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

A Randomized, Placebo-controlled Study to Investigate the Efficacy and Safety of Circadin® to Alleviate Sleep Disturbances in Children With Neurodevelopmental Disabilities

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01906866

Enrollment

125

Registered

2013-07-24

Start date

2013-10-31

Completion date

2018-03-27

Last updated

2024-04-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Sleep Disorders

Keywords

Sleep disturbance, Circadian, Prolong release melatonin, Autism Spectrum Disorder, Smith-Magenis Syndrome, Angelman Syndrome, tuberous sclerosis

Brief summary

The purpose of this study is to establish the efficacy and safety of Circadin in children with neurodevelopmental disorders and to determine the dose, this randomized, placebo-controlled study is planned to evaluate the efficacy of a double-blind, 13 week treatment period with Circadin 2/5mg in improving maintenance of sleep, sleep latency and additional parameters in children with neurodevelopmental disabilities. The efficacy and safety of Circadin 2/5 mg will continue to be assessed during an open-label extension period of 13 weeks.

Detailed description

This is a randomized placebo-controlled study in children diagnosed with autism spectrum disorders (ASDs) and neurodevelopmental disabilities caused by neurogenetic diseases. Children who are found to be eligible for the study will follow a 4-week, basic sleep hygiene and behavioral intervention wash-out period, and will continue in a 2-week single-blind (SB) placebo run-in period. Then, they will be randomized in a 1:1 ratio to receive either Circadin® 2 mg or placebo for 3 weeks in a double-blind treatment period. After 3 weeks of treatment, on the last day of Week 5 ±3 days (Visit 3), sleep variables will be assessed to determine if dose modification (an increase to 5 mg) is required. Children will then continue on 2 or 5 mg of Circadin® or placebo for an additional double-blind period of 10 weeks. This double-blind period will be followed by an open-label period of 13 weeks. At the end of the 13-week open-label period on the last day of Week 28 ±3 days (Visit 5), sleep variables will be assessed to determine if a potential additional dose modification (i.e., an increase either to 5 mg for patients who are still on 2 mg or an increase to 10 mg for patients who are on 5 mg) is necessary (If a dose increase is decided upon, the dose increase should be from 2 mg to 5 mg, or 5 mg to 10 mg). Children will continue at 2, 5, or 10 mg Circadin® in an open-label period for another 78 weeks of follow-up, which will include continuous safety monitoring and 2 efficacy assessment time points at Weeks 41 and 54. The study will end with a 2-week SB placebo run-out period. Each patient will participate in the study until the end of the second open-label safety follow-up period, and 2 week run-out period. The study duration will be 112 weeks, including the 4-week wash-out period with sleep hygiene and behavioral intervention.

Interventions

DRUGCircadin 2/5/10 mg

Circadin 2/5/10 mg. Active arm

DRUGPlacebo

Control arm

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

2 Years to 17 Years

Healthy volunteers

Inclusion criteria

To be eligible for study entry, all patients must satisfy all of the following criteria at screening: 1. Must be children 2 to 17.5 years of age at Visit 2 who comply with taking the study drug 2. Must have written informed consent provided by a legal guardian and assent (if needed) 3. Must have a documented history of ASD according to or consistent with the ICD-10 (International Classification of Diseases) or DSM-5/4 (Diagnostic and Statistical Manual of Mental Disorders) criteria, or neurodevelopmental disabilities caused by neurogenetic diseases (i.e., Smith-Magenis syndrome, Angelman syndrome, Bourneville's disease \[tuberous sclerosis\]) as confirmed by case note review showing that diagnosis was reached through assessment by a community pediatrician or pediatric neurologist or other health care professionals experienced in the diagnosis who took into account early developmental history and school records. 4. Must have current sleep problems including: a minimum of 3 months of impaired sleep defined as ≤6 hours of continuous sleep AND/OR ≥0.5 hour sleep latency from light off in 3 out of 5 nights based on parent reports and patient medical history. (The maintenance and latency problems do not necessarily have to be in the same 3 nights of the week.) 5. May be on a stable dose of non-excluded medication for 3 months, including anti- epileptics, anti-depressants (selective serotonin reuptake inhibitors \[SSRIs\]), stimulants, all mood changing drugs and β-blockers. (Only morning administration of β-blockers is allowed since β-blockers at night have the potential to reduce endogenous melatonin levels and might cause disturbed sleep) 6. The sleep disturbance is not due to the direct physiological effects of any concomitant medications such as SSRIs, stimulants, etc. After completing 4 weeks of sleep hygiene training (for those who need it) and 2 weeks of placebo run-in, patients will be eligible to continue the study if they comply with the following: * Continue to fulfill sleep problem criteria (see Inclusion Criterion 4) based on the completed Sleep and Nap Diary entered into the electronic case report form * Parents demonstrate compliance in Sleep and Nap Diary completion (5 out of 7 nights). Compliance means that in at least 5 out of 7 nights per week (total of 2 weeks before each scheduled visit) the parents complete the diary pages with all mandatory questions * Continue to fulfil all other eligibility criteria

Exclusion criteria

Children who meet any of the following criteria will be excluded from participating in the study: 1. Have had treatment with any form of melatonin within 2 weeks prior to Visit 1 2. Have a known allergy to melatonin or lactose 3. Have a known moderate to severe sleep apnea 4. Have an untreated medical/ineffectively treated/psychological condition that may be the etiology of sleep disturbances 5. Did not respond to previous Circadin® therapy based on past medical history records in the last 2 years 6. Are taking or have been taking prohibited medication within 2 weeks prior to Visit 1 (Section 7.1) 7. Are females of child-bearing potential that are not using contraceptives and/or breastfeeding and that are sexually active (Abstinence is an acceptable method of contraception.) 8. Pregnant females 9. Are currently participating in a clinical trial or have participated in a clinical trial involving medicinal product within the last 3 months prior to the study \[this does not include patients who participated in the Phase I Pharmacokinetics (PK) study who can be already included in the study\] 10. Children with known renal or hepatic insufficiency

Design outcomes

Primary

Measure	Time frame	Description
Total Sleep Time (TST)	13 weeks	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

Secondary

Measure	Time frame	Description
Duration of Wake After Sleep	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.
Number of Awakenings Per Night	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.
Longest Sleep Period	13 weeks	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.
Social Functioning - Children Global Assessment Scale (CGAS)	13 weeks	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.
Behavior at Home and in School - Strengths and Difficulties Questionnaire (SDQ)	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.
Number of Dropouts	13 weeks	Number of dropouts during the 13 weeks of double-blind treatment in the Circadin 2/5 mg and placebo arms.
Sleep Latency (Mins)	13 weeks	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.
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary.	13 weeks, 26 weeks, 52 weeks.	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.
Safety and Tolerability - Blood Pressure (mmHg)	13 weeks, 26 weeks, 52 weeks.	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.
Safety and Tolerability - Pulse (Beats Per Minute)	13 weeks, 26 weeks, 52 weeks.	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.
Safety and Tolerability - Respiratory Rate (Bpm)	13 weeks, 26 weeks, 52 weeks.	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.
Safety and Tolerability - Body Temperature (°C)	13 weeks, 26 weeks, 52 weeks.	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.
Assessment of Sleep Parameters by Actigraphy	13 weeks	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.

Countries

Finland, France, Netherlands, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
Circadin 2/5/10 mg Circadin 2/5/10 mg: Active arm	60
Placebo Placebo arm Placebo	65
Total	125

Baseline characteristics

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

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 60	0 / 65	0 / 95
other Total, other adverse events	51 / 60	50 / 65	80 / 95
serious Total, serious adverse events	0 / 60	1 / 65	6 / 95

Outcome results

Primary

Total Sleep Time (TST)

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

Time frame: 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.

Arm	Measure	Value (MEAN)
Circadin 2/5/10 mg	Total Sleep Time (TST)	51.03 minutes
Placebo	Total Sleep Time (TST)	18.71 minutes

p-value: =0.03595% CI: [2.38, 62.26]Mixed Models Analysis

Secondary

Assessment of Sleep Parameters by Actigraphy

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.

Time frame: 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.

Arm	Measure	Group	Value (MEAN)	Dispersion
Circadin 2/5/10 mg	Assessment of Sleep Parameters by Actigraphy	Change in TST (total sleep time)	7.23 minutes	Standard Deviation 96.521
Circadin 2/5/10 mg	Assessment of Sleep Parameters by Actigraphy	Change in sleep latency	25.11 minutes	Standard Deviation 38.371
Placebo	Assessment of Sleep Parameters by Actigraphy	Change in TST (total sleep time)	-23.94 minutes	Standard Deviation 61.86
Placebo	Assessment of Sleep Parameters by Actigraphy	Change in sleep latency	-12.50 minutes	Standard Deviation 24.744

Secondary

Behavior at Home and in School - Strengths and Difficulties Questionnaire (SDQ)

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.

Time frame: 13 weeks

Arm	Measure	Value (MEAN)	Dispersion
Circadin 2/5/10 mg	Behavior at Home and in School - Strengths and Difficulties Questionnaire (SDQ)	19.6 score on a scale	Standard Deviation 5.09
Placebo	Behavior at Home and in School - Strengths and Difficulties Questionnaire (SDQ)	20.7 score on a scale	Standard Deviation 6.09

p-value: 0.077MMRM

Secondary

Duration of Wake After Sleep

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.

Time frame: 13 weeks

Arm	Measure	Group	Value (MEAN)	Dispersion
Circadin 2/5/10 mg	Duration of Wake After Sleep	Baseline	64.4 minutes	Standard Deviation 24.421
Circadin 2/5/10 mg	Duration of Wake After Sleep	13 weeks	68.75 minutes	Standard Deviation 32.199
Placebo	Duration of Wake After Sleep	Baseline	64.89 minutes	Standard Deviation 32.525
Placebo	Duration of Wake After Sleep	13 weeks	70.89 minutes	Standard Deviation 51.59

Secondary

Longest Sleep Period

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.

Time frame: 13 weeks

Population: FAS (Full analysis set)

Arm	Measure	Group	Value (MEAN)	Dispersion
Circadin 2/5/10 mg	Longest Sleep Period	Baseline	383.79 minutes	Standard Deviation 117.677
Circadin 2/5/10 mg	Longest Sleep Period	13 weeks	451.45 minutes	Standard Deviation 124.933
Placebo	Longest Sleep Period	Baseline	380.58 minutes	Standard Deviation 118.429
Placebo	Longest Sleep Period	13 weeks	414.65 minutes	Standard Deviation 124.993

Comparison: Mixed Models for Repeated Measures (MMRM) analysisp-value: 0.053MMRM

p-value: 0.039MI analysis

Secondary

Number of Awakenings Per Night

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.

Time frame: 13 weeks

Arm	Measure	Group	Value (MEAN)	Dispersion
Circadin 2/5/10 mg	Number of Awakenings Per Night	Baseline	2.11 Number of awakenings per night	Standard Deviation 1.655
Circadin 2/5/10 mg	Number of Awakenings Per Night	13 weeks	2.37 Number of awakenings per night	Standard Deviation 2.095
Placebo	Number of Awakenings Per Night	Baseline	1.92 Number of awakenings per night	Standard Deviation 1.441
Placebo	Number of Awakenings Per Night	13 weeks	2.14 Number of awakenings per night	Standard Deviation 1.895

Secondary

Number of Dropouts

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

Time frame: 13 weeks

Population: Safety set

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Circadin 2/5/10 mg	Number of Dropouts	9 Participants
Placebo	Number of Dropouts	21 Participants

p-value: 0.04Chi-squared

Secondary

Safety and Tolerability - Blood Pressure (mmHg)

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.