Rheumatoid Arthritis Clinical Trial
Official title:
Addition of Rituximab to Leflunomide in Patients With Active Rheumatoid Arthritis - a Multicenter Randomised Double-blind Clinical Trial
Verified date | March 2016 |
Source | Johann Wolfgang Goethe University Hospitals |
Contact | n/a |
Is FDA regulated | No |
Health authority | Germany: Paul-Ehrlich-Institut |
Study type | Interventional |
Combination of rituximab (RTX) with several different chemotherapeutic regimes has proven synergistic effects in patients with either lymphoma or autoimmune diseases. First data of uncontrolled trials with the combination of RTX and leflunomide (LEF) are available.
Status | Completed |
Enrollment | 156 |
Est. completion date | February 2015 |
Est. primary completion date | February 2015 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years to 75 Years |
Eligibility |
Inclusion Criteria: Male and female patients, 18 to 75 years of age, with active rheumatoid arthritis (RA) who have had an inadequate response to disease modifying anti-rheumatic drugs, not more than 3 non-biological DMARDs including leflunomide, and not more than one inadequate response to anti-TNF-therapy, and currently have active disease despite at least 3-month treatment with leflunomide. Active disease is defined as DAS 28 >3.2 and at least swollen joint count (SJC) = 3 and tender joint count (TJC) = 3 included in the 28 joint count. - Male and female patients with rheumatoid arthritis for at least 3 months diagnosed according to the revised 1987 ACR criteria for the classification of rheumatoid arthritis. - Willingness and capability to give written informed consent, and willingness to participate and to comply with the study protocol. - Not more than 2 non-biological DMARDs other than leflunomide in history, which are washed out at least 4 weeks prior to first rituximab infusion - Previous use of anti-TNF therapy is allowed. Patient will only be allowed to be pre-treated with a maximum of two anti-TNF therapies and only one stopped due to inadequate response. The second anti-TNF could be stopped for instance due to intolerance, e.g. injection site reactions. Anti-TNF treatment must be discontinued prior to baseline considering the different characteristics of the specific compound: Use of infliximab, adalimumab, certolizumab, golimumab within 8 weeks of baseline, use of etanercept within 4 weeks of baseline. Exclusion Criteria: - RA functional class IV: limited in ability to perform usual self-care, work, and other activities - Male and female patients with other chronic inflammatory articular disease or systemic autoimmune disease - Any active infection, a history of recurrent clinically significant infection, a history of recurrent bacterial infections with encapsulated organisms (Hepatitis B, C and HIV (human immune deficiency virus) - will be tested at screening) - Chronic, latent and acute infections of the lung - Positive result of a Tuberculosis specific Interferon gamma release assay (will be tested at screening) - Primary or secondary immunodeficiency - History of cancer with curative treatment not longer than 5 years ago except basal-cell carcinoma of the skin that had been excised - Evidence of significant uncontrolled concomitant diseases or serious and / or uncontrolled diseases that are likely to interfere with the evaluation of the patient's safety and of the study outcome - Neuropathy that can interfere with filling out the patient's questionnaires - History of a severe psychological illness or condition - Known hypersensitivity to any component of the product or to murine proteins - Severe heart failure (New York Heart Association Class III and IV) or severe,uncontrolled cardiac disease. - Women lactating, pregnant, nursing or of childbearing potential with a positive pregnancy test or planned pregnancy. - Women of childbearing potential without adequate contraception (medically acceptable methods (pearl Index < 1) are contraceptive implant, contraceptive injection, intrauterine device (IUD), or oral contraceptives taken for at least 3 months,which the patient agrees to continue using during the study, or a double-barrier method which must consist of a combination of any of the following: diaphragma,cervical cap, condom, or spermicide) - History of alcohol, drug or chemical abuse (defined as impaired / questionable reliability) as well as neurotic personality. - Participation in another investigational study within 4 weeks prior to the screening visit. - Previous treatment with any B-cell depleting agents including rituximab - Intolerance to ingredients of rituximab or murine proteins - Pre-treatment with abatacept, tocilizumab or other anti-TNF biologicals. - Inadequate response to more than one anti-TNF-therapy - Pre-treatment of more than two anti-TNF, only one is allowed to be stopped due to inadequate response. The second anti-TNF could be stopped due to intolerance, e.g. injection site reactions - Corticosteroids at doses exceeding 10 mg per day of prednisolone or equivalents within the last 2 weeks or corticosteroids at instable doses within the last 2 weeks - Intolerance or contraindication to drugs required for the treatment of the side effects of rituximab - Previous treatment with any investigational medicinal product within last 3 months prior to baseline - Receipt of a live vaccine within 4 weeks prior to treatment - Intra- articular or parenteral corticosteroids within 4 weeks prior to screening visit - Haemoglobin < 8.5 g / dl (equivalent to < 5,28 mmol/l Haemoglobin) - Neutrophil counts < 1.500 / µl (equivalent to 1,5 / nl) - Platelet count < 75.000 / µl (equivalent to 75 / nl) - Lower than 500 / µl (equivalent to 0,5 / nl) lymphocytes - Serum creatinine > 1.4 mg / dl for women or 1.6 mg / dl for men - Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) > 2.5 times upper limit of normal - IgG (immunoglobulin G) level < 5g/l |
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
Germany | Schwerpunktpraxis | Bad Kösen | Sachsen-Anhalt |
Germany | Kerckhoff-Klinik GmbH Abtlg. Rheumatologie und Klin. Immunologie | Bad Nauheim | |
Germany | Rheumazentrum Baden-Baden | Baden-Baden | |
Germany | Praxis Remstedt | Berlin | |
Germany | Rheumaklinik Berlin-Buch Immanuel Krankenhaus | Berlin | |
Germany | Schlosspark-Klinik | Berlin | |
Germany | Universitätsmedizin Berlin-Campus Charité | Berlin | |
Germany | Krankenhaus Friedrichstadt | Dresden | |
Germany | Rheumatologische Schwerpunktpraxis | Erlangen | |
Germany | Department of Medicine II / Rheumatology Johann Wolfgang Goethe-Universität | Frankfurt | |
Germany | Rheumatologie Endokrinologikum Frankfurt | Frankfurt | |
Germany | Universität Freiburg Innere Medizin - Abtlg. Rheumatologie | Freiburg | |
Germany | Gemeinschaftspraxis für Innere Medizin | Gießen | |
Germany | Praxis, Innere Medizin und Rheumatologie | Goslar | |
Germany | Universitätsmedizin Göttingen Georg-August-Universität Abtlg. Nephrologie u. Rheumatologie | Göttingen | |
Germany | Klinik u. Poliklinik f. Innere Medizin A, Nephrologie u. Rheumatolog Uniklinik Greifswald | Greifswald | |
Germany | Uniklinik Halle - Poliklinik für Innere Medizin I | Halle | |
Germany | Medizinische Hochschule Hannover Klinik f. Immunologie u. Rheumatologie | Hannover | |
Germany | Rheumapraxis Heidelberg | Heidelberg | |
Germany | Praxis, Innere Medizin und Rheumatologie | Hildesheim | |
Germany | Internistisch - Rheumatologische Praxis | Hofheim | |
Germany | Klinik für Innere Medizin I Universitätsklinikum des Saarlandes | Homburg | |
Germany | Rheumapraxis Karlsruhe | Karlsruhe | |
Germany | Krankenhaus Porz am Rhein | Köln | |
Germany | Universitätsklinikum Köln Med I | Köln | |
Germany | Universität Leipzig | Leipzig | |
Germany | Praxis Kaufmann | Ludwigsfelde | |
Germany | Medizinsche Klinik A, Rheumatologie, Nephrologie Klinikum der Stadt Ludwigshafen, | Ludwigshafen | |
Germany | Katholisches Klinikum Mainz, St. Vincenz und Elisabeth Hospital | Mainz | |
Germany | Praxis Prof. Dr. Kellner | München | |
Germany | Praxiszentrum St. Bonifatius | München | |
Germany | Rheumatologische Schwerpunktpraxis | Neuss | |
Germany | Klinikum Offenbach GmbH | Offenbach | |
Germany | Praxis. Gauler und Fliedner | Osnabrück | |
Germany | Praxis Gräßler | Pirna | |
Germany | Rheumatologie Praxis | Planegg | |
Germany | Evangelisches Fachkrankenhaus | Ratingen | |
Germany | Uni Klinik Regensburg | Regensburg | |
Germany | Krankenhaus der Barmherzigen Brüder Trier | Trier | |
Germany | Abt. II Medizinische Universitätsklinik und Poliklinik | Tübingen | |
Germany | Universitätsklinikum Ulm Klinik f. Innere Medizin III | Ulm | |
Germany | Innere Medizin und Rheumatologie | Villingen-Schwenningen | |
Germany | Rheumatologische Praxis Dr. Wörth | Wiesbaden | |
Germany | Rheumatologische Schwerpunktpraxis | Wuppertal | |
Germany | Med. Klinik und Poliklinik III, Schwerpunkt Rheumatologie | Würzburg |
Lead Sponsor | Collaborator |
---|---|
Frank Behrens |
Germany,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | ACR 50 - Part I of the Study - 50% improvement of ACR defined disease activity | Proportion of patients with an ACR 50 response at week 24 | Week 24 | No |
Primary | DAS28 - Part II of the study - evaluation of Disease activity score (DAS)28 | Mean of DAS28 at week 52 | week 52 | No |
Secondary | Evaluation of 50 % improvement of ACR defined disease activity (ACR 50) | To determine the efficacy and safety at week 24 of rituximab treatment of 2x1000 mg i.v. vs. placebo and the efficacy and safety at week 52 of rituximab 2x1000 mg i.v. vs 2x500 mg | From baseline (day of IMP administration) until up to 52 weeks | Yes |
Secondary | EULAR response - response to therapy defined by European League against Rheumatism (EULAR) | EULAR response rates at week 16, 24, 40, 48 | From baseline (day of IMP administration) until up to 52 weeks | No |
Secondary | Assessment of ACR core set consisting of SJC, TJC, HAQ, patient's and physician's global assessments - Visual analog scales (VAS), Subject's pain-scale, CRP, ESR | Change in ACR core set (Swollen Joint count (SJC), Tender Joint Count (TJC), Health Assessment Questionnaire (HAQ), patient's and physician's global assessments visual analog Scale (VAS), subject's pain scale, C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR))compared to baseline at all follow-up visits | From baseline (day of IMP administration) until up to 52 weeks | No |
Secondary | Assessment of SF-36 scores (Health survey) | Change in SF-36 scores compared to baseline at all followup visits | From baseline (day of IMP administration) until up to 52 weeks | No |
Secondary | Assessment of FACIT (Functional assessment of chronical illness therapy)-fatigue- Questionnaire | Change in FACIT-fatigue assessment compared to baseline at all follow-up visits at week 16, 24, 40 and 48 | From baseline (day of IMP administration) until up to 52 weeks | No |
Secondary | HAQ (health assessment questionnaire)- assessment | Change in HAQ assessment compared to baseline at follow-up visits at week 8, 12, 16, 24, 32, (36), 40, 48, 52 | From baseline (day of IMP administration) until up to 52 weeks | No |
Secondary | proportion of DAS28-ESR remission - remission using DAS28 based on the erythrocyte sedimentation rate (ESR) defined as DAS28 < 2.6 | Proportion of patients achieving DAS28-ESR remission (DAS28 < 2.6) at week 16, 24, 40, 48 | from week 16 until 48 weeks | No |
Secondary | Proportion of patient with disease activity score in 28 joints (DAS28) based on the erythrocyte sedimentation rate (ESR) (DAS28-ESR) - low disease is defined DAS28 < 3.2 | Proportion of patients achieving DAS28-ESR low disease (DAS28 < 3.2) at week 16, 24, 40, 48 | from week 16 until 48 weeks | No |
Secondary | Assessment of changes in c-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR) values | Change of CRP and ESR compared to baseline at all follow-up visits at week 2, 8, 12, 16, 24, 32, (36), 40, 48, 52 | From baseline (day of IMP administration) until up to 52 weeks | Yes |
Secondary | Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values | Change of RF and aCCP compared at Screening, 16, 24, and 48 | At Screening | No |
Secondary | Performance of standardized ultrasound synovitis score (US7)in subgroup of patients | Change in ultrasound synovitis score (if possible 3rd party blind observer, imaging subgroup only) performed at baseline and week 16, 24, 40, 48 | From baseline (day of IMP administration) until up to 48 weeks | No |
Secondary | Assessment of changes of rheumatoid nodules (number and diameter of target nodule) during therapy | Numbers of rheumatoid nodules and the diameter of one target nodule at baseline, week 24 and 48 | From baseline (day of IMP administration) until up to 48 weeks | No |
Secondary | Assessment of main safety parameters as SAE, deaths, duration of B-cell depletion and rate of infections + malignancies | Safety parameters: Number of deaths, drop-out rates, causes of drop-outs, summary of SAEs per treatment group and severity of adverse events Extent and duration of B cell depletion Rates of infections, malignancies |
From week 2 until up to 52 weeks | Yes |
Secondary | Documentation of used standard care treatment by patients that are non-responder to therapy | Explorative analysis of the effect of standard care treatment in patients with insufficient response to the investigational medicinal product | Week 26 | Yes |
Secondary | Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative) | Descriptive analysis of change in ACR20/50/70, EULAR Response and DAS28 in RF-positive and RF-negative patients, respectively | At Screening | No |
Secondary | Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values | Change of RF and aCCP compared at Screening, 16, 24, and 48 | week 16 | No |
Secondary | Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values | Change of RF and aCCP compared at Screening, 16, 24, and 48 | week 24 | No |
Secondary | Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values | Change of RF and aCCP compared at Screening, 16, 24, and 48 | week 48 | No |
Secondary | Assessment of changes of rheumatoid nodules (number and diameter of target nodule) during therapy | Numbers of rheumatoid nodules and the diameter of one target nodule at baseline, week 24 and 48 | week 24 | No |
Secondary | Assessment of changes of rheumatoid nodules (number and diameter of target nodule) during therapy | Numbers of rheumatoid nodules and the diameter of one target nodule at baseline, week 24 and 48 | week 48 | No |
Secondary | Documentation of used standard care treatment by patients that are non-responder to therapy | Explorative analysis of the effect of standard care treatment in patients with insufficient response to the investigational medicinal product | Week 36 | Yes |
Secondary | Documentation of used standard care treatment by patients that are non-responder to therapy | Explorative analysis of the effect of standard care treatment in patients with insufficient response to the investigational medicinal product | Week 48 | Yes |
Secondary | Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative) | Descriptive analysis of change in ACR20/50/70, EULAR Response and DAS28 in RF-positive and RF-negative patients, respectively | week 16 | No |
Secondary | Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative) | Descriptive analysis of change in ACR20/50/70, EULAR Response and DAS28 in RF-positive and RF-negative patients, respectively | week 24 | No |
Secondary | Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative) | Descriptive analysis of change in ACR20/50/70, EULAR Response and DAS28 in RF-positive and RF-negative patients, respectively | week 48 | No |
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