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

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ClinicalTrials.gov Identifier: NCT03049462
Recruitment Status : Recruiting
First Posted : February 10, 2017
Last Update Posted : April 11, 2019
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
Healthy Volunteers Drug: Mirabegron Other: Placebo 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 insulinreleasing 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 beta 3-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 days while an inpatient on the Metabolic Patient Care Unit at the NIH Clinical Center. Participants will then take the medication or placebo for four weeks during which time they will continue their standard daily routines. At two weeks, participants will return for one day for the assessment of any interim changes and to validate safety. At the end of the four weeks there will be a second set of inpatient testing over two 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 the change in BAT metabolic activity as measured by 18F-FDG PET/CT. 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 : 75 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 50mg tablets.

Placebo Comparator: Cohort 2
B Complex Plus Vitamin C Tablets-Placebo
Other: Placebo
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 3
Males taking 200 mg mirabegron
Drug: Mirabegron
Women will take 100mg daily for 4 weeks. Men will take 200mg daily for 4 weeks. The medication is available in 50mg tablets.




Primary Outcome Measures :
  1. The primary outcome is the change in BAT metabolic activity as measured by 18FFDG PET/CT. [ Time Frame: 12/31/2020 ]
    to determine if there is more brown fat volume and/or activity with the intervention compared to placebo.


Secondary Outcome Measures :
  1. Secondary endpoints will examine multiple other factors, including body weight, fat mass, glucose tolerance, changes in levels of hormones, and improved liver function. [ Time Frame: ongoing ]


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:

Men and Women ages 18-40 years

  • All ethnicities
  • BMI 18.0-40.0 kg/m2

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 >140 mg/dL), an HbA1c test >7.0%, 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 or other iron deficiency (Ferritin <15 mcg/L for women and <30 mcg/L for men)
  • 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 (MAO) 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; current use of drugs or alcohol (CAGE greater than or equal to 2)
  • 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, or received 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
  • Has elevated liver enzymes and is believed to have liver disease other than fatty liver disease,
  • 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.

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     History of Changes
Other Study ID Numbers: 170054
17-DK-0054
First Posted: February 10, 2017    Key Record Dates
Last Update Posted: April 11, 2019
Last Verified: January 14, 2019

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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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Mirabegron
Adrenergic Agents
Adrenergic Agonists
Adrenergic beta-3 Receptor Agonists
Adrenergic beta-Agonists
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Urological Agents