Efficacy and Safety of Ecopipam for Tourette Syndrome (TS): Results From a Phase 3, Randomized, Double-Blind, Placebo-Controlled Withdrawal Trial

Objective: To evaluate the efficacy and safety of ecopipam, a dopamine D1 receptor antagonist, as a maintenance therapy in children, adolescents, and adults with TS. Background: Current TS pharmacotherapies are limited by the risk for weight gain, metabolic abnormalities, and drug-induced movement disorders. A previous pediatric phase 2b trial showed ecopipam significantly reduced TS tics versus placebo with a favorable adverse event (AE) profile. Method: Patients aged ≥6 y with TS were included in a randomized, double-blind, placebo-controlled, withdrawal trial. Ecopipam was titrated, over 4 weeks, up to a target dose of 1.8 mg/kg/day during a 12-week open-label period. Patients with a clinically meaningful reduction (≥25%) in Yale Global Tic Severity Scale Total Tic Score (YGTSS-TTS) at Week 8 and at Week 12 were randomized to either ecopipam (1.8 mg/kg/day) or placebo during a 12-week double-blind period. During this period, visits occurred weekly for the first 4 weeks, then every 2 weeks through Week 24. The primary efficacy endpoint was time (from randomization [Week 12]) to relapse (defined as ≥50% decrease in YGTSS-TTS improvement observed at open-label period Week 12) in the pediatric cohort (6 to <18 years) during the withdrawal period. Results: 216 patients were enrolled in the 12-week open-label phase. Overall, 104 patients (90 pediatric) were randomized to the 12-week double-blind period to continue ecopipam (n=51; 84.3% pediatric and 72.5% male) or switch to placebo (n=53; 88.7% pediatric and 66.0% male). In the pediatric population (primary efficacy endpoint), there was a 50% risk reduction for relapse for ecopipam compared with placebo (hazard ratio [95% CI], 0.5 [0.3, 0.8]; P=0.008 [log-rank test]). In the overall population (pediatrics and adults; secondary endpoint), there was a 50% risk reduction for relapse for ecopipam compared with placebo (hazard ratio [95% CI], 0.5 [0.3, 0.8]; P=0.005 [log-rank test]). The most commonly reported AEs (≥5.0%), regardless of causality, in the ecopipam group during 24-week study were somnolence (11.1%), anxiety (9.7%), headache (9.7%), insomnia (8.8%), tic (7.9%), and fatigue (6.5%). Conclusion: This phase 3 trial provided confirmatory evidence that clinically meaningful improvements in TS symptoms were maintained with continued ecopipam treatment, which was generally well tolerated.