Abstract 700: The Anti-TNF Certolizumab Pegol in Combination with Methotrexate is Significantly More Effective than Methotrexate Alone in the Treatment of Patients with Active Rheumatoid Arthritis: 1-Year Results from the RAPID 1 Study
Authors
E Keystone, D Mason, B Combe
Methods:
RAPID 1 was a double-blind, placebo-controlled, parallel-group, 52-week study of the lyophilized preparation of CZP. Co-primary endpoints were ACR20 at Week 24 and change in modified Total Sharp Score from baseline at Week 52. Patients who withdrew for any reason were considered non-responders.
Results:
982 patients were randomized, of these, 572 completed. At Weeks 24 and 52, ACR20, ACR50, and ACR70 responder rates for patients receiving CZP were significantly greater than those for patients receiving placebo (Table). Proportions of patients who experienced an adverse event (AE) was 74.7% and 76.6% in the CZP 200 mg and 400 mg groups, respectively, and 57.8% in the placebo group. Most AEs were mild to moderate and discontinuation due to AEs was low (4.3%, 5.7% and 1.5% in the CZP 200 mg, 400 mg, and placebo groups, respectively).
Table. ACR Responder Rates at Weeks 24 and 52 (ITT) |
||||
|
Placebo |
CZP 200 mg (n = 393) |
CZP 400 mg (n = 390) |
P-Value (active vs placebo) |
Week 24 |
|
|
|
|
ACR20 |
13.6% |
58.8% |
60.8% |
< 0.001 |
ACR50 |
7.6% |
37.1% |
39.9% |
< 0.001 |
ACR70 |
3.0% |
21.4% |
20.6% |
< 0.001 |
Week 52 |
|
|
|
|
ACR20 |
13.1% |
53.1% |
54.9% |
< 0.001 |
ACR50 |
7.6% |
38.0% |
39.9% |
< 0.001 |
ACR70 |
3.5% |
21.2% |
23.2% |
< 0.001 |
Conclusions:
CZP 200 mg every 2 weeks, after 3 initial doses of 400 mg, added to MTX showed significant reduction in signs and symptoms of active RA compared with MTX alone at 24 weeks, with sustained results through 52 weeks. The higher dose of 400 mg every 2 weeks provided a similar benefit.
Editorial Comment:
Inhibition of TNF is effective in decreasing signs and symptoms of RA. In these studies of a novel TNF antagonist, certolizumab pegol (CZP) administered via SQ route every 2 weeks in either a liquid or lyophilized formulation decreased RA activity, though ACR70 responses were slightly higher in the study of the lyophilized formulation. CZP 200 mg SQ every 2 weeks after three initial doses of 400 mg every 2 weeks when added to MTX in MTX inadequate responders, reduced signs and symptoms of RA compared with patients continued on MTX alone. Continuing a higher dose of 400 mg every 2 weeks, after an initial 3 doses of 400 mg, did not provide additional symptomatic benefit. Clinical responses to MTX therapy alone were extremely low in comparison to many other RA studies of other biologic agents. The higher loading dose of the medication followed by a lower maintenance dose is an interesting approach to achieving more rapid symptom control. In fact in time course data presented in RAPID-1, there was a rapid improvement and plateau of ACR 50 and ACR 70 responses by 14-16 weeks and 16-20 weeks respectively. All doses of CZP were well tolerated, with a low incidence of discontinuation due to AEs, but higher than in the MTX only comparator group. Based on mechanism of action of TNF inhibition, the expected adverse event profile in terms of infection was as expected. Interestingly cases of TB were seen in the CZP groups in spite of screening arguing that TNF inhibition in general and not cell lysis due to monoclonal antibody fixation is operative in the development of TB. The radiographic data presented showed no surprises, and was consistent with other TNF antagonists slowing radiographic progression in total Sharp scores and its component measurements of erosions and joint space narrowing. Longer term outcome studies are needed, but these data are encouraging.
