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Addition of Rituximab to Leflunomide in Patients With Active Rheumatoid Arthritis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Frank Behrens, Johann Wolfgang Goethe University Hospitals
ClinicalTrials.gov Identifier:
NCT01244958
First received: September 28, 2010
Last updated: March 23, 2016
Last verified: March 2016
  Purpose
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.

Condition Intervention Phase
Rheumatoid Arthritis
Biological: Rituximab
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Addition of Rituximab to Leflunomide in Patients With Active Rheumatoid Arthritis - a Multicenter Randomised Double-blind Clinical Trial

Resource links provided by NLM:


Further study details as provided by Johann Wolfgang Goethe University Hospital:

Primary Outcome Measures:
  • ACR 50 - Part I of the Study - 50% improvement of ACR defined disease activity [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    Proportion of patients with an ACR 50 response at week 24

  • DAS28 - Part II of the study - evaluation of Disease activity score (DAS)28 [ Time Frame: week 52 ] [ Designated as safety issue: No ]
    Mean of DAS28 at week 52


Secondary Outcome Measures:
  • Evaluation of 50 % improvement of ACR defined disease activity (ACR 50) [ Time Frame: From baseline (day of IMP administration) until up to 52 weeks ] [ Designated as safety issue: Yes ]
    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

  • EULAR response - response to therapy defined by European League against Rheumatism (EULAR) [ Time Frame: From baseline (day of IMP administration) until up to 52 weeks ] [ Designated as safety issue: No ]
    EULAR response rates at week 16, 24, 40, 48

  • 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 [ Time Frame: From baseline (day of IMP administration) until up to 52 weeks ] [ Designated as safety issue: No ]
    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

  • Assessment of SF-36 scores (Health survey) [ Time Frame: From baseline (day of IMP administration) until up to 52 weeks ] [ Designated as safety issue: No ]
    Change in SF-36 scores compared to baseline at all followup visits

  • Assessment of FACIT (Functional assessment of chronical illness therapy)-fatigue- Questionnaire [ Time Frame: From baseline (day of IMP administration) until up to 52 weeks ] [ Designated as safety issue: No ]
    Change in FACIT-fatigue assessment compared to baseline at all follow-up visits at week 16, 24, 40 and 48

  • HAQ (health assessment questionnaire)- assessment [ Time Frame: From baseline (day of IMP administration) until up to 52 weeks ] [ Designated as safety issue: No ]
    Change in HAQ assessment compared to baseline at follow-up visits at week 8, 12, 16, 24, 32, (36), 40, 48, 52

  • proportion of DAS28-ESR remission - remission using DAS28 based on the erythrocyte sedimentation rate (ESR) defined as DAS28 < 2.6 [ Time Frame: from week 16 until 48 weeks ] [ Designated as safety issue: No ]
    Proportion of patients achieving DAS28-ESR remission (DAS28 < 2.6) at week 16, 24, 40, 48

  • 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 [ Time Frame: from week 16 until 48 weeks ] [ Designated as safety issue: No ]
    Proportion of patients achieving DAS28-ESR low disease (DAS28 < 3.2) at week 16, 24, 40, 48

  • Assessment of changes in c-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR) values [ Time Frame: From baseline (day of IMP administration) until up to 52 weeks ] [ Designated as safety issue: Yes ]
    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

  • Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values [ Time Frame: At Screening ] [ Designated as safety issue: No ]
    Change of RF and aCCP compared at Screening, 16, 24, and 48

  • Performance of standardized ultrasound synovitis score (US7)in subgroup of patients [ Time Frame: From baseline (day of IMP administration) until up to 48 weeks ] [ Designated as safety issue: No ]
    Change in ultrasound synovitis score (if possible 3rd party blind observer, imaging subgroup only) performed at baseline and week 16, 24, 40, 48

  • Assessment of changes of rheumatoid nodules (number and diameter of target nodule) during therapy [ Time Frame: From baseline (day of IMP administration) until up to 48 weeks ] [ Designated as safety issue: No ]
    Numbers of rheumatoid nodules and the diameter of one target nodule at baseline, week 24 and 48

  • Assessment of main safety parameters as SAE, deaths, duration of B-cell depletion and rate of infections + malignancies [ Time Frame: From week 2 until up to 52 weeks ] [ Designated as safety issue: Yes ]

    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

  • Documentation of used standard care treatment by patients that are non-responder to therapy [ Time Frame: Week 26 ] [ Designated as safety issue: Yes ]
    Explorative analysis of the effect of standard care treatment in patients with insufficient response to the investigational medicinal product

  • Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative) [ Time Frame: At Screening ] [ Designated as safety issue: No ]
    Descriptive analysis of change in ACR20/50/70, EULAR Response and DAS28 in RF-positive and RF-negative patients, respectively

  • Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values [ Time Frame: week 16 ] [ Designated as safety issue: No ]
    Change of RF and aCCP compared at Screening, 16, 24, and 48

  • Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values [ Time Frame: week 24 ] [ Designated as safety issue: No ]
    Change of RF and aCCP compared at Screening, 16, 24, and 48

  • Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values [ Time Frame: week 48 ] [ Designated as safety issue: No ]
    Change of RF and aCCP compared at Screening, 16, 24, and 48

  • Assessment of changes of rheumatoid nodules (number and diameter of target nodule) during therapy [ Time Frame: week 24 ] [ Designated as safety issue: No ]
    Numbers of rheumatoid nodules and the diameter of one target nodule at baseline, week 24 and 48

  • Assessment of changes of rheumatoid nodules (number and diameter of target nodule) during therapy [ Time Frame: week 48 ] [ Designated as safety issue: No ]
    Numbers of rheumatoid nodules and the diameter of one target nodule at baseline, week 24 and 48

  • Documentation of used standard care treatment by patients that are non-responder to therapy [ Time Frame: Week 36 ] [ Designated as safety issue: Yes ]
    Explorative analysis of the effect of standard care treatment in patients with insufficient response to the investigational medicinal product

  • Documentation of used standard care treatment by patients that are non-responder to therapy [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    Explorative analysis of the effect of standard care treatment in patients with insufficient response to the investigational medicinal product

  • Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative) [ Time Frame: week 16 ] [ Designated as safety issue: No ]
    Descriptive analysis of change in ACR20/50/70, EULAR Response and DAS28 in RF-positive and RF-negative patients, respectively

  • Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative) [ Time Frame: week 24 ] [ Designated as safety issue: No ]
    Descriptive analysis of change in ACR20/50/70, EULAR Response and DAS28 in RF-positive and RF-negative patients, respectively

  • Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative) [ Time Frame: week 48 ] [ Designated as safety issue: No ]
    Descriptive analysis of change in ACR20/50/70, EULAR Response and DAS28 in RF-positive and RF-negative patients, respectively


Enrollment: 156
Study Start Date: August 2010
Study Completion Date: February 2015
Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Rituximab 1000 mg
Administration of 1000 mg Rituximab in Part I, followed by either re-treatment with 1000 mg Rituximab or with 500 mg Rituximab in Part II of the study
Biological: Rituximab
1000 mg Rituximab infusion
Other Name: Mab Thera
Placebo Comparator: Placebo
Administration of Placebo in Part I followed by re-treatment with either 1000 mg Rituximab or with 500 mg Rituximab in Part II of the study
Drug: Placebo
infusion of Sodium citrate, Polysorbate, Sodium chloride

Detailed Description:

Rituximab provides lasting improvement in the signs and symptoms of rheumatoid arthritis (RA) after two infusions per treatment course in tumor necrosis factor (TNF) inhibitor inadequate responder (IR) patients. Importantly, MabThera® has been shown to inhibit radiographic progression in this highly pre-treated patient population. Rituximab is licensed for adult patients with severe active RA in combination with methotrexate after inadequate response to previous treatment, including TNF alpha- Inhibitors.

In daily practice the combination with methotrexate is often limited to side effects or contraindications to Methotrexate (MTX). Therefore there is an unmet medical need for evidence for the combination of RTX with other Disease modifying anti-rheumatic drugs (DMARDs)than MTX.

Leflunomide is a DMARD that selectively inhibits de novo pyrimidine synthesis by blocking the enzyme dihydro-orotate dehydrogenase, thereby preventing DNA synthesis. The efficacy and safety of leflunomide in patients with active RA have been demonstrated in three phase III studies. Leflunomide was shown to be better than placebo and at least as effective as methotrexate in improving individual signs and symptoms of RA; these responses were seen as early as 4 weeks and were maintained for up to 2 years. Leflunomide was also effective in slowing disease progression as assessed by radiographic analysis of joint damage, and in improving functional activity as measured by the Stanford Health Assessment Questionnaire Disease Activity Index. An open label extension study of patients treated with leflunomide demonstrated that these improvements are maintained for up to 5 years in a subset of patients, with no new or unexpected adverse events emerging compared with the initial phase III studies.

In Europe leflunomide is often used in daily clinical practice as an alterative to MTX in patients with active RA.

Recently published data of a small open label trial (Vital et al. 2008) and data of a German non-interventional study (NIS) (Wendler et al. 2009) demonstrated the effectiveness of the addition of RTX to leflunomide in patients with active RA. The proportion of patients achieving EULAR (European League against Rheumatism) moderate to good response was 61% for RTX alone, 65 % for RTX plus MTX and 79% for RTX plus leflunomide in the German NIS. In the Leeds study of Vital et al.

33% of the patients achieved ACR (American College of Rheumatology)50 response (ACR 20: 68%, ACR 70: 20%) despite multiple pre-treatments, including patients with inadequate response to three TNF-Inhibitors.

The low rate of serious adverse drug reactions in the different groups of the German NIS demonstrated the safety of the combination of RTX and leflunomide (n=90) (1.6 / 1.1 / 0,5% for RTX+MTX / RTX+LEF / RTX Mono, 5.1 / 6,7 / 3,8% experienced infusion reactions)

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01244958

Locations
Germany
Schwerpunktpraxis
Bad Kösen, Sachsen-Anhalt, Germany, 06628
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, 60528
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
Klinik u. Poliklinik f. Innere Medizin A, Nephrologie u. Rheumatolog Uniklinik Greifswald
Greifswald, Germany
Universitätsmedizin Göttingen Georg-August-Universität Abtlg. Nephrologie u. Rheumatologie
Göttingen, 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, Germany
Sponsors and Collaborators
Frank Behrens
Investigators
Principal Investigator: Frank Behrens, Dr. med. Department of Medicine II / Rheumatology Johann Wolfgang Goethe-Universität
  More Information

Responsible Party: Frank Behrens, Dr. med Frank Behrens, Johann Wolfgang Goethe University Hospitals
ClinicalTrials.gov Identifier: NCT01244958     History of Changes
Other Study ID Numbers: FFM07-Rtx-Lef  2009-015950-39 
Study First Received: September 28, 2010
Last Updated: March 23, 2016
Health Authority: Germany: Paul-Ehrlich-Institut

Keywords provided by Johann Wolfgang Goethe University Hospital:
Active rheumatoid arthritis
leflunomide
rituximab
inadequate clinical response to leflunomide

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Rituximab
Leflunomide
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents

ClinicalTrials.gov processed this record on December 05, 2016