To compare the treatment effect of Circadin 2/5 mg to that of placebo on sleep maintenance (TST) as assessed by the Sleep and Nap Diary after 13 weeks of double-blind treatment.
ID
Source
Brief title
Condition
- Sleep disturbances (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy parameter is TST time as assessed by a Sleep and Nap Diary
after the 13-week, double-blind treatment period.
Secondary outcome
* Sleep latency as assessed by a Sleep and Nap Diary after 13 weeks (Week 15)
of double blind treatment
* Duration of wake after sleep onset from the Sleep and Nap Diary after 13
weeks (Week 15) of double blind treatment
* Number of awakenings from the Sleep and Nap Diary after 13 weeks (Week 15) of
double blind treatment
* Longest sleep period from the Sleep and Nap Diary after 13 weeks (Week 15) of
double blind treatment
* Social functioning at home, in school, and in community settings as assessed
by the CGAS after 13 weeks (Week 15) of double
blind treatment
* Behavior at home and in school as assessed by the SDQ after 13 weeks (Week
15) of double blind treatment
* Number of dropouts during the 13 week (Week 15) double blind treatment period
* Assessment of sleep parameters by actigraphy after 13 weeks (Week 15) of
double blind treatment
Background summary
Sleep disturbance is one of the most common complaints in children with autism
spectrum disorder (ASD), mental retardation or other developmental delays. High
prevalence for moderate sleep disturbances in these child populations are
associated with significant sleep problems and subsequent distress for the
families of these children, which in many cases, lead to the decision to
institutionalize the children. Specifically, a frequent cause of families
giving up their care is discontinuous sleep with frequent awakenings throughout
the night. There is a growing body of evidence on abnormal melatonin secretion
in children with neurodevelopmental disorders, which prompted the use of
melatonin to treat sleep disorders in these populations. Several exploratory
studies and case reports have led to strong consensus among researchers that
exogenous melatonin is beneficial for treating chronic sleep disturbances of
children who have neurodevelopmental and neuropsychiatric difficulties.
Study objective
To compare the treatment effect of Circadin 2/5 mg to that of placebo on sleep
maintenance (TST) as assessed by the Sleep and Nap Diary after 13 weeks of
double-blind treatment.
Study design
This is a randomized placebo controlled study in children diagnosed with autism
spectrum disorders (ASDs) and neurodevelopmental disabilities caused by
neurogenetic diseases. Children will have a documented history of these
disorders, as confirmed or consistent with the International Classification of
Diseases (ICD 10) or Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition (Text Revision; DSM 5/4) criteria, having International
Classification of Sleep Disorders (ICSD) criteria based sleep disturbances
modified to take into account the uniqueness of insomnia in the pediatric
population at screening. The children will undergo 4 weeks of basic sleep
hygiene and behavioral intervention, which will serve as a wash out period from
any hypnotics; a gradual withdrawal will take place during the first 2 weeks
and a complete withdrawal of disallowed medications will take place during the
last 2 weeks.
Children who are still found to be eligible for the study after the 4 week,
basic sleep hygiene and behavioral intervention wash out period, will continue
in a 2 week single blind (SB) placebo run in period. In order to be eligible
for the 2 week SB placebo run-in period, the patients will not have responded
to sleep hygiene and behavioral intervention during the first 4 weeks and
therefore will not need to continue this therapy during the study. Children
with a documented history of sleep hygiene and behavioral intervention, who are
still found eligible, will enter directly into the 2 week SB placebo run in
period. After the 4 week sleep hygiene wash out and 2 week SB placebo run in
periods, children who are still found eligible for study participation 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 weekopen 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 (an increase to 5 mg
or 10 mg) is necessary (If a dose increase is decided upon, the dose increase
should be from 2 mg to 5 mg, or from 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. Study duration will
be 112 weeks, including the 4 week wash out period with sleep hygiene and
behavioral intervention.
Circadin and placebo are to be administered orally, 1 portion of minitablets
daily, taken postprandial at 0.5 to 1hour before desired bedtime (bedtime
should be age appropriate bedtime). The minitablets should be swallowed whole
and should not be crushed or halved.
A minimum of 90 children are expected to complete the double-blind and first
open-label period. A minimum of 50 children are expected to complete the second
open-label safety follow-up period.
Intervention
Children who are still found eligible for the study after the 4-week, basic
sleep hygiene and behavioral intervention will continue in a 2-week,
single-blind, placebo run-in period. Children with a documented history of
sleep hygiene and behavioral intervention, who are still found eligible, will
enter directly into a 2-week, single-blind, placebo run-in period. After these
2 periods, children who are still found eligible for study participation will
be randomized in a 1:1 ratio to receive either Circadin 2 mg or placebo for 3
weeks. After 3 weeks of treatment, sleep variables will be assessed to
determine if dose modification (an increase to 5 mg) is required. Children will
then continue on the selected dose of Circadin (2 or 5 mg) 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. Children will continue in the
study for another 78 weeks of follow-up with continuous safety monitoring and
another 2 efficacy assessment time points (at Weeks 41 and 54). At the
beginning of the additional 78 week open-label period (Visit 5), a second
titration opportunity will be introduced (an increase to 10 mg). The study will
end with a 2-week single-blind 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 weeks run-out.
Study burden and risks
The study is designed to investigate if Circadin helps children with autistic
spectrum disorders and neurodevelopmental disabilities caused by neurogenetic
diseases to better fall asleep and to maintain sleep during the night. The
study consists of:
* 4 weeks sleep hygiene and behavioural intervention (which means taking no
medication - will only be performed if not done previously)
* 2 weeks single blind (only the participant will not know what they are
taking) placebo 'wash out' to eliminate certain previous treatments (hypnotics)
which are not allowed during the trial
* 13 weeks double blind (neither the participants or the study team know which
medication is being taken) during which patients will receive either Circadin
or placebo (ratio 1:1); the placebo control is needed to objectively
demonstrate the effects of Circadin. This phase will be double blinded to avoid
any bias.
* 91 weeks of treatment with Circadin (no placebo control anymore)
* 2 weeks single blind placebo run out (to wash out Circadin)
During the study there will be 10 visits during which the following procedures
will be performed:
* Check-ups similar to those done for regular medical care including vital
signs and check for concomitant medications.
* Assessment of puberty status; For female participants, information about
birth control, including a pregnancy test (at certain visits only)
* Providing and checking diaries and actiwatches (diaries have to be completed
daily at home; Actiwatches have to be worn on the wrist at night to measure
activity during the night)
* Inmterview with the parents/guardians for completion of questionnaires (7) by
the inverstigator.
* Providing study medication (the start dose for Circadin is 2 mg and can be
increased to up to 10 mg if needed); the medication has to be taken once daily
before bed time.
No blood samples will be taken for this study.
Habarzel Street 27
Tel Aviv 69710
IL
Habarzel Street 27
Tel Aviv 69710
IL
Listed location countries
Age
Inclusion criteria
1.1. 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 or DSM 5/4 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 inhibitor [SSRIs]), stimulants, all mood changing drugs and * blockers. (Only morning administration of * blockers is allowed since * 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 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 (mandatory questions are marked with an asterisk [*] in Appendix 1).
* Continue to fulfil all other eligibility criteria
Exclusion criteria
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 disallowed 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 PK study who can be already included in the study)
10. Children with known renal or hepatic insufficiency
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-001832-23-NL |
| ClinicalTrials.gov | NCT01906866 |
| CCMO | NL46261.101.14 |