Clinical Trial Result Information
Title of Study:
A randomized, double dummy controlled, parallel group study of the efficacy and safety of MabThera (rituximab) alone or in combination with either cyclophosphamide or methotrexate, in patients with rheumatoid arthritis.
Fast Facts:
| Protocol number: | WA16291 |
| Sponsor: | Roche Products Ltd; Genentech Inc. |
| Company division: | Pharmaceutical |
| Product name: | MabThera/Rituxan |
| Generic name: | rituximab |
| Phase of development: | II |
| Therapeutic area, approved indication: | Rheumatoid Arthritis |
| Date of report: | 6/1/2004 |
Clinical study summary:
This was a randomized, double-dummy controlled, parallel group study to evaluate the effect of methotrexate (MTX) alone, MabThera alone, MabThera plus cyclophosphamide (cyclo.), and MabThera plus MTX in patients with RA who had failed on previous DMARD therapy.
Study center(s) :
26 centers in Australia, Belgium, Canada, Czech Republic, Germany, Israel, Italy, Netherlands, Poland, Spain and UK.
Objectives:
To determine the safety and efficacy of MabThera used either as monotherapy or in combination with methotrexate or cyclophosphamide, in patients with rheumatoid arthritis (RA) who have failed prior DMARD therapy and currently have an inadequate clinical response to methotrexate; to explore the pharmacokinetics of MabThera in this population of patients; to explore the pharmacodynamics of MabThera in this population of patients (e.g. extent and duration of B-cell depletion, and effects on immunoglobulins).
Methodology:
Patients were randomized into one of 4 treatment arms, to receive MTX monotherapy (≥ 10mg po weekly), MabThera monotherapy (1g iv on day 1 and day 15), MabThera plus cyclophosphamide (750g iv on day 1 and day 15) or MabThera plus MTX. Matching placebo tablets/infusions were given to maintain blinding. All patients also received folic acid and prednisolone. The primary endpoint (ACR50 response) was determined at week 24; subsequently, patients were followed for a further 80 weeks. Results from the 24 and 48 week analyses are presented here.
Number of patients (planned/analyzed):
160 patients planned; 161 enrolled.
Diagnosis and main criteria for inclusion:
Adult (≥21 years) patients with RA who have failed treatment with 1-5 DMARDs (other than MTX), and who have received MTX as a single DMARD for at least 16 weeks, of which the last 4 weeks prior to baseline was at a stable oral dose ≥10 mg/week.
Test product, dose and mode of administration or test procedure:
MabThera/Rituxan (rituximab) (1g) administered by intravenous infusion, on days 1 and 15.
Duration of treatment:
2 infusions, on days 1 and 15.
Reference therapy, dose and mode of administration or reference procedure:
Cyclophosphamide (750 mg) administered by intravenous infusion on days 1 and 15.
All patients received methotrexate (≥10 mg po) weekly.
Criteria for evaluation (efficacy, safety):
Efficacy: Primary: Proportion of patients with an ACR50 response at week 24. Secondary: Proportion of patients with ACR20 and 70 responses at week 24; AUC of the ACRn (specific % change in ACR score); AUC of the mean disease activity score (DAS); mean changes from baseline in the individual ACR core set parameters and in rheumatoid factor (IU/mL) at 24 weeks; proportion of patients withdrawn due to lack of therapeutic response.
Pharmacodynamics: B cell and T cell counts, quantitative Ig and RF levels.
Pharmacokinetics: Cmax, T1/2, AUC, Tmax, CL and Vss.
Safety: Adverse events, standard hematology and biochemistry, urinalysis.
Statistical methods:
The difference in ACR50 response between the placebo plus MTX arm and each of the MabThera arms was tested by the Fisher’s exact test (two-tailed). Since this was an exploratory study no adjustment to the type I error was made for multiple treatment comparisons. Secondary endpoints and all data relating to safety were listed and summarized by treatment group using descriptive statistics and interval estimation as appropriate.
Summary (efficacy, safety, other results):
Efficacy: 24 weeks The regimens of MabThera in combination with either MTX or cyclophosphamide resulted in levels of response (ACR50 at Week 24) that were statistically significantly higher (p=0.005) than that in the control arm (MTX alone). The response in the MabThera monotherapy arm was also higher than in the control arm but the difference was not statistically significant (p=0.059). All secondary endpoints (ACR20, ACR70, DAS and ACR core set parameters) reflected the observations seen with the primary endpoint.
| |
MTX
N=40 |
MabThera
N=40 |
MabThera plus cyclo
N=41 |
MabThera plus MTX
N=40 |
| ACR50 |
|
|
|
|
| % of responders |
13% |
33% |
41% |
43% |
| Tmt Diff (95% CI) |
|
0.20 (0.02, 0.38) |
0.28 (0.10, 0.46) |
0.30 (0.11, 0.49) |
| p-value |
|
0.059 |
0.005 |
0.005 |
| ACR20 |
|
|
|
|
| % of responders |
38% |
65% |
76% |
73% |
| Tmt Diff (95% CI) |
|
0.27 (0.06, 0.48) |
0.38 (0.18, 0.58) |
0.35 (0.15, 0.55) |
| p-value |
|
0.025 |
0.001 |
0.003 |
| ACR70 |
|
|
|
|
| % of responders |
5% |
15% |
15% |
23% |
| Tmt Diff (95% CI) |
|
0.10 (-0.03, 0.23) |
0.10 (-0.03, 0.23) |
0.18 (0.03, 0.33) |
| p-value |
|
0.263 |
0.264 |
0.048 |
Efficacy: 48 weeks. Exploratory analyses of ACR responses at week 48 showed ACR70, ACR50 and ACR20 responses in 0%, 5%, and 20% of patients in the MTX arm, respectively, compared with 15%, 35%, and 65% of patients in the MabThera plus MTX arm (P=0.03, P=0.002 and P=0.001, respectively). In the MabThera plus cyclophosphamide arm, 27% and 49% of patients had ACR50 and ACR20 responses, respectively (P=0.01 for both comparisons). All other comparisons of ACR responses at week 48 favoured MabThera therapy, but did not reach statistical significance.
Pharmacodynamics: MabThera treatment alone or in combination with cyclophophamide or MTX resulted in sustained peripheral B cell depletion. Apart from a transient post-infusion decrease (on days 1 and 15), mean peripheral T cell counts remained stable during the study in all treatment groups. MabThera treatment was associated with marked and sustained falls in rheumatoid factor (RF) levels in all arms. MabThera in combination with either cyclophosphamide or MTX resulted in more pronounced falls in RF levels than MabThera monotherapy.
Pharmacokinetics: PK parameters were similar whether MabThera was administered alone or in combination with cyclophosphamide or MTX. The mean half-life after the second infusion was 19-22 days, systemic clearance was very low, and volume of distribution was similar to blood volume.
Safety: 24 weeks The overall incidence of AEs in each treatment arm was similar (~80% of patients). MabThera treatment was generally well tolerated, with the majority of events being of mild or moderate intensity. Only 6 patients stopped treatment for safety reasons.
The adverse event profile of MabThera observed in this study was consistent with the known safety profile of MabThera. Events with an increased incidence in any MabThera arm compared with the control arm included symptoms generally associated with the first infusion of MabThera: i.e. transient hypo/hypertension, nausea, rash, pruritus, cough, dyspnea, and pyrexia. The frequency of these events was lower with the second infusion than with the first. No infusion-associated event was serious and only one led to withdrawal (transient hypotension in a patient in the MabThera monotherapy arm).
The overall incidence of infections was similar across treatment groups. No clear pattern emerged in the incidence of infections by type of pathogen where this was known (viral, bacterial, or fungal).
In total there were 16 serious AEs in 14 patients, with the highest incidence in the MabThera plus cyclophosphamide group (6 patients). Five patients developed serious infections, four of whom were in MabThera treatment arms. Of these four, one developed pneumonia and died (no causative organism was isolated and the patient had a concomitant cardiac condition which may have contributed to the death.). Two had septic arthritis, one of whom developed a systemic staphylococcal infection. The fourth patient, who had a history of pseudomonal infection and bronchiectasis, had two episodes of pseudomonal pneumonia exacerbation.
Safety: 48 weeks. Between weeks 24 and 48, the profile of adverse events reported remained consistent with those observed during the initial 24 weeks. During this period, a further 3 patients withdrew owing to adverse events, one in the MTX monotherapy arm and 2 in the MabThera monotherapy arm. There were 6 additional serious AEs, including 2 serious infections (gastroenteritis in a patient who had received MabThera alone, and pyelonephritis in a patient receiving MabThera plus MTX,
Conclusions:
MabThera given either as monotherapy or in combination with MTX or cyclophosphamide provided a high level of sustained improvement in disease activity in RA patients. ACR50 response and secondary disease activity parameters indicated the superior efficacy of MabThera treatment over MTX alone, with greatest efficacy in the combination treatment arms. There was no apparent difference in the efficacy observed between the combinations of MabThera with either cyclophosphamide or MTX. MabThera was well-tolerated in RA patients. The adverse event profile in this study was consistent with the known safety profile of MabThera, events being primarily associated with infusions. The pharmacokinetics of MabThera were not altered by co-administration of cyclophosphamide or MTX. The PK parameters of MabThera in RA patients were similar to those observed in patients with NHL, but showed less variability in RA patients than in NHL patients. MabThera treatment alone or in combination with cyclophosphamide or MTX resulted in almost complete and sustained peripheral B cell depletion and marked falls in rheumatoid factor levels.
Publications (references, if available):
Edwards J, Szczepanski L, Szechinski J et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004; 350:2572-81
