Objective:

To design an efficient, maintenance-of-effect trial for ecopipam in Tourette Syndrome (TS) while further informing the risk profile.

Background:

Ecopipam is a selective dopamine 1 receptor antagonist in development for TS.  A 12-week, parallel group, Phase 2b trial of ecopipam in TS demonstrated a clinically meaningful, statistically significant reduction in tics without inducing weight gain, metabolic syndrome, EKG changes, or drug-induced movement disorders associated with dopamine 2 receptor antagonists.  Ideally, a Phase 3 trial should both confirm efficacy and observe safety over a longer duration of exposure.

Design/Methods:

We designed an enriched-enrollment, randomized withdrawal (EERW) clinical trial to best meet maintenance-of-efficacy and safety objectives. All enrolled subjects receive ecopipam for 12 weeks.  Those with a ≥25% improvement in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) at both weeks 8 and 12 are randomized, double-blinded, 1:1 to continue ecopipam or down-titrate to placebo, for an additional 12 weeks. The primary maintenance-of-effect endpoint is time-to-relapse where relapse is defined as 1. a ≥50% loss of the YGTSS-TTS improvement, 2. required use of tic rescue medication, or 3. hospitalization for TS.  The trial completes when the number of relapses has reached the pre-specified target sufficient to differentiate ecopipam from placebo with 85% power.  Trial simulations and sensitivity analysis were performed across key variables.

Results:

The number of relapses required is a function of the two relapse rates individually.  Previous results suggest, conservatively, that 34% of participants randomized to ecopipam and 65% randomized to placebo will relapse, yielding a target of 49 relapse events for completion.  Simulations informed both enrollment and duration requirements.

Conclusions:

This EERW design meets feasibility requirements, provides up to 24 weeks of safety data, and is powered to determine maintenance of efficacy of ecopipam for TS while reducing placebo exposure for this serious disorder.