Clinical Trial Results:
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.
Summary
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EudraCT number |
2011-000467-27 |
Trial protocol |
HU |
Global end of trial date |
06 Nov 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Mar 2016
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First version publication date |
06 Aug 2015
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
31-10-272
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01418339 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Otsuka Pharmaceutical Development &Commercialization, Inc.
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Sponsor organisation address |
2440 Research Boulevard, Rockville, United States, Maryland 20850
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Public contact |
Eva Kohegyi, MD, Otsuka Pharmaceutical Development &Commercialization, Inc., 1 609 524-6790,
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Scientific contact |
Eva Kohegyi, MD, Otsuka Pharmaceutical Development &Commercialization, Inc., 1 609 524-6790,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Apr 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
06 Nov 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Nov 2013
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Primary: To compare the efficacy of aripiprazole with placebo in the suppression of tics in children and adolescents (7-17 years) with a diagnosis of Tourette’s Disorder (TD). The primary efficacy measure is change from Baseline to endpoint (Week 8) on the Total Tic score (TTS) of the Yale Global Tic Severity Scale (YGTSS). The secondary objective was to evaluate the safety and tolerability of aripiprazole treatment with oral tablets in children and adolescents with a diagnosis of TD. Secondary efficacy measures include Clinical Global Impressions Scale for Tourette’s Syndrome (CGI-TS) and Gilles de la Tourette Syndrome - Quality of Life Scale (GTS-QOL).
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Protection of trial subjects |
The trial was conducted in accordance with the protocol, legal and regulatory requirements, as well as the general principles set forth in Guidelines for Good Clinical Practice (GCP) (International Conference on Harmonization [ICH] 1996). In addition, the study was conducted in accordance with applicable local regulatory requirements and laws.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Jul 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 23
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Country: Number of subjects enrolled |
Hungary: 14
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Country: Number of subjects enrolled |
Korea, Republic of: 17
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Country: Number of subjects enrolled |
Mexico: 17
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Country: Number of subjects enrolled |
Taiwan: 22
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Country: Number of subjects enrolled |
United States: 42
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Worldwide total number of subjects |
135
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EEA total number of subjects |
14
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
61
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Adolescents (12-17 years) |
74
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 152 participants were screened and 135 were randomised to 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. 124 participants were included in the modified intention-to-treat (mITT) population. | |||||||||||||||||||||
Pre-assignment
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Screening details |
The trial consisted of a pretreatment and treatment phase. The pretreatment phase consisted of a Screening period, a washout period (when applicable), and a Baseline visit. This was followed by an 8-week treatment phase. There was also a follow-up period (30 ± 3 days) for those participants who did not roll over into the open-label study. | |||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||||||||
Blinding implementation details |
During the trial, the treatment assignment code list was available only to an independent biostatistician. Except in cases of emergency unblinding, subjects, investigational site personnel, OPDC employees, and all other trial personnel remained blinded to the identity of the treatment assignments until every participant had completed trial treatment and the database had been locked.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Aripiprazole | |||||||||||||||||||||
Arm description |
Aripiprazole was administered orally once a week (QW) for 8 weeks. Participants randomised to aripiprazole began on a 52.5 milligrams (mg) QW dose on Day 0. At the Week 1 visit, 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 for efficacy as early as Week 2. For the remainder of the trial, the dose was to be adjusted up and down among these 3 dose levels, as determined by investigator discretion. 82 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Apipiprazole
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Investigational medicinal product code |
OPC-14597
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Other name |
Abilify
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
52.5 mg to 110 mg QW for 8 weeks.
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
Participants received matching placebo tablets in the same way as aripiprazole. 42 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Participants received matching placebo tablets in the same way as aripiprazole
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Baseline characteristics reporting groups
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Reporting group title |
Aripiprazole
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Reporting group description |
Aripiprazole was administered orally once a week (QW) for 8 weeks. Participants randomised to aripiprazole began on a 52.5 milligrams (mg) QW dose on Day 0. At the Week 1 visit, 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 for efficacy as early as Week 2. For the remainder of the trial, the dose was to be adjusted up and down among these 3 dose levels, as determined by investigator discretion. 82 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received matching placebo tablets in the same way as aripiprazole. 42 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Aripiprazole
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Reporting group description |
Aripiprazole was administered orally once a week (QW) for 8 weeks. Participants randomised to aripiprazole began on a 52.5 milligrams (mg) QW dose on Day 0. At the Week 1 visit, 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 for efficacy as early as Week 2. For the remainder of the trial, the dose was to be adjusted up and down among these 3 dose levels, as determined by investigator discretion. 82 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements. | ||
Reporting group title |
Placebo
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Reporting group description |
Participants received matching placebo tablets in the same way as aripiprazole. 42 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements. |
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End point title |
Change from Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) TTS | ||||||||||||
End point description |
YGTSS is a semi-structured clinical interview designed to measure current (time frame of the past 1 week) tic severity. The scale consists of a tic inventory, with 5 separate rating scales to rate 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. Total tic score ranges from 0 to 50 with a higher score for more severe symptoms. The scale assesses 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. Data are presented for the modified intention-to-treat population (mITT).
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End point type |
Primary
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End point timeframe |
Baseline to Week 8
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Notes [1] - Number of participants in the mITT with Baseline and Week 8 measurement of YGTSS-TTS. [2] - Number of participants in the mITT with Baseline and Week 8 measurement of YGTSS-TTS. |
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Statistical analysis title |
Statistical analysis 1 at Week 8 | ||||||||||||
Statistical analysis description |
The objective of the primary analysis was to compare the efficacy of QW oral aripiprazole with that of placebo through the change from baseline in YGTSS TTS. The statistical comparison was performed using a mixed model repeated measures (MMRM) linear model with treatment and visit week as factors, baseline YGTSS TTS as a covariate, and treatment-by-week interactions in the model at a significance level of 0.05 (2-sided).
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Comparison groups |
Aripiprazole v Placebo
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Number of subjects included in analysis |
105
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.028 [3] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-4.63
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-7.62 | ||||||||||||
upper limit |
-1.63 | ||||||||||||
Notes [3] - 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. |
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End point title |
Change in CGI-TS Score at Week 8 | ||||||||||||
End point description |
To CGI-TS 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. Data are presented for the mITT population.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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Notes [4] - Number of participants in mITT with baseline CGI-TS severity and Week 8 CGI-TS change score. [5] - Number of participants in mITT with baseline CGI-TS severity and Week 8 CGI-TS change score. |
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Statistical analysis title |
Statisitcal analysis at Week8 | ||||||||||||
Comparison groups |
Aripiprazole v Placebo
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Number of subjects included in analysis |
103
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.0124 [6] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-0.52
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.93 | ||||||||||||
upper limit |
-0.12 | ||||||||||||
Notes [6] - Derived from a repeated measures linear model with treatment, week, and treatment by week interaction as fixed categorical effects, the baseline CGI-TS severity score as a fixed covariate, and week as the time variable for repeated measures. |
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End point title |
Change from Baseline to Week 8 in GTS-QOL | ||||||||||||
End point description |
The GTS-QOL is a disease-specific patient-reported scale for the measurement of health-related quality of life in patients with TD, taking into account the complexity of the clinical picture of the disease.he questionnaire consists of a 27-item, TD-specific scale with 4 subscales (psychological, physical, obsessional, and cognitive).
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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Notes [7] - Number of participants in the mITT with baseline and Week 8 GTS-QOL Overall Score. [8] - Number of participants in the mITT with baseline and Week 8 GTS-QOL Overall Score. |
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Statistical analysis title |
Statistical analysis at Week 8 | ||||||||||||
Comparison groups |
Aripiprazole v Placebo
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Number of subjects included in analysis |
105
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.5317 [9] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-2
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-8.31 | ||||||||||||
upper limit |
4.32 | ||||||||||||
Notes [9] - 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. |
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End point title |
Change from Baseline to Endpoint (Week 8) in Total YGTSS Score | ||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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Notes [10] - Number of participants in the mITT with baseline and Week 8 Total YGTSS Score. [11] - Number of participants in the mITT with baseline and Week 8 Total YGTSS Score. |
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Statistical analysis title |
Statistical analysis at Week 8 | ||||||||||||
Comparison groups |
Aripiprazole v Placebo
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Number of subjects included in analysis |
105
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.0046 [12] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-9.44
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-15.92 | ||||||||||||
upper limit |
-2.97 | ||||||||||||
Notes [12] - 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. |
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End point title |
Change from Baseline to Endpoint (Week 8) in CGI-TS Severity | ||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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Notes [13] - Number of participants in the mITT with baseline and Week 8 measurement of the given variable. [14] - Number of participants in the mITT with baseline and Week 8 measurement of the given variable. |
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Statistical analysis title |
Statistical analysis at Week 8 | ||||||||||||
Comparison groups |
Aripiprazole v Placebo
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Number of subjects included in analysis |
105
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.0043 [15] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-0.6
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.02 | ||||||||||||
upper limit |
-0.19 | ||||||||||||
Notes [15] - 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. |
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End point title |
Clinical Response | ||||||||||||
End point description |
Clinical response was defined as > 25% improvement from baseline to endpoint (Week 8) in YGTSS TTS or a CGI-TS change score of 1 (very much improved) or 2 (much improved) at endpoint (Week 8).
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End point type |
Secondary
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End point timeframe |
Week 8
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Notes [16] - Number of subjects with YGTSS or CGI change score at week 8. [17] - Number of subjects with YGTSS or CGI change score at week 8. |
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Statistical analysis title |
Statitical Analysis at Week 8 | ||||||||||||
Comparison groups |
Aripiprazole v Placebo
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Number of subjects included in analysis |
105
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.0269 [18] | ||||||||||||
Method |
Chi-squared | ||||||||||||
Parameter type |
Response ratio | ||||||||||||
Point estimate |
1.32
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.99 | ||||||||||||
upper limit |
1.76 | ||||||||||||
Notes [18] - Response Ratio > 1 favours aripiprazole. P-value derived from Chi-square test. |
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End point title |
Treatment discontinuation rate | ||||||||||||
End point description |
Treatment discontinuation rate was 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.
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End point type |
Secondary
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End point timeframe |
Week 8
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Statistical analysis title |
Statitical analysis 1 at Week 8 | ||||||||||||
Comparison groups |
Aripiprazole v Placebo
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Number of subjects included in analysis |
124
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.2056 [19] | ||||||||||||
Method |
Chi-squared | ||||||||||||
Parameter type |
Response ratio | ||||||||||||
Point estimate |
0.61
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.29 | ||||||||||||
upper limit |
1.3 | ||||||||||||
Notes [19] - Discontinuation ratio < 1 favours aripiprazole. P-value derived from Chi-square test. |
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Statistical analysis title |
Statistical analysis 2 at Week 8 | ||||||||||||
Comparison groups |
Aripiprazole v Placebo
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Number of subjects included in analysis |
124
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.2376 [20] | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Cox proportional hazard | ||||||||||||
Point estimate |
0.6
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.29 | ||||||||||||
upper limit |
1.3 | ||||||||||||
Notes [20] - Hazard ratio < 1 favours aripiprazole. P-value derived from Cox proportional hazard regression. |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. Adverse events reported for safety population (N=135).
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Adverse event reporting additional description |
AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling/incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.0
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Reporting groups
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Reporting group title |
Aripiprazole
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Reporting group description |
Aripiprazole was administered orally once a week (QW) for 8 weeks. Participantsd to aripiprazole began on a 52.5 milligrams (mg) QW dose on Day 0. At the Week 1 visit, 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 for efficacy as early as Week 2. For the remainder of the trial, the dose was to be adjusted up and down among these 3 dose levels, as determined by investigator discretion. 82 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received matching placebo tablets in the same way as aripiprazole. 42 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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14 Feb 2013 |
In the amendment, the protocol was modified to remove the option to allow participants who discontinued due to lack of efficacy at Week 5 to enter the open-label extension trial. To clarify the protocol, new text was added describing exclusion of participants for QTc values > 450 milliseconds and the process for breaking the blind for an individual participant. The duration of the conduct of the trial was increased, based on the then current enrolment rates, and the statistical methods were updated. Vyvanse [lisdexamphetamine] was added throughout the protocol to the list of psychostimulant medications prescribed for the treatment of symptoms of Attention-Deficit Disorder/Attention-Deficit Hyperactivity Disorder, which were permitted during the trial. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |