Hormonal Mechanisms of Sleep Restriction
Condition: Insulin Resistance
MeSH terms: Insulin Resistance
Study type: Interventional
Phase: Early Phase 1

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.
    

Detailed 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.
    

Intervention name(s): Ketoconazole; Hydrocortisone; Testosterone; Placebo for ketoconazole; Placebo for hydrocortisone; Placebo for testosterone
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Ketoconazole is taken 4 times a day; Hydrocortisone is taken 3 times a day; Testosterone gel is applied once a day; Placebo for ketoconazole; Placebo for hydrocortisone; Placebo for testosterone
Other intervention name(s): Nizoral; Cortef, Cortril, Hydrocortone; AndroGel
Intervention MeSH terms: Ketoconazole; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Methyltestosterone; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Sleep Restriction; Insulin Resistance; Testosterone; Cortisol