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 |
To demonstrate the efficacy of ofatumumab in reducing clinical signs and symptoms in adult RA patients after a single course of ofatumumab |
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E.2.2 | Secondary objectives of the trial |
1) To evaluate long-term efficacy of repeated courses of ofatumumab 2) To evaluate the effect on biomarkers of clinical response after single and repeated courses of ofatumumab 3) To evaluate ofatumumab with respect to impact on patient reported outcomes after single and repeated courses of ofatumumab 4) To evaluate the risk of host immune response against ofatumumab after single and repeated courses of ofatumumab 5) To evaluate the safety of ofatumumab after single and repeated courses of ofatumumab
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Age ≥ 18 years 2) A diagnosis of rheumatoid arthritis according to the American College of Rheumatology (ACR1987 classification) of at least six months’ duration from diagnosis at screening 3) Active disease at the time of screening as defined by: - ≥ 8 swollen joints (of 66 joints assessed) and - ≥ 8 tender joints (of 68 joints assessed) and - C-Reactive Protein (CRP) ≥ 1.0 mg/dL or Erythrocyte Sedimentation Rate (ESR) ≥ 22 mm/hour and - DAS28≥3.2 (based on ESR) Note: The swollen and tender joints must be reassessed at baseline (Visit 2) to ensure these eligibility criteria are fulfilled prior to randomization. Where possible joint count reassessment must be performed at the baseline visit (Visit 2); if this is not possible it can be performed ≤ 3 days prior to Visit 2. 4) RA functional class I, II or III 5) Inadequate response to previous or current methotrexate treatment defined as: i) Inadequate efficacy according to the investigator’s judgment following at least 12 weeks of treatment receiving at least 15 mg methotrexate per week and/or ii) Intolerance defined as one or more side effects during treatment with at least 15 mg per week for at least two weeks, that reasonably results in the discontinuation or reduction in dose of methotrexate 6) Treatment with methotrexate (MTX), 7.5-25 mg/week, for at least 12 weeks and at a stable dose for at least 4 weeks prior to Visit 2. Doses of MTX as low as 7.5mg per week are permitted for patients who could not tolerate higher doses 7) Following receipt of verbal and written information about the study, the patient must provide signed informed consent before any study related activity including wash-out of other drug products is carried out France: In France, a patient will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
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E.4 | Principal exclusion criteria |
1) Patients with a history of a rheumatic autoimmune disease other than RA (except secondary Sjögren's syndrome) or with significant systemic involvement secondary to RA (vasculitis, pulmonary fibrosis or Felty's syndrome) 2) Previous exposure to biologic anti-rheumatic therapies (with exceptions specified in (3)), including investigational compounds (e.g. anti-CD11a, anti-CD19, anti-CD20, anti-CD22, anti-BLyS/BAFF, anti-CD3, anti-CD4, anti-CD5, CAMPATH, anti-IL6 receptor) 3) Previous exposure to biologic DMARDs 4) Received any of the following treatments within 4 weeks prior to Visit 2: - Anti-cancer therapy (e.g. alkylating agents, anti-metabolites, purine analogues, monoclonal antibodies) - Glucocorticoid unless given in doses equivalent to ≤ 10 mg of prednisolone /day - Intra-articular, i.m. or i.v. corticosteorids - Live/attenuated vaccinations - Cyclosporine - Azathioprine - Penicillamine - Bucillamine - Chloroquine - Hydroxychloroquine - Sulfasalazine 5) Exposure to leflunomide within 12 weeks prior to Visit 2 unless the patient has completed peroral cholestyramine treatment for washout according to manufacturer's instructions and locally accepted clinical practices 6) Exposure to gold therapy ≤ 12 weeks prior to Visit 2 7) Exposure to i.v. immunogammaglobulins ≤ 24 weeks prior to Visit 2 8) Past or current malignant melanoma 9) Past or current malignancy, except for: - Cervical carcinoma Stage 1B or less - Non-invasive basal cell and squamous cell skin carcinoma - Other cancer with a complete response duration of > 5 years 10) Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active hepatitis B and C Note 1) Subjects with screening chest X-ray suggestive of TB without adequate TB treatment documented should be excluded 2) Subjects with positive skin tuberculin test should be excluded if judged at risk of latent TB infection. 11) Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months from screening, congestive heart failure, known QT abnormalities, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities 12) Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral psychiatric disease, or evidence of demyelinating disease 13) History of significant cerebrovascular disease 14) Known HIV positive 15) Screening laboratory values (according to central laboratory): - Hemoglobin < 5.6 mmol/L (9.0 g/dL) - Neutrophils < 2 x 109/ L - Platelets < 100 x 109/ L - Serum IgG < lower limit of normal - S-ALAT > 3.0 times the upper limit of normal - S-AST > 1.5 times the upper limit of normal - S-ALP > 2 times the upper limit of normal - S-creatinine > 133 µmol/L (1.5 mg/dL) 16) Positive serology for hepatitis B (HB) defined in terms of HBsAg, anti-HBc and anti-HBs antibodies: - Patients positive for HBsAg should be excluded - Patients negative for HBsAg and anti-HBs antibody, but positive for anti-HBc antibody should be tested for HB DNA and if positive excluded. Patients with documented vaccination against Hepatitis B (primary and secondary immunization and booster) will be considered negative 17) Positive for Hep C antibody and positive or indeterminant Hep C RIBA immunoblot. 18) Positive plasma / white cell JC Virus (JCV) PCR (either compartment) 19) Known hypersensitivity to components of the investigational medicinal product 20) Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to screening 21) Current participation in any other interventional clinical study 22) Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder) 23) Breast feeding women or women with a positive pregnancy test at screening 24) Women of childbearing potential not willing to use adequate contraception during study and one year after last dose of ofatumumab. Adequate contraception is defined as abstinence, oral hormonal birth control, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device, and male partner sterilization if male partner is sole partner for that patient. 25) Males with female partner of childbearing potential not willing to use condom or abstinence for duration of study. Contraceptive measures should only be discontinued after completion of or withdrawal from the study following advice of the physician prescribing methotrexate and in accordance with local methotrexate label. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Initial double blind period: randomoised, double-blind, parallel group. Extension period: open label |
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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 | 26 |
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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End of trial will be LPLV in follow-up phase which starts after patients complete: week 144 or week 24 evaluations if they either have rescue meds in the double-blind phase or discontinue from treatment for another reason during study. Patients will be followed up every 12 weeks until B cells, IgM and if appropriate IgG, return to LLN or baseline. CSR will be prepared based on the data through study week 144. An addendum will be prepared once all patients have completed the follow up period. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |