| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Tics associated with Tourette’s Disorder in children and adolescents |
|
| E.1.1.1 | Medical condition in easily understood language |
| Sudden, repetitive and involuntary physical movements and vocal utterances associated with Tourette’s Disorder |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| 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 |
|
| 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 |
To compare the efficacy of aripiprazole with placebo in the suppression of tics in children and adolescents (7-17 years) with a diagnosis of Tourette’s Disorder.
|
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of aripiprazole once-daily treatment with oral tablets in children and adolescents with a diagnosis of Tourette’s Disorder |
|
| 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, 7-17 years of age (inclusive) at the time of signing the informed consent/assent.
2. The subject meets current DSM-IV-TR diagnostic criteria for Tourette’s Disorder, as confirmed by the K-SADS-PL, including the Diagnostic Supplement 5 (Substance Abuse and Other Diseases, ie, Tic Disorders).
3. The subject has a TTS ≥ 20 on the YGTSS at Screening and Baseline (randomization).
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 (defined by menarche and not having undergone surgical sterilization/hysterectomy) must have a negative pregnancy test, must be practicing acceptable double-barrier methods of contraception (or can confirm abstinence at each scheduled visit), and must not be pregnant or lactating.
6. Written informed consent must be obtained from a legally acceptable representative (eg, guardian or caregiver), in accordance with local law and the requirements of the trial center’s institutional review board (IRB) or independent ethics committee (IEC), 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. The subject and the designated guardian(s) or caregiver(s) are able to comprehend and satisfactorily comply with the protocol requirements, as evaluated by the investigator. |
|
| 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:
- Transient Tic disorder
- Huntington's disease
- Parkinson's disease
- Sydenham's chorea
- Wilson's disease
- Mental retardation
- Pervasive developmental disorder
- 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 ADD/ADHD and who have developed and/or had exacerbations of the tic disorder after the initiation of stimulant treatment (Note that subjects with ADD/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 meets DSM-IV-TR criteria for a primary mood disorder.
5. The subject has severe obsessive-compulsive disease (OCD), 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. Subjects who received any investigational agent in a clinical trial within 30 days prior to Screening; or who were previously enrolled in Studies 31-10-272, 31-10-273, or 31-10-274; or who were randomized into a clinical trial with once-daily aripiprazole at any time.
8. The subject has a history of neuroleptic malignant syndrome.
9. Sexually active males who will not commit to utilizing 2 of the approved birth control methods or who will not remain abstinent during the trial and for 90 days following the last dose of study drug, or sexually active females of childbearing potential who will not commit to utilizing 2 of the approved birth control methods or who will not remain abstinent during the trial and for 30 days following the last dose of study drug. Abstinence will be permitted if it is confirmed and documented at every trial visit. If employing birth control, 2 of the following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pill, birth control depot injections, implant, condom or sponge with spermicide.
10. Females who are breast-feeding and/or who have a positive serum pregnancy test result prior to receiving trial drug.
11. 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 have 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).
12. Body weight is lower than 16 kg.
13. Subjects who have taken neuroleptic or antiparkinson drugs less than 14 days prior to randomization.
14. Subjects requiring cognitive-behavioral therapy (CBT) for
Tourette’s Disorder during the trial period. CBT for other nonexclusionary disorders must remain consistent throughout the trial.
15. The subject has met DSM-IV-TR criteria for any significant psychoactive substance use disorder (abuse, dependence, and/or withdrawal) within the past 3 months.
16. A positive drug screen for cocaine, alcohol, or other drugs of abuse (excluding caffeine, nicotine, or prescribed psychostimulants for ADD/ADHD). Investigators can chose to repeat a positive drug screen one time during Screening period after concurrence with the medical monitor. A second positive test for any drug of abuse would be exclusionary.
17. Subject requiring medication not allowed per protocol.
18. Use of any Cytochrome P450 (CYP)2D6 and CYP3A4 inhibitors or CYP3A4 inducers within 14 days prior to dosing and for the duration of the trial.
19. Use of herbal medications of any kind and nutritional or dietary supplements for Tourette’s disorder within 7 days prior to dosing and for the duration of the trial.
20. The inability to swallow tablets or tolerate oral medication.
21. The following laboratory test results, vital sign, measurements, and electrocardiogram (ECG) results are exclusionary:
1) Platelets ≤ 75,000/mm3
2) Hemoglobin ≤ 9 g/dL
3) Neutrophils, absolute ≤ 1000/mm3
4) Aspartate aminotransferase (AST) > 3x ULN as defined by the central laboratory
5) Alanine aminotransferase (ALT) > 3x ULN as defined by the central laboratory
6) Creatinine ≥ 2 mg/dL
7) Diastolic blood pressure > 105 mmHg
8) QTc ≥ 450 msec on either the QTcB (Bazett’s) or QTcF (Fridericia) corrections on 2 of 3 time points |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline to endpoint on the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Clinical Global Impressions Scale for Tourette’s Syndrome (CGI-TS) change score at endpoint (change score obtained from CGI-TS improvement scale assessment). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| 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 |
| Argentina |
| Belgium |
| Bulgaria |
| Canada |
| Finland |
| France |
| Germany |
| Hungary |
| Italy |
| Mexico |
| Netherlands |
| Peru |
| Poland |
| Romania |
| Spain |
| Sweden |
| United Kingdom |
| 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
|
| Last Date of Contact or the Date of Final Contact Attempt from the Post-treatment Follow-up eCRF page for the last subject completing or withdrawing from the trial |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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