Mirabegron and Physiological Function in Cold Environments

Phase 1

Completed

Conditions: Thermogenesis
Resting Energy Expenditure
Brown Adipose Tissue

Interventions: Drug: Placebo
Drug: Mirabegron

Registration Number: NCT04766021

Lead Sponsor: Indiana University

Brief Summary: Many Navy diving operations are performed in cold water. Despite technical advances to improve thermal protection for cold water diving, these applications are cumbersome and do not provide complete thermal protection as thermal discomfort is subjectively reported by many Navy divers. Brown adipose tissue is highly thermogenic in humans. Therefore, activation of brown adipose tissue might improve cold water tolerance and lower thermal discomfort during cold water diving operations. Mirabegron is a beta-3-adrenergic receptor agonist that is used to treat overactive bladder. Beta-3-adrenergic receptors are located on the urinary bladder, gallbladder and brown adipose tissue. Recent evidence has demonstrated that acute mirabegron administration increases thermogenesis for \~3 hours in humans. However, it is currently not known which dose of mirabegron can increase thermogenesis for longer durations. It is also not known if mirabegron administration can improve cold water tolerance and thermal discomfort during cold water immersion. Finally, it is not known if mirabegron can increase thermogenesis during sympathetic stimulation. This project will fill these knowledge gaps by determining which dose of mirabegron administration will increase thermogenesis during 6 hours of a mild cold stress challenge. This study is part of a collection of studies that will show if mirabegron is a potential ergogenic aid that can be used to improve cold water tolerance in Navy divers which will ultimately improve the likelihood of successful missions.

Detailed Description: This is a randomized, double-blind, placebo-controlled, cross-over experimental design. Participants will be asked to complete 5 visits to the laboratory; one informed consent/screening visit and 4 study visits. On study visit days, participants will report to the laboratory following a 12-hour fast, and 24-hour abstention from exercise, caffeine, and alcohol. During the study visits, participants will be instrumented for skin temperature (12-sites: calf, shin, front of the thigh, back of the thigh, chest, upper back, forehead, lower back, abdomen, forearm, hand, and foot; iButtons) core temperature (rectal thermistor), indices of shivering (surface mechanomyography using triaxial accelerometers at 3 anatomic sites (chest, upper back, and thigh) and the bedside shivering assessment scale), brachial artery blood pressure (brachial artery auscultation), and heart rate (3-lead ECG). Thermal perceptions will be assessed using Likert scales for thermal discomfort and thermal sensation. Participants will be shirtless (sports bra for women) and will wear shorts throughout the study. After 20 minutes of quiet resting in the supine position, 5 minutes of baseline measurements will be taken, thermal perceptions and an infrared thermography image of the supraclavicular fossa will be obtained as an indicator of brown adipose tissue activation (6), and a whole blood sample will be obtained.

Participants will then ingest mirabegron (100 mg, 150 mg, or 200 mg) or placebo. Thirty minutes after mirabegron or placebo has been ingested, participants will enter the whole-body indirect calorimeter; the internal temperature of the calorimeter will be set to 20 degrees C (68 degrees F). This will elicit a mild cold stress over the 6 hours of observation in the whole-body indirect calorimeter. The whole-body indirect calorimeter provides an accurate and continuous measure of thermogenesis (in the form of energy expenditure) that can be used over long periods of time in a stable environment. The whole-body calorimeter is designed to perform human studies that are up to 48 hours in duration and contains a private washroom. While in the whole-body indirect calorimeter, participants will be instructed to be sedentary and will be allowed to watch television or read. In order to stay consistent between study visits, participants will be instructed to spend the same amount of time watching television or reading for each study visit. Every 30 minutes, we will record skin temperatures, core temperature, blood pressure, and heart rate. Thermogenesis will be determined by having participants lie supine for 30 minutes and resting energy expenditure will be calculated using the abbreviated Weir formula every hour (5). Thermal perceptions and an infrared thermography image will also be obtained at these time points. At approximately the midpoint of the 6-hour measurement period, participants will have the opportunity to use the restroom and an additional urine sample will be collected at this time. At the end of the 6-hour measurement period, participants will exit the whole-body indirect calorimeter and final measurements of skin temperature, core temperature, heart rate, and blood pressure will be obtained as well as a final infrared thermography image and a whole blood sample. After the experiment is complete, participants will be given a mylar blanket to re-warm themselves prior to leaving the laboratory.

Participants will be asked to return to the laboratory after 10-14 days to repeat the experiment until all 4 dosing conditions (placebo, 100 mg, 150 mg, and 200 mg of mirabegron) have been tested. Each participant's order of assignment to placebo or drug dosing over the 4 study visits will be randomly assigned.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

Inclusion Criteria

Men and women
18-40 years old
Participate in 150 minutes or more of at least moderate intensity exercise per week during the previous 2 years

Exclusion Criteria

diagnosed autonomic disease
diagnosed cardiovascular disease
diagnosed metabolic disease
diagnosed neurologic disease
diagnosed endocrine disease
diagnosed respiratory disease
diagnosed liver dysfunction
diagnosed kidney dysfunction
Women who are pregnant or breastfeeding
Individuals currently taking a medication (with the exception of birth control, including hormonal contraception) that cannot be safely discontinued for 5 biological half-lifes prior to each study visit based on consultation with the study physician.
Current tobacco or electronic cigarette use or consistent use within the last 1 year

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Given once, followed by observation for 6 hours in a 20 degree Celsius (68 degree Fahrenheit) room
150 mg Mirabegron	Mirabegron	Given once, followed by observation for 6 hours in a 20 degree Celsius (68 degree Fahrenheit) room
200 mg Mirabegron	Mirabegron	Given once, followed by observation for 6 hours in a 20 degree Celsius (68 degree Fahrenheit) room
100 mg Mirabegron	Mirabegron	Given once, followed by observation for 6 hours in a 20 degree Celsius (68 degree Fahrenheit) room

Primary Outcome Measures

Name	Time	Method
Cumulative Resting Energy Expenditure	360 minutes	The cumulative resting energy expenditure will be calculated to reflect the cumulative effect of mirabegron over time.

Secondary Outcome Measures

Name	Time	Method
Thermal Comfort Scale	Baseline and every 30 minutes through 360 minutes	Participants will complete a Likert scale to assess their thermal comfort (range: 1-4; 1 = comfortable, 4 = very uncomfortable).The mean value was calculated.
Bedside Shivering Scale	Baseline and every 30 minutes through 360 minutes	Two investigators will subjectively assess shivering by the participants using a Likert scale (range 0-3; 0 = none, 3 = Severe) and the scores will be averaged. The mean value was calculated.
Core Body Temperature	Baseline and every 30 minutes through 360 minutes	Core Body temperature will be measured via rectal temperature during the experiment. The mean value was calculated.
Weighted Mean Skin Temperature	Baseline and every 30 minutes through 360 minutes	Fourteen iButtons will be adhered to the skin using adhesive tape on the calf, shin, front thigh, back thigh, foot, chest, upper back, lower back, forearm, hand, forehead, fingertip, toetip, and abdomen area to measure weighted skin temperature. Temperature readings will be taken every 30 minutes during the experiment. The mean value was calculated.
Heart Rate	Baseline and every 30 minutes through 360 minutes	Heart rate will be obtained using a 3-lead electrocardiogram. The mean value was calculated.
Mean Arterial Pressure	Baseline and every 30 minutes through 360 minutes	Blood pressure will be monitored using a cuff placed on the upper arm that is inflated and deflated periodically. The mean value was calculated.
Brown Adipose Tissue Activation	Baseline and hourly through 360 minutes	Infrared thermography will be used to measure supraclavicular skin temperature as an estimate of brown adipose tissue activation. The mean value was calculated.
Relative Oxygen Consumption	Baseline and every 30 minutes through 360 minutes	A pneumotach connected to a mouthpiece or facemask will be used to measure the flow of inspired and expired air. Expired gases will be sampled using oxygen and carbon dioxide sensors to determine oxygen consumption and carbon dioxide production. The mean value was calculated.
Thermal Sensation Scale	Baseline and every 30 minutes through 360 minutes	Participants will complete a Likert scale to assess their thermal sensation (range: 1-7; 1 = cold, 4 = neutral, 7 = hot). The mean value was calculated.