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

Glucocorticoid Effect Clinical Trial

Official title:

The Role of Glucocorticoids to Maintain Energy Homeostasis During Starvation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05919992
• Other study ID #: EKNZ 2022-01837
• Status: Recruiting
• Phase: Early Phase 1
• Start date: May 15, 2023
• Est. completion date: August 31, 2024

Study information

• Verified date: June 2023
• Source: University Hospital, Basel, Switzerland
• Contact: Eleonora Seelig, MD
• Phone: 0041 61 328 63 23
• Email: eleonora.seelig[@]usb.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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:

A) 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).

B) 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: August 31, 2024
• Est. primary completion date: August 31, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• Glucocorticoid Effect
• Starvation

Intervention

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
• 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 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
• 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

Locations

Country	Name	City	State
Switzerland	University Hospital Basel	Basel	Basel-Stadt

Sponsors (1)

Lead Sponsor	Collaborator
Eleonora Seelig

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Satiation	Amount of food intake with ad libitum buffet	Two 7-day intervention periods
Secondary	Satiety	Appetite rating by visual analog scale, minimum value 0, maximum value 100	Two 7-day intervention periods
Secondary	Food preference	Amount of fat/ protein/carbohydrates consumed during ad libitum buffet	Two 7-day intervention periods
Secondary	Energy expenditure	Basal metabolic rate, diet-induced thermogenesis	Two 7-day intervention periods
Secondary	Substrate utilization	Respiratory quotient	Two 7-day intervention periods
Secondary	Blood pressure	Blood pressure	Two 7-day intervention periods
Secondary	Weight	Body weight	Two 7-day intervention periods
Secondary	Body composition	measured with DEXA-Scans and body impedance analysis	Two 7-day intervention periods
Secondary	Neuroendocrine hormones	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	Two 7-day intervention periods
Secondary	Lipids	Total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides	Two 7-day intervention periods
Secondary	Glucose	measured via blood sample	Two 7-day intervention periods
Secondary	Insulin sensitivity	measured via blood sample	Two 7-day intervention periods
Secondary	Ketone bodies	measured via blood sample	Two 7-day intervention periods
Secondary	Sympathetic nervous system activity	measured via ECG: Heart rate, interbeat interval, high-frequency activity, low-frequency activity, root mean square of successive differences	Two 7-day intervention periods
Secondary	Immune cells	Peripheral blood mononuclear cells (PBMCs)	Two 7-day intervention periods
Secondary	Inflammatory markers	IL-6, IL-1RA, IL-8, CRP	Two 7-day intervention periods
Secondary	Motivation to eat	clicking speed computer test	Two 7-day intervention periods
Secondary	Pleasure from eating	Fonts rating test	Two 7-day intervention periods
Secondary	Measure of behavioural approach and behavioural inhibition system	Questionnaire	Two 7-day intervention periods
Secondary	Eating behaviour type	Questionnaire	Two 7-day intervention periods