Mirabegron and Physiological Function in Cold Environments

Study Overview
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Brief Summary
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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
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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.

Official Title
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Mirabegron and Physiological Function in Cold Environments - Aim 1

Conditions
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Resting Energy Expenditure, Thermogenesis, Brown Adipose Tissue

Intervention / Treatment
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* Drug: Mirabegron
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Given once, followed by observation for 6 hours in a 20 degree Celsius (68 degree Fahrenheit) room | Drug: Placebo<br>* Placebo control condition<br>|
| Experimental: 100 mg Mirabegron<br>Given once, followed by observation for 6 hours in a 20 degree Celsius (68 degree Fahrenheit) room | Drug: Mirabegron<br>* Dose-response effect on thermogenesis<br>* Other names: Myrbetriq;|
| Experimental: 150 mg Mirabegron<br>Given once, followed by observation for 6 hours in a 20 degree Celsius (68 degree Fahrenheit) room | Drug: Mirabegron<br>* Dose-response effect on thermogenesis<br>* Other names: Myrbetriq;|
| Experimental: 200 mg Mirabegron<br>Given once, followed by observation for 6 hours in a 20 degree Celsius (68 degree Fahrenheit) room | Drug: Mirabegron<br>* Dose-response effect on thermogenesis<br>* Other names: Myrbetriq;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Resting Energy Expenditure | Area under the curve for resting energy expenditure will be calculated to reflect the cumulative effect of mirabegron over time. | 360 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Greatest Change in Core Body Temperature | Core Body temperature will be measured via rectal temperature during the experiment. | Baseline and hourly through 360 minutes | 
| Greatest change in brown adipose tissue activation | Infrared thermography will be used to measure supraclavicular skin temperature as an estimate of brown adipose tissue activation. | Baseline and hourly through 360 minutes | 
| Greatest change in mean skin temperature | 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 skin temperature. Temperature readings will be taken every 30 minutes during the experiment. | Baseline and every 30 minutes through 360 minutes | 
| Greatest change in heart rate | Heart rate will be obtained using a 3-lead electrocardiogram. | Baseline and every 30 minutes through 360 minutes | 
| Greatest changes in mean, systolic, and diastolic blood pressure | Blood pressure will be monitored using a cuff placed on the upper arm that is inflated and deflated periodically. | Baseline and every 30 minutes through 360 minutes | 
| Greatest change in oxygen consumption | 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. | Baseline and every 30 minutes through 360 minutes | 
| Greatest change in surface mechanomyography | Three triaxial accelerometers adhered to the skin using adhesive tape on the chest, upper back, and thigh will be used to assess shivering. | Baseline and every 30 minutes through 360 minutes | 
| Greatest change in Bedside Shivering Scale | Two investigators will subjectively assess shivering by the participants using a Likert scale (0 = none, 3 = Severe) and the scores will be averaged. | Baseline and every 30 minutes through 360 minutes | 
| Greatest change in Thermal Comfort Scale | Participants will complete a Likert scale to assess their thermal comfort (1 = comfortable, 4 = very uncomfortable). | Baseline and every 30 minutes through 360 minutes | 
| Greatest change in Thermal Sensation Scale | Participants will complete a Likert scale to assess their thermal sensation (1 = cold, 4 = neutral, 7 = hot). | Baseline and every 30 minutes through 360 minutes |