Placebo Effects in Clinical Trials Evaluating Patients with Uncontrolled Persistent Asthma

Rationale: Patients with uncontrolled, persistent asthma can show substantial health improvements when administered placebo.Objectives: We analyzed five randomized, placebo-controlled clinical trials that assessed subjects with uncontrolled, persistent asthma to determine the magnitudes of placebo effects across different clinical outcomes.Methods: Placebo effects for objective asthma-related outcomes, healthcare utilization outcomes, and patient-reported outcomes were estimated, with adjustments for regression to the mean.Results: Statistically significant improvements in all clinical outcomes were seen in patients randomized to placebo across all trials. Placebo effects were largest for healthcare utilization outcomes, including exacerbations (median reduction, 0.44 events/yr; 31% risk reduction; range, 19-56%), emergency department visits (median reduction, 0.19 events/yr; 50% risk reduction; range, 36-82%), and hospitalizations for asthma (median reduction, 0.26 events/yr; 66% risk reduction; range, 61-74%). Patient-reported outcomes exhibited intermediate placebo effects. Median improvements in the Asthma Control Questionnaire and St. George's Respiratory Questionnaire scores in placebo-treated patients were 0.53 units (25% improvement; range, 18-30%) and 8.3 units (19.5% improvement; range 19-20%), respectively. Forced expiratory volume in 1 second exhibited the smallest relative placebo effects (median increase, 77 ml; 4.2% improvement; range, 3.4-4.9%). Subgroup analyses did not reveal patient subgroups that were more susceptible to placebo effects. Pre- and postrandomization counts for asthma exacerbations showed patterns consistent with the expected negative binomial distribution except for significant departures in prerandomization exacerbations for two trials.Conclusions: Patients with uncontrolled asthma derived consistent benefit from randomization to placebo. Observed placebo effects may represent beneficial effects of both sham therapy and a structured asthma regimen dictated by the study protocol. In the case of healthcare utilization outcomes, recall errors in self-reported healthcare events may have introduced biases that inflated placebo effect estimates.