Hormonal Mechanisms of Sleep Restriction - Axis Study in Older Men and Postmenopausal Women

Sponsor

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

Overall Status

Recruiting

CT.gov ID

NCT04037605

Collaborator

(none)

Enrollment

Location

Arms

41.4

Anticipated Duration (Months)

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 and 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 (also known as nizoral) Drug: Ganirelix Drug: Dexamethasone Pill Drug: Dexamethasone injection Drug: Cosyntropin Injectable Product Drug: Recombinant Human Luteinizing Hormone (also known as luveris) Drug: Hydrocortisone Injection (also known as solu-cortef) Drug: Gonadorelin (also known as Lutrepulse) Drug: Corticorelin (also known as Acthrel) Drug: Placebo oral tablet Drug: Saline Solution Drug: Saline solution for injection	Early Phase 1

Detailed Description

Sleep restriction and its consequences are major public health problems, especially in older adults. Among the more severe physiological sequelae of sleep restriction is the development of insulin resistance. The mechanisms by which sleep restriction leads to increased insulin resistance are unknown, especially in vulnerable older adults; such research informs development of targeted interventions against the sleep loss/insulin resistance link.

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 40 participants can be enrolled. However, participants will be allowed an opportunity to be randomized to all 4 conditions so that as few as 10 participants may be required. We anticipate 5 men and 5 women will be enrolled assuming each undergoes all 4 clamp conditions.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Blood is sampled every 10 minutes from 4 pm to 9 pm for future mathematical deconvolution in order to determine hormone pulse characteristics in response to the clamp conditions.Blood is sampled every 10 minutes from 4 pm to 9 pm for future mathematical deconvolution in order to determine hormone pulse characteristics in response to the clamp conditions.

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 in Older Men and Postmenopausal Women

Actual Study Start Date :

Feb 9, 2020

Anticipated Primary Completion Date :

Jul 24, 2022

Anticipated Study Completion Date :

Jul 24, 2023

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 (also known as Lutrepulse) Gonadorelin IV injection is given twice per inpatient visit Drug: Corticorelin (also known as Acthrel) Corticorelin IV injection is given twice per inpatient visit Drug: Placebo oral tablet Placebo for Ketoconazole are given 4 times per inpatient visit Drug: Saline Solution Saline Solution (Placebo) for Dexamethasone IV injection or hydrocortisone IV injection given up to four times per inpatient visit 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 blood sample	Drug: Ganirelix Ganirelix subcutaneous injection is administered twice per inpatient visit Drug: Dexamethasone injection Dexamethasone IV injection is given twice per inpatient visit Drug: Gonadorelin (also known as Lutrepulse) Gonadorelin IV injection is given twice per inpatient visit Drug: Corticorelin (also known as Acthrel) Corticorelin IV injection is given twice per inpatient visit Drug: Placebo oral tablet Placebo for Ketoconazole are given 4 times per inpatient visit Drug: Saline solution for injection Saline Solution (placebo) for ganirelix subcutaneous injection
Experimental: Pituitary Condition 8 am - Saline Solution for Injection 10 am - Ketoconazole Pill 1 pm - Saline Solution for Injection 4 pm - Ketoconazole Pill & start of hourly blood sampling 7 pm - GnRH and CRH 9 pm - Hydrocortisone Injection and last blood sample	Drug: Ketoconazole Pill (also known as nizoral) Ketoconazole pill is taken 4 times per inpatient visit Drug: Hydrocortisone Injection (also known as solu-cortef) Hydrocortisone IV push is given twice per inpatient visit Drug: Gonadorelin (also known as Lutrepulse) Gonadorelin IV injection is given twice per inpatient visit Drug: Corticorelin (also known as Acthrel) Corticorelin IV injection is given twice per inpatient visit Drug: Saline Solution Saline Solution (Placebo) for Dexamethasone IV injection or hydrocortisone IV injection given up to four times per inpatient visit
Experimental: Adrenal/Testis Condition 10 pm - Ganirelix Injection & Dexamethasone Pills (night before) 8 am - Start of hourly blood sampling 10 am - Dexamethasone Pills 11 am - Last hourly blood sample taken 11:30 am - Start of blood sampling every 10 minutes 1 pm - Recombinant Human Luteinizing Hormone (rhLH) Injection 3 pm - rhLH Injection 5 pm - rhLH Injection 5 pm - Cosyntropin Injectable product 7 pm - GnRH and CRH Injections 9 pm - Last blood sample	Drug: Ganirelix Ganirelix subcutaneous injection is administered twice per inpatient visit Drug: Dexamethasone Pill Dexamethasone pills is taken twice per inpatient visit Drug: Cosyntropin Injectable Product Cosyntropin injection is given twice per inpatient visit Drug: Recombinant Human Luteinizing Hormone (also known as luveris) Recombinant Human Luteinizing Hormone is given as 6 IV infusion pulses per inpatient visit Drug: Gonadorelin (also known as Lutrepulse) Gonadorelin IV injection is given twice per inpatient visit Drug: Corticorelin (also known as Acthrel) Corticorelin IV injection is given twice per inpatient visit

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 [5 days]
Hunger levels are assessed using the Flint visual analogue scale (VAS) to assess how 4 nights of sleep restriction affects participants' appetite.The Flint VAS asks the participant to rate 8 aspects of their hunger level on a scale from 1-5.
Food Cravings [5 days]
Food cravings are measured using the Food Cravings Index (FCI) scale to assess which food groups each participant has cravings for and how their cravings change during 4 nights of sleep restriction. The participant ranks their craving for 33 food items on a scale from 1-5.

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Men or postmenopausal women aged 60-80 years
Willingness to provide written informed consent
Stable weight over preceding 6 weeks
Body Mass index (BMI) 22-28 kg/m2
Physically and psychologically healthy
Good habitual sleep with regular bedtimes
Neither extreme morning- nor extreme evening-type using Horne-Ostberg Morningness-Eveningness criteria

Exclusion Criteria:

Medications that interfere with the adrenal or gonadal axis will be excluded
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
Mini- mental state examination (MMSE) < 27