Addition of Rituximab to Leflunomide in Patients With Active Rheumatoid Arthritis

NCT01244958 | Completed Phase 3 DMC

• 2 other identifiers: FFM07-Rtx-Lef2009-015950-39
• Study Type: interventional
• Target: 156
• Locations: 1 country
• Sites: 45

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.

Conditions

Rheumatoid Arthritis

Keywords

Active rheumatoid arthritis; leflunomide; rituximab; inadequate clinical response to leflunomide

Outcome Measures

Primary Outcomes (2)

• 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

• DAS28 - Part II of the study - evaluation of Disease activity score (DAS)28

  Mean of DAS28 at week 52

  week 52

Secondary Outcomes (25)

• Evaluation of 50 % improvement of ACR defined disease activity (ACR 50)

  From baseline (day of IMP administration) until up to 52 weeks

• EULAR response - response to therapy defined by European League against Rheumatism (EULAR)

  From baseline (day of IMP administration) until up to 52 weeks

• 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

  From baseline (day of IMP administration) until up to 52 weeks

• Assessment of SF-36 scores (Health survey)

  From baseline (day of IMP administration) until up to 52 weeks

• Assessment of FACIT (Functional assessment of chronical illness therapy)-fatigue- Questionnaire

  From baseline (day of IMP administration) until up to 52 weeks

Study Arms (2)

Rituximab 1000 mg

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Rituximab BIOLOGICAL

1000 mg Rituximab infusion

Also known as: Mab Thera

Rituximab 1000 mg

Placebo DRUG

infusion of Sodium citrate, Polysorbate, Sodium chloride

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Frank Behrens: lead

Study Sites (45)

Schwerpunktpraxis

Bad Kösen, Saxony-Anhalt, 06628, Germany

Location

Kerckhoff-Klinik GmbH Abtlg. Rheumatologie und Klin. Immunologie

Bad Nauheim, Germany

Location

Rheumazentrum Baden-Baden

Baden-Baden, Germany

Location

Praxis Remstedt

Berlin, Germany

Location

Rheumaklinik Berlin-Buch Immanuel Krankenhaus

Berlin, Germany

Location

Schlosspark-Klinik

Berlin, Germany

Location

Universitätsmedizin Berlin-Campus Charité

Berlin, Germany

Location

Krankenhaus Porz am Rhein

Cologne, Germany

Location

Universitätsklinikum Köln Med I

Cologne, Germany

Location

Krankenhaus Friedrichstadt

Dresden, Germany

Location

Rheumatologische Schwerpunktpraxis

Erlangen, Germany

Location

Department of Medicine II / Rheumatology Johann Wolfgang Goethe-Universität

Frankfurt, 60528, Germany

Location

Rheumatologie Endokrinologikum Frankfurt

Frankfurt, Germany

Location

Universität Freiburg Innere Medizin - Abtlg. Rheumatologie

Freiburg im Breisgau, Germany

Location

Gemeinschaftspraxis für Innere Medizin

Giessen, Germany

Location

Praxis, Innere Medizin und Rheumatologie

Goslar, Germany

Location

Universitätsmedizin Göttingen Georg-August-Universität Abtlg. Nephrologie u. Rheumatologie

Göttingen, Germany

Location

Klinik u. Poliklinik f. Innere Medizin A, Nephrologie u. Rheumatolog Uniklinik Greifswald

Greifswald, Germany

Location

Uniklinik Halle - Poliklinik für Innere Medizin I

Halle, Germany

Location

Medizinische Hochschule Hannover Klinik f. Immunologie u. Rheumatologie

Hanover, Germany

Location

Rheumapraxis Heidelberg

Heidelberg, Germany

Location

Praxis, Innere Medizin und Rheumatologie

Hildesheim, Germany

Location

Internistisch - Rheumatologische Praxis

Hofheim, Germany

Location

Klinik für Innere Medizin I Universitätsklinikum des Saarlandes

Homburg, Germany

Location

Rheumapraxis Karlsruhe

Karlsruhe, Germany

Location

Universität Leipzig

Leipzig, Germany

Location

Praxis Kaufmann

Ludwigsfelde, Germany

Location

Medizinsche Klinik A, Rheumatologie, Nephrologie Klinikum der Stadt Ludwigshafen,

Ludwigshafen, Germany

Location

Katholisches Klinikum Mainz, St. Vincenz und Elisabeth Hospital

Mainz, Germany

Location

Praxis Prof. Dr. Kellner

München, Germany

Location

Praxiszentrum St. Bonifatius

München, Germany

Location

Rheumatologische Schwerpunktpraxis

Neuss, Germany

Location

Klinikum Offenbach GmbH

Offenbach, Germany

Location

Praxis. Gauler und Fliedner

Osnabrück, Germany

Location

Praxis Gräßler

Pirna, Germany

Location

Rheumatologie Praxis

Planegg, Germany

Location

Evangelisches Fachkrankenhaus

Ratingen, Germany

Location

Uni Klinik Regensburg

Regensburg, Germany

Location

Krankenhaus der Barmherzigen Brüder Trier

Trier, Germany

Location

Abt. II Medizinische Universitätsklinik und Poliklinik

Tübingen, Germany

Location

Universitätsklinikum Ulm Klinik f. Innere Medizin III

Ulm, Germany

Location

Innere Medizin und Rheumatologie

Villingen-Schwenningen, Germany

Location

Rheumatologische Praxis Dr. Wörth

Wiesbaden, Germany

Location

Rheumatologische Schwerpunktpraxis

Wuppertal, Germany

Location

Med. Klinik und Poliklinik III, Schwerpunkt Rheumatologie

Würzburg, Germany

Location

Related Publications (2)

• Koehm M, Foldenauer AC, Rossmanith T, Alten R, Aringer M, Backhaus M, Burmester GR, Feist E, Kellner H, Krueger K, Muller-Ladner U, Rubbert-Roth A, Tony HP, Wassenberg S, Burkhardt H, Behrens F. Effectiveness of Different Rituximab Doses Combined with Leflunomide in the Treatment or Retreatment of Rheumatoid Arthritis: Part 2 of a Randomized, Placebo-Controlled, Investigator-Initiated Clinical Trial (AMARA). J Clin Med. 2022 Dec 9;11(24):7316. doi: 10.3390/jcm11247316.

  PMID: 36555933 DERIVED

• 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.

  PMID: 33738492 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Rituximab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Frank Behrens, Dr. med.

  Department of Medicine II / Rheumatology Johann Wolfgang Goethe-Universität

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dr. med Frank Behrens

Study Record Dates

• First Submitted: September 28, 2010
• First Posted: November 22, 2010
• Study Start: August 1, 2010
• Primary Completion: February 1, 2015
• Study Completion: February 1, 2015
• Last Updated: March 24, 2016

Record last verified: 2016-03

Locations

DE (45)