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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Sleep Restriction
• Intervention / Treatment: Drug: Gonadorelin (also known as Lutrepulse); Drug: Corticorelin (also known as Acthrel); Drug: Placebo oral tablet; Drug: Saline Solution; Drug: Saline solution for injection; Drug: Ganirelix; Drug: Dexamethasone injection; Drug: Ketoconazole Pill (also known as nizoral); Drug: Hydrocortisone Injection (also known as solu-cortef); Drug: Dexamethasone Pill; Drug: Cosyntropin Injectable Product; Drug: Recombinant Human Luteinizing Hormone (also known as luveris)

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 Type: Interventional
• Enrollment (Actual): 5
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Torrance, California, United States, 90509
      • Los Angeles Biomedical Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / 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: 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; Drug: Ganirelix; Ganirelix subcutaneous injection is administered twice per inpatient visit; Drug: Dexamethasone injection; Dexamethasone IV injection is given twice per inpatient visit
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: 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; 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
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: 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: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Blood Cortisol Concentration	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.	5 days
Average Blood Testosterone Concentration	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.	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Blood Cortisol Concentration	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.	5 days
Peak Blood Testosterone Concentration	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.	5 days
Trough Blood Cortisol Concentration	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.	5 days
Trough Blood Testosterone Concentration	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.	5 days
Reaction time on Psychomotor Vigilance Task	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.	5 days
Karolinska Sleepiness Scale	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.	5 days
Two card gambling task	Computerized neurobehavioral testing to determine how 4 nights of sleep restriction affects participants' decision making. The end point is discriminability index, d'.	5 days
Modified Sternberg working memory test	Computerized neurobehavioral testing to determine how 4 nights of sleep restriction affects reaction time and accuracy.	5 days
Caloric Intake	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.	5 days
Hunger	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.	5 days
Food Cravings	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.	5 days

Collaborators and Investigators

• Sponsor: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
• Investigators: Principal Investigator: Peter Liu, MD, PhD, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2020
• Primary Completion (Actual): July 24, 2022
• Study Completion (Estimated): July 24, 2024

Study Registration Dates

• First Submitted: July 24, 2019
• First Submitted That Met QC Criteria: July 29, 2019
• First Posted (Actual): July 30, 2019

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 2, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Cortisol; Testosterone
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Dexamethasone; Dexamethasone acetate; BB 1101; Pharmaceutical Solutions; Hormones; Ketoconazole; Hydrocortisone; Hydrocortisone hemisuccinate; Ganirelix; Prolactin Release-Inhibiting Factors; Cosyntropin
• Other Study ID Numbers: P31056-01R

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No