Article Text

Download PDFPDF
Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis
  1. Andreas Kerschbaumer1,
  2. Nina Maria Stimakovits1,
  3. Josef S Smolen1,
  4. Tijen Stefanova1,
  5. Eva Chwala2,
  6. Daniel Aletaha1
  1. 1Division of Rheumatology, Department of Medicine III, Medical University of Vienna, Wien, Austria
  2. 2University Library, Medical University of Vienna, Wien, Austria
  1. Correspondence to Professor Daniel Aletaha, Department of Medicine III, Medical University of Vienna, Wien 1090, Austria; daniel.aletaha{at}meduniwien.ac.at

Abstract

Objectives To investigate whether treatment effects of pharmaceutical compounds compared with placebo controls are systematically different to the effects of the same compounds compared with active treatment controls in rheumatoid arthritis (RA) clinical trials.

Methods We systematically identified randomised controlled trials (RCTs) in RA, and matched active treatment arms with comparable regimens, populations, background therapy, and outcome reporting, by the nature of their control group (active comparator or placebo). Medline, EMBASE and CENTRAL were used to identify RCTs investigating disease modifying anti-rheumatic drug therapies until December 2021. Using mixed-model logistic regression we estimated OddsRatios (OR) for achieving an American College of Rheumatology (ACR) 20/50/70% response at weeks 12 and 24. Risk of bias was assessed using the Cochrane Tool.

Results We screened 8328 studies and included 40 for analysis after detailed review of 590 manuscripts; unique compounds had significantly higher responses in active comparator trials compared with their effects observed in placebo controlled trials, with ORs of 1.67 (95% CI 1.46 to 1.91; p<0.001) for ACR20, 1.50 (95% CI 1.29 to 1.75; p<0.001) for ACR50 and 1.65 (95% CI 1.30 to 2.10; p<0.001) for ACR70 (week 12); corresponding ORs for ACR 20, 50, and 70 (week 24) were 1.93 (95% CI 1.50 to 2.48; p<0.001), 1.75 (95% CI 1.32 to 2.33; p<0.001) and 1.68 (95% CI 1.21 to 2.34; p<0.001), respectively. Sensitivity analyses showed consistent results.

Conclusion Placebo controlled trials lead to smaller effect sizes of active compounds in RCTs compared with the same compound in head-to-head trials. This difference may be explained by potential nocebo effects in placebo-controlled settings and needs to be considered when interpreting head-to-head and placebo-controlled trials, by patients, investigators, sponsors and regulatory agencies.

  • Rheumatoid Arthritis
  • Biological Therapy
  • Outcome Assessment, Health Care
  • Therapeutics

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study. Due to the nature of this analysis, data that was used during analysis of this study were published previously. Primary outcomes used for the analyses of this study are shown in rthe online supplemental information. All references for the trials included for analyses are also listed in online supplemental information.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study. Due to the nature of this analysis, data that was used during analysis of this study were published previously. Primary outcomes used for the analyses of this study are shown in rthe online supplemental information. All references for the trials included for analyses are also listed in online supplemental information.

View Full Text

Footnotes

  • Handling editor Dimitrios T Boumpas

  • Contributors AK: planning and conception of the study, interpretation of results, statistical analysis, figure development, manuscript draft and preparation. NMS: statistical analysis, manuscript draft and preparation, figure development, abstract screening, data extraction, risk of bias assessment. JSS: planning and conception of the study, figure development, interpretation of results, manuscript preparation. TS: abstract screening, data extraction, risk of bias assessment, manuscript preparation. EC: development of search strategy, systematic literature search, manuscript preparation. DA: 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. AK 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, Consultancy: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck Sharp and Dohme, Novartis, UCB and Pfizer. NMS: Nothing to declare. TS: Nothing to declare. EC: Nothing to declare. JSS: received grants from Abbvie, Astra-Zeneca, Janssen, Lilly, Novartis, Roche and honoraria from Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB. DA received grants from Abbvie, Amgen, Lilly, Novartis, Roche, SoBi, Sanofi; and honoraria (speakers bureau/consultancy) from Abbvie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • 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.