Rituximab-Treatment in Addition to Leflunomide in Patients with active rheumatoid arthritis

• Register: EUCTR
• Last refreshed on: 25 January 2016
• Main ID: EUCTR2009-015950-39-DE
• Date of registration: 28/12/2009
• Prospective Registration: Yes
• Primary sponsor: Johann Wolfgang Goethe-Universität Frankfurt/M.
• Public title: Rituximab-Treatment in Addition to Leflunomide in Patients with active rheumatoid arthritis
• Scientific title: Addition of Rituximab to Leflunomide in patients with active rheumatoid arthritis - AMARA
• Date of first enrolment: 12/05/2010
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-015950-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Germany

Key inclusion & exclusion 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 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.




Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 90
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 90

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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

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.
MedDRA version: 14.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Intervention(s)

Trade Name: MabThera®
Product Name: Rituximab
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Concentrate for solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Main Objective: 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

Secondary Objective: 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

Primary 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

Timepoint(s) of evaluation of this end point: Part I:
week 24

Part II:
week 52

Secondary Outcome(s)

Timepoint(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

Secondary 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

Secondary ID(s)

FFM07-Rtx-Lef

Source(s) of Monetary Support

Roche Pharma AG

University Hospital Goethe-University, Department of rheumatology