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    Clinical Trial Results:
    The effect of Mirabegron on brown adipose tissue in healthy young white Caucasian and South Asian men

    Summary
    EudraCT number
    		 2016-000237-48
    Trial protocol
    		 NL  
    Global end of trial date
    10 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Dec 2021
    First version publication date
    01 Dec 2021
    Other versions
    Summary report(s)
    		 Published article

    Trial information

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    Trial identification
    Sponsor protocol code
    MiraBAT01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03012113
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Leiden University Medical Center
    Sponsor organisation address
    Albinusdreef 2, Leiden, Netherlands, 2333 ZA
    Public contact
    Clinical trial information, Leiden University Medical Center, 0031 648126425, m.r.boon@lumc.nl
    Scientific contact
    Clinical trial information, Leiden University Medical Center, 0031 648126425, m.r.boon@lumc.nl
    Sponsor organisation name
    Leiden University Medical Center
    Sponsor organisation address
    Albinusdreef 2, Leiden, Netherlands, 2333 ZA
    Public contact
    Mariëtte Boon, Leiden University Medical Center, 0031 648126425, m.r.boon@lumc.nl
    Scientific contact
    Mariëtte Boon, Leiden University Medical Center, 0031 648126425, m.r.boon@lumc.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of Mirabegron treatment on brown fat activity measured by MRI in South Asians compared with white Caucasians.
    Protection of trial subjects
    Subjects were made as comfortable as possible during the study days.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 20 Participants, of which 10 South Asian and 10 white Caucasian, were enrolled in a randomized, double-blinded, placebo-controlled cross-over study. Participants were recruited through advertisements and by approaching subjects that participated in previous studies.

    Pre-assignment
    Screening details
    		 At screening a thorough medical history and physical examination were performed. Subjects were examined while in the fasting state. Anthropometric measurements were performed as well as a BIA measurement for determination of body fat percentage and basal blood sample was taken to assess kidney, liver, thyroid, Hb and electrolites.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    Beforehand an unblinded pharmacist set up a list in which each study subject number was coupled to a box number. The pharmacy then gave the medication according to the randomisation list. Therefore, the study was conducted double blind. Furthermore, the staff performing the MRI analyses and the laboratory measures only got samples (or the scans) with a subject and occasion number on it.

    Arms
    Arm title
    		 Baseline period
    Arm description
    		 Baseline period
    Arm type
    		 Active comparator

    Investigational medicinal product name
    mirabegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg, divided in 4 tablets of 50 mg

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg, divided in 4 tablets of 50 mg

    Number of subjects in period 1
    		Baseline period
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 Baseline characteristics for South Asian (n=10) and white Caucasian (n=10) subjects

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 20 20
    Age categorical
    Adults
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 20 20
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 20 20
    Subject analysis sets

    Subject analysis set title
    Cold exposure
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Effects of cold exposure

    Subject analysis set title
    Mirabegron
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Effects of mirabegron treatment

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo treatment

    Subject analysis sets values
    		 Cold exposure Mirabegron Placebo
    Number of subjects
    20
    20
    20
    Age categorical
    Adults
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units:
        
    23,6 ± 2,6
    23,6 ± 2,6
    23,6 ± 2,6
    Gender categorical
    Units: Subjects
        Female
    0
    0
    0
        Male
    20
    20
    20

    End points

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    End points reporting groups
    Reporting group title
    Baseline period
    Reporting group description
    		 Baseline period

    Subject analysis set title
    Cold exposure
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Effects of cold exposure

    Subject analysis set title
    Mirabegron
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Effects of mirabegron treatment

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo treatment

    Primary: Brown adipose tissue activity

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    End point title
    		 Brown adipose tissue activity
    End point description
    Brown adipose tissue (BAT) activity was measured using MRI. To this end, we assessed the fat fraction percentage in the left supraclavicular BAT depot. The average fat fraction was computed for pre- and post- cooling and post-mirabegron treatment. Only voxels with a fat fraction between 50-100% were included for data analysis. One participant was excluded from all MRI analyses because of failure to reconstruct the scan due to excessive movement.
    End point type
    Primary
    End point timeframe
    2 hours after cold exposure, mirabegron or placebo treatment
    End point values
    		 Cold exposure Mirabegron Placebo
    Number of subjects analysed
    20
    20
    20
    Units: percentage
        arithmetic mean (standard deviation)
    69 ± 4
    71 ± 4
    73 ± 4
    Attachments
    		 Untitled (Filename: BAT FF figure.docx)
    Statistical analysis title
    		 Fat fraction analysis
    Statistical analysis description
    One-way ANOVA was performed to study differences in BAT parameters between treatments
    Comparison groups
    Mirabegron v Cold exposure v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 < 0.01 [2]
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 4.1
    Variability estimate
    Standard deviation
    Notes
    [1] - Data were analysed using IBM SPSS Statistics for Windows version 22.0 (SPSS Inc, Chicago, IL, USA). All main analyses were also presented per ethnicity (Europids vs. South Asians). However, as we did not observe interaction between ethnicity, treatment and metabolic outcome parameters in any statistical test (all p>0.05), we here show all analyses combined for both ethnicities to increase the statistical power. Of note, in total 20 subjects were in the analysis since it was a crossover design!
    [2] - When both ethnicities were combined in a single analysis, cold exposure lowered BAT fat fraction compared with placebo (−2.3%, P < 0.001). The average BAT fat fraction was lower after mirabegron versus placebo treatment (−1.4%, P <0.01).

    Primary: BAT T2*

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    End point title
    		 BAT T2*
    End point description
    Transverse relaxation time (T2*) was assessed using a three-dimensional six-point chemical-shift encoded gradient echo sequence.
    End point type
    Primary
    End point timeframe
    2 hours after treatment with cold, placebo or mirabegron
    End point values
    		 Cold exposure Mirabegron Placebo
    Number of subjects analysed
    20
    20
    20
    Units: ms
        arithmetic mean (standard deviation)
    16 ± 3
    17 ± 5
    16 ± 3
    Attachments
    		 Untitled (Filename: BAT T2 figure.docx)
    Statistical analysis title
    		 T2*
    Statistical analysis description
    Data were analysed using IBM SPSS Statistics for Windows version 22.0 (SPSS Inc, Chicago, IL, USA). All main analyses were also presented per ethnicity (Europids vs. South Asians). However, as we did not observe interaction between ethnicity, treatment and metabolic outcome parameters in any statistical test (all p>0.05), we here show all analyses combined for both ethnicities to increase the statistical power. Of note, in total 20 subjects were in the analysis since it was a crossover design!
    Comparison groups
    Cold exposure v Mirabegron v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 10.8
    Variability estimate
    Standard deviation
    Notes
    [3] - See description FF

    Primary: BAT volume

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    End point title
    		 BAT volume
    End point description
    BAT volume was calculated through MRI, as mentioned in the Methods section of the manuscript
    End point type
    Primary
    End point timeframe
    2 hours after treatment with cold, placebo or mirabegron
    End point values
    		 Cold exposure Mirabegron Placebo
    Number of subjects analysed
    20
    20
    20
    Units: mL
        arithmetic mean (standard deviation)
    23 ± 9
    23 ± 10
    24 ± 9
    Attachments
    		 Untitled (Filename: BAT volume figure.docx)
    Statistical analysis title
    		 BAT volume
    Statistical analysis description
    see description under BAT FF
    Comparison groups
    Cold exposure v Mirabegron v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    P-value
    		 > 0.05 [5]
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.4
    Notes
    [4] - see description under BAT FF
    [5] - For all comparisons, P-value was > 0.05

    Secondary: Resting energy expenditure

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    End point title
    		 Resting energy expenditure
    End point description
    Resting energy expenditure was measured using indirect calorimetry and expressed as kcal/day.
    End point type
    Secondary
    End point timeframe
    Resting energy expenditure was measured before and at the end of two hours of cold exposure. Furthermore, energy expenditure was measured at baseline and every hour up to 3 hours after treatment with placebo or mirabegron.
    End point values
    		 Cold exposure Mirabegron Placebo
    Number of subjects analysed
    20
    20
    20
    Units: kcal/day
        arithmetic mean (standard deviation)
    1808 ± 384
    1584 ± 264
    1409 ± 291
    Attachments
    		 Energy expenditure
    Statistical analysis title
    		 Energy expenditure
    Statistical analysis description
    Paired T tests were performed to study the effect of cold exposure on energy expenditure (pre- vs post-cold exposure). The effect of mirabegron or placebo on energy expenditure was studied by a repated measures two-way ANOVA with 'time' (0,1,2 and 3 hours) and 'treatment (mirabegron or placebo) as within-subjects factors.
    Comparison groups
    Mirabegron v Placebo v Cold exposure
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    P-value
    		 < 0.05 [7]
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.17
    Variability estimate
    Standard deviation
    Dispersion value
    0.09
    Notes
    [6] - see above
    [7] - Cold exposure significantly increased energy expenditure (P<0.05) Using a two-way ANOVA, we found that mirabegron significantly increased REE compared with placebo, specifically in the second hour of treatment. Below, I show the cold mean difference

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    7 hours (during the whole study day)
    Adverse event reporting additional description
    We studied the occurence of adverse events following either cold treatment or the other treatments (placebo and mirabegron)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CPMP
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Cold exposure
    Reporting group description
    		 Subjects that were exposed to 2 hours of cold exposure

    Reporting group title
    Mirabegron
    Reporting group description
    		 Subjects that received mirabegron treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects that received a placebo capsule

    Serious adverse events
    		 Cold exposure Mirabegron Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cold exposure Mirabegron Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    Nervous system disorders
    headache
    Additional description: Cold exposure group
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Psychiatric disorders
    Feeling of fear
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    In this summary of results, we have only reported on the primary outcome, namely the effects on BAT activity measured by fat fraction. For an extensive overview of results, please see our publication.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32558052
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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