The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta3-Adrenergic Receptor Agonists

Polycystic Ovary Syndrome Clinical Trial

Official title:

The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta3-Adrenergic Receptor Agonists

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03049462
• Other study ID #: 170054
• Secondary ID: 17-DK-0054
• Status: Recruiting
• Phase: Phase 1
• Start date: March 13, 2017
• Est. completion date: September 30, 2026

Study information

• Verified date: June 11, 2024
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Ashley M Schmitz, C.R.N.P.
• Phone: (920) 948-1186
• Email: ashley.schmitz[@]nih.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

Brown adipose tissue (BAT) is a type of fat in the body. It may prevent weight gain, improve insulin sensitivity, and reduce fatty liver. Researchers want to see if BAT helps the body burn energy.

Objective:

To learn more about how BAT works to burn energy.

Eligibility:

People ages 18-40 with a body mass index between 18 and 40

Design:

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

Dietitian interview

Participants will have an overnight baseline visit. This includes:

Repeats of screening tests

Exercise test

Scans. For one scan, a radioactive substance is injected into the arm.

FSIVGIT: An IV is inserted into veins in the right and left arms. Glucose and insulin are injected in one arm. Blood glucose and insulin levels are measured from the other.

Metabolic suite: Participants stay 18 19 hours in a room that measures their metabolic rate. Monitors on the body measure heart rate, movement, and temperature.

Optional fat biopsy: A small piece of tissue is removed with a needle.

Participants will take 2-4 pills daily for 4 weeks. All women will take the drug mirabegron. Men will be randomly get either the drug or a placebo.

All participants will have a visit after 2 weeks of the pills. They will repeat the screening tests.

Participants will have an overnight visit 2 weeks later. They will repeat the baseline tests.

Participants will keep food and medication diaries.

Participants will have a follow-up visit 2 weeks after stopping the pills. This includes heart tests.

...

Description:

Background issues and controversies

More than ever before, there is a rise in the rates of obesity and diabetes. As opposed to white fat which stores excess calories, brown fat - also known as brown adipose tissue or BAT

• consumes this energy to generate heat. In settings of increased food consumption and cold-exposure, studies show that human BAT becomes more active, potentially combatting weight gain. Other emerging evidence indicates that human BAT may be an endocrine organ, releasing hormones into the blood and regulating other organs like skeletal muscle, liver, and the insulin-releasing pancreatic Beta-cell. However, alongside these promising studies are those people who believe that there is not enough BAT in humans to be functionally relevant, and it contributes little to heat generation or overall health.

Purpose/Rationale of the proposed study

One of the principal reasons for skepticism about the ability to utilize human BAT is that there is not very much compared to smaller animals in which BAT activation has shown such promise. Therefore, a critical step is to develop medicines that can grow BAT in people and evaluate what kind of health benefits can be achieved.

Specific objectives

This study will administer the clinically-available beta3-AR agonist, mirabegron (Myrbetriq(R), Astellas Pharma). We will determine whether we can increase BAT volume and activity in people after they have taken this medication daily for four weeks. Our current goal is to see if chronic administration of mirabegron leads to an increase in BAT volume and metabolic activity and if it produces health benefits.

Key elements of what is involved

At the beginning of the study, the participants will undergo a series of tests to determine their baseline amounts of BAT, blood sugar status, and levels of specified hormones. The testing will take place over the course of two to three days while an inpatient on the Metabolic Patient Care Unit at the NIH Clinical Center. Depending on the Cohort, participants will then take the medication alone for four weeks or both the medication and placebo for four weeks each, during which time they will continue their standard daily routines. At two weeks after starting placebo or mirabegron, participants will return for one day for the assessment of any interim changes and to validate safety. At the end of each set of four weeks there will be a second set of inpatient testing over two to three days. Participants will be brought back two weeks after finishing the study for a follow-up safety visit, at which time they will receive an ECG and heart rate monitoring.

Primary outcomes

The primary outcome is either the change in BAT metabolic activity as measured by 18FFDG PET/CT or glucose infusion rate as measured by a hyperinsulinemic euglycemic clamp. Secondary endpoints will examine multiple other factors, including body weight, fat mass, glucose tolerance, changes in levels of hormones, and improved liver function.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: September 30, 2026
• Est. primary completion date: September 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 40 Years

Eligibility

• INCLUSION CRITERIA:

• Cohorts 1 and 2:

• Men and Women ages 18-40 years; All ethnicities

• BMI 18.0-40.0 kg/m2

• Cohort 3:

• Women ages 18-40 years; All ethnicities

• BMI 25.0-50.0 kg/m2

• Use of birth control such as intrauterine devices (hormonal or copper), hormonal implants, or oral contraceptives and with stable use for at least 3 months excluding exclusive use of barrier methods

• Insulin Resistance defined by either:

• HOMA-IR (a) >5.9 or (b) 2.8 < HOMA-IR < 5.9 with HDL< 51 mg/dL or

• Fasting Insulin >10.6 microU/mL

EXCLUSION CRITERIA:

• Self-reported weight loss or weight gain >5% in the preceding 6 months

• Abnormal bladder function, diagnosis of bladder outlet obstruction, urinary incontinence, urgency, and urinary frequency or use of antimuscarinic medication to treat overactive bladder (OAB)

• Type 1 or Type 2 Diabetes mellitus (fasting serum glucose >125 mg/dL), an HbA1c test >6.5%, or medications used to treat diabetes mellitus

• Elevated blood pressure that is >135/85 mmHg or currently taking antihypertensive therapy

• Hypo- or hyper-thyroid disease (TSH >5.0, <0.4 miU/L) that is controlled for less than one year

• Hypersensitivity and associated allergic reactions to mirabegron or similar drug substances or components of this medication

• Anemia, defined by Hemoglobin <= 13.8 g/dL (males) or 11.3 g/dL (females)

• Cardiovascular disease, cardiac arrhythmias, orthostasis, unstable vasomotor system, or renal impairment

• A clinically-significant abnormal ECG, QTc interval above normal, or the current use of any QT-prolonging drug

• Use of any known adrenergic agonists, CYP3A or CYP2D6 substrates, cardiac beta-blockers, calcium channel blockers, systemic corticosteroids, monoamine oxidase (Nirengi et al.) inhibitors

• Concomitant use of spironolactone is permissible in participants in Cohort 3. Investigators will monitor for side effects of

study drug and spironolactone use during study participation.

• Use of medications related to glucose metabolism or known to cause insulin resistance (in preceding 6 months)

• Psychological conditions including (but not limited to) claustrophobia, untreated clinical depression, bipolar disorders, or forms of mental incapacity that would be incompatible with safe and successful participation in this study

• Concomitant use of bupropion, desvenlafaxine, venlafaxine, and/or escitalopram are permissible due to high incidence of depression and anxiety disorders. Investigators will monitor participants closely for side effects of both the study drug and their

antidepressants, when applicable.

• Addiction to alcohol or substances of abuse within the last 5 years; self-reported current use of drugs

• Self-reported current alcohol consumption of more than 2 servings of alcohol per day

• Self-reported current use of nicotine and/or tobacco products

• Pregnancy, childbirth within the last year, or breastfeeding in the past 12 months (for women only)

• Current use of medications/dietary supplements/alternative therapies known to alter energy metabolism

• Has participated in a clinical trial where there has been treatment with an investigational or marketed drug within 2 months prior to the start of the study

• Have had previous radiation exposure (X-rays, PET scans, etc.) within the last year or anticipate radiation exposure in the upcoming year - clinical and/or research - that would exceed research limits

• Donated blood within last 2 months

• Recent history (4 weeks) of any local or systemic infectious disease with fever or requiring antibiotics

• Raynaud s disease or intolerance of cold that would prevent the individual from spending 6 hours in a chilled room with a cooling vest

• Has elevated liver enzymes and is believed to have liver disease other than fatty liver disease

• Sickle cell anemia or other blood disorder such as hypercoagulable clotting disorders,

• Tissue conditions such as local infection or wound healing problems,

• Individuals who spend >70% of daily hours outdoors since the exposure to varied environmental temperatures will potentially impact the ability to influence and measure BAT activity.

All subjects will be fully informed of the aims, nature, and risks of the study prior to giving written informed consent.

Related Conditions & MeSH terms

• Polycystic Ovary Syndrome

Intervention

Drug:
• Mirabegron
Women will take 100mg daily for 4 weeks. Men will take 200mg daily for 4 weeks. The medication is available in 50 mg tablets.

Other:
• B Complex Plus Vitamin C Tablets
Males will be randomized to take placebo versus active drug (mirabegron). Those taking placebo will take 4 tablets each day to mirror to active group (taking 4 tablets of 50 mg each).

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (1)

O'Mara AE, Johnson JW, Linderman JD, Brychta RJ, McGehee S, Fletcher LA, Fink YA, Kapuria D, Cassimatis TM, Kelsey N, Cero C, Sater ZA, Piccinini F, Baskin AS, Leitner BP, Cai H, Millo CM, Dieckmann W, Walter M, Javitt NB, Rotman Y, Walter PJ, Ader M, Bergman RN, Herscovitch P, Chen KY, Cypess AM. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. J Clin Invest. 2020 May 1;130(5):2209-2219. doi: 10.1172/JCI131126. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cohorts 1 and 2: Change in BAT metabolic activity	Change in brown adipose tissue (BAT) metabolic activity as measured by 18FFDG PET/CT	4 weeks
Primary	Cohort 3: Change in insulin sensitivity	Change in glucose infusion rate, as measured by the hyperinsulinemic euglycemic clamp	4 weeks
Secondary	Identify changes in metabolic health arising from BAT activation and/or prolonged treatment with mirabegron	Change in metabolic health parameters including body weight, fat mass, glucose tolerance, changes in levels of hormones, and improved liver function	4 weeks
Secondary	Cohort 3: Changes in BAT metabolic activity	Change in brown adipose tissue (BAT) metabolic activity as measured by 18FFDG PET/CT	4 weeks
Secondary	Cohorts 1 and 2: Changes in insulin sensitivity	Changes in glucose infusion rate, as measured by the hyperinsulinemic euglycemic clamp	4 weeks

External Links

•   NIH Clinical Center Detailed Web Page