Hormonal Mechanisms of Sleep Restriction - Axis Study

Sponsor

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03142893

Collaborator

(none)

Enrollment

Location

Arms

66.8

Anticipated Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to 1) determine how hypothalamic-pituitary-adrenal axis (HPA axis) activation occurs with sleep restriction 2) evaluate how hypothalamic-pituitary-gonadal axis (HPG axis) deactivation occurs with sleep restriction. The investigator will also examine the cognitive function associated with sleep restriction, including food intake and food cravings.

Condition or Disease	Intervention/Treatment	Phase
Sleep Restriction	Drug: Ketoconazole Pill Drug: Ganirelix Drug: Dexamethasone Drug: Dexamethasone Injection Drug: Cosyntropin Injectable Product Drug: Recombinant Human Luteinizing Hormone Drug: Hydrocortisone Injection Drug: Gonadorelin Drug: Corticorelin Drug: Placebo oral capsule Drug: Saline Solution Drug: Saline Solution for Injection	Phase 1

Detailed Description

Sleep restriction increases evening cortisol and decreases testosterone. These are the main catabolic and anabolic hormones in men, respectively. This catabolic-anabolic imbalance likely leads to metabolic and reproductive ill-health. The hypothalamic-pituitary-end organ (adrenal or testis) mechanisms that must underpin these changes are unknown. This study will administer drugs to clamp the function of each of these nodes to determine the regulatory changes that have occurred with sleep restriction. Even though the study is randomized order in design, the main comparison is before and after sleep restriction under each of these clamp conditions. Participants are admitted to the chronobiology laboratory where they are given 1 night of 10 hours sleep opportunity, followed by 4 nights of 4 hours sleep opportunity. Up to 80 participants (assuming twenty different participant for each of the 4 clamp conditions) can be enrolled. However, participants will be allowed an opportunity to be randomized to all 4 conditions so that as few as 20 participants may be required. Urn randomization will be used to ensure that 20 different participants are involved in each of the 4 conditions.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Blood is sampled every 10 minutes from 4PM to 9PM for future mathematical deconvolution in order to determine hormone pulse characteristics in response to the clamp conditions. These values are the primary endpoints.Blood is sampled every 10 minutes from 4PM to 9PM for future mathematical deconvolution in order to determine hormone pulse characteristics in response to the clamp conditions. These values are the primary endpoints.

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

3 of the 4 conditions are masked by use of identical injections and pills. However one condition (adrenal testis) is not masked. Hence the study is partially masked.

Primary Purpose:

Basic Science

Official Title:

Hormonal Mechanisms of Sleep Restriction - Axis Study

Actual Study Start Date :

May 8, 2017

Actual Primary Completion Date :

Oct 30, 2020

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Control Condition 8 am - Saline Solution for Injection 10 am - Placebo oral capsule 1 pm - Saline Solution for Injection 4 pm - Placebo oral capsule & start hourly blood sampling 7 pm - Gonadorelin (GnRH) and Corticorelin (CRH) injections 9 pm - Saline Solution for Injection & last blood sample	Drug: Gonadorelin Gonadorelin IV injection is given twice per Inpatient Stay Other Names: Lutrepulse Drug: Corticorelin Corticorelin IV injection is given twice per Inpatient Stay Other Names: Acthrel Drug: Placebo oral capsule Placebo for ketoconazole are given 4 times per Inpatient Stay Drug: Saline Solution Saline Solution (Placebo) for Dexamethasone IV injection or hydrocortisone IV injection given up to four times per Inpatient Stay Drug: Saline Solution for Injection Saline Solution (placebo) for ganirelix subcutaneous injection
Experimental: Hypothalamic Condition 8 am - Ganirelix 10 am - Placebo oral capsule 1 pm - Dexamethasone injection 4 pm - Placebo oral capsule and start of hourly blood sampling 7 pm - GnRH and CRH injections 9 pm - Saline Solution for Injection and last sample of blood taken	Drug: Ganirelix Ganirelix subcutaneous injection is administered twice per Inpatient Stay Drug: Dexamethasone Injection Dexamethasone IV injection is given twice per Inpatient Stay Drug: Gonadorelin Gonadorelin IV injection is given twice per Inpatient Stay Other Names: Lutrepulse Drug: Corticorelin Corticorelin IV injection is given twice per Inpatient Stay Other Names: Acthrel Drug: Placebo oral capsule Placebo for ketoconazole are given 4 times per Inpatient Stay Drug: Saline Solution for Injection Saline Solution (placebo) for ganirelix subcutaneous injection
Experimental: Pituitary Condition 8am - Saline Solution for Injection 10am - Ketoconazole Pill 1pm - Saline Solution for Injection 4pm - Ketoconazole Pill & start of hourly blood sampling 7pm - GnRH and CRH 9pm - Hydrocortisone Injection & last blood sample	Drug: Ketoconazole Pill Ketoconazole pill is taken 4 times per Inpatient Stay Other Names: Nizoral Drug: Hydrocortisone Injection Hydrocortisone IV push is given twice per Inpatient Visit Other Names: solu-cortef Drug: Gonadorelin Gonadorelin IV injection is given twice per Inpatient Stay Other Names: Lutrepulse Drug: Corticorelin Corticorelin IV injection is given twice per Inpatient Stay Other Names: Acthrel Drug: Saline Solution Saline Solution (Placebo) for Dexamethasone IV injection or hydrocortisone IV injection given up to four times per Inpatient Stay
Experimental: Adrenal/Testis Condition 10pm - Ganirelix Injection & Dexamethasone Pills (night before) 8am - start of hourly blood sampling 10am - Dexamethasone Pills 11am - last hourly blood sample taken 11:30am - start of blood sampling every 10 minutes 1pm - Recombinant Human Luteinizing Hormone (rhLH) Injection 3pm - rhLH Injection 5pm - rhLH Injection 5pm - Cosyntropin Injectable product 7pm - GnRH and CRH Injections 9pm - last blood sample taken	Drug: Ganirelix Ganirelix subcutaneous injection is administered twice per Inpatient Stay Drug: Dexamethasone Dexamethasone Pills is taken twice per Inpatient Stay Drug: Cosyntropin Injectable Product cosyntropin injection is given twice per Inpatient Stay Drug: Recombinant Human Luteinizing Hormone Leutinizing-Releasing Hormone is given 6 IV infusion pulses per Inpatient Visit Other Names: Luveris Drug: Gonadorelin Gonadorelin IV injection is given twice per Inpatient Stay Other Names: Lutrepulse Drug: Corticorelin Corticorelin IV injection is given twice per Inpatient Stay Other Names: Acthrel

Outcome Measures

Primary Outcome Measures

Average Blood Cortisol Concentration [5 days]
Cortisol is measured in blood every 10 minutes for a 5 hour period, at the beginning and at the end of 4 nights of sleep restriction. The average cortisol is the parameter of interest.
Average Blood Testosterone Concentration [5 days]
Testosterone is measured in blood every 10 minutes for a 5 hour period, at the beginning and at the end of 4 nights of sleep restriction. The average cortisol is the parameter of interest.

Secondary Outcome Measures

Peak Blood Cortisol Concentration [5 days]
This is the single maximal blood cortisol concentration that is measured during the entire 5 hour period, at the beginning and at the end of 4 nights of sleep restriction.
Peak Blood Testosterone Concentration [5 days]
This is the single maximal blood testosterone concentration that is measured during the entire 5 hour period, at the beginning and at the end of 4 nights of sleep restriction.
Trough Blood Cortisol Concentration [5 days]
This is the single minimal blood cortisol concentration that is measured during the entire 5 hour period, at the beginning and at the end of 4 nights of sleep restriction.
Trough Blood Testosterone Concentration [5 days]
This is the single minimal blood testosterone concentration that is measured during the entire 5 hour period, at the beginning and at the end of 4 nights of sleep restriction.
Reaction time on Psychomotor Vigilance Task [5 days]
This is measured by lapses in attention. As the person becomes more sleepy, there are more lapses (reaction time >500 ms), at the beginning and at the end of 4 nights of sleep restriction.
Karolinska Sleepiness Scale [5 days]
Measures how sleepy participants are using a scale of 1 (extremely alert) through 9. This scale will be used to assess changes in sleepiness throughout the day and through 4 nights of sleep restriction.
Two card gambling task [5 days]
Computerized neurobehavioral testing to determine how 4 nights of sleep restriction affects participants' decision making. The end point is discriminability index, d'.
Modified Sternberg working memory test [5 days]
Computerized neurobehavioral testing to determine how 4 nights of sleep restriction affects reaction time and accuracy.
Caloric Intake [5 days]
The food given to participants is weighed. The amount that is not consumed is also weighed. The difference in weight is the amount of calories consumed.
Hunger Scale [5 days]
Hunger scale using Flint visual analogue scale to assess how 4 nights of sleep restriction affects participants' appetite.
Food Cravings [5 days]
Food cravings is measured using Food Cravings Index scale to assess which food groups participants have cravings for and how their cravings change during 4 nights of sleep restriction.

Eligibility Criteria

Criteria

Ages Eligible for Study:

22 Years to 45 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

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 (Internal Review Board)-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 (luteinizing hormone) or FSH (follicle stimulating hormone) 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 (prostate-specific antigen) >4ng/ml
Previous adverse reaction to sleep deprivation or any of the drugs to be administered
Concurrent participation in another research study