Hormonal Mechanisms of Sleep Restriction

Insulin Resistance Clinical Trial

Official title:

Hormonal Mechanisms of Sleep Restriction

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02256865
• Other study ID #: 30068-01
• Status: Completed
• Phase: Early Phase 1
• Start date: October 2014
• Est. completion date: October 2023

Study information

• Verified date: April 2023
• Source: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to study the effects of sleep restriction on the production of two hormones, cortisol and testosterone. The investigators aim to show that changing these hormones leads to insulin resistance, which is an important cause of type 2 diabetes mellitus. The investigators may also study the effect of sleep restriction on your food intake and cravings, mood, inflammation, metabolism (including bone), and other hormones. Inflammation is your body's response to stress and injury. Bone metabolism is a process of how your body regenerates (renews) new bone cells and removes old bone cells. Hormones are natural substances (materials) that are produced in the body and that influences (effects) the way the body grows or develops.

Description:

Screening Visits

• To see if you are able to take part in this study, you will first have an outpatient visit at the CTRC (Clinical and Translational Research Center). This visit will take about 90 minutes.

• The following tests/procedures will be done at this visit:

• We will ask you about your medical history and past health

• We will give you a physical examination (including digital rectal examination of the prostate gland if you are over the age of 40)

• We will ask you to answer sleep, mood and general health screening questionnaires.

• We will ask you to complete a questionnaire to help us understand how testosterone and other hormones control sexual function and drive.

• We will draw about 1 tablespoon of blood from a needle placed in a vein in your arm for routine safety tests and to check to see if you have any hormonal problems.

• We will give you an ECG (recording of heartbeat). For this test we will attach 12-lead sensors to your chest.

• We will collect urine sample from you for a drug screening test.

• A dietitian will review meal plans for the inpatient stay (Study Visit 1 and 3 only).

If the first screening visit shows that you are able to continue to take part in this study, you will continue the screening part of the study at home. The following will be done at home: We will ask you to undergo an at-home actigraphy and keep a daily sleep diary for two weeks to document your sleeping habits. For the actigraphy you will be asked to wear a small wrist-watch like device. This device will monitor and record your motion, and will also test your sleep and wake periods. It may be worn for up to 2 weeks, 24 hours per day (except while taking a shower).

If the results of the at-home actigraphy show that you are still able to take part in this study, you will continue the final part of the screening procedure which is an inpatient visit to conduct a sleep study. The following tests/procedures will be done for this final screening visit: We will ask you to come into the sleep laboratory to sleep overnight (sleep study). A technician will attach the leads (wires) to your body and you will need to keep these leads on during the night. The attached wires will be connected to a machine to measure chest and abdominal (stomach area) movements, airflow at your mouth and lips, blood oxygen level, muscle tone, eye movements, heart rate and electrical activity of the brain. In the morning, the technician will remove the attached wires.

If the exams, tests and procedures during the screening visits show that you can continue to be in the study, you will have 2 inpatient visits and 2 outpatient clinical visits.

Before beginning the study, we will assign you to one of the two study groups described below. Which one you are assigned to will be decided by chance (like tossing a coin) and you will have a one in two chance of being in any one group. A computer program will place you in one of the study groups.

GROUP 1: If you are assigned to group 1, then you will receive active drug during visit 1 (first inpatient visit) and placebo (inactive drug which is same as receiving no drug) during visit 3 (second inpatient visit). GROUP 2: If you are assigned to group 2, then you will receive placebo (inactive drug which is same as receiving no drug) during visit 1 (first inpatient visit) and active drug for visit 3 (second inpatient visit).

Neither you nor your study doctor can choose the group you will be in. Neither your study doctor or his staff nor you will know which study group or medicine you will be receiving. However should a medical emergency occur, this information will be made immediately available to your study doctor.

During the inpatient visit when you receive active drug, you will receive: Ketoconazole pills. You will swallow these pills every 6 hours (4 times per day). Testosterone gel. You will rub this gel into your skin once a day in the morning. Hydrocortisone pills. You will swallow these pills 3 times a day.

During the inpatient visit when you receive placebo (inactive drug), you will receive:

• Inactive placebo pills (looks like ketoconazole). You will swallow these pills every 6 hours (4 times per day).

• Inactive placebo gel (looks like testosterone gel). You will rub this gel into your skin once a day in the morning.

• Inactive placebo pills (looks like hydrocortisone). You will swallow these pills 3 times a day.

Night before First Inpatient Visit Before coming to the CTRC for your first inpatient visit, you will be asked to sleep 10 hours for two consecutive nights (from 10 PM to 8 AM) at home. During your sleep, you will be wearing an actiwatch to monitor your sleep at home. You cannot drink any alcohol during this 2 day period. We will send you a text message or telephone you to remind you to sleep during these times and not to drink alcohol. The inpatient study visit will be cancelled if you didn't have enough sleep at home or if you consumed alcohol.

Study Visit 1 (First Inpatient) For this visit we will ask you to arrive at the CTRC no later than 5 PM on the first day. We will allow you to go home sometime after lunch after the 5th night. We will give you breakfast, lunch and dinner at set times while you are in the CTRC. The meals are standard, so that what you may have eaten before will not interfere with the study results. The following tests/procedures will be done at this visit: We will download the information from your actiwatch to verify your sleep at home. We will be putting external leads on your body, as occurred during the sleep study, so that we can continuously check your sleep EEG, actiwatch activity and heart rate. We will expose you to dim light (this is so we can measure your "body clock"). From 7 PM until your bedtime every night, saliva will be collected hourly so we can measure your "body clock". We will ask you to fill out a short questionnaire to measure how sleepy you are, how hungry you are and do a computerized test of cognitive function every 2 hours (on odd, not even, hours). This will take about 5 minutes. Starting at 8PM on your first night, urine will collected until 8AM of the following day. This will be repeated every 12-hour period whilst in-lab for measurements of components of in the urine. We will give you an Oral Glucose Tolerance Test (OGTT) in the morning of the first and last days (on two occasions) while you are in the CTRC. The OGTT is the test that measures the body's ability to use a type of sugar, called glucose, which is the body's main source of energy.

• Before the test begins, we will insert a cannula into a vein in your arm and a sample of blood will be taken. The cannula is a small plastic tube through which we will sample your blood. It is inserted over a metal needle into your vein. The metal needle is removed once the cannula is in place.

• We will ask you to drink a liquid that is high in glucose (75 grams).

• In the first hour, we will draw about 5ml (1 teaspoon) of blood will be taken from the cannula every 5 minutes.

• In the second hour, about 5ml (1 teaspoon) of blood will be taken from the cannula every 10 minutes

• In the third hour, about 5ml (1teaspoon) of blood will be taken from the cannula every 20 minutes.

• We will draw an additional 10ml (2 teaspoons) of blood to measure inflammation, hormones, gene expression, and bone metabolism

• The entire test will take about 3 hours.

We will give you an opportunity to sleep before we discharge you and we will test you for sleepiness. Arrangements will be made for you to be driven home if necessary. During this time you cannot drink caffeinated drinks, or use nicotine products.

Study Visit 2 (First Outpatient) This visit will take place one week after you are discharged from your first inpatient visit. At this visit we will ask you about any side effects and draw about 1 tablespoon of blood for complete blood count and routine chemistry check, including liver function tests.

Study Visit 3 (Second Inpatient) This visit will take place one week after your first outpatient visit (about 2 weeks after your first inpatient visit). This visit is identical the first inpatient study Visit 1. For this visit, if you received active study drug during your first inpatient visit, you will receive a placebo. If you received the placebo during the first inpatient study Visit 1, then you will receive active study drug during this visit.

Study Visit 4 (Second Outpatient) This visit will take place one week after you are discharged from your second inpatient visit. At this visit we will ask you about any side effects and draw about 1 tablespoon of blood for complete blood count and routine chemistry check, including liver function tests.

All visits A total of about half a pint (16 tablespoons) of blood will be collected for this study. We will collect less than what you would donate to the blood bank.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: October 2023
• Est. primary completion date: November 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 22 Years to 45 Years

Eligibility

Inclusion Criteria:

• Men aged 22-45 years

• Willingness to provide written informed consent

• Stable weight over preceding 6 weeks

• Body Mass index (BMI) 20-28 kg/m2

Exclusion Criteria:

• Unable or unwilling to provide IRB-approved informed consent

• Clinical disorders and/or illnesses

• Current medical or drug treatment, as assessed by questionnaire

• History of brain injury or of learning disability

• Vision or hearing impairment unless corrected back to normal

• Anemia (Hct <38%)

• History of psychiatric illness

• Clinically significant abnormalities in blood and urine, and free of traces of drugs Other endocrine abnormalities including hypothyroidism or adrenal failure; primary gonadal disease as indicated by serum LH or FSH concentration >10 or >15 IU/L, respectively, hyperprolactinemia indicated by prolactin >25ug/L

• Type 2 Diabetes (HgbA1C)

• Current smoker

• Recent or concurrent drug or alcohol abuse

• Blood donation in previous eight weeks

• Travel across time zones within one month of entering the study

• Sleep or circadian disorder

• Shift work within three months of entering the study

• Irregular bedtimes (not between 6 and 10 hours in duration)

• Unoperated obstructive uropathy, recurrent prostatitis, indeterminate prostatic nodularity, Hx or Suspicion of cancer of the prostate gland or PSA >4ng/ml

• Previous adverse reaction to sleep deprivation or any of the drugs to be administered

• Concurrent participation in another research study

Related Conditions & MeSH terms

• Insulin Resistance

Intervention

Drug:
• Ketoconazole
Ketoconazole is taken 4 times a day
• Hydrocortisone
Hydrocortisone is taken 3 times a day
• Testosterone
Testosterone gel is applied once a day
• Placebo for ketoconazole
Placebo for ketoconazole
• Placebo for hydrocortisone
Placebo for hydrocortisone
• Placebo for testosterone
Placebo for testosterone

Locations

Country	Name	City	State
United States	Los Angeles Biomedical Research Institute	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (3)

Liu PY, Lawrence-Sidebottom D, Piotrowska K, Zhang W, Iranmanesh A, Auchus RJ, Veldhuis JD, Van Dongen HPA. Clamping Cortisol and Testosterone Mitigates the Development of Insulin Resistance during Sleep Restriction in Men. J Clin Endocrinol Metab. 2021 A — View Citation

O'Byrne NA, Yuen F, Butt WZ, Liu PY. Sleep and Circadian Regulation of Cortisol: A Short Review. Curr Opin Endocr Metab Res. 2021 Jun;18:178-186. doi: 10.1016/j.coemr.2021.03.011. Epub 2021 May 5. — View Citation

O'Byrne NA, Yuen F, Niaz W, Liu PY. Sleep and the Testis. Curr Opin Endocr Metab Res. 2021 Jun;18:83-93. doi: 10.1016/j.coemr.2021.03.002. Epub 2021 Mar 11. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Epigenetics	Explorative study	3 years
Primary	Insulin Sensitivity	Insulin sensitivity determined by minimal model of a frequently sampled oral glucose tolerance test (OGTT).This method is extensively validated, and previously utilized by us.	3 years
Secondary	Disposition index	Disposition index (determined by minimal model of the same OGTT)	3 years
Secondary	C-peptide glucose dose-response	C-peptide glucose dose-response (also calculated from the same OGTT)	3 years
Secondary	Lapses on Psychomotor Vigilance Task	Measure of psychomotor performance	3 years
Secondary	Karolinska Sleepiness Scale	Measures sleepiness	3 years
Secondary	Urinary Catecholamines	Measures sympathetic/parasympathetic activity	3 years
Secondary	Heart Rate Variability	Measures sympathetic/parasympathetic activity	3 years
Secondary	Free Fatty Acid Concentrations	Measures potential mediator of insulin resistance	3 years
Secondary	Inflammatory marker panel	blood interleukin-6, sTNFr2, IL1ra, CRP, NFkB concentrations	3 years
Secondary	Computerized cognitive testing	Two card gambling task, modified Sternberg working memory task	3 years
Secondary	Bone turnover panel	P1NP (bone formation marker) and NTX (bone resorption marker)	3 years
Secondary	Food cravings,	Food Craving Index	3 years
Secondary	Assessment of mood states.	Profile of Mood States (POMS)	3 years
Secondary	Food intake	meal and snack consumption calculation	3 years
Secondary	Hunger measurement	Flint visual analogue scale	3 years