Trial Outcomes & Findings for Safety and Tolerability of Once-daily Oral Aripiprazole in Children and Adolescents With Tourette's Disorder (NCT NCT01727713)

Last Updated: 2015-10-16

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

110 participants

Primary outcome timeframe

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

Results posted on

2015-10-16

Participant Flow

The trial was conducted in 110 participants at 37 trials sites in 4 countries. Participants who were aged 7 to 17 years at screening or who turned 18 years during their participation in Trial 31-12-293 (NCT01727700) were enrolled in this extension trial

Participant milestones

Participant milestones
Measure	Open-label Aripiprazole All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Overall Study STARTED	110
Overall Study COMPLETED	75
Overall Study NOT COMPLETED	35

Reasons for withdrawal

Reasons for withdrawal
Measure	Open-label Aripiprazole All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Overall Study Lost to Follow-up	5
Overall Study Adverse Event	10
Overall Study Participant Met Withdrawal Criteria	5
Overall Study Withdrawal by Subject	13
Overall Study Protocol Deviation	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Age, Continuous	11.7 Years STANDARD_DEVIATION 2.9 • n=5 Participants
Sex: Female, Male Female	24 Participants n=5 Participants
Sex: Female, Male Male	86 Participants n=5 Participants

PRIMARY outcome

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

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Percentage of Participants With Adverse Events. Participants with TEAEs	76.4 Percentage of participants
Percentage of Participants With Adverse Events. Participants with serious TEAEs	3.6 Percentage of participants
Percentage of Participants With Adverse Events. Participants with severe TEAEs	4.5 Percentage of participants

PRIMARY outcome

Timeframe: Baseline to Week 52

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial and who had at least one post-baseline laboratory value were included.

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.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Eosinophils (high) (N=108)	3.7 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Absolute neutrophils (low) (N=108)	13.0 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. White blood count (low) (N=108)	4.6 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Triglycerides (high) (N=92)	17.4 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Prolactin (high) (N=104)	3.8 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. LDL cholesterol (high) (N=92)	3.3 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Uric acid (high) (N=108)	0.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Potassium (high) (N=108)	0.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Urine glucose (high) (N=104)	1.0 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Urine protein (high) (N=104)	1.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Hemoglobin A1C (high) (N=107)	0.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Total bilirubin (high) (N=108)	1.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Creatine phosphokinase (high) (N=108)	0.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Laboratory Test Results. Fasting glucose (high) (N=93)	3.2 Percentage of participants

PRIMARY outcome

Timeframe: Baseline to Week 52

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial and who who had at least one post-baseline vital sign result were included.

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.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Percentage of Participants With Clinically Significant Abnormal Vital Signs. Orthostatic hypotension (N=110)	2.7 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Vital Signs. Heart rate-Supine (increase) (N=108)	0.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Vital Signs. Heart rate-Supine (decrease) (N=108)	0.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Vital Signs. Heart rate-Standing (increase) (N=108)	9.3 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Vital Signs. Systolic Supine BP (decrease) (N=108)	6.5 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Vital Signs. Systolic Standing BP (decrease) (N=108)	3.7 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Vital Signs. Diastolic Supine BP (decrease) (N=108)	0.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Vital Signs. Diastolic Standing BP (decrease) (N=108)	5.6 Percentage of participants

PRIMARY outcome

Timeframe: Baseline to Week 52

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial and who who had at least one post-baseline ECG result were included.

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.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Percentage of Participants With Clinically Significant Abnormal Electrocardiogram (ECG). Tachycardia (N=106)	0.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Electrocardiogram (ECG). Sinus Tachycardia (N=106)	0.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Electrocardiogram (ECG). Supraventricular premature beat (N=106)	1.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Electrocardiogram (ECG). Ventricular premature beat (N=106)	0.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Electrocardiogram (ECG). Right bundle branch block (N=106)	1.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Electrocardiogram (ECG). QTcB (N=106)	0.9 Percentage of participants
Percentage of Participants With Clinically Significant Abnormal Electrocardiogram (ECG). QTcN (N=106)	0.9 Percentage of participants

PRIMARY outcome

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

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial and who had at least one post-baseline weight measurement.

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

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Mean Change From Baseline in Body Weight. Week 12 (N=102)	1.8 Kilogram Standard Deviation 2.3
Mean Change From Baseline in Body Weight. Week 28 (N=90)	4.8 Kilogram Standard Deviation 3.8
Mean Change From Baseline in Body Weight. Week 36 (N=88)	5.8 Kilogram Standard Deviation 4.4
Mean Change From Baseline in Body Weight. Week 44 (N=81)	6.8 Kilogram Standard Deviation 5.3
Mean Change From Baseline in Body Weight. Week 52 (N=77)	8.0 Kilogram Standard Deviation 5.4
Mean Change From Baseline in Body Weight. Last visit (N=106)	7.2 Kilogram Standard Deviation 5.8

PRIMARY outcome

Timeframe: Baseline to Weeks 28, 52 and Last visit.

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug and who had a least one post-baseline BMI measurement.

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.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Mean Change From Baseline in Body Mass Index (BMI). Week 28 (N=90)	3.3 Kg/M^2 Standard Deviation 16.2
Mean Change From Baseline in Body Mass Index (BMI). Week 52 (N=77)	1.9 Kg/M^2 Standard Deviation 2.3
Mean Change From Baseline in Body Mass Index (BMI). Last visit (N=106)	1.8 Kg/M^2 Standard Deviation 2.3

PRIMARY outcome

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

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug and who had a least one post-baseline waist circumference measurement.

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

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Mean Change From Baseline in Waist Circumference. Week 44 (N=80)	4.5 Centimeter Standard Deviation 6.7
Mean Change From Baseline in Waist Circumference. Week 52 (N=75)	5.5 Centimeter Standard Deviation 6.5
Mean Change From Baseline in Waist Circumference. Week 12 (N=102)	2.2 Centimeter Standard Deviation 8.3
Mean Change From Baseline in Waist Circumference. Week 28 (N=90)	3.7 Centimeter Standard Deviation 9.7
Mean Change From Baseline in Waist Circumference. Week 36 (N=87)	3.5 Centimeter Standard Deviation 6.5
Mean Change From Baseline in Waist Circumference. Last visit (N=106)	4.6 Centimeter Standard Deviation 6.4

PRIMARY outcome

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

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial.

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).

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score. Week 28 (N=92)	-2.0 Units on a scale Standard Deviation 4.3
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score. Week 52 (N=77)	-2.3 Units on a scale Standard Deviation 4.7
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score. Week 4 (N=107)	-1.0 Units on a scale Standard Deviation 3.0
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score. Week 8 (N=105)	-1.3 Units on a scale Standard Deviation 3.4
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score. Week 12 (N=104)	-1.7 Units on a scale Standard Deviation 3.7
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score. Week 20 (N=100)	-1.8 Units on a scale Standard Deviation 3.9
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score. Week 36 (N=88)	-2.2 Units on a scale Standard Deviation 4.5
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score. Week 44 (N=82)	-2.3 Units on a scale Standard Deviation 4.6
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score. Last vist (N=109)	-1.8 Units on a scale Standard Deviation 4.3

PRIMARY outcome

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

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial.

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.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Change From Baseline in Simpson-Angus Scale (SAS) Total Score. Week 4 (N=107)	0.0 Units on a scale Standard Deviation 0.9
Change From Baseline in Simpson-Angus Scale (SAS) Total Score. Week 8 (N=104)	-0.0 Units on a scale Standard Deviation 0.9
Change From Baseline in Simpson-Angus Scale (SAS) Total Score. Week 12 (N=104)	-0.0 Units on a scale Standard Deviation 0.9
Change From Baseline in Simpson-Angus Scale (SAS) Total Score. Week 20 (N=100)	-0.1 Units on a scale Standard Deviation 0.7
Change From Baseline in Simpson-Angus Scale (SAS) Total Score. Week 28 (N=92)	-0.2 Units on a scale Standard Deviation 0.8
Change From Baseline in Simpson-Angus Scale (SAS) Total Score. Week 36 (N=88)	-0.2 Units on a scale Standard Deviation 0.8
Change From Baseline in Simpson-Angus Scale (SAS) Total Score. Week 44 (N=82)	-0.2 Units on a scale Standard Deviation 0.8
Change From Baseline in Simpson-Angus Scale (SAS) Total Score. Week 52 (N=77)	-0.1 Units on a scale Standard Deviation 0.8
Change From Baseline in Simpson-Angus Scale (SAS) Total Score. Last vist (N=109)	-0.1 Units on a scale Standard Deviation 0.7

PRIMARY outcome

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

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial.

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.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score. Week 12 (N=104)	-0.0 Units on a scale Standard Deviation 0.3
Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score. Week 20 (N=100)	-0.1 Units on a scale Standard Deviation 0.3
Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score. Week 4 (N=107)	0.0 Units on a scale Standard Deviation 0.4
Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score. Week 8 (N=105)	0.0 Units on a scale Standard Deviation 0.4
Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score. Week 28 (N=92)	-0.1 Units on a scale Standard Deviation 0.3
Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score. Week 36 (N=88)	-0.1 Units on a scale Standard Deviation 0.3
Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score. Week 44 (N=82)	-0.1 Units on a scale Standard Deviation 0.3
Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score. Week 52 (N=77)	-0.1 Units on a scale Standard Deviation 0.3
Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score. Last vist (N=109)	-0.0 Units on a scale Standard Deviation 0.3

PRIMARY outcome

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

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial.

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.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS). Week 36 (N=88)	0.1 Units on a scale Standard Deviation 1.3
Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS). Last vist (N=110)	0.0 Units on a scale Standard Deviation 1.3
Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS). Week 1 (N=108)	-0.1 Units on a scale Standard Deviation 0.7
Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS). Week 2 (N=106)	-0.0 Units on a scale Standard Deviation 0.5
Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS). Week 4 (N=107)	0.0 Units on a scale Standard Deviation 0.8
Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS). Week 8 (N=105)	-0.1 Units on a scale Standard Deviation 0.8
Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS). Week 12 (N=104)	-0.0 Units on a scale Standard Deviation 0.5
Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS). Week 20 (N=100)	-0.1 Units on a scale Standard Deviation 0.5
Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS). Week 28 (N=92)	0.1 Units on a scale Standard Deviation 1.0
Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS). Week 44 (N=82)	0.0 Units on a scale Standard Deviation 0.0
Change From Baseline in Suicidal Ideation Intensity Total Score Based on Columbia-Suicide Severity Rating Scale (C-SSRS). Week 52 (N=77)	0.2 Units on a scale Standard Deviation 1.3

PRIMARY outcome

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

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial.

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.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
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). Week 52 (N=77)	-0.2 Units on a scale Standard Deviation 0.4
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). Week 4 (N=107)	-0.2 Units on a scale Standard Deviation 0.4
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). Week 8 (N=105)	-0.2 Units on a scale Standard Deviation 0.4
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). Week 12 (N=104)	-0.3 Units on a scale Standard Deviation 0.4
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). Week 20 (N=100)	-0.2 Units on a scale Standard Deviation 0.4
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). Week 28 (N=92)	-0.2 Units on a scale Standard Deviation 0.4
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). Week 36 (N=88)	-0.2 Units on a scale Standard Deviation 0.4
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). Week 44 (N=82)	-0.2 Units on a scale Standard Deviation 0.4
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). Last vist (N=109)	-0.2 Units on a scale Standard Deviation 0.5

PRIMARY outcome

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

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial.

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.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Week 52 (N=77)	-0.9 Units on a scale Standard Deviation 3.9
Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Week 4 (N=107)	-0.2 Units on a scale Standard Deviation 2.6
Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Week 8 (N=105)	-0.1 Units on a scale Standard Deviation 3.0
Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Week 12 (N=104)	-0.5 Units on a scale Standard Deviation 2.7
Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Week 20 (N=100)	-0.6 Units on a scale Standard Deviation 3.0
Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Week 28 (N=92)	-0.5 Units on a scale Standard Deviation 3.3
Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Week 36 (N=88)	-0.7 Units on a scale Standard Deviation 3.4
Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Week 44 (N=82)	-0.8 Units on a scale Standard Deviation 3.7
Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Last vist (N=109)	-0.7 Units on a scale Standard Deviation 3.4

PRIMARY outcome

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

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial.

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.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=109 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Change From Baseline in Children's Depression Rating Scale - Revised (CDRS-R). Last vist (N=107)	0.7 Units on a scale Standard Deviation 4.5
Change From Baseline in Children's Depression Rating Scale - Revised (CDRS-R). Week 8 (N=100)	-0.4 Units on a scale Standard Deviation 3.8
Change From Baseline in Children's Depression Rating Scale - Revised (CDRS-R). Week 12 (N=100)	-0.3 Units on a scale Standard Deviation 3.2
Change From Baseline in Children's Depression Rating Scale - Revised (CDRS-R). Week 20 (N=97)	-0.1 Units on a scale Standard Deviation 4.2
Change From Baseline in Children's Depression Rating Scale - Revised (CDRS-R). Week 28 (N=91)	0.2 Units on a scale Standard Deviation 5.0
Change From Baseline in Children's Depression Rating Scale - Revised (CDRS-R). Week 36 (N=87)	0.4 Units on a scale Standard Deviation 4.4
Change From Baseline in Children's Depression Rating Scale - Revised (CDRS-R). Week 44 (N=82)	-0.3 Units on a scale Standard Deviation 3.3
Change From Baseline in Children's Depression Rating Scale - Revised (CDRS-R). Week 52 (N=77)	0.6 Units on a scale Standard Deviation 3.8
Change From Baseline in Children's Depression Rating Scale - Revised (CDRS-R). Week 4 (N=104)	-0.4 Units on a scale Standard Deviation 4.4

PRIMARY outcome

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

Population: Safety Sample: All participants who received at least 1 dose of open-label study drug in this trial.

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).

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Change From Baseline in Pediatric Anxiety Rating Scale (PARS). Week 4 (N=107)	-0.3 Units on a scale Standard Deviation 3.0
Change From Baseline in Pediatric Anxiety Rating Scale (PARS). Week 8 (N=105)	-0.3 Units on a scale Standard Deviation 3.6
Change From Baseline in Pediatric Anxiety Rating Scale (PARS). Week 12 (N=104)	-0.5 Units on a scale Standard Deviation 2.6
Change From Baseline in Pediatric Anxiety Rating Scale (PARS). Week 20 (N=100)	-0.4 Units on a scale Standard Deviation 2.9
Change From Baseline in Pediatric Anxiety Rating Scale (PARS). Week 28 (N=91)	-0.2 Units on a scale Standard Deviation 3.1
Change From Baseline in Pediatric Anxiety Rating Scale (PARS). Week 36 (N=88)	-0.7 Units on a scale Standard Deviation 3.0
Change From Baseline in Pediatric Anxiety Rating Scale (PARS). Week 44 (N=82)	-0.5 Units on a scale Standard Deviation 2.7
Change From Baseline in Pediatric Anxiety Rating Scale (PARS). Week 52 (N=77)	-0.4 Units on a scale Standard Deviation 3.5
Change From Baseline in Pediatric Anxiety Rating Scale (PARS). Last vist (N=109)	-0.4 Units on a scale Standard Deviation 3.5

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: All participants who receive at least 1 dose of open-label study drug in this trial, and have baseline and at least 1 post-baseline efficacy evaluation.

The YGTSS is a semi-structured clinical interview which consists of a tic inventory, with 5 separate ratings to assess the number, intensity, frequency, complexity and interference of tics, plus an overall impairment/disability score. 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 secondary outcome measure in this trial. The YGTSS ranking of impairment, with a maximum of 50 points, is based on the impact of the tic disorder on areas of self-esteem, family life, social acceptance, and school scores. The total severity score ranged from 0 (no impairment) to 50 (worst impairment).

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Change From Baseline to Endpoint on the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS). Week 52 (N=77)	-8.6 Units on a scale Standard Deviation 10.2
Change From Baseline to Endpoint on the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS). Last visit (N=109)	-6.6 Units on a scale Standard Deviation 10.9

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: All participants who receive at least 1 dose of open-label study drug in this trial, and have baseline and at least 1 post-baseline efficacy evaluation.

The CGI is a 7-point Likert scale used in a multitude of clinical trials as a clinical global measure to assess the severity and change in disease symptomatology (ie, tics). The CGI was included as a secondary scale to provide a more complete assessment of clinical efficacy. To assess CGI-TS severity, the rater or investigator will answer 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 will be limited to manifestations of Tourette's Disorder only. Response choices include: 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.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Mean Clinical Global Impressions for Tourette's Syndrome (CGI-TS) Change Score at Endpoint. Week 52 (N=77)	2.5 Units on a scale Standard Deviation 1.6
Mean Clinical Global Impressions for Tourette's Syndrome (CGI-TS) Change Score at Endpoint. Last visit (N=109)	2.5 Units on a scale Standard Deviation 1.6

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: All participants who receive at least 1 dose of open-label study drug in this trial, and have baseline and at least 1 post-baseline efficacy evaluation.

The final CGI-TS score was compared to the participant's baseline condition at the time of entry into the open-label study, rather than the CGI-TS baseline condition at the time participants enrolled into the preceding study. Response choices include: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Change From Baseline to Endpoint in CGI-TS Severity of Illness Score. Week 52 (N=77)	-0.9 Units on a scale Standard Deviation 1.2
Change From Baseline to Endpoint in CGI-TS Severity of Illness Score. Last visit (N=109)	-0.7 Units on a scale Standard Deviation 1.3

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: All participants who receive at least 1 dose of open-label study drug in this trial, and have baseline and at least 1 post-baseline efficacy evaluation.

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) for motor and vocal tics, and an impairment ranking. The YGTSS TTS is the summation of the severity scores of motor and vocal tics (range of 0 \[no impairment\] to 50 \[maximum impairment\]). The total YGTSS score is the summation of the severity scores of motor and vocal tics and the ranking of impairment (total range of 0 \[no impairment\] to 100 \[maximum impairment\]).

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Mean Change From Baseline to Endpoint in Total YGTSS Score. Week 52 (N=77)	-18.0 Units on a scale Standard Deviation 23.7
Mean Change From Baseline to Endpoint in Total YGTSS Score. Last visit (N=109)	-14.0 Units on a scale Standard Deviation 24.3

SECONDARY outcome

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

Population: All participants who receive at least 1 dose of open-label study drug in this trial, and have baseline and at least 1 post-baseline efficacy evaluation.

Clinical response was defined as \> 25% improvement from Baseline to endpoint in YGTSS TTS or a CGI-TS change score of 1 (very much improved) or 2 (much improved) at endpoint.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Percentage of Participants With Response (Response Rate). Week 4 (N=107)	80.4 Percentage of participants with response
Percentage of Participants With Response (Response Rate). Week 8 (N=105)	81.9 Percentage of participants with response
Percentage of Participants With Response (Response Rate). Week 12 (N=104)	82.7 Percentage of participants with response
Percentage of Participants With Response (Response Rate). Week 20 (N=100)	75.0 Percentage of participants with response
Percentage of Participants With Response (Response Rate). Week 28 (N=92)	77.2 Percentage of participants with response
Percentage of Participants With Response (Response Rate). Week 36 (N=88)	75.0 Percentage of participants with response
Percentage of Participants With Response (Response Rate). Week 44 (N=81)	75.3 Percentage of participants with response
Percentage of Participants With Response (Response Rate). Week 52 (N=77)	67.5 Percentage of participants with response

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: All participants who receive at least 1 dose of open-label study drug in this trial, and have baseline and at least 1 post-baseline efficacy evaluation.

The treatment discontinuation rate was calculated as the number of discontinued participants (ie, those withdrawn from the study without completing the Week 52 visit) divided by the number of all enrolled participants.

Outcome measures

Outcome measures
Measure	Open-label Aripiprazole n=110 Participants All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Percentage of Participants With Treatment Discontinuation (Treatment Discontinuation Rate).	31.8 Percentage of discontinued participants

Adverse Events

Open-label Aripiprazole

Serious events: 4 serious events

Other events: 84 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Open-label Aripiprazole n=110 participants at risk All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Congenital, familial and genetic disorders Tourette's disorder	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Appendicitis	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Infectious mononucleosis	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Injury, poisoning and procedural complications Concussion	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Injury, poisoning and procedural complications Intentional overdose	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.

Other adverse events

Other adverse events
Measure	Open-label Aripiprazole n=110 participants at risk All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
Blood and lymphatic system disorders Leukopenia	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Blood and lymphatic system disorders Neutropenia	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Cardiac disorders Tachycardia	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Ear and labyrinth disorders Ear pain	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Ear and labyrinth disorders Middle ear effusion	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Ear and labyrinth disorders Tympanic membrane perforation	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Eye disorders Excessive eye blinking	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Eye disorders Eye inflammation	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Eye disorders Strabismus	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Eye disorders Vision blurred	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Abdominal discomfort	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Abdominal pain	0.91% 1/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Abdominal pain upper	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Aphthous stomatitis	0.91% 1/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Constipation	2.7% 3/110 • Number of events 4 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Diarrhoea	2.7% 3/110 • Number of events 3 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Dry mouth	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Eructation	0.91% 1/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Flatulence	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Nausea	7.3% 8/110 • Number of events 9 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Retching	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Salivary hypersecretion	1.8% 2/110 • Number of events 3 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Gastrointestinal disorders Vomiting	9.1% 10/110 • Number of events 12 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
General disorders Fatigue	10.0% 11/110 • Number of events 12 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
General disorders Influenza like illness	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
General disorders Irritability	1.8% 2/110 • Number of events 3 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
General disorders Malaise	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
General disorders Pyrexia	6.4% 7/110 • Number of events 8 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Hepatobiliary disorders Hepatitis acute	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Immune system disorders House dust allergy	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Immune system disorders Multiple allergies	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Immune system disorders Seasonal allergy	2.7% 3/110 • Number of events 3 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Ear infection	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Gastroenteritis	4.5% 5/110 • Number of events 5 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Gastroenteritis viral	3.6% 4/110 • Number of events 5 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Gastrointestinal viral infection	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Influenza	3.6% 4/110 • Number of events 4 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Localised infection	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Nasopharyngitis	10.0% 11/110 • Number of events 12 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Otitis media	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Pharyngitis	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Pharyngitis streptococcal	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Pneumonia	0.91% 1/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Sinusitis	4.5% 5/110 • Number of events 5 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Tonsillitis	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Upper respiratory tract infection	3.6% 4/110 • Number of events 4 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Viral infection	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Infections and infestations Viral rash	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Injury, poisoning and procedural complications Animal bite	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Injury, poisoning and procedural complications Contusion	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Injury, poisoning and procedural complications Excoriation	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Injury, poisoning and procedural complications Hand fracture	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Injury, poisoning and procedural complications Ligament sprain	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Injury, poisoning and procedural complications Patella fracture	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Investigations Bilirubin conjugated increased	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Investigations Blood creatine phosphokinase increased	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Investigations Blood pressure increased	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Investigations Blood thyroid stimulating hormone increased	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Investigations Protein urine present	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Investigations Weight increased	23.6% 26/110 • Number of events 27 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Investigations White blood cell count decreased	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Metabolism and nutrition disorders Hyperinsulinaemia	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Metabolism and nutrition disorders Increased appetite	5.5% 6/110 • Number of events 6 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Metabolism and nutrition disorders Insulin resistance	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Metabolism and nutrition disorders Iron deficiency	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Metabolism and nutrition disorders Vitamin D deficiency	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Musculoskeletal and connective tissue disorders Arthralgia	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Musculoskeletal and connective tissue disorders Muscle spasms	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Musculoskeletal and connective tissue disorders Pain in extremity	2.7% 3/110 • Number of events 3 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Akathisia	2.7% 3/110 • Number of events 3 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Cognitive disorder	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Dizziness	4.5% 5/110 • Number of events 6 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Dyskinesia	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Dystonia	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Headache	10.0% 11/110 • Number of events 12 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Migraine	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Migraine with aura	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Paresthesia	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Psychomotor hyperactivity	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Sedation	5.5% 6/110 • Number of events 6 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Somnolence	11.8% 13/110 • Number of events 14 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Syncope	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Nervous system disorders Tremor	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Aggression	2.7% 3/110 • Number of events 4 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Agitation	3.6% 4/110 • Number of events 6 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Anger	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Anxiety	5.5% 6/110 • Number of events 6 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Attention deficit/hyperactivity disorder	4.5% 5/110 • Number of events 6 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Blunted affect	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Bruxism	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Depression	1.8% 2/110 • Number of events 3 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Depressed mood	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Emotional disorder	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Emotional poverty	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Flat affect	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Head banging	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Initial insomnia	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Insomnia	2.7% 3/110 • Number of events 3 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Mood altered	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Obsessive-compulsive disorder	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Restlessness	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Sleep disorder	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Somnambulism	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders Suicidal ideation	2.7% 3/110 • Number of events 3 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Psychiatric disorders TIC	5.5% 6/110 • Number of events 9 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Renal and urinary disorders Pollakiuria	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Renal and urinary disorders Urinary hesitation	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Renal and urinary disorders Urinary incontinence	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Renal and urinary disorders Urinary retention	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Reproductive system and breast disorders Dysmenorrhoea	1.8% 2/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Respiratory, thoracic and mediastinal disorders Cough	1.8% 2/110 • Number of events 3 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Respiratory, thoracic and mediastinal disorders Epistaxis	1.8% 2/110 • Number of events 4 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Respiratory, thoracic and mediastinal disorders Hiccups	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.91% 1/110 • Number of events 2 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.7% 3/110 • Number of events 3 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	2.7% 3/110 • Number of events 4 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Respiratory, thoracic and mediastinal disorders Vocal cord disorder	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Skin and subcutaneous tissue disorders Acne	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Skin and subcutaneous tissue disorders Rash	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
Vascular disorders Hot flush	0.91% 1/110 • Number of events 1 • Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.

Additional Information

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Principal investigator is a sponsor employee
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