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

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01418352
• Collaborator: (none)
• Enrollment: 83
• Locations: 35
• Arms: 4
• Actual Duration (Months): 31.3
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 83 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 Fixed-Dose Once-weekly Oral Aripiprazole in Children and Adolescents With Tourette's Disorder
• Actual Study Start Date: Aug 2, 2011
• Actual Primary Completion Date: Mar 12, 2014
• Actual Study Completion Date: Mar 12, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Matching Placebo Participants received aripiprazole matching placebo, tablets, orally, once weekly for 8 weeks in the Double-blind Treatment Period.	Drug: Placebo; Aripiprazole matching-placebo once-weekly for 8 weeks.
Experimental: Aripiprazole 52.5 mg Participants received aripiprazole 52.5 mg, tablets, orally, once weekly for 8 weeks in the Double-blind Treatment Period.	Drug: Aripiprazole; Aripiprazole tablets once weekly for 8 weeks.; Other Names: ABILIFY
Experimental: Aripiprazole 77.5 mg Participants received aripiprazole 77.5 mg, tablets, orally, once weekly for 8 weeks in the Double-blind Treatment Period.	Drug: Aripiprazole; Aripiprazole tablets once weekly for 8 weeks.; Other Names: ABILIFY
Experimental: Aripiprazole 110 mg Participants received aripiprazole 110 mg, tablets, orally, once weekly for 8 weeks in the Double-blind Treatment Period.	Drug: Aripiprazole; Aripiprazole tablets once weekly for 8 weeks.; Other Names: ABILIFY

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

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		Dothan	Alabama	United States	36303
2		San Francisco	California	United States	94143
3		Gainesville	Florida	United States	32610
4		Miami	Florida	United States	33126
5		Atlanta	Georgia	United States	30308
6		Atlanta	Georgia	United States	30329
7		Chicago	Illinois	United States	60612
8		Omaha	Nebraska	United States	68131
9		Manhasset	New York	United States	11030
10		Cincinnati	Ohio	United States	45229-3039
11		Oklahoma City	Oklahoma	United States	73112
12		Charlottesville	Virginia	United States	22903
13		La Crosse	Wisconsin	United States	54601
14		Ruse		Bulgaria	7004
15		Sofia		Bulgaria	1431
16		Varna		Bulgaria	9010
17		Aachen		Germany	52074
18		Dresden		Germany	01307
19		Hannover		Germany	30625
20		Muenchen		Germany	80336
21		Ulm		Germany	89075
22		Bucuresti		Romania	041914
23		Cluj-Napoca		Romania	400660
24		Craiova		Romania	200620
25		Iasi		Romania	700282
26		Donetsk		Ukraine	83008
27		Kharkiv		Ukraine	61068
28		Kharkiv		Ukraine	61153
29		Kyiv		Ukraine	01030
30		Kyiv		Ukraine	03049
31		Kyiv		Ukraine	04209
32		Lugansk		Ukraine	91045
33		Poltava		Ukraine	36006
34		Stepanivka		Ukraine	73488
35		Vinnytsia		Ukraine	21005

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: NCT01418352
• Other Study ID Numbers: 31-10-273
• 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
• 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 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 Detail	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).

Arm/Group Title	Aripiprazole 52.5 mg	Aripiprazole 77.5 mg	Aripiprazole 110 mg	Matching Placebo
Arm/Group Description	Participants received aripiprazole 52.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole 77.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole 110 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole matching placebo, tablets, orally, once weekly for the 8-week Double-blind Treatment Period.
Period Title: Overall Study
STARTED	20	21	21	21
COMPLETED	17	17	16	18
NOT COMPLETED	3	4	5	3

Baseline Characteristics

Arm/Group Title	Aripiprazole 52.5 mg	Aripiprazole 77.5 mg	Aripiprazole 110 mg	Matching Placebo	Total
Arm/Group Description	Participants received aripiprazole 52.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole 77.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole 110 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole matching placebo tablets, orally, once weekly for the 8-week Double-blind Treatment Period.	Total of all reporting groups
Overall Participants	20	21	21	21	83
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	11.5 (3.4)	11.7 (2.8)	12.5 (2.7)	11.8 (2.7)	11.9 (2.9)
Age, Customized (Count of Participants)
7 to 12 years	12 60%	11 52.4%	11 52.4%	14 66.7%	48 57.8%
13 to 17 years	8 40%	10 47.6%	10 47.6%	7 33.3%	35 42.2%
Sex: Female, Male (Count of Participants)
Female	3 15%	8 38.1%	3 14.3%	6 28.6%	20 24.1%
Male	17 85%	13 61.9%	18 85.7%	15 71.4%	63 75.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 9.5%	1 4.8%	2 9.5%	5 6%
Not Hispanic or Latino	20 100%	19 90.5%	20 95.2%	19 90.5%	78 94%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Number) [Number]
White	12 60%	19 90.5%	19 90.5%	19 90.5%	69 83.1%
Black or African American	8 40%	2 9.5%	2 9.5%	2 9.5%	14 16.9%
Weight (Kilogram) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilogram]	44.7 (16.3)	49.0 (16.2)	52.8 (19.6)	45.0 (12.5)	47.9 (16.4)
Height (centimeter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter]	148.5 (19.0)	151.8 (16.5)	157.5 (14.8)	151.8 (14.4)	152.4 (16.3)
BMI (Body Mass Index) (kilogram per meter squared (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per meter squared (kg/m^2)]	19.6 (3.7)	20.7 (3.8)	20.6 (4.9)	19.3 (3.7)	20.0 (4.0)
Time since first diagnosis for Tourette's Disorder (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.5 (3.0)	1.8 (2.5)	3.0 (3.5)	2.6 (2.3)	2.7 (2.9)
Yale Global Tic Severity Scale Total Tic Score (YGTSS TTS) (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	28.2 (5.6)	30.1 (5.8)	31.4 (6.7)	31.1 (5.5)	30.2 (6)

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score
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 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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aripiprazole 52.5 mg	Aripiprazole 77.5 mg	Aripiprazole 110 mg	Matching Placebo
Arm/Group Description	Participants received aripiprazole 52.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole 77.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole 110 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole matching placebo, tablets, orally, once weekly for the 8-week Double-blind Treatment Period.
Measure Participants	17	17	16	18
Mean (Standard Deviation) [score on scale]	-8.2 (4.8)	-9.9 (6.7)	-14.5 (7.7)	-9.6 (7.5)

2. Secondary Outcome

Title	Mean 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 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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aripiprazole 52.5 mg	Aripiprazole 77.5 mg	Aripiprazole 110 mg	Matching Placebo
Arm/Group Description	Participants received aripiprazole 52.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole 77.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole 110 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole matching placebo, tablets, orally, once weekly for the 8-week Double-blind Treatment Period.
Measure Participants	17	17	16	18
Mean (Standard Deviation) [score on scale]	-0.9 (0.6)	-1.1 (0.9)	-1.3 (1.0)	-1.0 (0.9)

3. Secondary Outcome

Title	Mean Change From Baseline in Gilles de la Tourette Quality of Life (GTS-QOL) Overall Score at Week 8
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.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

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/Group Title	Aripiprazole 52.5 mg	Aripiprazole 77.5 mg	Aripiprazole 110 mg	Matching Placebo
Arm/Group Description	Participants received aripiprazole 52.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole 77.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole 110 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.	Participants received aripiprazole matching placebo, tablets, orally, once weekly for the 8-week Double-blind Treatment Period.
Measure Participants	17	17	16	18
Mean (Standard Deviation) [score on scale]	8.8 (14.1)	3.8 (24.4)	13.1 (20.9)	13.4 (15.9)

Adverse Events

Time Frame	From first dose up to 30 days post last dose (Up to approximately 12 weeks)
Arm/Group Title	Aripiprazole 52.5 mg		Aripiprazole 77.5 mg		Aripiprazole 110 mg		Matching Placebo
Arm/Group Description	Participants received aripiprazole 52.5 mg, tablet, orally, once weekly for the 8-week Double-blind Treatment Period.		Participants received aripiprazole 77.5 mg, tablet, orally once weekly for the 8-week Double-blind Treatment Period.		Participants received aripiprazole 110 mg, tablet, orally once weekly for the 8-week Double-blind Treatment Period.		Participants received aripiprazole matching placebo, tablets, orally, once weekly for the 8-week Double-blind Treatment Period.
All Cause Mortality
	Aripiprazole 52.5 mg		Aripiprazole 77.5 mg		Aripiprazole 110 mg		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Serious Adverse Events
	Aripiprazole 52.5 mg		Aripiprazole 77.5 mg		Aripiprazole 110 mg		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Aripiprazole 52.5 mg		Aripiprazole 77.5 mg		Aripiprazole 110 mg		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/20 (40%)		4/21 (19%)		16/21 (76.2%)		4/21 (19%)
Cardiac disorders
Tachycardia	1/20 (5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/21 (0%)	0
Gastrointestinal disorders
Abdominal Pain	1/20 (5%)	1	1/21 (4.8%)	1	2/21 (9.5%)	2	0/21 (0%)	0
Diarrhoea	0/20 (0%)	0	0/21 (0%)	0	2/21 (9.5%)	2	0/21 (0%)	0
Nausea	2/20 (10%)	2	0/21 (0%)	0	3/21 (14.3%)	3	1/21 (4.8%)	1
Vomiting	1/20 (5%)	1	1/21 (4.8%)	1	2/21 (9.5%)	2	0/21 (0%)	0
General disorders
Fatigue	0/20 (0%)	0	1/21 (4.8%)	1	4/21 (19%)	4	1/21 (4.8%)	1
Infections and infestations
Nasopharyngitis	0/20 (0%)	0	1/21 (4.8%)	1	2/21 (9.5%)	2	1/21 (4.8%)	1
Investigations
Drug Prolactin Decreased	1/20 (5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/21 (0%)	0
Weight Increased	1/20 (5%)	1	0/21 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0
Metabolism and nutrition disorders
Decreased Appetite	0/20 (0%)	0	0/21 (0%)	0	2/21 (9.5%)	2	0/21 (0%)	0
Nervous system disorders
Dizziness	2/20 (10%)	2	0/21 (0%)	0	2/21 (9.5%)	2	0/21 (0%)	0
Headache	2/20 (10%)	2	2/21 (9.5%)	2	8/21 (38.1%)	8	2/21 (9.5%)	2
Sedation	1/20 (5%)	1	0/21 (0%)	0	0/21 (0%)	0	1/21 (4.8%)	1
Somnolence	1/20 (5%)	1	3/21 (14.3%)	3	6/21 (28.6%)	6	0/21 (0%)	0
Tremor	1/20 (5%)	1	0/21 (0%)	0	0/21 (0%)	0	0/21 (0%)	0

Limitations/Caveats

Limitations of the trial such as small numbers of subjects analyzed or technical problems leading to unreliable data.

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.