Ecopipam for Tourette Syndrome:

A Randomized Trial
Donald L. Gilbert, MD, MS,a,b Jordan S. Dubow, MD,c Timothy M. Cunniff, PharmD,d Stephen P. Wanaski, PhD,d
Sarah D. Atkinson, MD,e Atul R. Mahableshwarkar, MDf

BACKGROUND AND OBJECTIVES:All US Food and Drug Administration-approved medications for abstract
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 5 76) or placebo (n 5 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 5 .01). Improvement in Clinical Global Impression of Tourette Syndrome
Severity was also greater in the ecopipam group (P 5 .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
a
Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; bDepartment of Pediatrics, receptor and, although effective, can cause weight gain
University of Cincinnati College of Medicine, Cincinnati, Ohio; cClintrex Research Corporation, Sarasota, Florida; and drug-induced movements. Ecopipam is a first-in-class
d
Paragon Biosciences, LLC., Chicago, Illinois; eERG Clinical, Berkeley Heights, New Jersey; and fEmalex Biosciences, D1 receptor blocker in development for Tourette
Inc., Chicago, Illinois syndrome.
Dr Gilbert created and managed the writing and editing of the manuscript, was a clinical WHAT THIS STUDY ADDS: In this randomized clinical trial,
investigator, and contributed to the design of the trial, the creation of data collection ecopipam, a D1 receptor blocker, was more effective than
instruments, and the analysis plan; Dr Atkinson was a clinical investigator and contributed to a placebo in reducing tic severity in children and
the design of the trial, the creation of data collection instruments, and the analysis plan; adolescents with Tourette syndrome. Ecopipam was well
Drs Mahableshwarkar, Wanaski, Dubow, and Cunniff contributed to the design of the trial, the tolerated and did not cause weight gain or movement
creation of data collection instruments, and the analysis plan; and all authors reviewed and disorders.
revised the manuscript, approved the final submission, and agree to be accountable for all
aspects of the work.
To cite: Gilbert DL, Dubow JS, Cunniff TM, et al. Ecopipam for
This trial has been registered at www.clinicaltrials.gov (identifier NCT04007991).
Tourette Syndrome: A Randomized Trial. Pediatrics. 2023;
DOI: https://doi.org/10.1542/peds.2022-059574 151(2):e2022059574

PEDIATRICS Volume 151, number 2, February 2023:e2022059574 ARTICLE

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 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.11–13 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.14–16 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,
2 GILBERT et al
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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.
METHODS
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 Declara-
tion 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. only at baseline and study completion groups with respect to change from
Ecopipam dosages were adjusted by visits), vital signs (heart rate, postural baseline for the YGTSS-TTS of 3 points
weight to 1 of 6 doses ranging from blood pressure, respiratory rate), with a standard deviation of 6.1 and a
37.5 mg to 200 mg as a single nightly physical examination, and ECG were of 0.05, assuming a 10% drop out rate.
dose: 37.5 mg for subjects $18 to obtained at screening, baseline, during
<23 kg, 50 mg for subjects $23 to treatment, and at 7- and 14-day For the primary endpoint, YGTSS-TTS,
<34 kg, 75 mg for subjects $34 follow up visits. a mixed model for repeated measures
to <44 kg, 100 mg daily for subjects (MMRM) was used with fixed effects
$44 to <68 kg, 150 mg for subjects To detect potential mood or for treatment, visit, interaction
$68 to <83 kg and 200 mg for behavioral changes, drug-induced between treatment and visit, region,
subjects >83 kg at baseline without movement disorders, or impact on age group, and a covariate for
any on-study dose modification. comorbid conditions, the following baseline value. For subjects with the
Randomization, supervised by the validated scales were obtained at intercurrent events of treatment
sponsor, was centralized by using baseline and weeks 4, 6, 8, and 12: the discontinuation due to treatment-
interactive response technology and Columbia-Suicide Severity Rating Scale related adverse events (AEs) or lack
stratified by weight band. Throughout (C-SSRS),35 the Abnormal Involuntary of efficacy, missing data were
the study, all personnel involved with Movement Scale,36 the Barnes multiple-imputed by using similar
the conduct and interpretation of the Akathisia Rating Scale,37 the Children’s subjects (relevant demographic/
study, including the subject, parents/ baseline characteristics) from the
Depression Rating Scale, revised,38
guardians, investigators, site placebo arm. The treatment difference
the Children's Yale-Brown Obsessive
personnel, and sponsor staff were at weeks 4, 8, and 12 was estimated
Compulsive Scale (CY-BOCS),39 the
blinded as to the treatment arm. At on the basis of the MMRM. To
Pediatric Anxiety Rating Scale,40 and
the end of the 8-week treatment compensate for multiplicity, all
the Swanson, Nolan and Pelham
phase, subjects were titrated off the secondary outcome measures were
questionnaire (SNAP-IV).41
study drug (ecopipam or placebo) at a ordered hierarchically with the key
rate of 25 mg/day. Signs of symptoms prespecified primary secondary
of withdrawal were monitored. STATISTICAL ANALYSIS efficacy endpoint of CGI-TS-S.
A sample size of 75 subjects per YGTSS-GS, CGI-TS-S, CGI-TS-I, CaGI-C,
The primary efficacy endpoint was treatment group was estimated to and C&A-GTS-QoL were analyzed
the change from baseline to week 12 provide >80% power to detect a using MMRM. The percentage of
in YGTSS-TTS.29 Secondary endpoints difference between the treatment subjects with at least a 25%
included the Clinical Global
Impression of Tourette Syndrome TABLE 1 Baseline Characteristics (Safety Population)
Severity (CGI-TS-S),30 Clinical Global Placebo (n 5 77) Ecopipam (n 5 76)
Impression of Tourette Syndrome
Age, years, mean ± SD 12.6 ± 2.6 12.6 ± 2.8
Improvement (CGI-TS-I),30 Yale Global
6 to 11 y, n (%) 26 (33.8) 27 (35.5)
Tic Severity Score, Global Score 12 to <18 y, n (%) 51 (66.2) 49 (64.5)
(YGTSS-GS),29 Caregiver Global Male, n (%) 53 (68.8) 59 (77.6)
Impression of Change (CaGI-C),31 Race, n (%)
Gilles de la Tourette Syndrome, White 72 (93.5) 66 (86.8)
Black/African American 3 (3.9) 6 (7.9)
Quality of Life Scale for Children and
Asian 2 (2.6) 1 (1.3)
Adolescents (C&A-GTS-QoL),32,33 and Other 0 3 (4.0)
the proportion of subjects with Wt, kg, mean ± SD 56.1 ± 21.5 58.2 ± 25.8
$25% improvement, considered to North America, n (%) 60 (77.9) 64 (84.2)
be a clinically meaningful change,34 Europe, n (%) 17 (22.1) 12 (15.8)
Medical history, n (%)
on the YGTSS-TTS.
Attention-deficit/hyperactivity disorder 30 (39.0) 39 (51.3)
Depression 5 (6.5) 4 (5.3)
Efficacy and safety assessments were Obsessive-compulsive disorder 11 (14.3) 14 (19.4)
conducted at weeks 4, 6, 8, and 12, Medication use, n (%)
and safety was assessed on follow-up Antipsychotics (previous) 20 (26.0) 20 (26.3)
visits at 7, 14, and 30 days after the Antidepressants (concomitant) 19 (24.7) 23 (30.1)
Baseline tic scores mean ± SD
last dose of study medication. Clinical YGTSS-TTS 34.7 ± 5.6 34.6 ± 6.3
laboratory testing (hematology, blood YGTSS-GS 66.4 ± 11.6 68.0 ± 13.0
chemistry, and urinalysis), CGI-TS 4.8 ± 0.68 4.8 ± 0.94
hemoglobulin A1c (HbA1c assessed SD, standard deviation.

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 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).

RESULTS
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).
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 5 .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 base-
line 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
FIGURE 1
CONSORT diagram of subject disposition.
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 5 .01), and vocal tics was 1.46
[0.78] (95% CI: 2.97 to 0.06;
P 5 .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).
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 5 .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 5 .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.
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

4 GILBERT et al
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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.
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.
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 re-
ported in 16 subjects (21.1%) randomly
assigned to ecopipam and 12 subjects
(15.6%) randomly assigned to placebo.
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During the dosing period, suicidal ide-
ation 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 sui-
cidal behavior during the study. One
subject receiving ecopipam experi-
enced 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 in-
terval, corrected interval was
3.8 ms (32.1) with ecopipam and
4.0 ms (25.7) with placebo.
DISCUSSION
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 a-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,
5

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.
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.
FIGURE 4
LS mean (SE) change from baseline for the CaGI-C (mITT population). MMRM analysis.
6 GILBERT et al
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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
 TABLE 2 Incidence of Treatment-Emergent AEs (At Least 5% Greater Incidence With Ecopipam, preparation of this manuscript. This
Safety Population) study was sponsored by Emalex Bio-
Number (%) of Subjects sciences, Chicago, IL.

Placebo (n 5 77) Ecopipam (n 5 76)

Headache 7 (9.1) 12 (15.8) ABBREVIATIONS
Insomnia 2 (2.6) 10 (13.1)
Fatigue 0 6 (7.9) AE: adverse event
Somnolence 2 (2.6) 6 (7.9) ADHD: attention deficit
Anxiety 0 4 (5.3) hyperactivity disorder
Nausea 1 (1.3) 4 (5.3)
Restlessness 0 4 (5.3)
CaGI-C: Caregiver Global
Any AE 38 (49.4) 47 (61.8) Impression of Change
Treatment-related AE 16 (20.8) 26 (34.2) CY-BOCS: Children's Yale-Brown
AE leading to withdrawal 1 (1.3)a 4 (5.3)b Obsessive Compulsive
Serious AE 1 (1.3)c 2 (2.6)d Scale
Treatment-related AEs were AEs with relationship to treatment as “Possibly Related” or “Probably Related.”
a CGI-TS-I: Clinical Global
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. Impression of
c
d
Suicidal ideation. Tourette’s Syndrome
Coronavirus disease 2019 infection, vomiting.
Improvement
CGI-TS-S: Clinical Global
Impression of
was no evidence for an emerging 24-week, randomized, withdrawal Tourette’s Syndrome
metabolic syndrome,26 as reflected in study is planned to include a Severity
lipid and HbA1c levels, cardiac greater diversity of subjects, C-SSRS: Columbia Suicide
changes, such as prolonged QT including adults, to better define Severity Rating Scale
interval, corrected or orthostatic the durability of benefit, safety, and CI: confidence interval
hypotension,14 or drug-induced tolerability. D1r: dopamine 1 receptor
dyskinesias.14 There also was no D2r: dopamine 2 receptor
evidence that ecopipam adversely In summary, ecopipam revealed
FDA: Food and Drug
affected common concomitant significant and clinically meaningful
Administration
conditions, such as ADHD, OCD, or improvement in TS on the basis of
ECG: electrocardiogram
depression, as reported clinically or clinician ratings of tics and overall
C&A-GTS-QOL: Gilles de la
measured by the SNAP-IV, CY-BOCS, symptom severity. Tic improvement
Tourette’s
and Children’s Depression Rating was also observed in subjects with
Syndrome,
Scale, revised. Headache, somnolence, concomitant ADHD, OCD, or anxiety
Quality of Life
insomnia, fatigue, and restlessness disorders at baseline. The spectrum
Scale for Children
occurred in a higher proportion of of metabolic, psychiatric, neurologic,
and Adolescents
subjects in the ecopipam group and cardiac complications associated
HbA1c: hemoglobin A1c
compared with the placebo. with approved D2r antagonists in TS
LS: least square
was not seen. Ecopipam may be a
MMRM: mixed model for
Limitations of this study include the safe and effective treatment of TS
repeated measures
lack of a more racially and ethnically with advantages over other currently
OCD: obsessive-compulsive
diverse population. Similarly, approved therapeutic agents.
disorder
idiosyncratic or rare complications SNAP-IV: Swanson, Nolan and
may not be detectable in a study of ACKNOWLEDGMENTS
Pelham Questionnaire
this size. The durability of treatment The authors would like to acknowl- TS: Tourette’s syndrome
effect and safety beyond 12 weeks is edge the participating families and YGTSS-GS: Yale Global Tic
also not established but may be research teams and the support of Severity Scale, Global
informed by an ongoing open-label the Tourette Association of America Score
extension of the D1AMOND trial in recruiting participants. We also YGTSS-TTS: Yale Global Tic
(NCT04114539). Because this study acknowledge the insight of Richard Severity Scale, Total
only included children and Chipkin, PhD, in proposing ecopipam Tic Score
adolescents, generalization to adults for TS and the editorial assistance of
is also not possible. A future, Phase 3, Richard Perry, PharmD, in the

PEDIATRICS Volume 151, number 2, February 2023 7

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 Accepted for publication Oct 25, 2022
Address correspondence to Donald L. Gilbert, MD, MS, Division of Neurology, ML #2015 Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH
45229. E-mail: donald.gilbert@cchmc.org
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://
creativecommons.org/licenses/by-nc-nd/4.0/), which permits noncommercial distribution and reproduction in any medium, provided the original author and source are
credited.
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.

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.

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