Roche trials database

Protocol number:

ML20934

Title of Study:

An open-label study to evaluate the effect of MabThera in combination with methotrexate on treatment response in patients with active rheumatoid arthritis who have had an inadequate response to anti-TNF therapies

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

rituximab [MabThera/Rituxan]

Generic name:

rituximab

Therapeutic area:

• Rheumatoid Arthritis

Clinical study summary:

Phase IV study to evaluate the safety and efficacy of rituximab in combination with methotrexate (MTX) in patients with active rheumatoid arthritis who have had an inadequate response to anti-TNF therapies.

Study center(s):

5 centers in Republic of Korea

Phase of development:

IV

Objectives:

To determine the efficacy and safety of rituximab when used in combination with methotrexate (MTX) in patients with active rheumatoid arthritis who have had an inadequate response to one or more anti-TNF therapies.

Methodology:

Rituximab 1000 mg i.v. on Day 1 and Day 15 + Methotrexate (10-25 mg/week p.o or parenteral) were administered together with a corticosteroid regimen consisting of methylprednisolone 100mg i.v. 30 minutes prior to infusion of retuximab.

All patients also received a stable dose of folate (≥5 mg/week) given as either a single dose or as divided daily doses. 

All patients continued to receive any background corticosteroid (≤10mg/day prednisone or equivalent) or oral NSAIDs at a stable dose. 

The primary endpoints was determined at 24 weeks. After 24 weeks, eligible patients were able to receive re-treatment. 

A second course of rituximab + MTX was administered when the following was achieved:

• Minimum of 24 weeks has passed since the first infusion of the last course of study medication.
• DAS28-ESR ≥2.6.

Number of patients (planned/analyzed):

40 patients recruited

Diagnosis and main criteria for inclusion:

- adult patients, 18-80 years of age; - rheumatoid arthritis for >=6 months; - receiving outpatient treatment; - an inadequate response to at least one anti-TNF therapy; - stable methotrexate for >=12 weeks.

Test product, dose and mode of administration or test procedure:

1000mg of rituximab (Mabthera) was administered by intravenous infusion on Day 1 and Day 15.

Duration of treatment:

The initial phase of the study was 24 weeks. After 24 weeks, eligible patients were able to receive re-treatment.

Reference therapy, dose and mode of administration or reference procedure:

Patients also received concomitant MTX (10-25 mg/week p.o. or parenteral), together with a corticosteroid regimen consisting of methylprednisolone 100 mg i.v. 30 minutes prior to both infusions of rituximab.

All patients also received folate (≥5 mg/week) given as either a single dose or as divided daily doses.

All patients continued to receive any background corticosteroid (≤10mg/d prednisone or equivalent). 

Criteria for evaluation (efficacy, safety):

EFFICACY
Primary: The primary endpoint was the proportion of patients with an ACR20 response at Week 24.

Secondary: 

• Proportion of patients with ACR50 and 70 responses at Week 24. These were analyzed as specified for the primary endpoint.
• Change in Disease Activity Score (DAS) from baseline to Week 24. Descriptive statistics were reported for this parameter.
• Categorical DAS responders (EULAR response) at Week 24. These were reported using frequency and percentage. 
• Changes from baseline in ACR core set (SJC, TJC, patient’s and physician’s global assessments, HAQ, pain, CRP, and ESR). Descriptive statistics were reported for these parameters.
• Changes from screening in SF-36. Descriptive statistics were reported for the 8 domain scores and the mental and physical component scores. In addition, the mental and physical component scores were further categorized and analyzed.
• Change in modified Sharp radiographic total score, erosion score, and joint space narrowing score. Descriptive statistics were reported for these parameters.  

SAFETY
All adverse events were collected and graded according to CTC version 3.

The following laboratory tests were recorded:

Hematology/CBC: hemoglobin, hematocrit, RBC, WBC & absolute differential, platelet counts

Blood chemistry: AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, albumin, total bilirubin, urea, uric acid, creatinine, random non-fasting glucose, potassium, sodium, chloride, calcium, phosphorous.

Urinalysis: dipstick for blood, protein and glucose (microscopic examination if abnormal and applicable).

Immunology: B cell (CD19), IgG, IgM, total RF, HBsAg, HBcAb and HCV antibody

Pregnancy Test: All women of childbearing potential had regular urine pregnancy tests. 

Statistical methods:

ACR(20/50/70 and ACR n) and change in DAS responses over Weeks 8, 12, 16, 20, 24 and beyond were assessed descriptively.

Exploratory radiographic analyses including proportion of patients with no erosive progression were assessed at weeks 24 and beyond.

Summary (efficacy, safety, other results):

EFFICACY
At week 24, ACR20/ACR50/ACR70 were 47.5%, 7.5% and 5.0%, respectively. The good responder in DAS response was 5.0%. At week 48. ACR20/ACR50/ACR70 were 82.5%, 37.5% and 15.0%, respectively. The good responder in DAS response was 20.0%.

In addition, this study demonstrated that RA symptoms including score in parameters were improved after infusion of rituximab treatment in terms of 8 parameters of ACR core set, DAS score, SF-36 and Sharp score. Furthermore, re-treatment of rituximab induced the maintenance of improvement in RA symptoms.

Therefore, it proved that RA symptoms in respects of all efficacy parameters were improved after receiving 1^st course of rituximab at week 24 and more improved after receiving 2^nd course of rituximab at week 48.

SAFETY
38 of 40 subjects experienced AEs. AEs with relationship occurred with 20 subjects. Seven SAE cases occurred in 6 subjects and there was no reporting of death.

The result of Immunology showed that IgG, IgM, and CD 19 B cell decreased after administration of the study medication. Considerable number of subjects who were positive with RF on screening became negative after administration of the study medication.

There was nothing special in other hematology, blood chemistry and vital signs. 

Conclusions:

As a result of this study, we conclude that there was improvement in rheumatoid arthritis after administration of rituximab and it showed the better improvement after the re-treatment of rituximab. Therefore, rituximab is considered as an effective agent for improving symptoms of RA patients.

Date of report:

01.04.2010

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