Impact of pre-existing background therapy on placebo responses in randomised controlled clinical trials of rheumatoid arthritis.

ABSTRACT

OBJECTIVES: Various hypotheses exist for the explanation of placebo response rates in randomised controlled trials (RCTs) of patients with rheumatoid arthritis with IR to methotrexate (MTX). We hypothesised that placebo responses may be related to more consequent intake of MTX during the tightly monitored trial period. METHODS: We conducted a post hoc analysis of placebo-treated patients included in two RCTs that had allowed inclusion of patients with and without ongoing MTX the GO-AFTER and the SIRROUND-T trials. We pooled placebo patients of both trials and compared American College of Rheumatology (ACR) 20%/50%/70% response rates and Clinical Disease Activity Index (CDAI) low disease activity (LDA; ie, CDAI ≤10) responses between those receiving placebo on top of continued MTX and those receiving placebo without any background disease modifying antirheumatic drugs (DMARDs). RESULTS: Of 398 placebo patients, 285 continued MTX and 113 had no background DMARDs. Baseline characteristics were similar. At week 16, ACR20 response was achieved by 72/285 (25.3%) of placebo+continued MTX and 14/113 (12.4%) of placebo only patients (nominal p=0.005); for ACR50 these numbers were 25/285 (8.4%) versus 1/113 (0.9%; nominal p=0.003) and for ACR70 they were 8/285 (2.8%) versus 0/113 (0%; nominal p=0.112). Also, more patients with placebo+continued MTX achieved CDAI-LDA at week 16 (25/285; 8.8%) compared with placebo only (2/113; 1.8%; nominal p=0.013). CONCLUSION: Clinical responses to placebo are higher in patients who continue an insufficient MTX background therapy. This suggests an inadvertently more consequent intake of background therapy during the trial. Background therapy should therefore be effectively aligned before enrollment into a clinical trial.