Safety and Tolerability Study of Once-weekly Oral Aripiprazole in Children and Adolescents With Tourette's Disorder

Study Overview
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Brief Summary
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The goal of the current trial is to obtain long term efficacy, safety and tolerability data of once weekly aripiprazole in children and adolescents with Tourette's Disorder.

Official Title
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An Open-Label, Multicenter Study Evaluating the Safety and Tolerability of Once-weekly Oral Aripiprazole in Children and Adolescents With Tourette's Disorder

Conditions
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Tourette's Disorder

Intervention / Treatment
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* Drug: Aripiprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participants successfully completed the final assessment visit in either Study 31-10-272 (NCT01418339) or 31-10-273 (NCT01418352). The participants completed all required assessments for the Week 8/Early Termination Visit to be eligible for rollover in to this open-label trial. Written informed consent form (ICF) obtained from a legally acceptable representative & informed assent at Baseline as applicable by trial center's Institutional review board/independent ethics committee (IRB/IEC). The participant, designated guardian(s) or caregiver(s) are able to comprehend and satisfactorily comply with the protocol requirements, as evaluated by the investigator. Exclusion Criteria: The participants experienced adverse events (AEs) during the double-blind study 31-10-272 (NCT01418339) or 31-10-273 (NCT01418352) that would, in the investigator's judgment, preclude further exposure to aripiprazole. The participants had protocol violations during the double-blind trial considered major in the judgment of the investigator which would deem the participant a poor candidate for the trial. A positive drug screen at baseline for cocaine, alcohol or other drugs of abuse which will result in early termination at Week 1. Sexually active patients 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 and 30 days following the last dose of study drug for male and female respectively. Participants representing Risk of committing suicide. Body weight lower than 16 kg. Abnormal laboratory test results (Platelet, Hemoglobin, Neutrophils, Aspartate aminotransferase, Alanine aminotransferase, Creatinine) vital signs and Electrocardiogram (ECG) results.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aripiprazole<br>Participants received oral aripiprazole tablets once weekly (QW) with a titrated dose starting from 52.5 milligram (mg), on Day 1 and increasing to 77.5 mg and 110 mg for the remainder of the trial (Up to Week 52), the dose could be adjusted between these 3 dose levels as determined by investigator's discretion based on safety and tolerability. | Drug: Aripiprazole<br>* Aripiprazole tablets orally once daily.<br>* Other names: ABILIFY;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Severe TEAEs and TEAEs Leading Treatment Discontinuation | An Adverse Event (AE) is defined as any untoward medical occurrence in a participant enrolled in a clinical trial and which did not necessarily have a causal relationship with the study medication. Treatment emergent adverse events (TEAE) are adverse events occurring after the onset of study drug administration. | From signing of the informed consent up to 30 days after the last dose (Up to Week 52) | 
| Number of Participants With Clinically Significant Changes in Laboratory Parameter Values | The laboratory values were one of the parameters to measure the safety and tolerability of individual participants. Participants with potentially clinically significant lab values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria were reported. Any value outside the normal range was flagged for the attention of the investigator who assessed whether or not a flagged value is of clinical significance. | Baseline to Week 52 | 
| Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Values | Incidence of clinically relevant abnormal ECG values were reported as change from Baseline in heart rate (Tachycardia - ≥15 beats per minute (bpm), Bradycardia ≤15 bpm; Rhythm (Sinus tachycardia ≥15 bpm increase, Sinus bradycardia decrease of ≥15 bpm from Baseline); Presence of - supraventricular premature beat; ventricular premature beat; supraventricular tachycardia; ventricular tachycardia; atrial fibrillation and flutter. Conduction - Presence of primary, secondary or tertiary atrioventricular block, left bundle-branch block, right bundle-branch block, pre-excitation syndrome, other intraventricular conduction blocked QRS ≥0.12 second increase of ≥0.02 second. Acute, subacute or old Infarction, Presence of myocardial ischemia, symmetrical T-wave inversion. Increase in QTc - QTc ≥450 msec ≥10% increase. Any clinically significant change from Baseline assessed by the Investigator are reported. | Baseline to Week 52 | 
| Number of Participants With Emergence of Suicidal Ideation, TEAEs Related to Suicide and Suicidality and Suicide Ideation From the Potential Suicide Events Recorded on the Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidality was defined as reporting at least one occurrence of any suicidal behavior or suicidal ideation. Suicidal behavior was defined as reporting any type of suicidal behaviors (actual attempt, interrupted attempt, aborted attempt, and preparatory acts or behavior). Suicidal ideation was defined as reporting any type of suicidal ideation. The suicidal ideation intensity total score is the sum of intensity scores of 5 items (frequency, duration, controllability, deterrents, and reasons for ideation). The score of each intensity item ranges from 0 (none) to 5 (worst) which leads to the range of the total score from 0 to 25. A missing score of any item resulted in a missing total score. If no suicidal ideation was reported, a score of 0 was given to the intensity scale. | Baseline to Week 52 | 
| Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Score | The AIMS Scale is an extrapyramidal symptoms (EPS) rating scale. The AIMS is a 12 item scale. The first 10 items e.g. facial and oral movements (items 1-4), extremity movements (items 5 and 6), trunk movements (item 7), investigators global assessment of dyskinesia (items 8 to 10) are rated from 0 to 4 (0=best, 4=worst). Items 11 and 12, related to dental status, have dichotomous responses, 0=no and 1=yes. The AIMS Total Score is the sum of the ratings for the first seven items. The possible total scores are from 0 to 28. A negative change from Baseline indicates improvement. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32, 40, 52; Last Visit (Week 52 or early termination Visit before Week 52) | 
| Mean Change From Baseline in Body Mass Index (BMI) | The BMI kilogram/meter square (i.e. kg/m^2) was calculated from the Baseline height and the weight at the current visit using one of the following formulae, as appropriate: Weight (kg) divided by [Height (meters)]^2. | Baseline and Weeks 12, 24, 52 and Last Visit (Week 52 or early termination Visit before Week 52) | 
| Number of Participants With Clinically Significant Changes in Vital Signs | Vital signs assessments included orthostatic (supine and standing) blood pressure (BP) measured as millimeter of mercury [mmHg]), heart rate, (measured in beats per minute [bpm]), body weight (measured in kilograms [kg]) and body temperature. Incidence of clinically relevant abnormal values in heart rate, systolic and diastolic blood pressure and weight were identified based on pre-defined criteria. Orthostatic assessments of blood pressure and heart rate were made after the participant has been supine for at least 5 minutes and again after the participant has been standing for approximately 2 minutes, but not more than 3 minutes. | Baseline to Week 52 | 
| Mean Change From Baseline in Simpson Angus Scale (SAS) Score | The SAS is a rating scale used to measure Extrapyramidal symptoms (EPS). The SAS scale consists of a list of 10 symptoms of parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia), with each item rated from 0 to 4, with 0 being normal and 4 being the worst. The SAS Total score is sum of ratings for all 10 items, with possible Total scores from 0 to 40. A negative change from Baseline indicates improvement. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32, 40, 52; Last Visit (Week 52 or early termination Visit before Week 52) | 
| Mean Change From Baseline in Barnes Akathisia Rating Scale (BARS) Score | The BARS was an EPS rating scale. The BARS was used to assess the presence and severity of akathisia. This scale consists of 4 items. Only the 4th item, the Global Clinical Assessment of Akathisia, was evaluated in this trial. This item is rated on a 6 point scale, with 0 being best (absent) and 5 being worst (severe akathisia). A negative change from Baseline indicates improvement. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32,40, 52; Last Visit (Week 52 or early termination Visit before Week 52) | 
| Mean Change From Baseline in Average Score of Attention-Deficit Disorder/Attention-Deficit Hyperactivity Disorder (ADD/ADHD) Sub-scale of the Swanson, Nolan and Pelham-IV (SNAP-IV) | The SNAP-IV, ADHD Inattention subscale contains 19 items, items 1 to 9 measure inattention, items 11 to 19 measure hyperactivity/impulsivity, and item 10 for inattention domain that scores the intensity of each item during the last seven days on a 0 to 3 scale (0=not at all, 1=just a little, 2=pretty much, 3=very much). The lowest possible score is 0; highest is 57. The negative change from Baseline indicates improvement. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32,40, 52; Last Visit (Week 52 or early termination Visit before Week 52) | 
| Mean Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) Total Score | The CY-BOCS is used to assess characteristics of obsession and compulsion for the week prior to the interview. Nineteen items are rated in the CY-BOCS, but the total score is the sum of only items 1 to 10 (excluding items 1b and 6b). The obsession and compulsion subtotals are the sums of items 1 to 5 (excluding 1b) and 6 to 10 (excluding 6b), respectively. A missing value for any CY-BOCS item scale could result in a missing total score or obsession and compulsion subtotals of which the item scale is a component. At baseline, the full CY-BOCS interview is conducted. At all post-baseline time points, the Questions on Obsessions (items 1 to 5) and Questions on Compulsions (items 6 to 10) are reviewed and the target symptoms identified at baseline are the primary focus for rating severity. CY-BOCS total score could range from 0 to 40. Higher scores indicate worse outcome. A negative change from Baseline indicates improvement. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32,40, 52; Last Visit (Week 52 or early termination Visit before Week 52) | 
| Mean Change From Baseline in Children's Depression Rating Scale Revised (CDRS-R) Total Score | The CDRS-R is composed of 17 interviewer-rated symptom areas: impaired schoolwork, difficulty having fun, social withdrawal, appetite disturbance, sleep disturbance, excessive fatigue, physical complaints, irritability, excessive guilt, low self-esteem, depressed feelings, morbid ideas, suicidal ideas, excessive weeping, depressed facial affect, listless speech, and hypoactivity. The CDRS-R total score is the sum of scores for the 17 symptom areas. A missing value for any CDRS-R item scale or a not rated item scale (indicated by the value of 0) could result in a missing total score. The CDRS-R total score is the sum of scores for the 17 symptom areas and could range from 17 to 113 with higher values indicating worse outcome. A negative change from Baseline indicates improvement. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32,40, 52; Last Visit (Week 52 or early termination Visit before Week 52) | 
| Mean Change From Baseline in Pediatric Anxiety Rating Scale (PARS) Total Severity Score | The PARS has 2 sections: the symptom checklist and the severity items. The symptom checklist is used to determine the child's repertoire of symptoms during the past week. Information is elicited from the child and parent(s) and the rater then combines information from all informants using his/her best judgment. The 7-item severity list is used to determine severity of symptoms and the PARS total score. The time frame for the PARS rating is the past week. Only those symptoms endorsed for the past week are included in the symptom checklist and rated on the severity items. The PARS total severity score is the sum of items 2, 3, 5, 6, and 7. The total severity score ranges from 0 to 25, with 25 being the worst. Codes 8 (Not applicable) and 9 (Does not know) are not included in the summation (ie, equivalent to a score of 0 in the summation). A negative change from Baseline indicates improvement. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32,40, 52; Last Visit (Week 52 or early termination Visit before Week 52) | 
| Mean Change From Baseline in Body Weight |  | Baseline to Weeks 12, 24, 52 and Last Visit (Week 52 or early termination Visit before Week 52) | 
| Mean Change From Baseline in Waist Circumference | Waist circumference was recorded before a participant's meal and at approximately the same time at each visit. Measurement was accomplished by locating the upper hip bone and the top of the right iliac crest and placing the measuring tape in a horizontal plane around the abdomen at the level of the crest. Before reading the tape measure, the assessor assured that the tape was snug, but did not compress the skin, and is parallel to the floor. The measurement was made at the end of a normal exhalation. | Baseline to Weeks 12, 24, 52 and Last Visit (Week 52 or early termination Visit before Week 52) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Yale Global Tic Severity Scale (YGTSS) Total Tic Score | The YGTSS is a semi-structured clinical interview designed to measure the tic severity. This scale consisted of a tic inventory, with 5 separate rating scales to rate the severity of symptoms, and an impairment ranking. Ratings were made along 5 different dimensions on a scale of 0 to 5 for motor and vocal tics, each including number, frequency, intensity, complexity, and interference. The YGTSS TTS was the summation of the severity scores of motor and vocal tics. The total tic score (TTS) ranged from 0 (none) to 50 (severe) with higher score represent more severe symptoms (A negative change from Baseline indicates improvement). | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32,40, 52; Last Visit (Week 52 or early termination Visit before Week 52) | 
| Mean Change From Baseline in Clinical Global Impression for Tourette's Syndrome (CGI-TS) Severity of Illness Score | The severity of illness and efficacy of study medication for each participant were rated using the CGI-TS scale. The study physician rated the participants total improvement whether or not it is due to study treatment. All responses were compared to the participants condition at Baseline (Day 0). Response choices include: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. A negative change from Baseline indicates improvement. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32,40, 52; Last Visit (Week 52 or early termination Visit before Week 52) | 
| Mean Change From Baseline in Total YGTSS Score | The YGTSS consists of a tic inventory, with 5 separate rating scales to rate the severity of symptoms (on a scale of 0 to 5 for 5 different dimensions, including number, frequency, intensity, complexity, and interference) of motor and vocal tics, and an impairment ranking. The Total YGTSS score is the summation of the severity scores of motor and vocal tics and also the ranking of impairment (range of 0 to 100). A missing value of a YGTSS item scale could result in a missing Total YGTSS score. A negative change in Total YGTSS score from baseline represents an improvement in symptoms. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32,40, 52; Last Visit (Week 52 or early termination Visit before Week 52) | 
| Response Rates | Response rates - clinical response was defined as percentage of participants >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. The YGTSS consists of a tic inventory, with 5 separate rating scales to rate the severity of symptoms (on a scale of 0 to 5 for 5 different dimensions, including number, frequency, intensity, complexity, and interference) of motor and vocal tics, and an impairment ranking. The Total YGTSS score is the summation of the severity scores of motor and vocal tics and also the ranking of impairment (range of 0 to 100) with higher score representing severe symptoms. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32,40, 52; Last Visit (Week 52 or early termination Visit before Week 52) | 
| Treatment Discontinuation Rates | Treatment discontinuation rate was calculated as the percentage of participants who discontinued treatment. | Up to Week 53 | 
| Mean Change From Baseline in Gilles de la Tourette Quality of Life (GTS-QOL) Overall Score | The GTS-QOL is a disease-specific patient-reported scale for the measurement of health-related quality of life in participants with Tourette's Disorder, taking into account the complexity of the clinical picture of the disease. The questionnaire consists of a 27-item Tourette's Disorder-specific scale with 4 subscales (psychological, physical, obsessional, and cognitive). The GTS-QOL total score ranged from 0 (extremely dissatisfied with life) and 100 (extremely satisfied with life). A positive change from Baseline indicates improvement. | Baseline and Weeks 4, 24, 52 and Last Visit (Week 52 or early termination Visit before Week 52) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tourette's Disorder, Tic Disorders