Estimating Causal Treatment Effects in Placebo-Controlled Trials with High Placebo Response

Music City Center 

In placebo-controlled RCTs, the placebo response significantly modifies treatment effects and diminishes the ITT treatment effect, Δ_ITT. This study presents a novel design consisting of two stages to estimate the standardized causal treatment effect, Δ_STD, among ITT subjects, had they exhibited lower levels of placebo response when using the active drug at home. Stage one involves an open-label placebo lead-in phase designed to estimate the expected placebo response had the active treatment been self-administered in daily use. In stage two, a double-blinded randomized phase is employed to estimate the CATE as a function of placebo response levels and other effect modifiers. To simplify CATE estimation, prognostic scores serve as placebo responses at both stages. The causal estimand Δ_STD is computed by averaging the CATE across the placebo response levels at stage one. We derive theoretical values of Δ_ITT- Δ_STD under normality and parametric assumptions to quantify bias attributable to the presence of placebo response. The validity of the proposed estimand is further evaluated through a series of simulations.

Placebo Response

Causal Treatment Effect

Placebo-controlled Randomized Clinical Trials (RCTs)

Conditional Average Treatment Effect (CATE)

Prognostic Score 

Section on Statistics in Epidemiology