Primary Insomnia
Conditions
Keywords
Primary insomnia as defined by DSM IV criteria
Brief summary
This is a randomised, placebo controlled study to evaluate the efficacy of a 3 week treatment period with Circadin® 2 mg in shortening sleep latency in patients with primary insomnia aged 18-80 with melatonin deficiency.
Detailed description
Studies throughout the world have shown that insomnia is a common complaint that occurs in 10-50% of the population depending on age, sex and country. Among the wide variety of available treatments of sleep disturbances, the most commonly prescribed hypnotics are the benzodiazepines (BZD) and non-BZD hypnotics. However, these hypnotics were often associated with rebound, dependency, tolerance, higher risk of falls mainly in the elderly population, anterograde memory disturbances and increased risk for motor accidents the next day. In response to the unmet clinical need for a safe and efficacious alternative treatment for primary insomnia, that in addition to treating quantitative sleep problems, would improve sleep quality and daytime functioning, a clinical development program on melatonin for the treatment of primary insomnia was initiated. This study is conducted using a randomised, double-blind, placebo controlled parallel group design, after a single-blind placebo period. Primary insomnia patients aged 18-80 will be screened for entry into the study. After the initial 3 weeks double-blind treatment period, patients will be given the option to enter a six-month double-blind continuation study. Primary parameter is sleep latency, secondary parameter is sleep maintenance. Exploratory parameters are total sleep time, sleep quality, morning alertness and quality of life.
Interventions
DRUGCircadin
Prolonged release melatonin 2 mg
DRUGplacebo circadin
placebo circadin tablets
Sponsors
Neurim Pharmaceuticals Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female and aged 18-80 years. * Are willing to take a 6-SMT level evaluation test. * Suffering from primary insomnia according to DSM-IV. criteria (307.42 primary insomnia, Appendix 24.3) . * Sleep latency of at least 20 minutes. * Have not been using benzodiazepines (BZD) and non-BZD hypnotics for the past 2 weeks or more. * Have not been using psychotropic treatments for the past 3 months or more. * Are stabilized on non-psychotropic treatments for more than 1 month. * Are willing to sign a written informed consent to participate in the study.
Exclusion criteria
* Use of benzodiazepines or other hypnotics (including psychotropic treatments) during the study and preceding two weeks. * Alcohol intake more than 30 g of pure alcohol per day and any intake after lunch-time. * Pharmacological immunosuppression. * Participation in a clinical trial with any investigational agent within two months prior to study enrollment. * According to DSM IV, subjects belonging to the following groups are excluded: 780.59 (breathing related sleep disorder); 307.45 (circadian rhythm sleep disorder); 307.47 (dyssomnia not otherwise specified); 780.xx (sleep disorder due to general medical condition). * Severe neurological, psychiatric disorders (especially psychosis, anxiety and depression) and alcoholism. * Other serious diseases that could interfere with patient assessment. * Pregnant or breast feeding women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Change From Baseline in Subjective Sleep Latency. | Baseline and 3 weeks | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Change From Baseline in Subjective Sleep Maintenance. | 3 weeks | 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. |
Countries
United Kingdom
Participant flow
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)
Participants by arm
| Arm | Count |
|---|---|
| Circadin Prolonged release melatonin 2 mg. Tablets should be taken 1-2 hours before going to bed. | 360 |
| Placebo Identical tablets to Circadin. Tablets should be taken 1-2 hours before going to bed. | 362 |
| Total | 722 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 3 Weeks Period | Adverse Event | 3 | 2 |
| 3 Weeks Period | Lost to Follow-up | 5 | 4 |
| 3 Weeks Period | Other | 0 | 2 |
| 3 Weeks Period | Physician Decision | 0 | 2 |
| 3 Weeks Period | Protocol Violation | 0 | 3 |
| 3 Weeks Period | Withdrawal by Subject | 13 | 9 |
Baseline characteristics
| Characteristic | Placebo | Circadin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 144 Participants | 137 Participants | 281 Participants |
| Age, Categorical Between 18 and 65 years | 218 Participants | 223 Participants | 441 Participants |
| Age, Continuous | 61.5 years STANDARD_DEVIATION 10.5 | 61.9 years STANDARD_DEVIATION 10 | 61.7 years STANDARD_DEVIATION 10.2 |
| Region of Enrollment United Kingdom | 362 participants | 360 participants | 722 participants |
| Sex: Female, Male Female | 244 Participants | 253 Participants | 497 Participants |
| Sex: Female, Male Male | 118 Participants | 107 Participants | 225 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 394 | 42 / 395 |
| serious Total, serious adverse events | 1 / 394 | 3 / 395 |
Outcome results
Primary
The Change From Baseline in Subjective Sleep Latency.
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
Population: Pre-planned analysis on ITT population age 65-80
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Circadin | The Change From Baseline in Subjective Sleep Latency. | -19.1 minutes | Standard Deviation 47.3 |
| Placebo | The Change From Baseline in Subjective Sleep Latency. | -1.7 minutes | Standard Deviation 47.8 |
Comparison: 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.p-value: <0.0595% CI: [-25.3, -6]ANCOVA
Secondary
The Change From Baseline in Subjective Sleep Maintenance.
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Circadin | The Change From Baseline in Subjective Sleep Maintenance. | -0.24 Awakenings |
| Placebo | The Change From Baseline in Subjective Sleep Maintenance. | -0.09 Awakenings |