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

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ClinicalTrials.gov Identifier: NCT04037605
Recruitment Status : Recruiting
First Posted : July 30, 2019
Last Update Posted : January 7, 2020
Sponsor:
Information provided by (Responsible Party):
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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.
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
Estimated Study Start Date : February 2020
Estimated Primary Completion Date : July 24, 2022
Estimated Study Completion Date : July 24, 2022

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




Primary Outcome Measures :
  1. Average Blood Cortisol Concentration [ Time Frame: 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.

  2. Average Blood Testosterone Concentration [ Time Frame: 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 :
  1. Peak Blood Cortisol Concentration [ Time Frame: 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.

  2. Peak Blood Testosterone Concentration [ Time Frame: 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.

  3. Trough Blood Cortisol Concentration [ Time Frame: 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.

  4. Trough Blood Testosterone Concentration [ Time Frame: 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.

  5. Reaction time on Psychomotor Vigilance Task [ Time Frame: 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.

  6. Karolinska Sleepiness Scale [ Time Frame: 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.

  7. Two card gambling task [ Time Frame: 5 days ]
    Computerized neurobehavioral testing to determine how 4 nights of sleep restriction affects participants' decision making. The end point is discriminability index, d'.

  8. Modified Sternberg working memory test [ Time Frame: 5 days ]
    Computerized neurobehavioral testing to determine how 4 nights of sleep restriction affects reaction time and accuracy.

  9. Caloric Intake [ Time Frame: 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.

  10. Hunger [ Time Frame: 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.

  11. Food Cravings [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04037605


Contacts
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Contact: Peter Liu, MD, PhD 310-222-1860 sleependo@labiomed.org
Contact: Brenda Castillo 310-222-1860 brenda.castillo@labiomed.org

Locations
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United States, California
Los Angeles Biomedical Research Institute Recruiting
Torrance, California, United States, 90509
Contact: Brenda Castillo, BA    310-222-1860    brenda.castillo@labiomed.org   
Principal Investigator: Peter Y Liu, MD, PhD         
Sponsors and Collaborators
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Investigators
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Principal Investigator: Peter Liu, MD, PhD Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

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Responsible Party: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
ClinicalTrials.gov Identifier: NCT04037605    
Other Study ID Numbers: P31056-01R
First Posted: July 30, 2019    Key Record Dates
Last Update Posted: January 7, 2020
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center:
Testosterone
Cortisol
Additional relevant MeSH terms:
Layout table for MeSH terms
Ketoconazole
Dexamethasone
Dexamethasone acetate
Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate
Pharmaceutical Solutions
Hormones
Cosyntropin
Prolactin Release-Inhibiting Factors
Corticotropin-Releasing Hormone
BB 1101
Ganirelix
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors