Mirabegron and Brown Adipose Tissue (Mirab)

January 4, 2017 updated by: Ingrid Jazet

The Effect of Mirabegron on Brown Adipose Tissue in Healthy Young White Caucasian and South Asian Men

Obesity and type 2 diabetes (T2D) are emerging problems worldwide. In particular South Asian individuals (representing 20% of the world population) have an increased risk of obesity and related disorders. They are at higher risk for the development of T2D as compared to white Caucasians and develop T2D at a younger age and with lower BMI. The underlying mechanisms that might explain these ethnical differences have not been clarified or understood yet. As a consequence, treatment options are limited and unfocussed, and novel specific strategies are needed.

Brown adipose tissue (BAT) has recently been discovered as a major player in energy metabolism in humans. In a process known as thermogenesis, BAT takes up fatty acids (FA) and glucose from the circulation and subsequently combusts FA and glucose into heat, thereby increasing energy expenditure and improving glucose and FA metabolism. Using 18F-fluorodeoxyglucose (18F-FDG) (positron emission tomography/computed tomography) PET-CT scan analysis investigators have recently shown that South Asian individuals have less brown adipose tissue (BAT) than white Caucasians. This might suggest that they have a lower energy metabolism, which could underlie their increased predisposition for obesity and the development of T2D.

Activation of BAT, for example by cold exposure, was shown to have beneficial metabolic effects in humans. Cold acclimatization can increase BAT volume, nonshivering thermogenesis, glucose uptake by BAT, as well as decrease fat mass in healthy young men. Therefore activation of BAT is considered as a novel therapeutic target in the treatment of obesity and T2D. As cold exposure is not the most desired therapeutic strategy for humans, current pre-clinical research focuses on pharmacological activation of BAT.

β3-receptor agonists can be used to mimic sympathetic innervation of BAT. Our recent studies using mice with a human-like lipoprotein profile showed that treatment with a β3-receptor agonist decreased fat mass, improved dyslipidemia, increased insulin sensitivity and even attenuated the development of atherosclerosis. Likewise, the novel β3-receptor agonist (Mirabegron) has recently been shown to activate BAT in healthy young men as effectively as cold exposure. Therefore, ß3-receptor agonism would be a promising treatment option to activate BAT and enhance energy expenditure, especially for South Asians.

Currently the most common way to visualize BAT in humans is by 18F-FDG PET-CT scan. However this method is both expensive and invasive, as it uses ionizing radiation. Recently, MRI, which has no radiation burden, has emerged as a novel method to visualize BAT in humans. Activation of BAT results in combustion of intracellular lipid stores, which eventually leads to a lower triglyceride (TG) content. MRI can measure TG content of tissue, and using MRI technology the activation of BAT can be quantified by the relative reduction in the TG content of BAT. The use of MRI to visualize and quantify BAT activity is a safe, cost-effective and innovative alternative to PET-CT, which has a potential to become a new gold standard in the nearby future.

To investigate whether β3-receptor agonism has therapeutic potential to improve the metabolic phenotype of South Asians, investigators will perform a randomized cross-over study in which 20 healthy young men aged 18-30 years with a lean body type (BMI <25 kg/m2) are included. Dutch South Asian individuals (n=10) and matched Dutch white Caucasian individuals (n=10) will participate in a cross-over study consisting of three different regimes.

This study will investigate whether β3-receptor agonism has therapeutic potential to improve the metabolic phenotype of South Asians. The effects of a β3-receptor agonist on BAT activity in South Asians have never been studied before. Elucidating the effects of this β3-receptor agonist on BAT activity in South Asians might have major clinical implications, as it might result in the discovery of a potential novel treatment strategy to combat obesity and T2D in this especially vulnerable population.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

In the current study, the effect of one single dose of Mirabegron (200 mg) versus placebo and cold-exposure will be studied in health young (18-30 years) Dutch South Asian (n=10) and Dutch Caucasian (n=10) men.

All study subjects will be screened. If the subject meets all the inclusion criteria, is willing to participate in the study and has signed the informed consent, he will be included. All subjects will be asked not to make any changes in their usual diets and physical activities before the start of the whole study.

At screening a thorough medical history and physical examination will be performed. Subjects will be examined while in the fasting state. Anthropometric measurements will be performed as well as a BIA measurement for determination of body fat percentage and basal blood sample will be taken by means of a venapunction. Basal blood measurements include kidney, liver, thyroid, hemoglobulin, natrium, kalium, ureum and lipid parameters as well as glucose concentrations.

If subjects are eligible to participate they first will complete Study day 1, on which we will measure BAT activity and volume before and after cold exposure. Subject will undergo a baseline oxycon and finapres measurement to determine REE and blood pressure and heart rate (30 min). After this a baseline MRI scan will be made followed by an individualized cooling protocol so that the maximum non-shivering thermogenesis is reached. During the cold exposure, skin temperature will be measured via 'iButtons'. One iButtons will be placed under the armpit as an approximation of the 'core temperature'. When shivering temperature is reached, stable cooling period will start (t=0). After 30 minutes of stable cold exposure (t=30) REE and blood pressure and heart rate will be analyzed a second time using a ventilated hood system and the finapres. Thereafter (t=60) BAT activity and volume will be measured using a second MRI scan. Furthermore, during the cooling procedure a venous blood sample will be obtained every 15 minutes to monitor dynamic changes in plasma lipids. In addition, plasma catecholamine concentrations will be determined. If there is no increased BAT activity upon cold stimulation the subject will be excluded from further participation in the study. If there is detectable BAT activity on Study day 1, subjects will participate in Study days 2 and 3 and will be randomized to receive first Mirabegron or placebo to minimize bias.

On study day 2 first baseline oxycon and finapres measurements will be performed to determine REE and blood pressure and heart rate (30 min). Thereafter, the subject will receive a single dose of 200 mg Mirabegron (four tables of 50 mg) (or placebo) (t=0). Again skin temperature will be measured via 'iButtons'. One iButton will be placed under the armpit as an approximation of the 'core temperature'. After 1, 2 and 3 hours (t=60, t=120 and t=180) REE is analyzed using a ventilated hood system and blood pressure and heart rate are monitored using the finapres. Thereafter, 3.5 hours after the administration of the compound (t=210) BAT activity and volume will be determined using an MRI scan. Furthermore, a venous blood sample will be drawn every 15 minutes to monitor changes in plasma lipids. In addition, plasma catecholamine concentrations will be determined.Study day 3 is exactly the same as study day 2, except this time the subject will receive the other compound (either 200 mg Mirabegron or placebo).

All study days will take place at the Leiden University Medical Centre (LUMC). Between study days 2 and 3 a wash-out period of 13 days will be maintained to make sure that the drug is out of the body during the next exam.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
20

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

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Study Locations

  • Netherlands
    • Zuid-Holland
      • Leiden, Zuid-Holland, Netherlands, 2333 ZA
        • Recruiting
        • Leiden University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 26 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • Male volunteers. 10 white Caucasians, born in the Netherlands. 10 South Asians, living in the Netherlands.
  • Age: 18-30 years
  • BMI ≤ 25 kg/m2

Exclusion Criteria:

  • BMI > 25 kg/m2
  • Recent excessive weight loss or exercise
  • Alcohol and/ or drugs abuse
  • Smoking
  • Any significant chronic disease, including diabetes
  • Renal, hepatic or endocrine disease
  • Heart disease or arrhythmias
  • Thyroid disease or thyroid medication
  • Hypertension
  • Use of medication known to influence glucose and/or lipid metabolism or BAT activity (e.g. beta blockers or calcium channel blockers)
  • Use of drugs that influence cardiac function or affect QT time
  • Use of MAO inhibitor
  • Use of systemic corticosteroids in previous six weeks
  • Recent participation in other research projects (within the last 3 months), participation in 2 or more projects in one year
  • Contraindications for undergoing an MRI scan:
  • Presence of non-MR safe metal implants or objects in the body.
  • Pacemaker, neurostimulator, hydrocephalus pump, drug pump, non-removable hearing aid, large recent tattoos.
  • Claustrophobia
  • Tinnitus or hyperacusis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Other: Short term mild cooling
Subjects will undergo a short term mild cooling protocol consisting of personalized water cooling method for approximately 2 hours.
Other: Short term mild cooling
Active Comparator: Mirabegron
Subjects will receive one dosage of 200 mg Mirabegron (Astellas Pharma).
Drug: Mirabegron
Other Names:
  • Betmiga
Placebo Comparator: Placebo
Subjects will receive one dosage of Placebo, which is packed and labeled to mach the active compound.
Drug: Placebo Oral Capsule

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
The effect of Mirabegron treatment on BAT activity measured by MRI in South Asians compared with white Caucasians.
Time Frame: Up to 1 year
Brown adipose tissue activity will be measured by means of MRI
Up to 1 year

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Effect of Mirabegron treatment on REE between South Asian and white Caucasian individuals.
Time Frame: Up to 1 year
Indirect calorimetry will be performed to asses resting energy expenditure
Up to 1 year
Mild cold exposure and Mirabegron on plasma lipoprotein profiles
Time Frame: Up to 1 year
Use NMR to analyse lipoproteins in venous blood samples taken during the cooling protocol
Up to 1 year
Mirabegron treatment on plasma lipid levels between South Asian and white Caucasian individuals.
Time Frame: Up to 1 year
Use enzymatic assays to determine lipid levels in plasma
Up to 1 year
The effect of Mirabegron treatment on sympathetic output in South Asian and white Caucasian individuals.
Time Frame: Up to 1 year
Measure noradrenalin and adrenaline levels in plasma
Up to 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Ingrid Jazet

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2016

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2017

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 1, 2017

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 15, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 4, 2017

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 6, 2017

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 6, 2017

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 4, 2017

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2017

More Information

Terms related to this study

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Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • P16.023

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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