Mechanisms of Sleep Latency and Health: The Effect of a Melatonin Receptor Agonist in Inflammation and Insulin Resistance

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02156271
• Collaborator: (none)
• Enrollment: 75
• Arms: 2

Study Details

Study Description

Brief Summary

The purpose of this study is to help scientist better understand the effect of a 12-week single daily evening dose of ramelteon (Rozerem ©), a drug that has been approved by the U.

1. Food and Drug Administration (FDA) for the treatment of insomnia (trouble falling asleep or staying asleep). The study will measure levels of inflammation, fasting insulin and fasting glucose (sugar) in subjects who are taking either ramelteon (8 mg) or placebo.

Condition or Disease	Intervention/Treatment	Phase
Insomnia	Drug: ramelteon; Drug: placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Mechanisms of Sleep Latency and Health: The Effect of a Melatonin Receptor Agonist in Inflammation and Insulin Resistance
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Jun 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: ramelteon Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon.	Drug: ramelteon; Other Names: Rozerem
Placebo Comparator: placebo 15 subjects will be randomized to receive the placebo	Drug: placebo

Outcome Measures

Primary Outcome Measures

1. Sleep Onset Latency (SOL) as Measured by Self Report (Sleep Diary) [Day 89-90]

   The average of a week of sleep onset latency data from the sleep diary filled out in the morning by the participating subjects. Sleep latency is defined as the length of time it takes from lying down for the night until sleep onset.

2. Mean Latency to Persistent Sleep (LPS) Via Polysomnography [Day 89-90]

   Elapsed time from the beginning of the Polysomnography recording to the onset of the first 20 minutes of continuous sleep was measured.

3. Change in Metabolic Syndrome (MetSyn) [Baseline, Day 30, Day 60, Day 89-90]

4. Sleep Onset Latency (SOL) as Measured by Pittsburgh Sleep Qualtiy Index (PSQI) [baseline]

   Subjects completed component 2 of the PSQI questionnaire. Component 2 asks questions about sleep latency and is scored on a scale from 0 (better) to 3 (worse).

5. Sleep Onset Latency (SOL) as Measured by Pittsburgh Sleep Qualtiy Index (PSQI) [day 89 - 90]

   Subjects completed component 2 of the PSQI questionnaire. Component 2 asks questions about sleep latency and is scored on a scale from 0 (better) to 3 (worse).

6. Mean Latency to Persistent Sleep (LPS) Via Polysomnography [Baseline]

   Elapsed time from the beginning of the Polysomnography recording to the onset of the first 20 minutes of continuous sleep was measured.

7. Sleep Onset Latency (SOL) as Measured by Self Report (Sleep Diary) [Baseline]

   The average of a week of sleep onset latency data from the sleep diary filled out in the morning by the participating subjects.

Secondary Outcome Measures

1. Change in Total Sleep Time [Day -1-0, Day 89-90]

   Change in sleep time will be determined by PSG.

2. Inflammatory Biomarkers C-reactive Protein (CRP) [Day 89-90]

3. Interleukin 6 (IL-6) [Day 89-90]

4. Insulin Resistance (IR) [Day 89-90]

   In each subject, an insulin resistance score based on Homeostasis Model Assessment (HOMA-IR) was estimated at day 89-90. Formula: fasting plasma glucose (mmol/l) times fasting serum insulin (mU/l) divided by 22.5. Low HOMA-IR values indicate high insulin sensitivity, whereas high HOMA-IR values indicate low insulin sensitivity (insulin resistance).

5. Inflammatory Biomarkers C-reactive Protein (CRP) [Baseline]

6. Insulin Resistance (IR) [Baseline]

   In each subject, an insulin resistance score based on Homeostasis Model Assessment (HOMA-IR) was estimated at baseline. Formula: fasting plasma glucose (mmol/l) times fasting serum insulin (mU/l) divided by 22.5. Low HOMA-IR values indicate high insulin sensitivity, whereas high HOMA-IR values indicate low insulin sensitivity (insulin resistance).

7. Interleukin 6 (IL-6) [Baseline]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

At screening visit:

• aged 18-65

• nonsmokers

• for women: oral contraceptive (OC) or hormone replacement therapy (HRT) nonusers

To schedule the baseline PSG (Visit 2), subjects must meet the following inclusion criteria:

• ages 18-65 inclusive;

• PSQI-Component 2 (sleep latency) score of greater than 1;

• non-smoker (e.g., less than 20 cigarettes in the past 5 years);

• habitual bedtime between 8:30 pm and midnight

• For premenopausal women:

• regular menstrual cycles determined by Framingham Study criteria;

• not pregnant and no history of oral contraceptive (OC) usage in last 6-months.

• For postmenopausal women:

• no recent (< 6 months) use of Hormone Replacement Therapy (HRT)

• no surgical menopause

Exclusion Criteria:

• positive urine drug screen

• Potential subjects with hypersensitivity to ramelteon or any components of the formulation will be excluded from participation.

• Given that ramelteon should not be used by individuals with severe hepatic impairment, or in patients in combination with fluvoxamine, individuals who report liver problem or use of fluvox will be excluded.

• use of rifampin (Rifadin ©); ketoconazole (Nizora ©l); or fluconazole (Diflucan ©).

• Ramelteon has not been studied in children or adolescents, and the effects in these populations are unknown, thus only individuals above 18 years will participate.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Duke University

Investigators

• Principal Investigator: Andrew Krystal, MD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT02156271
• Other Study ID Numbers: Pro00013501
• First Posted: Jun 5, 2014
• Last Update Posted: Jul 28, 2015
• Last Verified: May 1, 2014

• Keywords provided by Duke University: Insomnia
• Additional relevant MeSH terms: Sleep Initiation and Maintenance Disorders; Insulin Resistance; Inflammation

Study Results

Participant Flow

Pre-assignment Detail	A total of 75 subjects signed consent and were enrolled in the study. Of these, 23 (31%) failed to qualify to participate in the study based on screening assessments, 12 (16%) withdrew consent prior to randomization, and 4 (5%) dropped out before randomization. As a result, 39 subjects were randomized.

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Period Title: Overall Study
STARTED	26	13
COMPLETED	22	10
NOT COMPLETED	4	3

Baseline Characteristics

Arm/Group Title	Ramelteon	Placebo	Total
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo	Total of all reporting groups
Overall Participants	26	13	39
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	26 100%	13 100%	39 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	16 61.5%	8 61.5%	24 61.5%
Male	10 38.5%	5 38.5%	15 38.5%
Region of Enrollment (participants) [Number]
United States	26 100%	13 100%	39 100%

Outcome Measures

1. Primary Outcome

Title	Sleep Onset Latency (SOL) as Measured by Self Report (Sleep Diary)
Description	The average of a week of sleep onset latency data from the sleep diary filled out in the morning by the participating subjects. Sleep latency is defined as the length of time it takes from lying down for the night until sleep onset.
Time Frame	Day 89-90

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	22	10
Least Squares Mean (Standard Deviation) [minutes]	29.7 (21.7)	24.8 (15.2)

2. Primary Outcome

Title	Mean Latency to Persistent Sleep (LPS) Via Polysomnography
Description	Elapsed time from the beginning of the Polysomnography recording to the onset of the first 20 minutes of continuous sleep was measured.
Time Frame	Day 89-90

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	22	10
Least Squares Mean (Standard Deviation) [minutes]	19.2 (11.3)	48.6 (33.0)

3. Primary Outcome

Title	Change in Metabolic Syndrome (MetSyn)
Time Frame	Baseline, Day 30, Day 60, Day 89-90

Outcome Measure Data

Analysis Population Description

Data was not collected, and therefore not analyzed.

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	0	0

4. Primary Outcome

Title	Sleep Onset Latency (SOL) as Measured by Pittsburgh Sleep Qualtiy Index (PSQI)
Description	Subjects completed component 2 of the PSQI questionnaire. Component 2 asks questions about sleep latency and is scored on a scale from 0 (better) to 3 (worse).
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	26	13
Mean (Standard Deviation) [units on a scale]	2.5 (0.7)	2.8 (0.6)

5. Secondary Outcome

Title	Change in Total Sleep Time
Description	Change in sleep time will be determined by PSG.
Time Frame	Day -1-0, Day 89-90

Outcome Measure Data

Analysis Population Description

Data was not collected, and therefore not analyzed.

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	0	0

6. Secondary Outcome

Title	Inflammatory Biomarkers C-reactive Protein (CRP)
Time Frame	Day 89-90

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	22	10
Least Squares Mean (Standard Deviation) [ng/mL]	11.9 (12.7)	7.3 (28.1)

7. Secondary Outcome

Title	Interleukin 6 (IL-6)
Time Frame	Day 89-90

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	22	10
Least Squares Mean (Standard Deviation) [pg/mL]	2.2 (1.4)	1.3 (1.0)

8. Secondary Outcome

Title	Insulin Resistance (IR)
Description	In each subject, an insulin resistance score based on Homeostasis Model Assessment (HOMA-IR) was estimated at day 89-90. Formula: fasting plasma glucose (mmol/l) times fasting serum insulin (mU/l) divided by 22.5. Low HOMA-IR values indicate high insulin sensitivity, whereas high HOMA-IR values indicate low insulin sensitivity (insulin resistance).
Time Frame	Day 89-90

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	22	10
Least Squares Mean (Standard Deviation) [HOMA-IR value]	12.6 (12.2)	7.9 (6.6)

9. Primary Outcome

Title	Sleep Onset Latency (SOL) as Measured by Pittsburgh Sleep Qualtiy Index (PSQI)
Description	Subjects completed component 2 of the PSQI questionnaire. Component 2 asks questions about sleep latency and is scored on a scale from 0 (better) to 3 (worse).
Time Frame	day 89 - 90

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	22	10
Least Squares Mean (Standard Deviation) [units on a scale]	1.72 (0.9)	0.93 (1.1)

10. Primary Outcome

Title	Mean Latency to Persistent Sleep (LPS) Via Polysomnography
Description	Elapsed time from the beginning of the Polysomnography recording to the onset of the first 20 minutes of continuous sleep was measured.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	26	13
Mean (Standard Deviation) [minutes]	41.0 (25.4)	46.3 (20.1)

11. Primary Outcome

Title	Sleep Onset Latency (SOL) as Measured by Self Report (Sleep Diary)
Description	The average of a week of sleep onset latency data from the sleep diary filled out in the morning by the participating subjects.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	26	13
Mean (Standard Deviation) [minutes]	41.3 (32.9)	38.8 (19.8)

12. Secondary Outcome

Title	Inflammatory Biomarkers C-reactive Protein (CRP)
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	26	13
Mean (Standard Deviation) [mg/L]	11.8 (16.9)	26.1 (38.9)

13. Secondary Outcome

Title	Insulin Resistance (IR)
Description	In each subject, an insulin resistance score based on Homeostasis Model Assessment (HOMA-IR) was estimated at baseline. Formula: fasting plasma glucose (mmol/l) times fasting serum insulin (mU/l) divided by 22.5. Low HOMA-IR values indicate high insulin sensitivity, whereas high HOMA-IR values indicate low insulin sensitivity (insulin resistance).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	26	13
Mean (Standard Deviation) [HOMA-IR value]	16.9 (10.8)	12.4 (9.2)

14. Secondary Outcome

Title	Interleukin 6 (IL-6)
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon	15 subjects will be randomized to receive the placebo placebo
Measure Participants	26	13
Mean (Standard Deviation) [pg/mL]	1.6 (1.1)	2.5 (2.4)

Adverse Events

Arm/Group Title	Ramelteon		Placebo
Arm/Group Description	Subjects will take ramelteon 8mg one time daily 30 minutes before bedtime with approximately 8 ounces of water. Subjects have a 2 out of 3 chance of receiving ramelteon. ramelteon		15 subjects will be randomized to receive the placebo placebo
All Cause Mortality
	Ramelteon		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ramelteon		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Ramelteon		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/26 (30.8%)		3/13 (23.1%)
Gastrointestinal disorders
Diarrhea	0/26 (0%)		1/13 (7.7%)
General disorders
Body Aches	0/26 (0%)		1/13 (7.7%)
cold symptoms	1/26 (3.8%)		0/13 (0%)
Musculoskeletal and connective tissue disorders
Back Ache	0/26 (0%)		1/13 (7.7%)
Sore Ankle	1/26 (3.8%)		0/13 (0%)
Knee Pain	1/26 (3.8%)		0/13 (0%)
dislocated shoulder	1/26 (3.8%)		0/13 (0%)
Nervous system disorders
Dizziness	1/26 (3.8%)		0/13 (0%)
Drowsiness	4/26 (15.4%)		0/13 (0%)
Psychiatric disorders
Depression	1/26 (3.8%)		0/13 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.