| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children and Adolescent Subjects with Tourette’s Syndrome grater than or equal to 6 and less than 18 years of age. |
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| E.1.1.1 | Medical condition in easily understood language |
Tourette’s Syndrome is a neurological disorder characterized by motor or vocal tics that begin in childhood and persists over time .
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary:
The primary objective of this study is to evaluate the efficacy of ecopipam tablets in pediatric subjects (aged ≥6 to <18 years) with Tourette’s Syndrome (TS). |
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| E.2.2 | Secondary objectives of the trial |
Secondary:
The secondary objectives of this study are to evaluate the safety of ecopipam tablets in pediatric subjects (aged ≥6 to <18 years) with TS and characterize the pharmacokinetics (PK) of ecopipam. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria:
1) Subject’s parent or legal guardian must sign a written informed consent.
2) Subject must sign a written informed assent.
3) Subjects must be age (≥6 to <18 years of age) at time of screening.
4) Subjects must weigh ≥18 kg (39.6 lbs).
5) Subjects must have TS based on Diagnostic and Statistical Manual for Mental Disorders – 5th Edition (DSM-5 diagnostic criteria) for TS.
6) Subjects must exhibit both motor and vocal tics that cause impairment with normal routines.
7) Subjects must have a minimum score of 20 on the YGTSS-TTS at Screening and at Baseline visits with tic symptoms causing impairment in the subject’s normal routines, including academic achievement, occupational functioning, social activities, and/or relationships.
8) Subjects must be off all medications used to treat motor or vocal tics for at least 21 days prior to Screening.
9) Adolescent females of childbearing potential who are sexually active must be using effective contraception (i.e., oral contraceptives, intrauterine device, double barrier method of condom and spermicide) and agree to continue use of contraception for the duration of their participation in the study. They must also agree to use contraception for 30 days after their last dose of study drug.
10) Sexually active male subjects must use a barrier method of contraception during the study and agree to continue the use of male contraception for at least 30 days after the last dose of study drug. |
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| E.4 | Principal exclusion criteria |
Exclusion Criteria:
1) Subjects with any primary mood disorder (DSM-5 criteria) at Screening.
2) Subjects who have unstable medical illness or clinically significant abnormalities on laboratory tests, or ECG at Screening.
3) Subjects with a significant risk of committing suicide based on history, routine psychiatric status examination, investigator’s judgment, or who had an answer of ‘‘yes’’ on any question other than 1–3 (currently or within the past 30 days) on the baseline/screening version of the Columbia Suicide Severity Rating Scale (C-SSRS).
4) Subjects with a clinical presentation at Screening and/or history consistent with another neurologic condition that may have had accompanying abnormal movements (e.g., Huntington’s disease, Parkinson’s disease, Wilson’s disease, stroke, Restless Legs Syndrome).
5) Female subjects who are currently pregnant or lactating or planning to become pregnant during the course of the study.
6) Subjects who have moderate to severe renal insufficiency at Screening given the large increase in systemic exposure of ecopipam and its active metabolite SCH 40853 observed in adults with moderate to severe renal impairment.
7) Subjects who have hepatic impairment at Screening
8) Subjects with current or recent (past 3 months) history of DSM-5 substance use disorder (with the exception of nicotine).
9) Subjects with positive urine drug screen (cocaine, amphetamine, methamphetamine, tetrahydrocannabinol (THC), benzodiazepines, barbiturates, phencyclidine (PCP), opiates at Screening.
10) Subjects with a change from grater than 25% or grater than or equal to 25% difference in the absolute change in YGTSS-TTS score between the Screening visit and the Baseline visit
11) Subjects with a lifetime history of bipolar disorder type I or II, dementia, schizophrenia, or any psychotic disorder.
12) Subjects with a major depressive episode in the past 2 years.
13) Subjects with a history of attempted suicide.
14) Subjects with a first-degree relative with a major depressive episode that resulted in any psychiatric hospitalization, or attempted suicide with the exception of a hospitalization for post-partum depression.
15) Subjects with a history of seizures (excluding febrile seizures that occurred >2 years in the past).
16) Subjects with a history of neuroleptic malignant syndrome.
17) Subjects with a myocardial infarction within 6 months.
18) Subjects who have had previous treatment with ecopipam.
19) Subjects who have had previous treatment with:
o investigational medication within 3 months prior to Screening
o depot neuroleptics within 3 months prior to Screening
o other medications with possible effects on TS symptoms (i.e., lithium, pyschostimulants, naltrexone, VMAT2 inhibitors such as tetrabenazine, deutotetrabenazine, and valbenazine, baclofen, guanfacine, baclofen, benzodiazepines and botulinum toxin injections) within 2 weeks prior to Screening.
o oral neuroleptics within 4 weeks prior to Screening
20) Subjects receiving anti-depressant, anti-anxiety and anti-ADHD medications unless the dosage has been stable for a minimum of 4 weeks prior to Screening and not prescribed to relieve the neurological signs of TS.
21) Subjects who received psychostimulants for the treatment of Attention Deficit Disorder (ADD)/Attention Deficit Hyperactivity Disorder (ADHD) and developed and/or had exacerbations of the tic disorder after the initiation of stimulant treatment.
22) Subjects who have a need for medications which would have unfavorable interactions with ecopipam,e.g., dopamine antagonists or agonists [including bupropion], tetrabenazine, or monoamine oxidase inhibitors.
23) Initiation or changes in behavioral therapies for TS during the course of the study (i.e., Habit Reversal Training or Comprehensive Behavioral Intervention for Tics) as well as deep brain stimulation.
24) Subjects who have initiated new behavioral therapies to treat TS fewer than 10 weeks prior to Baseline visit
25) Subjects unable to swallow tablets |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
Primary Efficacy Endpoint:
The primary efficacy endpoint is the change in the Yale Global Tic Severity Scale – Total Tic Score (YGTSS-TTS, i.e., sum of the motor and phonic tic scores) from baseline (YGTSS-TTS score from Baseline visit) to end of therapy (YGTSS-TTS score from Week 12). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from baseline (YGTSS-TTS score from Baseline visit) to end of therapy (YGTSS-TTS score from Week 12). |
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| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoint:
• Change in Clinical Global Impression of Tourette Syndrome Severity (CGI-TS-S) from Baseline to Week 12
Other Secondary efficacy endpoints include:
• Change in Clinician Global Impression Tourette Syndrome of Improvement (CGI-TS-I) from Baseline to Week 12
• Change in YGTSS-Global Score (GS) from Baseline to Week 12
• Change in Caregiver Global Impression of Change (CaGI-C) from Baseline to Week 12
• Change in Gilles de la Tourette Syndrome–Quality of Life Scale for Children and Adolescents (C&A-GTS-QOL) from Baseline to Week12
• Percentage of subjects with a 25% improvement on the YGTSS-TTS
• Percentage of subjects with complete remission of tics on the YGTSS-TTS
• Change in YGTSS-TTS from Baseline to Weeks 4, 6, and 8
• Change in CGI-TS-S from Baseline to Weeks 4, 6, and 8
• Change in CGI-TS-I from Baseline to Weeks 4, 6, and 8
• Change in YGTSS-GS from Baseline to Weeks 4, 6, and 8
• Change in CaGI-C from Baseline to Weeks 4, 6, and 8
• Change in the C&A-GTS-QOL from Baseline to Weeks 4, 6, and 8
Rank order of hierarchy of the secondary endpoints will be outlined in the statistical analysis plan. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Duration of treatment:
LPLV |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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