Tourette's Disorder
Conditions
Keywords
Tourette's Disorder, Tic disorders
Brief summary
The goal of the current study 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 tablet administered orally once a week.
DRUGPlacebo
Aripiprazole-matching placebo tablet administered orally once a week.
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 |
|---|---|---|
| Change From Baseline in Yale Global Tic Severity Scale (YGTSS) - Total Tic Score (TTS) | Baseline to 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 TTS ranged from 0 (none) to 50 (severe) with a higher score represent more severe symptoms (greater reduction from baseline for greater improvement). Mixed Effect Repeated Measure Model (MMRM) analysis was performed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS) Score | Baseline to 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 included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients), with lower score indicating better improvement. A negative change from Baseline indicates improvement. MMRM analysis was performed. |
| Change From Baseline in Gilles de la Tourette Syndrome - Quality of Life Scale (GTS-QOL) Total Score | Baseline to 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. MMRM analysis was performed. |
Countries
Canada, Hungary, Mexico, South Korea, Taiwan, United States
Participant flow
Recruitment details
A total of 152 participants were screened and 135 were randomized to the treatment. The randomized participants were recruited from 45 study sites in the following 6 countries: United States (US), Hungary, Canada, Taiwan, South Korea, and Mexico. Out of 135, 124 participants were included in the modified intention-to-treat (mITT) population.
Pre-assignment details
The study consisted of a Pretreatment and Treatment Phase. The Pretreatment Phase consisted of a Screening Period, Washout Period (when applicable), and Baseline visit. This was followed by an 8-week Treatment Phase. There was also a Follow-up Period (30 days) for participants who did not roll over into the open-label study 31-10-274 (NCT01416441).
Participants by arm
| Arm | Count |
|---|---|
| Aripiprazole Aripiprazole was administered orally once a week (QW) for 8 weeks in a double-blind manner. Participants randomized to aripiprazole received aripiprazole tablets at a starting dose of 52.5 milligrams (mg) QW on Day 0. At Week 1, according to the investigator's discretion based on efficacy and tolerability, the dose of aripiprazole could remain at 52.5 mg QW or could be increased to 77.5 mg QW. The dose could be increased to 110 mg QW as early as Week 2. For the remainder of the study (up to Week 8), the dose was to be adjusted up and down among these three dose levels, as determined by the investigator. | 90 |
| Placebo Participants randomized to placebo received aripiprazole-matching placebo tablet, orally, QW for 8 weeks in a double-blind manner | 45 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Lack of Efficacy as Determined by the Investigator | 6 | 6 |
| Overall Study | Subject Withdrew Consent | 1 | 2 |
Baseline characteristics
| Characteristic | Aripiprazole | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 11.9 Years STANDARD_DEVIATION 2.8 | 11.9 Years STANDARD_DEVIATION 2.7 | 11.7 Years STANDARD_DEVIATION 2.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 33 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants | 98 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 28 Participants | 40 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 53 Participants | 84 Participants | 31 Participants |
| Sex: Female, Male Female | 17 Participants | 31 Participants | 14 Participants |
| Sex: Female, Male Male | 73 Participants | 104 Participants | 31 Participants |
| Yale Global Tic Severity Scale (YGTSS) -Total Tic Score (TTS) | 30.5 score on a scale STANDARD_DEVIATION 6.6 | 30.1 score on a scale STANDARD_DEVIATION 6.7 | 29.3 score on a scale STANDARD_DEVIATION 7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 90 | 0 / 45 |
| other Total, other adverse events | 38 / 90 | 8 / 45 |
| serious Total, serious adverse events | 3 / 90 | 0 / 45 |
Outcome results
Primary
Change From Baseline in Yale Global Tic Severity Scale (YGTSS) - Total Tic Score (TTS)
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 TTS ranged from 0 (none) to 50 (severe) with a higher score represent more severe symptoms (greater reduction from baseline for greater improvement). Mixed Effect Repeated Measure Model (MMRM) analysis was performed.
Time frame: Baseline to Week 8
Population: Modified Intention-to-Treat (mITT) included all participants randomly assigned to the double-blind treatment, excluding participants from the two sites that were terminated. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Change From Baseline in Yale Global Tic Severity Scale (YGTSS) - Total Tic Score (TTS) | -12.34 score on a scale | Standard Error 0.88 |
| Placebo | Change From Baseline in Yale Global Tic Severity Scale (YGTSS) - Total Tic Score (TTS) | -7.72 score on a scale | Standard Error 1.23 |
Comparison: The statistical comparison was performed using MMRM model at a significance level of 0.05 (2-sided).p-value: =0.002895% CI: [-7.62, -1.63]MMRM
Secondary
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 included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients), with lower score indicating better improvement. A negative change from Baseline indicates improvement. MMRM analysis was performed.
Time frame: Baseline to Week 8
Population: mITT included all participants randomly assigned to the double-blind treatment, excluding participants from the two sites that were terminated. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Change From Baseline in Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS) Score | 2.29 score on a scale | Standard Error 0.12 |
| Placebo | Change From Baseline in Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS) Score | 2.81 score on a scale | Standard Error 0.17 |
Comparison: The statistical comparison was performed using MMRM model at a significance level of 0.05 (2-sided).p-value: =0.012495% CI: [-0.93, -0.12]MMRM
Secondary
Change From Baseline in Gilles de la Tourette Syndrome - Quality of Life Scale (GTS-QOL) Total 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. MMRM analysis was performed.
Time frame: Baseline to Week 8
Population: mITT included all participants randomly assigned to the double-blind treatment, excluding participants from the two sites that were terminated. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Change From Baseline in Gilles de la Tourette Syndrome - Quality of Life Scale (GTS-QOL) Total Score | 10.04 score on a scale | Standard Error 1.83 |
| Placebo | Change From Baseline in Gilles de la Tourette Syndrome - Quality of Life Scale (GTS-QOL) Total Score | 12.04 score on a scale | Standard Error 2.6 |
Comparison: The statistical comparison was performed using MMRM model at a significance level of 0.05 (2-sided).p-value: =0.531795% CI: [-8.31, 4.32]MMRM