Clinical Trial Results:
The effect of Mirabegron on brown adipose tissue in healthy young white Caucasian and South Asian men
Summary
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EudraCT number |
2016-000237-48 |
Trial protocol |
NL |
Global end of trial date |
10 Aug 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Dec 2021
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First version publication date |
01 Dec 2021
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Other versions |
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Summary report(s) |
Published article |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MiraBAT01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03012113 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Leiden University Medical Center
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Sponsor organisation address |
Albinusdreef 2, Leiden, Netherlands, 2333 ZA
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Public contact |
Clinical trial information, Leiden University Medical Center, 0031 648126425, m.r.boon@lumc.nl
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Scientific contact |
Clinical trial information, Leiden University Medical Center, 0031 648126425, m.r.boon@lumc.nl
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Sponsor organisation name |
Leiden University Medical Center
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Sponsor organisation address |
Albinusdreef 2, Leiden, Netherlands, 2333 ZA
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Public contact |
Mariëtte Boon, Leiden University Medical Center, 0031 648126425, m.r.boon@lumc.nl
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Scientific contact |
Mariëtte Boon, Leiden University Medical Center, 0031 648126425, m.r.boon@lumc.nl
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
02 Jan 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
11 Jul 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Aug 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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Protection of trial subjects |
Subjects were made as comfortable as possible during the study days.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Apr 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 20
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Worldwide total number of subjects |
20
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EEA total number of subjects |
20
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
20
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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
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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
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Period 1 title |
Baseline (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Arm title
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Baseline period | ||||||
Arm description |
Baseline period | ||||||
Arm type |
Active comparator | ||||||
Investigational medicinal product name |
mirabegron
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
200 mg, divided in 4 tablets of 50 mg
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Investigational medicinal product name |
placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
200 mg, divided in 4 tablets of 50 mg
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Baseline characteristics reporting groups
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Reporting group title |
Baseline
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Reporting group description |
Baseline characteristics for South Asian (n=10) and white Caucasian (n=10) subjects | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Cold exposure
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Effects of cold exposure
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Subject analysis set title |
Mirabegron
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Effects of mirabegron treatment
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Subject analysis set title |
Placebo
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Placebo treatment
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End points reporting groups
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Reporting group title |
Baseline period
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Reporting group description |
Baseline period | ||
Subject analysis set title |
Cold exposure
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Effects of cold exposure
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Subject analysis set title |
Mirabegron
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Effects of mirabegron treatment
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Subject analysis set title |
Placebo
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Placebo treatment
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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.
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End point type |
Primary
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End point timeframe |
2 hours after cold exposure, mirabegron or placebo treatment
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Attachments |
Untitled (Filename: BAT FF figure.docx) |
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Statistical analysis title |
Fat fraction analysis | ||||||||||||||||
Statistical analysis description |
One-way ANOVA was performed to study differences in BAT parameters between treatments
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Comparison groups |
Mirabegron v Cold exposure v Placebo
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [1] | ||||||||||||||||
P-value |
< 0.01 [2] | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
2.5
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Confidence interval |
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level |
90% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.5 | ||||||||||||||||
upper limit |
4.1 | ||||||||||||||||
Variability estimate |
Standard deviation
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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). |
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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.
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End point type |
Primary
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End point timeframe |
2 hours after treatment with cold, placebo or mirabegron
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Attachments |
Untitled (Filename: BAT T2 figure.docx) |
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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!
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Comparison groups |
Cold exposure v Mirabegron v Placebo
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [3] | ||||||||||||||||
P-value |
> 0.05 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
3.7
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Confidence interval |
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level |
90% | ||||||||||||||||
sides |
2-sided
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lower limit |
-3.5 | ||||||||||||||||
upper limit |
10.8 | ||||||||||||||||
Variability estimate |
Standard deviation
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Notes [3] - See description FF |
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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
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End point type |
Primary
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End point timeframe |
2 hours after treatment with cold, placebo or mirabegron
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Attachments |
Untitled (Filename: BAT volume figure.docx) |
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Statistical analysis title |
BAT volume | ||||||||||||||||
Statistical analysis description |
see description under BAT FF
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Comparison groups |
Cold exposure v Mirabegron v Placebo
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [4] | ||||||||||||||||
P-value |
> 0.05 [5] | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.24
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.23 | ||||||||||||||||
upper limit |
0.4 | ||||||||||||||||
Notes [4] - see description under BAT FF [5] - For all comparisons, P-value was > 0.05 |
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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.
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End point type |
Secondary
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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.
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Attachments |
Energy expenditure |
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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.
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Comparison groups |
Mirabegron v Placebo v Cold exposure
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [6] | ||||||||||||||||
P-value |
< 0.05 [7] | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.1
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.03 | ||||||||||||||||
upper limit |
0.17 | ||||||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
0.09
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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 |
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Adverse events information
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Timeframe for reporting adverse events |
7 hours (during the whole study day)
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Adverse event reporting additional description |
We studied the occurence of adverse events following either cold treatment or the other treatments (placebo and mirabegron)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
CPMP | ||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
Cold exposure
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Reporting group description |
Subjects that were exposed to 2 hours of cold exposure | ||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Mirabegron
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Reporting group description |
Subjects that received mirabegron treatment | ||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects that received a placebo capsule | ||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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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 |
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http://www.ncbi.nlm.nih.gov/pubmed/32558052 |