Safety and Tolerability of Once-daily Oral Aripiprazole in Children and Adolescents With Tourette's Disorder

NCT01727713 | Completed Phase 3 Results

• 1 other identifier: 31-12-294
• Study Type: interventional
• Target: 110
• Locations: 4 countries
• Sites: 33

Brief Summary

The goal of the current trial is to determine safety of Once-daily aripiprazole in reducing Total Tic Severity in children and adolescents with Tourette's Disorder.

Conditions

Tourette's Disorder; Tic Disorder

Keywords

Tourette Syndrome; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Tic Disorders; Tics; Movement Disorders; Mental Disorders; Aripiprazole

Outcome Measures

Primary Outcomes (15)

• Percentage of Participants With Adverse Events.

  An AE is defined as any untoward medical occurrence in a patient or participant enrolled in the clinical trial and which does not necessarily have to have a causal relationship with the study drug. A treatment emergent adverse event (TEAE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug, whether or not considered related to have a causal relationship with the study drug. Serious adverse event (SAE) or reaction is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires in-patient hospitalization or prolonged hospitalization, results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect.

  Baseline, throighout the 52-week treatmetn and 30±3 days after last trial visit

• Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results.

  Laboratory tests including hematology, serum chemistry, and urinalysis were performed for all the participants. The central laboratory was used for all laboratory testing whenever possible. Any value outside the normal range was flagged for the attention of the study physician who was to indicate whether the value was clinically significant based on the pre-defined criteria for identifying laboratory values of potential clinical relevance. Percentage of participants noted with abnormal laboratory values are reported below.

  Baseline to Week 52

• Percentage of Participants With Clinically Significant Abnormal Vital Signs.

  Vital sign measurements included systolic and diastolic blood pressure (BP) and heart rate, which were performed at all clinic visits. Criteria for identifying vital signs of potential clinical relevance included: Heart rate: ≥ 15 beats per minute (bpm) increase/decrease from Baseline (final visit of study 31-12-293); Systolic BP: ≥ 20 mmHg increase/decrease from Baseline; Diastolic BP: ≥ 15mmHg increase/decrease from Baseline; Orthostatic hypotension: ≥ 20 mmHg decrease in systolic BP and a ≥ 25 bpm increase in heart rate from supine to sitting/standing. Percentage of participants noted with abnormal vital sign measurements are reported below.

  Baseline to Week 52

• Percentage of Participants With Clinically Significant Abnormal Electrocardiogram (ECG).

  Three 12-lead ECGs (scheduled 5 minutes apart) were recorded. Some of the pre-defined criteria for identifying ECG measurements of potential clinical relevance included: Tachycardia/sinus tachycardia: increase of ≥15 bpm from Baseline; increase in QTc of ≥10% from Baseline. The other abnormalities not present at Baseline and were present during the time of measurement were recorded. Percentage of participants noted with abnormal ECG findings are reported below.

  Baseline to Week 52

• Mean Change From Baseline in Body Weight.

  Criteria for identifying weight of potential clinical relevance was: ≥ 7% kilogram increase/decrease from Baseline (Final visit of Trial 31-12-293).

  Baseline to Weeks 12, 28, 36, 44, 52/Last visit.

• Mean Change From Baseline in Body Mass Index (BMI).

  BMI was calculated at the Baseline visit (using the Baseline height from study 31-12-293) and at Weeks 28 and 52/ET where height measured at baseline in the current trial was used to calculate BMI.

  Baseline to Weeks 28, 52 and Last visit.

• Mean Change From Baseline in Waist Circumference.

  Waist circumference was measured at Baseline, Weeks 12, 28, 36, 44, and the Week 52/last visit in centimeters.

  Baseline to Weeks 12, 28, 36, 44, and 52/last visit.

• Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score.

  The AIMS assessment consists of 10 items describing symptoms of dyskinesia. Facial and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk movements (item 7) were observed unobtrusively while the participant was at rest, and the investigator also made global judgments on the participant's dyskinesias (items 8 through 10). Each item was rated on a 5-point scale, with a score of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, awareness/severe distress). In addition, the AIMS included 2 yes/no questions that addressed the subject's dental status (since an edentulous state can cause lingual dyskinesias). The AIMS movement rating score (range 0 to 28) was the sum of the rating scores for facial and oral moments (ie, items 1 to 4), extremity movements (ie, items 5 and 6), and trunk movements (ie, item 7).

  Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit

• Change From Baseline in Simpson-Angus Scale (SAS) Total Score.

  The SAS consists of a list of 10 symptoms of Parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia). Each item was rated on a 5-point scale, with a score of 1 representing absence of symptoms, and a score of 5 representing a severe condition. The SAS total score (range 10 to 50) was the sum of the rating scores for 10 items from the SAS panel.

  Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit

• Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score.

  The BARS Global Score is derived from the global clinical evaluation of akathisia on a 6-point scale, with 0 representing absence of symptoms and a score of 5 representing severe akathisia.

  Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit

• Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS).

  The C-SSRS consists of a baseline evaluation that assesses the lifetime experience of the participant with suicide events and suicidal ideation and a post baseline/"since last visit" evaluation that focuses on suicidality since the last trial visit. The C-SSRS data at Baseline and post baseline were summarized for incidence of reporting: Suicidality, Suicidal behavior (and its 4 types), Suicidal ideation (and its 5 types). The intensity score of each item ranges from 1 (least severe) to 5 (most severe), which leads to the range of the total score from 0 to 25.

  Baseline, Weeks 1, 2, 4, 8, 12, 20, 28, 36, 44, 52, and Last visit

• Change From Baseline in Average Score of Attention Deficit Disorder/Attention-deficit Hyperactivity Disorder (ADD/ADHD) of Swanson, Nolan, and Pelham-IV Rating Scale (SNAP-IV).

  The SNAP-IV Rating Scale is a revision of the SNAP Questionnaire. The SNAP-IV assesses inattention and hyperactivity/impulsivity, as well as oppositional defiant disorder that are often present in children with ADD/ADHD. The SNAP-IV was administered as a semi-structured interview with the participant and caregiver. The SNAP-IV is based on a 0 to 3 rating scale: not at all = 0, just a little = 1, quite a bit = 2, and very much = 3. The ADD/ADHD subscale includes items 1 through 19 (items 1-9 measure inattention, items 11-19 measure hyperactivity/ impulsivity, and item 10 for inattention domain), items 4, 8, 11, 31, and 32 measure inattention/overactivity, and items 21, 23, 29, 34, and 35 measure aggression/defiance. Items 4, 8, 11, 21, 32, 33, 36, 37, 38, and 39 form the Conners Index. Subscale average scores on the SNAP IV were calculated by summing the scores on the items in the subset and dividing by the number of items in the subset.

  Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit

• Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS).

  The CY-BOCS is a semi-structured interview used with children and adolescents aged 6 to 17 years to rate the severity and type of symptoms in participants with obsessive compulsive disorder. In general, the items depend on the participant's report; however, the final rating is based on the clinical judgment of the interviewer and should include additional information supplied by others. Nineteen items are rated in the CY-BOCS, but only items 1 through 10 (excluding items lb and 6b) are used to determine the total score. The total CY-BOCS score is the sum of items 1 through 10 (excluding lb and 6b), whereas the obsession and compulsion subtotals are the sums of items 1 through 5 (excluding lb) and 6 through 10 (excluding 6b), respectively. CY-BOCS total score could range from 0 to 40, and the obsession and compulsion subscale total scores could each range from 0 to 20. Higher scores indicate worse outcome.

  Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit

• Change From Baseline in Children's Depression Rating Scale - Revised (CDRS-R).

  The CDRS-R is a brief rating scale based on a semi-structured interview with the child and an adult informant who knows the child well. Designed for 6- to 12-year-old children, and successfully used with adolescents, it can be administered in 15 to 20 minutes. The interviewer rates 17 symptom areas (including those that serve as Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision criteria for a diagnosis of depression): impaired schoolwork, difficulty having fun, social withdrawal, appetite disturbance, sleep disturbance, excessive fatigue, physical complaints, irritability, excessive guilt, low self-esteem, depressed feelings, morbid ideas, suicidal ideas, excessive weeping, depressed facial affect, listless speech, and hypoactivity. The CDRS-R total score is the sum of scores for the 17 symptom areas and could range from 17 to 113 with higher values indicating worse outcome.

  Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit

• Change From Baseline in Pediatric Anxiety Rating Scale (PARS).

  The PARS is used to rate the severity of anxiety in children and adolescents, aged 6 to 17 years. The PARS has 2 sections: the symptom checklist and the severity items. The symptom checklist is used to determine the child's repertoire of symptoms during the past week. The 7-item severity list is used to determine severity of symptoms and the PARS total score. The time frame for the PARS is the past week. Only those symptoms endorsed for the past week are included in the symptom checklist and rated on the severity items. The PARS total severity score was the sum of items 2, 3, 5, 6, and 7. The total severity score ranged from 0 (no anxiety) to 25 (worst anxiety).

  Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit

Secondary Outcomes (6)

• Change From Baseline to Endpoint on the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS).

  Baseline to Week 52

• Mean Clinical Global Impressions for Tourette's Syndrome (CGI-TS) Change Score at Endpoint.

  Baseline to Week 52

• Change From Baseline to Endpoint in CGI-TS Severity of Illness Score.

  Baseline to Week 52

• Mean Change From Baseline to Endpoint in Total YGTSS Score.

  Baseline to Week 52

• Percentage of Participants With Response (Response Rate).

  Weeks 4, 8, 12, 20, 28, 36, 44 and 52

Study Arms (1)

Aripiprazole

EXPERIMENTAL

Aripiprazole Immediate Release Once-Daily

Drug: Aripiprazole

Interventions

Aripiprazole DRUG

Open Label: Once-Daily formulation of aripiprazole flex dose regimine

Also known as: Abilify

Aripiprazole

Eligibility Criteria

• Age: 7 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Completed participation in Trial 31-12-293
• Written ICF obtained from a legally acceptable representative \& informed assent at Baseline 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

You may not qualify if:

• Experienced AEs during the double-blind trial (31-12-293) that would, in the investigator's judgment, preclude further exposure to aripiprazole.
• The subject had protocol violations during the double-blind trial considered major in the judgment of the investigator which would deem the subject a poor candidate for the trial
• A positive drug screen
• 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
• Abnormal laboratory test results, vital signs and ECG results

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (33)

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Dothan, Alabama, United States

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Goodyear, Arizona, United States

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Orange, California, United States

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Sacramento, California, United States

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Wildomar, California, United States

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Norwich, Connecticut, United States

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Bradenton, Florida, United States

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Orange City, Florida, United States

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Tampa, Florida, United States

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Atlanta, Georgia, United States

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Indianapolis, Indiana, United States

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Waldorf, Maryland, United States

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Bloomfield Hills, Michigan, United States

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Mount Arlington, New Jersey, United States

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Summit, New Jersey, United States

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Manhasset, New York, United States

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Rochester, New York, United States

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Avon Lake, Ohio, United States

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Cleveland, Ohio, United States

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Houston, Texas, United States

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San Antonio, Texas, United States

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Orem, Utah, United States

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Salt Lake City, Utah, United States

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Norfolk, Virginia, United States

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Petersburg, Virginia, United States

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Bellevue, Washington, United States

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Toronto, Ontario, Canada

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Whitby, Ontario, Canada

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Nova Scotia, Canada

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Budapest, Hungary

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Szeged, Hungary

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Catania, Italy

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Milan, Italy

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MeSH Terms

Conditions

Tourette Syndrome; Tic Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Tics; Movement Disorders; Mental Disorders

Interventions

Aripiprazole

Condition Hierarchy (Ancestors)

Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neurodevelopmental Disorders; Dyskinesias; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Global Medical Affairs
• Organization: Otsuka Pharmaceutical Development & Commercialization, Inc

800 562-3974

Study Officials

• Eva Kohegyi, MD

  Otsuka Pharmaceutical Development & Commercialization, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 12, 2012
• First Posted: November 16, 2012
• Study Start: January 1, 2013
• Primary Completion: August 1, 2014
• Study Completion: September 1, 2014
• Last Updated: October 16, 2015
• Results First Posted: October 16, 2015

Record last verified: 2015-09

Locations

IT (2); CA (3); HU (2); US (26)