BACKGROUND AND OBJECTIVES

All US Food and Drug Administration-approved medications for Tourette syndrome are antipsychotics, and their use is limited by the risk of weight gain, metabolic changes, and drug-induced movement disorders. Several small trials suggest that ecopipam, a first-in-class, selective dopamine 1 receptor antagonist, reduces tics with a low risk for these adverse events. This trial sought to further evaluate the efficacy, safety, and tolerability of ecopipam in children and adolescents with moderate to severe Tourette syndrome.

METHODS

This was a multicenter, randomized, double-blind, placebo-controlled, phase 2b trial. Subjects aged ≥6 to <18 years with a baseline Yale Global Tic Severity Score Total Tic Score of ≥20 were randomly assigned 1:1 to ecopipam (n = 76) or placebo (n = 77). The primary endpoint was mean change over 12 weeks in the Yale Global Tic Severity Score Total Tic Score. The Clinical Global Impression of Tourette Syndrome Severity was the secondary endpoint. Safety and tolerability were evaluated at each study visit.

RESULTS

Total tic scores were significantly reduced from baseline to 12 weeks in the ecopipam group compared with placebo (least squares mean differences −3.44, 95% confidence interval −6.09 to −0.79, P = .01). Improvement in Clinical Global Impression of Tourette Syndrome Severity was also greater in the ecopipam group (P = .03). More weight gain was seen in subjects assigned to placebo. No metabolic or electrocardiogram changes were identified. Headache (15.8%), insomnia (14.5%), fatigue (7.9%), and somnolence (7.9%) were the most common adverse events.

CONCLUSIONS

Among children and adolescents with TS, ecopipam reduces tics to a greater extent than placebo, without observable evidence of common antipsychotic-associated side effects.

What’s Known on This Subject:

All US Food and Drug Administration-approved medications to treat Tourette syndrome are antipsychotics that block the D2 dopamine receptor and, although effective, can cause weight gain and drug-induced movements. Ecopipam is a first-in-class D1 receptor blocker in development for Tourette syndrome.

What This Study Adds:

In this randomized clinical trial, ecopipam, a D1 receptor blocker, was more effective than a placebo in reducing tic severity in children and adolescents with Tourette syndrome. Ecopipam was well tolerated and did not cause weight gain or movement disorders.

Tourette syndrome (TS) is a chronic, childhood-onset neurodevelopmental disorder characterized by both motor and vocal tics.1,2  In the United States, approximately 1 in 200 children are diagnosed with TS.3,4  The onset of TS occurs most often between ages 4 to 10 years, is more common in boys than in girls, and the severity peaks in early adolescence.2,5  Although global impairment arises from a broad spectrum of symptoms,6  severity of tics plays an important role.7  Surveys of TS-affected youth and their parents show tic-related impairment in home, school, and social domains8  as well as discrimination and bullying.9,10  The authors of recent studies have raised concerns about adverse social and medical outcomes in adulthood as well.1113  Antipsychotics, the only approved class of pharmacological treatments for tic suppression, have an unfavorable risk profile associated with weight gain, metabolic abnormalities, electrocardiogram (ECG) alterations, and movement disorders.1416  Behavioral therapies, in particular Habit Reversal Training, are recommended as first-line treatment17  but are time-consuming and are only effective for ∼50% of TS patients.18 

The pathophysiology of tics in TS is hypothesized to involve dysregulation of dopaminergic signaling in cortico-striatal-thalamo-cortical circuits.19,20  In this complex system, dopamine modulates motor control, as well as behavioral impulsivity, reward valence, and learning21,22  via the D2-like receptors (D2r, D3r, D4r) and the D1-like receptors (D1r, D5r).22  All 3 medications approved by the US Food and Drug Administration (FDA) to treat tics in TS are antipsychotics that act at the D2r. Two older, high-potency, typical antipsychotics, haloperidol and pimozide, have been FDA-approved for TS for decades.23  Aripiprazole, a partial D2r agonist/antagonist, is also FDA-approved for tic reduction.24  Risperidone, a potent, second-generation D2r antagonist, although not indicated specifically for TS, is nonetheless widely prescribed for tic reduction.25  Although effective, both first- and second-generation D2r antagonists are associated with somnolence, dysphoria, and the risk of drug-induced movement disorders, including dystonia, akathisia, withdrawal dyskinesias, and, rarely, tardive dyskinesia.17  Even more limiting to the broad use of D2r antagonists in TS is the risk of increased weight gain, elevated prolactin, dyslipidemia, and hyperglycemia, including diabetes.26 

Ecopipam, a first-in-class selective D1r antagonist, is in clinical development for children and adolescents with TS. In previous Phase 2 studies in TS, ecopipam reduced tics in both children and adults without evidence for metabolic or drug-induced movement disorders.27,28  The objective of the D1AMOND study (NCT0400799) reported here was to assess whether, in children and adolescents with TS, ecopipam could achieve a clinically meaningful reduction in tics without the disadvantages of D2r antagonists.

This was a multicenter, randomized, double-blind, placebo-controlled study conducted at 68 sites in the United States, Canada, Germany, France, and Poland between May 2019 and September 2021 (Supplemental Fig 5). The study complied with the Declaration of Helsinki and the International Council on Harmonization of Good Clinical Practice. The protocol, amendments, and informed consent were reviewed and approved by the appropriate institutional review boards and regulatory bodies. All subjects provided written informed consent before any study procedures.

Subjects ≥6 to <18 years of age, weighing ≥18 kg, with confirmed TS1  and a minimum score of 20 on the Yale Global Tic Severity Score, Total Tic Score (YGTSS-TTS)29  at screening were included. Additionally, the investigator judged the tic disorder was of sufficient severity to result in either (1) subjective discomfort (eg, pain or injury), (2) sustained social problems (eg, social isolation or bullying), (3) emotional problems, or (4) functional interference with daily activities including academic performance. Subjects were excluded for unstable primary mood disorder (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition), significant risk of suicide, history of other serious neurologic conditions, unstable medical illness, or clinically significant laboratory or ECG abnormalities. Subjects needed to be free of any tic-reducing medications for at least 14 days before baseline. Medications without D2r blocking activity for anxiety, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD) were allowed if the dosage was stable for 4 weeks before screening and not specifically prescribed for tics. Nonpharmacological treatments were permitted as long as they were not initiated within 10 weeks before baseline. Sexually active subjects were required to use a highly effective method of birth control for the duration of the study and for 30 days after the last dose. For subjects enrolled outside North America, an adequate trial of nonpharmacological treatment was required. Detailed inclusion and exclusion criteria, as well as excluded medications, are provided in the Supplemental Information.

At all sites, investigators were specifically trained on all scales and, when possible, the same evaluator performed assessments for each subject at all visits. After a 28-day screening period and a baseline visit, eligible subjects were randomly assigned 1:1 to receive either a target steady-state dose of 2 mg/kg/day of ecopipam or a matching placebo for a 4-week titration period followed by an 8-week treatment period. Ecopipam dosages were adjusted by weight to 1 of 6 doses ranging from 37.5 mg to 200 mg as a single nightly dose: 37.5 mg for subjects ≥18 to <23 kg, 50 mg for subjects ≥23 to <34 kg, 75 mg for subjects ≥34 to <44 kg, 100 mg daily for subjects ≥44 to <68 kg, 150 mg for subjects ≥68 to <83 kg and 200 mg for subjects >83 kg at baseline without any on-study dose modification. Randomization, supervised by the sponsor, was centralized by using interactive response technology and stratified by weight band. Throughout the study, all personnel involved with the conduct and interpretation of the study, including the subject, parents/guardians, investigators, site personnel, and sponsor staff were blinded as to the treatment arm. At the end of the 8-week treatment phase, subjects were titrated off the study drug (ecopipam or placebo) at a rate of 25 mg/day. Signs of symptoms of withdrawal were monitored.

The primary efficacy endpoint was the change from baseline to week 12 in YGTSS-TTS.29  Secondary endpoints included the Clinical Global Impression of Tourette Syndrome Severity (CGI-TS-S),30  Clinical Global Impression of Tourette Syndrome Improvement (CGI-TS-I),30  Yale Global Tic Severity Score, Global Score (YGTSS-GS),29  Caregiver Global Impression of Change (CaGI-C),31  Gilles de la Tourette Syndrome, Quality of Life Scale for Children and Adolescents (C&A-GTS-QoL),32,33  and the proportion of subjects with ≥25% improvement, considered to be a clinically meaningful change,34  on the YGTSS-TTS.

Efficacy and safety assessments were conducted at weeks 4, 6, 8, and 12, and safety was assessed on follow-up visits at 7, 14, and 30 days after the last dose of study medication. Clinical laboratory testing (hematology, blood chemistry, and urinalysis), hemoglobulin A1c (HbA1c assessed only at baseline and study completion visits), vital signs (heart rate, postural blood pressure, respiratory rate), physical examination, and ECG were obtained at screening, baseline, during treatment, and at 7- and 14-day follow up visits.

To detect potential mood or behavioral changes, drug-induced movement disorders, or impact on comorbid conditions, the following validated scales were obtained at baseline and weeks 4, 6, 8, and 12: the Columbia-Suicide Severity Rating Scale (C-SSRS),35  the Abnormal Involuntary Movement Scale,36  the Barnes Akathisia Rating Scale,37  the Children’s Depression Rating Scale, revised,38  the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS),39  the Pediatric Anxiety Rating Scale,40  and the Swanson, Nolan and Pelham questionnaire (SNAP-IV).41 

A sample size of 75 subjects per treatment group was estimated to provide >80% power to detect a difference between the treatment groups with respect to change from baseline for the YGTSS-TTS of 3 points with a standard deviation of 6.1 and α of 0.05, assuming a 10% drop out rate.

For the primary endpoint, YGTSS-TTS, a mixed model for repeated measures (MMRM) was used with fixed effects for treatment, visit, interaction between treatment and visit, region, age group, and a covariate for baseline value. For subjects with the intercurrent events of treatment discontinuation due to treatment-related adverse events (AEs) or lack of efficacy, missing data were multiple-imputed by using similar subjects (relevant demographic/baseline characteristics) from the placebo arm. The treatment difference at weeks 4, 8, and 12 was estimated on the basis of the MMRM. To compensate for multiplicity, all secondary outcome measures were ordered hierarchically with the key prespecified primary secondary efficacy endpoint of CGI-TS-S. YGTSS-GS, CGI-TS-S, CGI-TS-I, CaGI-C, and C&A-GTS-QoL were analyzed using MMRM. The percentage of subjects with at least a 25% improvement from baseline on the YGTSS-TS was tested by using logistic regression with treatment as a predictor and baseline YGTSS-TTS score as a covariate. All efficacy analyses were performed as prespecified on the modified intention-to-treat population defined as all participants who received at least 1 dose and at least 1 postbaseline clinical evaluation. Results for safety and tolerability assessments were reported by using descriptive statistics. The statistical analyses were performed by using SAS 9.4 (Cary, NC).

A total of 153 subjects were randomly assigned between September 2019 and August 2021. Baseline characteristics were similar between treatment groups (Table 1). Of these 16 (10.5%) discontinued the study prematurely (6 subjects in the placebo group, 10 subjects in the ecopipam group). The most common reasons for premature discontinuation from the study were an AE (5 subjects) and withdrawal by parent/caregiver (4 subjects; Fig 1).

FIGURE 1

CONSORT diagram of subject disposition.

FIGURE 1

CONSORT diagram of subject disposition.

Close modal
TABLE 1

Baseline Characteristics (Safety Population)

Placebo (n = 77)Ecopipam (n = 76)
Age, years, mean ± SD 12.6 ± 2.6 12.6 ± 2.8 
 6 to 11 y, n (%) 26 (33.8) 27 (35.5) 
 12 to <18 y, n (%) 51 (66.2) 49 (64.5) 
Male, n (%) 53 (68.8) 59 (77.6) 
Race, n (%)   
 White 72 (93.5) 66 (86.8) 
 Black/African American 3 (3.9) 6 (7.9) 
 Asian 2 (2.6) 1 (1.3) 
 Other 3 (4.0) 
Wt, kg, mean ± SD 56.1 ± 21.5 58.2 ± 25.8 
North America, n (%) 60 (77.9) 64 (84.2) 
Europe, n (%) 17 (22.1) 12 (15.8) 
Medical history, n (%)   
 Attention-deficit/hyperactivity disorder 30 (39.0) 39 (51.3) 
 Depression 5 (6.5) 4 (5.3) 
 Obsessive-compulsive disorder 11 (14.3) 14 (19.4) 
Medication use, n (%)   
 Antipsychotics (previous) 20 (26.0) 20 (26.3) 
 Antidepressants (concomitant) 19 (24.7) 23 (30.1) 
Baseline tic scores mean ± SD   
 YGTSS-TTS 34.7 ± 5.6 34.6 ± 6.3 
 YGTSS-GS 66.4 ± 11.6 68.0 ± 13.0 
 CGI-TS 4.8 ± 0.68 4.8 ± 0.94 
Placebo (n = 77)Ecopipam (n = 76)
Age, years, mean ± SD 12.6 ± 2.6 12.6 ± 2.8 
 6 to 11 y, n (%) 26 (33.8) 27 (35.5) 
 12 to <18 y, n (%) 51 (66.2) 49 (64.5) 
Male, n (%) 53 (68.8) 59 (77.6) 
Race, n (%)   
 White 72 (93.5) 66 (86.8) 
 Black/African American 3 (3.9) 6 (7.9) 
 Asian 2 (2.6) 1 (1.3) 
 Other 3 (4.0) 
Wt, kg, mean ± SD 56.1 ± 21.5 58.2 ± 25.8 
North America, n (%) 60 (77.9) 64 (84.2) 
Europe, n (%) 17 (22.1) 12 (15.8) 
Medical history, n (%)   
 Attention-deficit/hyperactivity disorder 30 (39.0) 39 (51.3) 
 Depression 5 (6.5) 4 (5.3) 
 Obsessive-compulsive disorder 11 (14.3) 14 (19.4) 
Medication use, n (%)   
 Antipsychotics (previous) 20 (26.0) 20 (26.3) 
 Antidepressants (concomitant) 19 (24.7) 23 (30.1) 
Baseline tic scores mean ± SD   
 YGTSS-TTS 34.7 ± 5.6 34.6 ± 6.3 
 YGTSS-GS 66.4 ± 11.6 68.0 ± 13.0 
 CGI-TS 4.8 ± 0.68 4.8 ± 0.94 

SD, standard deviation.

For the primary endpoint, in the modified intention-to-treat analysis, mean change from baseline to week 12 for the YGTSS-TTS, a statistically significant improvement (least square [LS] mean difference: -3.44 [1.35], 95% confidence interval [CI]: −6.09 to −0.79, P = .01) was observed for ecopipam versus placebo (Fig 2A). This represented a 30% reduction from baseline to week 12 for the ecopipam group. A significant benefit was seen at the first evaluation (week 4) and persisted across all visits. Subgroup analyses using MMRM models are presented in Supplemental Fig 6 A response of ≥25% improvement in the YGTSS-TTS at any time between baseline and week 12 occurred in 73.6% on ecopipam and 43.2% on placebo (odds ratio: 3.7, 95% CI: 1.8 to 7.4; P <.001). The corresponding number needed to treat for this outcome is 3.0. At week 12, the mean change from baseline in motor tics was −1.99 [0.73] (95% CI: −3.43 to −0.55; P = .01), and vocal tics was 1.46 [0.78] (95% CI: − 2.97 to 0.06; P = .06). Significant improvement from baseline was observed in the YGTSS-GS at all time points for the ecopipam group (week 12 difference: −7.9 [2.7] (95% CI: −13.2 to −2.5; P <.004; Fig 2B).

FIGURE 2

(A) YGTSS-TTS LS mean (SE) change from baseline to week 4, 6, 8 and 12 and (B) YGTSS-GS LS mean (SE) change from baseline to week 4, 6, 8, and 12. P values from MMRM analysis.

FIGURE 2

(A) YGTSS-TTS LS mean (SE) change from baseline to week 4, 6, 8 and 12 and (B) YGTSS-GS LS mean (SE) change from baseline to week 4, 6, 8, and 12. P values from MMRM analysis.

Close modal

The predefined key secondary efficacy measure, CGI-TS-S, was also statistically significantly improved in the ecopipam group (12-week difference −0.37 [0.17]; 95% CI −0.70 to −0.04; P = .03; Fig 3A). For CGI-TS-I at week 12, LS mean (standard error [SE]) was 3.42 (0.17) with placebo and 3.04 (0.18) with ecopipam (difference: −0.38 [0.22]; 95% CI: −0.81 to −0.04; P = .08; Fig 3B). For the CaGI-C, improvement was nominally significantly (P <.01) greater with ecopipam versus placebo at each time point (Fig 4). For the C&A-GTS-QoL scores, the LS mean change from baseline was greater with ecopipam at weeks 4, 6, and 8, but the differences were not statistically significant. The results for subgroup analyses are found in Supplemental Fig 6.

FIGURE 3

(A) CGI-TS-S LS mean (SE) change from baseline to week 4, 6, 8, and 12 and (B) CGI-TS-I LS mean (SE) change from baseline to week 4, 6, 8, and 12.

FIGURE 3

(A) CGI-TS-S LS mean (SE) change from baseline to week 4, 6, 8, and 12 and (B) CGI-TS-I LS mean (SE) change from baseline to week 4, 6, 8, and 12.

Close modal
FIGURE 4

LS mean (SE) change from baseline for the CaGI-C (mITT population). MMRM analysis.

FIGURE 4

LS mean (SE) change from baseline for the CaGI-C (mITT population). MMRM analysis.

Close modal

The secondary objective of this study was to evaluate the safety and tolerability of ecopipam in pediatric subjects (aged ≥6 to <18 years) with TS. No fatal or life-threatening AEs were reported during the study. The majority of AEs reported in both treatment groups were mild to moderate in severity (Table 2). The most common AEs were headaches, insomnia, fatigue, and somnolence. Three subjects (all adolescents) experienced Aes defined as serious during the study. In the placebo group, 1 subject reported suicidal ideation. Of the 2 in the ecopipam group, 1 experienced vomiting subsequently attributed to inflammatory bowel disease, and the other contracted coronavirus disease 2019, which resolved after 8 days; both were considered unrelated to ecopipam.

TABLE 2

Incidence of Treatment-Emergent AEs (At Least 5% Greater Incidence With Ecopipam, Safety Population)

Number (%) of Subjects
Placebo (n = 77)Ecopipam (n = 76)
Headache 7 (9.1) 12 (15.8) 
Insomnia 2 (2.6) 10 (13.1) 
Fatigue 6 (7.9) 
Somnolence 2 (2.6) 6 (7.9) 
Anxiety 4 (5.3) 
Nausea 1 (1.3) 4 (5.3) 
Restlessness 4 (5.3) 
Any AE 38 (49.4) 47 (61.8) 
Treatment-related AE 16 (20.8) 26 (34.2) 
AE leading to withdrawal 1 (1.3)a 4 (5.3)b 
Serious AE 1 (1.3)c 2 (2.6)d 
Number (%) of Subjects
Placebo (n = 77)Ecopipam (n = 76)
Headache 7 (9.1) 12 (15.8) 
Insomnia 2 (2.6) 10 (13.1) 
Fatigue 6 (7.9) 
Somnolence 2 (2.6) 6 (7.9) 
Anxiety 4 (5.3) 
Nausea 1 (1.3) 4 (5.3) 
Restlessness 4 (5.3) 
Any AE 38 (49.4) 47 (61.8) 
Treatment-related AE 16 (20.8) 26 (34.2) 
AE leading to withdrawal 1 (1.3)a 4 (5.3)b 
Serious AE 1 (1.3)c 2 (2.6)d 

Treatment-related AEs were AEs with relationship to treatment as “Possibly Related” or “Probably Related.”

a

Suicidal ideation based on C-SSRS defined as nonspecific suicidal thoughts or active suicidal ideation without intent to act.

b

4 subjects with nausea, anxiety, depressed mood, self-injurious ideation, suicidal ideation, tic.

c

Suicidal ideation.

d

Coronavirus disease 2019 infection, vomiting.

In terms of mood and behavioral measures, at the end of 12 weeks, there were no meaningful differences for SNAP-IV (global or subgroup; Supplemental Fig 7), Pediatric Anxiety Rating Scale, CDRS-S, or CY-BOCS scores (Supplemental Table 3). At entry into the study, lifetime suicidal ideation identified by the C-SSRS was reported in 16 subjects (21.1%) randomly assigned to ecopipam and 12 subjects (15.6%) randomly assigned to placebo. During the dosing period, suicidal ideation was reported in 8 subjects (10.4%) in the placebo group and no subjects in the ecopipam group. One subject (1.3%) in the ecopipam group reported suicidal ideation at the 7-day postdosing follow-up. No subjects reported suicidal behavior during the study. One subject receiving ecopipam experienced multiple episodes of depression and was discontinued from the study on day 79. Another ecopipam subject discontinued secondary to anxiety. With respect to potential motor AEs, no drug-induced movement disorders were observed in either the ecopipam or placebo subjects and there were no observed differences in the Barnes Akathisia Rating Scale or Abnormal Involuntary Movement Scale (Supplemental Table 3).

As for the potential for weight change or metabolic adverse effects associated with ecopipam, 17.1% of ecopipam subjects and 20.3% of placebo subjects had a >7% increase in weight over the study duration. At week 12, mean body weight increased from baseline by 1.8 kg in the ecopipam and 2.4 kg in the placebo groups. No shifts from baseline in blood glucose, HbA1c, total cholesterol, or triglyceride levels were observed in either treatment group (Supplemental Table 4). No clinically meaningful changes from baseline were observed with ecopipam or placebo for pulse, blood pressure (including orthostatic change), clinical laboratory findings, or electrocardiogram. The mean change from baseline for the QT interval, corrected interval was −3.8 ms (32.1) with ecopipam and −4.0 ms (25.7) with placebo.

Treatment decisions for TS require an assessment of disease severity and burden, comorbid conditions, and the concerns of patients and their caregivers regarding the cost, time, and side effects of treatments.7,17  Although expert groups in both North America and Europe have established evidenced-based practice guidelines indicating behavioral treatments should be first-line,17  efficacy, cost, and access barriers support pharmacological treatments in many cases.14 

Currently, first-line pharmacological treatment of tics with α-2 adrenergic agonists has low efficacy in the case of long-acting guanfacine42  and excessive sedation, in the case of clonidine.43  Second-line pharmacological treatments for tics with antipsychotics, for example, risperidone (32% to 42% reduction in YGTSS-TTS25,44 ) and aripiprazole (43% to 54% reduction24,45 ), recently FDA-approved for Tourette’s syndrome, show higher efficacy. However, antipsychotics are associated with risks of weight gain and somnolence, cognitive, metabolic, and endocrine side effects, as well as ECG changes and risk for suicidality. The current study supports that ecopipam may be an effective alternative to currently available pharmacological treatments for tics.

Ecopipam is a high-affinity, highly selective antagonist for D1r.46,47  On the basis of several animal models, initial clinical studies utilizing this drug were conducted in adults with schizophrenia,48  cocaine addiction,49  and obesity.50  Although none of these studies revealed high clinical efficacy, they did establish a profile of safety and tolerability. The pathway to TS treatment was supported by a transgenic mouse model expressing a neuropotentiating protein within D1r-expressing neurons. This mouse exhibits frequent repetitive movements (“ticcy behaviors”) and sensorimotor gating deficits51,52  that are decreased by a D1r antagonist (SCH23390). Similarly, in a primate model, ecopipam (SCH39166)51  blocked tic induction by apomorphine (a nonselective dopamine agonist).53 

Two previous studies of ecopipam for TS also provided evidence of benefit. The first, an 8-week, open-label study in adults (mean age 36 years), tested 50 mg ecopipam daily for 2 weeks, followed by 100 mg ecopipam daily for 6 weeks. Most participants had previously been prescribed 1 or more antipsychotics for tics, and the majority also had ADHD. This study was stopped at 18 subjects when a planned interim analysis revealed a statistically significant tic reduction on the YGTSS-TTS, estimated not to change through completing the study.27  The second, a placebo-controlled crossover study in 40 children and adolescents (mean age 13 years; mean weight 56 kg), tested 50 mg or 100 mg ecopipam, based on baseline body weight, daily for 30 days. There was a 2-week washout between treatment arms. Relative to the placebo, the reduction of tics on the YGTSS-TSS was greater on ecopipam.28  Safety profiles were favorable in both studies.

In the current study, despite the higher average dose (2 mg/kg/day) and longer duration (12 weeks) than in the previous studies of ecopipam in TS, efficacy was maintained without an increase in AEs, including those associated with the use of FDA-approved medications for tics haloperidol, pimozide, and aripiprazole. Weight gain26  was less in the ecopipam group compared with the placebo. Additionally, there was no evidence for an emerging metabolic syndrome,26  as reflected in lipid and HbA1c levels, cardiac changes, such as prolonged QT interval, corrected or orthostatic hypotension,14  or drug-induced dyskinesias.14  There also was no evidence that ecopipam adversely affected common concomitant conditions, such as ADHD, OCD, or depression, as reported clinically or measured by the SNAP-IV, CY-BOCS, and Children’s Depression Rating Scale, revised. Headache, somnolence, insomnia, fatigue, and restlessness occurred in a higher proportion of subjects in the ecopipam group compared with the placebo.

Limitations of this study include the lack of a more racially and ethnically diverse population. Similarly, idiosyncratic or rare complications may not be detectable in a study of this size. The durability of treatment effect and safety beyond 12 weeks is also not established but may be informed by an ongoing open-label extension of the D1AMOND trial (NCT04114539). Because this study only included children and adolescents, generalization to adults is also not possible. A future, Phase 3, 24-week, randomized, withdrawal study is planned to include a greater diversity of subjects, including adults, to better define the durability of benefit, safety, and tolerability.

In summary, ecopipam revealed significant and clinically meaningful improvement in TS on the basis of clinician ratings of tics and overall symptom severity. Tic improvement was also observed in subjects with concomitant ADHD, OCD, or anxiety disorders at baseline. The spectrum of metabolic, psychiatric, neurologic, and cardiac complications associated with approved D2r antagonists in TS was not seen. Ecopipam may be a safe and effective treatment of TS with advantages over other currently approved therapeutic agents.

The authors would like to acknowledge the participating families and research teams and the support of the Tourette Association of America in recruiting participants. We also acknowledge the insight of Richard Chipkin, PhD, in proposing ecopipam for TS and the editorial assistance of Richard Perry, PharmD, in the preparation of this manuscript. This study was sponsored by Emalex Biosciences, Chicago, IL.

Dr Gilbert created and managed the writing and editing of the manuscript, was a clinical investigator, and contributed to the design of the trial, the creation of data collection instruments, and the analysis plan; Dr Atkinson was a clinical investigator and contributed to the design of the trial, the creation of data collection instruments, and the analysis plan; Drs Mahableshwarkar, Wanaski, Dubow, and Cunniff contributed to the design of the trial, the creation of data collection instruments, and the analysis plan; and all authors reviewed and revised the manuscript, approved the final submission, and agree to be accountable for all aspects of the work.

This trial has been registered at www.clinicaltrials.gov (identifier NCT04007991).

DATA SHARING STATEMENT: The Study Protocol and Statistical Analysis Plan will be posted on clinicaltrials.gov 3 months after acceptance. After deidentification, individual participant data supporting the results reported in this article will be made available on Welcome.com beginning 5 months after publication and for a period of 5 years. Qualified researchers may gain access to the individual data by submitting a methodologically sound proposal to donald.gilbert@cchmc.org. Approved data requestors will be required to sign a data access agreement.

FUNDING: This study was funded by Emalex Biosciences Inc, Chicago, Illinois.

CONFLICT OF INTEREST DISCLOSURES: Dr Gilbert has received consulting fees from Biogen and PTC therapeutics. Dr Atkinson has received consulting fees from Alkermes, Inc. Drs Cunniff and Wanaski are employees of Paragon Biosciences, which has controlling equity interest in Emalex and both have personal equity interest in Emalex. Dr Dubow has received compensation from Paragon Biosciences for consulting activities. Dr Mahableshwarkar is an employee of Emalex Biosciences and has equity interest in Emalex.

AE

adverse event

ADHD

attention deficit hyperactivity disorder

CaGI-C

Caregiver Global Impression of Change

CY-BOCS

Children's Yale-Brown Obsessive Compulsive Scale

CGI-TS-I

Clinical Global Impression of Tourette’s Syndrome Improvement

CGI-TS-S

Clinical Global Impression of Tourette’s Syndrome Severity

C-SSRS

Columbia Suicide Severity Rating Scale

CI

confidence interval

D1r

dopamine 1 receptor

D2r

dopamine 2 receptor

FDA

Food and Drug Administration

ECG

electrocardiogram

C&A-GTS-QOL

Gilles de la Tourette’s Syndrome, Quality of Life Scale for Children and Adolescents

HbA1c

hemoglobin A1c

LS

least square

MMRM

mixed model for repeated measures

OCD

obsessive-compulsive disorder

SNAP-IV

Swanson, Nolan and Pelham Questionnaire

TS

Tourette’s syndrome

YGTSS-GS

Yale Global Tic Severity Scale, Global Score

YGTSS-TTS

Yale Global Tic Severity Scale, Total Tic Score

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