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    Summary
    EudraCT Number:2009-015950-39
    Sponsor's Protocol Code Number:FFM07-Rtx-Lef
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-12-28
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2009-015950-39
    A.3Full title of the trial
    Addition of Rituximab to Leflunomide in patients with active rheumatoid arthritis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Rituximab-Treatment in Addition to Leflunomide in Patients with active rheumatoid arthritis
    A.3.2Name or abbreviated title of the trial where available
    AMARA
    A.4.1Sponsor's protocol code numberFFM07-Rtx-Lef
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorJohann Wolfgang Goethe-Universität Frankfurt/M.
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUniversity Hospital Goethe-University, Department of rheumatology
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportRoche Pharma AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name MabThera®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRituximab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibody
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Active rheumatoid arthritis (RA)
    Patients who have had an inadequate response to disease modifying anti-rheumatic drugs (not more than 3 DMARDs including leflunomide, not more than one anti-TNF failure) 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.
    E.1.1.1Medical condition in easily understood language
    Active rheumatoid arthritis despite therapy with leflunomide. A history of a maximum of 3 DMARDs including leflunomide and not more than one failure with anti-TNF-therapy
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part I
    To determine the efficacy and safety at week 24 of rituximab treatment of 1000 mg i.v. versus placebo when used on top of leflunomide in patients with active rheumatoid arthritis that currently have an inadequate response to leflunomide
    • Proportion of patients with an ACR 50 response at week 24.

    Part II
    To determine the efficacy at week 52 of rituximab treatment of two times 1000 mg vs. two times 500 mg rituximab in weeks 24 and 26 respectivley in patients who completed Part I and were treated in Part I with 2x1000mg rituximab.
    • Mean of DAS28 at week 52
    E.2.2Secondary objectives of the trial
    Part I and Part II:
    - ACR20/50/70 response to defined timepoints
    - EULAR response to defined timepoints
    - DAS28 response to defined timepoints
    - Patient derived outcomes (FACIT-Fatigue, HAQ, SF26, SGA-VAS, S-VAS-Pain)
    - Imaging changes in ultrasound subgroup
    - Safety parameters
    E.2.3Trial contains a sub-study No
    E.3Principal 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 DMARDs including leflunomide, not more than one anti-TNF failure) 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
    - Inadequat response to no more than one anti-TNF treatment
    - 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.
    E.4Principal 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)
    - Primary or secondary immunodeficiency
    - Chronic, latent and acute infections of the lung
    - Positive result of a Tb specific Interferon gamma release assay
    - 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 non 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
    -Neutrophil counts < 1.500 / µl
    -Platelet count < 75.000 / µl
    - 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
    -AST or ALT > 2.5 times upper limit of normal
    -IgG level < 5g/l
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy (Part I):
    -To determine the efficacy and safety at week 24 of rituximab treatment of 2x1000 mg i.v. vs. placebo when used on top of leflunomide in patients with active rheumatoid arthritis that currently have an inadequate response to leflunomide
    -Proportion of patients with an ACR 50 response at week 24

    Primary efficacy (Part II):
    -To determine the efficacy at week 52 of rituximab treatment of
    1000 mg at week 24 and 1000 mg at week 26 i.v. vs. 500 mg
    rituximab at week 24 and 500 mg rituximab at week 26 in patients who completed Part I and were treated in Part I with 2x1000 mg rituximab.
    -Mean of DAS28 at week 52
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part I:
    week 24

    Part II:
    week 52
    E.5.2Secondary end point(s)
    Part I and II:
    -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
    -Proportion of ACR 50 response at week 8, 12, 16, 32, (36), 40, 48 and 52
    -Proportion of ACR 20 / 70 and of DAS 28 at week 8, 12, 16, 24, 32, (36), 40, 48 and 52
    -DAS28 and change in DAS28 compared to baseline at all follow-up visits
    - EULAR response rates at week 16, 24, 40, 48
    - Change in ACR core set (SJC, TJC, HAQ, patient's and physician's global assessments, pain, CRP and ESR) compared to baseline at all follow-up visits
    - Change in SF-36 scores compared to baseline at all follow-up visits
    - Change in FACIT-fatigue assessment compared to baseline at all follow-up visits at week 16, 24, 40 and 48
    - Change in HAQ assessment compared to baseline at follow-up visits at week 8, 12, 16, 24, 32, (36), 40, 48, 52
    - Proportion of patients achieving DAS28-ESR remission
    E.5.2.1Timepoint(s) of evaluation of this end point
    -efficacy and safety at week 24
    -ACR 50 response at week 8, 12, 16, 32, (36), 40, 48 and 52
    -ACR 20 / 70 and of DAS 28 at week 8, 12, 16, 24, 32, (36), 40, 48 and 52
    -DAS28 and change in DAS28 compared to baseline at all follow-up visits
    -EULAR response rates at week 16, 24, 40, 48
    -ACR core set (SJC, TJC, HAQ, patient's and physician's global assessments, pain, CRP and ESR) compared to baseline at all follow-up visits
    -SF-36 scores compared to baseline at all follow-up visits
    -FACIT-fatigue assessment compared to baseline at all follow-up visits at week 16, 24, 40 and 48
    -HAQ assessment compared to baseline at follow-up visits at week 8, 12, 16, 24, 32, (36), 40, 48, 52
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned46
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state180
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    none
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2010-05-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-02-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-12-17
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