score 3.3. Study Design Description of Study Global, multicenter, prospective observational study in RA patients treated with a TNF inhibitor or tocilizumab as a first biologic therapy. Number of Patients Approximately 2000 patients will be recruited in this observational study. Target Population Patients must meet the following criteria for study entry: At least 18 years of age. Suffering from RA and is a non-responder or intolerant to DMARD therapy. Has been prescribed a first biologic therapy (in accordance with the approved local prescribing information) by his/her rheumatologist up to 6 weeks prior to the inclusion visit, irrespective of the treatment prescribed. Has been given oral and written information about the study and has no objections to the data concerning him/her being subject to computerized data processing. Patients who meet any of the following criteria will be excluded from study entry: Patients whose first biologic therapy is given as part of a clinical trial studying RA treatment. Patients who are receiving or have received experimental DMARDs as part of a clinical trial studying RA treatment in the last 12 months Patients whose first biologic is rituximab, abatacept or anakinra. Patients who have received any biologic therapy for more than 6 weeks prior to the inclusion visit. Length of Study Enrolment will take place over a period of approximately 18 months. Patients may be enrolled up to 6 weeks after commencing a TNF inhibitor or tocilizumab. The duration of observation for each patient will be 52 weeks following the start of the first biologic therapy. End of Study End of study is expected to be approximately 52 weeks after enrollment of last patient in the study, approximately Q Protocol MA 27950, Version

11 Clinical Effectiveness Measures The primary efficacy observation is the mean change in calculated disease activity score based on 28 joint count (DAS28)-erythrocyte sedimentation rate (ESR), 24 weeks after the start of biologic therapy at Week 0 (baseline). Where available, the following efficacy parameters will be documented to enable description of the change over time (at 0, 24, and 52 weeks as available according to local practice): Tender and swollen joint counts (based on 28 joint count), C-reactive protein and/or ESR, Physician Global Assessment and Patient Global Assessment of Disease Activity (where available). Calculated DAS28/CDAI/SDAI score based on 28 joint count (where components are available). Where available, the following information will be captured: Loss of efficacy or development of intolerance to biologic therapy. Rates and reasons for dose modifications (dose discontinuation, interruption, reintroduction and dosing frequency modifications). Rates, reasons, frequency and timing of permanent discontinuation of first biologic therapy and subsequent therapy introduced. Safety Outcome Measures Incidence of infusion reactions or injection site reactions during the study following the start of the first biologic therapy. Incidence of serious and non-serious AEs during the study. Incidence of serious and non-serious AEs of special interest, including infections, during the study. Patient Reported Outcomes Health Assessment Questionnaire-Disability Index (HAQ-DI) score, Functional Assessment of Chronic Illness Therapy, visual analogue scale pain and morning stiffness where available. Investigational Medicinal Products As this is an observational trial, TNF inhibitors or tocilizumab will be prescribed according to local prescribing information as per clinical practice and will not be considered as investigational medicinal products. Statistical Methods The statistical analysis of this non-randomized observational study will be exploratory and will primarily be based on descriptive statistical methods. In addition, statistical tests and modeling techniques will be used to highlight interesting aspects of the data. No correction for multiplicity will be applied. All included patients receiving a TNF inhibitor or tocilizumab will be included in the analysis and, unless otherwise specified, missing data will not be imputed. Subpopulations, such as patients completing the study on the original biologic treatment or receiving monotherapy with a biologic agent may additionally be performed. Primary Analysis Efficacy evaluations will include the analysis of the change from at Week 0 (baseline) in calculated DAS28 as well as in other continuous variables, which will be analyzed in Protocol MA 27950, Version

12 the two groups defined by the biologic treatment received at enrollment (a TNF inhibitor or tocilizumab) using linear models or non-parametric alternatives. The same methods will be applied to similar variables, e.g., QoL scores. Binary and categorical efficacy and safety variables (e.g., EULAR response, serious AE or serious infection [SI] rates) will be analyzed by means of Clopper-Pearson confidence intervals and/or logistic regression as appropriate. Interim Analysis Interim analyses of baseline characteristics, efficacy and safety variables may be performed during the study, none of which will have confirmatory character. Determination of Sample Size Approximately 2000 patients will be recruited in this observational study. In the main analysis of efficacy parameters, the DAS28 change from baseline to Week 24 will be estimated in the TNF inhibitor and in the tocilizumab cohorts. Assuming a 1:1 proportion of patients in the two cohorts, a 20% overall drop-out rate in the whole population and a standard deviation of 1.7 DAS28 units for the change, under normality assumption a two-sided 95% confidence interval around the estimated mean will extend between to 0.12 units from the mean (half-width = 0.12 units). Assuming comparability of the two cohorts, a two-sided t-test at the 5% significance level will allow the detection of a difference of about 0.3 DAS28 units with 90% statistical power. In a patient subgroup including 20% of the study population, such as presumably for patients on monotherapy, the half-width will be 0.26 units and the detectable difference 0.6 units. In case of an unbalanced size of the two cohorts (e.g., a 2:1 proportion in favor of tocilizumab or of TNF inhibitors), the detectable differences will be almost identical. Protocol MA 27950, Version

13 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS Abbreviation ACR AE ALT ANC AST CCP CDAI CRO CRP DAS28 DMARD EC (e)crf EDC EMA ESR EU EULAR FACIT FDA HAQ-DI GI HDL ICH IL IND IRB LDL PRO QoL RA RF SAE SAP SDAI Definition American College of Rheumatology adverse event alanine aminotransferase absolute neutrophil count aspartate aminotransferase citrullinated cyclic peptides Clinical Disease Activity Index contract research organization C-reactive protein disease activity score based on 28 joint count disease-modifying anti-rheumatic drug Ethics Committee (electronic) Case Report Form electronic data capture European Medicines Agency erythrocyte sedimentation rate European Union European League Against Rheumatism Functional Assessment of Chronic Illness Therapy Food and Drug Administration Health Assessment Questionnaire-Disability Index gastrointestinal high density lipoprotein International Conference on Harmonization interleukin Investigational New Drug (application) Institutional Review Board low density lipoprotein patient-reported outcome quality of life rheumatoid arthritis rheumatoid factor serious adverse event statistical analysis plan Simplified Disease Activity Index Protocol MA 27950, Version

14 SGPT SGOT SI SJC SPC TJC TNF ULN US VAS serum glutamate pyruvate transaminase serum glutamate oxaloacetic transaminase serious infection swollen joint count summary of product characteristics tender joint count tumor necrosis factor upper limit of normal United States visual analogue scale Protocol MA 27950, Version

15 1. BACKGROUND 1.1 BACKGROUND ON RHEUMATOID ARTHRITIS DISEASE Rheumatoid arthritis (RA) is an autoimmune inflammatory chronic disease characterized by a progressive destruction of joints [1-2] which, depending on the severity, may be accompanied by systemic manifestations involving skin, blood vessels and internal organs, and disease activity flares which lead to progressive joint damage, functional disability and impaired quality of life (QoL) [3]. In the absence of treatment, RA may cause a severe functional disability of the individual, an important reduction in QoL and an increase in mortality [2; 4-8]. The prevalence of RA worldwide is estimated to be in a range between 0.5 and 1% of the adult population [9], thus it has important socioeconomic consequences [6]. The etiology of RA is unknown although it is considered to be multifactorial with the most important risk factors being, besides the genetic susceptibility, gender (3-4 times more frequent in women than in men), age (40-70 years is the most common age, and in this range, it increases with age) and smoking [1-2; 9-13]. Early diagnosis and implementation of adequate therapy are very important to reach clinical disease control [2; 11]. Clinical diagnosis traditionally includes the determination of the rheumatoid factor (RF), one of the components of the American College of Rheumatology (ACR) classification criteria for RA [14]. Recently, other specific antibodies were also assessed, including the anti-citrullinated cyclic peptides (CCP) antibodies which recognize peptides post-translationally modified through citrullinization [2; 15]. These antibodies appear before symptoms of the disease PATHOGENESIS AND TREATMENT In RA pathogenesis, hyperplasia of the synovial lining cells of the joint occurs by recruiting cells from the immune system [16]. Normal lymphocyte differentiation and activation in the synovial membrane can lead to a disorder of pro-inflammatory cytokines levels and antibody production [17-18]. These pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL) -1, IL-6, IL-17, interferon-gamma and transforming growth factor-beta, stimulate the release of other cytokines by the surrounding cells. In the pharmacological management of RA, long term efficacy and safety of drugs are of paramount importance. Treatment of RA focuses on the alleviation of disease signs and symptoms (e.g., inflammation, tumefaction and pain), reducing joint damage to a minimum, maintaining function and QoL, and reducing premature mortality associated with this disorder. Current treatments consist of non-steroidal anti-inflammatory drugs, which mitigate pain and stiffness, and disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, which have anti-inflammatory and immunosuppressive effects [19]. Protocol MA 27950, Version

16 Biological approaches include neutralizing cytokines such as TNF-α and IL-1, which have been shown to both control signs and symptoms of joint inflammation and retard progression of joint destruction. Tumor necrosis factor-α is one of the cytokines produced in mononuclear cell cultures isolated from the RA joint synovial membrane; when blocked, inhibition of other pro-inflammatory cytokines occurs [20]. Currently there are five authorized treatments targeting TNF-α activity (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) [21-24]. Although anti-tnf agents have revolutionized RA treatment, the percentage of treated patients who do not reach an adequate disease control is 50%, and 30-40% do not respond at all [25]. To address this un-met medical need, other biological agents have been developed including anakinra, rituximab, abatacept, and tocilizumab [26-29]. Tocilizumab is the first approved biological agent for RA treatment which specifically inhibits the IL-6 receptor. Information regarding the efficacy and safety of tocilizumab comes from phase I-III clinical trials and their extension phases; the phase III program alone comprises over 4000 patients. 1.2 BACKGROUND ON TOCILIZUMAB Interleukin-6 is a cytokine which is abundantly expressed in the synovial fluid of RA patients, strongly contributing to the development of the inflammatory process and joint destruction and to the systemic manifestations of the disease [30-31]. While anti-tnf agents have been the most widely used biologics, inhibition of IL-6 signaling by tocilizumab has been shown to be a highly effective treatment for RA patients, including those showing an inadequate response to anti-tnf agents. Although TNF-α, as well as IL-6, are important immunomodulators, playing a central role in the pathogenesis of inflammation in RA, the pleiotropic effects of IL-6 over multiple types of cells may explain at least some of the differences in the mechanism of action between IL-6 and TNF-α in the blocking of inflammatory pathways, especially regarding the systemic effects of RA. Tocilizumab (Actemra /RoActemra ) is a humanized monoclonal antibody targeting the human IL-6 receptor, which inhibits the binding of this cytokine to its receptor [32]. It is the first monoclonal antibody developed for RA treatment with this mechanism of action and has been recently approved by regulatory authorities in several regions and countries (e.g., the European Medicines Agency [33], United States [US] Food and Drug Administration [FDA], Health Canada, Japan, Mexico and Australia). Data from five phase III studies with over 4000 recruited patients have shown that tocilizumab at a dose of 8 mg/kg, in combination with methotrexate/dmards or as monotherapy, can produce a quick and clinically relevant improvement in RA signs and symptoms, health status, and joint damage prevention, not only in patients who have not been previously treated but also in patients refractory to treatment with methotrexate, other DMARDs or anti-tnf agents [34-39]. Further details regarding tocilizumab are available in the local prescribing information and summary of product characteristics (SPC). Protocol MA 27950, Version

17 1.3 STUDY RATIONALE AND BENEFIT RISK ASSESSMENT Biologic agents have transformed the management of RA with significant impact on the symptoms and signs of RA, as well as evidence of structural retardation. Tumor necrosis factor inhibitors were the first biologics to be introduced, followed by abatacept, rituximab and tocilizumab. Tocilizumab is licensed for the management of RA patients who have not responded to DMARDs and or TNF inhibitor therapy, supported by a significant phase III programme. Recent European League Against Rheumatism (EULAR) guidelines recommend the use of TNF inhibitors as the first biologic agents [40]. There have been no large-scale, comparative studies evaluating effectiveness and safety outcomes of the various biologic therapies following DMARD failure to further inform current guidance and clinical practice. Registration trials are performed using validated inclusion and exclusion criteria with a remarkable influence in selected patients, who are closely observed. Real life studies on the other hand include patients that are not otherwise eligible for the stringent randomized controlled studies. This study aims to evaluate in routine practice the relative comparative clinical effectiveness and safety outcomes of a TNF inhibitor or tocilizumab prescribed to patients starting their first biologic therapy. The two cohorts of patients will be observed for a period of approximately 52 weeks from the start of the first biologic therapy, with attention to biologic treatment effectiveness and biologic treatment drug survival and safety outcomes. The study will explore the possible predictors of response to the first biologic of choice. 2. OBJECTIVES 2.1 PRIMARY OBJECTIVE The primary objective for this study is: To observe, in routine clinical practice over the 52-week observation period, clinical effectiveness in patients suffering from RA who have been prescribed a TNF inhibitor or tocilizumab after experiencing an insufficient response or intolerance to non-biologic DMARD therapy. The main assessment time-point is Week SECONDARY OBJECTIVES The secondary objectives for this study are: To describe demographic and RA disease characteristics at the time of initiating the first biologic therapy. To identify predictors of response to treatment that differentiate tocilizumab from TNF inhibitors. To observe efficacy by RA patient types following initiation of first biologic therapy. To observe QoL, health economics and safety outcomes with biologic therapy. Protocol MA 27950, Version

18 To observe patterns of treatment, such as use of concomitant medication or persistence with biologic therapy. To observe rates, reasons and timing of biologic treatment discontinuation, and the subsequent biologic choice. To observe and compare treatment safety over time with the biologics of choice, with focus on the following: o o o Incidence of infusion reactions or injection site reactions during the study following the start of first biologic therapy. Incidence of serious and non-serious AEs during the study. Incidence of serious and non-serious AEs of special interest, including infections, during the study. To observe the additional effects of TNF inhibitors and tocilizumab by assessing (where components of the score are available): o o o o Proportion of patients achieving remission at Week 24 according to the ACR/EULAR criteria definition. Proportion of patients achieving disease activity score remission and Low Disease Activity state at Week 24. Proportion of patients achieving remission at Week 24 as defined by Clinical Disease Activity Index (CDAI) score 2.8. Proportion of patients achieving remission at Week 24 as defined by Simplified Disease Activity Index (SDAI) score STUDY DESIGN 3.1 DESCRIPTION OF STUDY This global study will be conducted by F. Hoffmann-La Roche Ltd. who will be referred to as the Sponsor OVERVIEW This is a global, observational, post-marketing, multi-center study in RA patients who are currently being treated with a TNF inhibitor or tocilizumab as a first biologic therapy. This study is observational, therefore no additional clinic visits or laboratory testing will be required outside of routine clinical practice. No study-specific medication will be administered and no other interventional procedures additional to those comprising routine clinical practice will be performed. Approximately 2000 patients will be recruited to this observational study. Around two hundred (200) centers in approximately 23 countries will participate in the study. Since patients may have initiated treatment prior to study start-up, data collection may be partially retrospective. Protocol MA 27950, Version

19 Patients who stop treatment with the prescribed TNF inhibitor or tocilizumab for reasons of inefficacy or intolerance will continue to be observed for the planned period of 52 weeks. Patients data will be analyzed based on the RA treatment they have been prescribed (a TNF inhibitor or tocilizumab). Since the study is observational, visits are those pre-scheduled as part of usual clinical practice. These include: One enrolment visit (this visit may occur up to 6 weeks after the start of the first biologic therapy, and in this case data collection will be retrospectively collected up to the time of enrolment). Usual follow-up visits according to the center s practice, which will take place during the study observation period up to 52 weeks after the start of the first biologic therapy, with data collection planned at Week 0 (baseline) and at Week 24 and Week 52 (where available). One final visit, corresponding to that performed nearest to 52 weeks after starting first biologic therapy. Where available, data will be recorded by the principal investigator and collaborators at the enrolment visit and 24 and 52 weeks after the patient starts the first biologic therapy. Additional tests for the recruited patients are not foreseen, since this is an observational study. The TNF inhibitor or tocilizumab administration may occur as per routine practice and following the local prescribing information. Treatment-related information (including efficacy and safety information, where available) may be collected at the same time-points as TNF inhibitor or tocilizumab administration, but will be at the discretion of the Investigator in line with local routine practice. A schedule of data to be collected during the observation period (where available) is provided in Table 1 in appendix. 3.2 END OF STUDY End of study is expected to be approximately 52 weeks after enrollment of last patient in the study, approximately Q RATIONALE FOR OBSERVATIONAL STUDY There have been no large-scale, comparative studies evaluating effectiveness and safety outcomes of the various RA biologic therapies following DMARD failure to further inform current guidance and clinical practice. This study will explore the possible predictors of response to the first biologic of choice RATIONALE FOR TEST PRODUCT DOSAGE As the objective of the study is to observe routine practice patterns of usage, the study protocol does not stipulate any specific dosing regimen. The doses and duration of Protocol MA 27950, Version

20 treatment will be stipulated by the Investigator, according to the approved product information, local treatment guidelines and/or routine clinical practice RATIONALE FOR PATIENT POPULATION AND ANALYSIS GROUPS This study aims to evaluate in routine practice the relative comparative clinical effectiveness and safety outcomes of a TNF inhibitor or tocilizumab prescribed to patients starting their first biologic therapy. The two cohorts of patients will be observed for a period of 52 weeks from the start of the first biologic therapy, with attention to biologic treatment effectiveness and biologic treatment drug survival and safety outcomes. 3.4 OUTCOME MEASURES CLINICAL EFFECTIVENESS MEASURES The primary efficacy observation is the mean change in calculated DAS28-erythrocyte sedimentation rate (ESR) 24 weeks after start of biologic therapy at Week 0 (baseline). Where available, the following efficacy parameters will be documented to enable description of the change over time (at 0, 24 and 52 weeks as available according to local practice): Tender joint count (TJC) and swollen joint count (SJC) based on 28 joint count, C- reactive protein (CRP) and/or ESR, Physician Global Assessment and Patient Global Assessment of Disease Activity (where available). Calculated DAS28/CDAI/SDAI score based on 28 joint count (where components are available). Where available, the following information will be captured: Loss of efficacy or development of intolerance to biologic therapy. Rates and reasons for dose modifications (dose discontinuation, interruption, reintroduction and dosing frequency modifications). Rates, reasons, frequency and timing of permanent discontinuation of first biologic therapy and subsequent therapy introduced SAFETY OUTCOME MEASURES The safety outcome measures for this study are as follows: Incidence of infusion reactions or injection site reactions during the study following the start of the first biologic therapy. Incidence of serious and non-serious AEs during the study. Incidence of serious and non-serious AEs of special interest, including infections, during the study. Protocol MA 27950, Version

21 3.4.3 PATIENT REPORTED OUTCOME MEASURES The patient reported outcome measures for this study are as follows: Health Assessment Questionnaire-Disability Index (HAQ-DI) score, Functional Assessment of Chronic Illness Therapy (FACIT), visual analogue scale (VAS) pain and morning stiffness where available. 4. MATERIALS AND METHODS 4.1 PATIENTS The study population will include patients with moderate to severe RA, according to ACR criteria [14], of at least 24 weeks of evolution, in whom the treating physician has made the decision to commence treatment with a TNF inhibitor or tocilizumab (in accordance with the local label) within 6 weeks prior to the enrollment visit. Furthermore, patients must have given their informed consent and must fulfill all inclusion criteria and exclusion criteria detailed in Section and Approximately 2000 patients will be observed during this observational study INCLUSION CRITERIA Patients must meet the following criteria for study entry: At least 18 years of age. Suffering from RA and is a non-responder or intolerant to DMARD therapy. Has been prescribed a first biologic therapy (in accordance with the approved local prescribing information) by his/her rheumatologist up to 6 weeks prior to the inclusion visit, irrespective of the treatment prescribed. Has been given oral and written information about the study and has no objections to the data concerning him/her being subject to computerized data processing EXCLUSION CRITERIA Patients who meet any of the following criteria will be excluded from study entry: Patients whose first biologic therapy is given as part of a clinical trial studying RA treatment. Patients who are receiving or have received experimental DMARDs as part of a clinical trial studying RA treatment in the last 12 months Patients whose first biologic is rituximab, abatacept or anakinra. Patients who have received any biologic therapy for more than 6 weeks prior to the inclusion visit. 4.2 METHOD OF TREATMENT ASSIGNMENT No study treatment will be administered; TNF inhibitors and tocilizumab will be prescribed according to the approved product information, local treatment guidelines and/or routine clinical practice. Protocol MA 27950, Version

22 4.3 STUDY TREATMENT Not applicable. No study treatment will be administered. The TNF inhibitor or tocilizumab will be prescribed according to the approved product information, local treatment guidelines and/or routine clinical practice and will not be considered as investigational medicinal products. 4.4 CONCOMITANT THERAPY For the purpose of this protocol concomitant treatments for RA may be defined as corticosteroids (e.g., dexamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone), hydroxychloroquine, sulfasalazine, methotrexate, leflunomide, gold compounds, cyclosporine, and other treatments administered with the objective of limiting the progression of RA. Concomitant medication and treatment should be prescribed according to the investigator s judgment. 4.5 STUDY OBSERVATIONS DESCRIPTION OF STUDY OBSERVATIONS Medical History and Demographic Data Medical history includes the following co-morbidities reported prior to the enrolment visit: History of angina or other heart disease. Past history of severe and progressive infection. History of severe immunosuppression. Demyelination of the central nervous system. Past history of malignant tumor. History of lymphoproliferative syndrome. History of chronic hepatic impairment. Other clinically significant co-morbidities. History of other concomitant auto-immune diseases. History of overlap syndrome. Demographic data will include year of birth, age, gender, height, weight, smoking status, alcohol intake status, child-bearing potential and type of contraception for women Other Disease-Specific Data to be collected History of RA will be collected during enrolment and will include the following: Year of initial RA diagnosis. Available diagnostic data (e.g., RF status [positive/negative, titer]). Protocol MA 27950, Version

23 Presence of anti-ccp. Evidence of structural joint damage. Number of surgical procedures related to RA (including number of prostheses). Efficacy of the TNF inhibitor and tocilizumab during the observation period will be assessed using the following: TJC and SJC using a 28-joint count evaluation (see Appendix 1), The calculated DAS28 score [41-42] (see Appendix 2), Physician Global Assessment of Disease Activity, SDAI and CDAI [43]. Previous and concomitant RA treatments will be recorded at enrolment and throughout the observation period, respectively (see Section 4.4). The start and end date, route and dose will be collected when available. Details of the first biologic will also be recorded at enrolment. The change and reason for change in RA treatment will be recorded where available Laboratory Data to be collected When available, laboratory results for the following parameters will be collected and all clinically significant abnormalities will be reported as an adverse event (AE): Haematology: haemoglobin, neutrophil count, platelet count. Biochemistry: alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) and aspartate aminotransferase (AST)/serum glutamate oxaloacetic transaminase (SGOT) blood urea nitrogen, serum electrolytes (potassium, sodium, chloride, calcium, phosphate). Lipid profile (total cholesterol, triglycerides, high density lipoprotein [HDL], low density lipoprotein [LDL]) following overnight fasting (>8 hours). Acute phase inflammatory markers (CRP and ESR) Patient-Reported Outcomes Patient-reported outcome (PRO) and QoL data will be collected to more fully characterize the clinical profile of tocilizumab. These will include: Patient Global Assessment of Disease Activity. HAQ-DI [44-45]. See Appendix 3. FACIT [46]. See Appendix 4. Severity of pain (VAS). Morning stiffness. Protocol MA 27950, Version

24 The PRO instruments, translated as required in the local language, will be distributed by the investigator staff and completed in their entirety by the patient at specified timepoints during the study TIMING OF STUDY DATA TO BE COLLECTED This is an observational study, therefore no additional visits of laboratory tests will be required outside of local routine clinical practice. Dosing and treatment duration are at the discretion of the Investigator, in accordance with the SPC and local prescribing information Enrolment Visit and Eligibility Screening Form Patients must sign and date the most current Independent Ethics Committee (EC)- approved written informed consent before any study-specific data are collected. An enrolment screening visit should be performed up to 6 weeks after commencing first biologic therapy. In patients enrolled up to 6 weeks after starting biologic therapy, the data collected at this visit will be the data available at the time of the start of biologic therapy. Patients must fulfill all the entry criteria for participation in the study. An Eligibility Screening Form documenting the Investigator s assessment of each patient with regard to the protocol s inclusion and exclusion criteria is to be completed by the Investigator. Patients qualifying for the study will be assigned to individual study patient numbers in the order of enrolment. Each participating center will be identified by a unique center number assigned by Roche or its designee (see Section 7.1). The following data will be captured, where available: Demographics and co-morbidities (see Section ). Baseline RA data collection, including RA history and past and current concomitant RA treatments (see Section ). Baseline PRO and QoL data collection (see Section ). Baseline safety data collection, including AEs (see Section 5.3), concomitant medication (see Section 4.4. and Section ) and laboratory data (see Section ). The Investigator or designee will use the electronic case report form (ecrf) with the assigned patient number to enter the data collected during the enrolment visit. A schedule of data to be collected during enrolment (where available) is provided in Table Data To Be Collected during Observation Period During treatment with a biologic agent, RA assessments are routinely performed in accordance with current guidelines and local standard of care, and it is routine clinical practice to closely monitor RA patients over long periods of time. When performed Protocol MA 27950, Version

25 during the 52-week observation period, available results from the range of assessments described below will be documented in the ecrf. The Investigator or designee will use the ecrf with the assigned patient number to enter the data collected during each visit. Since patients may initiate treatment up to 6 weeks before the enrolment visit, data collection is retrospective starting from the first biologic therapy and prospective during the 52-week observation period. The following data will be captured, where available: RA data collection (see Section ). PRO and QoL data collection (see Section ). Safety data collection, including AEs (see Section 5.3), concomitant medication (see Section 4.4. and Section ) and laboratory data (see Section ). A schedule of data to be collected during the observation period (where available) is provided in Table Data To Be Collected at Study Completion/Early Termination Visit At a final visit, data will be collected closest to the 52-week time-point after first biologic administration. In case of premature withdrawal, withdrawal data will be collected in an unscheduled visit, including the reason for premature withdrawal. Please see Table 1 for details of the data to be collected at the study completion/early termination visit. 4.6 DRUG, PATIENT, STUDY, AND SITE DISCONTINUATION DRUG AND PATIENT DISCONTINUATION The Investigator has the right to discontinue a patient from the TNF inhibitor or tocilizumab or withdraw a patient from the study at any time. In addition, patients have the right to voluntarily discontinue the TNF inhibitor or tocilizumab or withdraw from the study at any time for any reason Withdrawal from drug Where available, all details relating to the discontinued first biologic will be collected as well as the next RA treatment introduced. Patients will be followed-up for up to 52 weeks after initiation of the first biologic therapy. All assessments will be performed as detailed for planned visits at 24 and 52 weeks. Reasons for discontinuation of the TNF inhibitor or tocilizumab or withdrawal from the study may include, but are not limited to, the following: Lack of efficacy or intolerance to first biologic therapy Patient withdrawal of consent at any time. Protocol MA 27950, Version

26 Any medical condition that the Investigator or Sponsor determines may jeopardize the patient s safety if he or she continues in the study. Investigator or Sponsor determines it is in the best interest of the patient. The primary reason for discontinuation of the TNF inhibitor or tocilizumab should be documented on the appropriate ecrf. Patients who discontinue the TNF inhibitor or tocilizumab will not be replaced Withdrawal from Study Data will be collected up to the date when a patient discontinued from the study (where available). Data will be collected as per usual observational visits as an unscheduled visit for premature discontinuation. Every effort should be made to obtain information on patients who withdraw from the study. The primary reason for withdrawal from the study should be documented on the appropriate ecrf. Patients will not be followed for any reason after consent has been withdrawn. Patients who withdraw from the study will not be replaced STUDY AND SITE DISCONTINUATION The Sponsor has the right to terminate this study at any time. Reasons for terminating the study may include, but are not limited to, the following: Patient enrollment is unsatisfactory. The Sponsor will notify the Investigator if the study is placed on hold, or if the Sponsor decides to discontinue the study or development program. The Sponsor has the right to replace a site at any time. Reasons for replacing a site may include, but are not limited to, the following: Excessively slow recruitment Poor protocol adherence Inaccurate or incomplete data recording Non-compliance with the International Conference on Harmonization (ICH) guideline for Good Clinical Practice. 5. ASSESSMENT OF SAFETY 5.1 SAFETY PLAN MANAGEMENT OF SPECIFIC ADVERSE EVENTS Certain side effects were characterized early on during the clinical development program for tocilizumab and have been shown to be mechanistically linked to its mode of action and its effect on inflammation. In the case of tocilizumab these include neutropenia, thrombocytopenia, elevation of liver enzymes as indicated by the results of liver function tests (ALT/SGPT and AST/SGOT), and lipid disorders (elevation of total cholesterol, Protocol MA 27950, Version

27 HDL and LDL) [34, 36, 38]. In the case of TNF inhibitors, reference should be made to local prescribing information as appropriate. The correlation between side effects and clinically relevant safety outcomes is still to be determined. In the European Union (EU) and other countries, local prescribing information for tocilizumab offers recommendations for managing such adverse reactions (laboratory abnormalities), where the treatment dose and the concomitant medications might be temporarily adjusted (DMARDs dose decrease/withdrawal, tocilizumab dose decrease from 8 mg/kg to 4 mg/kg or tocilizumab transient interruption) depending on the AE and clinical criterion. The following risk mitigation and dose modification rules apply to patients receiving tocilizumab. Recommendations for surveillance of signs and symptoms of tocilizumab AEs of special interest are summarized in the following sections. Review of the local TNF inhibitor prescribing information with regards to the management of AEs of special interest and SAEs is also advised Opportunistic Infections and Serious Infections Physicians should exercise caution when considering the use of tocilizumab in patients with a history of recurring infection or with underlying conditions (e.g., diabetes) which may predispose patients to infections. Tocilizumab should not be administered to patients with active infection. The effects of tocilizumab on high-sensitivity CRP, neutrophils, and the signs and symptoms of infection should be considered when evaluating a patient for a potential infection. Vigilance for timely detection of serious infection (SI) is recommended for patients receiving biologic agents for treatment of RA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reaction. Patients must be instructed to contact their physician immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment. If a patient develops an SI, administration of tocilizumab is to be interrupted until the infection is controlled. The clinician should consider the benefit-risk before resuming treatment with tocilizumab Gastrointestinal Perforations Timely diagnosis and appropriate treatment may reduce the potential for complications of diverticulitis and thus reduce the risk of gastrointestinal (GI) perforations. Therefore, patients should be made aware of the symptoms potentially indicative of diverticular disease, and they should be instructed to alert their healthcare provider as soon as possible if these symptoms arise. In patients with a history of symptomatic diverticulosis, diverticulitis or chronic ulcerative lower GI disease such as Crohn s disease, ulcerative colitis or other chronic lower GI conditions that might predispose to perforation, the clinician should consider the benefit-risk before using tocilizumab. Discontinuation of tocilizumab is recommended for patients who develop GI perforation. Protocol MA 27950, Version

28 Demyelinating Disorders The impact of treatment with tocilizumab on demyelinating disorders is not known; events were rarely reported. Patients should be closely monitored for signs and symptoms potentially indicative of central demyelinating disorders. Physicians should exercise caution in considering the use of tocilizumab in patients with pre-existing or recent onset demyelinating disorders. Treatment with tocilizumab should be interrupted during assessment of a potential demyelination event and should only resume if continuing treatment with tocilizumab is considered to be beneficial Haematologic Abnormalities Decreases in neutrophil and platelet counts have been observed during treatment with tocilizumab. The recommended dose modification strategies for neutropenia and thrombocytopenia are summarized in Table 2 and Table 3, respectively. For patients taking concomitant medications associated with haematologic toxicity, reduction or interruption of the suspected medication is recommended prior to modifying the dose of tocilizumab. Table 2 Decreases in Neutrophil Count ANC (cells/mm 3 ) Action >1000 Maintain dose Interrupt tocilizumab dosing. When ANC increases to >1000 cells/mm 3, resume tocilizumab at 4 mg/kg and increase to 8 m/kg as clinically appropriate. <500 Permanently discontinue tocilizumab. Patients withdrawn from tocilizumab treatment due to a reduced neutrophil count should be monitored for signs of infection, with treatment as deemed appropriate by the Investigator, and should have a repeat white blood cell count with differential performed weekly until the absolute neutrophil count (ANC) is above 1000 cells/mm 3 (1.0 x 10 9 /L). If the ANC does not return to above 1000 cells/mm 3 (1.0 x 10 9 /L) within 2 months (or sooner if deemed necessary by the Investigator), a haematology referral is recommended. Protocol MA 27950, Version

29 Table 3 Decreases in Platelet Count Platelet count (cells/mm 3 ) Action >100,000 Maintain dose. 50, ,000 Interrupt tocilizumab dosing. When platelet count increases to >100,000 cells/mm 3, resume tocilizumab treatment at 4 mg/kg and increase to 8 mg/kg as clinically appropriate. <50,000 Permanently discontinue tocilizumab. Patients withdrawn from tocilizumab treatment due to a reduced platelet count should have a repeat platelet count performed weekly until the count is above 100,000 cells/mm 3 (100 x 10 9 /L). If the platelets do not return to above 100,000 cells/mm 3 (100 x 10 9 /L) within 2 months (or sooner if deemed necessary by the Investigator), a haematology referral is recommended Elevated Liver Enzymes Elevations in ALT/SGPT and AST/SGOT have been observed during treatment with tocilizumab. The recommended dose modification strategies for elevations in ALT/SGPT and AST/SGOT are summarized in Table 4. Table 4 ALT/SGPT and/or AST/SGOT Values a Elevations in ALT/SGPT and AST/SGOT Action 1 to 3 x ULN Modify dose of concomitant DMARDs if appropriate. For persistent increases in this range, reduce tocilizumab dose to 4 mg/kg or interrupt tocilizumab until ALT (SGPT)/AST (SGOT) have normalized. Restart with 4 mg/kg or 8 mg/kg, as clinically appropriate. >3 to 5 x ULN Interrupt tocilizumab dosing until <3 x ULN and follow recommendations above for >1 to 3 x ULN. For persistent increases >3 x ULN, permanently discontinue tocilizumab. >5 x ULN Permanently discontinue tocilizumab. a Whichever is higher. Patients withdrawn from tocilizumab treatment due to elevated liver function tests should have repeat tests performed, as clinically appropriate, until levels return to Week 0 levels (baseline). If the patient s liver function tests have not returned to baseline within 24 weeks (or sooner, if deemed necessary by the Investigator), an ultrasound and/or liver biopsy should be considered. Protocol MA 27950, Version

30 5.1.2 CARDIOVASCULAR EVENTS AND ELEVATED LIPIDS Patients with RA have an increased risk for cardiovascular disorders, therefore, risk factors for cardiovascular disease (e.g., hypertension, hyperlipidemia) should be managed as part of their standard of care. For patients with LDL cholesterol 160 mg/dl, it is recommended that investigators advise the patient regarding therapeutic lifestyle changes and consider initiation of lipid lowering agents or modification of existing therapies. Lipid-lowering agents and lifestyle changes should also be considered for patients with lower LDL cholesterol levels, depending on their overall cardiovascular risk as defined by local guidelines or the National Cholesterol Education Program Adult Treatment Panel III guidelines MALIGNANCIES The impact of immunosuppression on the development of malignancies is not known, however an increased rate of some malignancies, notably lymphoma, has been observed in RA patients. Although no imbalance of malignancies was observed in controlled clinical trials of tocilizumab, malignancies have been identified as a concern for other biologics. It is recognized that identification of such events in tocilizumabtreated patients may require a longer period of surveillance. Tocilizumab should be discontinued in patients with malignancies (with the exception of local basal or squamous cell carcinoma of the skin that is completely excised with free margins) INFUSION REACTIONS An infusion/dose reaction is defined as an AE occurring during and within 24 hours after the infusion of tocilizumab. This may include hypersensitivity reactions or anaphylactic reactions. Signs of a possible hypersensitivity reaction include but are not limited to: Fever, chills, pruritus, urticaria, angioedema, and skin rash. Cardiopulmonary reactions, including chest pain, dyspnea, hypertension or hypotension. Healthcare professionals administering tocilizumab infusions should be trained in the appropriate administration procedures, be able to recognize the symptoms associated with potential anaphylactic or hypersensitivity reactions, and have the appropriate medication available for immediate use in case of anaphylaxis or hypersensitivity reaction during or after administration of tocilizumab. Healthcare professionals should also instruct patients to seek medical attention if they experience symptoms of a hypersensitivity reaction outside of the clinic. If a patient has symptoms of anaphylaxis or serious hypersensitivity, or requires an interruption of the study drug because of symptoms of anaphylaxis or hypersensitivity, it is recommended that the administration of tocilizumab be discontinued permanently. The patient should be treated according to the standard of care for management of the hypersensitivity reaction. A blood sample for the presence of anti-tocilizumab antibodies should be obtained at the time of the event and 6 weeks after the event. Protocol MA 27950, Version

31 5.2 SAFETY PARAMETERS AND DEFINITIONS Safety assessments will consist of monitoring and recording AEs, including serious adverse events (SAEs) and non-serious AEs of special interest; measurement of safety laboratory assessments; measurement of vital signs; and other tests that are deemed critical to the safety evaluation of the study. Certain types of events require immediate reporting to the Sponsor, as outlined in Section ADVERSE EVENTS According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any of the following: Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any new disease or exacerbation of an existing disease (a worsening in the character, frequency, or severity of a known condition), except as described in Section Recurrence of an intermittent medical condition (e.g., headache) not present at Week 0 (baseline). Any deterioration in a laboratory value or other clinical test (e.g., electrocardiogram, X-ray) that is associated with symptoms or leads to a change in the TNF inhibitor or tocilizumab or concomitant treatment or discontinuation from the TNF inhibitor or tocilizumab SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE TO ROCHE) An SAE is any AE that meets any of the following criteria: Fatal (i.e., the AE actually causes or leads to death). Life threatening (i.e., the AE, in the view of the Investigator, places the patient at immediate risk of death). o This does not include any AE that had it occurred in a more severe form or was allowed to continue might have caused death. Requires or prolongs inpatient hospitalization (see Section ). Results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the patient s ability to conduct normal life functions). Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug. Protocol MA 27950, Version

32 Significant medical event in the investigator's judgment (e.g., may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above). The terms severe and serious are not synonymous. Severity refers to the intensity of an AE (rated as mild, moderate, or severe; see Section 5.3.3); the event itself may be of relatively minor medical significance (such as severe headache without any further findings). Severity and seriousness need to be independently assessed for each AE recorded on the ecrf. Serious AEs are required to be reported by the Investigator to the Sponsor within 1 working day after learning of the event (see Section for reporting instructions) NON-SERIOUS ADVERSE EVENTS OF SPECIAL INTEREST (IMMEDIATELY REPORTABLE TO ROCHE) Non-serious AEs of special interest are required to be reported by the Investigator to the Sponsor within 1 working day after learning of the event (see Section for reporting instructions). Adverse events of special interest for this study include the following: Infections (including opportunistic infections). Myocardial infarction/acute coronary syndrome. GI perforation and related events. Malignancies. Anaphylaxis / Hypersensitivity reactions. Demyelinating disorders. Stroke. Bleeding events. Hepatic events. The notification of AEs of special interest (including non-serious events of special interest) will follow the established procedures for AEs and SAEs in the study (i.e., documented and reported to the Sponsor or its designee within 1 working day [see Section 5.3.1]). Guided questionnaires have been prepared for the AEs of special interest and will be sent to the investigators to obtain more detailed information, as necessary. The documentation and reporting requirements for those AEs of special interest will be further described in a separate document (Actemra Events of Special Interest Guidance). Protocol MA 27950, Version

33 5.3 METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY PARAMETERS The Investigator is responsible for ensuring that all AEs (see Section for definition) are recorded on the Adverse Event ecrf and reported to the Sponsor in accordance with instructions provided in this section and in Sections For each AE recorded on the Adverse Event ecrf, the Investigator will make an assessment of seriousness (see Section for seriousness criteria), severity (see Section 5.3.3) and causality (see Section 5.3.4) ADVERSE EVENT REPORTING PERIOD Investigators will seek information on AEs at each patient contact. All AEs, whether reported by the patient or noted by study personnel, will be recorded in the patient s medical record and on the Adverse Event ecrf. All AEs, regardless of relationship to the TNF inhibitor or tocilizumab, will be reported until 52 weeks after initiation of the first biologic therapy. After this period, investigators should report any deaths, SAEs, or other AEs of concern that are believed to be related to prior treatment with the TNF inhibitor or tocilizumab (see Section 5.6) ELICITING ADVERSE EVENT INFORMATION A consistent methodology of non-directive questioning should be adopted for eliciting AE information at all patient evaluation time-points. Examples of non-directive questions include the following: How have you felt since your last clinic visit? Have you had any new or changed health problems since you were last here? ASSESSMENT OF SEVERITY OF ADVERSE EVENTS Table 5 provides guidance for assessing AE severity. Protocol MA 27950, Version

34 Table 5 Adverse Event Severity Grading Scale Severity Mild Moderate Severe Description Discomfort noticed, but no disruption of normal daily activity Discomfort sufficient to reduce or affect normal daily activity Incapacitating with inability to work or to perform normal daily activity Note: Regardless of severity, some events may also meet seriousness criteria. Refer to definition of an SAE (see Section 5.2.2) ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS Investigators should use their knowledge of the patient, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether or not an AE is considered to be related to the TNF inhibitor or tocilizumab, indicating "yes" or "no" accordingly. The following guidance should be taken into consideration: Temporal relationship of event onset to the initiation of the TNF inhibitor or tocilizumab. Course of the event, considering especially the effects of dose reduction, discontinuation of the TNF inhibitor or tocilizumab, or reintroduction of the TNF inhibitor or tocilizumab (where applicable). Known association of the event with the TNF inhibitor or tocilizumab, or with similar treatments. Known association of the event with the disease under study. Presence of risk factors in the patient or use of concomitant medications known to increase the occurrence of the event. Presence of non-treatment-related factors that are known to be associated with the occurrence of the event PROCEDURES FOR RECORDING ADVERSE EVENTS Investigators should use correct medical terminology/concepts when recording AEs on the Adverse Event ecrf, avoiding colloquialisms and abbreviations. Only one AE term should be recorded in the event field on the Adverse Event ecrf Diagnosis versus Signs and Symptoms Infusion-Related Reactions Adverse events that occur during or within 24 hours after study drug infusion should be captured as individual signs and symptoms rather than a diagnosis of allergic reaction or infusion reaction. Protocol MA 27950, Version

35 Other Adverse Events For AEs other than infusion-related reactions, a diagnosis (if known) should be recorded on the Adverse Event ecrf rather than individual signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, each individual event should be recorded on the Adverse Event ecrf. If a diagnosis is subsequently established, all previously reported AEs based on signs and symptoms should be nullified and replaced by one AE report based on the single diagnosis, with a starting date that corresponds to the starting date of the first symptom of the eventual diagnosis Adverse Events Occurring Secondary to Other Events In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) should be identified by their primary cause, with the exception of severe or serious secondary events. However, medically significant AEs occurring secondary to an initiating event that are separated in time should be recorded as independent events on the Adverse Event ecrf. For example: If vomiting results in mild dehydration with no additional treatment in a healthy adult, only vomiting should be reported on the ecrf. If vomiting results in severe dehydration, both events should be reported separately on the ecrf. If a severe gastrointestinal haemorrhage leads to renal failure, both events should be reported separately on the ecrf. If dizziness leads to a fall and subsequent fracture, all three events should be reported separately on the ecrf. If neutropenia is accompanied by a mild, non-serious infection, only neutropenia should be reported on the ecrf. If neutropenia is accompanied by a severe or serious infection, both events should be reported separately on the ecrf. All AEs should be recorded separately on the Adverse Event ecrf if it is unclear as to whether the events are associated Persistent or Recurrent Adverse Events A persistent AE is one that extends continuously, without resolution, between patient evaluation time-points. Such events should only be recorded once on the Adverse Event ecrf. The initial severity of the event should be recorded, and the severity should be updated to reflect the most extreme severity any time the event worsens. If the event becomes serious, the Adverse Event ecrf should be updated to reflect this. A recurrent AE is one that resolves between patient evaluation time-points and subsequently recurs. Each recurrence of an AE should be recorded separately on the Adverse Event ecrf. Protocol MA 27950, Version

36 Abnormal Laboratory Values Not every laboratory abnormality qualifies as an AE. A laboratory test result should be reported as an AE if it meets any of the following criteria: Accompanied by clinical symptoms Results in a change in RA treatment (e.g., dosage modification, treatment interruption, or treatment discontinuation) Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a change in concomitant therapy Clinically significant in the investigator s judgment. It is the investigator s responsibility to review all laboratory findings. Medical and scientific judgment should be exercised in deciding whether an isolated laboratory abnormality should be classified as an AE. If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline phosphatase and bilirubin 5 times the ULN associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event ecrf. If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the abnormality itself should be recorded on the Adverse Event ecrf, along with a descriptor indicating if the test result is above or below the normal range (e.g., "elevated potassium," as opposed to "abnormal potassium"). If the laboratory abnormality can be characterized by a precise clinical term per standard definitions, the clinical term should be recorded as the AE. For example, an elevated serum potassium level of 7.0 meq/l should be recorded as hyperkalemia. Observations of the same clinically significant laboratory abnormality from visit to visit should not be repeatedly recorded on the Adverse Event ecrf, unless the etiology changes. The initial severity of the event should be recorded, and the severity or seriousness should be updated any time the event worsens Abnormal Vital Sign Values Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported as an AE if it meets any of the following criteria: Accompanied by clinical symptoms. Results in a change in RA treatment (e.g., dosage modification, treatment interruption, or treatment discontinuation). Results in a medical intervention or a change in concomitant therapy. Clinically significant in the investigator s judgment. It is the investigator s responsibility to review all vital sign findings. Medical and scientific judgment should be exercised in deciding whether an isolated vital sign abnormality should be classified as an AE. Protocol MA 27950, Version

37 If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event ecrf. Observations of the same clinically significant vital sign abnormality from visit to visit should not be repeatedly recorded on the Adverse Event ecrf, unless the etiology changes. The initial severity of the event should be recorded, and the severity or seriousness should be updated any time the event worsens Abnormal Liver Function Tests The finding of an elevated ALT/SGPT or AST/SGOT (> 3 ULN) in combination with either an elevated total bilirubin (> 2 ULN) or clinical jaundice in the absence of cholestasis or other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. Therefore, investigators must report as an AE the occurrence of either of the following: Treatment-emergent ALT/SGPT or AST/SGOT > 3 ULN in combination with total bilirubin > 2 ULN. Treatment-emergent ALT/SGPT or AST/SGOT > 3 ULN in combination with clinical jaundice. The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory values should be recorded on the Adverse Event ecrf (see Section ) and reported to the Sponsor within 1 working day after learning of the event, either as an SAE or a non-serious AE of special interest (see Section 5.4.2). See also Section Deaths All deaths that occur during the protocol-specified AE reporting period (see Section 5.3.1), regardless of relationship to RA biologic, must be recorded on the Adverse Event ecrf and immediately reported to the Sponsor (see Section 5.4.2). This includes death attributed to progression of RA. Death should be considered an outcome and not a distinct event. The event or condition that caused or contributed to the fatal outcome should be recorded as the single medical concept on the Adverse Event ecrf. Generally, only one such event should be reported. The term sudden death should only be used for the occurrence of an abrupt and unexpected death due to presumed cardiac causes in a patient with or without preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the case of an unwitnessed death, within 24 hours after the patient was last seen alive and stable. If the cause of death is unknown and cannot be ascertained at the time of reporting, unexplained death should be recorded on the Adverse Event ecrf. If the cause of death later becomes available (e.g., after autopsy), unexplained death should be replaced by the established cause of death. Protocol MA 27950, Version

38 If the death is attributed to progression of RA, rheumatoid arthritis progression should be recorded on the Adverse Event ecrf Preexisting Medical Conditions A preexisting medical condition is one that is present at the enrolment visit for this study. Such conditions should be recorded on the General Medical History and Baseline Conditions ecrf. A preexisting medical condition should be recorded as an AE only if the frequency, severity, or character of the condition worsens during the study. When recording such events on the Adverse Event ecrf, it is important to convey the concept that the preexisting condition has changed by including applicable descriptors (e.g., more frequent headaches ) Lack of Efficacy or Worsening of Rheumatoid Arthritis Medical occurrences or symptoms of deterioration that are anticipated as part of RA should be recorded as an AE if judged by the investigator to have unexpectedly worsened in severity or frequency or changed in nature at any time during the study. When recording an unanticipated worsening of RA on the Adverse Event ecrf, it is important to convey the concept that the condition has changed by including applicable descriptors (e.g., accelerated RA ). Events that are clearly consistent with the expected pattern of progression of the underlying disease should not be recorded as AEs. These data will be captured as efficacy assessment data only. In most cases, the expected pattern of progression will be based on ACR criteria. In rare cases, the determination of clinical progression will be based on symptomatic deterioration. However, every effort should be made to document progression using objective criteria. If there is any uncertainty as to whether an event is due to disease progression, it should be reported as an AE Hospitalization or Prolonged Hospitalization Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as an SAE (per the definition of SAE in Section 5.2.2), except as outlined below. The following hospitalization scenarios are not considered to be SAEs: Hospitalization for respite care. Planned hospitalization for surgery (less than 24 hours duration). Planned hospitalization for procedures not related to RA and of less than 24 hours duration. Planned hospitalization required by the protocol (e.g., for drug administration). Protocol MA 27950, Version

39 Hospitalization for a preexisting condition, provided that all of the following criteria are met: o o The hospitalization was planned prior to the study or was scheduled during the study when elective surgery became necessary because of the expected normal progression of the disease. The patient has not suffered an AE Overdoses Study drug overdose is the accidental or intentional use of the drug in an amount higher than the dose being studied. An overdose or incorrect administration of study drug is not an AE unless it results in untoward medical effects. Any study drug overdose or incorrect administration of study drug should be noted on the Study Drug Administration ecrf. All AEs associated with an overdose or incorrect administration of study drug should be recorded on the Adverse Event ecrf. If the associated AE fulfills serious criteria, the event should be reported to the Sponsor within 1 working day after learning of the event (see Section 5.4.2) Patient-Reported Outcome Data Adverse event reports will not be derived from PRO data. However, if any patient responses suggestive of a possible AE are identified during site review of the PRO questionnaires, site staff will alert the Investigator, who will determine if the criteria for an AE have been met and will document the outcome of this assessment in the patient's medical record per site practice. If the event meets the criteria for an AE, it will be reported on the Adverse Event ecrf. 5.4 IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO SPONSOR The Investigator must report the following events to the Sponsor within 1 working day after learning of the event, regardless of relationship to study drug: SAEs. Non-serious AEs of special interest. Pregnancies. The Investigator must report new significant follow-up information for these events to the Sponsor within 1 working day after becoming aware of the information. New significant information includes the following: New signs or symptoms or a change in the diagnosis. Significant new diagnostic test results. Change in causality based on new information. Protocol MA 27950, Version

40 Change in the event s outcome, including recovery. Additional narrative information on the clinical course of the event. Investigators must also comply with local requirements for reporting SAEs to the local health authority and Institutional Review Board (IRB)/EC EMERGENCY MEDICAL CONTACTS Medical Monitor (Roche Medical Responsible) Contact Information will be detailed in a separate document. To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will access the Roche Medical Emergency List, escalate emergency medical calls, provide medical translation service (if necessary), connect the Investigator with a Roche Medical Monitor, and track all calls. The Emergency Medical Call Center Help Desk will be available 24 hours per day, 7 days per week. Toll-free numbers for the Help Desk and Medical Monitor contact information will be distributed to all investigators (see "Protocol Administrative and Contact Information & List of Investigators") REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL INTEREST For reports of SAEs and non-serious AEs of special interest, investigators should record all case details that can be gathered within 1 working day on the Adverse Event ecrf and submit the report via the electronic data capture (EDC) system. A report will be generated and sent to Roche Safety Risk Management by the EDC system. In the event that the EDC system is unavailable, a paper Serious Adverse Event/Non- Serious Adverse Event of Special Interest CRF and Fax Coversheet should be completed and faxed to Roche Safety Risk Management or its designee within 1 working day after learning of the event, using the fax numbers provided to investigators (see "Protocol Administrative and Contact Information & List of Investigators"). Once the EDC system is available, all information will need to be entered and submitted via the EDC system REPORTING REQUIREMENTS FOR PREGNANCIES Pregnancies in Female Patients Female patients of child-bearing potential will be instructed to immediately inform the Investigator if they become pregnant during the study and up to 5 months after receiving the last infusion of the TNF inhibitor or tocilizumab. A Pregnancy Report ecrf should be completed by the Investigator within 1 working day after learning of the pregnancy and submitted via the EDC system. A pregnancy report will automatically be generated and sent to Roche Safety Risk Management. Pregnancy should not be recorded on the Adverse Event ecrf. The investigator should counsel the patient, discussing the risks Protocol MA 27950, Version

41 of the pregnancy and the possible effects on the fetus. Monitoring of the patient should continue until conclusion of the pregnancy. In the event that the EDC system is unavailable, a Pregnancy Report worksheet and Pregnancy Fax Coversheet should be completed and faxed to Roche Safety Risk Management or its designee within 1 working day after learning of the pregnancy, using the fax numbers provided to investigators (see "Protocol Administrative and Contact Information & List of Investigators") Pregnancies in Female Partners of Male Patients Male patients will be instructed through the Informed Consent Form to immediately inform the Investigator if their partner becomes pregnant during the study and up to 5 months after the patient received the last infusion of the TNF inhibitor or tocilizumab. A Pregnancy Report ecrf should be completed by the Investigator within 1 working day after learning of the pregnancy and submitted via the EDC system. Attempts should be made to collect and report details of the course and outcome of any pregnancy in the partner of a male patient exposed to a TNF inhibitor or tocilizumab. The pregnant partner will need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy. Once the authorization has been signed, the Investigator will update the Pregnancy Report ecrf with additional information on the course and outcome of the pregnancy. An Investigator who is contacted by the male patient or his pregnant partner may provide information on the risks of the pregnancy and the possible effects on the fetus, to support an informed decision in cooperation with the treating physician and/or obstetrician. In the event that the EDC system is unavailable, follow reporting instructions provided in Section Abortions Any spontaneous abortion should be classified as an SAE (as the Sponsor considers spontaneous abortions to be medically significant events), recorded on the Adverse Event ecrf, and reported to the Sponsor within 1 working day after learning of the event (see Section 5.4.2) Congenital Anomalies/Birth Defects Any congenital anomaly/birth defect in a child born to a female patient or female partner of a male patient exposed to study drug should be classified as an SAE, recorded on the Adverse Event ecrf, and reported to the Sponsor within 1 working day after learning of the event (see Section 5.4.2). Protocol MA 27950, Version

42 5.5 FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS INVESTIGATOR FOLLOW-UP The Investigator should follow each AE until the event has resolved to the Week 0 (baseline) grade or better, the event is assessed as stable by the Investigator, the patient is lost to follow up, or the patient withdraws consent. Every effort should be made to follow all SAEs considered to be related to the TNF inhibitor, tocilizumab or trial-related procedures until a final outcome can be reported. During the study period, resolution of AEs (with dates) should be documented on the Adverse Event ecrf and in the patient s medical record to facilitate source data verification. If, after follow-up, return to the Week 0 (baseline) status or stabilization cannot be established, an explanation should be recorded on the Adverse Event ecrf. All pregnancies reported during the study should be followed until pregnancy outcome. If the EDC system is not available at the time of pregnancy outcome, follow reporting instructions provided in Section SPONSOR FOLLOW-UP For SAEs, non-serious AEs of special interest, and pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details and outcome information (e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to perform an independent medical assessment of the reported case. 5.6 POST-STUDY ADVERSE EVENTS The Investigator should notify the Sponsor of any death, SAE, or other AE of concern occurring at any time after a patient has discontinued study participation. The Sponsor should also be notified if the Investigator becomes aware of the development of cancer or a congenital anomaly/birth defect in a subsequently conceived offspring of a patient that participated in this study. The Investigator should report these events to Roche Safety Risk Management on the Adverse Event ecrf. If the Adverse Event ecrf is no longer available, the Investigator should report the event directly to Roche Safety Risk Management via telephone (see "Protocol Administrative and Contact Information & List of Investigators"). Protocol MA 27950, Version

43 5.7 EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS COMMITTEES To determine reporting requirements for single AE cases, the Sponsor will assess the expectedness of these events using the local prescribing information for the TNF inhibitor or tocilizumab. The Sponsor will compare the severity of each event and the cumulative event frequency reported for the study with the severity and frequency reported in the applicable reference document. Reporting requirements will also be based on the investigator's assessment of causality and seriousness, with allowance for upgrading by the Sponsor as needed. 6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN The following is an outline of the statistical methodology that will be used to analyze the study. A more detailed description will be provided in a separate statistical analysis plan (SAP) that will be finalized prior to the analysis and that may include additional exploratory analysis not explicitly mentioned in the following sections. The analysis of the present study will be exploratory and primarily make use of descriptive statistical methods. In addition, exploratory statistical testing and modeling will be used to highlight interesting aspects of the data and to investigate differences between the two groups defined by the biologic treatment received at enrollment (a TNF inhibitor or tocilizumab). Unless otherwise specified, all statistical tests will be two-sided and carried out with a 5% α-error rate without correction for multiplicity. Corresponding 95% confidence intervals will be provided as appropriate. The main time-points of interest are Week 0 (baseline and first biologic treatment initiation), Week 24 and Week 52 post-baseline. As this is an observational trial and the timing of assessment cannot be mandated, appropriate windows around these timepoints will be defined based on the date of each assessment as entered in the ecrf. 6.1 ANALYSIS POPULATIONS AND SUBGROUPS ANALYSIS POPULATIONS All recruited patients who received at least one dose of a TNF inhibitor or tocilizumab during the study will be included in the primary analysis population, which will be used for all efficacy and safety analyses. Patients will be grouped according to the biologic treatment at Week 0 (baseline). Other analysis populations may be defined based on more restrictive criteria, such as fulfillment of eligibility criteria or a minimum duration of the observation period. Protocol MA 27950, Version

44 6.1.2 ANALYSIS OF SUBGROUPS The analysis of key treatment, efficacy, and safety variables will be carried out in the entire primary analysis population as well as in specific subgroups of interest such as patients receiving TNF inhibitor or tocilizumab monotherapy (assumed size: 500 patients or 20% of the entire population), patients from selected regions or patients with specific systemic manifestations of RA. 6.2 EFFICACY ANALYSES PRIMARY EFFICACY VARIABLE The primary efficacy observation of this study is the mean change in calculated DAS28- ESR 24 weeks after the start of biologic therapy at Week 0 (baseline). Descriptive summaries by biologic treatment group will be provided. Estimation of the primary analysis variable in the two treatment groups will be based on an analysis of covariance model including the baseline DAS28-ESR score as a covariate. The primary model may also include adjustment for other relevant baseline characteristics, such as the use of concomitant DMARDs, gender or RA duration. Differences between the two biologic treatments (a TNF inhibitor or tocilizumab) will be explored using statistical models, such as analysis of covariance, that account for differences in the baseline characteristics of two groups. Propensity scoring and sensitivity analyses will be used as appropriate to corroborate findings from these models. The SAP will provide details on such adjustments and further models as well as on alternative methods (e.g., non-parametric techniques) in case models will violate specific statistical assumptions. The SAP will also describe under which conditions DAS28-CRP can be used to replace missing DAS28-ESR values as well as other imputation strategies for missing values SECONDARY EFFICACY VARIABLES Where available, the following efficacy parameters will be documented to enable description of the change over time (at 0, 24 and 52 weeks as available according to local practice): Mean change in DAS28-ESR 52 weeks after the start of biologic therapy at Week 0 (baseline). Mean change over time in TJC, SJC, ESR and CRP at 24 and 52 weeks after the start of biologic therapy. Mean change over time in CDAI and SDAI score at 24 and 52 weeks after the start of biologic therapy. Mean change in Physician Global Assessment score at 24 and 52 weeks after the start of biologic therapy. Secondary variables will be summarized descriptively by biologic treatment group. In addition selected continuous variables will be analyzed using linear models or non- Protocol MA 27950, Version

45 parametric alternatives as for the primary variable. Binary and categorical variables (e.g., EULAR response, serious AE or SI rates) will be analyzed by means of Clopper-Pearson confidence intervals and/or logistic regression as appropriate. 6.3 SAFETY ANALYSES Safety parameters include: Incidence of infusion reactions or injection site reactions during the study following the start of the first biologic therapy. Incidence of serious and non-serious AEs during the study. Incidence of serious and non-serious AEs of special interest, including infections, during the study. Adverse events will be coded and categorized into body systems. Coded AEs will be tabulated by treatment group, body system and preferred term for individual events within each body system. Adverse events will also be tabulated by severity and relationship to medication. Serious AEs and AEs of special interest will be summarized separately. The value at each time point and the change from Week 0 (baseline) for each of the vital sign variables and laboratory assessments as well as abnormal laboratory values will be summarized descriptively. Adverse events associated with laboratory abnormalities (in particular neutropenia, thrombocytopenia and transaminase elevation) will be listed. 6.4 PATIENT-REPORTED OUTCOMES, QUALITY OF LIFE AND OTHER OBSERVATIONS Where available, the following information will be captured: Patient Global Assessment of Disease Activity. HAQ-DI score, FACIT, VAS pain and morning stiffness. Disease activity based on DAS28, CDAI and SDAI. Loss of efficacy or development of intolerance to biologic therapy. Rates and reasons for dose modifications (dose discontinuation, interruption, reintroduction and dosing frequency modifications). Rates, reasons, frequency and timing of permanent discontinuation of first biologic therapy and subsequent therapy introduced. 6.5 INTERIM ANALYSIS Interim analysis of baseline characteristics, efficacy and safety variables may be performed during the study, none of which will have confirmatory character. Protocol MA 27950, Version

46 6.6 DETERMINATION OF SAMPLE SIZE Approximately 2000 patients will be recruited in this observational study. In the main analysis of efficacy parameters, the DAS28 change from baseline to Week 24 will be estimated in the TNF inhibitor and in the tocilizumab cohorts. Assuming a 1:1 proportion of patients in the two cohorts, a 20% overall drop-out rate in the whole population and a standard deviation of 1.7 DAS28 units for the change, under normality assumption a two-sided 95% confidence interval around the estimated mean will extend between to 0.12 units from the mean (half-width = 0.12 units). Assuming comparability of the two cohorts, a two-sided t-test at the 5% significance level will allow the detection of a difference of about 0.3 DAS28 units with 90% statistical power. In a patient subgroup including 20% of the study population, such as presumably for patients on monotherapy, the half-width will be 0.26 units and the detectable difference 0.6 units. In case of an unbalanced size of the two cohorts (e.g., a 2:1 proportion in favor of TNF inhibitors or of tocilizumab), the detectable differences will be almost identical. 7. DATA COLLECTION AND MANAGEMENT Roche will supply ecrf specifications for this study. A contract research organization (CRO) will be responsible for data management of this study, including quality checking of the data. Data entered manually will be collected via EDC using ecrfs. Sites will be responsible for data entry into the EDC system. In the event of discrepant data, the CRO will request data clarification from the sites, which the sites will resolve electronically in the EDC system. The CRO will produce a Data Quality Plan that describes the quality checks to be performed on the data. Other electronic data will be sent directly to the CRO, using the CRO's standard procedures to handle and process the electronic transfer of these data. Roche will perform oversight of the data management of this study, including approval of the CRO s data management plans and specifications. Data will be periodically transferred electronically from the CRO to Roche, and Roche s standard procedures will be used to handle and process the electronic transfer of these data. Electronic CRFs and correction documentation will be maintained in the EDC system s audit trail. System backups for data stored at the CRO and records retention for the study data will be consistent with the CRO s standard procedures. Protocol MA 27950, Version

47 7.1 ELECTRONIC CASE REPORT FORMS Electronic CRFs are to be completed using a Sponsor-designated EDC system. Sites will receive training and a have access to a manual for appropriate ecrf completion. Electronic CRFs will be submitted electronically to Roche and should be handled in accordance with instructions from Roche. All ecrfs should be completed by designated, trained site staff. Electronic CRFs should be reviewed and electronically signed and dated by the Investigator or a designee. At the end of the study, the Investigator will receive patient data for his or her site in a readable format on a compact disc that must be kept with the study records. Acknowledgement of receipt of the compact disc is required. 7.2 SOURCE DATA DOCUMENTATION Study monitors will perform ongoing source data verification to confirm that critical protocol data (i.e., source data) entered into the ecrfs by authorized site personnel are accurate, complete, and verifiable from source documents. Source documents (paper or electronic) are those in which patient data are recorded and documented for the first time. They include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies of transcriptions that are certified after verification as being accurate and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, and records kept at pharmacies, laboratories, and medico-technical departments involved in a clinical trial. Before study initiation, the types of source documents that are to be generated will be clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered directly into the ecrfs (i.e., no prior written or electronic record of the data) and considered source data. Source documents that are required to verify the validity and completeness of data entered into the ecrfs must not be obliterated or destroyed and must be retained per the policy for retention of records described in Section 7.4. To facilitate source data verification, the investigators and institutions must provide the Sponsor direct access to applicable source documents and reports for trial-related monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow inspection by applicable health authorities. 7.3 USE OF COMPUTERIZED SYSTEMS When clinical observations are entered directly into an investigational site s computerized medical record system (i.e., in lieu of original hardcopy records), the electronic record can serve as the source document if the system has been validated in accordance with health authority requirements pertaining to computerized systems used Protocol MA 27950, Version

48 in clinical research. An acceptable computerized data collection system allows preservation of the original entry of data. If original data are modified, the system should maintain a viewable audit trail that shows the original data as well as the reason for the change, name of the person making the change, and date of the change. 7.4 RETENTION OF RECORDS Records and documents pertaining to the conduct of this study, including ecrfs, PRO data (if applicable), Informed Consent Forms, laboratory test results, and medication inventory records, must be retained by the Principal Investigator for at least 15 years after completion or discontinuation of the study, or for the length of time required by relevant national or local health authorities, whichever is longer. After that period of time, the documents may be destroyed, subject to local regulations. No records may be disposed of without the written approval of Roche. Written notification should be provided to Roche prior to transferring any records to another party or moving them to another location. 8. ETHICAL CONSIDERATIONS 8.1 COMPLIANCE WITH LAWS AND REGULATIONS The investigator will ensure that this study is conducted in full conformance with the principles of the Declaration of Helsinki and GPP or with the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The procedures set out in this study protocol are designed to ensure that the sponsor and investigator abide by the principles of the ISPE GPP, the European Federation of Pharmaceutical Industries and Associations (EFPIA) Code on the Promotion of Prescription-only Medicines to, and Interactions With, Healthcare Professionals, and Volume 9A of The Rules Governing Medicinal Products in the EU. The study will also be carried out in keeping with local legal requirements. Good Clinical Practice guidance is not applicable to this non-interventional study. 8.2 INFORMED CONSENT Roche s sample Informed Consent Form (and ancillary sample Informed Consent Forms such as a Child s Assent or Caregiver's Informed Consent Form, if applicable) will be provided to each site. If applicable, it will be provided in a certified translation of the local language. Roche or its designee must review and approve any proposed deviations from Roche's sample Informed Consent Forms or any alternate consent forms proposed by the site (collectively, the Consent Forms ) before IRB/EC submission. The final IRB/EC-approved Consent Forms must be provided to Roche for health authority submission purposes according to local requirements. Protocol MA 27950, Version

49 8.3 INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE If applicable based on local regulations, this protocol, the Informed Consent Forms, any information to be given to the patient, and relevant supporting information must be submitted to the IRB/EC by the Principal Investigator and reviewed and approved by the IRB/EC before the study is initiated. In addition, any patient recruitment materials must be approved by the IRB/EC. The Principal Investigator is responsible for providing written summaries of the status of the study to the IRB/EC annually or more frequently in accordance with the requirements, policies, and procedures established by the IRB/EC. Investigators are also responsible for promptly informing the IRB/EC of any protocol amendments (see Section 9.5). In addition to the requirements for reporting all AEs to the Sponsor, investigators must comply with requirements for reporting SAEs to the local health authority and IRB/EC. Investigators may receive written IND safety reports or other safety-related communications from Roche. Investigators are responsible for ensuring that such reports are reviewed and processed in accordance with health authority requirements and the policies and procedures established by their IRB/EC, and archived in the site s study file. 8.4 CONFIDENTIALITY Roche maintains confidentiality standards by coding each patient enrolled in the study through assignment of a unique patient identification number. This means that patient names are not included in data sets that are transmitted to any Roche location. Patient medical information obtained by this study is confidential and may only be disclosed to third parties as permitted by the Informed Consent Form (or separate authorization for use and disclosure of personal health information) signed by the patient, unless permitted or required by law. Medical information may be given to a patient s personal physician or other appropriate medical personnel responsible for the patient s welfare, for treatment purposes. Data generated by this study must be available for inspection upon request by representatives of the US FDA and other national and local health authorities, Roche monitors, representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 8.5 FINANCIAL DISCLOSURE Investigators will provide the Sponsor with sufficient, accurate financial information in accordance with local regulations to allow the Sponsor to submit complete and accurate financial certification or disclosure statements to the appropriate health authorities. Investigators are responsible for providing information on financial interests during the course of the study and for 1 year after completion of the study (i.e., when the last patient completes a 52-week observation period). Protocol MA 27950, Version

50 9. STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 9.1 STUDY DOCUMENTATION The Investigator must maintain adequate and accurate records to enable the conduct of the study to be fully documented, including but not limited to the protocol, protocol amendments, Informed Consent Forms, and documentation of IRB/EC and governmental approval. In addition, at the end of the study, the Investigator will receive the patient data, which includes an audit trail containing a complete record of all changes to data. 9.2 SITE INSPECTIONS Site visits will be conducted by Roche or an authorized representative for inspection of study data, patients medical records, and ecrfs. The Investigator will permit national and local health authorities, Roche monitors, representatives, and collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 9.3 ADMINISTRATIVE STRUCTURE A steering committee will be established to provide input on the study protocol and study data. A global CRO will be responsible for Medical Monitoring and safety processing, data management, biostatistics and project management. 9.4 PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS The results of this study may be published or presented at scientific meetings. If this is foreseen, the Investigator agrees to submit all manuscripts or abstracts to Roche prior to submission. This allows the Sponsor to protect proprietary information and to provide comments based on information from other studies that may not yet be available to the Investigator. Roche will comply with the requirements for publication of study results. In accordance with standard editorial and ethical practice, Roche will generally support publication of multicenter trials only in their entirety and not as individual center data. In this case, a coordinating investigator will be designated by mutual agreement. Authorship will be determined by mutual agreement and in line with International Committee of Medical Journal Editors authorship requirements. Any formal publication of the study in which contribution of Roche personnel exceeded that of conventional monitoring will be considered as a joint publication by the Investigator and the appropriate Roche personnel. Protocol MA 27950, Version

51 Any inventions and resulting patents, improvements, and/or know-how originating from the use of data from this study will become and remain the exclusive and unburdened property of Roche, except where agreed otherwise. 9.5 PROTOCOL AMENDMENTS Any protocol amendments will be prepared by the Sponsor. Investigators are responsible for promptly informing the IRB/EC of any amendments to the protocol. Approval must be obtained from the IRB/EC before implementation of any changes, except for changes necessary to eliminate an immediate hazard to patients or changes that involve logistical or administrative aspects only (e.g., change in Medical Monitor or contact information). Protocol MA 27950, Version

52 10. REFERENCES 1. Ku IA et al. Rheumatoid arthritis: model of systemic inflammation driving atherosclerosis. Circ J 2009;73(6): Egerer K, Feist E, Burmester GR. The serological diagnosis of rheumatoid arthritis: antibodies to citrullinated antigens. Dtsch Arztebl Int 2009;106(10): Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet 2009 Feb 21;373(9664): Kojima M et al. Psychosocial factors, disease status, and quality of life in patients with rheumatoid arthritis. J Psychosom Res 2009;67(5): Makisara GL, Makisara P. Prognosis of functional capacity and work capacity in rheumatoid arthritis. Clin Rheumatol 1982;1(2): Backman CL. Employment and work disability in rheumatoid arthritis. Curr Opin Rheumatol 2004;16(2): Wolfe F et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994;37(4): Sokka T et al. Functional disability in rheumatoid arthritis patients compared with a community population in Finland. Arthritis Rheum 2003;48(1): Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 2005;4(3): Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001;358(9285): Gardner DL. Problems and paradigms in joint pathology. J Anat 1994;184 (Pt 3): Pratt AG, Isaacs JD, Mattey DL. Current concepts in the pathogenesis of early rheumatoid arthritis. Best Pract Res Clin Rheumatol 2009;23(1): Stolt, P et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis 2003;62(9): Arnett FC et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31(3): Balsa A, Pascual-Salcedo D, Martin J. [Antibodies to citrullinated peptides in rheumathoid arthritis]. Med Clin (Barc) 2007;128(17): Henderson B, Revell PA, Edwards JC. Synovial lining cell hyperplasia in rheumatoid arthritis: dogma and fact. Ann Rheum Dis 1988;47(4): Watts RA, Isaacs JD. Immunotherapy of rheumatoid arthritis. Ann Rheum Dis 1992;51(5): Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 2008;118(11): Willkens RF, Watson MA. Methotrexate: a perspective of its use in the treatment of rheumatic diseases. J Lab Clin Med 1982;100(3): Brennan FM. Role of cytokines in experimental arthritis. Clin Exp Immunol 1994;97(1): Favalli EG et al. Pattern of use, economic burden and vial optimization of infliximab for rheumatoid arthritis in Italy. Clin Exp Rheumatol 2008;26(1): den Broeder A et al. A single dose, placebo controlled study of the fully human antitumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis. J Rheumatol 2002;29(11): Moreland LW et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999;130(6): Protocol MA 27950, Version

53 24. Goldenberg MM. Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis. Clin Ther 1999;21(1):75-87; discussion Koller MD. Targeted therapy in rheumatoid arthritis. Wien Med Wochenschr 2006;156(1-2): Sharma R, Sharma CL, Mahajan A. Biological agents targeting beyond TNF-alpha. Indian J Crit Care Med 2008;12(4): Summers KM, Kockler DR. Rituximab treatment of refractory rheumatoid arthritis. Ann Pharmacother 2005;39(12): Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther 2009;11 Suppl 1:S Keystone E et al. Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies. Ann Rheum Dis 2009;68(2): Sack U et al. Interleukin-6 in synovial fluid is closely associated with chronic synovitis in rheumatoid arthritis. Rheumatol Int 1993;13(2): Madhok R et al. Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 1993;52(3): Mihara M et al. Tocilizumab inhibits signal transduction mediated by both mil-6r and sil-6r, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol 2005;5(12): EMA: Product Information (16/01/2009 RoActemra-H-C ). 34. Smolen JS et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008;371(9617): Genovese MC et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008;58(10): Emery P et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008;67(11): Jones G et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010;69(1): Maini RN et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006;54(9): Nishimoto N et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis 2007;66(9): Aletaha D et al rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010;69(9): Prevoo MLL, Van T Hof MA, Kuper HH, et al. Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38: Makinen H et al. Is DAS28 an appropriate tool to assess remission in rheumatoid arthritis? Ann Rheum Dis 2005;64(10): Protocol MA 27950, Version

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55 APPENDIX 1 JOINT COUNTS (28/28) The 28 joints to be assessed for tenderness and swelling are listed below: Shoulders Elbows Wrists Proximal interphalangeal joints on digits 1 5 Metacarpophalangeal joints on digits 1 5 Knees Source: Protocol MA 27950, Version