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    Clinical Trial Results:
    The effect of sitagliptin on brown adipose tissue and whole-body metabolism in overweight pre-diabetic men

    Summary
    EudraCT number
    		 2014-003532-39
    Trial protocol
    		 NL  
    Global end of trial date
    01 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions
    Summary report(s)
    		 Nahon et al, Diabetologia 2018

    Trial information

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    Trial identification
    Sponsor protocol code
    SitaBAT01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02294084
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Leiden University Medical Center
    Sponsor organisation address
    Albinusdreef 2, Leiden, Netherlands, 2333 ZA
    Public contact
    dr MR Boon (m.r.boon@lumc.nl), Leiden University Medical Center, 0031 648126425, m.r.boon@lumc.nl
    Scientific contact
    dr MR Boon (m.r.boon@lumc.nl), 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 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main object of the trial is to evaluate the effect of sitagliptin treatment on BAT activity in overweight, pre-diabetic subjects.
    Protection of trial subjects
    Subjects were placed in a comfortable room and at any time, a medical doctor was present during the study days to make subjects feel safe and comfortable.
    Background therapy
    		 Half of the subjects received the approved medicine Sitagliptin (100 mg/day) for 12 weeks and half of the subjects a placebo. Sitagliptin is a DPP4 inhibitor that increases the action of the intestinal hormone GLP-1. This medicine is currently used in the treatment of type 2 diabetes mellitus.
    Evidence for comparator
    		 The dipeptidyl peptidase-4 (DPP4) inhibitor sitagliptin, which enhances the bioavailability of incretin hormones, improves both glucose tolerance and lipid metabolism in individuals with type 2 diabetes, thereby targeting both microvascular and macrovascular complications. The precise mechanism by which sitagliptin exerts these positive metabolic effects remains largely unknown and in the current study, we aimed to study whether it worked by enhancing activity of metabolically active brown adipose tissue.
    Actual start date of recruitment
    01 Jan 2015
    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: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from approximately June 2015 until October 2016. Recruitment was done via advertisements.

    Pre-assignment
    Screening details
    		 We performed a thorough medical history and physical examination. Furthermore, we performed anthropometric measurements and assessed a venous blood sample to exclude the presence of type 2 diabetes, liver and kidney disease. In addition, we performed an OGTT.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    On forehand, an unblinded pharmacist set up a list in which each study subject number was coupled to a box number. All boxes (sitagliptin and placebo) were labeled together with a component ID list (this contained the information which box holded the placebo or sitagliptin). The pharmacy then gave out the boxes according to the randomisation list. Therefore, the study was conducted double blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sitagliptin
    Arm description
    		 Sitagliptin (100 mg/day) treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/day per os, for 12 weeks in total

    Arm title
    		 Placebo
    Arm description
    		 Placebo treatment
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet 100 mg, in total 12 weeks treatment

    Number of subjects in period 1
    		Sitagliptin Placebo
    Started
    15
    15
    Start with study
    15
    15
    Completed
    15
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    		 Sitagliptin (100 mg/day) treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo treatment

    Reporting group values
    		 Sitagliptin Placebo Total
    Number of subjects
    		 15 15 30
    Age categorical
    Subjects were between 35 and 50 years old.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 15 15 30
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Subjects were between 35 and 50 years.
    Units: years
        geometric mean (standard deviation)
    		 45 ( 5 ) 47 ( 4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 15 15 30

    End points

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    End points reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    		 Sitagliptin (100 mg/day) treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo treatment

    Primary: Change in brown adipose tissue activity

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    End point title
    		 Change in brown adipose tissue activity
    End point description
    Before and after 12 weeks of sitagliptin or placebo treatment brown adipose tissue volume and activity were measured using PET-CT scan.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    15
    15
    Units: 0-100
        arithmetic mean (standard error)
    2.3 ( 0.3 )
    2.2 ( 0.2 )
    Attachments
    		 Overview effects brown fat
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    Mixed model analyses with treatment and occasion as fixed effects and subject specific deviances from the mean as random effects were used to assess the effect of the treatment.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.8
         upper limit
    		 2.1
    Variability estimate
    Standard deviation
    Dispersion value
    0.1
    Notes
    [1] - we compared whether sitagliptin was superior to placebo treatment in inducing brown adipose tissue activation
    [2] - We considered a P-vlaue < 0.05 as statistically significant

    Primary: Change in brown adipose tissue volume

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    End point title
    		 Change in brown adipose tissue volume
    End point description
    Brown adipose tissue volume was measured in mL and was assessed via 18F-FDG PET-CT scan
    End point type
    Primary
    End point timeframe
    Before and after 12 weeks of treatment with sitagliptin and placebo effects on brown adipose tissue volume were measured.
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    15
    15
    Units: mL
        geometric mean (standard error)
    32 ( 13 )
    14 ( 12 )
    Attachments
    		 Overview effects brown fat
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    Mixed model analyses with treatment and occasion as fixed effects and subject specific deviances from the mean as random effects were used to assess the effect of the treatment
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.05 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12
         upper limit
    		 33
    Variability estimate
    Standard deviation
    Dispersion value
    12
    Notes
    [3] - We assessed whether sitagliptin was superior to enhance brown adipose tissue volume compared with placebo
    [4] - We considered a P-value < 0.05 as statistically significant.

    Secondary: Change in incremental glucose during OGTT

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    End point title
    		 Change in incremental glucose during OGTT
    End point description
    see above
    End point type
    Secondary
    End point timeframe
    An OGTT was performed before and 12 weeks after sitagliptin treatment. From this OGTT, amongst others, an incremental glucose was assessed.
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    14
    15
    Units: mmol/L
        arithmetic mean (standard error)
    166 ( 33 )
    371 ( 38 )
    Statistical analysis title
    		 AUC of the incremental glucose (OGTT)
    Statistical analysis description
    Mixed model analysis was used to assess differences in the AUC of the incremental glucose during OGTT
    Comparison groups
    Placebo v Sitagliptin
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    P-value
    		 < 0.003 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 4.1
    Notes
    [5] - Mixed model analysis was used
    [6] - We also assessed the P-value for the difference between t=0 and t=12 weeks, this was also P<0.003

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    during the 12 week treatment period we assess adverse events.
    Adverse event reporting additional description
    We assessed this by weekly calling the study subjects.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 via sponsor
    Dictionary version
    1
    Reporting groups
    Reporting group title
    sitagliptin
    Reporting group description
    		 subjects who received sitagliptin treatment (100 mg/day)

    Reporting group title
    placebo
    Reporting group description
    		 subjects that received placebo treatment for 12 weeks

    Serious adverse events
    		 sitagliptin placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 sitagliptin placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    14
    14

    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 overview, we only report on the effects on brown adipose tissue. The very interesting effects on secondary parameters (glucose and lipid metabolism) can be read in the manuscript that is attached.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30145664
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    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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