2. OBJECTIVES Primary Objective Secondary Objectives Tertiary Objectives, Exploratory and Methodological...

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2 TABLE OF CONTENTS 1. BACKGROUND AND RATIONALE Background Introduction Rheumatoid Arthritis and Its Treatment Tocilizumab Rationale for the Study OBJECTIVES Primary Objective Secondary Objectives Tertiary Objectives, Exploratory and Methodological STUDY DESIGN Overview of Study Design and Dosing Regimen Rationale for Study Design Rationale for Dose Selection End of Study Number of Subjects / Assignment to Treatment Groups Centers STUDY POPULATION Overview Inclusion Criteria Exclusion Criteria Concomitant Medication and Treatment Use of Treatments for Rheumatoid Arthritis Prohibited treatments Criteria for Premature Withdrawal Replacement Policy For Subjects For Centers SCHEDULE OF ASSESSMENTS AND PROCEDURES Screening Examination and Eligibility Screening Form Procedures for Enrollment of Eligible Subjects Re-Testing-Laboratory Inclusion/Exclusion Criteria Re-Screening Clinical Assessments and Procedures At screening Efficacy Patient Health Outcomes Assessment Safety Laboratory Assessments

3 5.5 Additional lab samples for biomarkers Quality of Life Assessments Withdrawal visit Post Study Provisional Care INVESTIGATIONAL MEDICINAL PRODUCT Dose and Schedule of IMP and Comparators Dose Modifications, Interruptions and Delays Preparation and Administration of the Investigational Medicinal Products Formulation, Packaging and Labeling Blinding and Unblinding Assessment of Compliance Destruction of the IMP/Comparator SAFETY INSTRUCTIONS AND GUIDANCE Definitions Adverse event Laboratory Test Abnormalities Safety Reporting Safety collection period Pregnancy Warnings and Precautions HYPERSENSITIVITY / ANAPHYLAXIS AN INFUSION REACTION IS DEFINED AS AN ADVERSE EVENT OCCURRING DURING AND WITHIN 24 HOURS AFTER THE INFUSION OR SUBCUTANEOUS INJECTION OF TOCILIZUMAB. THIS MAY INCLUDE HYPERSENSITIVITY REACTIONS OR ANAPHYLACTIC REACTIONS STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN Primary and Secondary Study Endpoints Primary Endpoints Secondary Endpoints Safety Statistical and Analytical Methods Statistical Model Hypothesis Testing Analysis Populations Efficacy Analysis Safety Data Analysis Other Analyses Sample Size

4 9. DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE Assignment of Preferred Terms and Original Terminology REFERENCES ETHICAL ASPECTS Local Regulations/Declaration of Helsinki Informed Consent Independent Ethics Committees CONDITIONS FOR MODIFYING THE PROTOCOL CONDITIONS FOR TERMINATING THE STUDY STUDY DOCUMENTATION, ECRFS AND RECORD KEEPING Investigator's Files / Retention of Documents Source Documents and Background Data Audits and Inspections Electronic Case Report Forms MONITORING THE STUDY CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS APPENDICES Appendix 2 - ICH Guidelines for Clinical Safety Data Management, Definitionsand Standards for Expedited Reporting, Topic E Appendix 3 Questionnaires Dutch consensus HAQ FACIT- fatigue IPQR SF VAS pain and general wellbeing questionnaires Dutch Healthcare resource use and work participation questionnaire EuroQol Appendix 4 - Disease activity score

5 GLOSSARY OF ABBREVIATIONS AE Adverse Event ACR ALP ALT Anti CCP ANOVA AST AUC BCG-vaccine BP CRP CXR DAS28 DMARD DMARD-IR DSMB ECG ecrf EDC Eform ESF ESR EURAC EULAR GCP GH GI GMP American College of Rheumatology Alkaline phosphatase Alanine aminotransferase Anti cyclic citrullinated peptide Analysis of variance Aspartate aminotransferase Area under the curve Bacillus Calmette-Guérin vaccine Blood pressure C-reactive protein Chest X-Ray Disease Activity score, scoring 28 joints Disease-modifying antirheumatic drug DMARD inadequate responders Data Safety Monitoring Board Electrocardiogram Electronic Case Report Form(s) Electronic Data Capture Electronic form (page) Eligibility screening form Erythrocytes Sedimentation Rate Early Utrecht Rheumatoid Arthritis Cohort study group European League Against Rheumatism Good Clinical Practice General Health Gastrointestinal Good manufacturing practice 5

6 HAQ HBsAG HCQ HCV HDL HIV hscrp ICH IEC IL-6 IL-6R IM IMP INH IRB ITT IV IVRS JSN Kg LDL LLN LPLV Mg Ml MTD MTX NSAIDS PP Health Assessment Questionnaire Hepatitis B surface antigen Hydroxychloroquine Hepatitis C virus High-density lipoprotein Human immunodeficiency virus High sensitivity CRP International Conference on Harmonization Independent ethics committee Interleukin-6 IL-6 receptor Intra muscular Investigational Medicinal Product Isonicotinyl hydrazine Institutional Review Board Intention to treat Intravenous Interactive Voice Response System Joint space narrowing Kilograms Low Density Lipoprotein Lower limit of normal Last Patient Last Visit Milligrams Milliliter Maximum Tolerated Dose Methotrexate Non-steroidal anti-inflammatory drugs Per Protocol 6

7 PPD PR QoL RA RANKL RF SAE SAP SJC SMT SPC SRR SRU TB TCZ TJC TNF ULN VAS SvdHS WBC Wk Purified protein derivative tuberculin skin test Pulse rate Quality of Life Rheumatoid Arthritis Receptor activator of NF-kB ligand Reuma factor Serious adverse event Statistical analysis plan Swollen joint count Study management team Summary of product characteristics Sustained remission rate Stichting reumaonderzoek Utrecht Tuberculosis Tocilizumab Tender joint count Tumor necrosis factor Upper limit of normal Visual analogue scale Sharp/vanderHeijde Score White blood cell Week 7

8 Protocol synopsis TITLE A multi-center, randomized, double blind, placebo controlled study to evaluate remission in DMARD and biological naive early rheumatoid arthritis (RA) subjects treated with tocilizumab (TCZ) plus tight control methotrexate (MTX) treatment, TCZ monotherapy or tight control MTX monotherapy. SPONSOR Hoffmann-LaRoche CLINICAL PHASE III INDICATION Early Rheumatoid Arthritis (RA) OBJECTIVES I To compare the number of patients with early RA who achieve sustained remission with three different regimens: tocilizumab combined with tightly controlled MTX, tightly controlled MTX as monotherapy and tocilizumab as monotherapy. The main focus is the contrast between the combination therapy and the MTX monotherapy followed by the contrast between the two monotherapy treatments. II To compare the progression of radiographic characteristics of joint damage among the three treatment strategies by use of the change in SharpvanderHeijde score. III To compare clinical efficacy between the three treatment strategies by use of the ACR and EULAR response criteria. IV To study safety in the context of the three treatment strategies, including the: - occurrence of serious adverse events leading to withdrawal. - occurrence of serious infections - number of patients who are unable to use adequate dosage of MTX due to increase of liver enzymes V To study differences in changes in functional disability, fatigue, quality of life and cost effectiveness in the three treatment strategy groups by use of the: Dutch consensus HAQ, the FACIT-fatigue, the IPQR, the SF-36, VAS pain and general wellbeing Questionnaires, a Dutch Healthcare resource use and work participation questionnaire, and the EuroQol (EQ5D) questionnaire. VI To monitor and/or predict response in the three treatment groups by biomarkers expressed in blood and/or urine, mrna analyses and phenotyping of mononuclear cells obtained from blood. VII To examine the number of patients who need to change therapy strategy during the study. TRIAL DESIGN Multi-center, randomized, double-blind, placebo-controlled phase III study NUMBER OF SUBJECTS 300 subjects TARGET POPULATION Adult men and women with early RA (disease symptoms < 1 year) meeting the ACR classification criteria of 1987 and/or ACR/EULAR classification criteria of 2010, who have not had previous treatment with DMARDs or systemic or intra-articular glucocorticoids or biological agents, will be eligible for this study. To be eligible for this trial, patients must meet all of the following criteria: 1. Male or non-pregnant, non-nursing female years of age 8

9 3. Early RA (disease symptoms <1 year) according to the revised 1987 ACR criteria and/or ACR/EULAR classification criteria of 2010 for RA 4. Disease activity measured by DAS Patients able and willing to give written informed consent and comply with the requirements of the study protocol 6. Immunization status current for pneumovax, influenza asassessed according to standard of care for RA patients receiving a biological agent Patients with any of the following criteria will not be eligible to participate in the study: Other joint disease 1. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma, polymyositis. Patients with interstitial pulmonary fibrosis and still able to tolerate MTX therapy are permitted. Sjögren s Syndrome with RA is permitted 2. Current inflammatory joint disease other than RA (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) Drug-specific 3. Glucocorticoids used for RA < 6 weeks prior to baseline (NB: inhaled glucocorticoids are allowed) 4. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline 5. Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational agent, whichever is longer) before screening 6. Previous treatment with any biologic drug that is used in the treatment of RA 7. Previous treatment with any DMARD that is used in the treatment of RA 8. Any previous treatment with alkylating agents, such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation 9. Treatment with IV gamma globulin, plasmapheresis or Prosorba column within 6 months before baseline Laboratory analyses (at screening) 10. Serum creatinine > 142 μmol/l in female patients and > 168 μmol/l in male patients or an active renal disease 11. ALT or AST > 1.5 x ULN (if initial sample yields ALT or AST > 1.5 x ULN, a second sample may be taken and tested during the screening period) 12. Platelet count < 100 x 10 9 /L (100,000/mm 3 ) 13. Hemoglobin < 1.5 mmol/l below LLN for gender 14. WBC count < 4.0 x 10 9 /L (4000/mm 3 ), 15. Absolute neutrophil count < 2.0 x 10 9 /L (2000/mm 3 ) 16. Absolute lymphocyte count < 0.5 x 10 9 /L (500/mm 3 ) 17. Positive HBsAg or HCV antibody 18. Triglycerides > 10 mmol/l (> 900 mg/dl) at screening (fasted) 9

10 LENGTH OF STUDY END OF STUDY General medical 19. Pregnant women or nursing (breastfeeding) mothers 20. Females of child-bearing potential who are not using reliable means of contraception (such as physical barrier [patient and partner], contraceptive pill or patch, spermicide and barrier, or intrauterine device) 21. History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies 22. Chest X-ray (CXR) at screening showing evidence of any clinically significant abnormality 23. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or GI disease 24. In patients with a history of complicated diverticulitis, the treating physician needs to consider the benefit-risk ratio 25. A known history of chronic ulcerative lower GI disease such as Crohn s disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose to perforations 26. Active TB, requiring treatment within the previous 3 years. Patients with a positive purified protein derivative tuberculin skin test (PPD) at screening as per local guidelines are not eligible for the study unless they complete treatment for latent TB and have a negative CXR at enrollment. Patients treated for TB with no recurrence in 3 years are permitted 27. Known uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease, where flares are commonly treated with oral or parenteral glucocorticoids 28. Current liver disease as determined by investigator. Patients with prior history of ALT elevation are not excluded 29. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to atypical mycobacterial disease, clinically significant abnormalities on CXR as determined by the investigator, hepatitis B and C, and herpes zoster for which systemic treatment is needed, but excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening 30. History of, or currently active, primary or secondary immunodeficiency, such as HIV or AIDS 31. Evidence of active malignant disease, malignancies diagnosed within the previous 5 years (including hematological malignancies and solid tumors, except nonmelanoma skin cancer that has been excised and cured) 32. History of alcohol, drug, or chemical abuse within the 6 months prior to screening 33. Neuropathies or other painful conditions that might interfere with pain evaluation 34. Patients with lack of peripheral venous access 35. Patients with documented lactose intolerance 4 years: two years recruitment and two year treatment/follow-up of subjects. The end of the trial is defined as the date of the last visit of the last participating subject in this study (LPLV; week 104) 10

11 INVESTIGATIONAL MEDICAL PRODUCT(S) DOSE/ ROUTE/ REGIMEN Tocilizumab or placebo will be administered intravenously every 4 weeks at a dose of 8 mg/kg, with a maximum of 800 mg. Methotrexate or placebo will be administered orally every week in a climbing dose, starting at 10 mg/week. ASSESSMENTS OF: - EFFICACY Remission will be evaluated according to the DAS28 score, using a 44 joint count. Additionally progressive joint destruction will be evaluated through Xray with a SvdHS score - SAFETY The incidence of clincial and laboratory adverse events will be reported and analysed. - PHARMACOECONOMICS/ QUALITY OF LIFE (QOL) - EXPLORATORY - BIOMARKERS Patient health outcome assessment using: Dutch consensus HAQ, the FACIT-fatigue, the IPQR, the SF-36, VAS pain and general wellbeing Questionnaires, a Dutch Healthcare resource use and work participation questionnaire, and the EuroQol (EQ5D) questionnaire Blood and urine samples will be collected to study the association of biomarkers with efficacy and safety of tocilizumab. The samples for RNA will be collected at screening and baseline. SUMMARY OF PROCEDURES: All subjects must sign and date the most current IRB/IEC-approved version of the informed consent before any study specific assessments or procedures are performed. Medical history, including demographics, physical examination, vital signs, weight, ECG, Chest X-ray, concomitant medication, joint count and x-ray hands/feet will be assessed, blood and urine samples will be taking and questionnaires have to be filled out by the subjects at screening. Eligible subjects will be randomized to one of the three treatment groups and will receive either tocilizumab plus tightly controlled methotrexate, tocilizumab monotherapy or methotrexate monotherapy. Routine study assessments can include physical examination, vital signs, weight and joint count. Blood and urine samples will be taking and the subject is asked to fill out questionnaires. Concomitant medication will be checked every study visit. Subjects will be assessed for adverse events during every study visit and as necessary throughout the study. Routine study visits will take place every 4 weeks for 104 weeks. STATISTICAL ANALYSES: Primary endpoint of the present study is the sustained remission rate (SRR), i.e. the proportion of patients with early RA who achieve sustained remission. In individual patients, sustained remission is considered to be achieved if an uninterrupted period of approximately 6 months (at least 23 weeks) can be identified, over which: At least 6 DAS28 values are available, including one at the beginning and one at the end of the period All values are <2.6 with no more than 4 swollen joints, with the exception of up to 2 values which can be between 2.6 and 3.2. Secondary Endpoints DAS28 remission rate at each schedule visit Time to first DAS28 remission, cumulative remission rates and duration of remissions. Change from baseline in DAS28 at each scheduled visit EULAR response rate at each scheduled visit and time to first EULAR response ACR20, ACR50, ACR70, and ACR90 response rate at each scheduled visit (week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and throughout year 2) and time to first ACR20, ACR50, ACR70 and ACR90 response. Change from baseline in individual parameters of ACR core set at each scheduled visit 11

12 Measure of progressive joint destruction between baseline and weeks 52 and 104: absolute change from screening in the vdhss Score Proportion of patients between the three treatment strategies who need to change therapy strategy during the study Rate of withdrawals due to lack of sufficient therapeutic response and/or safety Change from baseline in HAQ at each scheduled visit (see table 1) Change from baseline in Euroqol questionnaire at each scheduled visit (see table 1) Safety Safety of the treatment will be evaluated by AEs, laboratory tests, vital signs, safety-related treatment discontinuations. The following events/parameters are of particular interest: Adverse events leading to withdrawal Infections including all opportunistic infections and non-serious infections as defined by those treated with IV anti-infectives Myocardial infarction/acute coronary syndrome Gastrointestinal perforations and related events Malignancies Anaphylaxis/Hypersensitivity reactions Demyelinating disorders Stroke Bleeding events Hepatic events Changes in ALT and AST and elevations of ALT above 3x the upper limit of normal Increase of liver enzymes leading to a change in treatment Changes in serum total cholesterol, LDL cholesterol and HDL cholesterol Change in absolute neutrophil count and values < 1.0 x 10 9 /l, change in neutrophil count and thrombocyte count, and in particular values < 100 x /l Discontinuation of TCZ or blinded MTX/Placebo or other DMARDs because of AE(s) Discontinuation of TCZ or blinded MTX/Placebo or other DMARDs for any reason other than remission Infusion reactions HYPOTHESIS TESTING The analysis of the primary efficacy endpoint will be based on pair-wise comparisons of the rate (proportion) of patients achieving a sustained remission rate between the treatment groups. The three resulting null-hypotheses are: H 0,1 : SRR TCZ + MTX = SRR placebo + MTX (Group I vs. III: combination vs. MTX) H 0,2 : SRR TCZ + placebo = SRR placebo + MTX (Group II vs. III: TCZ vs. MTX) H 0,3 : SRR TCZ + MTX = SRR TCZ+ placebo (Group I vs. II: combination vs. TCZ) 12

13 Part I: Study design and conduct 1. BACKGROUND AND RATIONALE 1.1 Background Introduction This protocol describes a multi-center, randomized, double-blind, placebo-controlled parallel-group study designed to evaluate achievement of remission in rheumatoid arthritis (RA) patients who have not been treated with DMARDs or biological agents, and will be randomly treated in this study with tocilizumab (TCZ) plus tight control methotrexate (MTX) treatment or TCZ monotherapy or tight control MTX monotherapy Rheumatoid Arthritis and Its Treatment RA is a progressive, systemic autoimmune disease characterized by inflammation of the synovial membrane lining the joint cavity. This inflammation causes pain, stiffness, and swelling, and bone erosion leading to irreversible joint destruction, deformity and loss of function, resulting ultimately in disability. Systemic symptoms and signs of RA include fatigue, anemia, and osteoporosis. RA is the most common chronic inflammatory disease in the western world with a prevalence of 0.5% to 1.0% [1]. It affects men and women of all ages with peak incidence of onset between 40 and 60 years of age. The exact cause of RA is not known; however, immunogenetic predisposition to the disease is a contributing factor. NSAIDs provide some symptomatic relief, but they do not measurably suppress the rate of cartilage degradation and bone erosion or alter the natural course of the disease. DMARDs are of utmost importance in RA treatment throughout all stages of the disease [2] as there is evidence that these agents may maintain or improve physical function and retard radiographic joint damage [3]. However, for many patients, treatment is limited by toxicity and/or ineffectiveness. Biological compounds that target TNF-α, B-cells or T-cells have been used successfully to treat RA, but approximately 30 to 40% of patients fail to respond to these therapies [4, 5]. Their effects on systemic manifestations, such as anemia of chronic inflammation, osteopenia or increased cardiovascular risk, are also limited. There is a medical need for more effective treatments for RA based on an understanding of the underlying pathophysiology of the course of the disease. There are limited data comparing the addition of biologicals or other DMARDs to MTX versus switching to biologicals or DMARDs [6, 7]. In general, combination treatment with MTX appears to be superior to monotherapy without MTX. However, with TCZ, monotherapy in MTX and DMARD-naive patients has been shown to be superior to MTX [8]. EURAC study group treatment strategy studies: MTX tight control principles 13

14 The Early Utrecht Rheumatoid Arthritis Cohort study group (EURAC) is an initiative of the SRU (Stichting Reuma onderzoek Utrecht). The SRU is a consortium of rheumatologists in the region of Utrecht, The Netherlands: Meander Medical Center Amersfoort and Baarn, Tergooi Hospital Hilversum and Blaricum, St. Antonius Hospital Nieuwegein, St. Jansdal Harderwijk, Flevo Hospital Almere, Diakonessen Hospital Utrecht, Maartenskliniek Woerden and the University Medical Center Utrecht, Utrecht. This fruitful research collaboration was instigated to perform treatment strategy studies. Since 1989 all patients with early rheumatoid arthritis (RA) (disease duration < 12 months) are (and will be) included in these treatment strategy studies. Of all patients, data on clinical and laboratory variables, radiographic damage, medication use, and serum samples are collected at predefined assessment points. These data in the past decade have been used to evaluate and predict several outcomes such as radiographic joint damage, economic consequences and remission. In RA, the concept of a window of opportunity for treatment of early arthritis (with the need of starting adequate medication as early as possible) is generally accepted. Several studies, including several performed by the EURAC, on strategic treatment of early RA indicate further improvement through intensive DMARD therapy including tight controlled methotrexate (MTX) treatment (3, 9, 10). Characteristics of tight control MTX treatment are: seeing the patient frequently to enable frequent adjustments to the therapy; be as objective as possible in the judgement of disease activity; being rigorous in adjusting therapy e.g. increase therapy according to protocol (9). However, even in these studies remission rates of at least 50% of patients are hardly ever reached. Thus, despite these efforts, remission is reached in an insufficient number of patients. Interleukin -6 Interleukin-6 (IL-6) is a pleiotropic cytokine, regulating autoimmune responses, inflammation and haematopoiesis (reviewed in 11). In RA, overproduction of IL-6 is a key feature of the pathogenesis. Elevated IL-6 levels have been observed in serum and synovial fluid of RA patients, and serum IL-6 levels correlate with both disease activity and radiographic damage. IL-6 is suggested to contribute to inflammation and tissue destruction in RA by activation of B cells, macrophages, fibroblasts and osteoclasts (11). In addition, IL-6 might enhance cartilage destruction (13, 14). Recent findings confirm that IL-6 also plays a pivotal role in T cell-orchestrated arthritis and tissue destruction. IL-6 in contrast to TNFα and IL-1 induces autoreactive Th17 cells that initiate arthritis (16). IL-17 (produced by Th17 cells) is known to facilitate TNF -independent arthritis and joint pathology (17). This corroborates the finding that IL-6 -/- knockout mice have reduced arthritis and tissue destruction associated with diminished T cell-derived IL-17. Moreover, these knockout mice have decreased RANKL levels associated with a reduced numbers of osteoclasts (16, 18). In addition, IL-6 is able to promote T celldependent joint inflammation in mice that is critically dependent on IL-7-induced T cell activation (19). This IL-7-driven pathway that is largely independent of TNF has 14

15 recently been shown to mediate T cell/tnf /RANKL-dependent bone loss in mice and also in RA patients (20, 21). In arthritic individuals, IL-6 and IL-7 levels are strongly correlated (21). Initiation phase Chronic phase x Tregs IL-6 xil-6 CD25+CD127- (FoxP3); Th2 (IL-4);Th3 (TGF ); Tr1 (IL-10) Fibrob last IL-6 Trigger X (1) Auto-reactive/ TCR-activated T cell T-cell + Th17 IL-23, IL-7, IL-12, IL-6 Diverse cytokine-activated /Th1 bystander IFN autoimmunity B- T- IL-17 cell cell srankl + IL-6 Pathogenic autoantibodies + IL cell-cell contact + Monocyte, Macrophage DC IL-6, IL-23, IL-7, IL-12 IL-17, IL-6, TNF, IFN IL-6 OC RANKL precursor IL-17 TNF Osteoclast Fibroblast Catabolic factors IL-6 Chemotaxis (IL-8, IP10, MIP-1a) Chondrocyte TNF IL-8 Angiogenesis (VEGF) VEGF IL-1 RANKL Survival/Proliferation Oxygen radicals factors (IL-7, IL-15) Matrix breakdown MMP-3 Inflammation Cartilage and Bone destruction Figure 1: The role of IL-6 in the initiation of the inflammatory process in RA. These observations indicate the unique ways through which IL-6 activates autoreactive T cells, initiating arthritis leading to down-stream immune responses with subsequent joint inflammation and destruction of bone and cartilage Tocilizumab TCZ (Ro , formerly known as myeloma receptor antibody [MRA]) is a recombinant humanized anti-human monoclonal antibody of the immunoglobulin IgG1 subclass directed against the IL-6R and produced by recombinant DNA technology. Clinical efficacy and safety studies with TCZ have been conducted or are ongoing by Roche and Chugai in various disease areas, including adult-onset RA, systemic-onset juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis. In the European Phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study LRO301 (the CHARISMA study) conducted by Chugai, patients with active RA and either an inadequate response or a disease flare while receiving MTX received 2, 4, or 8 mg/kg TCZ in combination with placebo or MTX, or MTX in 15

16 combination with placebo, over 16 weeks. The percentage of patients achieving an ACR20 response was proportional to the dose and duration of TCZ treatment. Logistic regression showed that all treatment groups, except the 2 mg/kg TCZ in combination with placebo group, resulted in a significantly higher percentage of ACR20 responders at week 16 than MTX in combination with placebo (22). In addition, the percentage of ACR50 or ACR70 responders at week 16 was significantly higher in patients treated with 8 mg/kg TCZ in combination with MTX compared with MTX in combination with placebo [23]. The safety of tocilizumab has been studied in 5 Phase III, double-blind controlled trials and their extension periods and in some earlier phase studies adding up to a total number of 4211 patients with RA. The all controlled population includes all patients who received at least one dose of tocilizumab in the double-blind controlled period of the 5 studies. The controlled period in 4 of the studies was 6 months and in 1 study was up to 2 years. In the double-blind controlled studies 774 patients received tocilizumab 4 mg/kg in combination with MTX, 1870 patients received tocilizumab 8 mg/kg in combination with MTX/other DMARDs and 288 patients received tocilizumab 8 mg/kg monotherapy. The all exposure population includes all patients who received at least one dose of tocilizumab either in the double-blind control period or open label extension phase in studies: Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3296 for at least one year; 2806 received treatment for at least 2 years and 1222 for 3 years. TCZ was generally well tolerated, with the majority of AEs being of mild to moderate intensity. In the 6 month controlled trials, the rate of all infections reported with tocilizumab 8 mg/kg+dmard treatment was 127 events per 100 patient (pt) years compared to 112 events per 100 pt years in the placebo+dmard group. In the all exposure population the overall rate of infections with tocilizumab was 108 events per 100 pt years exposure. In 6 month controlled clinical trials rate of serious infections (bacterial, viral and fungal) with tocilizumab 8 mg/kg+dmard was 5.3 events per 100 pt years exposure compared to 3.9 events per 100 pt years exposure in the placebo+dmard group. In the monotherapy study the rate of serious infections was 3.6 events per 100 pt years of exposure in the tocilizumab group and 1.5 events per 100 pt years of exposure in the MTX group. In the all exposure population the overall rate of serious infections was 4.7 events per 100 pt years. Reported serious infections, some with fatal outcome, included pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have also been reported. In the 6 month controlled trials adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9% of patients in the tocilizumab 8 mg/kg+dmard and 5.1% of patients in the placebo+dmard group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting. A total of 2876 patients have been tested for anti-tocilizumab antibodies in the controlled clinical trials using G4 product. Forty six patients (1.6%) developed positive anti-tocilizumab 16

17 antibodies of whom 5 had an associated medically significant hypersensitivity reaction leading to withdrawal. Thirty patients (1.1%) developed neutralizing antibodies. During the 6 month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 pt years with tocilizumab therapy. In the all exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports of gastrointestinal perforation on tocilizumab were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. In the 6 month controlled trials decreases in neutrophil counts below 1 x 10 9 /L occurred in 3.4% of patients on tocilizumab 8 mg/kg+dmard compared to <0.1% of patients on placebo+dmard. Approximately half of the instances of ANC below 1 x 109/l occurred within 8 weeks of starting therapy. Decreases below 0.5 x 109/L were reported in 0.3% patients receiving tocilizumab 8 mg/kg +DMARD. There was no clear relationship between decreases in neutrophils below 1 x 10 9 /L and the occurrence of serious infections. In the all controlled and all exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6 month controlled clinical trials. In healthy subjects administered tocilizumab in doses from 2 to 28 mg/kg, absolute neutrophil counts decreased to their lowest 3 to 5 days following administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following tocilizumab administration. The mechanism of this effect is under investigation, and an association with infection has not been identified. Preclinical studies suggest that IL-6 is associated with demargination of neutrophils and egression from the bone marrow so that the opposite effect may occur with IL-6R inhibition. In the 6 month controlled trials decreases in platelet counts below 100 x 10 3 / μl occurred in 1.7% of patients on tocilizumab 8 mg/kg plus traditional DMARDs compared to <1% of patients on placebo plus traditional DMARDs, without associated bleeding events. In the all control and all exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6 month controlled clinical trials. During the 6 month controlled trials transient elevations in ALT/AST > 3 x ULN were observed in 2.1% of patients on tocilizumab 8 mg/kg compared to 4.9% of patients on MTX, and in 6.5% of patients who received tocilizumab 8 mg/kg + DMARD compared to 1.5% of patients on placebo+dmard. The addition of potentially hepatotoxic drugs (e.g. MTX) to tocilizumab monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed in 0.7% of tocilizumab monotherapy patients and 1.4% of tocilizumab+dmard patients, the majority of whom were discontinued from tocilizumab treatment. These elevations were not associated with any clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency. The incidence of indirect bilirubin greater than the upper limit of normal is 6.2% in patients treated with 8 mg/kg tocilizumab. In the all controlled and all exposure population, the pattern and incidence of elevations in ALT/AST remained consistent with what was seen in the 6 month controlled clinical trials. 17

18 During the 6 month controlled trials elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were observed in patients treated with tocilizumab. Approximately 24% of patients receiving tocilizumab in clinical trials experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dl), with 15% experiencing a sustained increase in LDL to > 4.1 mmol/l (160 mg/dl). In the all controlled and all exposure population, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6 month controlled clinical trials. The impact of dyslipidaemia on cardiovascular risk is currently not known as patients usually experience a concurrent decrease/normalization of hscrp. In the long term safety extension study there is no increase in cardiovascular events observed. The pivotal clinical trial program consists of four 24-week Phase III studies on signs and symptoms, and an ongoing 2-year Phase III study with 24-week and 1-year interim analyses designed to evaluate physical function and prevention of joint damage. A brief description of the five Phase III studies is provided below: The OPTION study (WA17822) was a three-arm, randomized, double-blind, placebocontrolled, parallel-group, international, multicenter Phase III study in patients with moderate to severe active RA who had an inadequate response to MTX [24]. The study was designed to assess safety and reduction in the signs and symptoms of RA after 24 weeks of TCZ therapy (4 or 8 mg/kg) in combination with MTX versus MTX in combination with placebo. The study met all primary and secondary endpoints. The TOWARD study (WA18063) was a two-arm, randomized, double-blind, placebocontrolled, parallel-group, international, multicenter Phase III study in patients with moderate to severe active RA who had an inadequate response to current DMARD therapy [25]. The study was designed to assess safety and reduction in signs and symptoms of RA after 24 weeks of TCZ therapy (8 mg/kg) in combination with background DMARD therapy versus DMARD therapy in combination with placebo. The study met all primary and secondary endpoints. The RADIATE study (WA18062) was a three-arm, randomized, double-blind, placebocontrolled, international, multicenter Phase III study in patients with moderate to severe active RA who had an inadequate clinical response or were intolerant to one or more anti-tnf therapies. The anti-tnf agent was discontinued prior to randomization [26]. The study was designed to assess safety and reduction in signs and symptoms of RA after 24 weeks of TCZ therapy (4 or 8 mg/kg) in combination with MTX versus MTX in combination with placebo. The study met its primary endpoint (25). The AMBITION study (WA17824) was a two-arm, randomized, double-blind, doubledummy, parallel-group, international, multicenter, non-inferiority Phase III study comparing TCZ (8 mg/kg) with MTX, in patients with active RA who were MTX naive or who had discontinued MTX, but not due to lack of efficacy or toxic effects[27]. The study was designed to assess safety and reduction in signs and symptoms of RA after 24 weeks of therapy. As an internal control for efficacy, the study also included a three-arm, 8-week sub study that included a placebo arm. The study met its primary endpoint and demonstrated superiority of TCZ over MTX (8). The LITHE study (WA17823) was a three-arm, randomized, double-blind, placebo controlled, parallel-group, international, multicenter Phase III study in patients with moderate to severe active RA who had an inadequate response to MTX. The study was 18

19 designed to assess safety, reduction in signs and symptoms of RA after 24 weeks in an interim analysis, prevention of joint damage (evaluated by radiographs) at 52 weeks (with confirmation at 104 weeks), and physical function at 52 weeks (with confirmation at 104 weeks) of TCZ therapy (4 or 8 mg/kg) in combination with MTX versus MTX in combination with placebo. The study was at the time of this protocol being written still ongoing but interim analysis showed that it met its primary endpoint (26). Further information about TCZ can be found in the Summary of Product Characteristics (SPC). 1.2 Rationale for the Study Treatment with tocilizumab in patients with long standing RA was well tolerated, whilst significantly reducing disease activity in these patients (22, 27). Since IL-6 seems to play an important role in the initiation of the disease, the hypothesis is that IL-6R blockade is of specific value in the prevention of early IL-6-driven T cellmediated immune responses that are upstream in the inflammatory cascade specifically in early RA (reviewed in 11, 28, 29) The 24 week results of the AMBITION study are pertinent to the conduct of this study, as approximately 40% of patients had RA < 2 years duration. In that subpopulation of about 120 patients per group, the benefit-risk of TCZ monotherapy was shown by the DAS28 remission rate of 41.7% in TCZ-treated patients vs. 18% in patients receiving MTX (mean dose achieved at week 8, 17 mg/week). The DAS28 remission rate in patients with RA duration > 2 years was 28% in the TCZ group, vs. 7.3% in the MTX group. In the study as a whole, among 288 patients receiving TCZ 8 mg/kg every 4 weeks, and 284 patients receiving MTX there were 4 serious infections in the TCZ group, and 2 in the MTX-group. There were 11 events with TCZ and 15 with MTX leading to withdrawal. Hepatic aminotransferase elevations were more common in the MTX-treated group. In a post hoc analysis, conducted by pooling response data for DMARD-IR patients treated in the TCZ Phase III program, the DAS28 remission rate at 24 weeks for 274 TCZ-treated patients with disease duration < 2 years was 37.1%, compared to 3.5% for 208 MTX-treated patients. This response rate is considered a conservative estimate for early, MTX-naive RA patients, given that these patients had experienced an inadequate response to MTX, as evidenced by the low DAS28 remission rate in the MTX control population. The infrastructure of the EURAC study group to evaluate treatment strategies aiming for remission in a tight control fashion for early RA gives the opportunity to test TCZ in early RA. 19

20 2. OBJECTIVES To compare the efficacy and safety of a direct start with three different regimens: tocilizumab combined with tightly controlled MTX, tightly controlled MTX as monotherapy and tocilizumab as monotherapy in early RA patients aiming at remission. 2.1 Primary Objective I To compare the number of patients with early RA who achieve sustained remission with three different regimens: tocilizumab combined with tightly controlled MTX, tightly controlled MTX as monotherapy and tocilizumab as monotherapy. The main focus is the contrast between the combination therapy and the MTX monotherapy followed by the contrast between the two monotherapy treatments. 2.2 Secondary Objectives II To compare the progression of radiographic characteristics of joint damage among the three treatment strategies by use of the change in SharpvanderHeijde score. III To compare clinical efficacy between the three treatment strategies by use of the ACR and EULAR response criteria. IV To study safety in the context of the three treatment strategies, including the: - occurrence of serious adverse events leading to withdrawal. - occurrence of serious infections - number of patients who are unable to use adequate dosage of MTX due to increase of liver enzymes V To study differences in changes in functional disability, fatigue, quality of life and cost effectiveness in the three treatment strategy groups by use of the: Dutch consensus HAQ, the FACIT-fatigue, the IPQR, the SF-36, VAS pain and general wellbeing Questionnaires, a Dutch Healthcare resource use and work participation questionnaire, and the EuroQol (EQ5D) questionnaire. 2.3 Tertiary Objectives, Exploratory and Methodological VI To monitor and/or predict response in the three treatment groups by biomarkers expressed in blood and/or urine, mrna analyses and phenotyping of mononuclear cells obtained from blood. 20

21 VII To examine the number of patients who need to change therapy strategy during the study. 3. STUDY DESIGN 3.1 Overview of Study Design and Dosing Regimen This is a multi-center, randomized, double blind, placebo controlled (double placebo) three-parallel group, comparative study to evaluate remission and duration of remission in DMARD and biological naive early RA subjects treated with TCZ plus tight control MTX treatment, TCZ monotherapy or tight control MTX monotherapy. RA patients meeting the selection criteria will, after written informed consent, be randomized into one of three treatment strategies and will be followed for 24 months. treatment I MTX TCZ methotrexate tocilizumab TCZ 8 mg/kg i.v. every 4 weeks + weekly oral MTX in climbing dosages II MTX-PB TCZ placebo- methotrexate tocilizumab TCZ 8 mg/kg i.v. every 4 weeks + weekly oral placebo MTX in climbing dosages III MTX TCZ-PB methotrexate placebo- tocilizumab Placebo TCZ - i.v. every 4 weeks + weekly oral MTX in climbing dosages Figure 2: Schematic representation of the three treatment arms The three patient groups will be treated with MTX or placebo in climbing dosages: start 10 mg every week for the first 4 weeks, 15 mg every week in week 5-8, 20 mg every week in week 9-12, 25 mg every week in week 13-16, 30 mg every week from week 17 onwards. The increase in MTX or placebo dosage will be only implemented if remission is not yet reached, and if no adverse effects have occurred. Folic acid 5 mg twice a week is added in all three groups. The patients will additionally be treated with TCZ 8 mg/kg body weight or placebo intravenously at baseline and every 4 weeks thereafter. Treatment regimens For each patient treatment consists of capsules once weekly (MTX or placebo) and an infusion once every 4 weeks (tocilizumab or placebo). 21

22 Patients are evaluated every 4 weeks and at each visit a decision is made based on efficacy parameters (DAS28) and possible occurrence of adverse events. If at the scheduled visits of evaluation remission is not yet reached the dosage of MTX/Placebo will be increased until remission or the maximum tolerated dose is reached. In case remission is reached MTX/Placebo and TCZ/Placebo will be decreased and in case the maximum tolerated dose of MTX/Placebo is reached and remission has not been achieved, medication is adjusted. Treatment regimen violations In case in a specific individual patient there is an important clinical reason not to adhere to the predefined treatment step, the treating rheumatologist will contact the CRA in order to discuss this exception. Arguments and consultation will be well documented; in case of doubt the CRA will contact the Medical Monitor and/or Scientific Leader. When this non adherence occurs more than 4 times over a period of one year, the Medical Monitor will be contacted. In that case the Medical Monitor will decide if the patient can stay in the study. If the patient is considered a drop-out from the trial, he/she will be followed three monthly till 24 months (assessments according to visit 28 except for the X-ray, AEs, concomitant medication not for RA, lipids, RF, anti CCP and QoL questionnaires, see table 1). Participants in the U Act After study (ML28388) can follow the U Act After schedule of Assessments Rationale for Study Design - Combination therapy vs. MTX monotherapy: Previous Phase III studies (OPTION and TOWARD) have shown that the combination of TCZ with MTX achieves significant clinical efficacy with a positive benefit-risk profile in patients with moderate to severe active RA who had an inadequate response to MTX or other DMARDs [24, 25]. - Combination therapy vs. TCZ monotherapy: From the AMBITION trial it was concluded that TCZ monotherapy is superior to MTX monotherapy, with rapid improvement in RA signs and symptoms, and a favorable benefit-risk, in patients who have not previously failed methotrexate or biologics treatment [27]. - Outcome: The outcome is based on clinical efficacy and safety. Clinical efficacy is based on regular clinical and laboratory parameters for treatment strategies in established and Early RA including radiographic joint damage based on annually taken radiographs of hand and feet. AE and SAE are registered according to Dutch and international regulations. In addition for tertiary outcome serum and urine samples as well as mrna from blood mononuclear cells are stored for analyses of markers to monitor response and potentially to predict efficacy. 22

23 3.1.2 Rationale for Dose Selection - TCZ: Previous clinical studies of TCZ in patients with RA have evaluated doses up to 8 mg/kg given every 2-4 weeks. Phase II and III studies have shown that doses of 4 mg/kg and 8 mg/kg given in combination with MTX every 4 weeks are efficacious and have a positive benefit-risk profile. The results from the CHARISMA study show that in patients with relatively long duration RA with an inadequate response to MTX, 8 mg/kg TCZ in combination with MTX led to significant improvements in ACR20, ACR50 and ACR70 responses compared with MTX in combination with placebo [23]. The maximum reduction in DAS28 was achieved with the 8 mg/kg TCZ dose in combination with placebo or traditional DMARDs [8, 22, and 27]. In addition, the 8 mg/kg dose elicited a rapid and sustained normalization and marked suppression of a major marker of inflammation, CRP, throughout the 4-week inter-dosing interval, in contrast to the sawtooth pattern observed with the 4 mg/kg dose. The Phase III program also showed that a higher proportion of patients (2-3 fold higher) treated with 4 mg/kg TCZ required rescue therapy than in the 8 mg/kg TCZ group. Moreover, clinically relevant additional improvements were noted in patients switching from 4 mg/kg TCZ to 8 mg/kg TCZ, either as rescue therapy or when entering the extension studies, indicating less disease control on the lower dose. Therefore, 8 mg/kg every 4 weeks, resulting in the highest response rate with a positive benefit-risk ratio, was selected as the dosage for this study. However, in phase III studies tocilizumab AUC, Cmin and Cmax increased with increase of body weight. At body weight 100 kg, the predicted mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were ± μg h/ml, 19.0 ± 12.0 μg/ml, and 269 ± 57 μg/ml, respectively, which are higher than mean exposure values for the overall patient population. In addition, these data show that patients weighing more than 100 kg, who would receive a total dose exceeding 800 mg, do not derive benefit proportional to the increase in exposure. Simulated response data confirm that administration of the maximum total dose of 800 mg results in response levels that are comparable to those obtained with the dose of 8 mg/kg. Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended in patients 100 kg. This change of dosing is being implemented in amendment A. - MTX: Amongst various other studies, the CAMERA study from the SRU clearly showed that using MTX in a tight control setting led to a considerable improvement of disease activity in early RA. A program to increase the dose of MTX to mg/week in a more rapid manner led to earlier identification of patients who are partial responders on MTX and might benefit from combination therapy. Tight control is a promising new paradigm for reaching the aim of low disease activity, or even better remission in the first two years of the treatment of RA (2, 3, 9, and 10). Experience in the CAMERA and Best studies have shown that a dosage of 30 mg MTX is feasible in over 70% of the patients (no SAE or AE that prompted stop or reduction of MTX). Not all patients, however, needed these high dosages; the mean MTX dosage in the tight control arm of the CAMERA study was below 20 mg/wk. As in the CAMERA study rules are defined in the present study to handle possible adverse events (10). 23

24 3.1.3 End of Study The end of the trial is defined as the date of the last visit of the last participating patient in this study (LPLV; week 104). 3.2 Number of Subjects / Assignment to Treatment Groups 300 subjects, 100 per treatment arm with early RA will be recruited over a planned recruitment period of approximately 24 months. Patients will be allocated to a treatment group in a 1:1:1 ratio, TCZ + MTX, or TCZ + placebo MTX, or TCZ placebo + MTX. Randomization will be stratified for participating center and baseline DAS28 (< 5.1 or 5.1), based on a list with blocks and will take place through an IVRS. The investigator/ trial staff at site, patient, and sponsor trial personnel will be blinded to the trial treatment allocated to each individual patient. 3.3 Centers Approximately study centers will participate in this study with approximately 12 to 30 patients per centre. 4. STUDY POPULATION 4.1 Overview Adult men and women with early RA (disease symptoms < 1 year) meeting the ACR classification criteria, who have not had previous treatment with DMARDs or systemic or intra-articular glucocorticoids or biological agents for RA, will be eligible for this study. 4.2 Inclusion Criteria To be eligible for this trial, patients must meet all of the following criteria: 1. Male or non-pregnant, non-nursing female years of age 3. Early RA (disease symptoms <1 year) according to the revised 1987 ACR criteria and/or ACR/EULAR classification criteria of 2010 for RA 4. Disease activity measured by DAS28 2,6 5. Patients able and willing to give written informed consent and comply with the requirements of the study protocol 6. Immunization status current for pneumovax, influenza as assessed according to standard of care for RA patients receiving a biological agent 24

25 4.3 Exclusion Criteria Patients with any of the following criteria will not be eligible to participate in the study: Other joint disease 1. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma, polymyositis. Patients with interstitial pulmonary fibrosis and still able to tolerate MTX therapy are permitted. Sjögren s Syndrome with RA is permitted 2. Current inflammatory joint disease other than RA (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) Drug-specific 3. Glucocorticoids used for RA < 6 weeks prior to baseline (NB: inhaled glucocorticoids are allowed) 4. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline 5. Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational agent, whichever is longer) before screening 6. Previous treatment with any biologic drug that is used in the treatment of RA 7. Previous treatment with any DMARD that is used in the treatment of RA 8. Any previous treatment with alkylating agents, such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation 9. Treatment with IV gamma globulin, plasmapheresis or Prosorba column within 6 months before baseline Laboratory analyses (at screening) 10. Serum creatinine > 142 μmol/l in female patients and > 168 μmol/l in male patients or an active renal disease 11. ALT or AST > 1.5 x ULN (if initial sample yields ALT or AST > 1.5 x ULN, a second sample may be taken and tested during the screening period) 12. Platelet count < 100 x 10 9 /L (100,000/mm 3 ) 13. Hemoglobin < 1.5 mmol/l below LLN for gender 14. WBC count < 4.0 x 10 9 /L (4000/mm 3 ) 15. Absolute neutrophil count < 2.0 x 10 9 /L (2000/mm 3 ) 16. Absolute lymphocyte count < 0.5 x 10 9 /L (500/mm 3 ) 17. Positive HBsAg or HCV antibody 18. Triglycerides > 10 mmol/l (> 900 mg/dl) at screening (fasted) General medical 19. Pregnant women or nursing (breastfeeding) mothers 20. Females of child-bearing potential who are not using reliable means of contraception (such as physical barrier [patient and partner], contraceptive pill or patch, spermicide and barrier, or intrauterine device) 25

26 21. History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies 22. Chest X-ray (CXR) at screening showing evidence of any clinically significant abnormality 23. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or GI disease 24. In patients with a history of complicated diverticulitis, the treating physician needs to consider the benefit-risk ratio 25. A known history of chronic ulcerative lower GI disease such as Crohn s disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose to perforations 26. Active TB, requiring treatment within the previous 3 years. Patients with a positive purified protein derivative tuberculin skin test (PPD) at screening as per local guidelines are not eligible for the study unless they complete treatment for latent TB and have a negative CXR at enrollment. Patients treated for TB with no recurrence in 3 years are permitted 27. Known uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease, where flares are commonly treated with oral or parenteral glucocorticoids 28. Current liver disease as determined by investigator. Patients with prior history of ALT elevation are not excluded 29. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to atypical mycobacterial disease, clinically significant abnormalities on CXR as determined by the investigator, hepatitis B and C, and herpes zoster (for which systemic treatment is needed), but excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening 30. History of, or currently active, primary or secondary immunodeficiency, such as HIV or AIDS 31. Evidence of active malignant disease, malignancies diagnosed within the previous 5 years (including hematological malignancies and solid tumors, except non-melanoma skin cancer that has been excised and cured) 32. History of alcohol, drug, or chemical abuse within the 6 months prior to screening 33. Neuropathies or other painful conditions that might interfere with pain evaluation 34. Patients with lack of peripheral venous access 35. Patients with documented lactose intolerance 4.4 Concomitant Medication and Treatment Concomitant medication is any drug or substance taken during the study period regardless of route of administration. All concomitant medications (including over-thecounter medications, herbal medications, preventative vaccines, vitamins and food supplements) and procedures must be recorded in the ecrf. A description of the type of drug or procedure, the amount, duration, reason for administration of drug, and the outcome of any procedures must be documented. 26

27 AEs related to the administration of a concomitant medication or the performance of a procedure must also be documented on the appropriate AE page of the ecrf. Particular attention must be paid on registering any concomitant antirheumatic and pain medications as well as lipid-lowering agents given during the trial. Lipid-lowering agents prescribed in patients with elevated lipids will be based on the treating physician's clinical judgement and following Dutch guidelines. In this trial we classify RA patients as "high risk" according to the Dutch guidelines. A cholesterol synthesis inhibitor (1 dd 40 mg simvastatin or pravastatin) is given at a LDL of > 2.5 mmol/l (determined at baseline). Aim for a decrease of the LDL to <2.5 mmol/l or a decrease of at least 1.0 mmol/l (checked after 12 weeks). Dose may need to be titrated upward, and in those patients who are already receiving a statin at baseline, consider that dose of simvastatin or atorvastatin, which are metabolized by CYP450, may need to be increased as metabolism improves to normal with control of inflammation (see SPC) Use of Treatments for Rheumatoid Arthritis Non-steroidal anti-inflammatory drugs (NSAIDs) The choice and doses of NSAID/COXIBs used to treat patients will be at the discretion of the investigator physician and will be recorded meticulously. In case an NSAID is indicated, preferably another NSAID than diclofenac is prescribed, since this drug is associated with more frequent liver function test changes than other NSAIDs. Acetylsalicylic acid (ASA, not to exceed 100 mg/day) may be taken to reduce cardiovascular risk. Analgesics (other than NSAIDs) Analgesics up to the maximum recommended doses may be used for pain relief as required. Patients should not take analgesics within 24 hours prior to a visit where clinical efficacy assessments are performed. Intravenous, intramuscular, intra-articular or oral glucocorticoids Glucocorticoids for RA will not be permitted within 6 weeks prior to baseline (NB inhaled glucocorticoids are allowed). Injection of intra-articular glucocorticoids while on study medication is discouraged but may be used in a limited manner. The use of intraarticular glucocorticoids will be kept as low as possible and will be recorded. IV or IM glucocorticosticoids will not be permitted in the study. In exceptional situations a short oral course of maximum 14 days glucocorticoids, with a maximum dosage of 10 mg/daily prednisone equivalents can be allowed; however, not during the first 3 months and only once every 6 months. In these situations disease assessments within a period of 2 weeks after intra-articular or oral glucocorticoids cannot be evaluated validly, and need to be postponed to the next 4 weeks evaluation point. In case of intra-articular glucocorticoids, the injected joint is counted as swollen and in case of oral 27

28 glucocorticoids, the DAS from previous visit will be used to determine the next predefined study medication step. 4.5 Prohibited treatments DMARDS, including etanercept, infliximab, adalimumab, rituximab, abatacept or other newer or investigational biologicals. Glucocorticoids other than defined under Recent immunization with a live/attenuated vaccine Chlorambucil Cyclophosphamide Calcineurin inhibitors (e.g. tacrolimus and cyclosporine) Mycophenolate mofetil or mycophenolic acid sodium Cotrimoxazol 4.6 Criteria for Premature Withdrawal Subjects have the right to withdraw from the study at any time for any reason. In the case that the subject decides to prematurely discontinue study treatment [ refuses treatment ], he/she should be asked if he/she can still be contacted for further information. The outcome of that discussion should be documented in both the medical records and in the ecrf. If lost to follow-up, the investigator should contact the subject or a responsible relative by telephone followed by registered mail or through a personal visit to establish as completely as possible the reason for the withdrawal. A complete final evaluation at the time of the subject s withdrawal should be made with an explanation of why the subject is withdrawing from the study. When applicable, subjects should be informed of circumstances under which their participation may be terminated by the investigator without the subject s consent. The investigator may withdraw subjects from the study in the event of intercurrent illness, adverse events, treatment failure after a prescribed procedure, lack of compliance with the study and/or study procedures (e.g., dosing instructions, study visits), treatment cure or any reason when the investigator feels it is in the best interest of the subject to be withdrawn from the study. Any administrative or other reasons for withdrawal must be documented and explained to the subject. If the reason for removal of a subject from the study is an Adverse Event, the principal specific event will be recorded on the ecrf. The subject should be followed until the Adverse Event has resolved, if possible. An excessive rate of withdrawals can render the study non-interpretable; therefore, unnecessary withdrawal of subjects should be avoided. Should a subject decide to withdraw, all efforts will be made to complete and report the observations prior to withdrawal as thoroughly as possible. 28

29 4.7 Replacement Policy For Subjects No subject prematurely discontinued from the study for any reason will be replaced For Centers A center may be replaced for the following administrative reasons: Lack of recruitment Poor protocol adherence GCP/ICH related censure 29

30 5. SCHEDULE OF ASSESSMENTS AND PROCEDURES The assessments and procedures at each visit are to be standardized as follows (at visits as specified in Table 1): 1. Laboratory samples must be drawn either at least 30 min before nurse/investigator assessments or at any time after nurse/investigator assessments but prior to study drug infusion, as defined in more detail under 5.4. and Patient health outcomes assessments consists of the following: Dutch consensus HAQ, the FACIT-fatigue, the IPQR, the SF-36, VAS pain and general wellbeing Questionnaires, a Dutch Healthcare resource use and work participation questionnaire, and the EuroQol (EQ5D) questionnaire 3. Assessments: Joint assessor: joint counts by an experienced and qualified clinical assessor. Preferably done by the same assessor for consistency Treating physician: physician s global assessment of disease activity (VAS) (can also be done by trained other staff) and safety assessments (AEs, concomitant and/or previous medications, review of laboratory data) 4. X-ray for SvdHS Score (may be performed at any time during the study visit) 5. TCZ / placebo infusion takes place after lab samples have been taken and physician's VAS has been assessed 6. Post-dose AEs 30

31 Table 1 Schedule of Assessments Screen Treatment period: 104 weeks Visit No WD Week -4-0 Bas Visit window +/ calendar days Written informed consent X In- / exclusion criteria X X Demographics & medical X history Pregnancy test 1 X X X X X X X X X X X X X X X X X X X X X X X X X X X HBsAg & HCV antibody X Randomization X Physical examination X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Vital signs / weight X X X X X X X X X X X X X X X X X X X X X X X X X X X X X ECG X 2 CXR X 2 AE evaluation X X X X X X X X X X X X X X X X X X X X X X X X X X X X Concomitant medication 5 X X X X X X X X X Hematology X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Blood chemistry X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Lipids panel X X X X X Bas: Baseline WD: Withdrawal visit 31

32 Screen Treatment period: 104 weeks Visit No WD Week -4 Bas Visit window +/- calendar days (hs)crp X X X X X X X X X X X X X X X X X X X X X X X X X X X X X ESR X X X X X X X X X X X X X X X X X X X X X X X X X X X X X RF, anti-ccp X X X Joint counts (44) X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Anti-TCZ antibodies X 6 X-rays hand and feet X 3 X 3 X X X**** Quality of life questionnaires X X 4 X X X X X Patient / Phys. VAS X X X X X X X X X X X X X X X X X X X X X X X X X X X X X VAS pain and gen. well b X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Serum / urine (biomarker) X blood for RNA (subset) X Total RNA (Paxgene) X X TCZ or Placebo infusion** X X X X X X X X X X X X X X X X X X X X X X X X X X Dispense MTX or Pla*** X X X X X X X X X X X X X X X X X X X X X X X X X X 1 A urine pregnancy test (dipstick test or serum) must be performed within 4 weeks prior to baseline for all female patients of childbearing potential. A positive or inconclusive pregnancy test renders the patient ineligible for the study. (All pregnancies must be reported to the sponsor) (see also section 7.2.2). 2 If a CXR or ECG showing no clinically significant abnormality has been taken within 4 weeks prior to screening, the CXR/ECG does not need to be repeated 3 At screening or baseline, if X-ray has been taken within 3 months prior to screening, the X ray does not need to be repeated 4 If baseline is within 7 days of screening visit, these do not have to be repeated 5 Treatments for RA will be monitored every visit 6 Serum for anti-tcz antibody testing will be taken in any cases of anaphylaxis or serious hypersensitivity events and any hypersensitivity event (including non-serious events) that leads to treatment withdrawal (at the time of the event and at least 6 weeks after the event). A withdrawal visit is only required, if a patient does not complete the study **Please note that at baseline a 7 day time window is allowed and that certain patients might discontinue TCZ or Placebo during the trial *** Bottles with capsules of either 5 mg MTX or Placebo will be dispensed to each patient according to the MTX dose the patient needs to receive and the patient s randomization number. Once weekly the patient will take the appropriate number of capsules on one particular day of the week (for example every Friday). Please note that patients might discontinue MTX or Placebo during the trial. ****If the radiograph performed at the time of withdrawal is within the 60 days after previous radiographs of hands and feet were taken, the radiograph does not need to be repeated. 32

33 5.1 Screening Examination and Eligibility Screening Form All subjects must sign and date the most current IRB/IEC-approved written informed consent before any study specific assessment or procedure is performed. A screening examination should be performed maximum 4 weeks prior to start of the study. Subjects must fulfill all the entry criteria for participation in the study. An Eligibility Screening Form [ESF] documenting the investigator s assessment of each screened subject with regard to the protocol s inclusion and exclusion criteria is to be completed by the investigator. A screen failure log must be maintained by the investigator. 5.2 Procedures for Enrollment of Eligible Subjects To ensure accurate and timely monitoring of patient enrollment, the following procedures will be implemented: All patients must sign the informed consent form prior to screening and prior to any changes to their existing medication for the purposes of enrollment into the study. Patients who are candidates for enrollment into the study will be evaluated for eligibility by the investigator to ensure that the criteria given in Sections 4.2 and 4.3 have been satisfied, and that the patient is eligible for participation in this clinical study. Eligible patients are randomized prior to receiving any study medication. Patients will be randomly assigned to one of the treatment groups. The patient randomization numbers will be generated by the Sponsor or its designee. Randomization will be based on a list of blocks and will be stratified by site and baseline DAS28. Patient eligibility information will be filled out in the ecrf. The patient will be randomized and assigned a unique randomization number. Immediately after the procedures and assessments for the baseline visit have been performed, treatment with TCZ + MTX or TCZ + Placebo or Placebo + MTX will be initiated Re-Testing-Laboratory Inclusion/Exclusion Criteria If a patient fails any laboratory inclusion/or fulfills any laboratory exclusion criterion at screening (Sections 4.2 and 4.3), the investigator may repeat the test twice within the screening period. If the patient fails the laboratory criteria for the third time, he/she will be considered a screen failure. It is possible to re-screen a patient as described in Section It will not be considered re-testing if blood samples have to be redrawn due to technical and/or handling procedures. 33

34 5.2.2 Re-Screening Re-screening refers to repeating the whole screening process (see Section 5.3). Rescreening is required if a patient has not met all the eligibility criteria within 4 weeks of the original screening visit. Patients are only allowed to be re-screened once. Each patient must be re-consented before re-screening occurs. 5.3 Clinical Assessments and Procedures At screening At the screening visit, clinical and laboratory assessments will be performed to determine patient eligibility based on inclusion/exclusion criteria (see Section 4.2 and 4.3). The following procedures and assessments are to be completed at the screening visit: Written Informed Consent Demographics and medical history Pregnancy test Review patient eligibility and ensure that all inclusion and exclusion criteria are met Physical examination, including pulse rate, systolic and diastolic blood pressure (after the patient has been in a semi-supine position for at least 5 minutes), body temperature, body weight and physician s global assessment of disease status ECG: Twelve lead electrocardiograms should be taken at screening and reviewed by the investigator or designee. Patients should be supine for 5 minutes before the recording is performed. If an ECG showing no clinically significant abnormality has been taken within 4 weeks prior to screening and no cardiac problems have emerged since that time, a new ECG does not need to be taken at screening. CXR: Posterior-anterior and lateral chest radiographs with formal readings should be obtained at screening and reviewed by the investigator or designee. If a CXR showing no clinically significant abnormality has been taken within 4 weeks prior to screening, the CXR does not need to be repeated. Swollen and tender joint counts 44 (including shoulders) Concomitant and/or medications Blood samples for laboratory tests o (hs)crp o ESR o Hematology o Blood chemistry o Lipid panel o HBsAg and HCV antibody screening o RF and anti CCP If TB screen is positive (patient has not received BCG vaccine), and patient has not been previously prophylaxed, treatment with isoniazid INH should be initiated. Once the patient has completed at least 4 weeks of INH treatment without toxicity (to be 34

35 continued for recommended duration), the patient may be enrolled. The screening period in this case may be maximum of 8 weeks. Patient health outcomes assessments Radiographs of hands and feet, if taken within 3 months prior to screening these do not need have to be repeated. At baseline patient eligibility is reviewed and ensured that all inclusion and exclusion criteria are met, for the lab criteria the lab results from screening visit are reviewed Efficacy With respect to the first and third objective of the study swollen and tender joints, ESR, CRP, and VAS global well-being will be determined at screening, at baseline, and every four weeks. A DAS28 will be calculated. Remission is defined as DAS28 < 2.6. With respect to the second objective: radiographs of hands and feet will be scored for erosions and joint space narrowing according to standard procedures, annually starting before treatment and annually after start of treatment (for Schedule of assessments see Table 1). Disease Activity Score 28 The DAS28 is a composite index for measuring disease activity in RA. The index includes swollen (range 0-28) and tender joint counts (range 0-28), acute phase response (ESR), and general health status (range 1-100). The DAS28, which uses a 28 joint count including shoulders (see appendix 5), is derived from the original DAS, which includes a 44 swollen joint count. The DAS28 has been validated in RA. The index is calculated using the following formula: DAS28 = (TJC) (SJC) ln(esr) GH where TJC = tender joint count on 28 joints, SJC = swollen joint count on 28 joints, ln = natural log, ESR = erythrocyte sedimentation rate (mm/hr), and GH = general health, i.e. patient s global assessment of disease activity (100 mm VAS). The DAS28 ranges from 0 to 9.3, where higher scores represent higher disease activity. Sharp/van der Heijde Score Radiographs of hands (posterior/anterior) and feet (anterior/posterior) will be taken at screening, weeks 52 and 104. The primary assessment will be the change in the modified SharpvanderHeijde Score (SvdHS) from screening. The modified SvdHS combines an erosion score and a joint space narrowing score of both hands and feet. The maximum total erosion score in the hands is 160 and in the feet 120. The maximum scores for joint space narrowing (JSN) in the hands is 120 and in the feet 48. The total score is the sum of scores for erosions and JSN. The maximum total modified SvdHS is 448. Radiographic grading is performed at the end of the study using the SvdHS. Original radiographs will be assessed by a blinded, central (experienced and trained) observer to 35

36 ensure conformity with the required specifications and quality control. The three annually taken radiographs of hands and feet are scored as a set, blinded to time sequence of the radiographs. All radiology technicians will follow the current guidelines for specific beam positioning and joint placement. The radiology technician will ensure the quality of each radiograph prior to the patient leaving the radiology facility Patient Health Outcomes Assessment The Health Assessment Questionnaire (HAQ) disability score is a patient-completed questionnaire specific for RA (appendix 3). It consists of 20 questions referring to 8 component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The SF 36 measures quality of life in a generic way (appendix 3, the validated Dutch version, RAND36 [30]). The two fatigue questionnaire (FACIT-fatigue and IPQR- R) measure the occurrence and severity of fatigue (appendix 3) Safety With respect to the fifth objective: During the study a predefined list of adverse effects is registered according to standard protocol at the time points given in table 1. Laboratory results at treatment visits should be known before the patients take MTX, in case adjustment of oral medication is needed. When lab results are of consequence to administration or dosage of infusion, results should be known before infusion. In addition, laboratory tests and clinical examinations will be used for the evaluation of safety. Physical Examination A general physical examination (including the cardiovascular, respiratory, GI and neurological systems) should be performed and recorded as normal or abnormal with specified abnormalities at the times indicated in table 1. Any persisting abnormalities should be stated each time the examination is performed. Diagnosis of new abnormalities, or worsening abnormalities, should be recorded as an AE if appropriate. Vital Signs/Body Weight Vital signs (pulse rate, systolic and diastolic blood pressure, and temperature) and body weight will be taken at the times indicated in table of assessments (Table 1). Vital signs should be taken after the patient has been in a semi-supine position for at least 5 minutes. 5.4 Laboratory Assessments The following laboratory tests will be recorded at the time points indicated in the Schedule of Assessments (table 1). Tests will be performed at each institute according to local regulations and practice. Importantly, fasting (> 8 hours; with no alcohol intake the previous evening; >12 hours) is a prerequisite for the screening, baseline, week 12, week 104 and potential early WD time points (see Table 1) because of diet disturbance 36

37 in biomarker and lipid analyses (see 5.5.). At the other time points fasting blood sampling is not a prerequisite. The need for fasting may not lead to premature withdrawal, as such if needed non-fasted blood samples will be taken. In all cases fasting / non-fasting condition will be recorded. For acute phase reactants efficacy assessments: (hs)crp (mg/dl) and ESR (mm/hr) both will be determined according to local practice. Hematology/complete blood count: Hemoglobin, hematocrit, red blood cells, WBC with differential (absolute or %) count, platelet counts Blood chemistry: ALT, AST, alkaline phosphatase, creatinine Lipid panel: Total cholesterol, triglycerides, HDL, LDL Pregnancy testing, as appropriate HBsAg and HCV antibody at screening 5.5 Additional lab samples for biomarkers With respect to a separate biomarker protocol, blood and urine samples will be taken according to the schedule of assessments (see table 1). Biomarker samples are collected to promote, facilitate and improve individualized health care by better understanding of response and to predict response to therapy: TCZ and MTX efficacy, dose responses, safety, TCZ and MTX mode of action, progression of RA and associated diseases. The following samples are collected. At baseline - 10 ml urine (second morning void) is collected (to store 8 urine samples of 1000 μl) for analyses of multiple biochemical markers ml blood is collected in heparin tubes (for mrna isolation and phenotyping of isolated mononuclear cell subsets) ml blood is collected in a gel clotting tube (for analyses of multiple biochemical markers) ml blood is collected in EDTA tubes (for DNA isolation) - two paxgene tubes of 2.5 ml blood is collected (for total mrna isolation). At week 8, a single paxgene tube of 2.5 ml blood is collected (for total mrna isolation). 5.6 Quality of Life Assessments With respect to the fifth objective: according to the time schedule in Table 1. Patients are asked to fill out Dutch consensus HAQ and FACIT-fatigue, IPQR, SF-36, VAS pain and general wellbeing Questionnaires, a Dutch Healthcare resource use and work participation questionnaire, and the EuroQol. 5.7 Withdrawal visit The reason of a withdrawal is recorded in the ecrf. 37

38 5.8 Post Study Provisional Care TCZ has been approved and is commercially available at the end of the 2-year study period. 6. INVESTIGATIONAL MEDICINAL PRODUCT 6.1 Dose and Schedule of IMP and Comparators The duration of study drug treatment will be 104 weeks, starting from baseline (day 1). Patients will receive either: I Tocilizumab 8 mg/kg i.v. every 4 weeks + weekly oral MTX in climbing dosages II Tocilizumab 8 mg/kg i.v. every 4 weeks + weekly oral placebo in climbing dosages III Placebo - i.v. every 4 weeks + weekly oral MTX in climbing dosages TCZ Patients will receive a blinded infusion of 8 mg/kg intravenous TCZ or placebo every 4 weeks on an outpatients basis for maximally 26 infusion (every 4 weeks from baseline to week 100). TCZ will be adminstered in a setting that is standard of care for biologicals. MTX Patients will receive blinded weekly oral MTX or placebo in climbing dosages of 5 mg starting at 10 mg up till a maximum dosage of 30 mg/week (standard care in the Netherlands). Patients must not have received pre-study MTX. In order to minimize potential MTX toxicity, all patients will receive folic acid 5 mg twice a week. 6.2 Dose Modifications, Interruptions and Delays Patients are evaluated every 4 weeks and at each visit a dosage decision is made based on efficacy parameters (DAS28) and possible occurrence of adverse events. In case at the start of the evaluation visit remission is not yet reached the dosage of MTX/Placebo will be increased until remission or the maximum tolerable dose is reached (see table 2 as a guide, recognizing that there may be need for adjustment of timing if dose escalation of oral medication requires more time). The maximum tolerable dose (MTD) is the last dose on which the patient did not yet experience the predefined AE. In case of a second or third predefined AE, a new MTD is set. 38

39 Table 2: schedule for increasing MTX/placebo treatment in case remission is not yet reached and MTX/placebo is tolerated well Week DAS 28 tocilizumab (8 mg/kg iv) HCQ MTX (mg/wk orally) or placebo or placebo 0 X X X X X X X 30 In case sustained remission (defined as DAS < 2.6 during 24 weeks and no more than 4 swollen joints due to RA at week 24 of remission) is reached, MTX/Placebo and TCZ/placebo will be decreased following table 3. In case the maximum tolerated dose MTX/Placebo is reached and remission has not been achieved, medication is adjusted following figure 3. Remission not reached with maximum tolerable dose MTX/Placebo When remission (DAS28 < 2.6) is not reached with the maximum tolerable dosage of capsules (MTX or placebo) hydroxychloroquine 2 times 200 mg/day will be added (see figure 3). If after 12 additional weeks still remission is not reached, the IWRS will check in an blinded fashion into which treatment strategy (I, II or III) the patient has been randomized. If the patient is in group I, (the group with patients treated with the combination TCZ and MTX) TCZ, MTX (study medication) and HCQ will be stopped and replaced by standard of care therapy, such as a combination of MTX and anti TNF alpha therapy (e.g. adalimumab 40 mg sc biweekly); this means that blinding for these patients is broken and that these patients will be considered as failures for the treatment strategy. Failures will be followed at least every three months until the end of the 2-year study period (see 3.1). If the patient is in group II and III, the placebo therapy will be replaced by the verum therapy. Thus in patients not in remission in both groups then the combination TCZ with MTX are used. The original treatment assignment for these patients will not be revealed. In order to manage patients in a blinded manner, patients from group II, who received the 6 capsules before the therapy switch, will start with 10 mg MTX per week. To maintain blinding, the patient will remain receiving 6 capsules, with 2 of them being verum MTX, and 4 of them being placebo. Dose increase according to the original MTX escalation scheme will be attained by increasing the number of verum capsules and decreasing the number of placebo capsules, keeping the total number of capsules the same. Patients in group III will also remain to receive 6 capsules, the same dosage as the last dosage before the switch to verum TCZ. 39

40 Patients in group II and III will be considered failures in case 16 weeks after adding verum instead of placebo this is ineffective after having reached the maximum tolerable dose. In this case TCZ, MTX (study medication) will be replaced by standard of care therapy, such as the combination of MTX with anti TNF alpha therapy (e.g. adalimumab 40 mg sc- biweekly) (see figure 3). Failures will be followed at least every three months until the end of the 2-year study. Patients are treated with protocol strategy for a minimum of 32 weeks before being considered a failure. Figure 3: Schematic overview of treatment regimens when remission is not reached with maximum tolerated dose of MTX/placebo. group 1 st strategy max tolerable dose and DAS weeks and DAS 2.6 max tolerable dose and DAS 2.6 I MTX MTX MTX TCZ TCZ?-TNF α-tnfα? HCQ II MTX -PB MTX -PB MTX MTX TCZ TCZ TCZ?-TNF? HCQ III MTX MTX MTX MTX TCZ -PB TCZ -PB TCZ?-TNF? HCQ Remission If remission(das28 < 2.6) is reached, medication is continued (blinded) unchanged for 24 weeks. When remission is continuously present and still observed after 24 weeks and the patient at that timepoint has no more than 4 swollen joints, MTX/placebo will be decreased every 4 weeks with 5 mg/week as long as remission is maintained. If the patient has remission (DAS28 < 2.6) but has > 4 swollen joints, MTX dosages remain at same level until the patient has 4 swollen joints or less. When 4 weeks after stopping the 40

41 MTX/placebo sustained remission is maintained the dosage of TCZ/placebo will be halved (4 mg/kg every 4 weeks) during 3 infusions. When remission is still maintained at that moment as well, the infusions will be stopped (see table 3). Table 3: Schedule for decreasing treatment in case sustained remission is still maintained after 24 weeks unchanged treatment with 30 mg MTX or placebo Week DAS 28 Tocilizumab or placebo MTX or placebo Dose dose used Remission < weeks 8 mg/kg -5 mg + 4 <2.6 8 mg/kg -10 mg + 8 <2.6 8 mg/kg -15 mg + 12 <2.6 8 mg/kg -20 mg + 16 <2.6 8 mg/kg stop + 20 <2.6 4 mg/kg <2.6 4 mg/kg <2.6 4 mg/kg <2.6 stop < NB. The treatment schedule differs for each remission dosage Flare after remission If remission (DAS28 < 2.6, an increase of DAS28 below 2.6 is not considered flare) was reached at one point during the study, but the patient experiences more disease activity afterwards (DAS28 2.6) the patient returns to the dosage steps according to Table 4 until remission is reached again. Table 4: Schedule for increase of study medicaton after flare Week DAS 28 Tocilizumab or placebo MTX or placebo Dose dose used Flare mg/kg mg/kg mg/kg 10 mg mg/kg 15 mg mg/kg 20 mg mg/kg 25 mg mg/kg 30 mg Note: depending on the last effective dose, the dose step up can start from any point in Table 4 Use of glucocorticoids, NSAIDS and COXIBs The use of intra-articular glucocorticoids will be kept as low as possible and will be recorded (see ). The injected joint will be counted as swollen in the DAS28. 41

42 Prescription of NSAIDs / COXIBs is at the discretion of the treating physician and will be recorded meticulously. If the patient requires glucocorticoids for non-ra indication (e.g. acute allergy), or control of RA symptoms (after first 12 weeks in study, no more than 10 mg/day x 2 weeks) this will be recorded as an adverse event and the treatment regimen noted in the medication section of the ecrf. The efficacy evaluation in the subsequent 4 weeks will be flagged and the DAS from the previous visit will be used to determine the next predefined medication step. If the patient is undergoing evaluation for sustained remission, the assessment of disease activity of this visit will not be included. Adverse events The following dose modification rules apply to patients receiving the study medication and experiencing the predefined adverse events (that are according to the investigator at least possibly related to MTX and/or TCZ) referred to in this section. Whether intermittent adverse events will influence the titration step at a specific visit is up to the discretion of the investigator. Predefined Adverse Events: Leukocytes < 3.0 x 10 9 /l Thrombocytes < 100 x 10 9 /l Anemia (Hb > 1.5 mmol/l below lower limit of normal for gender) Very severe oral ulcera leading to difficulty in eating Deterioration of serum creatinine to level ULN + 75 µmol ALT 3 times ULN If one of the predefined adverse events occurs, the dosage MTX or placebo (or TCZ/placebo, if the patient is on TCZ only) will be reduced by at least 50%. If there is no improvement after an additional 4 weeks the capsules (MTX or placebo) will be stopped (see table 5). If 4 weeks after reducing the MTX or placebo the adverse event has even worsened (> 10% further deterioration), the dosage of the TCZ infusion will be halved and hydroxychloroquine 2 times 200 mg daily will be added; if not improved 4 weeks thereafter the infusions will be stopped. At that point, patients will be considered failing the strategy and will obtain treatment according to the discretion of the treating physician. Predefined Adverse Events: liver enzyme abnormalities: ALT > 1 but < 3 times ULN once: no action needed ALT > 1 but < 3 times ULN persistent (after 4 weeks); follow treatment steps for predefined Adverse Events (table 5); In case of an improvement or disappearance of predefined AE the patient on 4 mg/kg TCZ will first go back to 8 mg TCZ and subsequently (4 weeks later) add MTX according the original MTX escalation scheme. In case TCZ was still on 8 mg, the MTX escalation scheme will be regained again 4 weeks after improvement of side effects. Definition of improvement of predefined adverse events: Leukocytes > 3.0 x 10 9 /l, Thrombocytes > 100 x 10 9 /l 42

43 Table 5: treatment regimen when predefined adverse events occur (NB note difference between "no improvement" and "worsened") Example A Week predefined MTX TCZ HCQ adverse events or placebo or placebo xx mg 8 mg/kg +4 present - 50% 8 mg/kg +8 no improvement stop 8 mg/kg +12 no improvement stop 4 mg/kg 2 x 200 mg/day +16 no improvement - stop FAILURE Example B Week predefined MTX TCZ HCQ adverse events or placebo or placebo xx mg 8 mg/kg +4 present - 50% 8 mg/kg +8 worsened stop 4 mg/kg 2 x 200 mg/day +12 no improvement - stop FAILURE Subjective Adverse Events: Subjective adverse events possibly related to mtx/tcz (such as, but not limited to) are: gastro-intestinal discomfort, nausea, stomach ache, headache, dizziness, fatigue. If subjective adverse events occur, the predefined increase in dosage (if needed) can be postponed twice (eight weeks). In case subjective events then remain, the strategy of predefined adverse events as described above should be followed. Pneumonitis: Stopping rule: pneumonitis as diagnosed by pulmonologist: stop study medication (MTX/placebo and TCZ/placebo) 6.3 Preparation and Administration of the Investigational Medicinal Products Blinded TCZ/Placebo TCZ will be supplied in vials containing either 10 ml of a sterile solution of 20 mg tocilizumab/ml or matching placebo. Two vials containing 200 mg TCZ each will be required for each 50 kg body weight to achieve an 8 mg/kg dose. The number of vials to be used depends on the patient s body weight as follows: 1. Two 10 ml TCZ or placebo vials are used for patients with a body weight of 50 kg. 43

44 2. Three 10 ml TCZ or placebo vials are used for patients with a body weight of >50 kg and 75 kg. 3. Four 10 ml TCZ or placebo vials are used for patients with a body weight of > 75 kg. The patient s body weight recorded before infusion should be used for calculating TCZ volumes for each infusion. The maximum dosage to be given is 800 mg.) For the preparation of the infusion bag, 0.4 ml per kg of the patient s body weight will be withdrawn from a 100 ml bag of normal saline. This volume will be replaced in the saline bag with an equal volume of TCZ or placebo from the patient s assigned study medication vials. To achieve the total calculated volume of TCZ required at the appropriate dose, volumes should be withdrawn from each of the vial combinations (1 to 4) detailed above. All study medication volumes must be recorded in the pharmacy records. The TCZ and placebo vials will be stored at a temperature of 2-8 C. The infusion bag of study medication (after it has been prepared) may be stored at 2-8 C for 24 hours providing that the infusion is prepared aseptically and allowed to return to room temperature before administration (1 to 2 hours depending on ambient room temperatures). A temperature log must be kept, recording the storage temperature of the TCZ and infusion bags at least once a day. TCZ or placebo will be administered at room temperature by controlled infusion into an arm vein over a 60-minute infusion period. For a 100 ml infusion bag the infusion time is 1 hr. The entire 100 ml content of the infusion bag must be administered. Following the infusion of study medication, 20 ml of normal saline will be administered to flush the remaining study medication through the IV set. Study medication must be administered under close supervision of the investigator or sub investigator in a setting where resuscitation facilities are available. The following assessments need to be done before infusion: weight, blood pressure, pulse and temperature; during infusion (30 minutes after infusion start) blood pressure, pulse and temperature. Blinded MTX/Placebo MTX and placebo will be supplied in bottles containing 6 capsules of either 5 mg MTX or matching placebo and will be dispensed to each patient every 4 weeks according to the MTX dose the patient needs to receive and the patient s randomization number. Once weekly the patient will take the MTX/placebo capsules. The weekly dose is to be taken on one particular day of the week (for example every Friday). All study medication volumes must be recorded in the pharmacy records. Medication volumes and additional details of the infusion preparation will be provided in the site documentation. 44

45 6.4 Formulation, Packaging and Labeling TCZ TCZ is packed in 10 ml glass vials, with concentration 20 mg/ml. The active product being used is TCZ 200 mg/10 ml with matching placebo. The drug label indicates the storage temperature. All TCZ and placebo vials must be stored at a controlled temperature of 2 8 C and handled according to GMP and GCP procedures. A temperature log must be kept recording the storage temperature of the tocilizumab and placebo and infusion bags at least once a day. The investigator or designated person (e.g. pharmacist) will be responsible for maintaining accurate records for all supplies used. After accounting of supplies, the sponsor will give written authorization to the investigator to return or destroy any remaining study medication as instructed. Details of the packaging and labeling of the study medication will be provided in the protocol-supporting documents. MTX/Placebo MTX/Placebo is supplied in plastic bottles containing sufficient capsules for one week dose. Study centers will be provided with a supply of MTX/Placebo bottles in advance of the study. All bottles must be stored and handled according to GMP and GCP procedures. The drug label indicates the storage temperature (i.e. room temperature not above 25 0 C. Details of the packaging and labeling of the study medication will be provided in the protocol-supporting documents. 6.5 Blinding and Unblinding The randomization list will be available in case of an emergency via the Roche affiliate office and at the pharmacist. The randomization list will not be available to the Roche monitors, project Statisticians or to the project team at Roche until release of the randomization list following database closure (for procedures related to the interim analysis, see 8.2.5). Unblinding for individual patients by the investigational team (with the exception of the unblinded statistician) should not occur during the trial except in case of emergency situations or in case the subject does not achieve remission at the maximum tolerated dose of MTX or placebo and unblinding needs to occur to adjust the treatment of the patient according to figure 3. Any request from the investigator for information about the treatment administered to study subjects for another purpose must be discussed with Roche. Unblinding will be performed by the pharmacist at the participating site As per regulatory reporting requirement, Roche will unblind the identity of the study medication for the unexpected serious adverse events that will influence 45

46 patient's care or will impact the label of tocilizumab. Details of subjects who are unblinded during the study will be included in the Clinical Study Report In exceptional circumstances, for medical reasons it is necessary to deblind patients at the end of their treatment but before 104 weeks or in order to optimize RA treatment after the trial, at week 104. This can only occur after the CRF has been completed, the data has been monitored by the monitor and data manager. Only the PI is deblinded for the MTX and/or TCZ treatment, after both the PI and Medical Monitor have provided their written agreement. 6.6 Assessment of Compliance Accountability and subject compliance will be assessed by maintaining adequate drug dispensing and return records. Subjects will be asked to return all used and unused drug supply containers at the end of the treatment as a measure of compliance. A Drug Dispensing Log must be kept current and should contain the following information: the identification of the subject to whom the study medication was dispensed medication number of bottle supplied the date[s], quantity of the study medication dispensed to the subject the date[s] and quantity of the study medication returned by the subject This inventory must be available for inspection by the Monitor. All supplies, including partially used or empty containers and the dispensing logs, must be returned to the Roche Monitor at the end of the study. 6.7 Destruction of the IMP/Comparator Local or institutional regulations may require immediate destruction of used IMP for safety reasons. In these cases, it may be acceptable for investigational site staff to destroy dispensed IMP before a monitoring inspection provided that source document verification is performed on the remaining inventory and reconciled against the documentation of quantity shipped, dispensed, returned and destroyed. Written authorization must be obtained from the sponsor at study start up before destruction. Written documentation of destruction must contain the following: Identity [batch numbers or subject numbers] of IMPs Quantity of IMPs destroyed Date of destruction Method of destruction 46

47 Name and signature of responsible person [or company] who destroyed investigational products 7. SAFETY INSTRUCTIONS AND GUIDANCE 7.1 Definitions Adverse event According to the International Conference of Harmonisation (ICH), an AE is any untoward medical occurrence in a patient or 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) Recurrence of an intermittent medical condition (e.g., headache) not present at baseline Any deterioration in a laboratory value or other clinical test (e.g., electrocardiogram [ECG], X ray) that is associated with symptoms or leads to a change in study treatment or concomitant treatment or discontinuation from study drug. Serious Adverse Event (SAE) Any untoward medical occurrence that, at any dose: results in death Note: death is an outcome, not an event is life-threatening Note: The term life-threatening refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe. requires inpatient hospitalization or prolongation of existing hospitalization results in persistent or significant disability/incapacity is a congenital anomaly/birth defect is medically significant or requires intervention to prevent one of the outcomes listed above 47

48 The term sudden death should only be used when the cause is of a cardiac origin as per standard definition. The terms death and sudden death are clearly distinct and must not be used interchangeably. The study will adhere to the full requirements of the ICH Guideline for Clinical Safety Data Management, Definitions and Standards for Expedited Reporting, Topic E2 (see Appendix 2 GCP guidelines) For the purposes of this study, the following are not considered a SAE: Elective hospitalizations or surgical procedures that are a result of a patient s preexisting condition(s) which have not worsened since receiving study medication. Examples may include, but are not limited to: cholecystectomy for gallstones, joint replacement surgery, diagnostic testing. Such events must be recorded as AEs on the ecrf but are not considered SAEs. Hospitalization for exacerbations of articular/periarticular manifestations of RA. Such events must be recorded as AEs on the ecrf but are not considered SAEs. (Hospitalizations for new onset or worsening of extra-articular manifestations of RA should be reported as an SAE.) Hospitalization to receive trial medication such as infusions of TCZ unless this is prolonged (more than 24 hours). Adverse Event of Special Interest (AESI) The sponsor may identify AESI from toxicology, other non-clinical and existing clinical data, or from experiences with similar compounds that require special collection and reporting arrangements. AESI can be non-serious as well as serious. AESI defined in this section will be identified as AEs that must be collected and reported as per the SAE reporting requirements. The following Adverse Events of special interest have been identified with tocilizumab:: o Infections including all opportunistic infections and non-serious infections as defined by those treated with IV anti-infectives o Myocardial Infarction/ Acute Coronary Syndrome o Gastrointestinal perforations and related events o Malignant neoplasms o Anaphylaxis/Hypersensitivity reactions o Demyelinating disorders o Stroke o Bleeding events o Hepatic events All clinical AEs encountered during the study will be reported on the AE page of the ecrf. 48

49 Intensity Intensity of AEs will be graded on a 3-point scale [mild, moderate, severe,] and reported in detail on the ecrf. Mild Moderate Severe discomfort noticed but no disruption of normal daily activity. discomfort sufficient to reduce or affect daily activity. inability to work or perform normal daily activity Causality Relationship of the AE to the treatment should always be assessed by the investigator. The causality relationship will be assessed by the investigator as either YES or NO. The following criteria should be considered in order to assess the relationship. YES AE is related to the drug If there is a plausible temporal relationship between the onset of the AE and the administration of the drug, and the AE cannot be readily explained by the subject s clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to the drug; and/or the AE abates or resolves upon discontinuation or the drug or dose reduction and, if applicable, reappears upon re-challenge. NO The AE is not related to the drug If clear evidence exists that the AE has an etiology other than the drug (e.g. preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal relationship to administration of the study drug; and/or does not follow a known pattern of response to the drug; and/or does not reappear or worsen when the drug is readministered Laboratory Test Abnormalities Laboratory test results will be recorded on the laboratory results eform of the ecrf. Any laboratory result abnormality fulfilling the criteria for a serious adverse event [SAE] should be reported as such, in addition to being recorded as an AE in the ecrf. Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., meeting one or more of the following conditions, should be recorded as a single diagnosis on the AE eform in the ecrf: Accompanied by clinical symptoms Leading to a change in study medication [e.g. dose modification, interruption or permanent discontinuation] Requiring a change in concomitant therapy [e.g. addition of, interruption of, discontinuation of, or any other change in a concomitant medication, therapy or treatment]. 49

50 This applies to any protocol and non-protocol specified safety and efficacy laboratory result from tests performed after the first dose of study medication, which falls outside the laboratory reference range and meets the clinical significance criteria. This does not apply to any abnormal laboratory result which falls outside the laboratory reference range but which does not meet the clinical significance criteria [these will be analyzed and reported as laboratory abnormalities]; those which are considered AEs of the type explicitly exempted by the protocol; or those which are a result of an AE which has already been reported. Follow-up of Abnormal Laboratory Test Values In the event of medically significant unexplained abnormal laboratory test values, the tests should be repeated and followed up until they have returned to the normal range and/or an adequate explanation of the abnormality is found. If a clear explanation is established it should be recorded on the ecrf. 7.2 Safety Reporting Safety collection period For each subject who has consented and enrolled in the study, the timeframe for collection and reporting of AE/SAE/AESI/pregnancy begins from the time of consent and enrollment until end of follow-up, loss to follow-up, withdrawal of consent, or death. AEs, especially those for which the relationship to study medication(s) is not unrelated, should be followed up until they have returned to baseline status or stabilized. If after follow-up, return to baseline status or stabilization cannot be established an explanation should be recorded on the ecrf. All related new AEs are reported regardless of last dose of study medication and all unrelated new AEs are reported if within 3 months since last dose of study medication Related Serious Adverse Events MUST be collected and reported regardless of the time elapsed from the last study drug administration, even if the study has been closed. Unrelated Serious Adverse Events must be collected and reported during the study and for up to 3 months after the last dose of study medication. Collection of AEs AEs, both non-serious and serious, are documented by the study personnel on the AE pages of the ecrf. Reporting of Serious Adverse Events [immediately reportable] Any SAE/AESI/pregnancy, regardless of relationship to the study drug and treatment arm, must be reported to Roche within 24 hours of the investigator becoming aware of 50

51 the event on the Roche SAE reporting form and forward it to the SAE Responsible. For follow-up information for these events the same timeline is applicable. Safety data will be monitored at least every 3-4 months by a medical monitor. Exact procedures for handling all collected and reported AE/SAE/AESI/pregnancy are described in the Safety Plan Reporting of Adverse Events of Special Interest AESIs are required to be reported by the Investigator to the Sponsor within 24 hours after learning of the event. GQs have been prepared for the potential and identified risks listed above. The GQs are to be used regardless of whether the AESI is serious or nonserious (including non-serious infections). AESIs are to be reported manually via paper based GQs, and according to the most recent ACTEMRA (tocilizumab) Events of Special Interest Guidance Document Pregnancy A female subject must be instructed to stop taking the study medication and immediately inform the investigator if she becomes pregnant during the study. The investigator should report all pregnancies within 24 hours to the sponsor. The investigator should counsel the subject, discuss the risks of continuing with the pregnancy and the possible effects on the fetus. Monitoring of the patient should continue until conclusion of the pregnancy. Pregnancies occurring up to 90 days after the completion of the study medication must also be reported to the investigator. Pregnancy occurring in the partner of a male subject participating in the study should be reported to the investigator and the sponsor. The partner should be counseled, the risks of continuing the pregnancy discussed, as well as the possible effects on the fetus. 7.3 Warnings and Precautions Opportunistic Infections and Serious Infections Though rarely reported within the TCZ program due to exclusion criteria at study entry, reactivation of viral and other serious infections (e.g. EBV or TB) has been observed with biologic therapies for RA, including TCZ. Physicians should exercise caution when considering the use of TCZ in patients with a history of recurring infection or with underlying conditions (eg diabetes) which may predispose patients to infections. Tocilizumab should not be administered in patients with active infection. The effects of TCZ on 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 is recommended for patients receiving biologic agents for treatment of moderate to severe RA as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reaction. Patients must be instructed 51

52 to contact their physician immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment. If a patient develops a serious infection, administration of TCZ is to be interrupted until the infection is controlled. The clinician should consider the benefit-risk before resuming treatment with tocilizumab. Gastrointestinal (GI) Perforations Timely diagnosis and appropriate treatment may reduce the potential for complications of diverticulitis and thus reduce the risk of GI perforations. Therefore, patients should be made aware of the symptomatology 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 perforations, the clinician should consider the benefit-risk before using TCZ. Discontinuation of TCZ is recommended for patients who develop GI perforations. Haematologic Abnormalities and Bleeding Events Decreases in neutrophil and platelet counts have been observed following treatment with TCZ in combination with MTX. In addition, there may be an increased risk of neutropenia in patients who have previously been treated with a TNF antagonist. The risk mitigation strategies for neutropenia and thrombocytopenia are summarized in chapter 6.2. For patients with concomitant medications associated with haematologic toxicity, the reduction or interruption of the suspected medication is recommended prior to modifying TCZ. Hypersensitivity / Anaphylaxis An infusion reaction is defined as an adverse event occurring during and within 24 hours after the infusion or subcutaneous injection 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, hypotension or hypertension. Healthcare professionals administering TCZ infusions should be trained in the appropriate administrative 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 TCZ. 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, administration of TCZ must be discontinued permanently. The patient should be treated 52

53 according to the standard of care for management of the hypersensitivity reaction. Serum for anti-tcz antibody testing will be taken in any cases of anaphylaxis or serious hypersensitivity events and any hypersensitivity event (including non-serious events) that leads to treatment withdrawal (at the time of the event and at least 6 weeks after the event). Active Hepatic Disease, Elevated Liver Enzymes and Hepatic Events Treatment with TCZ, particularly when administered concomitantly with MTX, may be associated with elevations in hepatic transaminases. Therefore, caution should be exercised when considering treatment of patients with active hepatic disease or hepatic impairment. The risk mitigation strategy for elevated liver enzymes and hepatic events is described in section 6.2. Cardiovascular Events and Elevated Lipids Patients with RA have an increased risk for cardiovascular disorders. Therefore, risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia) should be managed as part of their standard of care. Malignancies 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 TCZ, malignancies have been identified as a concern for other biologics. It is recognized that identification of such events in TCZ-treated patients may require a longer period of surveillance. TCZ 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). Demyelinating Disorders The impact of treatment with TCZ 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 TCZ in patients with pre-existing or recent onset demyelinating disorders. Treatment with tocilizumab should be interrupted during assessment of a potential demyelination event and only resumed if the benefit of continuing study drug is favorable. Viral Reactivation Though rarely reported within the TCZ program due to exclusion criteria at study entry, reactivation of viral and other serious infections (e.g. EBV or TB) has been observed with biologic therapies for RA, including TCZ Ongoing assessment of safety Safety will be monitored continuously by the study sponsor. Particular attention will be paid to safety-related study discontinuations: if 15 or more discontinuations will occur in the first 50 enrolled patients within the first 6 months, or if the discontinuation rate will 53

54 exceed 20% at any time when at least 100 patients will be included, a team including at least the PI, the Roche Clinical Science Leader, Medical Monitor and the study statistician will review the cases in a blinded manner and decide if an independent DSMB should be appointed to review data and have access to unblinded information. The decisions of the team will be documented. 8. STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN The following is an outline of the statistical methodology that will be used to analyze this study. A more detailed description will be provided in a separate statistical analysis plan (SAP) which may also include additional exploratory analyses not explicitly mentioned in the following sections. The SAP will be finalized before closure of the study database and deviations from the SAP will be reported and justified in the clinical study report. 8.1 Primary and Secondary Study Endpoints Primary Endpoints Primary endpoint of the present study is the sustained remission rate (SRR), i.e. the proportion of patients with early RA who achieve sustained remission. In individual patients, sustained remission is considered to be achieved if an uninterrupted period of approximately 6 months (at least 23 weeks) can be identified, over which: At least 6 DAS28 values are available, including one at the beginning and one at the end of the period All values are <2.6 with no more than 4 swollen joints, with the exception of up to 2 values which can be between 2.6 and Secondary Endpoints DAS28 remission rate at each schedule visit Time to first DAS28 remission, cumulative remission rates and duration of remissions. Change from baseline in DAS28 at each scheduled visit EULAR response rate at each scheduled visit and time to first EULAR response ACR20, ACR50, ACR70, and ACR90 response rate at each scheduled visit (week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and throughout year 2) and time to first ACR20, ACR50, ACR70 and ACR90 response. Change from baseline in individual parameters of ACR core set at each scheduled visit Measure of progressive joint destruction between baseline and weeks 52 and 104: absolute change from screening in the vdhss Score Proportion of patients between the three treatment strategies who need to change therapy strategy during the study Rate of withdrawals due to lack of sufficient therapeutic response and/or safety Change from baseline in HAQ at each scheduled visit (see table 1) 54

55 Change from baseline in EuroQol questionnaire at each scheduled visit (see table 1) Safety Safety of the treatment will be evaluated by AEs, laboratory tests, vital signs, safetyrelated treatment discontinuations. The following events/parameters are of particular interest: Infections including all opportunistic infections and non-serious infections as defined by those treated with IV anti-infectives Myocardial infarction/acute coronary syndrome Gastrointestinal perforations and related events Malignancies Anaphylaxis/Hypersensitivity reactions Demyelinating disorders Stroke Bleeding events Hepatic events Adverse events leading to withdrawal Changes in ALT (SGPT) and AST (SGOT) and elevations of ALT above 3x the upper limit of normal Increase of liver enzymes leading to a change in treatment Changes in serum total cholesterol, LDL cholesterol and HDL cholesterol Change in absolute neutrophil count and values < 1.0 x 10 9 /l, change in neutrophil count and thrombocyte count, and in particular values < 100 x /l Discontinuation of TCZ or blinded MTX / placebo or other DMARDs because of AE(s) Discontinuation of TCZ or blinded MTX / placebo or other DMARDs for any reason other than remission 8.2 Statistical and Analytical Methods Statistical Model Primary Variables The SRR will be compared between treatment groups by means of the Cochrane- Mantel-Haenszel test taking into account the stratification factors used for randomization. Supporting evaluations will use logistic regression models including group, center, baseline DAS28, gender and possibly other explanatory variables defined in the SAP prior to analysis. Secondary Variables Secondary endpoint will be analyzed by presenting summary statistics and graphical displays. In addition, exploratory between-group comparisons for secondary variables will be carried out based on the following methods (specified in more detail in the SAP): 55

56 The change from baseline in DAS28, Sharp/van der Heijde Score and similar variables that can be regarded as continuous will be submitted to an analysis of covariance including the factors described above or an appropriate non-parametric alternative (e.g. the Kruskal-Wallis test). The time course of DAS28 will be submitted to a repeated measures analysis of variance if appropriate. Binary response variables will be analyzed using the Cochrane Mantel-Haenszel test or in selected cases using logistic regression following the rules specified for the primary analysis. Time to event variables will be analyzed using the Kaplan-Meier method and comparisons of treatment groups will be performed using the log rank test Hypothesis Testing The analysis of the primary efficacy endpoint will be based on pair-wise comparisons of the rate (proportion) of patients achieving a sustained remission rate between the treatment groups. The three resulting null-hypotheses are: H 0,1 : SRR TCZ + MTX = SRR placebo + MTX (Group I vs. III: combination vs. MTX) H 0,2 : SRR TCZ + placebo = SRR placebo + MTX (Group II vs. III: TCZ vs. MTX) H 0,3 : SRR TCZ + MTX = SRR TCZ+ placebo (Group I vs. II: combination vs. TCZ) The three corresponding alternatives are that there is a difference between the response rates, i.e. two-sided tests will be carried out. According to the principle of the a-priori ordered hypotheses, H 0,1 will be tested and if it can be rejected H 0,2 will be tested. In case of rejection of H 0,2, H 0,3 will be tested. All tests will conducted at the significance level α=5%. This procedure limits the family-wise error rate at 5% for the primary endpoint. All other tests, including those of secondary endpoints, will be exploratory and will be carried out at the α=5% significance level without correction for multiplicity and corresponding 95% confidence intervals will be reported as appropriate Analysis Populations The primary analysis population for efficacy will be the ITT population. For the primary efficacy variable and selected secondary variables an analysis based on the PP population will be performed to confirm the findings from the ITT population Efficacy Analysis Exclusion of Data from Analysis ITT population: All subjects randomized will be included in the ITT population, if at least one dose of study medication was administered/taken at least one efficacy measurement was performed. Subjects will be assigned to treatment groups as randomized for analysis purposes. 56

57 Per-protocol population: The per-protocol population will be defined as the subset of the intent-to-treat population defined by the following exclusions: Violation of inclusion or exclusion criteria Withdrawal from the study before month 9 Other criteria will be detailed in the SAP Subjects will be assigned to treatment groups as treated for analysis purposes Safety Data Analysis The safety analysis population will include all subjects who receive at least one dose and had at least one safety assessment. All safety parameters will be summarized and presented in tables based on this safety population. All study emergent AEs will be listed and summarized. Descriptive statistics will be provided for the incidence of AEs, which will be listed and summarized by preferred term and system organ class. Vital signs (e.g. blood pressure) and physical examinations will be listed and summarized in a descriptive manner. Laboratory data will be analyzed and described as follows: listing, counting of values out of the reference value range, counting of marked abnormalities as defined in the SAP. Shift tables and shift plots will be used to evaluate categorical changes in clinical laboratory parameters by examining the proportion of patients whose test values are outside the specific ranges Other Analyses Quality of Life Analysis Quality of life assessments will be used to derive pre-specified QoL scores according to the QoL manual. These scores will be summarized by descriptive summary tables at baseline and over time. The overall health score will be further analyzed for the assessment at 52 weeks and the end of treatment with baseline and treatment as covariates in an analysis of covariance model. Pharmacoeconomic evaluations, such as those based on a Dutch Healthcare resource use and work participation questionnaire, will be reported separately from the clinical study data. Exploratory analyses Biomarkers, mrna analyses and phenotyping of mononuclear cells obtained from blood will be used in exploratory analyses to determine their predictive value with respect to remission and other clinically relevant variables. Descriptive statistics and modeling techniques will be used as appropriate. 57

58 8.2.7 Sample Size The assumptions regarding the primary efficacy endpoint for the present sample size calculations are based on the studies by Maini et al. (18), that tested MTX and tocilizumab in different dosages and combinations on MTX inadequate responders, Verstappen et al. (1), investigating intensive MTX treatment in early RA, as well as unpublished results from the tocilizumab registration program of Roche, in particular on early RA patients treated in the AMBITION study. The SRR in the combination group (Group I) is expected to be 42-47%, under tocilizumab monotherapy (Group II), 35-40% and under tightly controlled MTX monotherapy (Group III) it is assumed to be 23%. Because the primary endpoint of this investigation has not been used in previous studies, there is some uncertainty about these assumptions. Under the assumption of SRR=47% under TCZ + MTX combination therapy a sample size of 100 patients per group provides a power of 95% to detect a difference between this treatment and MTX monotherapy (Group I vs. III) at the 5% level using the Cochrane-Mantel-Haenszel test (i.e. to reject H 0,1 ). In case of SRR=42% in the combination group, the power would be 82%. Assuming that TCZ monotherapy leads to at least 15% more responses than MTX, the probability of detecting a difference between the two monotherapy arms would vary between 64% and 74%, (SRR in Group II = 40% and 38%, respectively), without considering the sequential testing procedure and the fact that the two tests are not independent. The power to reject the third nullhypothesis (comparison of TCZ+MTX combination and TCZ monotherapy) is expected to be low depending on the assumptions: if the addition of MTX to TCZ confers at least 8% more responses, it is expected to vary between 21% and 40%. The uncertainty with the expected outcomes and the interest in a reasonable power also for the comparison of the two monotherapy arms justifies the choice of recruiting 100 patients per group, i.e. 300 patients in total. 9. DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE The overall procedures for quality assurance of clinical study data are described in the Roche Standard Operational Procedures. Data for this study will be recorded via an Electronic Data Capture (EDC) system using electronic Case Report Forms. It will be transcribed by the site from the paper source documents onto the ecrf. Accurate and reliable data collection will be assured by verification and cross check of the ecrfs against the investigator s records by the study monitor (source document verification), and the maintenance of a drug dispensing log by the investigator. A comprehensive validation check program utilizing front-end checks in the ecrf and back-end checks in the Roche database will verify the data and discrepancies will be generated accordingly. These are transferred electronically to the ecrf at the site for resolution by the investigator. 58

59 Throughout the study the study management team will review data according to the Data Review Plan as described in the Data Quality Plan. Each of the participating institutes is responsible for adequate study documentation in the ecrf according to the regulations for this study provided by Roche. Roche is responsible for record keeping. The UMC Utrecht has at all-time direct and unlimited access to the ecrfs and database. At the end of the study, all crude data become electronically at the disposal of the UMC Utrecht for purposes of statistical analyses and medical writing. UMC Utrecht has the lead in analyzing the data and in publishing the results. 9.1 Assignment of Preferred Terms and Original Terminology For classification purposes, preferred terms will be assigned by the Sponsor to the original terms entered on the ecrf, using the most up-to-date version of the Medical Dictionary for Regulatory Activities (MedDRA) terminology for adverse events and diseases. 59

60 10. REFERENCES 1. Silman AJ. Epidemiology and the rheumatic diseases. In: Maddison PJ, Isenberg DA, Woo P, Glass DN, eds. Oxford Textbook of Rheumatology: Oxford: Oxford University Press; 1993: Bijlsma JWJ, Weinblatt ME. Optimal use of methotrexate: the advantages of tight control. Ann Rheum Dis 2007; 66: Bakker FM, Jacobs JWG, Verstappen SMM, Bijlsma JWJ. Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility. Ann Rheum Dis 2007; 66: iii Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC,et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, MacFarlane JD, et al. The therapeutic efficacy of multiple intravenous infusions of anti-tumour necrosis factor α monoclonal antibody combined with low dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41: Haagsma CJ, van Riel PLCM, de Jong AJL, van de Putte LBA. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: A randomized, controlled, double-blind, 52-week clinical trial. Br J Rheumatol 1997; 36: Kalden JR, Smolen JS, Emery P, van Riel PL, Dougados M, Strand CV, et al. Leflunomide in combination therapy. J Rheumatol Suppl 2004; 71: Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, Siri DA, Tomsic M, Alecock E, Woodworth T, Genovese MC. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The AMBITION study. Ann Rheum Dis Mar 17. [Epub ahead of print] 9. Verstappen SMM, Jacobs JWG, vander Veen MJ et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Ann Rheum Dis 2007: 66: Nishimoto N, Kishimoto T. Interleukin 6: from bench to bedside. Nat Clin Pract Rheumatol 2006; 2(11): Guerne PA, Desgeorges A, Jaspar JM, Relic B, Peter R, Hoffmeyer P et al. Effects of IL-6 and its soluble receptor on proteoglycan synthesis and NO release by human articular chondrocytes: comparison with IL-1. Modulation by dexamethasone. Matrix Biol 1999; 18: Nietfeld JJ, Wilbrink B, Helle M, van Roy JL, Den OW, Swaak AJ et al. Interleukin-1- induced interleukin-6 is required for the inhibition of proteoglycan synthesis by interleukin-1 in human articular cartilage. Arthritis Rheum 1990; 33:

61 13. Nietfeld JJ, Duits AJ, Tilanus MG, van den Bosch ME, Den OW, Capel PJ et al. Antisense oligonucleotides, a novel tool for the control of cytokine effects on human cartilage. Focus on interleukins 1 and 6 and proteoglycan synthesis. Arthritis Rheum 1994; 37(9): Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T et al. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J Exp Med 2007; 204(1): Koenders MI, Lubberts E, van de Loo FA, Oppers-Walgreen B, van den BL, Helsen MM et al. Interleukin-17 acts independently of TNF-alpha under arthritic conditions. J Immunol 2006; 176(10): Wong PK, Quinn JM, Sims NA, van NA, Campbell IK, Wicks IP. Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum 2006; 54(1): Sawa S, Kamimura D, Jin GH, Morikawa H, Kamon H, Nishihara M et al. Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells. J Exp Med 2006; 203(6): van Roon JA, Hartgring SA, Wenting-van Wijk M, Jacobs KM, Tak PP, Bijlsma JW et al. Persistence of IL-7 activity and IL-7 levels upon TNF& [alpha] blockade in patients with rheumatoid arthritis. Ann Rheum Dis Weitzmann MN, Cenci S, Rifas L, Brown C, Pacifici R. Interleukin-7 stimulates osteoclast formation by up-regulating the T-cell production of soluble osteoclastogenic cytokines. Blood 2000; 96(5): De Benedetti F, Massa M, Pignatti P, Kelley M, Faltynek CR, Martini A. Elevated circulating interleukin-7 levels in patients with systemic juvenile rheumatoid arthritis. J Rheumatol 1995; 22(8): Maini RN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G, et al. CHARISMA Study Group. 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: Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebocontrolled, randomised trial. Lancet 2008; 371: Genovese M, McKay J, Nasonov E, Mysler E, da Silva N, Alecock E, et al. IL-6 receptor inhibition with tocilizumab reduces disease activity in patients with rheumatoid arthritis with inadequate response to a range of DMARDs: The TOWARD Study. ACR Annual Meeting 2007; Presentation L15. 61

62 24. Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J. 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 placebocontrolled trial. Ann Rheum Dis Nov;67(11): J. Kremer, R. Fleischmann, J. Brzezicki, P. Ambs, E. Alecock, R. Burgos-Vargas, A. Halland. Tocilizumab inhibits structural joint damage, improves physical function, and increases DAS28 remission rates in RA patients who repond inadequately to methotrexate: the LITHE study. Oral presentation OP-0157, EULAR 2009, Kopenhagen 26. Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 2004; 50(6): Choy E. Clinical experience with inhibition of interleukin-6. Rheum Dis Clin North Am May;30(2):405-15, viii. 28. Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther. 2006;8 Suppl 2:S van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol Jan;27(1): Zee, Karen I. van der, Het meten van de algemene gezondheidstoestand, met de RAND36 : een handleiding / Karen I. van der Zee, Robbert Sanderman. - Groningen : Noordelijk, Centrum voor Gezondheidsvraagstukken, RAND 62

63 Part II: ethics and General Study Administration 11. ETHICAL ASPECTS 11.1 Local Regulations/Declaration of Helsinki The investigator will ensure that this study is conducted in full conformance with the principles of the Declaration of Helsinki or with the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study must fully adhere to the principles outlined in Guideline for Good Clinical Practice ICH Tripartite Guideline or with local law if it affords greater protection to the subject. For studies conducted in the EU/EEA countries, the investigator will ensure compliance with the EU Clinical Trial Directive [2001/20/EC]. For studies conducted in the USA or under US IND, the investigator will additionally ensure adherence to the basic principles of Good Clinical Practice as outlined in the current version of 21 CFR, subchapter D, part 312, Responsibilities of Sponsors and Investigators, part 50, Protection of Human Subjects, and part 56, Institutional Review Boards. In other countries where a Guideline for Good Clinical Practice exists, Roche and the investigators will strictly ensure adherence to the stated provisions Informed Consent Written Informed Consent from Subjects: It is the responsibility of the investigator, or a person designated by the investigator, to obtain signed informed consent from each subject prior to participating in this study after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. For the subject not qualified or incapable of giving legal consent, written consent must be obtained from the legally acceptable representative. In the case where both the subject and his/her legally acceptable representative are unable to read, an impartial witness should be present during the entire informed consent discussion. After the subject and representative have orally consented to participation in the trial, the witness signature on the form will attest that the information in the consent form was accurately explained and understood. The investigator or designee must also explain that the subjects are completely free to refuse to enter the study or to withdraw from it at any time, for any reason. The electronic Case Report Forms (ecrfs) for this study contain a section for documenting subject informed consent, and this must be completed appropriately. If new safety information results in significant changes in the risk/benefit assessment, the consent form should be reviewed and updated if necessary. All subjects (including those already being treated) should be informed of the new information, given a copy of the revised form and give their consent to continue in the study. In a life-threatening situation where a patient is unconscious or otherwise unable to communicate, the emergency is such that there is not enough time to obtain consent from the patient's legally acceptable representative, and there is no other or better treatment available, it is permissible to treat the patient under protocol with consent of the investigator, with appropriate documentation that the IEC had approved the 63

64 procedures used to enroll patients in such situations. In addition, the patient or his/her legally acceptable representative should be informed about the trial as soon as possible and consent to continue, giving written consent as described above Independent Ethics Committees Independent Ethics Committees (IECs) For EEA member states, the sponsor will submit to the Competent Authority and Ethics Committees the protocol and any accompanying material provided to the subject (such as subject information sheets or descriptions of the study used to obtain informed consent as well as any advertising or compensation given to the subject). Approval from the committee must be obtained before starting the study, and should be documented in a letter to the investigator specifying the date on which the committee met and granted the approval. Any modifications made to the protocol after receipt of the IEC s approval must be resubmitted by the investigator in the US and by the Sponsor in the EEA member states in accordance with local procedures and regulatory requirements. When no local review board exists, the investigator is expected to submit the protocol to a regional committee. If no regional committee exists, Roche will assist the investigator in submitting the protocol to the European Ethics Review Committee. 12. CONDITIONS FOR MODIFYING THE PROTOCOL Requests from investigators to modify the protocol to ongoing studies will be considered only by consultation between an appropriate representative of the sponsor and the investigator [investigator representative[s] in the case of a multicenter trial]. Protocol modifications must be prepared by a representative of the sponsor and initially reviewed and approved by the Clinical Science Leader. All protocol modifications must be submitted to the appropriate Independent Ethics Committee for information and approval in accordance with local requirements, and to Regulatory Agencies if required. Approval must be obtained before any changes can be implemented, except for changes necessary to eliminate an immediate hazard to trial subjects, or when the change[s] involves only logistical or administrative aspects of the trial [e.g. change in monitor[s], change of telephone number[s]. 13. CONDITIONS FOR TERMINATING THE STUDY Both the sponsor and the investigator reserve the right to terminate the study at any time. Should this be necessary, both parties will arrange the procedures on an individual study basis after review and consultation. In terminating the study, Roche and the investigator will assure that adequate consideration is given to the protection of the subjects interests. 64

65 14. STUDY DOCUMENTATION, ECRFS AND RECORD KEEPING 14.1 Investigator's Files / Retention of Documents The Investigator must maintain adequate and accurate records to enable the conduct of the study to be fully documented and the study data to be subsequently verified. These documents should be classified into two different separate categories [1] Investigator's Study File, and [2] subject clinical source documents. The Investigator's Study File will contain the protocol/amendments, DCS and schedule of assessments, Independent Ethics Committee/Institutional Review Board and governmental approval with correspondence, sample informed consent, drug records, staff curriculum vitae and authorization forms and other appropriate documents/correspondence, etc. 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, query resolution correspondence and reasons for changes, in human readable format on CD which also has to be kept with the Investigator s Study File. Subject clinical source documents [usually defined by the project in advance to record key efficacy/safety parameters independent of the ecrfs] would include subject hospital/clinic records, physician's and nurse's notes, appointment book, original laboratory reports, ECG, EEG, X-ray, pathology and special assessment reports, signed informed consent forms, consultant letters, and subject screening and enrollment logs. The Investigator must keep these two categories of documents (including the archival CD) on file for at least 15 years after completion or discontinuation of the study. After that period of time the documents may be destroyed, subject to local regulations. Should the Investigator wish to assign the study records to another party or move them to another location, Roche must be notified in advance. If the Investigator can not guarantee this archiving requirement at the investigational site for any or all of the documents, special arrangements must be made between the Investigator and Roche to store these in a sealed container[s] outside of the site so that they can be returned sealed to the Investigator in case of a regulatory audit. Where source documents are required for the continued care of the subject, appropriate copies should be made for storing outside of the site Source Documents and Background Data The investigator shall supply the sponsor on request with any required background data from the study documentation or clinic records. This is particularly important when errors in data transcription are suspected. In case of special problems and/or governmental queries or requests for audit inspections, it is also necessary to have access to the complete study records, provided that subject confidentiality is protected Audits and Inspections The investigator should understand that source documents for this trial should be made available to appropriately qualified personnel from the Roche Pharma Development Quality Assurance Unit or its designees, or to health authority inspectors after 65

66 appropriate notification. The verification of the ecrf data must be by direct inspection of source documents Electronic Case Report Forms Data for this study will be captured via an Electronic Data Capture (EDC) system by using ecrfs. An audit trail will maintain a record of initial entries and changes made; reasons for change; time and date of entry; and user name of person authorizing entry or change. For each subject enrolled, an ecrf must be completed and electronically signed by the principal investigator or authorized delegate from the study staff. This also applies to records for those patients who fail to complete the study [even during a prerandomization screening period if an ecrf was initiated]. If a patient withdraws from the study, the reason must be noted on the ecrf. If a patient is withdrawn from the study because of a treatment-limiting AE, thorough efforts should be made to clearly document the outcome. The investigator should ensure the accuracy, completeness and timeliness of the data reported to the sponsor in the ecrfs and in all required reports. 15. MONITORING THE STUDY It is understood that the responsible Roche monitor [or designee] will contact and visit the investigator regularly and will be allowed, on request, to inspect the various records of the trial [ecrfs and other pertinent data] provided that subject confidentiality is maintained in accord with local requirements. It will be the monitor's responsibility to inspect the ecrfs at regular intervals throughout the study, to verify the adherence to the protocol and the completeness, consistency and accuracy of the data being entered on them. The monitor should have access to laboratory test reports and other subject records needed to verify the entries on the ecrf. The monitor must verify that the subject received the study drug assigned by the pharmacist and must verify if the correct randomization procedure has been followed. The investigator [or deputy] agrees to cooperate with the monitor to ensure that any problems detected in the course of these monitoring visits are resolved. 16. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS The investigator must assure that subjects anonymity will be maintained and that their identities are protected from unauthorized parties. On ecrfs or other documents submitted to the sponsor, subjects should not be identified by their names, but by an identification code. The investigator should keep a subject enrollment log showing codes, names and addresses. The investigator should maintain documents not for submission to Roche, e.g., subjects written consent forms, in strict confidence. 17. 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 66

67 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. In accordance with standard editorial and ethical practice, Roche will support publication of this U-ACT-EARLY trial only in their entirety and not as individual center data. In this case, professor Johannes Bijlsma as principal investigator has been designated by mutual agreement. Any formal publication of the study in which input of Roche personnel exceeded that of conventional monitoring will be considered as a joint publication by the investigator and the appropriate Roche personnel. Authorship will be determined by mutual agreement. 67

68 18. APPENDICES 68

69 18.1 Appendix 2 - ICH Guidelines for Clinical Safety Data Management, Definitionsand Standards for Expedited Reporting, Topic E2 A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution. It is any AE that at any dose fulfills at least one of the following criteria: is fatal; [results in death] [NOTE: death is an outcome, not an event] is Life-Threatening [NOTE: the term "Life-Threatening" refers to an event in which the patient was at immediate risk of death at the time of the event; it does not refer to an event which could hypothetically have caused a death had it been more severe]. requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above Medical and scientific judgment should be exercised in deciding whether expedited reporting to the sponsor is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the outcomes listed in the definitions above. These situations should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse. An unexpected AE is one in which the nature or severity is not consistent with the applicable product information. Causality is initially assessed by the investigator. For Serious Adverse Events, possible causes of the event is indicated by selecting one or more options. (Check all that apply) Pre-existing/Underlying disease - specify Study treatment specify the drug(s) related to the event Other treatment (concomitant or previous) specify Protocol-related procedure Other (e.g. accident, new or intercurrent illness) - specify 69

70 The term severe is a measure of intensity, thus a severe AE is not necessarily serious. For example, nausea of several hours' duration may be rated as severe, but may not be clinically serious. [Cont.] A serious adverse event occurring during the study or which comes to the attention of the investigator within 15 days after stopping the treatment or during the protocol-defined follow-up period, if this is longer, whether considered treatment-related or not, must be reported. In addition, a serious adverse event that occurs after this time, if considered related to the study drugs, should be reported. Such preliminary reports will be followed by detailed descriptions later which will include copies of hospital case reports, autopsy reports and other documents when requested and applicable. For serious adverse events, the following must be assessed and recorded on the AEs eform of the ecrf: intensity, relationship to test substance, action taken, and outcome to date. The investigator must notify the Ethics Review Committee/Institutional Review Board of a serious adverse event in writing as soon as is practical and in accordance with international and local laws and regulations. ROCHE LOCAL COUNTRY CONTACT for SAEs: Local Monitor See details of administrative and contact information provided by the monitor. ROCHE HEADQUARTERS CONTACT for SAEs and other medical emergencies: Clinical Operations/Clinical Science See details of administrative and contact information provided by the monitor. MEDICAL COVERAGE: please call the appropriate emergency contact person, details will be provided by the monitor. 70

71 18.2 Appendix 3 Questionnaires Dutch consensus HAQ FACIT- fatigue IPQR SF VAS pain and general wellbeing questionnaires Dutch Healthcare resource use and work participation questionnaire EuroQol 71

72 Dutch consensus Health assessment questionnaire (DC-HAQ) 72

73 73