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

NCT ID: NCT05919992

Last Updated: 2024-08-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-05-15
• Study Completion Date: 2024-07-25

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.

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:

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.

Conditions

Glucocorticoid Effect

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

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).

Group Type: EXPERIMENTAL

Metyrapone 250 mg Oral Tablets

Intervention Type: DRUG

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

Intervention Type: DRUG

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

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

Group Type: PLACEBO_COMPARATOR

Placebo 250 mg Tablets

Intervention Type: DRUG

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)

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Eleonora Seelig

OTHER

Sponsor Role: lead

Responsible Party

Eleonora Seelig

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

University Hospital Basel

Basel, Canton of Basel-City, Switzerland

Countries

Switzerland

Other Identifiers

EKNZ 2022-01837

Identifier Type: -

Identifier Source: org_study_id