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Efficacy and Safety of Circadin® 2 mg in the Treatment of Primary Insomnia Patients

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ClinicalTrials.gov Identifier: NCT00397189
Recruitment Status : Completed
First Posted : November 8, 2006
Results First Posted : March 28, 2011
Last Update Posted : May 1, 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 Primary Insomnia
Interventions Drug: Circadin
Drug: placebo circadin
Enrollment 930
Recruitment Details The first patient entered the study on 24 October 2006 and the last patient completed the study (safety follow up) on 2 December 2008 (last patient completed the last visit on 24 October 2008).
Pre-assignment Details 930 patients were enrolled into the study and entered the run-in period; 139 of these patients were discontinued during the run-in period. The main reasons for discontinuation from the run-in were unwillingness to continue and ineligible to continue. Treatment periods were 3 weeks double-blind (DB) (1:1) and extension period 26 weeks DB (3:1)
Arm/Group Title Circadin Placebo
Hide Arm/Group Description Prolonged release melatonin 2 mg. Tablets should be taken 1-2 hours before going to bed. Identical tablets to Circadin. Tablets should be taken 1-2 hours before going to bed.
Period Title: 3 Weeks Period
Started 394 395
Completed 373 [1] 373 [2]
Not Completed 21 22
Reason Not Completed
Lost to Follow-up             5             4
Adverse Event             3             2
Withdrawal by Subject             13             9
Physician Decision             0             2
Protocol Violation             0             3
Other             0             2
[1]
out of 373, 360 were included in the ITT population detailed in the Baseline Characteristics.
[2]
out of 373, 362 were included in the ITT population detailed in the Baseline Characteristics
Period Title: Extension Period
Started 534 [1] 177 [2]
Completed 421 134
Not Completed 113 43
[1]
Not all completers continued to extension as only patients who wished to proceed were randomized.
[2]
Please note randomization ratio in extension is 3:1
Arm/Group Title Circadin Placebo Total
Hide Arm/Group Description Prolonged release melatonin 2 mg. Tablets should be taken 1-2 hours before going to bed. Identical tablets to Circadin. Tablets should be taken 1-2 hours before going to bed. Total of all reporting groups
Overall Number of Baseline Participants 360 362 722
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 360 participants 362 participants 722 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
223
  61.9%
218
  60.2%
441
  61.1%
>=65 years
137
  38.1%
144
  39.8%
281
  38.9%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 360 participants 362 participants 722 participants
61.9  (10) 61.5  (10.5) 61.7  (10.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 360 participants 362 participants 722 participants
Female
253
  70.3%
244
  67.4%
497
  68.8%
Male
107
  29.7%
118
  32.6%
225
  31.2%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United Kingdom Number Analyzed 360 participants 362 participants 722 participants
360 362 722
1.Primary Outcome
Title The Change From Baseline in Subjective Sleep Latency.
Hide Description Sleep latency (SL) after 3 weeks of treatment was assessed by Patient Daily Sleep Diary (National sleep foundation sleep diary). The patients reported subjectively of their SL. The Sleep Diary question 3 (SL) was summarised at baseline (end of the two-week run-in period) and after three weeks double-blind treatment (actual and change from baseline) for each treatment group using descriptive statistics. At each visit, the mean of the seven days prior to the visit were used. For each treatment group, the mean score at visit 3 was compared, adjusting for the visit 2 score. An ANCOVA model was used. Lower score indicates reduction in sleep latency and thus considered improvement
Time Frame Baseline and 3 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Pre-planned analysis on ITT population age 65-80
Arm/Group Title Circadin Placebo
Hide Arm/Group Description:
Prolonged release melatonin 2 mg. Tablets should be taken 1-2 hours before going to bed.
Identical tablets to Circadin. Tablets should be taken 1-2 hours before going to bed.
Overall Number of Participants Analyzed 137 144
Mean (Standard Deviation)
Unit of Measure: minutes
-19.1  (47.3) -1.7  (47.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Circadin, Placebo
Comments The analysis was a comparison of sleep latency as measured by the sleep diary at Visit 3 in the ITT 65-80 population, using a linear regression model with terms for treatment (Circadin® 2mg vs. Placebo) and baseline sleep latency.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -15.6
Confidence Interval (2-Sided) 95%
-25.3 to -6
Parameter Dispersion
Type: Standard Deviation
Value: 47
Estimation Comments [Not Specified]
2.Secondary Outcome
Title The Change From Baseline in Subjective Sleep Maintenance.
Hide Description Sleep maintenance as measured by number of awakening (NOA) after 3 weeks of treatment was assessed by Patient Daily Sleep Diary (National sleep foundation sleep diary). The patients reported subjectively of their NOA. The Sleep Diary question 4 (NOA) was summarized at baseline (end of the two-week run-in period) and after three weeks double-blind treatment (actual and change from baseline) for each treatment group using descriptive statistics. At each visit, the mean of the seven days prior to the visit were used. For each treatment group, the mean score at visit 3 was compared, adjusting for the visit 2 score. An ANCOVA model was used. Lower score indicates less awakenings and thus considered improvement.
Time Frame 3 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Circadin Placebo
Hide Arm/Group Description:
Circadin: Prolonged release melatonin 2 mg
placebo circadin: placebo circadin tablets
Overall Number of Participants Analyzed 137 144
Mean (95% Confidence Interval)
Unit of Measure: Awakenings
-0.24
(-0.33 to 0)
-0.09
(-0.33 to 0)
Time Frame 37 weeks (2 weeks baseline, 3 weeks double-blind, 26 weeks double-blind extension period and 2 weeks run-out,AEs were to be reported for up to 30 days after stopping study medication )
Adverse Event Reporting Description The safety variables were assessed at each visit and included spontaneously reported adverse events (AEs); unusual events and AEs recorded by the investigator
 
Arm/Group Title Circadin Placebo
Hide Arm/Group Description Prolonged release melatonin 2 mg. Tablets should be taken 1-2 hours before going to bed. Identical tablets to Circadin. Tablets should be taken 1-2 hours before going to bed.
All-Cause Mortality
Circadin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Circadin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/394 (0.25%)      3/395 (0.76%)    
General disorders     
chest pain  1  0/394 (0.00%)  0 1/395 (0.25%)  1
Infections and infestations     
cellulitis  1  1/394 (0.25%)  1 0/395 (0.00%)  0
upper respiratory tract infection  1  0/394 (0.00%)  0 1/395 (0.25%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
uterine cancer  1  0/394 (0.00%)  0 1/395 (0.25%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (10.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Circadin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   32/394 (8.12%)      42/395 (10.63%)    
Infections and infestations     
nasopharyngitis  1  13/394 (3.30%)  16/395 (4.05%) 
upper respiratory tract infection  1  8/394 (2.03%)  8/395 (2.03%) 
Nervous system disorders     
headache  1  11/394 (2.79%)  18/395 (4.56%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (10.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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
Layout table for Results Point of Contact information
Name/Title: VP clinical and regulatory affairs
Organization: Neurim Pharmaceuticals
Phone: +972-3-6499340
EMail: Talin@neurim.com
Layout table for additonal information
Responsible Party: Neurim Pharmaceuticals Ltd.
ClinicalTrials.gov Identifier: NCT00397189    
Other Study ID Numbers: NEU 112006
First Submitted: November 7, 2006
First Posted: November 8, 2006
Results First Submitted: August 26, 2010
Results First Posted: March 28, 2011
Last Update Posted: May 1, 2018