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Ann Rheum Dis 69:186-192 doi:10.1136/ard.2009.115832
  • Clinical and epidemiological research
  • Concise report

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

  1. M Boers
  1. Correspondence to Professor M Boers, Department of Epidemiology and Biostatistics, VU University Medical Centre, PK 6Z 165, PO Box 7057, 1007 MB Amsterdam, The Netherlands; eb{at}vumc.nl
  • Accepted 3 September 2009
  • Published Online First 22 September 2009

Abstract

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.

Conclusion: 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.

Footnotes