Understanding how brown fat responds to a medication for weight management

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

This study is testing how a weight management medication affects brown fat in young adults to see if it helps improve metabolism and insulin sensitivity.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 100 (estimated)
• Ages: 18 Years to 40 Years
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (NIH)
• Drugs / interventions: radiation
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT03049462 on ClinicalTrials.gov

What this trial studies

This study investigates the physiological responses and adaptations of brown adipose tissue (BAT) to chronic treatment with the beta3-adrenergic receptor agonist mirabegron. Participants aged 18-40 with varying body mass indices will undergo a series of tests, including metabolic assessments and imaging, to evaluate changes in BAT activity and insulin sensitivity after four weeks of treatment. The study is divided into cohorts based on gender and specific health criteria, focusing on the metabolic health implications of BAT activation. The methodology includes cold exposure tests and metabolic rate monitoring to gather comprehensive data on energy expenditure.

Who should consider this trial

Good fit: Ideal candidates are healthy men and women aged 18-40 with a BMI between 18 and 40, or women with a diagnosis of polycystic ovary syndrome (PCOS).

Not a fit: Patients outside the age range of 18-40 or those with significant health issues unrelated to the study's focus may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to new treatments for obesity and related metabolic disorders by enhancing our understanding of brown fat's role in energy metabolism.

How similar studies have performed: While the specific approach of this study is novel, previous research has indicated potential benefits of targeting brown adipose tissue for metabolic health improvements.

Eligibility criteria

* INCLUSION CRITERIA

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

Cohort 1: (complete)

1. Female
2. Age 18-40 years
3. BMI 18.00-40.0 kg/m\^2
4. Able to understand the research and willing to sign a written informed consent document

Cohort 2: (complete)

1. Male
2. Age 18-40 years
3. BMI 18.00-40.0 kg/m\^2
4. Able to understand the research and willing to sign a written informed consent document

Cohort 3:

1. Female
2. Age 18-40 years
3. BMI 25.0-50.0 kg/m\^2 or BMI \> 18.5 kg/m\^2 with PCOS diagnosis
4. Diagnosis of PCOS based on NIH Criteria; defined by the presence of both clinical and/or biochemical signs of hyperandrogenism and oligo- or chronic anovulation.
5. Women of childbearing potential must agree to use a highly effective method of birth control, confirmed by the Investigator, for at least 3 months prior to the first study visit and continuing throughout the study duration.

   a. Highly effective methods of birth control include:

   i. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal

   ii. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable

   iii. Intrauterine device

   iv. Intrauterine hormone-releasing system

   v. Bilateral tubal occlusion

   vi. Sexual abstinence, i.e., refraining from heterosexual intercourse (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant)

   vii. Vasectomized sexual partner (provided that partner is the sole sexual partner of the study participant and that the vasectomized partner has received medical assessment of the surgical success)

   b. Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for \>=12 months prior to the planned date of enrollment without an alternative medical cause.
6. Insulin resistance defined by either

   1. HOMA-IR score \> 5.9 OR
   2. HOMA-IR score \> 2.8 and \<5.9, with HDL \<51 mg/dL OR
   3. Fasting Insulin \> 10.6 microU/mL
7. Able to understand the research and willing to sign a written informed consent document

EXCLUSION CRITERIA

1. Hypersensitivity and associated allergic reactions to mirabegron (or similar drug substances or components)
2. Abnormal bladder function, diagnosis of bladder outlet obstruction, urinary incontinence, urgency, and urinary frequency or use of antimuscarinic medication to treat overactive bladder (OAB)
3. Type 1 or Type 2 Diabetes mellitus, fasting serum glucose \>125 mg/dL, and/or an HbA1c test \>6.5%
4. Hypertension, defined as blood pressure (Bullet)140/90 mmHg, based on WHO guidelines (https://www.who.int/news-room/fact-sheets/detail/hypertension)
5. Hypo- or hyper-thyroid disease (TSH \>5.0, \<0.4 miU/L) that is controlled for less than one year
6. Anemia, defined by hemoglobin \< 11.3 g/dL (females) or \< 13.8 g/dL (males); sickle cell anemia or other blood disorders; and/or wound healing problems
7. Cardiovascular disease, cardiac arrhythmias, orthostasis, unstable vasomotor system, or renal impairment
8. A clinically significant abnormal ECG and/or QTc interval above normal
9. Elevated liver enzymes with probable or diagnosed liver disease (other than fatty liver disease)
10. Psychological conditions such as claustrophobia, untreated clinical depression or anxiety, untreated bipolar disorders, or forms of mental incapacity that would be incompatible with safe and successful participation in this study
11. Recent history in last 4 weeks of any local or systemic infectious disease with fever or requiring antibiotics
12. Self-reported intolerance of cold that would prevent the individual from spending several hours in a chilled room with a cooling vest
13. Current use of any drugs known to:

    * have major drug-drug interactions with mirabegron
    * Prolong QT interval
    * Alter glucose metabolism or cause insulin resistance (in last six months)
    * Treat diabetes mellitus
    * Treat hypertension
    * Be drugs of abuse
14. Self-reported weight loss or weight gain \> 5% in the preceding 6 months.
15. Pregnancy, childbirth within the last year, or breastfeeding in the past 12 months
16. 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.
17. Addiction to alcohol or substances of abuse within the last 5 years
18. Self-reported current alcohol consumption of more than 2 servings of alcohol per day
19. Self-reported current use of nicotine and/or tobacco products
20. Has participated in a clinical trial with an investigational or marketed drug within 2 months
21. 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
22. Donated blood within last 2 months
23. Unwilling or unable to eat metabolic meals, as determined by dietitian consult.
24. Any other circumstances or criteria that would preclude safe participation in the study in the clinical judgment of the investigator

Where this trial is running

Bethesda, Maryland

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (Recruiting)

Study contacts

• Principal investigator: Aaron M Cypess, M.D. — National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Study coordinator: Ashley M Schmitz, C.R.N.P.

Conditions Polycystic Ovary Syndrome; Brown Adipose Tissue; Energy Expenditure; Energy Metabolism; Obesity