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Rheumatoid ArthritisPhase 3NCT01244958

Addition of Rituximab to Leflunomide in Patients With Active Rheumatoid Arthritis

A Phase 3 study testing Rituximab in people with Rheumatoid Arthritis, run by Frank Behrens at 45 sites in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Rheumatoid Arthritis
What is being tested?
Rituximab
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
156 participants
Where
45 sitesGermany
Study dates
Aug 2010to Feb 2015
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 33Show fewer
  • 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

Trial locations and contacts

45 sites in 1 country.

45 sites in 1 country

Germany45 sites

  • Schwerpunktpraxis

    Bad Kösen, Saxony-Anhalt, 06628

  • Kerckhoff-Klinik GmbH Abtlg. Rheumatologie und Klin. Immunologie

    Bad Nauheim

  • Rheumazentrum Baden-Baden

    Baden-Baden

  • Praxis Remstedt

    Berlin

  • Rheumaklinik Berlin-Buch Immanuel Krankenhaus

    Berlin

  • Schlosspark-Klinik

    Berlin

  • Universitätsmedizin Berlin-Campus Charité

    Berlin

  • Krankenhaus Porz am Rhein

    Cologne

  • Universitätsklinikum Köln Med I

    Cologne

  • Krankenhaus Friedrichstadt

    Dresden

  • Rheumatologische Schwerpunktpraxis

    Erlangen

  • Department of Medicine II / Rheumatology Johann Wolfgang Goethe-Universität

    Frankfurt, 60528

  • Rheumatologie Endokrinologikum Frankfurt

    Frankfurt

  • Universität Freiburg Innere Medizin - Abtlg. Rheumatologie

    Freiburg im Breisgau

  • Gemeinschaftspraxis für Innere Medizin

    Giessen

  • Praxis, Innere Medizin und Rheumatologie

    Goslar

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

    Göttingen

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

    Greifswald

  • Uniklinik Halle - Poliklinik für Innere Medizin I

    Halle

  • Medizinische Hochschule Hannover Klinik f. Immunologie u. Rheumatologie

    Hanover

  • Rheumapraxis Heidelberg

    Heidelberg

  • Praxis, Innere Medizin und Rheumatologie

    Hildesheim

  • Internistisch - Rheumatologische Praxis

    Hofheim

  • Klinik für Innere Medizin I Universitätsklinikum des Saarlandes

    Homburg

  • Rheumapraxis Karlsruhe

    Karlsruhe

  • Universität Leipzig

    Leipzig

  • Praxis Kaufmann

    Ludwigsfelde

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

    Ludwigshafen

  • Katholisches Klinikum Mainz, St. Vincenz und Elisabeth Hospital

    Mainz

  • Praxis Prof. Dr. Kellner

    München

  • Praxiszentrum St. Bonifatius

    München

  • Rheumatologische Schwerpunktpraxis

    Neuss

  • Klinikum Offenbach GmbH

    Offenbach

  • Praxis. Gauler und Fliedner

    Osnabrück

  • Praxis Gräßler

    Pirna

  • Rheumatologie Praxis

    Planegg

  • Evangelisches Fachkrankenhaus

    Ratingen

  • Uni Klinik Regensburg

    Regensburg

  • Krankenhaus der Barmherzigen Brüder Trier

    Trier

  • Abt. II Medizinische Universitätsklinik und Poliklinik

    Tübingen

  • Universitätsklinikum Ulm Klinik f. Innere Medizin III

    Ulm

  • Innere Medizin und Rheumatologie

    Villingen-Schwenningen

  • Rheumatologische Praxis Dr. Wörth

    Wiesbaden

  • Rheumatologische Schwerpunktpraxis

    Wuppertal

  • Med. Klinik und Poliklinik III, Schwerpunkt Rheumatologie

    Würzburg

Other trials in Germany

About this study

Official title: Addition of Rituximab to Leflunomide in Patients With Active Rheumatoid Arthritis - a Multicenter Randomised Double-blind Clinical Trial

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.

Read the 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)

Being tested
Rituximab, Placebo
Keywords
Active rheumatoid arthritis, leflunomide, rituximab, inadequate clinical response to leflunomide
Medical subject headings
Arthritis, Rheumatoid

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RituximabBiological

    Also called Mab Thera

    1000 mg Rituximab infusion

  • PlaceboDrug

    infusion of Sodium citrate, Polysorbate, Sodium chloride

Study groups in NCT01244958
Study groupRoleWhat they receive
Rituximab 1000 mgActive comparatorAdministration 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
Receives: Biological: Rituximab
PlaceboPlacebo comparatorAdministration 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
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: Week 24

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

    Mean of DAS28 at week 52

    Measured: week 52

Secondary outcomes (25)

  1. 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

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

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

    EULAR response rates at week 16, 24, 40, 48

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

  3. 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

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

  4. Assessment of SF-36 scores (Health survey)

    Change in SF-36 scores compared to baseline at all followup visits

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

  5. 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

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

  6. 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

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

  7. 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

    Measured: from week 16 until 48 weeks

  8. 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

    Measured: from week 16 until 48 weeks

  9. 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

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

  10. 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

    Measured: At Screening

  11. 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

    Measured: From baseline (day of IMP administration) until up to 48 weeks

  12. 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

    Measured: From baseline (day of IMP administration) until up to 48 weeks

  13. 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

    Measured: From week 2 until up to 52 weeks

  14. 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

    Measured: Week 26

  15. 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

    Measured: At Screening

  16. 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

    Measured: week 16

  17. 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

    Measured: week 24

  18. 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

    Measured: week 48

  19. 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

    Measured: week 24

  20. 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

    Measured: week 48

  21. 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

    Measured: Week 36

  22. 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

    Measured: Week 48

  23. 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

    Measured: week 16

  24. 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

    Measured: week 24

  25. 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

    Measured: week 48

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Nov 2010 (estimated)
  2. Study startAug 2010
  3. Primary completionFeb 2015
  4. Study completionFeb 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
156 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01244958
Sponsor's protocol ID
FFM07-Rtx-Lef
Other IDs
2009-015950-39, 2009
Status last verified
Mar 2016
First submitted
28 Sep 2010
Last updated
24 Mar 2016
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 36555933

  • 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.

    PubMed 33738492

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Rituximab in people with Rheumatoid Arthritis, run by Frank Behrens at 45 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 45 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

ACR 50 - Part I of the Study - 50% improvement of ACR defined disease activity (time frame: Week 24). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01244958, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Mar 2016.

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