Trial Outcomes & Findings for Study Evaluating the Safety and Efficacy of Fixed-dose Once-daily Oral Aripiprazole in Children and Adolescents With Tourette's Disorder (NCT NCT01727700)

Last Updated: 2015-02-13

Results Overview

The YGTSS is a semi-structured clinical interview designed to measure current (time frame of the past 1 week) tic severity. This scale consists of a tic inventory, with 5 separate rating scales to rate the severity of symptoms, and an impairment ranking. Ratings are made along 5 different dimensions on a scale of 0 to 5 for motor and vocal tics each, including number, frequency, intensity, complexity, and interference. Summation of these 10 scores (ie, 0-50) provides a TTS that was the primary outcome measure in this trial. The YGTSS ranking of impairment score rated on a 50-point scale anchored from 0 (no impairment) to 50 (severe impairment) to assess impairment experienced in areas of self-esteem, family life, social acceptance, and school scores. This is a fully validated scale in adults and has become a standard instrument for the evaluation of the severity of TD in children.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

133 participants

Primary outcome timeframe

Baseline to Week 8

Results posted on

2015-02-13

Participant Flow

This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial in children and adolescents (aged 7-17 years) with Tourette's disorder (TD). 171 participants were screened, of which 133 were randomized to treatment.

The trial consisted of a pretreatment phase and a treatment phase. Pretreatment phase consisted of a screening and washout (when applicable) period. This was followed by an 8-week treatment phase starting with the baseline visit (Day 0). Particpants were randomized 1:1:1 to aripiprazole high dose, aripiprazole low dose or placebo.

Participant milestones

Participant milestones
Measure	Aripiprazole Low Dose For participants who weighed \< 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Aripiprazole High Dose For participants who weighed \< 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Placebo Participants received matching placebo tablets in the same way as aripiprazole.
Overall Study STARTED	44	45	44
Overall Study COMPLETED	42	35	42
Overall Study NOT COMPLETED	2	10	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Aripiprazole Low Dose For participants who weighed \< 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Aripiprazole High Dose For participants who weighed \< 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Placebo Participants received matching placebo tablets in the same way as aripiprazole.
Overall Study Adverse Event	0	7	1
Overall Study Particpant withdrew consent	0	3	1
Overall Study Protocol Violation	2	0	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Aripiprazole Low Dose n=44 Participants For participants who weighed \< 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Aripiprazole High Dose n=45 Participants For participants who weighed \< 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Placebo n=44 Participants Participants received matching placebo tablets in the same way as aripiprazole.	Total n=133 Participants Total of all reporting groups
Age, Continuous	11.1 Years STANDARD_DEVIATION 3.1 • n=5 Participants	11.8 Years STANDARD_DEVIATION 2.8 • n=7 Participants	11.6 Years STANDARD_DEVIATION 2.8 • n=5 Participants	11.5 Years STANDARD_DEVIATION 2.9 • n=4 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	10 Participants n=7 Participants	11 Participants n=5 Participants	29 Participants n=4 Participants
Sex: Female, Male Male	36 Participants n=5 Participants	35 Participants n=7 Participants	33 Participants n=5 Participants	104 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline to Week 8

Population: Intent-to-Treat (ITT) Population: All participants randomly assigned to the double-blind treatment. At Week 8, data were available for 42 participants in the low dose, 35 in the high dose and 42 in the placebo group.

Outcome measures

Outcome measures
Measure	Aripiprazole Low Dose n=42 Participants For participants who weighed \< 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Aripiprazole High Dose n=35 Participants For participants who weighed \< 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Placebo n=42 Participants Participants received matching placebo tablets in the same way as aripiprazole.
Change From Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS).	-13.35 Units on a scale Standard Error 1.59	-16.94 Units on a scale Standard Error 1.61	-7.09 Units on a scale Standard Error 1.55

SECONDARY outcome

Timeframe: Week 8

Population: ITT Population: All participants randomly assigned to the double-blind treatment. At Week 8, data were available for 42 participants in the low dose, 35 in the high dose and 42 in the placebo group.

To assess CGI-TS severity, the rater or physician answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" However, the evaluation of illness was limited to manifestations of TD only. Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. The change score was obtained from CGI-TS improvement scale assessment: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.

Outcome measures

Outcome measures
Measure	Aripiprazole Low Dose n=42 Participants For participants who weighed \< 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Aripiprazole High Dose n=35 Participants For participants who weighed \< 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Placebo n=42 Participants Participants received matching placebo tablets in the same way as aripiprazole.
Change in Clinical Global Impressions Scale-Tourette's Syndrome (CGI-TS) Score at Week 8.	2.12 Units on a scale Standard Error 0.21	2.13 Units on a scale Standard Error 0.21	3.15 Units on a scale Standard Error 0.2

SECONDARY outcome

Timeframe: Baseline to Week 8

The YGTSS consists of a tic inventory, with 5 separate rating scales to rate the severity of symptoms (on a scale of 0 to 5 for 5 different dimensions, including number, frequency, intensity, complexity, and interference) of motor and vocal tics, and an impairment ranking. The Total YGTSS score is the summation of the severity scores of motor and vocal tics and also the ranking of impairment (range of 0 to 100). A missing value of a YGTSS item scale could result in a missing Total YGTSS score. A reduction in Total YGTSS score from baseline represents an improvement in symptoms.

Outcome measures

Outcome measures
Measure	Aripiprazole Low Dose n=42 Participants For participants who weighed \< 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Aripiprazole High Dose n=35 Participants For participants who weighed \< 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Placebo n=42 Participants Participants received matching placebo tablets in the same way as aripiprazole.
Mean Change From Baseline to Endpoint (Week 8) in Total YGTSS Score	-26.69 Units on a scale Standard Error 3.34	-32.80 Units on a scale Standard Error 3.39	-13.43 Units on a scale Standard Error 3.27

SECONDARY outcome

Timeframe: Baseline to Week 8

The CGI-TS Severity scale (range 0-7) is a single-item rating score, with higher scores representing greater severity or less improvement. A response of 0 (not assessed) is considered and handled as missing data.

Outcome measures

Outcome measures
Measure	Aripiprazole Low Dose n=42 Participants For participants who weighed \< 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Aripiprazole High Dose n=35 Participants For participants who weighed \< 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Placebo n=42 Participants Participants received matching placebo tablets in the same way as aripiprazole.
Mean Change From Baseline to Endpoint (Week 8) in CGI-TS Severity Score	-1.35 Units on a scale Standard Error 0.19	-1.47 Units on a scale Standard Error 0.19	-0.55 Units on a scale Standard Error 0.19

SECONDARY outcome

Timeframe: Week 8

Clinical response is defined as \> 25% improvement from baseline to Week 8 in YGTSS TTS or a CGI-TS Change score of 1 \[very much improved\] or 2 \[much improved\] at Week 8. Response will be considered as missing only if both YGTSS TTS and CGI-TS change score are missing. As long as one of them is non-missing, response outcome will be determined based on the non-missing score.

Outcome measures

Outcome measures
Measure	Aripiprazole Low Dose n=42 Participants For participants who weighed \< 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Aripiprazole High Dose n=35 Participants For participants who weighed \< 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Placebo n=42 Participants Participants received matching placebo tablets in the same way as aripiprazole.
Response Rate	73.8 Percentage of Responders	88.6 Percentage of Responders	54.8 Percentage of Responders

SECONDARY outcome

Timeframe: Week 8

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

Treatment discontinuation rate will be calculated as the number of discontinued participants (ie, those who were withdrawn from the trial without completing the Week 8 visit) over the number of all randomized participants.

Outcome measures

Outcome measures
Measure	Aripiprazole Low Dose n=44 Participants For participants who weighed \< 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Aripiprazole High Dose n=45 Participants For participants who weighed \< 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Placebo n=44 Participants Participants received matching placebo tablets in the same way as aripiprazole.
Treatment Discontinuation Rate	4.5 Percentage of participants	22.5 Percentage of participants	4.5 Percentage of participants

Adverse Events

Aripiprazole Low Dose

Serious events: 0 serious events

Other events: 21 other events

Deaths: 0 deaths

Aripiprazole High Dose

Serious events: 0 serious events

Other events: 29 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Aripiprazole Low Dose n=44 participants at risk For participants who weighed \< 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Aripiprazole High Dose n=45 participants at risk For participants who weighed \< 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.	Placebo n=44 participants at risk Participants received matching placebo tablets in the same way as aripiprazole.
Gastrointestinal disorders Nausea	6.8% 3/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	8.9% 4/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	2.3% 1/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
Gastrointestinal disorders Vomiting	4.5% 2/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	6.7% 3/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	4.5% 2/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
General disorders Fatigue	6.8% 3/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	15.6% 7/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	0.00% 0/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
Infections and infestations Nasopharyngitis	6.8% 3/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	8.9% 4/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	0.00% 0/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
Metabolism and nutrition disorders Increased appetite	9.1% 4/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	6.7% 3/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	2.3% 1/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
Nervous system disorders Akathisia	0.00% 0/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	6.7% 3/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	0.00% 0/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
Nervous system disorders Headache	6.8% 3/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	8.9% 4/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	2.3% 1/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
Nervous system disorders Lethargy	0.00% 0/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	11.1% 5/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	0.00% 0/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
Nervous system disorders Sedation	18.2% 8/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	8.9% 4/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	2.3% 1/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
Nervous system disorders Somnolence	11.4% 5/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	15.6% 7/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	2.3% 1/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
Psychiatric disorders Restlessness	0.00% 0/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	6.7% 3/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	2.3% 1/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
Infections and infestations Upper respiratory tract infection	2.3% 1/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	2.2% 1/45 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.	6.8% 3/44 • Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit. An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.

Additional Information

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