The Role of Glucocorticoids to Maintain Energy Homeostasis During Starvation (Gluco-Starve)

Sponsor

Eleonora Seelig (Other)

Overall Status

Recruiting

CT.gov ID

NCT05919992

Collaborator

(none)

Enrollment

Location

Arms

15.6

Anticipated Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In a randomized, cross-over study, 20 healthy volunteers will receive a block and replace therapy that mimics physiological GC rhythm (metyrapone plus hydrocortisone) or placebo. Participants will undergo two identical fasting periods with each treatment. With the block and replace therapy, fasting-induced GC peak will be suppressed. Metabolic and autonomic parameters will be compared to reveal whether GCs mediate the physiological adaptions to caloric restriction.

Understanding acute effects of GCs upon caloric restriction is critical, since repetitive disruptions of GC secretion may become harmful in chronic conditions.

Condition or Disease	Intervention/Treatment	Phase
Glucocorticoid Effect	Drug: Metyrapone 250 mg Oral Tablets Drug: Hydrocortisone 19.9mg s.c., pulsatile with a flow rate of 10μl/s Drug: Placebo 250 mg Tablets Drug: Placebo (0,9% NaCl solution)	Early Phase 1

Detailed Description

Obesity is one of the major causes of morbidity and mortality worldwide. Achieving long-term weight loss is challenging, as the body counteracts weight loss to preserve energy by increasing appetite and lowering energy expenditure. These physiological defense mechanisms are the main obstacle to successful weight reduction in obese people.

Therefore, identifying the signals that defend body weight during caloric restriction is essential for developing new antiobesity drugs. Corticosteroids mediate the physiological defense to starvation in rodents. Whether cortisol has the same impact on humans is unknown.

Therefore, we investigate whether cortisol regulates the physiological adaptions to caloric restriction in humans.

The general objective of this project is to investigate whether cortisol mediates physiological adaptions to caloric restriction.

The primary objective is to test whether cortisol mediates the increased appetite during caloric restriction.

Secondary objectives are to test whether the cortisol response to caloric restriction affects satiation, satiety, energy expenditure, substrate utilization, blood pressure, weight, body composition, secretion of neuroendocrine hormones, lipids, glucose, ketone bodies, sympathetic nervous system activity, immune cells, and inflammatory markers.

This is a double-blind, randomized, placebo-controlled crossover study.

After screening, subjects will be randomized to two crossover 7-day study periods with a wash-out period of 28 days:

Participants will receive hydrocortisone 19.9 mg/d subcutaneously via a pump in a pulsed fashion (eight times/day) and metyrapone capsules per os (starting with a dose of 500 mg/d on day 1 to 3000mg/d on day 5, and then will be kept constant until day 7).
Participants will receive a placebo (0,9% NaCl solution) subcutaneously via a pump in a pulsed fashion and identical-looking placebo capsules per os with the same regimen as for metyrapone.

During both study periods, participants will undergo two days of caloric restriction.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Double-blind, randomized, placebo-controlled cross-over studyDouble-blind, randomized, placebo-controlled cross-over study

Masking:

Double (Participant, Investigator)

Masking Description:

Placebo-controlled

Primary Purpose:

Prevention

Official Title:

The Role of Glucocorticoids to Maintain Energy Homeostasis During Starvation

Actual Study Start Date :

May 15, 2023

Anticipated Primary Completion Date :

Aug 31, 2024

Anticipated Study Completion Date :

Aug 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metyrapone And Hydrocortisone During one of the study periods, subjects receive hydrocortisone 19.9 mg/d subcutaneously via a pump in a pulsed fashion (eight times/day) and metyrapone per os (starting with a dose of 500 mg/d, then the dose will be increased the next days until 3000mg/d is achieved).	Drug: Metyrapone 250 mg Oral Tablets During one phase of the study: Metyrapone (pills of 250mg) on empty stomach: Day 1 0-1-1, day 2 1-2-2, day 3 2-3-3 day 4 3-4-4 day 5 4-4-4 day 6 4-4-4 day 7 4-0-0 Drug: Hydrocortisone 19.9mg s.c., pulsatile with a flow rate of 10μl/s Hydrocortisone will be delivered subcutaneously via a pump in a pulsed fashion with a flow rate of 10μl/s from day 1 to day 7 in a total daily dose of 19.9mg
Placebo Comparator: Placebo During the other study period, subjects receive placebo (0,9% NaCl solution) 19.9 mg/d subcutaneously via a pump in a pulsed fashion and the same dose of placebo tablets p.o instead of metyrapone	Drug: Placebo 250 mg Tablets During another phase of the study: identical looking placebo pills starting Day 1 0-1-1, day 2 1-2-2, day 3 2-3-3 day 4 3-4-4 day 5 4-4-4 day 6 4-4-4 day 7 4-0-0 Drug: Placebo (0,9% NaCl solution) Placebo (0,9% NaCl solution) 19.9 mg/d subcutaneously via a pump in a pulsed fashion with a flow rate of 10μl/s from day 1 to day 7

Arm

Intervention/Treatment

Experimental: Metyrapone And Hydrocortisone

During one of the study periods, subjects receive hydrocortisone 19.9 mg/d subcutaneously via a pump in a pulsed fashion (eight times/day) and metyrapone per os (starting with a dose of 500 mg/d, then the dose will be increased the next days until 3000mg/d is achieved).

Drug: Metyrapone 250 mg Oral Tablets

During one phase of the study: Metyrapone (pills of 250mg) on empty stomach: Day 1 0-1-1, day 2 1-2-2, day 3 2-3-3 day 4 3-4-4 day 5 4-4-4 day 6 4-4-4 day 7 4-0-0

Drug: Hydrocortisone 19.9mg s.c., pulsatile with a flow rate of 10μl/s

Hydrocortisone will be delivered subcutaneously via a pump in a pulsed fashion with a flow rate of 10μl/s from day 1 to day 7 in a total daily dose of 19.9mg

Placebo Comparator: Placebo

During the other study period, subjects receive placebo (0,9% NaCl solution) 19.9 mg/d subcutaneously via a pump in a pulsed fashion and the same dose of placebo tablets p.o instead of metyrapone

Drug: Placebo 250 mg Tablets

During another phase of the study: identical looking placebo pills starting Day 1 0-1-1, day 2 1-2-2, day 3 2-3-3 day 4 3-4-4 day 5 4-4-4 day 6 4-4-4 day 7 4-0-0

Drug: Placebo (0,9% NaCl solution)

Placebo (0,9% NaCl solution) 19.9 mg/d subcutaneously via a pump in a pulsed fashion with a flow rate of 10μl/s from day 1 to day 7

Outcome Measures

Primary Outcome Measures

Satiation [Two 7-day intervention periods]
Amount of food intake with ad libitum buffet

Secondary Outcome Measures

Satiety [Two 7-day intervention periods]
Appetite rating by visual analog scale, minimum value 0, maximum value 100
Food preference [Two 7-day intervention periods]
Amount of fat/ protein/carbohydrates consumed during ad libitum buffet
Energy expenditure [Two 7-day intervention periods]
Basal metabolic rate, diet-induced thermogenesis
Substrate utilization [Two 7-day intervention periods]
Respiratory quotient
Blood pressure [Two 7-day intervention periods]
Blood pressure
Weight [Two 7-day intervention periods]
Body weight
Body composition [Two 7-day intervention periods]
measured with DEXA-Scans and body impedance analysis
Neuroendocrine hormones [Two 7-day intervention periods]
Leptin, thyroid hormones, insulin, c-peptide, growth hormone, IGF1, catecholamines, GLP-1, GIP, glucagon, PYY, CCK, ghrelin, GDF-15, cortisol total and free, ACTH, renin, aldosterone, pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, oxytocin, FGF-21
Lipids [Two 7-day intervention periods]
Total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides
Glucose [Two 7-day intervention periods]
measured via blood sample
Insulin sensitivity [Two 7-day intervention periods]
measured via blood sample
Ketone bodies [Two 7-day intervention periods]
measured via blood sample
Sympathetic nervous system activity [Two 7-day intervention periods]
measured via ECG: Heart rate, interbeat interval, high-frequency activity, low-frequency activity, root mean square of successive differences
Immune cells [Two 7-day intervention periods]
Peripheral blood mononuclear cells (PBMCs)
Inflammatory markers [Two 7-day intervention periods]
IL-6, IL-1RA, IL-8, CRP
Motivation to eat [Two 7-day intervention periods]
clicking speed computer test
Pleasure from eating [Two 7-day intervention periods]
Fonts rating test
Measure of behavioural approach and behavioural inhibition system [Two 7-day intervention periods]
Questionnaire
Eating behaviour type [Two 7-day intervention periods]
Questionnaire

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

BMI 18.5 - 27 kg/m2
Weight stability for 6 months prior to the trial (+/- 2kg)

Exclusion Criteria:

Previous medical history for any chronic condition in the last three months, active disease or abnormal physical examination as verified by a qualified physician.
Casual smoking (>6 cigarettes per day)
Frequent, heavy alcohol consumption (>30g/day)
Frequent, heavy caffeine consumption (>4 caffeinated drinks/day)
Regular physical exercise (>4hrs per week)
Shift workers
Participation in an investigational drug trial within the past two months
Intake of any drugs (prescribed, over the counter or recreational), within 48 hours of the study initiation
Intake of any steroids (including topical or inhaler) six month prior to the study
Known allergy to metyrapone or hydrocortisone
Inability or unwillingness to provide informed consent