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

Sleep Disorders Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01906866
• Other study ID #: NEU_CH_7911
• Status: Completed
• Phase: Phase 3
• Start date: October 2013
• Est. completion date: March 27, 2018

Study information

• Verified date: April 2024
• Source: Neurim Pharmaceuticals Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 125
• Est. completion date: March 27, 2018
• Est. primary completion date: March 27, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 17 Years

Eligibility

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 ß-blockers. (Only morning administration of ß-blockers is allowed since ß-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

Related Conditions & MeSH terms

• Dyssomnias
• Parasomnias
• Sleep Disorders
• Sleep Wake Disorders

Intervention

Drug:
• Circadin 2/5/10 mg
Circadin 2/5/10 mg. Active arm
• Placebo
Control arm

Locations

Country	Name	City	State
Finland	Helsinki Sleep Clinic Vitalmed OY	Helsinki
France	Hospital Raymond Poincare	Garches
France	Strasbourg University Hospital Depatment of Child Psychiatry & Neurology	Strasbourg,
Netherlands	Yulius Mental Health Organization	Dordrecht
Netherlands	Hospital Gelderse Vallei	Ede
Netherlands	University Medical Center Groningen	Groningen
United Kingdom	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 States	Kennedy Krieger Institute	Baltimore	Maryland
United States	Pacific institute of medical science	Bothell	Washington
United States	Ericksen Research & Development	Clinton	Utah
United States	Geinsinger Clinic	Danville	Pennsylvania
United States	INSITE Clinical Research	DeSoto	Texas
United States	Child Neurology Specialists/ CRCN	Henderson	Nevada
United States	Red Oak Psychiatry Associates	Houston	Texas
United States	Crystal BioMedical Research, LLC	Miami Lakes	Florida
United States	AMR Baber research INC	Naperville	Illinois
United States	Vanderbilt University	Nashville	Tennessee
United States	Lake Mary Pediatrics	Orange City	Florida
United States	The children's hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Southwest Autism Research and Resource Center (SARRC)	Phoenix	Arizona
United States	Road Runner Research, Ltd	San Antonio	Texas
United States	Sleep Therapy & Research Center	San Antonio	Texas
United States	Attalla Consultants LLC, dba Institue for Behabiovral medicine	Smyrna	Georgia
United States	Clinical research center of New Jersey, LLC	Voorhees	New Jersey
United States	Mate Lazlo	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Neurim Pharmaceuticals Ltd.

Countries where clinical trial is conducted

United States,  Finland,  France,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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	13 weeks
Secondary	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
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.	13 weeks
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.	13 weeks
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.	13 weeks
Secondary	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
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.	13 weeks
Secondary	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
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.	13 weeks
Secondary	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.
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.	13 weeks, 26 weeks, 52 weeks.
Secondary	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.
Secondary	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.
Secondary	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.