Tic Disorder, Tourette's Disorder
Conditions
Keywords
Tourette Syndrome, Basal Ganglia Diseases, Brain Diseases, Central Nervous System Diseases, Tic Disorders, Tics, Movement Disorders, Mental Disorders, Aripiprazole
Brief summary
The goal of the current trial is to determine efficacy and safety of Once-daily aripiprazole in reducing Total Tic Severity in children and adolescents with Tourette's Disorder.
Detailed description
Tourette's Disorder is a neuropsychiatric condition that is characterized by the appearance of tics that can be simple or complex in nature. A tic is a sudden, rapid, recurrent, non-rhythmic, stereotyped motor movement or vocalization. There are a very limited number of medications approved for the treatment of Tourette's Disorder. The goal of the current trial is to obtain efficacy, safety, and tolerability data in a controlled condition of a Once-daily aripiprazole formulation in children and adolescents with Tourette's Disorder. The trial has an 8-week long double-blind treatment period after a pretreatment (screening/washout phase), and the subjects will be followed up for 1 month after the last treatment. The Once-daily tablet formulation that will be evaluated in this trial represents a daily dosage regimen that is intended to be administered to children and adolescents.
Interventions
DRUGAripiprazole
Once-daily, tablet
DRUGPlacebo
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
* male or female, 7 to 17 year old (inclusive) at the time of signing consent * meets DSM-IV-TR diagnostic criteria for Tourette's Disorder * Presenting tic symptoms cause impairment in the subject'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 obtained from a legally acceptable representative & informed assent at Screening as applicable by trial center's IRB/IEC * The subject, 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 * Subject receiving psychostimulants for treatment of 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) * Taken aripiprazole within 30 days of the Screening visit * Received any investigational agent in a clinical trial within 30 days prior to Screening, enrolled in studies 31-12-272, 31-12-273, 31-12-274; or who were randomized into a clinical trial with Once-daily aripiprazole at any time * History of neuroleptic malignant syndrome * Sexually active patients not using 2 approved methods of contraception * Females breastfeeding or pregnant (positive blood pregnancy test prior to receiving trial drug) * Risk of committing suicide * Body weight lower than 16 kg * Taken neuroleptic or antiparkinson drugs \< 14 days prior to randomization * Requiring cognitive behavioral therapy (CBT) for Tourette's during trial * Subject meets DSM-IV-TR criteria for any significant psychoactive substance use disorder within the past 3 months * Positive drug screen * Subject 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 trial * 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 * Inability to swallow tablets or tolerate oral medication * Abnormal laboratory test results, vital signs and ECG results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 8 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 current (time frame of the past 1 week) tic severity. This scale consists of a tic inventory, with 5 separate rating scales to rate the severity of symptoms, and an impairment ranking. Ratings are 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. Summation of these 10 scores (ie, 0-50) provides a TTS that was the primary outcome measure in this trial. The YGTSS ranking of impairment score rated on a 50-point scale anchored from 0 (no impairment) to 50 (severe impairment) to assess impairment experienced in areas of self-esteem, family life, social acceptance, and school scores. This is a fully validated scale in adults and has become a standard instrument for the evaluation of the severity of TD in children. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinical Global Impressions Scale-Tourette's Syndrome (CGI-TS) Score at Week 8. | Week 8 | To assess CGI-TS severity, the rater or physician answered the following question: Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? However, the evaluation of illness was limited to manifestations of TD only. 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. The change score was obtained from CGI-TS improvement scale assessment: 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. |
| Mean Change From Baseline to Endpoint (Week 8) in Total YGTSS Score | Baseline to Week 8 | 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 reduction in Total YGTSS score from baseline represents an improvement in symptoms. |
| Mean Change From Baseline to Endpoint (Week 8) in CGI-TS Severity Score | Baseline to Week 8 | The CGI-TS Severity scale (range 0-7) is a single-item rating score, with higher scores representing greater severity or less improvement. A response of 0 (not assessed) is considered and handled as missing data. |
| Response Rate | Week 8 | Clinical response is defined as \> 25% improvement from baseline to Week 8 in YGTSS TTS or a CGI-TS Change score of 1 \[very much improved\] or 2 \[much improved\] at Week 8. Response will be considered as missing only if both YGTSS TTS and CGI-TS change score are missing. As long as one of them is non-missing, response outcome will be determined based on the non-missing score. |
| Treatment Discontinuation Rate | Week 8 | Treatment discontinuation rate will be calculated as the number of discontinued participants (ie, those who were withdrawn from the trial without completing the Week 8 visit) over the number of all randomized participants. |
Countries
Canada, Germany, Hungary, Italy, Mexico, Romania, Spain, Sweden, United States
Participant flow
Recruitment details
This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial in children and adolescents (aged 7-17 years) with Tourette's disorder (TD). 171 participants were screened, of which 133 were randomized to treatment.
Pre-assignment details
The trial consisted of a pretreatment phase and a treatment phase. Pretreatment phase consisted of a screening and washout (when applicable) period. This was followed by an 8-week treatment phase starting with the baseline visit (Day 0). Particpants were randomized 1:1:1 to aripiprazole high dose, aripiprazole low dose or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Aripiprazole Low Dose For participants who weighed \< 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose. | 44 |
| Aripiprazole High Dose For participants who weighed \< 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose. | 45 |
| Placebo Participants received matching placebo tablets in the same way as aripiprazole. | 44 |
| Total | 133 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 7 | 1 |
| Overall Study | Particpant withdrew consent | 0 | 3 | 1 |
| Overall Study | Protocol Violation | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Aripiprazole Low Dose | Aripiprazole High Dose | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 11.1 Years STANDARD_DEVIATION 3.1 | 11.8 Years STANDARD_DEVIATION 2.8 | 11.6 Years STANDARD_DEVIATION 2.8 | 11.5 Years STANDARD_DEVIATION 2.9 |
| Sex: Female, Male Female | 8 Participants | 10 Participants | 11 Participants | 29 Participants |
| Sex: Female, Male Male | 36 Participants | 35 Participants | 33 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 44 | 29 / 45 | 8 / 44 |
| serious Total, serious adverse events | 0 / 44 | 0 / 45 | 0 / 44 |
Outcome results
Primary
Change From Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS).
The YGTSS is a semi-structured clinical interview designed to measure current (time frame of the past 1 week) tic severity. This scale consists of a tic inventory, with 5 separate rating scales to rate the severity of symptoms, and an impairment ranking. Ratings are 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. Summation of these 10 scores (ie, 0-50) provides a TTS that was the primary outcome measure in this trial. The YGTSS ranking of impairment score rated on a 50-point scale anchored from 0 (no impairment) to 50 (severe impairment) to assess impairment experienced in areas of self-esteem, family life, social acceptance, and school scores. This is a fully validated scale in adults and has become a standard instrument for the evaluation of the severity of TD in children.
Time frame: Baseline to Week 8
Population: Intent-to-Treat (ITT) Population: All participants randomly assigned to the double-blind treatment. At Week 8, data were available for 42 participants in the low dose, 35 in the high dose and 42 in the placebo group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole Low Dose | Change From Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS). | -13.35 Units on a scale | Standard Error 1.59 |
| Aripiprazole High Dose | Change From Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS). | -16.94 Units on a scale | Standard Error 1.61 |
| Placebo | Change From Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS). | -7.09 Units on a scale | Standard Error 1.55 |
Comparison: Assuming 5% of participants may drop out of the trial without a postbaseline efficacy evaluation, a total of 126 participants were required to provide at least 80% power to detect a treatment difference of -5 (common standard deviation \[SD\] of 8.5) between at least 1 of 2 aripiprazole dose levels and placebo in the primary outcome.p-value: 0.00295% CI: [-10.18, -2.34]Mixed Models Analysis
Comparison: Assuming 5% of participants may drop out of the trial without a postbaseline efficacy evaluation, a total of 126 participants were required to provide at least 80% power to detect a treatment difference of -5 (common standard SD of 8.5) between at least 1 of 2 aripiprazole dose levels and placebo in the primary outcome.p-value: <0.000195% CI: [-13.84, -5.86]Mixed Models Analysis
Secondary
Change in Clinical Global Impressions Scale-Tourette's Syndrome (CGI-TS) Score at Week 8.
To assess CGI-TS severity, the rater or physician answered the following question: Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? However, the evaluation of illness was limited to manifestations of TD only. 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. The change score was obtained from CGI-TS improvement scale assessment: 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.
Time frame: Week 8
Population: ITT Population: All participants randomly assigned to the double-blind treatment. At Week 8, data were available for 42 participants in the low dose, 35 in the high dose and 42 in the placebo group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole Low Dose | Change in Clinical Global Impressions Scale-Tourette's Syndrome (CGI-TS) Score at Week 8. | 2.12 Units on a scale | Standard Error 0.21 |
| Aripiprazole High Dose | Change in Clinical Global Impressions Scale-Tourette's Syndrome (CGI-TS) Score at Week 8. | 2.13 Units on a scale | Standard Error 0.21 |
| Placebo | Change in Clinical Global Impressions Scale-Tourette's Syndrome (CGI-TS) Score at Week 8. | 3.15 Units on a scale | Standard Error 0.2 |
p-value: 0.000195% CI: [-1.54, -0.52]Mixed Models Analysis
p-value: 0.000295% CI: [-1.54, -0.49]Mixed Models Analysis
Secondary
Mean Change From Baseline to Endpoint (Week 8) in CGI-TS Severity Score
The CGI-TS Severity scale (range 0-7) is a single-item rating score, with higher scores representing greater severity or less improvement. A response of 0 (not assessed) is considered and handled as missing data.
Time frame: Baseline to Week 8
Population: ITT Population: All participants randomly assigned to the double-blind treatment. At Week 8, data were available for 42 participants in the low dose, 35 in the high dose and 42 in the placebo group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole Low Dose | Mean Change From Baseline to Endpoint (Week 8) in CGI-TS Severity Score | -1.35 Units on a scale | Standard Error 0.19 |
| Aripiprazole High Dose | Mean Change From Baseline to Endpoint (Week 8) in CGI-TS Severity Score | -1.47 Units on a scale | Standard Error 0.19 |
| Placebo | Mean Change From Baseline to Endpoint (Week 8) in CGI-TS Severity Score | -0.55 Units on a scale | Standard Error 0.19 |
p-value: 0.00195% CI: [-1.27, -0.33]Mixed Models Analysis
p-value: 0.000295% CI: [-1.41, -0.44]Mixed Models Analysis
Secondary
Mean Change From Baseline to Endpoint (Week 8) 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 reduction in Total YGTSS score from baseline represents an improvement in symptoms.
Time frame: Baseline to Week 8
Population: ITT Population: All participants randomly assigned to the double-blind treatment. At Week 8, data were available for 42 participants in the low dose, 35 in the high dose and 42 in the placebo group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole Low Dose | Mean Change From Baseline to Endpoint (Week 8) in Total YGTSS Score | -26.69 Units on a scale | Standard Error 3.34 |
| Aripiprazole High Dose | Mean Change From Baseline to Endpoint (Week 8) in Total YGTSS Score | -32.80 Units on a scale | Standard Error 3.39 |
| Placebo | Mean Change From Baseline to Endpoint (Week 8) in Total YGTSS Score | -13.43 Units on a scale | Standard Error 3.27 |
p-value: <0.000195% CI: [-27.7, -11.04]Mixed Models Analysis
p-value: 0.001795% CI: [-21.43, -5.08]Mixed Models Analysis
Secondary
Response Rate
Clinical response is defined as \> 25% improvement from baseline to Week 8 in YGTSS TTS or a CGI-TS Change score of 1 \[very much improved\] or 2 \[much improved\] at Week 8. Response will be considered as missing only if both YGTSS TTS and CGI-TS change score are missing. As long as one of them is non-missing, response outcome will be determined based on the non-missing score.
Time frame: Week 8
Population: ITT Population: All participants randomly assigned to the double-blind treatment. At Week 8, data were available for 42 participants in the low dose, 35 in the high dose and 42 in the placebo group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aripiprazole Low Dose | Response Rate | 73.8 Percentage of Responders |
| Aripiprazole High Dose | Response Rate | 88.6 Percentage of Responders |
| Placebo | Response Rate | 54.8 Percentage of Responders |
p-value: 0.083595% CI: [0.98, 1.88]Cochran-Mantel-Haenszel
p-value: 0.001495% CI: [1.2, 2.16]Cochran-Mantel-Haenszel
Secondary
Treatment Discontinuation Rate
Treatment discontinuation rate will be calculated as the number of discontinued participants (ie, those who were withdrawn from the trial without completing the Week 8 visit) over the number of all randomized participants.
Time frame: Week 8
Population: ITT Population: All participants randomly assigned to the double-blind treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aripiprazole Low Dose | Treatment Discontinuation Rate | 4.5 Percentage of participants |
| Aripiprazole High Dose | Treatment Discontinuation Rate | 22.5 Percentage of participants |
| Placebo | Treatment Discontinuation Rate | 4.5 Percentage of participants |
p-value: 0.918795% CI: [0.19, 7.05]Cochran-Mantel-Haenszel
p-value: 0.9576Regression, Cox
p-value: 0.013295% CI: [1.1, 14.95]Cochran-Mantel-Haenszel
p-value: 0.0278Regression, Cox