| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10044126 |
| E.1.2 | Term | Tourette's disorder |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| 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 |
| The primary objective of the trial is to evaluate the long-term efficacy of aripiprazole once-daily treatment with oral tablets in pediatric subjects with TD. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective of the trial is to evaluate the safety and tolerability of aripiprazole once-daily treatment with oral tablets in pediatric subjects with a diagnosis of TD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) The subject is a male or female child or adolescent, 6 to 17 years of age (inclusive) at the time of signing the informed consent/assent.
2) The subject meets current DSM-5 diagnostic criteria for TD, documented at screening and made by an adequately trained clinician, as confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version.
3) The subject has a TTS ≥ 20 on the YGTSS at screening and baseline (Day 1).
4) The subject, a caregiver, and the investigator must all agree that the presenting tic symptoms cause impairment in the subject’s normal routines, which include academic achievement, occupational functioning, social activities, and/or relationships.
5) Females of childbearing potential (all female subjects ≥ 12 years of age and all female subjects < 12 years of age if menstruation has started) must have a negative pregnancy test and must not be pregnant or lactating.
6) Written informed consent must be obtained from the subject or a legally acceptable representative (eg, guardian or caregiver), in accordance with requirements of the trial site's institutional review board (IRB)/independent ethics committee (IEC) and local regulatory requirements, prior to the initiation of any protocol required procedures. In addition, the subject, as required by the trial center's IRB/IEC, must provide informed assent at screening and as such must be able to understand that he or she can withdraw from the trial at any time.
7) Ability, in the opinion of the principal investigator, of the subject and the subject’s legally acceptable representative (eg, guardian) or caregiver(s) to understand the nature of the trial and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, and discontinuation of prohibited concomitant medications, to read and understand the written word in order to complete subject-reported outcomes measures, and to be reliably rated on assessment scales. |
|
| E.4 | Principal exclusion criteria |
1) The subject presents with a clinical presentation and/or history that is consistent with another neurologic condition that may have accompanying abnormal movements.
These include, but are not limited to, the following:
• Transient tic disorder
• Huntington's disease
• Parkinson's disease
• Sydenham's chorea
• Wilson's disease
• Mental retardation
• Pervasive developmental disorder
• Tardive dyskinesia
• Traumatic brain injury
• Stroke
• Restless legs syndrome
2) The subject has a history of schizophrenia, bipolar disorder, or other psychotic disorder.
3) Subjects who receive psychostimulants for the treatment of attention-deficit hyperactivity disorder (ADHD) and who have developed and/or had exacerbations of the tic disorder after the initiation of stimulant treatment. (Note that subjects with ADHD who are treated with psychostimulants and have not developed new tics or a worsening of their current tics can be included if all other enrollment obligations are met).
4) The subject currently has a primary diagnosis that meets DSM-5 criteria for mood disorder.
5) The subject has severe obsessive-compulsive disease, as evidenced by a Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score > 16.
6) The subject has taken aripiprazole within 1 month (30 days) of the screening visit.
7) The subject has a history of neuroleptic malignant syndrome.
8) Subject is a sexually active male or female of childbearing potential (FOCBP) (all female subjects ≥ 12 years of age and all female subjects < 12 years of age if menstruation has started) who will not agree to practice 2 acceptable methods of birth control or who will not remain abstinent during the trial and for 30 or 90 days following the last dose of IMP for females and males, respectively. Abstinence will be permitted if it is confirmed and documented at every trial visit.
9) The subject represents a significant risk of committing suicide based on history (suicide attempt in past 1 year), routine psychiatric status examination, investigator’s judgment, or who has an answer of “yes” on any question other than 1-3 (current or over the last 30 days) on the baseline/screening version of the Columbia-Suicide Severity Rating Scale (C-SSRS).
10) The subject has a body weight < 16 kg.
11) Subjects who have taken neuroleptic or antiparkinson drugs within 14 days prior to baseline.
12) Subjects requiring cognitive-behavioral therapy (CBT) for TD during the trial period. CBT for other nonexclusionary disorders must remain consistent throughout the trial.
13) The subject has met DSM-5 criteria for any significant psychoactive substance use disorder within the past 3 months.
14) A positive drug screen for cocaine, alcohol, or other drugs of abuse (excluding caffeine, nicotine, or prescribed psychostimulants for ADHD). Investigators can choose to repeat a positive drug screen one time during screening period after concurrence from the medical monitor. A second positive test for any drug of abuse would be exclusionary.
15) Subject requiring medication not allowed per protocol.
16) Use of any cytochrome P450 (CYP)2D6 and CYP3A4 inhibitors or CYP3A4 inducers within 14 days prior to baseline and for the duration of the trial.
17) Other nutritional or dietary supplements and nonprescription herbal preparations for TD (eg, cannabinoids, N-aceytlcysteine, omega-3 fatty acids, kava extracts, GABA supplements) within 7 days prior to baseline and for the duration of the trial, unless approved in advance by the medical monitor.
18) The inability to swallow tablets or tolerate oral medication.
19) Subject has participated in a clinical trial involving either study medication or interventional (non-medication) treatment for TD within the last 60 days.
20) The following laboratory test results, vital signs and electrocardiogram (ECG) results are exclusionary:
a) Platelets ≤ 75,000/mm3
b) Hemoglobin ≤ 9 g/dL
c) Neutrophils, absolute ≤ 1000/mm3
d) Aspartate aminotransferase > 3 × upper limit of normal (ULN) as defined by the central laboratory
e) Alanine aminotransferase > 3 × ULN as defined by the central laboratory
f) Creatinine ≥ 2 mg/dL
g) Diastolic blood pressure > 105 mmHg
h) Corrected QT interval ≥ 450 msec (males) or ≥ 470 msec (females) using the corrected QT interval for heart rate using Fridericia’s formula. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the time from randomization to relapse during the double blind randomized withdrawal phase. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| time from randomization to relapse during the double blind randomized withdrawal phase. |
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| E.5.2 | Secondary end point(s) |
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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 | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | No |
| 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 | 3 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 |
| Hungary |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The last date of contact or the date of final contact attempt from the post -treatment follow up eSource page for the last subject completing or withdrawing from the trial. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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