Efficacy and Safety of Ecopipam for Tourette Syndrome: A Phase 3 Randomized Clinical Trial

Abstract

IMPORTANCE Current Tourette syndrome (TS) pharmacotherapy is hindered by adverse effects and high discontinuation rates. OBJECTIVE To evaluate the safety and maintenance of effect of ecopipam, a selective dopamine D1 receptor antagonist, for up to 24 weeks for TS. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was a phase 3, double-blind, placebo-controlled, randomized withdrawal study conducted between January 31, 2023, and February 4, 2025. Participants were enrolled at 77 sites in 12 countries. Individuals 6 years and older with TS were eligible. INTERVENTION In the 12-week, open-label period, ecopipam was titrated over 3 to 4 weeks (target dose, 1.8 mg/kg per day). Responders (25% improvement in Yale Global Tic Severity Scale Total Tic Score [YGTSS-TTS] at weeks 8 and 12) were randomized to continue ecopipam or taper to placebo for the 12-week double-blind period. MAIN OUTCOMES AND MEASURES Time to relapse (50% loss of open-label period YGTSS-TTS improvement) in participants aged 6 to 18 years (primary) and adults (exploratory). RESULTS The trial enrolled 216 participants (n = 167 [77.3%] pediatric; 146 [67.6%] male and 70 [32.4%] female) to the open-label ecopipam period. Of these, 43 pediatric participants (mean [SD] age, 14.3 [5.5] years) and 8 adult participants were randomized to receive ecopipam; 47 pediatric (mean [SD] age, 14.0 [5.8] years) and 6 adult participants were randomized to receive placebo. Ecopipam significantly reduced the relapse risk vs placebo in pediatric participants (hazard ratio [HR], 0.47; 95% CI, 0.26-0.84; P = .008; n = 90). In adults, the effect was directionally similar (HR, 0.51; 95% CI, 0.11-2.30; P = .37; n = 14) but not significant. The most frequently reported adverse events with ecopipam (open-label and double-blind periods) were somnolence (n = 24 [11.1%]), anxiety (n = 21 [9.7%]), headache (n = 21 [9.7%]), insomnia (n = 19 [8.8%]), tic (n = 17 [7.9%]), and fatigue (n = 14 [6.5%]). Ecopipam did not have a clinically meaningful impact on weight, metabolic parameters, or psychiatric scale measures. Drug-induced movement disorders were not observed. CONCLUSIONS AND RELEVANCE Ecopipam maintained clinically meaningful TS symptom improvements and was well tolerated for up to 24 weeks. Adverse events primarily affected the central nervous system. IMPORTANCE Current Tourette syndrome (TS) pharmacotherapy is hindered by adverse effects and high discontinuation rates. OBJECTIVE To evaluate the safety and maintenance of effect of ecopipam, a selective dopamine D1 receptor antagonist, for up to 24 weeks for TS. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was a phase 3, double-blind, placebo-controlled, randomized withdrawal study conducted between January 31, 2023, and February 4, 2025. Participants were enrolled at 77 sites in 12 countries. Individuals 6 years and older with TS were eligible. INTERVENTION In the 12-week, open-label period, ecopipam was titrated over 3 to 4 weeks (target dose, 1.8 mg/kg per day). Responders (25% improvement in Yale Global Tic Severity Scale Total Tic Score [YGTSS-TTS] at weeks 8 and 12) were randomized to continue ecopipam or taper to placebo for the 12-week double-blind period. MAIN OUTCOMES AND MEASURES Time to relapse (50% loss of open-label period YGTSS-TTS improvement) in participants aged 6 to 18 years (primary) and adults (exploratory). RESULTS The trial enrolled 216 participants (n = 167 [77.3%] pediatric; 146 [67.6%] male and 70 [32.4%] female) to the open-label ecopipam period. Of these, 43 pediatric participants (mean [SD] age, 14.3 [5.5] years) and 8 adult participants were randomized to receive ecopipam; 47 pediatric (mean [SD] age, 14.0 [5.8] years) and 6 adult participants were randomized to receive placebo. Ecopipam significantly reduced the relapse risk vs placebo in pediatric participants (hazard ratio [HR], 0.47; 95% CI, 0.26-0.84; P = .008; n = 90). In adults, the effect was directionally similar (HR, 0.51; 95% CI, 0.11-2.30; P = .37; n = 14) but not significant. The most frequently reported adverse events with ecopipam (open-label and double-blind periods) were somnolence (n = 24 [11.1%]), anxiety (n = 21 [9.7%]), headache (n = 21 [9.7%]), insomnia (n = 19 [8.8%]), tic (n = 17 [7.9%]), and fatigue (n = 14 [6.5%]). Ecopipam did not have a clinically meaningful impact on weight, metabolic parameters, or psychiatric scale measures. Drug-induced movement disorders were not observed. CONCLUSIONS AND RELEVANCE Ecopipam maintained clinically meaningful TS symptom improvements and was well tolerated for up to 24 weeks. Adverse events primarily affected the central nervous system.