Trial Outcomes & Findings for Efficacy and Safety of Circadin® in the Treatment of Sleep Disturbances in Children With Neurodevelopment Disabilities (NCT NCT01906866)

NCT ID: NCT01906866

Last Updated: 2024-04-23

Results Overview

The treatment effect of Circadin® 2/5 mg minitabs was compared to that of a placebo on total sleep time, as assessed by the Sleep and Nap Diary questionnaire, following 13 weeks of double-blind treatment

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 125 participants
• Primary outcome timeframe: 13 weeks
• Results posted on: 2024-04-23

Participant Flow

Participant milestones

Measure	Circadin 2/5/10 mg Circadin 2/5/10 mg: Active arm	Placebo Placebo arm Placebo
Overall Study STARTED	60	65
Overall Study COMPLETED	51	44
Overall Study NOT COMPLETED	9	21

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Efficacy and Safety of Circadin® in the Treatment of Sleep Disturbances in Children With Neurodevelopment Disabilities

Baseline characteristics by cohort

Measure	Circadin 2/5/10 mg n=60 Participants Circadin 2/5/10 mg: Active arm	Placebo n=65 Participants Placebo arm Placebo	Total n=125 Participants Total of all reporting groups
Age, Categorical <=18 years	60 Participants n=5 Participants	65 Participants n=7 Participants	125 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	9 years STANDARD_DEVIATION 4.08 • n=5 Participants	8.4 years STANDARD_DEVIATION 4.24 • n=7 Participants	8.7 years STANDARD_DEVIATION 4.15 • n=5 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	18 Participants n=7 Participants	33 Participants n=5 Participants
Sex: Female, Male Male	45 Participants n=5 Participants	47 Participants n=7 Participants	92 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	8 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) White	57 Participants n=5 Participants	55 Participants n=7 Participants	112 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Netherlands	5 participants n=5 Participants	4 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment United States	44 participants n=5 Participants	50 participants n=7 Participants	91 participants n=5 Participants
Region of Enrollment Finland	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment United Kingdom	8 participants n=5 Participants	8 participants n=7 Participants	16 participants n=5 Participants
Region of Enrollment France	3 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants

PRIMARY outcome

Timeframe: 13 weeks

Population: All patients in the Safety Analysis Set who satisfied all major entry criteria (I.Criteria 1-5) and who had a valid mean TST result recorded for baseline and at least one post-baseline period assessment during the double-blind phase. Patients were classified according to randomized treatment. This analysis set was used for all efficacy analyses.

The treatment effect of Circadin® 2/5 mg minitabs was compared to that of a placebo on total sleep time, as assessed by the Sleep and Nap Diary questionnaire, following 13 weeks of double-blind treatment

Outcome measures

Measure	Circadin 2/5/10 mg n=58 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=61 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Total Sleep Time (TST)	51.03 minutes Interval 30.3 to 71.76	18.71 minutes Interval -2.73 to 40.15

SECONDARY outcome

Timeframe: 13 weeks

Population: All patients in the Safety Analysis Set who satisfied all major entry criteria (I.Criteria 1-5) and who had a valid mean TST result recorded for baseline and at least one post-baseline period assessment during the double-blind phase. Patients were classified according to randomized treatment. This analysis set was used for all efficacy analyses

Sleep Latency (minutes) derived from Sleep and Nap Diary following 13 weeks of double-blind treatment with Circadin 2/5 mg minitabs versus placebo.

The lower the value for sleep latency, the better the outcome.

Outcome measures

Measure	Circadin 2/5/10 mg n=58 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=61 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Sleep Latency (Mins) Baseline	95.16 minutes Standard Error 59.253	98.76 minutes Standard Error 73.899
Sleep Latency (Mins) 13 weeks	60.74 minutes Standard Error 42.111	76.88 minutes Standard Error 82.589

SECONDARY outcome

Timeframe: 13 weeks

Duration of Wake after Sleep onset period derived from Sleep and Nap Diary following 13 weeks of double-blind treatment with Circadin 2/5 mg minitabs versus placebo.

The shorter the value, the better the outcome.

Outcome measures

Measure	Circadin 2/5/10 mg n=58 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=61 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Duration of Wake After Sleep Baseline	64.4 minutes Standard Deviation 24.421	64.89 minutes Standard Deviation 32.525
Duration of Wake After Sleep 13 weeks	68.75 minutes Standard Deviation 32.199	70.89 minutes Standard Deviation 51.590

SECONDARY outcome

Timeframe: 13 weeks

Number of awakenings per night will be assessed by a Sleep and Nap Diary and summarized after 13 weeks of double-blind treatment for each treatment group using descriptive statistics.

The smaller the number, the better the outcome.

Outcome measures

Measure	Circadin 2/5/10 mg n=58 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=61 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Number of Awakenings Per Night Baseline	2.11 Number of awakenings per night Standard Deviation 1.655	1.92 Number of awakenings per night Standard Deviation 1.441
Number of Awakenings Per Night 13 weeks	2.37 Number of awakenings per night Standard Deviation 2.095	2.14 Number of awakenings per night Standard Deviation 1.895

SECONDARY outcome

Timeframe: 13 weeks

Population: FAS (Full analysis set)

The longest sleep period following 13 weeks of double-blind treatment with Circadin 2/5 mg and placebo was evaluated by a Sleep and Nap Diary questionnaire.

The longer the sleep period, the better the outcome.

Outcome measures

Measure	Circadin 2/5/10 mg n=58 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=61 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Longest Sleep Period Baseline	383.79 minutes Standard Deviation 117.677	380.58 minutes Standard Deviation 118.429
Longest Sleep Period 13 weeks	451.45 minutes Standard Deviation 124.933	414.65 minutes Standard Deviation 124.993

SECONDARY outcome

Timeframe: 13 weeks

Population: FAS set

The Children's Global Assessment Scale (CGAS) Questionnaire measures social functioning at home, in school, and in community settings.

The scores range from 1, which is the very worst, to 100, which is the very best.

Outcome measures

Measure	Circadin 2/5/10 mg n=58 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=61 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Social Functioning - Children Global Assessment Scale (CGAS)	48.3 score on a scale Standard Deviation 17.93	51.5 score on a scale Standard Deviation 18.02

SECONDARY outcome

Timeframe: 13 weeks

The Strengths and Difficulties Questionnaire (SDQ) is a brief, 25-item, measure of behavioral and emotional difficulties that can be used to assess behavior at home and in school in children.

The SDQ consists of 25 items which are divided into 5 subscales: 1) emotional symptoms (5 items); 2) conduct problems (5 items); 3) hyperactivity/inattention (5 items); 4) peer relationship problems (5 items); and 5) prosocial behavior (5 items).

Subscales 1 to 4 are summed to generate a Total Difficulties Score (that ranges from 0 to 40). Each item on the SDQ is scored on a 3-point ordinal scale with 0 = not true, 1 = somewhat true, and 2 = certainly true, with higher scores indicating larger problems.

Outcome measures

Measure	Circadin 2/5/10 mg n=58 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=61 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Behavior at Home and in School - Strengths and Difficulties Questionnaire (SDQ)	19.6 score on a scale Standard Deviation 5.09	20.7 score on a scale Standard Deviation 6.09

SECONDARY outcome

Timeframe: 13 weeks

Population: Safety set

Number of dropouts during the 13 weeks of double-blind treatment in the Circadin 2/5 mg and placebo arms.

Outcome measures

Measure	Circadin 2/5/10 mg n=60 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=65 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Number of Dropouts	9 Participants	21 Participants

SECONDARY outcome

Timeframe: 13 weeks

Population: Despite major efforts to ensure adherence, actigraphy monitoring was challenging in this population, and a majority of patients (75% in the Circadin and 77% in the placebo group) refused to wear the device during one or both periods and/or took it off some time during the night. Only 12 patients in the Circadin and 13 in the placebo group had data for both baseline and 13 weeks of treatment, and even in those it was not possible to ascertain that they wore the device throughout the night.

Actigraphy is a validated method of objectively measuring sleep parameters and average motor activity over days to weeks using a noninvasive device.

Despite major efforts to ensure adherence, actigraphy monitoring was challenging in this population, and a majority of patients (75% in the Circadin and 77% in the placebo group) refused to wear the device and/or took it off sometime during the night. Only 12 patients in the Circadin and 13 in the placebo group had data for both baseline and 13 weeks of treatment, and even in those it was not possible to ascertain that they wore the device throughout the night.

Outcome measures

Measure	Circadin 2/5/10 mg n=12 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=13 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Assessment of Sleep Parameters by Actigraphy Change in TST (total sleep time)	7.23 minutes Standard Deviation 96.521	-23.94 minutes Standard Deviation 61.860
Assessment of Sleep Parameters by Actigraphy Change in sleep latency	25.11 minutes Standard Deviation 38.371	-12.50 minutes Standard Deviation 24.744

SECONDARY outcome

Timeframe: 13 weeks, 26 weeks, 52 weeks.

Population: Safety Set

Treatment Emergent Signs and Symptoms (TESS). Signs and symptoms not seen at baseline (i.e. before starting the treatment) and/or worsened even if present at baseline.

Outcome measures

Measure	Circadin 2/5/10 mg n=60 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=65 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - Baseline · No Symptoms	33 Participants	41 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - Baseline · Mild	10 Participants	11 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - Baseline · Moderate	13 Participants	11 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - Baseline · Severe	4 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 13 weeks · No Symptoms	42 Participants	53 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 13 weeks · Mild	8 Participants	11 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 13 weeks · Moderate	6 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 13 weeks · Severe	4 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 26 weeks · No Symptoms	45 Participants	51 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 26 weeks · Mild	4 Participants	13 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 26 weeks · Moderate	9 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 26 weeks · Severe	2 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 52 weeks · No Symptoms	47 Participants	56 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 52 weeks · Mild	9 Participants	9 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 52 weeks · Moderate	4 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Somnolence - 52 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - Baseline · No Symptoms	30 Participants	32 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - Baseline · Mild	13 Participants	15 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - Baseline · Moderate	11 Participants	10 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - Baseline · Severe	6 Participants	8 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 13 weeks · No Symptoms	33 Participants	47 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 13 weeks · Mild	16 Participants	12 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 13 weeks · Moderate	9 Participants	4 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 13 weeks · Severe	2 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 26 weeks · No Symptoms	39 Participants	49 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 26 weeks · Mild	14 Participants	9 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 26 weeks · Moderate	6 Participants	7 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 26 weeks · Severe	1 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 52 weeks · No Symptoms	44 Participants	52 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 52 weeks · Mild	13 Participants	9 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 52 weeks · Moderate	3 Participants	4 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Fatigue - 52 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - Baseline · No Symptoms	25 Participants	32 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - Baseline · Mild	17 Participants	8 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - Baseline · Moderate	11 Participants	16 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - Baseline · Severe	7 Participants	9 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 13 weeks · No Symptoms	34 Participants	42 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 13 weeks · Mild	8 Participants	8 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 13 weeks · Moderate	10 Participants	9 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 13 weeks · Severe	8 Participants	6 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 26 weeks · No Symptoms	35 Participants	49 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 26 weeks · Mild	6 Participants	7 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 26 weeks · Moderate	12 Participants	6 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 26 weeks · Severe	7 Participants	3 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 52 weeks · No Symptoms	42 Participants	52 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 52 weeks · Mild	3 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 52 weeks · Moderate	9 Participants	10 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Increased Excitability - 52 weeks · Severe	6 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - Baseline · No Symptoms	56 Participants	64 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - Baseline · Mild	3 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - Baseline · Moderate	1 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - Baseline · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 13 weeks · No Symptoms	57 Participants	64 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 13 weeks · Mild	3 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 13 weeks · Moderate	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 13 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 26 weeks · No Symptoms	59 Participants	65 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 26 weeks · Mild	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 26 weeks · Moderate	1 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 26 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 52 weeks · No Symptoms	60 Participants	64 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 52 weeks · Mild	0 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 52 weeks · Moderate	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Dizziness - 52 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - Baseline · No Symptoms	52 Participants	60 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - Baseline · Mild	8 Participants	4 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - Baseline · Moderate	0 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - Baseline · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 13 weeks · No Symptoms	52 Participants	61 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 13 weeks · Mild	6 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 13 weeks · Moderate	2 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 13 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 26 weeks · No Symptoms	55 Participants	64 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 26 weeks · Mild	3 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 26 weeks · Moderate	2 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 26 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 52 weeks · No Symptoms	57 Participants	64 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 52 weeks · Mild	2 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 52 weeks · Moderate	1 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hangover Feelings - 52 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - Baseline · No Symptoms	24 Participants	33 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - Baseline · Mild	13 Participants	10 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - Baseline · Moderate	21 Participants	14 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - Baseline · Severe	2 Participants	8 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 13 weeks · No Symptoms	28 Participants	41 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 13 weeks · Mild	15 Participants	13 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 13 weeks · Moderate	13 Participants	6 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 13 weeks · Severe	4 Participants	5 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 26 weeks · No Symptoms	31 Participants	45 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 26 weeks · Mild	13 Participants	9 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 26 weeks · Moderate	13 Participants	8 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 26 weeks · Severe	3 Participants	3 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 52 weeks · No Symptoms	40 Participants	50 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 52 weeks · Mild	10 Participants	8 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 52 weeks · Moderate	6 Participants	6 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Mood Swings - 52 weeks · Severe	4 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - Baseline · No Symptoms	55 Participants	64 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - Baseline · Mild	4 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - Baseline · Moderate	1 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - Baseline · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 13 weeks · No Symptoms	57 Participants	63 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 13 weeks · Mild	3 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 13 weeks · Moderate	0 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 13 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 26 weeks · No Symptoms	58 Participants	65 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 26 weeks · Mild	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 26 weeks · Moderate	2 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 26 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 52 weeks · No Symptoms	56 Participants	65 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 52 weeks · Mild	2 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 52 weeks · Moderate	2 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Tremor - 52 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - Baseline · No Symptoms	60 Participants	64 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - Baseline · Mild	0 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - Baseline · Moderate	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - Baseline · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 13 weeks · No Symptoms	60 Participants	64 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 13 weeks · Mild	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 13 weeks · Moderate	0 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 13 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 26 weeks · No Symptoms	60 Participants	63 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 26 weeks · Mild	0 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 26 weeks · Moderate	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 26 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 52 weeks · No Symptoms	59 Participants	64 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 52 weeks · Mild	0 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 52 weeks · Moderate	1 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Seizures - 52 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - Baseline · No Symptoms	47 Participants	56 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - Baseline · Mild	7 Participants	7 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - Baseline · Moderate	6 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - Baseline · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 13 weeks · No Symptoms	49 Participants	59 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 13 weeks · Mild	9 Participants	4 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 13 weeks · Moderate	2 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 13 weeks · Severe	0 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 26 weeks · No Symptoms	54 Participants	61 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 26 weeks · Mild	5 Participants	3 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 26 weeks · Moderate	1 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 26 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 52 weeks · No Symptoms	53 Participants	57 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 52 weeks · Mild	6 Participants	7 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 52 weeks · Moderate	1 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Headache - 52 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - Baseline · No Symptoms	52 Participants	60 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - Baseline · Mild	6 Participants	5 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - Baseline · Moderate	2 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - Baseline · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 13 weeks · No Symptoms	49 Participants	57 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 13 weeks · Mild	7 Participants	6 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 13 weeks · Moderate	4 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 13 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 26 weeks · No Symptoms	51 Participants	61 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 26 weeks · Mild	8 Participants	4 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 26 weeks · Moderate	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 26 weeks · Severe	1 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 52 weeks · No Symptoms	53 Participants	62 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 52 weeks · Mild	6 Participants	3 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 52 weeks · Moderate	1 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Nausea/ Vomiting - 52 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - Baseline · No Symptoms	56 Participants	58 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - Baseline · Mild	3 Participants	5 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - Baseline · Moderate	1 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - Baseline · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 13 weeks · No Symptoms	56 Participants	61 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 13 weeks · Mild	3 Participants	3 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 13 weeks · Moderate	0 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 13 weeks · Severe	1 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 26 weeks · No Symptoms	56 Participants	60 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 26 weeks · Mild	2 Participants	5 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 26 weeks · Moderate	2 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 26 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 52 weeks · No Symptoms	55 Participants	62 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 52 weeks · Mild	4 Participants	3 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 52 weeks · Moderate	1 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Rash - 52 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - Baseline · No Symptoms	56 Participants	63 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - Baseline · Mild	2 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - Baseline · Moderate	2 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - Baseline · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 13 weeks · No Symptoms	57 Participants	62 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 13 weeks · Mild	2 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 13 weeks · Moderate	1 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 13 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 26 weeks · No Symptoms	58 Participants	64 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 26 weeks · Mild	2 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 26 weeks · Moderate	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 26 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 52 weeks · No Symptoms	59 Participants	65 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 52 weeks · Mild	1 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 52 weeks · Moderate	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Hypothermia - 52 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - Baseline · No Symptoms	49 Participants	54 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - Baseline · Mild	7 Participants	8 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - Baseline · Moderate	3 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - Baseline · Severe	1 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 13 weeks · No Symptoms	48 Participants	55 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 13 weeks · Mild	10 Participants	7 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 13 weeks · Moderate	1 Participants	2 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 13 weeks · Severe	1 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 26 weeks · No Symptoms	55 Participants	55 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 26 weeks · Mild	4 Participants	7 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 26 weeks · Moderate	1 Participants	3 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 26 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 52 weeks · No Symptoms	54 Participants	59 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 52 weeks · Mild	4 Participants	5 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 52 weeks · Moderate	2 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Coughing/ Breathlessness - 52 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - Baseline · No Symptoms	48 Participants	56 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - Baseline · Mild	8 Participants	7 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - Baseline · Moderate	3 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - Baseline · Severe	1 Participants	1 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 13 weeks · No Symptoms	35 Participants	48 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 13 weeks · Mild	18 Participants	14 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 13 weeks · Moderate	7 Participants	3 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 13 weeks · Severe	0 Participants	0 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 26 weeks · No Symptoms	45 Participants	39 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 26 weeks · Mild	11 Participants	15 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 26 weeks · Moderate	3 Participants	7 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 26 weeks · Severe	1 Participants	4 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 52 weeks · No Symptoms	35 Participants	41 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 52 weeks · Mild	19 Participants	15 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 52 weeks · Moderate	6 Participants	7 Participants
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary. Other Adverse Event - 52 weeks · Severe	0 Participants	2 Participants

SECONDARY outcome

Timeframe: 13 weeks, 26 weeks, 52 weeks.

Population: Safety Set

Systolic and Diastolic Blood Pressure (mmHg) A normal blood pressure (BP) level is lower than 140/70 mmHg, meaning systolic BP values lower than 140 mmHg, and diastolic BP values lower than 70 mmHg.

Values within the normal range mean good safety and tolerability outcomes.

Outcome measures

Measure	Circadin 2/5/10 mg n=60 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=65 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Safety and Tolerability - Blood Pressure (mmHg) Diastolic - Baseline	64.3 mmHg Standard Deviation 8.31	63.9 mmHg Standard Deviation 10.11
Safety and Tolerability - Blood Pressure (mmHg) Systolic - Baseline	104.5 mmHg Standard Deviation 11.37	104.7 mmHg Standard Deviation 13.94
Safety and Tolerability - Blood Pressure (mmHg) Diastolic - 13 weeks	65.5 mmHg Standard Deviation 8.74	65.9 mmHg Standard Deviation 10.73
Safety and Tolerability - Blood Pressure (mmHg) Systolic - 13 weeks	105.5 mmHg Standard Deviation 11.34	106.5 mmHg Standard Deviation 12.57
Safety and Tolerability - Blood Pressure (mmHg) Diastolic - 26 weeks	64.5 mmHg Standard Deviation 9.65	65.1 mmHg Standard Deviation 10.06
Safety and Tolerability - Blood Pressure (mmHg) Systolic - 26 weeks	105.3 mmHg Standard Deviation 12.49	107.3 mmHg Standard Deviation 15.46
Safety and Tolerability - Blood Pressure (mmHg) Diastolic - 52 weeks	65.8 mmHg Standard Deviation 7.94	66.2 mmHg Standard Deviation 9.84
Safety and Tolerability - Blood Pressure (mmHg) Systolic - 52 weeks	106.9 mmHg Standard Deviation 12.81	108.1 mmHg Standard Deviation 14.46

SECONDARY outcome

Timeframe: 13 weeks, 26 weeks, 52 weeks.

Population: Safety Set

Safety and tolerability of Circadin treatment compared to placebo: Pulse rate. The normal pulse for healthy adults ranges from 60 to 100 beats per minute (bpm).

Values within the normal range mean good safety and tolerability outcomes.

Outcome measures

Measure	Circadin 2/5/10 mg n=60 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=65 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Safety and Tolerability - Pulse (Beats Per Minute) Baseline	89.2 beats per minute Standard Deviation 13.84	92.3 beats per minute Standard Deviation 21.42
Safety and Tolerability - Pulse (Beats Per Minute) 13 weeks	90.7 beats per minute Standard Deviation 15.98	94.4 beats per minute Standard Deviation 17.96
Safety and Tolerability - Pulse (Beats Per Minute) 26 weeks	86.1 beats per minute Standard Deviation 13.01	97 beats per minute Standard Deviation 20.16
Safety and Tolerability - Pulse (Beats Per Minute) 52 weeks	86.5 beats per minute Standard Deviation 14.46	94.2 beats per minute Standard Deviation 19.14

SECONDARY outcome

Timeframe: 13 weeks, 26 weeks, 52 weeks.

Population: Safety set

Respiratory rate (breaths per minute). The normal respiratory rate for elderly individuals living independently is 12-18 breaths per minute while it is 16-25 breaths per minute for those needing long-term care.

Values within the normal range mean good safety and tolerability outcomes.

Outcome measures

Measure	Circadin 2/5/10 mg n=60 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=65 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Safety and Tolerability - Respiratory Rate (Bpm) Baseline	19.2 breaths per minute Standard Deviation 3.40	19.6 breaths per minute Standard Deviation 4.33
Safety and Tolerability - Respiratory Rate (Bpm) 13 weeks	19.2 breaths per minute Standard Deviation 3.38	19.4 breaths per minute Standard Deviation 4.36
Safety and Tolerability - Respiratory Rate (Bpm) 26 weeks	18.7 breaths per minute Standard Deviation 3.77	20 breaths per minute Standard Deviation 4.97
Safety and Tolerability - Respiratory Rate (Bpm) 52 weeks	18.4 breaths per minute Standard Deviation 3.84	18.7 breaths per minute Standard Deviation 4.30

SECONDARY outcome

Timeframe: 13 weeks, 26 weeks, 52 weeks.

Population: Safety Set

Body Temperature (°C). Normal body temperature varies by person, age, activity, and time of day. It ranges from 36.1°C to 37.2°C.

Values within the normal range mean good safety and tolerability outcomes.

Outcome measures

Measure	Circadin 2/5/10 mg n=60 Participants Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)	Placebo n=65 Participants Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Safety and Tolerability - Body Temperature (°C) Baseline	36.69 °C Standard Deviation 0.479612	36.54 °C Standard Deviation 0.684174
Safety and Tolerability - Body Temperature (°C) 13 weeks	36.68 °C Standard Deviation 0.464637	36.63 °C Standard Deviation 0.369984
Safety and Tolerability - Body Temperature (°C) 26 weeks	36.76 °C Standard Deviation 0.459521	36.57 °C Standard Deviation 0.371819
Safety and Tolerability - Body Temperature (°C) 52 weeks	36.70 °C Standard Deviation 0.457630	36.65 °C Standard Deviation 0.439824

Adverse Events

Circadin 2/5/10 mg Double Blind

Serious events: 0 serious events

Other events: 51 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 50 other events

Deaths: 0 deaths

Circadin 2/5/10 mg Open Label

Serious events: 6 serious events

Other events: 80 other events

Deaths: 0 deaths

Serious adverse events

Measure	Circadin 2/5/10 mg Double Blind n=60 participants at risk Circadin 2/5/10 mg. Double blind period, active arm	Placebo n=65 participants at risk Placebo arm	Circadin 2/5/10 mg Open Label n=95 participants at risk Circadin 2/5/10 mg. Open-label period, active arm
Infections and infestations SAE - Serious adverse event	0.00% 0/60 • 104 weeks	1.5% 1/65 • Number of events 1 • 104 weeks	2.1% 2/95 • Number of events 2 • 104 weeks
Gastrointestinal disorders SAE -Serious adverse event	0.00% 0/60 • 104 weeks	0.00% 0/65 • 104 weeks	1.1% 1/95 • Number of events 1 • 104 weeks
Psychiatric disorders SAE -Serious adverse event	0.00% 0/60 • 104 weeks	0.00% 0/65 • 104 weeks	3.2% 3/95 • Number of events 3 • 104 weeks

Other adverse events

Measure	Circadin 2/5/10 mg Double Blind n=60 participants at risk Circadin 2/5/10 mg. Double blind period, active arm	Placebo n=65 participants at risk Placebo arm	Circadin 2/5/10 mg Open Label n=95 participants at risk Circadin 2/5/10 mg. Open-label period, active arm
Respiratory, thoracic and mediastinal disorders Non-serious adverse events	26.7% 16/60 • Number of events 16 • 104 weeks	15.4% 10/65 • Number of events 10 • 104 weeks	38.9% 37/95 • Number of events 50 • 104 weeks
Nervous system disorders Non-serious adverse events	41.7% 25/60 • Number of events 26 • 104 weeks	18.5% 12/65 • Number of events 12 • 104 weeks	44.2% 42/95 • Number of events 51 • 104 weeks
General disorders Non-serious adverse events	38.3% 23/60 • Number of events 28 • 104 weeks	29.2% 19/65 • Number of events 28 • 104 weeks	41.1% 39/95 • Number of events 49 • 104 weeks
Gastrointestinal disorders Non-serious adverse events	25.0% 15/60 • Number of events 15 • 104 weeks	23.1% 15/65 • Number of events 18 • 104 weeks	42.1% 40/95 • Number of events 58 • 104 weeks
Psychiatric disorders Non-serious adverse events	35.0% 21/60 • Number of events 22 • 104 weeks	27.7% 18/65 • Number of events 20 • 104 weeks	37.9% 36/95 • Number of events 47 • 104 weeks
Skin and subcutaneous tissue disorders Non-serious adverse events	5.0% 3/60 • Number of events 3 • 104 weeks	4.6% 3/65 • Number of events 3 • 104 weeks	10.5% 10/95 • Number of events 10 • 104 weeks
Infections and infestations Non-serious adverse events	15.0% 9/60 • Number of events 9 • 104 weeks	10.8% 7/65 • Number of events 8 • 104 weeks	48.4% 46/95 • Number of events 61 • 104 weeks

Additional Information

Dr. Tali Nir

Neurim Pharmaceuticals

Phone: 972-7684902

Email: talin@neurim.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place