Study Evaluating the Safety and Efficacy of Fixed-dose Once-daily Oral Aripiprazole in Children and Adolescents With Tourette's Disorder

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01727700
• Collaborator: (none)
• Enrollment: 133
• Locations: 75
• Arms: 3
• Duration (Months): 10
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

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

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 133 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-daily Oral Aripiprazole in Children and Adolescents With Tourette's Disorder
• Study Start Date: Nov 1, 2012
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Matching Placebo Once-Daily	Drug: Placebo
Experimental: Aripiprazole 5 mg or 10 mg Aripiprazole 5 mg or 10 mg Immediate Release Once-Daily	Drug: Aripiprazole; Once-daily, tablet; Other Names: Abilify
Experimental: Aripiprazole 10 mg or 20 mg Aripiprazole 10 mg 20 mg Immediate Release Once-Daily	Drug: Aripiprazole; Once-daily, tablet; Other Names: Abilify

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Dothan	Alabama	United States
2		Goodyear	Arizona	United States
3		Tucson	Arizona	United States
4		Corona	California	United States
5		Sacramento	California	United States
6		San Diego	California	United States
7		Santa Ana	California	United States
8		Wildomar	California	United States
9		Norwich	Connecticut	United States
10		Bradenton	Florida	United States
11		Gainsville	Florida	United States
12		Leesburg	Florida	United States
13		Maitland	Florida	United States
14		Miami	Florida	United States
15		Orange City	Florida	United States
16		Orlando	Florida	United States
17		St Petersburg	Florida	United States
18		Tampa	Florida	United States
19		Atlanta	Georgia	United States
20		Columbus	Georgia	United States
21		Savannah	Georgia	United States
22		Naperville	Illinois	United States
23		Indianapolis	Indiana	United States
24		Overland Park	Kansas	United States
25		Wichita	Kansas	United States
26		Louisville	Kentucky	United States
27		Waldorf	Maryland	United States
28		Bloomfield Hills	Michigan	United States
29		Mt Arlington	New Jersey	United States
30		Summit	New Jersey	United States
31		Albuquerque	New Mexico	United States
32		Manhasset	New York	United States
33		New York	New York	United States
34		Rochester	New York	United States
35		Staten Island	New York	United States
36		Durham	North Carolina	United States
37		Cleveland	Ohio	United States
38		Middleburg Heights	Ohio	United States
39		Oklahoma City	Oklahoma	United States
40		Eugene	Oregon	United States
41		Philadelphia	Pennsylvania	United States
42		Mt. Pleasant	South Carolina	United States
43		Nashville	Tennessee	United States
44		Austin	Texas	United States
45		Dallas	Texas	United States
46		Houston	Texas	United States
47		San Antonio	Texas	United States
48		Orem	Utah	United States
49		Salt Lake City	Utah	United States
50		Charlottesville	Virginia	United States
51		Henrico	Virginia	United States
52		Norfolk	Virginia	United States
53		Bellevue	Washington	United States
54		Bothell	Washington	United States
55		Middleton	Wisconsin	United States
56		Kentville	Nova Scotia	Canada
57		Parry Sound	Ontario	Canada
58		Toronto	Ontario	Canada
59		Whitby	Ontario	Canada
60		Dresden		Germany
61		Freiburg		Germany
62		Mannheim		Germany
63		Wurzburg		Germany
64		Budapest		Hungary
65		Szeged		Hungary
66		Catania		Italy
67		Milano		Italy
68		Roma		Italy
69		Durango		Mexico
70		Leon		Mexico
71		Mexico City		Mexico
72		Bucharest		Romania
73		Iasi		Romania
74		Madrid		Spain
75		Goteborg		Sweden

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: NCT01727700
• Other Study ID Numbers: 31-12-293
• First Posted: Nov 16, 2012
• Last Update Posted: Feb 13, 2015
• Last Verified: Feb 1, 2015

• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: Tourette Syndrome; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Tic Disorders; Tics; Movement Disorders; Mental Disorders; Aripiprazole
• Additional relevant MeSH terms: Tic Disorders; Tics; Tourette Syndrome; Disease; Aripiprazole

Study Results

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 Detail	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.

Arm/Group Title	Aripiprazole Low Dose	Aripiprazole High Dose	Placebo
Arm/Group Description	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.	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.	Participants received matching placebo tablets in the same way as aripiprazole.
Period Title: Overall Study
STARTED	44	45	44
COMPLETED	42	35	42
NOT COMPLETED	2	10	2

Baseline Characteristics

Arm/Group Title	Aripiprazole Low Dose	Aripiprazole High Dose	Placebo	Total
Arm/Group Description	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.	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.	Participants received matching placebo tablets in the same way as aripiprazole.	Total of all reporting groups
Overall Participants	44	45	44	133
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	11.1 (3.1)	11.8 (2.8)	11.6 (2.8)	11.5 (2.9)
Sex: Female, Male (Count of Participants)
Female	8 18.2%	10 22.2%	11 25%	29 21.8%
Male	36 81.8%	35 77.8%	33 75%	104 78.2%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aripiprazole Low Dose	Aripiprazole High Dose	Placebo
Arm/Group Description	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.	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.	Participants received matching placebo tablets in the same way as aripiprazole.
Measure Participants	42	35	42
Least Squares Mean (Standard Error) [Units on a scale]	-13.35 (1.59)	-16.94 (1.61)	-7.09 (1.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole Low Dose, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0020
	Comments	The Hochberg procedure was used to adjust for multiplicity.
	Method	Mixed Models Analysis
	Comments	Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-6.26
	Confidence Interval	(2-Sided) 95%; -10.18 to -2.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole High Dose, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The Hochberg procedure was used to adjust for multiplicity.
	Method	Mixed Models Analysis
	Comments	Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-9.85
	Confidence Interval	(2-Sided) 95%; -13.84 to -5.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Clinical Global Impressions Scale-Tourette's Syndrome (CGI-TS) Score at Week 8.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aripiprazole Low Dose	Aripiprazole High Dose	Placebo
Arm/Group Description	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.	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.	Participants received matching placebo tablets in the same way as aripiprazole.
Measure Participants	42	35	42
Least Squares Mean (Standard Error) [Units on a scale]	2.12 (0.21)	2.13 (0.21)	3.15 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole Low Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	The Hochberg procedure was used to adjust for multiplicity.
	Method	Mixed Models Analysis
	Comments	Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-1.03
	Confidence Interval	(2-Sided) 95%; -1.54 to -0.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole High Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	The Hochberg procedure was used to adjust for multiplicity.
	Method	Mixed Models Analysis
	Comments	Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-1.02
	Confidence Interval	(2-Sided) 95%; -1.54 to -0.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Mean Change From Baseline to Endpoint (Week 8) in Total YGTSS Score
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aripiprazole Low Dose	Aripiprazole High Dose	Placebo
Arm/Group Description	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.	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.	Participants received matching placebo tablets in the same way as aripiprazole.
Measure Participants	42	35	42
Least Squares Mean (Standard Error) [Units on a scale]	-26.69 (3.34)	-32.80 (3.39)	-13.43 (3.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole Low Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0017
	Comments	Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-13.26
	Confidence Interval	(2-Sided) 95%; -21.43 to -5.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole High Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-19.37
	Confidence Interval	(2-Sided) 95%; -27.70 to -11.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Mean Change From Baseline to Endpoint (Week 8) in CGI-TS Severity Score
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aripiprazole Low Dose	Aripiprazole High Dose	Placebo
Arm/Group Description	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.	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.	Participants received matching placebo tablets in the same way as aripiprazole.
Measure Participants	42	35	42
Least Squares Mean (Standard Error) [Units on a scale]	-1.35 (0.19)	-1.47 (0.19)	-0.55 (0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole Low Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments	Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.80
	Confidence Interval	(2-Sided) 95%; -1.27 to -0.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole High Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	MMRM
	Estimated Value	-0.92
	Confidence Interval	(2-Sided) 95%; -1.41 to -0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Response Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aripiprazole Low Dose	Aripiprazole High Dose	Placebo
Arm/Group Description	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.	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.	Participants received matching placebo tablets in the same way as aripiprazole.
Measure Participants	42	35	42
Number [Percentage of Responders]	73.8	88.6	54.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole Low Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0835
	Comments	P-value derived from Cochran-Mantel-Haenszel (CMH) General Association Test adjusting for region and weight group.
	Method	Cochran-Mantel-Haenszel
	Comments	Response ratio > 1 favors aripiprazole.
Method of Estimation	Estimation Parameter	Response ratio
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole High Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments	P-value derived from CMH General Association Test adjusting for region and weight group.
	Method	Cochran-Mantel-Haenszel
	Comments	Response ratio > 1 favors aripiprazole.
Method of Estimation	Estimation Parameter	Response ratio
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 1.20 to 2.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Treatment Discontinuation Rate
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population: All participants randomly assigned to the double-blind treatment.

Arm/Group Title	Aripiprazole Low Dose	Aripiprazole High Dose	Placebo
Arm/Group Description	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.	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.	Participants received matching placebo tablets in the same way as aripiprazole.
Measure Participants	44	45	44
Number [Percentage of participants]	4.5 10.2%	22.5 50%	4.5 10.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole Low Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9187
	Comments	Discontinuation ratio < 1 favors aripiprazole. P-value derived from CMH General Association Test adjusting for region and weight group.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Discontinuation ratio
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; 0.19 to 7.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole Low Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9576
	Comments	Hazard ratio < 1 favors aripiprazole. P-value derived from Cox proportional hazard regression adjusting for region and weight group.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.05
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole High Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0132
	Comments	Discontinuation ratio < 1 favors aripiprazole. P-value derived from CMH General Association Test adjusting for region and weight group.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Discontinuation ratio
	Estimated Value	4.06
	Confidence Interval	(2-Sided) 95%; 1.10 to 14.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole High Dose, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0278
	Comments	Hazard ratio < 1 favors aripiprazole. P-value derived from Cox proportional hazard regression adjusting for region and weight group.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	5.51
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit.
Adverse Event Reporting Description	An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
Arm/Group Title	Aripiprazole Low Dose		Aripiprazole High Dose		Placebo
Arm/Group Description	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.		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.		Participants received matching placebo tablets in the same way as aripiprazole.
All Cause Mortality
	Aripiprazole Low Dose		Aripiprazole High Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Aripiprazole Low Dose		Aripiprazole High Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/45 (0%)		0/44 (0%)
Other (Not Including Serious) Adverse Events
	Aripiprazole Low Dose		Aripiprazole High Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/44 (47.7%)		29/45 (64.4%)		8/44 (18.2%)
Gastrointestinal disorders
Nausea	3/44 (6.8%)		4/45 (8.9%)		1/44 (2.3%)
Vomiting	2/44 (4.5%)		3/45 (6.7%)		2/44 (4.5%)
General disorders
Fatigue	3/44 (6.8%)		7/45 (15.6%)		0/44 (0%)
Infections and infestations
Nasopharyngitis	3/44 (6.8%)		4/45 (8.9%)		0/44 (0%)
Upper respiratory tract infection	1/44 (2.3%)		1/45 (2.2%)		3/44 (6.8%)
Metabolism and nutrition disorders
Increased appetite	4/44 (9.1%)		3/45 (6.7%)		1/44 (2.3%)
Nervous system disorders
Akathisia	0/44 (0%)		3/45 (6.7%)		0/44 (0%)
Headache	3/44 (6.8%)		4/45 (8.9%)		1/44 (2.3%)
Lethargy	0/44 (0%)		5/45 (11.1%)		0/44 (0%)
Sedation	8/44 (18.2%)		4/45 (8.9%)		1/44 (2.3%)
Somnolence	5/44 (11.4%)		7/45 (15.6%)		1/44 (2.3%)
Psychiatric disorders
Restlessness	0/44 (0%)		3/45 (6.7%)		1/44 (2.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.