Clinical trials overview
Randomized Evaluation oF Long-term Efficacy of rituXimab in RA
REFLEX
Trial objective
To determine the efficacy and safety of MabThera® (rituximab) plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to tumour necrosis factor (TNF) inhibitors.
Study design
A multicentre, randomised, double-blind, placebo-controlled, Phase III study.
Patient population
Patients (n=520) with active RA and an inadequate response to TNF inhibitors, currently taking MTX.
Treatments
IV MabThera® (one course, consisting of 2 x 1000 mg) or placebo, both with MTX 10–25 mg/week orally or parenterally.
Primary endpoint
The proportion of patients with an ACR20 response at 24 weeks.
Baseline patient characteristics
Both study groups were balanced for baseline characteristics, disease activity, and previous and concomitant RA treatments.
| Characteristic | Placebo plus MTX (n=209) |
MabThera® plus MTX (n=308) |
|---|---|---|
|
Age, years |
52.8 |
52.2 |
|
Female, % |
81 |
81 |
|
Disease duration, years |
11.7 |
12.1 |
|
Swollen joint count |
22.9 |
23.4 |
|
Tender joint count |
33.0 |
33.9 |
|
RF, IU/L |
317 |
324 |
|
Erythrocyte sedimentation rate, mm/h |
48.4 |
48.0 |
|
DAS28 |
6.8 |
6.9 |
|
HAQ-DI score |
1.9 |
1.9 |
|
Total Genant-modified Sharp radiographic score |
47.9 |
48.3 |
|
Previous DMARDs (excluding MTX), n |
2.4 |
2.6 |
|
Previous TNF inhibitors, n |
1.5 |
1.5 |
|
Glucocorticoid use at baseline, % |
61 |
65 |
|
Weekly dose of MTX at baseline, mg |
16.7 |
16.4 |
All data are mean values except where stated
DAS28, disease activity score in 28 joints; DMARD, disease-modifying anti-rheumatic drug; HAQ-DI, health assessment questionnaire disability index; RF, rheumatoid factor
Primary endpoint results
The primary endpoint was met. At Week 24, significantly more MabThera®-treated patients demonstrated an ACR20 response compared with placebo-treated patients (see efficacy section for further details).
Conclusion
At 24 weeks, a single course of MabThera® 2 x 1000 mg plus MTX provided significant, clinically meaningful improvements in disease activity in patients with RA who had an inadequate response to TNF inhibitors.
Cohen SB, et al. Arthritis Rheum 2006;54:2793–2806.
Dose-ranging Assessment: iNternational Clinical Evaluation of Rituximab in RA
DANCER
Trial objective
To examine the efficacy and safety of different MabThera® doses plus MTX, with or without glucocorticoids, in patients with active RA resistant to DMARDs, including biologic agents.
Study design
An international, Phase IIb, randomised, double-blind, double-dummy, placebo-controlled study.
Patient population
Patients (n=465) with active RA and an inadequate response to 1–5 DMARDs (excluding MTX) and/or biologic DMARDs, currently taking MTX.
Treatments
A total of 465 patients were randomised into 3 treatment groups (placebo [n=149], 2 x 500 mg MabThera® [n=124] or 2 x 1000 mg MabThera® [n=192] on Day 1 and 15). Each group was further divided to receive placebo, IV methylprednisolone premedication or IV methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10–25 mg/week); no other DMARDs were permitted.
Primary endpoint
The proportion of RF-positive patients with an ACR20 response at 24 weeks.
Baseline patient characteristics
The study groups were well matched for baseline characteristics, disease activity and previous DMARD/biologic treatments.
|
Characteristic |
Placebo plus MTX |
MabThera® 2 x 500 mg plus MTX |
MabThera® 2 x 1000 mg plus MTX |
|---|---|---|---|
|
Age, years |
51.1 |
51.4 |
51.1 |
|
Female, % |
80 |
83 |
80 |
|
Disease duration, years |
9.3 |
11.1 |
10.8 |
|
Swollen joint count |
21 |
22 |
22 |
|
Tender joint count |
35 |
33 |
32 |
|
RF, IU/L |
437 |
421 |
437 |
|
Erythrocyte sedimentation rate, mm/h |
40 |
45 |
41 |
|
DAS28 |
6.8 |
6.8 |
6.7 |
|
HAQ-DI score |
1.7 |
1.8 |
1.7 |
|
Previous DMARDs (excluding MTX), n |
2.2 |
2.5 |
2.5 |
|
Use of previous TNF inhibitors, % |
26 |
33 |
28 |
|
Weekly dose of MTX at baseline, mg |
15.6 |
16.0 |
14.9 |
All data are mean values except where stated
Note: baseline data are shown for all patients receiving MabThera® therapy including RF-positive and RF-negative patients (n=465). Primary efficacy endpoint data were measured only in RF-positive patients (placebo, n=122; MabThera® 2 x 500 mg, n=123; MabThera® 2 x 1000 mg, n=122).
Primary endpoint results
The primary endpoint was met. At week 24, significantly more MabThera®-treated RF-positive patients achieved an ACR20 response compared with placebo-treated patients (see efficacy section for further details).
Conclusion
At 24 weeks, a single course of MabThera® 2 x 500 mg or 2 x 1000 mg plus MTX provided significant, clinical improvements in disease activity in patients with RA, which was independent of glucocorticoids, although IV glucocorticoid premedication improved tolerability during the first MabThera® dose. Both doses were generally well tolerated.
Emery P, et al. Arthritis Rheum 2006; 54: 1390–1400.
Phase IIa proof-of-concept study
Trial objective
To confirm that selective depletion of B cells with MabThera® leads to sustained clinical improvements in patients with active RA.
Study design
An international, randomised, double-blind, controlled study.
Patient population
Patients (n=161) with active RA despite treatment with at least 10 mg/week of MTX.
Treatments
There were four treatment groups: oral MTX (≥10 mg/week) (control); MabThera® 2 x 1000 mg (doses given on Day 1 and 15); MabThera® (2 x 1000 mg) plus cyclophosphamide (750 mg on Day 3 and 17); and MabThera® (2 x 1000 mg) plus MTX.
Primary endpoint
The proportion of patients with a response on the American College of Rheumatology 50% improvement criteria (ACR50) at 24 weeks.
Baseline patient characteristics
The study groups were similar for baseline characteristics and disease activity.
|
Characteristic |
MTX only |
MabThera® only (n=40) |
MabThera® plus cyclophos-phamide |
MabThera® plus MTX |
|---|---|---|---|---|
|
Age, years |
54 |
54 |
53 |
54 |
|
Female, % |
80 |
73 |
83 |
75 |
|
Disease duration, years |
11 |
9 |
10 |
12 |
|
Swollen joint count |
19 |
21 |
19 |
23 |
|
Tender joint count |
32 |
34 |
33 |
32 |
|
Erythrocyte sedimentation rate, mm/h |
52 |
47 |
55 |
53 |
|
DAS28 |
6.9 |
6.8 |
6.9 |
6.8 |
All data are mean values except where stated
Primary endpoint results
The primary endpoint was met. At week 24, the proportion of patients achieving an ACR50 response was significantly greater with the MabThera® plus MTX combination compared with MTX alone (see efficacy section for further details).
Conclusion
In patients with active RA despite MTX treatment, a single course of MabThera® 2 x 1000 mg, alone or in combination with either cyclophosphamide or continued MTX, provided significant improvement in disease symptoms at both Week 24 and 48.