Sleep Loss and Mechanisms of Impaired Glucose Metabolism

Primary Insomnia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00555750
• Other study ID #: BWH-HRC-2005-P-001997
• Secondary ID: ESRC0004M01RR002
• Status: Completed
• Phase: N/A
• First received: November 7, 2007
• Last updated: November 15, 2013
• Start date: March 2006
• Est. completion date: August 2008

Study information

• Verified date: November 2013
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: August 2008
• Est. primary completion date: July 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 25 Years to 55 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Primary Insomnia
• Sleep Initiation and Maintenance Disorders

Intervention

Drug:
• eszopiclone
3mg tablet, by mouth nightly 30 min before bed, for two months
• placebo
inactive placebo tablet, by mouth nightly 30 minutes before bed, for two months

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital, Division of Sleep Medicine	Boston	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	Mclean Hospital, National Center for Research Resources (NCRR), Sunovion

Country where clinical trial is conducted

United States, 

References & Publications (22)

Ayas NT, White DP, Al-Delaimy WK, Manson JE, Stampfer MJ, Speizer FE, Patel S, Hu FB. A prospective study of self-reported sleep duration and incident diabetes in women. Diabetes Care. 2003 Feb;26(2):380-4. — View Citation

Ayas NT, White DP, Manson JE, Stampfer MJ, Speizer FE, Malhotra A, Hu FB. A prospective study of sleep duration and coronary heart disease in women. Arch Intern Med. 2003 Jan 27;163(2):205-9. — View Citation

Beck-Nielsen H, Henriksen JE, Alford F, Hother-Nielson O. In vivo glucose metabolism, insulin secretion and, insulin action in Europids with non-insulin-dependent diabetes mellitus (NIDDM) and their first-degree relatives. Diabet Med. 1996 Sep;13(9 Suppl 6):S78-84. Review. — View Citation

Belenky G, Wesensten NJ, Thorne DR, Thomas ML, Sing HC, Redmond DP, Russo MB, Balkin TJ. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-response study. J Sleep Res. 2003 Mar;12(1):1-12. — View Citation

Boyne MS, Saudek CD. Effect of insulin therapy on macrovascular risk factors in type 2 diabetes. Diabetes Care. 1999 Apr;22 Suppl 3:C45-53. Review. — View Citation

Buxton OM, Spiegel K and Van Cauter E. Modulation of endocrine function and metabolism by sleep and sleep loss. In: Sleep Medicine, edited by Lee-Chiong M, Carskadon M and Sateia M. Philadelphia: Hanley & Belfus, Inc., 2002, p. 59-69.

Buysse DJ, Jarrett DB, Miewald JM, Kupfer DJ, Greenhouse JB. Minute-by-minute analysis of REM sleep timing in major depression. Biol Psychiatry. 1990 Nov 15;28(10):911-25. — View Citation

Czeisler CA, Winkelman JW and Richardson GS. Disorders of sleep and circadian rhythms. In: Harrison's Principles of Internal Medicine, edited by Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL and Jameson JL. New York: McGraw-Hill,Inc., 2000, p. 1-78.

Dijk DJ, Duffy JF, Czeisler CA. Circadian and sleep/wake dependent aspects of subjective alertness and cognitive performance. J Sleep Res. 1992 Jun;1(2):112-7. — View Citation

Dinges DF and Powell JW. Microcomputer analyses of performance on a portable, simple visual RT task during sustained operations. Behavior Research Methods, Instruments & Computers 17: 652-655, 1985.

Dinges DF, Kribbs NB, Bates BL and Carlin MM. A very brief probed-recall memory task: Sensitivity to sleep loss. Sleep Res 22: 330, 1993.

Gillberg M, Kecklund G, Akerstedt T. Relations between performance and subjective ratings of sleepiness during a night awake. Sleep. 1994 Apr;17(3):236-41. — View Citation

Gottlieb DJ, Punjabi NM, Newman AB, Resnick HE, Redline S, Baldwin CM, Nieto FJ. Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med. 2005 Apr 25;165(8):863-7. — View Citation

Hoddes E, Dement WC and Zarcone V. The development and use of the Stanford Sleepiness Scale (SSS). Psychophysiol 9: 150, 1971.

King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998 Sep;21(9):1414-31. — View Citation

King H, Zimmet P. Trends in the prevalence and incidence of diabetes: non-insulin-dependent diabetes mellitus. World Health Stat Q. 1988;41(3-4):190-6. — View Citation

Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002 Dec 4;288(21):2709-16. — View Citation

Nilsson PM, Rööst M, Engström G, Hedblad B, Berglund G. Incidence of diabetes in middle-aged men is related to sleep disturbances. Diabetes Care. 2004 Oct;27(10):2464-9. — View Citation

Simon GE, VonKorff M. Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry. 1997 Oct;154(10):1417-23. — View Citation

Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999 Oct 23;354(9188):1435-9. — View Citation

Spiegel K, Tasali E, Penev P, Van Cauter E. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004 Dec 7;141(11):846-50. — View Citation

Van Dongen HP, Maislin G, Mullington JM, Dinges DF. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep. 2003 Mar 15;26(2):117-26. Erratum in: Sleep. 2004 Jun 15;27(4):600. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Acute Insulin Response to Glucose (AIRg)	Change over two months in 1st phase Insulin secretion	baseline and 2 months post-treatment	No
Secondary	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	No
Secondary	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	No
Secondary	Change in HbA1c Levels	Difference in HbA1c levels following two months treatment with eszopiclone versus placebo	baseline and 2 months post-treatment	No
Secondary	Pre-Treatment Leptin Levels	Leptin Levels prior to two months treatment with eszopiclone or placebo, measure after an overnight fast	baseline	No
Secondary	Post-treatment Leptin Levels	Leptin levels following two months treatment with 3mg eszopiclone or placebo, measured after an overnight fast	two months post-treatment	No
Secondary	Pre-treatment Ghrelin Levels	Ghrelin levels prior to two months treatment with 3mg eszopiclone or placebo, measured after an overnight fast	baseline	No
Secondary	Post-treatment Ghrelin Levels	Ghrelin levels following two months treatment with 3mg eszopiclone or placebo, measured after an overnight fast	2 months post-treatment	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No