| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Tourette's syndrome is a neurological condition (a condition that affects the nervous system). It causes both physical and verbal tics, which are involuntary repetitive movements or sounds |
|
| 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 | 14.0 |
| 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 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| 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 safety and tolerability of aripiprazole Once-weekly treatment with oral tablets in children and adolescents (7 to 17 years) with a diagnosis of Tourette’s Disorder. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are the following:
• To evaluate the efficacy of Once-weekly aripiprazole in the suppression of tics in children and adolescents with a diagnosis of Tourette’s Disorder, as measured by change from Baseline to endpoint on the TTS of the YGTSS.
• To evaluate the long-term effect of Once-weekly aripiprazole on health-related quality of life in children and adolescents with a diagnosis of Tourette’s Disorder, as measured by the Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject successfully completed participation or discontinued because of lack of efficacy at Week 5 or later in either Trial 31-10-272 or Trial 31-10-273. In both instances, the subject must complete all required assessments for the Week 8/Early Termination Visit to be eligible for rollover in to this open-label trial.
2. Written informed consent must be obtained from a legally acceptable representative (eg, guardian or caregiver), in accordance with requirements of the trial center’s IRB/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 Baseline and as such must be able to understand that he or she can withdraw from the trial at any time.
3. 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 experienced AEs during the double-blind trial that would, in the investigator's judgment, preclude further exposure to aripiprazole.
2. The subject had protocol violations during the double-blind trial considered major in the judgment of the investigator (significant noncompliance, use of prohibited concomitant medications, concern with use of drugs of abuse, etc.), which would deem them poor candidates for this trial.
3. A positive drug screen at Baseline (ie, Day 0/last visit of double-blind trial, Protocol 31-10-272 or 31-10-273) for cocaine, alcohol, or other drugs of abuse (excluding caffeine, nicotine, or prescribed psychostimulants for ADD/ADHD) which will result in early termination on Week 1.
4. 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.
5. Females who have a positive urine pregnancy test result prior to receiving trial drug, or are pregnant or lactating.
6. The subject represents a significant risk of committing suicide based on a routine psychiatric status examination, investigator’s judgment or who have an answer of “yes” on any question other than 1-3 on the C-SSRS.
7. Body weight is lower than 16 kg.
8. The following vital signs and ECG results are exclusionary:
1) Diastolic blood pressure > 105 mmHg
2) QTc ≥ 450 msec on either the QTcB (Bazett’s) or QTcF (Fridericia) corrections on 2 of 3 time points (see NOTE below)
The following laboratory test results will result in discontinuation at the Week 1 visit:
1) Platelets ≤ 75,000/mm3
2) Hemoglobin ≤ 9 g/dL
3) Neutrophils, absolute ≤ 1000/mm3
4) Aspartate aminotransferase (AST) > 3x upper limit of normal as defined by the central laboratory
5) Alanine aminotransferase (ALT) > 3x upper limit of normal as defined by the central laboratory
6) Creatinine ≥ 2 mg/dL
NOTE: In addition, subjects should be excluded (or discontinued at the Week 1 visit for abnormal laboratory tests) if they have any other vital sign results or ECG findings which in the investigator’s judgment are medically significant and would impact the safety of the subject or the interpretation of the trial results. Criteria are provided in Appendix 5 to assist investigators in their assessments of results that may be potentially medically significant, depending on the subject’s medical history and clinical presentation. Abnormal results for laboratory parameters or vital signs should be repeated to ensure reproducibility of the abnormality before excluding a subject based on the criteria noted above. Based on the QTcB or QTcF corrections reported by the central service, a subject will be excluded if either of the corrections exceed 450 msec for 2 or more of the 3 time points of the ECGs conducted. If only 1 ECG time point has a corrected QTc greater than 450 msec on either correction factor and it is not reproduced at either of the other 2 time points, the subject meets the inclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this trial is safety, including the following:
• AEs
• Laboratory tests (hematology, serum chemistry [including prolactin and thyroidstimulating hormone (TSH)], urinalysis, and pregnancy tests)
• Vital signs
• ECGs
• AIMS and other EPS scales
• C-SSRS
• ADD/ADHD Subscale of SNAP-IV
• CY-BOCS
• CDRS-R
• PARS
• Body weight
• Waist circumference
• Body mass index (BMI) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 52 weeks plus a 30 day follow-up |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints will be the following:
• Change from Baseline to endpoint in YGTSS TTS.
• Mean CGI-TS change score at endpoint (change score obtained from CGI-TS improvement scale assessment)
• Mean change from Baseline to endpoint in Total YGTSS score
• Response rates (clinical response will be defined as > 25% improvement from
Baseline to endpoint in YGTSS TTS OR a CGI-TS change score of 1 [very much improved] or 2 [much improved] at endpoint)
• Treatment discontinuation rates
The functional outcome endpoint (considered a secondary endpoint) will be the mean changes from Baseline to endpoint in GTS-QOL overall score. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 52 weeks plus a 30 day follow-up |
|
| 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) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 16 |
| 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 |
| Bulgaria |
| Canada |
| Germany |
| Hungary |
| India |
| Korea, Republic of |
| Romania |
| Taiwan |
| Ukraine |
| 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 end of the trial is the final subject follow-up telephone call 30 days after last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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