Clinical trial NCT01244958: Addition of Rituximab to Leflunomide in Patients With Active Rheumatoid Arthritis
Official title: Addition of Rituximab to Leflunomide in Patients With Active Rheumatoid Arthritis - a Multicenter Randomised Double-blind Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Keywords: Active rheumatoid arthritis
leflunomide
rituximab
inadequate clinical response to leflunomide
Lead sponsor: Johann Wolfgang Goethe University Hospital
Sponsor class: OTHER
First posted: 2010-11-22
Enrollment: 156
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: ACR 50 - Part I of the Study - 50% improvement of ACR defined disease activity
timeFrame: Week 24
measure: DAS28 - Part II of the study - evaluation of Disease activity score (DAS)28
timeFrame: week 52
Secondary outcomes:
measure: Evaluation of 50 % improvement of ACR defined disease activity (ACR 50)
timeFrame: From baseline (day of IMP administration) until up to 52 weeks
measure: EULAR response - response to therapy defined by European League against Rheumatism (EULAR)
timeFrame: From baseline (day of IMP administration) until up to 52 weeks
measure: 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
timeFrame: From baseline (day of IMP administration) until up to 52 weeks
measure: Assessment of SF-36 scores (Health survey)
timeFrame: From baseline (day of IMP administration) until up to 52 weeks
measure: Assessment of FACIT (Functional assessment of chronical illness therapy)-fatigue- Questionnaire
timeFrame: From baseline (day of IMP administration) until up to 52 weeks
measure: HAQ (health assessment questionnaire)- assessment
timeFrame: From baseline (day of IMP administration) until up to 52 weeks
measure: proportion of DAS28-ESR remission - remission using DAS28 based on the erythrocyte sedimentation rate (ESR) defined as DAS28 < 2.6
timeFrame: from week 16 until 48 weeks
measure: 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
timeFrame: from week 16 until 48 weeks
measure: Assessment of changes in c-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR) values
timeFrame: From baseline (day of IMP administration) until up to 52 weeks
measure: Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values
timeFrame: At Screening
measure: Performance of standardized ultrasound synovitis score (US7)in subgroup of patients
timeFrame: From baseline (day of IMP administration) until up to 48 weeks
measure: Assessment of changes of rheumatoid nodules (number and diameter of target nodule) during therapy
timeFrame: From baseline (day of IMP administration) until up to 48 weeks
measure: Assessment of main safety parameters as SAE, deaths, duration of B-cell depletion and rate of infections + malignancies
timeFrame: From week 2 until up to 52 weeks
measure: Documentation of used standard care treatment by patients that are non-responder to therapy
timeFrame: Week 26
measure: Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative)
timeFrame: At Screening
measure: Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values
timeFrame: week 16
measure: Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values
timeFrame: week 24
measure: Assessment of changes in rheumatoid factor (RF) and Antibody against cyclic citrullinated peptide (aCCP) values
timeFrame: week 48
measure: Assessment of changes of rheumatoid nodules (number and diameter of target nodule) during therapy
timeFrame: week 24
measure: Assessment of changes of rheumatoid nodules (number and diameter of target nodule) during therapy
timeFrame: week 48
measure: Documentation of used standard care treatment by patients that are non-responder to therapy
timeFrame: Week 36
measure: Documentation of used standard care treatment by patients that are non-responder to therapy
timeFrame: Week 48
measure: Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative)
timeFrame: week 16
measure: Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative)
timeFrame: week 24
measure: Descriptive analysis of outcome measures in patients differentiated by presence of rheumatoid factor (RF-positive) or absence of rheumatoid factor(RF-negative)
timeFrame: week 48
Other outcomes:
Locations:
city: Bad Kösen
country: Germany
facility: Schwerpunktpraxis
state: Sachsen-Anhalt
city: Bad Nauheim
country: Germany
facility: Kerckhoff-Klinik GmbH Abtlg. Rheumatologie und Klin. Immunologie
city: Baden-Baden
country: Germany
facility: Rheumazentrum Baden-Baden
city: Berlin
country: Germany
facility: Praxis Remstedt
city: Berlin
country: Germany
facility: Rheumaklinik Berlin-Buch Immanuel Krankenhaus
city: Berlin
country: Germany
facility: Schlosspark-Klinik
city: Berlin
country: Germany
facility: Universitätsmedizin Berlin-Campus Charité
city: Dresden
country: Germany
facility: Krankenhaus Friedrichstadt
city: Erlangen
country: Germany
facility: Rheumatologische Schwerpunktpraxis
city: Frankfurt
country: Germany
facility: Department of Medicine II / Rheumatology Johann Wolfgang Goethe-Universität
city: Frankfurt
country: Germany
facility: Rheumatologie Endokrinologikum Frankfurt
city: Freiburg
country: Germany
facility: Universität Freiburg Innere Medizin - Abtlg. Rheumatologie
city: Gießen
country: Germany
facility: Gemeinschaftspraxis für Innere Medizin
city: Goslar
country: Germany
facility: Praxis, Innere Medizin und Rheumatologie
city: Greifswald
country: Germany
facility: Klinik u. Poliklinik f. Innere Medizin A, Nephrologie u. Rheumatolog Uniklinik Greifswald
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen Georg-August-Universität Abtlg. Nephrologie u. Rheumatologie
city: Halle
country: Germany
facility: Uniklinik Halle - Poliklinik für Innere Medizin I
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover Klinik f. Immunologie u. Rheumatologie
city: Heidelberg
country: Germany
facility: Rheumapraxis Heidelberg
city: Hildesheim
country: Germany
facility: Praxis, Innere Medizin und Rheumatologie
city: Hofheim
country: Germany
facility: Internistisch - Rheumatologische Praxis
city: Homburg
country: Germany
facility: Klinik für Innere Medizin I Universitätsklinikum des Saarlandes
city: Karlsruhe
country: Germany
facility: Rheumapraxis Karlsruhe
city: Köln
country: Germany
facility: Krankenhaus Porz am Rhein
city: Köln
country: Germany
facility: Universitätsklinikum Köln Med I
city: Leipzig
country: Germany
facility: Universität Leipzig
city: Ludwigsfelde
country: Germany
facility: Praxis Kaufmann
city: Ludwigshafen
country: Germany
facility: Medizinsche Klinik A, Rheumatologie, Nephrologie Klinikum der Stadt Ludwigshafen,
city: Mainz
country: Germany
facility: Katholisches Klinikum Mainz, St. Vincenz und Elisabeth Hospital
city: München
country: Germany
facility: Praxis Prof. Dr. Kellner
city: München
country: Germany
facility: Praxiszentrum St. Bonifatius
city: Neuss
country: Germany
facility: Rheumatologische Schwerpunktpraxis
city: Offenbach
country: Germany
facility: Klinikum Offenbach GmbH
city: Osnabrück
country: Germany
facility: Praxis. Gauler und Fliedner
city: Pirna
country: Germany
facility: Praxis Gräßler
city: Planegg
country: Germany
facility: Rheumatologie Praxis
city: Ratingen
country: Germany
facility: Evangelisches Fachkrankenhaus
city: Regensburg
country: Germany
facility: Uni Klinik Regensburg
city: Trier
country: Germany
facility: Krankenhaus der Barmherzigen Brüder Trier
city: Tübingen
country: Germany
facility: Abt. II Medizinische Universitätsklinik und Poliklinik
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm Klinik f. Innere Medizin III
city: Villingen-Schwenningen
country: Germany
facility: Innere Medizin und Rheumatologie
city: Wiesbaden
country: Germany
facility: Rheumatologische Praxis Dr. Wörth
city: Wuppertal
country: Germany
facility: Rheumatologische Schwerpunktpraxis
city: Würzburg
country: Germany
facility: Med. Klinik und Poliklinik III, Schwerpunkt Rheumatologie
Study officials:
affiliation: Department of Medicine II / Rheumatology Johann Wolfgang Goethe-Universität
name: Frank Behrens, Dr. med.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Behrens F, Koehm M, Rossmanith T, Alten R, Aringer M, Backhaus M, Burmester GR, Feist E, Herrmann E, Kellner H, Krueger K, Lehn A, Muller-Ladner U, Rubbert-Roth A, Tony HP, Wassenberg S, Burkhardt H. Rituximab plus leflunomide in rheumatoid arthritis: a randomized, placebo-controlled, investigator-initiated clinical trial (AMARA study). Rheumatology (Oxford). 2021 Nov 3;60(11):5318-5328. doi: 10.1093/rheumatology/keab153.