Does Mirabegron Increase the Body Heat Generated by the Nervous System

Study Overview
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Brief Summary
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Acute mirabegron administration has been shown to increase brown fat activity in humans. Long-term mirabegron administration upregulates brown fat, and appears to improve glucose regulation, and change skeletal muscle phenotype.

Detailed Description
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The Undersea Medicine Program at the Office of Naval Research has invited Indiana University, Rutgers and Colorado State University, to explore the potential of the medication, Mirabegron, to improve the cold tolerance of Navy personnel. Indiana University will submit the formal application for research funding. Research activities at Colorado State University will be supported by a sub-contact from Indiana University. The project will address four hypotheses. One of these hypotheses will be investigated exclusively at Colorado State University during the second year of the project. The proposed activities at Colorado State University will be unique; the link to activities performed by Indiana University and Rutgers is thematic only. Specialized Navy personnel are required to undertake duties while immersed in cold water for prolonged periods. These dives regularly require the use of external thermal protection (i.e., wet suits and dry suits). However, external thermal protection during prolonged cold-water diving is often times insufficient to maintain body temperature and thermal comfort, thereby potentially negatively impacting the safety and success of diving missions. Accordingly, developing an alternative strategy that can improve tolerance to cold-water immersion is of important interest to Navy divers and special forces. In this regard, the pharmaceutical, mirabegron, may hold considerable promise to mitigate the negative effects of cold-water immersion on cold-water tolerance by increasing thermogenesis (the generation of heat). Mirabegron (Myrbetriq®, extended-release tablet, Astellas Pharma), is a medication approved by the Food and Drug Administration for the treatment of overactive bladder. In 2020, it was the 160th most commonly prescribed medication in the United States, with more than three million prescriptions. The mechanism of action is stimulation of beta-3-adrenergic receptors (receptors that are usually stimulated by the sympathetic nervous system). Mirabegron is also known to stimulate brown fat, a metabolically active, heat-generating tissue. The overall goals of the project are to determine the efficacy of acute mirabegron administration to improve cold tolerance and determine if mirabegron can accentuate thermogenesis during sympathetic activation.

Official Title
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Does Mirabegron Increase the Body Heat Generated by the Nervous System

Conditions
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Thermoregulation

Intervention / Treatment
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* Drug: Myrbetriq 25Mg Extended-Release Tablet
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18-40 years, regular participation in more than 150 minutes of moderate intensity exercise, every week, during the previous two years. Exclusion Criteria: History of autonomic, cardio-pulmonary, and/or metabolic disease (including heart failure, hypertension, arrhythmia, vascular disease, and/or diabetes) contraindication for mirabegron ingestion, such as previously diagnosed liver and/or kidney dysfunction, use of medication that may unfavorably interact with mirabegron, including thioridazine (Mellaril™ and Mellaril-S™), flecainide (Tambocor®), propafenone (Rythmol®), digoxin (Lanoxin®) and solifenacin succinate (VESIcare®) pregnancy or breast feeding habitual use of tobacco/nicotine products (2 or more uses within the previous month) any type of bladder dysfunction, taking medication related to bladder issues, or a history of bladder issues. Sulfite Allergy '

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
Interventional Model Description: Crossover with a washout of at least 10 days
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mirabegron + Isoproterenol<br>100mg oral + Isoproterenol IV Infusion; 3 doses, 6, 12, 24ng/ kg Fat Free Mass | Drug: Myrbetriq 25Mg Extended-Release Tablet<br>* Participants take 4x 25mg Myrbetriq 25Mg Extended-Release Tablet orally.<br>|
| Placebo Comparator: Placebo + Isoproterenol<br>Empty Capsule + Isoproterenol IV Infusion; 3 doses, 6, 12, 24ng/ kg Fat Free Mass | Drug: Placebo<br>* Participants take empty capsule orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in metabolic rate compared to baseline during each stage as measured by indirect calorimetry | Participants will undergo a 45 minute resting metabolic rate assessment and then consume Mirabegron or Placebo. Afterwards, they will undergo three 30 minute infusions of Isoproterenol consisting of doses of 6, 12, and 24ng/kg FFM | Immediately after each infusion | 
| Change in temperature among the top 10% of hottest pixels as identified via thermal camera and FLIR research software in the supraclavicular region during each isoproterenol infusion. | At the conclusion of each of the 3 isoproterenol infusions, participants will have thermal images taken of their supraclavicular region to identify brown fat activation. | Immediately after each infusion. | 
| Change in core temperature measured via oral thermometer during each stage. | Core temperature will be measured via oral thermometer at the conclusion of each of the three isoproterenol infusions. | Immediately after each infusion. |