The time has come to limit the placebo period in rheumatoid arthritis trials to 3 months: a systematic comparison of 3- and 6-month response rates in trials of biological agents.
BACKGROUND
Most registration trials in rheumatoid arthritis (RA) include a placebo arm in the setting of an incomplete response to disease-modifying antirheumatic treatment (DMARD-IR). A minimum duration of 6 months is required despite serious methodological and ethical shortcomings.


OBJECTIVE
To study whether a 3-month placebo period is sufficient to prove efficacy.


METHODS
Meta-analysis of placebo- or active control trials of biological agents in DMARD-IR RA, comparing the contrast in ACR response between experimental and control groups at 3 and 6 months.


RESULTS
Twenty trials yielded 15 placebo and 18 active control contrasts (>10,000 patients). At 3 months active treatment showed a highly significant contrast with placebo for ACR20 and ACR50 in every instance. As all groups improved further the mean contrast at 6 months was unchanged. For ACR70 the contrast was clearly greater at 6 months owing to further improvement only in the experimental groups. In active control trials contrasts were smaller, and for ACR50 and ACR70 these decreased somewhat owing to "catch-up" responses in the control groups.


CONCLUSIONS
The placebo phase of registration trials for RA can be limited to 3 months. An accompanying viewpoint proposes that patients receiving placebo should then be switched to standard of care, allowing a more valid and comprehensive assessment, including safety.
Department of Epidemiology and Biostatistics, VU University Medical Centre, PK 6Z 165, PO Box 7057, 1007 MB Amsterdam, The Netherlands. eb@vumc.nl
M
M
Boers
D018501:Antirheumatic Agents / Q000008:administration & dosage*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004334:Drug Administration Schedule; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D010919:Placebos / Q000008:administration & dosage*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D013997:Time Factors; D017211:Treatment Failure; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D018501:Antirheumatic Agents; D007155:Immunologic Factors; D010919:Placebos; D014409:Tumor Necrosis Factor-alpha