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Impact of pre-existing background therapy on placebo responses in randomised controlled clinical trials of rheumatoid arthritis
  1. Andreas Kerschbaumer,
  2. Zaïda Iasha Rivai,
  3. Josef S Smolen,
  4. Daniel Aletaha
  1. Abteilung für Rheumatologie, Medizinische Universitat Wien Universitatsklinik fur Innere Medizin III, Wien, Austria
  1. Correspondence to Professor Daniel Aletaha, Department of Medicine III, Medical University of Vienna, Wien, Austria; daniel.aletaha{at}meduniwien.ac.at

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.

  • rheumatoid arthritis
  • methotrexate
  • biological therapy

Data availability statement

Data may be obtained from a third party and are not publicly available. This study, carried out under YODA Project # 2018-3704, used data obtained from the Yale University Open Data Access Project (https://yoda.yale.edu/), which has an agreement with Janssen Research & Development, LLC. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or Janssen Research & Development, LLC.

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Data availability statement

Data may be obtained from a third party and are not publicly available. This study, carried out under YODA Project # 2018-3704, used data obtained from the Yale University Open Data Access Project (https://yoda.yale.edu/), which has an agreement with Janssen Research & Development, LLC. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or Janssen Research & Development, LLC.

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Footnotes

  • Handling editor David S Pisetsky

  • Contributors AK contributed to planning and conception of the study, interpretation of results, statistical analysis, figure development, manuscript draft and preparation. ZIR contributed to statistical analysis, manuscript draft and preparation, figure development. JSS contributed to planning and conception of the study, figure development, interpretation of results, manuscript preparation. DA contributed to planning of the study, interpretation of results, figure development, manuscript preparation. AK and DA had access to the data, controlled the decision to publish and accept full responsibility for the finished work of the study. DA is the guarantor of the study. All authors gave their final approval of the final document version to be published.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests AK: Speakers bureau: Janssen. ZIR: Nothing to declare. JS: Received consulting fees and honoraria from Janssen and lead author of the GO-AFTER study. DA: Received consulting fees and honoraria from Janssen and lead author of the SIRROUND-T study.

  • Patient and public involvement Patients’ representatives and the public were not involved in the planning and conduction of this study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.