Feasibility of Simon Two‐Stage Futility Trials in People with Early, Symptomatically Treated Parkinson's Disease

Background Disease‐modifying treatments are a critical unmet need in Parkinson's disease (PD). Phase 2 futility trials using the Simon two‐stage design offer an efficient strategy to evaluate candidate treatments in an early PD population. Objective The aim was to assess the feasibility of Simon two‐stage futility trials in early, levodopa‐treated PD subjects using historical patient‐level clinical trial datasets. Methods We analyzed patient‐level data from two completed trials, that is, STEADY‐PD 3 (n = 336, untreated at baseline) and NET‐PD LS1 (n = 1741, treated at baseline). We defined disability progression as a ≥5‐point worsening on the motor (Part III) subscore of the Unified Parkinson's Disease Rating Scale at 12 and 24 months. We tested multiple scenarios, including the reanalysis of STEADY‐PD 3 participant data after starting dopaminergic treatment. We assessed predictors of progression using logistic regression analysis and calculated sample size estimates. Results Both trials showed similar progression rates at 12 months (~26%) and 24 months (~35%). In NET‐PD LS1, older age and lower baseline motor scores were associated with worsening; no predictors were significant in STEADY‐PD 3. We estimate that in futility trials that use OFF‐state scores to assess motor performance, 39 early PD participants are required to detect significant disability worsening over an observation period of 12 months. Conclusions Phase 2 futility trials using the Simon two‐stage methodology are feasible in early PD, including in treated and untreated patients. OFF‐state scores are preferable to ON‐state scores as the primary outcome measure. Futility trials offer a smaller‐scale, faster, and cost‐effective approach to assessing new candidate treatments in PD.