Dr. Maini has received consulting fees and honoraria (less than $10,000 each) from Roche and Centocor and has received consulting fees (more than $10,000) from Chugai Pharmaceuticals Ltd. Dr. Maini receives royalties from The Kennedy Institute of Rheumatology Trust for an anti–tumor necrosis factor patent. Dr. Maini is a coinventor of the coadministration of tocilizumab and methotrexate, for which a patent is pending. Dr. Maini previously owned stock in Johnson & Johnson, of which Centocor is a subsidiary. Dr. Maini is Non-Executive Director of Domantis and founder of Synovis Ltd. Dr. Taylor has received honoraria (less than $10,000) from Centocor. Dr. Emery has received consulting fees (less than $10,000) from Roche. Dr. Kishimoto holds a patent for tocilizumab.
Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate
Article first published online: 31 AUG 2006
Copyright © 2006 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 54, Issue 9, pages 2817–2829, September 2006
How to Cite
Maini, R. N., Taylor, P. C., Szechinski, J., Pavelka, K., Bröll, J., Balint, G., Emery, P., Raemen, F., Petersen, J., Smolen, J., Thomson, D. and Kishimoto, T. (2006), Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis & Rheumatism, 54: 2817–2829. doi: 10.1002/art.22033
- Issue published online: 31 AUG 2006
- Article first published online: 31 AUG 2006
- Manuscript Accepted: 11 MAY 2006
- Manuscript Received: 5 OCT 2005
- Chugai Pharmaceuticals Ltd.
To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti–interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA).
The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo.
A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX.
These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.