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

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01418339
• Collaborator: (none)
• Enrollment: 135
• Locations: 39
• Arms: 2
• Actual Duration (Months): 27.4
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Tourette's Disorder	Drug: Aripiprazole; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 135 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Safety and Efficacy of Flexible-Dose Once-weekly Oral Aripiprazole in Children and Adolescents With Tourette's Disorder
• Actual Study Start Date: Jul 27, 2011
• Actual Primary Completion Date: Nov 6, 2013
• Actual Study Completion Date: Nov 6, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Aripiprazole; Aripiprazole tablet administered orally once a week.; Other Names: ABILIFY
Placebo Comparator: Placebo Participants randomized to placebo received aripiprazole-matching placebo, tablet, orally, QW for 8 weeks in a double-blind manner.	Drug: Placebo; Aripiprazole-matching placebo tablet administered orally once a week.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Little Rock	Arkansas	United States	72205
2		Sacramento	California	United States	95815
3		Santa Ana	California	United States	92701
4		Wildomar	California	United States	92595
5		Hialeah	Florida	United States	33012
6		Orange City	Florida	United States	32763
7		Saint Petersburg	Florida	United States	33701
8		Overland Park	Kansas	United States	66211
9		New Orleans	Louisiana	United States	70114
10		Bloomfield Hills	Michigan	United States	48302
11		Staten Island	New York	United States	10312
12		Avon Lake	Ohio	United States	44012
13		Cleveland	Ohio	United States	44106
14		Middleburg Heights	Ohio	United States	44130
15		Philadelphia	Pennsylvania	United States	19139
16		Dallas	Texas	United States	75230
17		San Antonio	Texas	United States	78229
18		San Antonio	Texas	United States	78258
19		Salt Lake City	Utah	United States	84107
20		Bothell	Washington	United States	98011
21		Kelowna	British Columbia	Canada	V1Y 1Z9
22		Toronto	Ontario	Canada	M5B 1T8
23		Whitby	Ontario	Canada	L1N 8M7
24		Budapest		Hungary	1021
25		Szeged		Hungary	6725
26		Gyeonggi-do		Korea, Republic of	460727
27		Gyeongsang		Korea, Republic of	626-770
28		Incheon		Korea, Republic of	400-711
29		Seoul		Korea, Republic of	110-769
30		Seoul		Korea, Republic of	138-736
31		Seoul		Korea, Republic of	143-729
32		Leon	Guanajuato	Mexico	37000
33		Monterrey	Nuevo Leon	Mexico	64710
34		Durango		Mexico	34000
35		Changhua		Taiwan	50006
36		Kaohsiung		Taiwan	83301
37		Taichung		Taiwan	40447
38		Taipei		Taiwan	100
39		Taipei		Taiwan	114

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

• Study Director: Eva Kohegyi, MD, Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01418339
• Other Study ID Numbers: 31-10-272; 2011-000467-27
• First Posted: Aug 17, 2011
• Last Update Posted: Oct 7, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: Tourette's Disorder; Tic disorders
• Additional relevant MeSH terms: Tourette Syndrome; Disease; Aripiprazole

Study Results

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 Detail	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).

Arm/Group Title	Aripiprazole	Placebo
Arm/Group Description	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.	Participants randomized to placebo received aripiprazole-matching placebo tablet, orally, QW for 8 weeks in a double-blind manner.
Period Title: Overall Study
STARTED	90	45
COMPLETED	78	35
NOT COMPLETED	12	10

Baseline Characteristics

Arm/Group Title	Aripiprazole	Placebo	Total
Arm/Group Description	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.	Participants randomized to placebo received aripiprazole-matching placebo tablet, orally, QW for 8 weeks in a double-blind manner	Total of all reporting groups
Overall Participants	90	45	135
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	11.9 (2.8)	11.7 (2.6)	11.9 (2.7)
Sex: Female, Male (Count of Participants)
Female	17 18.9%	14 31.1%	31 23%
Male	73 81.1%	31 68.9%	104 77%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	20 22.2%	13 28.9%	33 24.4%
Not Hispanic or Latino	67 74.4%	31 68.9%	98 72.6%
Unknown or Not Reported	3 3.3%	1 2.2%	4 3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 2.2%	0 0%	2 1.5%
Asian	28 31.1%	12 26.7%	40 29.6%
Native Hawaiian or Other Pacific Islander	1 1.1%	0 0%	1 0.7%
Black or African American	3 3.3%	1 2.2%	4 3%
White	53 58.9%	31 68.9%	84 62.2%
More than one race	3 3.3%	1 2.2%	4 3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Yale Global Tic Severity Scale (YGTSS) -Total Tic Score (TTS) (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	30.5 (6.6)	29.3 (7.0)	30.1 (6.7)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Yale Global Tic Severity Scale (YGTSS) - Total Tic Score (TTS)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aripiprazole	Placebo
Arm/Group Description	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.	Participants randomized to placebo received aripiprazole-matching placebo tablet, orally, QW for 8 weeks in a double-blind manner.
Measure Participants	71	34
Least Squares Mean (Standard Error) [score on a scale]	-12.34 (0.88)	-7.72 (1.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Placebo
	Comments	The statistical comparison was performed using MMRM model at a significance level of 0.05 (2-sided).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0028
	Comments	P-value was derived from a repeated measures linear model with treatment, week, and treatment by week interaction as fixed categorical effects, the baseline value as a fixed covariate, and week as the time variable for repeated measures.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-4.63
	Confidence Interval	(2-Sided) 95%; -7.62 to -1.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS) Score
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aripiprazole	Placebo
Arm/Group Description	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.	Participants randomized to placebo received aripiprazole-matching placebo tablet, orally, QW for 8 weeks in a double-blind manner.
Measure Participants	70	33
Least Squares Mean (Standard Error) [score on a scale]	2.29 (0.12)	2.81 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Placebo
	Comments	The statistical comparison was performed using MMRM model at a significance level of 0.05 (2-sided).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0124
	Comments	P-value was derived from a repeated measures linear model with treatment, week, and treatment by week interaction as fixed categorical effects, the baseline value as a fixed covariate, and week as the time variable for repeated measures.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95%; -0.93 to -0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Gilles de la Tourette Syndrome - Quality of Life Scale (GTS-QOL) Total Score
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aripiprazole	Placebo
Arm/Group Description	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.	Participants randomized to placebo received aripiprazole-matching placebo tablet, orally, QW for 8 weeks in a double-blind manner.
Measure Participants	71	34
Least Squares Mean (Standard Error) [score on a scale]	10.04 (1.83)	12.04 (2.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Placebo
	Comments	The statistical comparison was performed using MMRM model at a significance level of 0.05 (2-sided).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.5317
	Comments	P-value was derived from a repeated measures linear model with treatment, week, and treatment by week interaction as fixed categorical effects, the baseline value as a fixed covariate, and week as the time variable for repeated measures.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-2.00
	Confidence Interval	(2-Sided) 95%; -8.31 to 4.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From first dose up to 30 days post last dose (Up to approximately 12 weeks)
Adverse Event Reporting Description	Safety Sample included all participants in the ITT Sample who received at least 1 dose of study drug.
Arm/Group Title	Aripiprazole		Placebo
Arm/Group Description	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.		Participants randomized to placebo received aripiprazole-matching placebo tablet, orally, QW for 8 weeks in a double-blind manner.
All Cause Mortality
	Aripiprazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/90 (0%)		0/45 (0%)
Serious Adverse Events
	Aripiprazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/90 (3.3%)		0/45 (0%)
General disorders
Hyperthermia	1/90 (1.1%)		0/45 (0%)
Investigations
Alanine aminotransferase increased	1/90 (1.1%)		0/45 (0%)
Aspartate aminotransferase increased	1/90 (1.1%)		0/45 (0%)
Blood creatine phosphokinase increased	1/90 (1.1%)		0/45 (0%)
Electrocardiogram QT prolonged	1/90 (1.1%)		0/45 (0%)
Nervous system disorders
Dystonia	2/90 (2.2%)		0/45 (0%)
Other (Not Including Serious) Adverse Events
	Aripiprazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/90 (42.2%)		8/45 (17.8%)
Gastrointestinal disorders
Nausea	12/90 (13.3%)		4/45 (8.9%)
Vomiting	9/90 (10%)		1/45 (2.2%)
General disorders
Fatigue	8/90 (8.9%)		0/45 (0%)
Metabolism and nutrition disorders
Increased Appetite	6/90 (6.7%)		1/45 (2.2%)
Nervous system disorders
Headache	12/90 (13.3%)		2/45 (4.4%)
Somnolence	15/90 (16.7%)		3/45 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor reserves the right to review results publications prior to public release and can delay such publications for a period greater than 60 days but no more than 120 days from the date that the publication is submitted to the Sponsor for review. Sponsor can require changes to the publication to protect Sponsor's intellectual property rights and/or confidential information and reserves the right to limit publication timing and scope of data published based on the number of study locations.