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Clinical Trial Result Information
Title of Study:
A randomized, double-blind, international study to evaluate the efficacy and safety of various re-treatment regimens of rituximab in combination with methotrexate in RA patients with an inadequate response to methotrexate.
Fast Facts:
| Protocol number: | WA17044 |
| Sponsor: | F Hoffman-La Roche Ltd |
| Company division: | Pharmaceutical |
| Product name: | MabThera/Rituxan |
| Generic name: | rituximab |
| Phase of development: | III |
| Therapeutic area, approved indication: | Rheumatoid Arthritis |
| Date of report: | 7/1/2008 |
Clinical study summary:
This was a randomized, double-blind, parallel group multicenter efficacy and safety study to evaluate the effect of various MabThera dosage regimens in combination with methotrexate (MTX) in rheumatoid arthritis (RA) patients with inadequate response to MTX.
Study center(s) :
81 centers in Australia, Belgium, Brazil, Canada, China, Finland, France, Germany, Hungary, Italy, Netherlands, New Zealand, Slovakia, South Africa, Spain, Taiwan, Thailand, United Kingdom
Objectives:
To determine if a second course with an increased dose of MabThera is associated with improved responses compared to retreatment with the same dose; to determine response rates to two courses of 2 x 500 mg MabThera and two courses of 2 x 1000 mg MabThera; and to investigate the pharmacokinetics of rituximab associated with 2 courses of treatment.
Methodology:
After screening, eligible patients were randomized to one of the three main treatment arms (MabThera 2 x 500 mg + MTX, MabThera 500 mg/1000 mg + MTX, MabThera 1000 mg/1000 mg + MTX) and received the first course of treatment on days 1 and 15. The second course of two infusions was given on days 168 and 182. At each scheduled visit to Week 48 patients underwent patient-reported assessments (patient’s global assessment of disease activity; pain; Health Assessment Questionnaire [HAQ]; Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT - F]; 36-Item Short-Form Health Survey [SF-36]), efficacy assessments (joint counts; physician’s global assessment of disease activity), safety assessments (adverse events, laboratory assessments) and pharmacokinetic sampling.
Number of patients (planned/analyzed):
Planned 375: Treated 378
Diagnosis and main criteria for inclusion:
Male or female patients ≥ 18 years with active RA responding inadequately to MTX or patients previously treated with no more than one biological agent approved for use in RA.
Test product, dose and mode of administration or test procedure:
MabThera (rituximab) (0.5 g, 1.0 g) administered by i.v. infusion on Days 1 and 15. The second course of two infusions was given at Week 24.
Duration of treatment:
Primary treatment period of 48 weeks: Total of 3 years treatment
Reference therapy, dose and mode of administration or reference procedure:
All patients received concomitant MTX 10-25 mg/week at a stable dose (p.o. or parenteral).
Criteria for evaluation (efficacy, safety):
Efficacy: The primary efficacy parameter was the percentage of patients with ACR20 at 48 weeks.
Secondary efficacy parameters were proportion of patients with ACR50 & ACR70 at Week 48, change in DAS28, SF-36, FACIT-fatigue assessment from baseline at Week 48. EULAR response rates at Week 48.
Pharmacokinetics parameters were maximum observed serum concentrations following first and second doses and half life.
Safety parameters were adverse events, standard hematology and biochemistry.
Statistical methods:
The primary endpoint was analyzed using the Cochran-Mantel Haenszel test, stratifying by region, prior biologic use and RF status.
Summary (efficacy, safety, other results):
αEfficacy: The majority (65%) of patients across the three main treatment arms achieved at least an ACR20 response, 41% had an ACR50 response and 20% had an ACR70 response at Week 48 relative to baseline. There was no significant difference in efficacy between the low dose and the other dosing regimens in either the ITT (as randomized) or ITT-M2 (as treated) analyses. However, several efficacy outcomes (e.g., EULAR response, proportion of patients achieving low disease or remission) suggest improved outcomes in the high dose group.
Summary of Clinical Efficacy at Week 48
|
(2 x 0.5 g, 2 x 0.5 g) + MTX |
(2 x 0.5 g, 2 x 1 g) +MTX |
(2 x 1 g, 2 x 1 g) +MTX | |
| ITT | N=123 | N=127 | N=113 |
| Primary endpoint | 79 (64) | 82 (65) | 77 (68) |
| ACR20 (%) p-valuea |
0.886 | 0.671 | |
| ITT-M2 | N=134 | N=119 | N=93 |
| ACR20 (%) p-valuea |
86 (64) | 76 (64) 0.816 |
67 (72) 0.242 |
| ACR50 (%) | 52 (39) | 46 (39) | 45 (48) |
| ACR70 (%) | 27 (20) | 23 (19) | 21 (23) |
| Change in DAS28 n [Mean (SD)] |
n=132 -2.3 (1.3) |
n=118 -2.4 (1.5) |
n=93 -2.6 (1.4) |
| EULAR Response (%) | |||
| None Moderate Good Low disease activity DAS remission |
36 (27) 68 (51) 30 (22) 31 (23) 12 (9) |
33 (28) 66 (56) 20 (17) 20 (17) 15 (13) |
10 (11) 58 (62) 25 (27) 25 (27) 18 (19) |
| HAQ-DI ≥ MCIDb (%) | 93 (69) | 86 (72) | 67 (72) |
| SF36 domains ≥ MCIDc (%) Mental Health Physical Health |
n=121 58 (43) 69 (52) |
n=112 48 (41) 66 (56) |
n=86 37 (40) 53 (57) |
| FACIT-F ≥ MCIDd (%) | n=125 72 (58) |
n=115 74 (64) |
n=91 63 (69) |
MCID = minimum clinically important difference
a p-value from CMH test, analysis was stratified by region, prior biologic use, RF status and treatment, b defined as decrease of >0.22, c defined as decrease of >6.33 for mental health score and change >5.42 for physical health score, d defined as increase ≥4
The proportion of responders increased over time. Response to repeat treatment was similar across dose regimens. Approximately 40% of nonresponding patients at Week 24 subsequently responded after the second course (Week 48) of treatment, irrespective of dose (low dose vs dose escalation). The majority (~80%) of ACR20 responders to the first course of treatment at Week 24 maintained their response (at least ACR20) after the second course of treatment (Week 48).
Response to Second Course of Treatment (Week 48) According to Response to First Course (Week 24) (ITT-M2)
| ACR20 nonresponders at Week 24 | ACR20 responders at Week 24 | |||||
| Low dose (N=65) |
Dose escalation (N=46) |
High dose (N=31) |
Low dose (N=69) |
Dose escalation (N=73) |
High dose (N=62) |
|
| ACR20 (%) | 27 (41.5) | 17 (37.0) | 15 (48.4) | 59 (85.5) | 59 (80.8) | 52 (83.9) |
| ACR50 (%) | 10 (15.4) | 3 (6.5) | 7 (22.6) | 42 (60.9) | 43 (58.9) | 38 (61.3) |
| ACR70 (%) | 5 (7.7) | 2 (4.3) | 2 (6.5) | 22 (31.9) | 21 (28.8) | 19 (30.6) |
| Change in DAS28 from Week 24 to Week 48 (adjusted mean) | -0.69 | -0.89 | -0.96 | -0.05 | -0.19 | -0.23 |
Low dose= MABTHERA (2 x 0.5g, 2 x 0.5g)+MTX, dose escalation = MABTHERA (2 x 0.5g, 2 x 1g) +MTX,
high dose = MABTHERA (2 x 1g,2 x 1g) +MTX
Imputation for missing data: Nonresponder imputation for categorical variables, LOCF for continuous
Adjusted means from ANOVA model containing Week 24 value, region, prior biologic use, RF status
Pharmacokinetic and pharmacodynamic results: The PK/PD profile of rituximab was comparable for the first and second courses of treatment. Half-life was similar across all doses and courses. Approximately 7% of patients with post-baseline assessments of HACA had at least one positive HACA titer during the study. The presence of HACA did not appear to influence the efficacy or safety of further courses of MabThera.
Safety: The safety profile was similar in the three main treatment arms over the 48-week study period. Infusion related reactions occurred in 27% of patients with the first course of treatment and 17% with the second course. Serious infusion reactions were rare (2/377 – 0.5%). The overall rate of serious infection was 3.66 per 100 patient-years. Overall, the safety profile was similar to previous experience with MabThera and no new safety signals were observed .
Conclusions:
MabThera was effective and well-tolerated in the DMARD-IR population, including patients receiving one prior biologic. The low dose (2 x 0.5g) and high dose (2 x 1g) of MabThera could not be clearly differentiated in terms of efficacy after 48 weeks of follow up. However, some efficacy outcomes (e.g., EULAR response, proportion of patients with low disease activity or remission) suggest improved outcomes for the high dose.
Overall, repeat treatment maintained response to the first course and may have had incremental benefit. PK/PD of rituximab was similar after a second course of treatment to that following the first course
Safety was comparable for all treatment regimes with a profile of events consistent with previous studies.
