E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary Objectives The primary objective of this study is to determine the efficacy and safety of 400 mg ocrelizumab, given as a single infusion, versus placebo, in combination with MTX, to reduce the signs and symptoms of RA at 24 weeks in patients with active RA who currently have an inadequate response to MTX therapy. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives Secondary objectives for this study are as follows: • To investigate and compare the pharmacokinetics and pharmacodynamics of a single and a dual infusion of ocrelizumab in this patient population • To assess the effect of a single infusion of ocrelizumab versus placebo on physical function in this patient population • To compare the safety and efficacy of single versus dual infusion at 24 and 48 weeks |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biomarker project (optional): Samples will be used for research purposes to identify biomarkers that help understand differences in RA disease process and/or ocrelizumab treatment response, in accordance with the Sponsor biomarker strategy. These may include measurement of cytokines and other inflammatory proteins in plasma, as well as analysis of peripheral blood gene expression patterns in the context of disease, drug response, and toxicity.
DNA sample collection: respond to treatment, those most susceptible to adverse events and those most likely to suffer disease progression and to identify genetic risk factors for the underlying disease. Several genetic pathways have been shown to be linked to the development of RA and to response to specific treatments . DNA will be collected in this study under two analysis categories: 1) clinical genotyping, to interrogate for specific genetic markers, and 2) pharmacogenomics, to enable whole genome association analysis for novel genetic markers that segregate with treatment response. |
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E.3 | Principal inclusion criteria |
Patients must meet the following criteria to be eligible for study entry: 1. Ability and willingness to provide written informed consent and to comply with the requirements of the protocol 2. Age ≥ 18 years 3. Current treatment for RA on an outpatient basis 4. Active disease, defined as the following: a. A diagnosis of RA using the American College of Rheumatology (ACR) criteria for RA. b. Swollen joint count (SJC) ≥ 4 (66 joint count) and tender joint count (TJC) ≥ 4 (68 joint count) at screening and baseline c. C-reactive protein (CRP) ≥ 0.6 mg/dL using a high-sensitivity assay or erythrocyte sedimentation rate (ESR) ≥ 28 mm/hour d. Positive rheumatoid factor or positive anti-cyclic citrullinated peptide (CCP) antibody, or both 5. Inadequate clinical response to MTX taken at a dose of 7.5-25 mg/week for at least 12 weeks, with the last 4 weeks prior to baseline at a stable dose 6. The patient must be willing to receive oral folic acid or equivalent. Previous and current treatments (beyond MTX) may include the following: 7. If the patient is receiving current treatment with corticosteroids, the dose must not exceed 10 mg/day of prednisolone or equivalent, and, during the 4 weeks prior to baseline, it must be at a stable dose and remain stable for the duration of the study. 8. If the patient is receiving current treatment with NSAIDs, the patient must be on a stable dose for the 4 weeks prior to baseline and remain stable for the duration of the study. 9. May have experienced an inadequate response to previous or current treatment with other DMARDs and biologics such as etanercept, infliximab, adalimumab, or abatacept because of toxicity or inadequate efficacy. 10. For patients of reproductive potential (males and females), a reliable means of contraception must be used for the duration of the study (e.g., hormonal contraceptive, intrauterine device, physical barrier) according to local guidelines. 11. Female patients of childbearing age must have a negative urine pregnancy test. |
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E.4 | Principal exclusion criteria |
Exclusion criteria related to RA: 1. Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (including, but not limited to, vasculitis, pulmonary fibrosis, or Felty’s syndrome). Patients with secondary Sjögren’s syndrome or secondary limited cutaneous vasculitis with RA are eligible. 2. Functional Class IV as defined by the ACR Classification of Functional Status in RA. 3. History of, or current, inflammatory joint disease other than RA (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune disorder (e.g. systemic lupus erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease, or other overlap syndrome) Exclusion criteria related to general health: 4. Any surgical procedure, including bone or joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to or planned within 48 weeks after baseline. 5. Sepsis in a prosthetic joint within the last 48 weeks or indefinitely if the prosthesis concerned remains in situ 6. Lack of peripheral venous access 7. Pregnancy or lactation 8. Known significant cardiac disease (New York Heart Association [NYHA] Class III and IV). 9. Known severe chronic obstructive pulmonary disease (COPD) (forced expiratory volume in 1 second [FEV1] < 50% predicted or functional dyspnea Grade≥ 3 on the Medical Research Council [MRC] Dyspnea Scale). 10. Evidence of significant uncontrolled concomitant diseases 11. Any neurological (congenital or acquired), psychiatric, vascular, or systemic disorder that could affect any of the efficacy assessments; in particular, joint pain and swelling 12. Uncontrolled disease states where flares are commonly treated with oral or parenteral corticosteroids 13. History of, or currently active, primary or secondary immunodeficiency including known history of HIV infection 14. Known active infection of any kind (excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with intravenous (IV) anti-infectives within 4 weeks prior to baseline or oral anti-infectives within 2 weeks prior to baseline 15. History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis, or septic arthritis of a native joint) within 48 weeks of baseline 16. Evidence of chronic active hepatitis B or C 17. Evidence of active tuberculosis. Patients receiving chemoprophylaxis for latent tuberculosis infection are eligible for the study 18. History of serious recurrent or chronic infections not specified above 19. History of cancer within the last 10 years, including solid tumors and hematologic malignancies and carcinoma in situ (except basal-cell and squamous-cell carcinomas of the skin or carcinoma in situ of the cervix uteri that have been excised and cured) 20. Currently active alcohol or drug abuse or history of alcohol or drug abuse within 24 weeks prior to baseline Exclusion criteria related to medications: 21. History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of ocrelizumab infusion 22. Concurrent treatment with any DMARD except MTX. All DMARDs except MTX should be withdrawn at least 4 weeks prior to baseline (8 weeks for infliximab, adalimumab, or abatacept; 4 weeks for etanercept; and 12 weeks for leflunomide or 4 weeks after 11 days of standard cholestyramine or activated charcoal drug removal) 23. Treatment with any investigational agent 12 weeks prior to baseline or five half-lives of the investigational drug prior to baseline, whichever is longer 24. Previous treatment with any cell-depleting therapies, including investigational agents (e.g., alemtuzumab, anti-CD3, anti-CD4, anti-CD5, anti-CD11a, anti-CD19, anti-CD22, anti-BLys/BAFF, or anti-CD20) 25. Treatment with IV γ-globulin or Prosorba® column (apheresis) within 24 weeks prior to baseline 26. Intra-articular or parenteral corticosteroids within 6 weeks prior to baseline 27. Receipt of any vaccine within 6 weeks prior to baseline. It is recommended that a patient’s vaccination record and the need for immunization prior to receiving ocrelizumab should be carefully reviewed prior to entry in the study 28. Intolerance or contraindications to IV methylprednisolone. Exclusion criteria related to laboratory values at screening: 29. Positive urine pregnancy test 30. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN) 31. Hypogammaglobulinemia (i.e., IgG < 4 mg/mL and/or IgM< 0.4 mg/mL) 32. Absolute neutrophil count < 1500 cells/μL
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint for this study is the proportion of patients with ACR20 responses at 24 weeks. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Please refer to Section 3.1.6 in the Protocol. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |