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

NCT01906866 | Completed Phase 3 Results DMC

• 1 other identifier: NEU_CH_7911
• Study Type: interventional
• Target: 125
• Locations: 5 countries
• Sites: 28

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.

Conditions

Sleep Disorders

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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

  13 weeks

Secondary Outcomes (13)

• Sleep Latency (Mins)

  13 weeks

• Duration of Wake After Sleep

  13 weeks

• Number of Awakenings Per Night

  13 weeks

• Longest Sleep Period

  13 weeks

• Social Functioning - Children Global Assessment Scale (CGAS)

  13 weeks

Study Arms (2)

Circadin 2/5/10 mg

ACTIVE COMPARATOR

Active arm

Drug: Circadin 2/5/10 mg

Placebo

PLACEBO COMPARATOR

Placebo arm

Drug: Placebo

Interventions

Circadin 2/5/10 mg DRUG

Circadin 2/5/10 mg. Active arm

Also known as: Active arm

Circadin 2/5/10 mg

Placebo DRUG

Control arm

Also known as: Control

Placebo

Eligibility Criteria

• Age: 2 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• To be eligible for study entry, all patients must satisfy all of the following criteria at screening:
• Must be children 2 to 17.5 years of age at Visit 2 who comply with taking the study drug
• Must have written informed consent provided by a legal guardian and assent (if needed)
• 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.
• 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.)
• 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)
• 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:
• 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

You may not qualify if:

• Children who meet any of the following criteria will be excluded from participating in the study:
• Have had treatment with any form of melatonin within 2 weeks prior to Visit 1
• Have a known allergy to melatonin or lactose
• Have a known moderate to severe sleep apnea
• Have an untreated medical/ineffectively treated/psychological condition that may be the etiology of sleep disturbances
• Did not respond to previous Circadin® therapy based on past medical history records in the last 2 years
• Are taking or have been taking prohibited medication within 2 weeks prior to Visit 1 (Section 7.1)
• 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.)
• Pregnant females
• 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 \[this does not include patients who participated in the Phase I Pharmacokinetics (PK) study who can be already included in the study\]
• Children with known renal or hepatic insufficiency

Sponsors & Collaborators

• Neurim Pharmaceuticals Ltd.: lead

Study Sites (28)

Southwest Autism Research and Resource Center (SARRC)

Phoenix, Arizona, 85006, United States

Location

Crystal BioMedical Research, LLC

Miami Lakes, Florida, 33014, United States

Location

Lake Mary Pediatrics

Orange City, Florida, 32763, United States

Location

Mate Lazlo

West Palm Beach, Florida, 33408, United States

Location

Attalla Consultants LLC, dba Institue for Behabiovral medicine

Smyrna, Georgia, 30080-6315, United States

Location

AMR Baber research INC

Naperville, Illinois, 60563, United States

Location

Kennedy Krieger Institute

Baltimore, Maryland, 21205, United States

Location

Child Neurology Specialists/ CRCN

Henderson, Nevada, 89052, United States

Location

Clinical research center of New Jersey, LLC

Voorhees Township, New Jersey, 08043, United States

Location

Geinsinger Clinic

Danville, Pennsylvania, 17822, United States

Location

The children's hospital of Philadelphia

Philadelphia, Pennsylvania, 19104-4399, United States

Location

Vanderbilt University

Nashville, Tennessee, 37240, United States

Location

INSITE Clinical Research

DeSoto, Texas, 75115, United States

Location

Red Oak Psychiatry Associates

Houston, Texas, 77090, United States

Location

Sleep Therapy & Research Center

San Antonio, Texas, 78229, United States

Location

Road Runner Research, Ltd

San Antonio, Texas, 78258, United States

Location

Ericksen Research & Development

Clinton, Utah, 32763, United States

Location

Pacific institute of medical science

Bothell, Washington, 98011, United States

Location

Helsinki Sleep Clinic Vitalmed OY

Helsinki, Finland

Location

Hospital Raymond Poincare

Garches, France

Location

Strasbourg University Hospital Depatment of Child Psychiatry & Neurology

Strasbourg, France

Location

Yulius Mental Health Organization

Dordrecht, Netherlands

Location

Hospital Gelderse Vallei

Ede, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Birmingham Childrens Hospital NHS FOUNDATION TRUST

Birmingham, United Kingdom

Location

Blackpool Victoria Teaching Hospitals NHS Foundation Trust

Blackpool, United Kingdom

Location

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

London, United Kingdom

Location

University Hospital Southampton NHS Foundation Trust

Southampton, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 31982581 DERIVED

• 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.

  PMID: 29096777 DERIVED

MeSH Terms

Conditions

Sleep Wake Disorders; Parasomnias; Autism Spectrum Disorder; Smith-Magenis Syndrome; Angelman Syndrome; Tuberous Sclerosis

Interventions

Melatonin

Condition Hierarchy (Ancestors)

Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Mental Disorders; Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Chronobiology Disorders; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Movement Disorders; Central Nervous System Diseases; Imprinting Disorders; Hamartoma; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Tryptamines; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Dr. Tali Nir
• Organization: Neurim Pharmaceuticals

talin@neurim.com

972-7684902

Study Officials

• Paul Gringras, PhD

  Thoma's Hospital, Westminster Bridge Rd, London

  PRINCIPAL INVESTIGATOR

• Robert Findling, MD

  Kennedy Krieger Institute, Baltimore, Maryland, USA

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 11, 2013
• First Posted: July 24, 2013
• Study Start: October 1, 2013
• Primary Completion: March 27, 2018
• Study Completion: March 27, 2018
• Last Updated: April 23, 2024
• Results First Posted: October 30, 2018

Record last verified: 2024-04

Locations

GB (4); US (18); FR (2); NL (3); FI (1)