Sleep Loss and Mechanisms of Impaired Glucose Metabolism

Study Overview
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Brief Summary
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The purpose of this study is to test the effects of sleep and eszopiclone, a drug that helps people sleep, on how the body processes glucose (sugar). Eszopiclone is approved by the U.S. Food and Drug Administration (FDA) for sale for the treatment of insomnia. It is marketed in the United States as LUNESTA. Main Hypothesis: Primary insomnia is associated with impairments of glucose metabolism that can be reversed by two months of eszopiclone for the primary insomnia

Detailed Description
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Insomnia is the most common sleep disorder, affecting nearly one-third of all adults in any given year, and chronically affecting 10-15% of the adult population. Reduced sleep time, independent of insomnia, has been associated with a variety of deleterious long term effects, including an increased risk of incident myocardial infarction and symptomatic diabetes. Chronic partial sleep loss or insomnia may impair glucose metabolism in the short term and are associated with the development of diabetes in the long term. Although the extent of sleep loss is more acute in the laboratory-based 'sleep debt' studies of healthy volunteers, chronic primary insomnia patients exhibit 'hyperarousal' (hypercortisolemia in the afternoon and evening, accelerated metabolism) similar to that seen with acute sleep deprivation. In addition, degradations of sleep quantity and quality in primary insomnia have been attributed to cognitive and somatic hyperarousal in the sleep setting. study examines and quantifies in adult men and women the link between primary insomnia and impaired glucose tolerance. This study examines the extent which adequate treatment of primary insomnia reverses impairments of glucose metabolism. If abnormalities of glucose metabolism are reversible, this study will demonstrate the importance of treatment of chronic primary insomnia.

Official Title
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The Effects of Eszopiclone Treatment (3mg for Two Months) to Counteract the Adverse Metabolic Consequences of Primary Insomnia

Conditions
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Primary Insomnia

Intervention / Treatment
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* Drug: eszopiclone
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 25-55 Complaint of insomnia of at least 6 months duration DSM-IV diagnosis of Primary Insomnia Sleep diary: mean Total Sleep Time < 6 hours and a mean total wake time (sleep latency + wake after sleep onset) of greater than 60 minutes (in previous 14 days as recorded on sleep diary) A willingness to comply with study procedures If of child-bearing potential, using a medically-accepted method of birth control, including abstinence, barrier method with spermicide, steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method, and intrauterine device [IUD]) Exclusion Criteria: Current diagnosis of DSM-IV Axis I disorder other than Primary Insomnia Regular treatment (more than 1 time/week) with CNS active medication within 1 month of fist inpatient visit Treatment with medications that interfere with glucose metabolism including anti-diabetic medications or steroidal contraceptives Uncontrolled medical illness that would interfere with participation in the study Body Mass Index >32 or <19.8 Current symptoms or diagnosis of any moderate to severe sleep disorder other than insomnia No menopausal or peri-menopausal symptoms that disrupt sleep Pregnant, lactating or planning to become pregnant Consumption of > 2 caffeinated beverages per day (including coffee, tea and/or other caffeine-containing beverages or food) during 3 weeks prior to the start of the study

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: eszopiclone (3mg)<br>active medication (eszopiclone 3mg tablet) by mouth nightly 30 min before bed | Drug: eszopiclone<br>* 3mg tablet, by mouth nightly 30 min before bed, for two months<br>* Other names: Lunesta;|
| Placebo Comparator: placebo<br>identical placebo tablet by mouth nightly 30 min before bed | Drug: placebo<br>* inactive placebo tablet, by mouth nightly 30 minutes before bed, for two months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glucose Tolerance (Kg) in Response to Insulin-modified Intravenous Glucose Tolerance Test | Difference in glucose tolerance (Kg) in response to insulin-modified intravenous glucose tolerance test. Glucose tolerance was calculated as the slope of the natural log of declining glucose values from minute 5 to minute 19 post-infusion. By convention, this negative slope is multiplied by -1, in other words, expressed as a rate of disposal. | baseline and 2 months post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Insulin Response to Glucose (AIRg) | Change over two months in 1st phase Insulin secretion | baseline and 2 months post-treatment | 
| Change in Insulin Sensitivity (SI) | Insulin sensitivity index (SI) was defined in quantitative terms as the effect of insulin to catalyse the disappearance of glucose from plasma. [R. Bergman, Horm Res 2005;64(suppl 3):8-15]. SI calculated using Bergman's Minimal model analyses (Minmod Millennium 2000; R. Bergman, University of South- ern California, Los Angeles, CA) | baseline and 2 months post-treatment | 
| Change in Glucose Effectiveness (SG) | Glucose effectiveness was defined as the ability of glucose itself to enhance its own disappearance independent of an increment in insulin. [R. Bergman, Horm Res 2005;64(suppl 3):8-15]. SG calculated using Bergman's Minimal model analyses (Minmod Millennium 2000; R. Bergman, University of South- ern California, Los Angeles, CA) | baseline and 2 months post-treatment | 
| Change in HbA1c Levels | Difference in HbA1c levels following two months treatment with eszopiclone versus placebo | baseline and 2 months post-treatment | 
| Pre-Treatment Leptin Levels | Leptin Levels prior to two months treatment with eszopiclone or placebo, measure after an overnight fast | baseline | 
| Post-treatment Leptin Levels | Leptin levels following two months treatment with 3mg eszopiclone or placebo, measured after an overnight fast | two months post-treatment | 
| Pre-treatment Ghrelin Levels | Ghrelin levels prior to two months treatment with 3mg eszopiclone or placebo, measured after an overnight fast | baseline | 
| Post-treatment Ghrelin Levels | Ghrelin levels following two months treatment with 3mg eszopiclone or placebo, measured after an overnight fast | 2 months post-treatment | 
| Change in Subjective Sleepiness as Measured on the Karolinska Sleepiness Scale (KSS) | At visits before and after two months treatment with 3mg eszopiclone or placebo, subjects completed a short test battery including the Karolinska Sleepiness Scale (KSS) every three hours during wake periods. KSS is a single-item scale of sleepiness on a scale from 1 (very alert) to 9 (very sleepy, fighting sleep, an effort to keep awake). Subjective sleepiness was defined as mean deviation from baseline KSS. | baseline and 2 months post-treatment | 
| Change in Mean Lapses of Attention | At visits before and after two months treatment with 3mg eszopiclone or placebo, subjects completed a short test battery every three hours during wake periods. The battery included the Psychomotor Vigilance Task (PVT). The PVT involved a 10-minute visual reaction time (RT) performance test in which the subject was instructed to maintain the fastest possible RT to a simple visual stimulus. Lapses of attention refer to the number of times the subject failed to respond to the signal within 500ms. Mean lapses per test across 6 tests given a 4 hour intervals during normal waking hours (and not during the IVGTT) during the 30-hr were compared for the post-treatment visit as the absolute deviation from the baseline mean lapses/test. | baseline and 2 months post-treatment | 
| Change in Total Sleep Time as Reported in Sleep Diaries | Total sleep time reported on sleep diaries prior to treatment with 3mg eszopiclone or placebo. Change defined as baseline minus post-treatment). | baseline and 2 months post-treatment | 
| Change in Total Sleep Time Measured by PSG | Change (baseline minus post-treatment) in total sleep time measured by polysomnography after two months treatment with 3mg eszopiclone or placebo | baseline and 2 months post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sleep, metabolism, insulin, glucose, actigraphy, diary, volumetry, GABA