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

NCT ID: NCT01906866

Last Updated: 2024-04-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 125 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-10-31
• Study Completion Date: 2018-03-27

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.

Conditions

Sleep Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Circadin 2/5/10 mg

Active arm

Group Type: ACTIVE_COMPARATOR

Circadin 2/5/10 mg

Intervention Type: DRUG

Circadin 2/5/10 mg. Active arm

Placebo

Placebo arm

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Control arm

Interventions

Circadin 2/5/10 mg

Circadin 2/5/10 mg. Active arm

Intervention Type: DRUG

Placebo

Control arm

Intervention Type: DRUG

Other Intervention Names

Active arm; Control

Eligibility Criteria

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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Neurim Pharmaceuticals Ltd.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Paul Gringras, PhD

Role: PRINCIPAL_INVESTIGATOR

Thoma's Hospital, Westminster Bridge Rd, London

Robert Findling, MD

Role: PRINCIPAL_INVESTIGATOR

Kennedy Krieger Institute, Baltimore, Maryland, USA

Locations

Southwest Autism Research and Resource Center (SARRC)

Phoenix, Arizona, United States

Crystal BioMedical Research, LLC

Miami Lakes, Florida, United States

Lake Mary Pediatrics

Orange City, Florida, United States

Mate Lazlo

West Palm Beach, Florida, United States

Attalla Consultants LLC, dba Institue for Behabiovral medicine

Smyrna, Georgia, United States

AMR Baber research INC

Naperville, Illinois, United States

Kennedy Krieger Institute

Baltimore, Maryland, United States

Child Neurology Specialists/ CRCN

Henderson, Nevada, United States

Clinical research center of New Jersey, LLC

Voorhees Township, New Jersey, United States

Geinsinger Clinic

Danville, Pennsylvania, United States

The children's hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Vanderbilt University

Nashville, Tennessee, United States

INSITE Clinical Research

DeSoto, Texas, United States

Red Oak Psychiatry Associates

Houston, Texas, United States

Sleep Therapy & Research Center

San Antonio, Texas, United States

Road Runner Research, Ltd

San Antonio, Texas, United States

Ericksen Research & Development

Clinton, Utah, United States

Pacific institute of medical science

Bothell, Washington, United States

Helsinki Sleep Clinic Vitalmed OY

Helsinki, , Finland

Hospital Raymond Poincare

Garches, , France

Strasbourg University Hospital Depatment of Child Psychiatry & Neurology

Strasbourg, , France

Yulius Mental Health Organization

Dordrecht, , Netherlands

Hospital Gelderse Vallei

Ede, , Netherlands

University Medical Center Groningen

Groningen, , Netherlands

Birmingham Childrens Hospital NHS FOUNDATION TRUST

Birmingham, , United Kingdom

Blackpool Victoria Teaching Hospitals NHS Foundation Trust

Blackpool, , United Kingdom

Guy's & St. Thomas's NHS Foundation Trust of St Thomas's Hospital

London, , United Kingdom

University Hospital Southampton NHS Foundation Trust

Southampton, , United Kingdom

Countries

United States; Finland; France; Netherlands; United Kingdom

References

Malow BA, Findling RL, Schroder CM, Maras A, Breddy J, Nir T, Zisapel N, Gringras P. Sleep, Growth, and Puberty After 2 Years of Prolonged-Release Melatonin in Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2021 Feb;60(2):252-261.e3. doi: 10.1016/j.jaac.2019.12.007. Epub 2020 Jan 23.

Reference Type: DERIVED

PMID: 31982581 (View on PubMed)

Gringras P, Nir T, Breddy J, Frydman-Marom A, Findling RL. Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2017 Nov;56(11):948-957.e4. doi: 10.1016/j.jaac.2017.09.414. Epub 2017 Sep 19.

Reference Type: DERIVED

PMID: 29096777 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

NEU_CH_7911

Identifier Type: -

Identifier Source: org_study_id