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

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.

Study Overview

• Status: Completed
• Conditions: Sleep Disorders
• Intervention / Treatment: Drug: Placebo; Drug: Circadin 2/5/10 mg

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.

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 3

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland
    • Helsinki Sleep Clinic Vitalmed OY
• France
  • Garches, France
    • Hospital Raymond Poincare
  • Strasbourg,, France
    • Strasbourg University Hospital Depatment of Child Psychiatry & Neurology
• Netherlands
  • Dordrecht, Netherlands
    • Yulius Mental Health Organization
  • Ede, Netherlands
    • Hospital Gelderse Vallei
  • Groningen, Netherlands
    • University Medical Center Groningen
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Childrens Hospital NHS FOUNDATION TRUST
  • Blackpool, United Kingdom
    • Blackpool Victoria Teaching Hospitals NHS Foundation Trust
  • London, United Kingdom
    • Guy's & St. Thomas's NHS Foundation Trust of St Thomas's Hospital
  • Southampton, United Kingdom
    • University Hospital Southampton NHS Foundation Trust
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Southwest Autism Research and Resource Center (SARRC)
  • Florida
    • Miami Lakes, Florida, United States, 33014
      • Crystal BioMedical Research, LLC
    • Orange City, Florida, United States, 32763
      • Lake Mary Pediatrics
    • West Palm Beach, Florida, United States, 33408
      • Mate Lazlo
  • Georgia
    • Smyrna, Georgia, United States, 30080-6315
      • Attalla Consultants LLC, dba Institue for Behabiovral medicine
  • Illinois
    • Naperville, Illinois, United States, 60563
      • AMR Baber research INC
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Kennedy Krieger Institute
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Child Neurology Specialists/ CRCN
  • New Jersey
    • Voorhees, New Jersey, United States, 08043
      • Clinical research center of New Jersey, LLC
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geinsinger Clinic
    • Philadelphia, Pennsylvania, United States, 19104-4399
      • The Children's Hospital of Philadelphia
  • Tennessee
    • Nashville, Tennessee, United States, 37240
      • Vanderbilt University
  • Texas
    • DeSoto, Texas, United States, 75115
      • InSite Clinical Research
    • Houston, Texas, United States, 77090
      • Red Oak Psychiatry Associates
    • San Antonio, Texas, United States, 78229
      • Sleep Therapy & Research Center
    • San Antonio, Texas, United States, 78258
      • Road Runner Research, Ltd
  • Utah
    • Clinton, Utah, United States, 32763
      • Ericksen Research & Development
  • Washington
    • Bothell, Washington, United States, 98011
      • Pacific institute of medical science

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo arm	Drug: Placebo; Control arm; Other Names: Control
Active Comparator: Circadin 2/5/10 mg; Active arm	Drug: Circadin 2/5/10 mg; Circadin 2/5/10 mg. Active arm; Other Names: Active arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep Latency (Mins)	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.	13 weeks
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.	13 weeks
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.	13 weeks
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.	13 weeks
Social Functioning - Children Global Assessment Scale (CGAS)	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.	13 weeks
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.	13 weeks
Number of Dropouts	Number of dropouts during the 13 weeks of double-blind treatment in the Circadin 2/5 mg and placebo arms.	13 weeks
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.	13 weeks
Safety and Tolerability - Treatment Emergent Signs and Symptoms (TESS) Summary.	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.	13 weeks, 26 weeks, 52 weeks.
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.	13 weeks, 26 weeks, 52 weeks.
Safety and Tolerability - Pulse (Beats Per Minute)	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.	13 weeks, 26 weeks, 52 weeks.
Safety and Tolerability - Respiratory Rate (Bpm)	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.	13 weeks, 26 weeks, 52 weeks.
Safety and Tolerability - Body Temperature (°C)	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.	13 weeks, 26 weeks, 52 weeks.

Collaborators and Investigators

• Sponsor: Neurim Pharmaceuticals Ltd.
• Investigators: Principal Investigator: Paul Gringras, PhD, Thoma's Hospital, Westminster Bridge Rd, London; Principal Investigator: Robert Findling, MD, Kennedy Krieger Institute, Baltimore, Maryland, USA

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): March 27, 2018
• Study Completion (Actual): March 27, 2018

Study Registration Dates

• First Submitted: July 11, 2013
• First Submitted That Met QC Criteria: July 21, 2013
• First Posted (Estimated): July 24, 2013

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 21, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Autism Spectrum Disorder; Sleep disturbance; Smith-Magenis Syndrome; Circadian; Angelman Syndrome; tuberous sclerosis; Prolong release melatonin
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Sleep Wake Disorders; Dyssomnias; Parasomnias; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: NEU_CH_7911