Evaluating the Feasibility of Using Historical Placebo Control in Osteoarthritis Trials

Background/Objectives: Randomized controlled trials (RCTs) are the gold standard for evaluating treatment efficacy, yet recruitment and retention remain challenging, particularly when placebo arms are required. Using historical placebo data may reduce the need for contemporaneous placebo groups, but comparability between historical and real-time placebo responses is uncertain. This study assessed the feasibility of replacing a placebo control group with a historical placebo arm in osteoarthritis (OA) RCTs using several matching approaches. Methods: Data from three published knee OA RCTs (2009, 2013, 2017) were analyzed. The study followed three steps: (1) development of matching techniques using the 2009 and 2013 trials, (2) validation in the 2017 trial, and (3) post hoc analyses comparing placebo responses across trials. Methods included direct covariate adjustment, exact and nearest-neighbor matching, and propensity score matching based on baseline characteristics (age, sex, BMI, OA duration, baseline pain). The main outcome was change in 100 mm visual analogue scale (VAS) pain. Results: Initial attempts showed moderate to good success in adjusting historical placebo response on the VAS using various adjustment methods. However, in the validation process, a significant discrepancy was observed between real placebo VAS changes data and historical placebo VAS changes data, and various matching techniques failed to sufficiently reduce this discrepancy. In the post hoc analysis, despite the application of advanced matching techniques, substantial variability in VAS placebo responses persisted across trials. Even among placebo patients with highly similar baseline characteristics, the VAS changes over time differed significantly between studies. Conclusions: The findings indicate that replacing a real placebo group with a historical placebo in osteoarthritis RCTs is hardly feasible. These results underscore the complexity of placebo effects in osteoarthritis trials and the limitations of historical control data in this context.