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Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta 3-Adrenergic Receptor Agonists

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03049462
Recruitment Status : Recruiting
First Posted : February 10, 2017
Last Update Posted : October 28, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )

Brief 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:

Healthy 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.

...


Condition or disease Intervention/treatment Phase
Polycystic Ovary Syndrome Healthy Volunteers Drug: Mirabegron Other: B Complex Plus Vitamin C Tablets Phase 1

Detailed 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 , 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta-3-Adrenergic Receptor Agonists
Actual Study Start Date : March 13, 2017
Estimated Primary Completion Date : October 1, 2021
Estimated Study Completion Date : October 1, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Mirabegron

Arm Intervention/treatment
Experimental: Cohort 1
Females taking 100 mg of mirabegron
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.

Active Comparator: Cohort 2A
Males taking 200mg mirabegron
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.

Placebo Comparator: Cohort 2B
Males taking placebo drug
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).

Active Comparator: Cohort 3A
Females taking 100 mg of mirabegron
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.

Placebo Comparator: Cohort 3B
Females taking placebo drug
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).




Primary Outcome Measures :
  1. Cohorts 1 and 2: Change in BAT metabolic activity [ Time Frame: 4 weeks ]
    Change in brown adipose tissue (BAT) metabolic activity as measured by 18FFDG PET/CT

  2. Cohort 3: Change in insulin sensitivity [ Time Frame: 4 weeks ]
    Change in glucose infusion rate, as measured by the hyperinsulinemic euglycemic clamp


Secondary Outcome Measures :
  1. Identify changes in metabolic health arising from BAT activation and/or prolonged treatment with mirabegron [ Time Frame: 4 weeks ]
    Change in metabolic health parameters including body weight, fat mass, glucose tolerance, changes in levels of hormones, and improved liver function

  2. Cohort 3: Changes in BAT metabolic activity [ Time Frame: 4 weeks ]
    Change in brown adipose tissue (BAT) metabolic activity as measured by 18FFDG PET/CT

  3. Cohorts 1 and 2: Changes in insulin sensitivity [ Time Frame: 4 weeks ]
    Changes in glucose infusion rate, as measured by the hyperinsulinemic euglycemic clamp



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • 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 20.0-45.0 kg/m2
    • Diagnosis on Polycystic Ovary Syndrome (PCOS) based on NIH Criteria with documentation from physician s note or laboratory reports confirming diagnosis with actual hormonal values and menstrual history. Women with a history of either partial hysterectomy or endometrial ablation can be included.
    • Use monophasic oral contraceptives and with stable use for at least 3 months
  • 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 (history or TSH >5.0, <0.4 miU/L); L-T4 replacement
  • Hypersensitivity and associated allergic reactions to mirabegron or similar drug substances or components of this medication
  • Anemia, defined by Hemoglobin less than or equal to 13.7 g/dL (males) or 11.2 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 inhibitors
  • 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, clinical depression, bipolar disorders, or forms of mental incapacity that would be incompatible with safe and successful participation in this study
  • Addiction to alcohol or substances of abuse within the last 5 years; self-reported current use of drugs or alcohol
  • Irregular menstrual cycle or menstrual cycle lasting fewer than 25 days or longer than 31 days, 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03049462


Contacts
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Contact: Joyce D Linderman, R.N. (301) 451-7006 lindermanj@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Aaron M Cypess, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Additional Information:
Publications:
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Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT03049462    
Other Study ID Numbers: 170054
17-DK-0054
First Posted: February 10, 2017    Key Record Dates
Last Update Posted: October 28, 2020
Last Verified: October 23, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):
Brown Adipose Tissue
Energy Expenditure
Energy Metabolism
Obesity
Additional relevant MeSH terms:
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Polycystic Ovary Syndrome
Ovarian Cysts
Cysts
Neoplasms
Ovarian Diseases
Adnexal Diseases
Gonadal Disorders
Endocrine System Diseases
Ascorbic Acid
Mirabegron
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Adrenergic beta-3 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Urological Agents