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

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ClinicalTrials.gov Identifier: NCT01906866
Recruitment Status : Completed
First Posted : July 24, 2013
Results First Posted : October 30, 2018
Last Update Posted : October 30, 2018
Sponsor:
Information provided by (Responsible Party):
Neurim Pharmaceuticals Ltd.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Sleep Disorders
Interventions Drug: Circadin 2/5/10 mg
Drug: Placebo
Enrollment 125
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Circadin 2/5/10 mg Placebo
Hide Arm/Group Description Circadin 2/5/10 mg: Active arm

Placebo arm

Placebo

Period Title: Overall Study
Started 60 65
Completed 51 44
Not Completed 9 21
Arm/Group Title Circadin 2/5/10 mg Placebo Total
Hide Arm/Group Description Circadin 2/5/10 mg: Active arm

Placebo arm

Placebo

Total of all reporting groups
Overall Number of Baseline Participants 60 65 125
Hide Baseline Analysis Population Description
All patients in the Safety Analysis Set who satisfied all major entry criteria (Criteria 1-5) and who had a valid mean TST result recorded for baseline and at least one post-baseline period assessment during the double blind phase. Patients were classified according to randomized treatment. This analysis set was used for all efficacy analysis
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 60 participants 65 participants 125 participants
<=18 years
60
 100.0%
65
 100.0%
125
 100.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 60 participants 65 participants 125 participants
9  (4.08) 8.4  (4.24) 8.7  (4.15)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 60 participants 65 participants 125 participants
Female
15
  25.0%
18
  27.7%
33
  26.4%
Male
45
  75.0%
47
  72.3%
92
  73.6%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 60 participants 65 participants 125 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
2
   3.1%
2
   1.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   1.7%
8
  12.3%
9
   7.2%
White
57
  95.0%
55
  84.6%
112
  89.6%
More than one race
2
   3.3%
0
   0.0%
2
   1.6%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 60 participants 65 participants 125 participants
Netherlands 5 4 9
United States 44 50 91
Finland 0 1 1
United Kingdom 8 8 16
France 3 2 5
1.Primary Outcome
Title The Total Sleep Time Will be Measured for the Circadin 2/5 mg and Placebo by a Sleep and Nap Diary Questionnaire After the 13 Week, Double-blind Treatment Period.
Hide Description Total Sleep Time - To compare the treatment effect of Circadin® 2/5 mg minitablets to that of placebo on total sleep time (TST) as assessed by the Sleep and Nap Diary after 13 weeks of double-blind treatment
Time Frame 13 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients in the Safety Analysis Set who satisfied all major entry criteria (I.Criteria 1-5) and who had a valid mean TST result recorded for baseline and at least one post-baseline period assessment during the double blind phase. Patients were classified according to randomized treatment. This analysis set was used for all efficacy analyses
Arm/Group Title Circadin 2/5/10 mg Placebo
Hide Arm/Group Description:
Circadin 2/5/10 mg: Active arm Units: minutes arithmetic mean (standard error): 51.03 (±10.46)
Placebo arm Units: minutes arithmetic mean (standard error): 18.71 (±10.82)
Overall Number of Participants Analyzed 58 61
Mean (95% Confidence Interval)
Unit of Measure: minutes
51.03
(30.3 to 71.76)
18.71
(-2.73 to 40.15)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Circadin 2/5/10 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.035
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 32.32
Confidence Interval (2-Sided) 95%
2.38 to 62.26
Parameter Dispersion
Type: Standard Error of the Mean
Value: 15.1
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Sleep Latency Will be Measured for the Circadin 2/5 mg and Placebo by a Sleep and Nap Diary After 13 Weeks of Double-blind Treatment.
Hide Description questionnaire - To compare the treatment effect of Circadin® 2/5 mg minitablets to that of placebo on sleep latency as derived from a Sleep and Nap Diary after 13 weeks of double-blind treatment
Time Frame 13 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients in the Safety Analysis Set who satisfied all major entry criteria (I.Criteria 1-5) and who had a valid mean TST result recorded for baseline and at least one post-baseline period assessment during the double blind phase. Patients were classified according to randomized treatment. This analysis set was used for all efficacy analyses
Arm/Group Title Circadin 2/5/10 mg Placebo
Hide Arm/Group Description:
Circadin 2/5/10 mg: Active arm

Placebo arm

Placebo

Overall Number of Participants Analyzed 58 61
Mean (Standard Error)
Unit of Measure: minutes
-37.77  (6.816) -12.57  (7.005)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Circadin 2/5/10 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.011
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -25.2
Confidence Interval (2-Sided) 95%
-44.61 to -5.8
Parameter Dispersion
Type: Standard Error of the Mean
Value: 9.787
Estimation Comments [Not Specified]
3.Secondary Outcome
Title The Duration of Wake After Sleep Onset Period Will be Measured for the Circadin 2/5 mg and Placebo by a Sleep and Nap Diary After 13 Weeks of Double-blind Treatment.
Hide Description Questionnaire
Time Frame up to 1.5 years
Outcome Measure Data Not Reported
4.Secondary Outcome
Title The Number of Awakenings During the Night Will be Measured for the Circadin 2/5 mg and Placebo by a Sleep and Nap Diary After 13 Weeks of Double-blind Treatment.
Hide Description Questionnaire
Time Frame up to 1.5 years
Outcome Measure Data Not Reported
5.Secondary Outcome
Title The Duration of the Longest Sleep Period Will be Measured for the Circadin 2/5 mg and Placebo by a Sleep and Nap Diary After 13 Weeks of Double-blind Treatment.
Hide Description Questionnaire
Time Frame up to 1.5 Years
Outcome Measure Data Not Reported
6.Secondary Outcome
Title The Children's Social Functioning at Home, in School, and Community Settings Will be Measured for the Circadin 2/5 mg and Placebo by the Children Global Assessment Scale (CGAS) Questionnaire After 13 Weeks of Double-blind Treatment.
Hide Description Questionnaire
Time Frame up to 1.5 years
Outcome Measure Data Not Reported
7.Secondary Outcome
Title The Children's Behavior at Home, in School, and Community Will be Measured for the Circadin 2/5 mg and Placebo by the Strength of Difficulties Questionnaire (SDQ) Questionnaire Filled Out by the Parents After 13 Weeks of Double-blind Treatment.
Hide Description Questionnaire
Time Frame up to 1.5 years
Outcome Measure Data Not Reported
8.Secondary Outcome
Title The Number of Dropouts Between Circadin 2/5 mg to That of Placebo Will be Compared During the 13 Weeks of Double-blind Treatment.
Hide Description [Not Specified]
Time Frame up to 1.5 years
Outcome Measure Data Not Reported
9.Secondary Outcome
Title Sleep Parameters (Rest/Activity Cycles) Will be Measured for the Circadin 2/5 mg and Placebo as Measured by Actigraphy After 13 Weeks of Double-blind Treatment.
Hide Description The Actigraph will be worn on the wrist at night and collect the Sleep parameters
Time Frame up to 1.5 years
Outcome Measure Data Not Reported
10.Secondary Outcome
Title Safety and Tolerability Throughout the Study Will be Measured for the Circadin 2/5 mg and Placebo Throughout the Study Using AE Eliciting Method Treatment Emergent Signs and Symptoms (TESS)
Hide Description Questionnaire
Time Frame up to 2.5 years
Outcome Measure Data Not Reported
11.Secondary Outcome
Title The Following Vital Signs Will be Measured: Blood Pressure, Pulse, Breathing and Body Temperature. They Will be Compared Between the Circadin and Placebo Groups.
Hide Description [Not Specified]
Time Frame up to 2.5 years
Outcome Measure Data Not Reported
Time Frame 104 weeks
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Circadin 2/5/10 mg Double Blind Placebo Circadin 2/5/10 mg Open Label
Hide Arm/Group Description Circadin 2/5/10 mg: Active arm

Placebo arm

Placebo

Circadin 2/5/10 mg Open label
All-Cause Mortality
Circadin 2/5/10 mg Double Blind Placebo Circadin 2/5/10 mg Open Label
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/60 (0.00%)      0/65 (0.00%)      0/95 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Circadin 2/5/10 mg Double Blind Placebo Circadin 2/5/10 mg Open Label
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/60 (0.00%)      1/65 (1.54%)      6/95 (6.32%)    
Gastrointestinal disorders       
SAE -Serious adverse event  1 [1]  0/60 (0.00%)  0/65 (0.00%)  0 1/95 (1.05%)  1
Infections and infestations       
SAE - Serious adverse event  1 [2]  0/60 (0.00%)  1/65 (1.54%)  1 2/95 (2.11%)  2
Psychiatric disorders       
SAE -Serious adverse event  1 [3]  0/60 (0.00%)  0/65 (0.00%)  3/95 (3.16%)  3
1
Term from vocabulary, MedDRA (18.0)
Indicates events were collected by systematic assessment
[1]
CONSTIPATION
[2]
PNEUMONIA EYE INFECTION OTITIS MEDIA ACUTE
[3]
AGGRESSION OPPOSITIONAL DEFIANT DISORDER Abnormal behaviour
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Circadin 2/5/10 mg Double Blind Placebo Circadin 2/5/10 mg Open Label
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   51/60 (85.00%)      50/65 (76.92%)      80/95 (84.21%)    
Gastrointestinal disorders       
Non-serious adverse events  1 [1]  15/60 (25.00%)  15 15/65 (23.08%)  18 40/95 (42.11%)  58
General disorders       
Non-serious adverse events  1 [2]  23/60 (38.33%)  28 19/65 (29.23%)  28 39/95 (41.05%)  49
Infections and infestations       
Non-serious adverse events  1 [3]  9/60 (15.00%)  9 7/65 (10.77%)  8 46/95 (48.42%)  61
Nervous system disorders       
Non-serious adverse events  1 [4]  25/60 (41.67%)  26 12/65 (18.46%)  12 42/95 (44.21%)  51
Psychiatric disorders       
Non-serious adverse events  1 [5]  21/60 (35.00%)  22 18/65 (27.69%)  20 36/95 (37.89%)  47
Respiratory, thoracic and mediastinal disorders       
Non-serious adverse events  1 [6]  16/60 (26.67%)  16 10/65 (15.38%)  10 37/95 (38.95%)  50
Skin and subcutaneous tissue disorders       
Non-serious adverse events  1 [7]  3/60 (5.00%)  3 3/65 (4.62%)  3 10/95 (10.53%)  10
1
Term from vocabulary, MedDRA (18.0)
Indicates events were collected by systematic assessment
[1]
VOMITING DIARRHOEA NAUSEA CONSTIPATION
[2]
FATIGUE PYREXIA HANGOVER
[3]
UPPER RESPIRATORY TRACT INFECTION INFLUENZA OTITIS MEDIA GASTROENTERITIS NASOPHARYNGITIS SINUSITIS
[4]
SOMNOLENCE HEADACHE
[5]
MOOD SWINGS AGITATION ANXIETY AGGRESSION
[6]
COUGH DYSPNOEA ASTHMA RHINORRHOEA
[7]
Rash
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Tali Nir
Organization: Neurim Pharmaceuticals
Phone: 972-7684902
Responsible Party: Neurim Pharmaceuticals Ltd.
ClinicalTrials.gov Identifier: NCT01906866     History of Changes
Other Study ID Numbers: NEU_CH_7911
First Submitted: July 11, 2013
First Posted: July 24, 2013
Results First Submitted: October 2, 2018
Results First Posted: October 30, 2018
Last Update Posted: October 30, 2018