Tourette's Disorder
Conditions
Keywords
Tourette's Disorder, Tic disorders
Brief summary
The goal of the current trial is to determine efficacy and safety of once-weekly aripiprazole in reducing Total Tic Severity (TTS) score in children and adolescents with Tourette's Disorder.
Interventions
DRUGAripiprazole
Aripiprazole tablets once weekly for 8 weeks.
DRUGPlacebo
Aripiprazole matching-placebo once-weekly for 8 weeks.
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* 7 to 17 year old with diagnostic and statistical manual of mental disorders, fourth edition -text revision (DSM-IV-TR) diagnostic criteria for Tourette's disorder (TD), confirmed by the kiddie schedule for affective disorders and schizophrenia - present and lifetime version (K-SADS-PL), including the Diagnostic Supplement 5 * Has a total tic score (TTS) ≥20 on the yale global tic severity scale (YGTSS) at Screening and Baseline * Presenting tic symptoms cause impairment in the participant's normal routines, which include academic achievement, occupational functioning, social activities, and/or relationships * Females of childbearing potential must have a negative pregnancy test, must be practicing acceptable double-barrier methods of contraception, and must not be pregnant or lactating. * Written informed consent form (ICF) obtained from a legally acceptable representative & informed assent at Screening as applicable by study 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
* Clinical presentation and/or history, consistent with another neurologic condition that may have accompanying abnormal movements. * History of schizophrenia, bipolar disorder, or other psychotic disorder. * Participant receiving psychostimulants for treatment of attention-deficit disorder/Attention-deficit hyperactivity disorder (ADD/ADHD) and who have developed and/or had exacerbations of tic disorder after initiation of stimulant treatment. * Currently meets DSM-IV-TR criteria for a primary mood disorder. * Severe obsessive-compulsive disorder (OCD), per children's yale-brown obsessive compulsive scale (CY-BOCS) score \>16. * Taken aripiprazole within 30 days of the Screening visit. * Received any investigational agent in a clinical trial within 30 days prior to Screening or who were randomized into a clinical trial with Once-weekly aripiprazole at any time. * History of neuroleptic malignant syndrome. * Sexually active participants not using 2 approved methods of contraception; breastfeeding or pregnant. * Risk of committing suicide * Bodyweight lower than 16 kg * Taken neuroleptic or antiparkinson drugs \<14 days prior to randomization. * Requiring cognitive-behavioral therapy (CBT) for TD during study. * Participant meets DSM-IV-TR criteria for any significant psychoactive substance use disorder within the past 3 months. * Positive drug screen * Participant requires medications not allowed per protocol * Use of CYP2D6 and CYP3A4 inhibitors or CYP3A4 inducers within 14 days prior to dosing and for duration of study. * Inability to swallow tablets or tolerate oral medication * Abnormal laboratory test results, vital signs and Electrocardiogram (ECG) results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score | Baseline and Week 8 | 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 (greater reduction from baseline for greater improvement). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS) Score | Baseline and Week 8 | 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. |
| Mean Change From Baseline in Gilles de la Tourette Quality of Life (GTS-QOL) Overall Score at Week 8 | Baseline and Week 8 | 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. |
Countries
Bulgaria, Germany, Romania, Ukraine, United States
Participant flow
Recruitment details
A total of 105 participants were screened and 83 were randomized to the treatment. The randomized participants were recruited at 38 sites in the following 5 countries: Bulgaria, Germany, Romania, Ukraine, and the US.
Pre-assignment details
This study consisted of 2 distinct phases: a Pre-treatment Phase and a Treatment Phase. The Pre-treatment Phase consisted of a Screening period, a Washout period, and a Baseline visit. This was followed by an 8-week Treatment Phase. There was a follow-up period (30 days) for those participants who did not roll-over into the Open-label Study 31-10-274 (NCT01416441).
Participants by arm
| Arm | Count |
|---|---|
| Aripiprazole 52.5 mg Participants received aripiprazole 52.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period. | 20 |
| Aripiprazole 77.5 mg Participants received aripiprazole 77.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period. | 21 |
| Aripiprazole 110 mg Participants received aripiprazole 110 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period. | 21 |
| Matching Placebo Participants received aripiprazole matching placebo tablets, orally, once weekly for the 8-week Double-blind Treatment Period. | 21 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy as Determined by the Investigator | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 | 0 | 0 |
| Overall Study | Protocol Deviation | 0 | 0 | 1 | 0 |
| Overall Study | Sponsor Discontinued Trial Site | 0 | 2 | 2 | 2 |
| Overall Study | Subject Withdrew Consent | 0 | 1 | 2 | 1 |
Baseline characteristics
| Characteristic | Aripiprazole 52.5 mg | Aripiprazole 77.5 mg | Aripiprazole 110 mg | Matching Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 11.5 Years STANDARD_DEVIATION 3.4 | 11.7 Years STANDARD_DEVIATION 2.8 | 12.5 Years STANDARD_DEVIATION 2.7 | 11.8 Years STANDARD_DEVIATION 2.7 | 11.9 Years STANDARD_DEVIATION 2.9 |
| Age, Customized 13 to 17 years | 8 Participants | 10 Participants | 10 Participants | 7 Participants | 35 Participants |
| Age, Customized 7 to 12 years | 12 Participants | 11 Participants | 11 Participants | 14 Participants | 48 Participants |
| BMI (Body Mass Index) | 19.6 kilogram per meter squared (kg/m^2) STANDARD_DEVIATION 3.7 | 20.7 kilogram per meter squared (kg/m^2) STANDARD_DEVIATION 3.8 | 20.6 kilogram per meter squared (kg/m^2) STANDARD_DEVIATION 4.9 | 19.3 kilogram per meter squared (kg/m^2) STANDARD_DEVIATION 3.7 | 20.0 kilogram per meter squared (kg/m^2) STANDARD_DEVIATION 4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 19 Participants | 20 Participants | 19 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 148.5 centimeter STANDARD_DEVIATION 19 | 151.8 centimeter STANDARD_DEVIATION 16.5 | 157.5 centimeter STANDARD_DEVIATION 14.8 | 151.8 centimeter STANDARD_DEVIATION 14.4 | 152.4 centimeter STANDARD_DEVIATION 16.3 |
| Race/Ethnicity, Customized Black or African American | 8 Participants | 2 Participants | 2 Participants | 2 Participants | 14 Participants |
| Race/Ethnicity, Customized White | 12 Participants | 19 Participants | 19 Participants | 19 Participants | 69 Participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 3 Participants | 6 Participants | 20 Participants |
| Sex: Female, Male Male | 17 Participants | 13 Participants | 18 Participants | 15 Participants | 63 Participants |
| Time since first diagnosis for Tourette's Disorder | 3.5 years STANDARD_DEVIATION 3 | 1.8 years STANDARD_DEVIATION 2.5 | 3.0 years STANDARD_DEVIATION 3.5 | 2.6 years STANDARD_DEVIATION 2.3 | 2.7 years STANDARD_DEVIATION 2.9 |
| Weight | 44.7 Kilogram STANDARD_DEVIATION 16.3 | 49.0 Kilogram STANDARD_DEVIATION 16.2 | 52.8 Kilogram STANDARD_DEVIATION 19.6 | 45.0 Kilogram STANDARD_DEVIATION 12.5 | 47.9 Kilogram STANDARD_DEVIATION 16.4 |
| Yale Global Tic Severity Scale Total Tic Score (YGTSS TTS) | 28.2 score on a scale STANDARD_DEVIATION 5.6 | 30.1 score on a scale STANDARD_DEVIATION 5.8 | 31.4 score on a scale STANDARD_DEVIATION 6.7 | 31.1 score on a scale STANDARD_DEVIATION 5.5 | 30.2 score on a scale STANDARD_DEVIATION 6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 21 | 0 / 21 | 0 / 21 |
| other Total, other adverse events | 8 / 20 | 4 / 21 | 16 / 21 | 4 / 21 |
| serious Total, serious adverse events | 0 / 20 | 0 / 21 | 0 / 21 | 0 / 21 |
Outcome results
Primary
Mean Change From Baseline to Week 8 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 (greater reduction from baseline for greater improvement).
Time frame: Baseline and Week 8
Population: The Intention-to-Treat (ITT) Sample included participants randomly assigned to the double-blind treatment (regardless of whether or not they were dosed with study drug). Overall number of participants analyzed are participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole 52.5 mg | Mean Change From Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score | -8.2 score on scale | Standard Deviation 4.8 |
| Aripiprazole 77.5 mg | Mean Change From Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score | -9.9 score on scale | Standard Deviation 6.7 |
| Aripiprazole 110 mg | Mean Change From Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score | -14.5 score on scale | Standard Deviation 7.7 |
| Matching Placebo | Mean Change From Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score | -9.6 score on scale | Standard Deviation 7.5 |
Secondary
Mean Change From Baseline in Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS) 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.
Time frame: Baseline and Week 8
Population: The Intention-to-Treat (ITT) Sample included participants randomly assigned to the double-blind treatment (regardless of whether or not they were dosed with study drug). Overall number of participants analyzed are participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole 52.5 mg | Mean Change From Baseline in Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS) Score | -0.9 score on scale | Standard Deviation 0.6 |
| Aripiprazole 77.5 mg | Mean Change From Baseline in Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS) Score | -1.1 score on scale | Standard Deviation 0.9 |
| Aripiprazole 110 mg | Mean Change From Baseline in Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS) Score | -1.3 score on scale | Standard Deviation 1 |
| Matching Placebo | Mean Change From Baseline in Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS) Score | -1.0 score on scale | Standard Deviation 0.9 |
Secondary
Mean Change From Baseline in Gilles de la Tourette Quality of Life (GTS-QOL) Overall Score at Week 8
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.
Time frame: Baseline and Week 8
Population: The Intention-to-Treat (ITT) Sample included participants randomly assigned to the double-blind treatment (regardless of whether or not they were dosed with study drug). Overall number of participants analyzed are participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole 52.5 mg | Mean Change From Baseline in Gilles de la Tourette Quality of Life (GTS-QOL) Overall Score at Week 8 | 8.8 score on scale | Standard Deviation 14.1 |
| Aripiprazole 77.5 mg | Mean Change From Baseline in Gilles de la Tourette Quality of Life (GTS-QOL) Overall Score at Week 8 | 3.8 score on scale | Standard Deviation 24.4 |
| Aripiprazole 110 mg | Mean Change From Baseline in Gilles de la Tourette Quality of Life (GTS-QOL) Overall Score at Week 8 | 13.1 score on scale | Standard Deviation 20.9 |
| Matching Placebo | Mean Change From Baseline in Gilles de la Tourette Quality of Life (GTS-QOL) Overall Score at Week 8 | 13.4 score on scale | Standard Deviation 15.9 |