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Mirabegron and Brown Adipose Tissue (Mirab)

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ClinicalTrials.gov Identifier: NCT03012113
Recruitment Status : Unknown
Verified January 2017 by Ingrid Jazet, Leiden University Medical Center.
Recruitment status was:  Recruiting
First Posted : January 6, 2017
Last Update Posted : January 6, 2017
Sponsor:
Information provided by (Responsible Party):
Ingrid Jazet, Leiden University Medical Center

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Obesity Drug: Mirabegron Other: Short term mild cooling Drug: Placebo Oral Capsule Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: The Effect of Mirabegron on Brown Adipose Tissue in Healthy Young White Caucasian and South Asian Men
Study Start Date : June 2016
Estimated Primary Completion Date : June 2017
Estimated Study Completion Date : September 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Mirabegron

Arm Intervention/treatment
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 Name: 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



Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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



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 30 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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

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): NCT03012113


Contacts
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Contact: Ingrid Jazet, MD +31 75262997 i.m.jazet@lumc.nl

Locations
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Netherlands
Leiden University Medical Center Recruiting
Leiden, Zuid-Holland, Netherlands, 2333 ZA
Contact: Ingrid Jazet, MD, PhD    +33-715268161    i.m.jazet@lumc.nl   
Contact: Mariëtte Boon, PhD    +31-715265462    m.r.boon@lumc.nl   
Sponsors and Collaborators
Ingrid Jazet
Investigators
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Principal Investigator: Ingrid Jazet, MD Leiden University Medical Center

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Responsible Party: Ingrid Jazet, Dr, Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT03012113     History of Changes
Other Study ID Numbers: P16.023
First Posted: January 6, 2017    Key Record Dates
Last Update Posted: January 6, 2017
Last Verified: January 2017
Keywords provided by Ingrid Jazet, Leiden University Medical Center:
Adipose tissue
Type 2 Diabetes
Additional relevant MeSH terms:
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Mirabegron
Adrenergic beta-3 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Urological Agents