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    Clinical Trial Results:
    Effects of Linagliptin on endothelial function and global arginine bioavailability ratio in coronary artery disease patients with early diabetes

    Summary
    EudraCT number
    		 2013-000330-35
    Trial protocol
    		 AT  
    Global end of trial date
    28 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jan 2020
    First version publication date
    01 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HS-2012-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02350478
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Graz
    Sponsor organisation address
    Auenbruggerplatz 2, Graz, Austria, 8010
    Public contact
    Harald Sourij, Medizinische Universität Graz, 0043 31638581310, ha.sourij@medunigraz.at
    Scientific contact
    Harald Sourij, Medical University of Graz, 0043 31638581310, ha.sourij@medunigraz.at
    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
    13 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to investigate the impact of a 12 week linagliptin treatment on endothelial function in patients with early type 2 diabetes.
    Protection of trial subjects
    All laboratory results will be reviewed and the reports signed by the study physician who will record whether it is normal, abnormal but not clinically significant, or abnormal and clinically significant. In the latter case, the eligibility of the subject will be reviewed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 49
    Worldwide total number of subjects
    49
    EEA total number of subjects
    49
    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)
    35
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In total 49 randomizations were performed. After randomization, two subjects were excluded due to screening failures without receiving the study medication. Therefore 47 subjects were enrolled in the study and received the study medication. Of those, 3 subjects were lost to follow up without available follow-up data and 1 subject was excluded.

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Linagliptin
    Arm description
    		 Linagliptin 5mg /daily oral
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5mg oral daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    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
    5mg daily oral

    Number of subjects in period 1
    		Linagliptin Placebo
    Started
    25
    24
    Completed
    20
    23
    Not completed
    5
    1
         Lost to follow-up
    3
    1
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Linagliptin
    Reporting group description
    		 Linagliptin 5mg /daily oral

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 Linagliptin Placebo Total
    Number of subjects
    		 25 24 49
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 10 12 22
        From 65-84 years
    		 15 12 27
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.3 ( 7.8 ) 63.3 ( 8.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 5 14
        Male
    		 16 19 35
    Blood pressure systolic
    Units: mmHg
        arithmetic mean (standard deviation)
    		 134 ( 17 ) 128 ( 18 ) -
    Blood pressure disatolic
    Units: mmHg
        arithmetic mean (standard deviation)
    		 79 ( 14 ) 78 ( 10 ) -

    End points

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    End points reporting groups
    Reporting group title
    Linagliptin
    Reporting group description
    		 Linagliptin 5mg /daily oral

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Primary: Changes in Flow Mediated Dilatation

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    End point title
    		 Changes in Flow Mediated Dilatation
    End point description
    Changes in Flow Mediated Dilatation from baseline to 12 weeks
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Linagliptin Placebo
    Number of subjects analysed
    20
    23
    Units: percent
        arithmetic mean (standard deviation)
    0.4 ( 4.8 )
    -0.5 ( 3.0 )
    Statistical analysis title
    		 Group comparison
    Comparison groups
    Placebo v Linagliptin
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Changes in Global Arginine Bioavailability Ratio

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    End point title
    		 Changes in Global Arginine Bioavailability Ratio
    End point description
    Changes in Global Arginine Bioavailability Ratio from Baseline to 12 weeks
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Linagliptin Placebo
    Number of subjects analysed
    20
    23
    Units: percent
        arithmetic mean (standard deviation)
    -0.11 ( 0.35 )
    -0.06 ( 0.39 )
    No statistical analyses for this end point

    Secondary: Changes in Arginine to Ornithine Ratio

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    End point title
    		 Changes in Arginine to Ornithine Ratio
    End point description
    Changes in Arginine to Ornithine Ratio from Baseline to 12 weeks
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Linagliptin Placebo
    Number of subjects analysed
    20
    23
    Units: percent
        arithmetic mean (standard deviation)
    -0.13 ( 0.45 )
    -0.05 ( 0.53 )
    No statistical analyses for this end point

    Secondary: Changes in Soluble cell adhesion molecules-1

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    End point title
    		 Changes in Soluble cell adhesion molecules-1
    End point description
    Changes in Soluble cell adhesion molecules-1 from Baseline to 12 weeks
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Linagliptin Placebo
    Number of subjects analysed
    20
    23
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    -15 (-272 to 103)
    -21 (-134 to 310)
    No statistical analyses for this end point

    Secondary: Changes in Soluble vascular cell adhesion molecule-1

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    End point title
    		 Changes in Soluble vascular cell adhesion molecule-1
    End point description
    Changes in Soluble vascular cell adhesion molecule-1 from Baseline to 12 weeks
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Linagliptin Placebo
    Number of subjects analysed
    20
    23
    Units: ng/mL
        arithmetic mean (standard deviation)
    -34 ( 84 )
    5 ( 130 )
    No statistical analyses for this end point

    Secondary: Changes in Area under curve for glucose

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    End point title
    		 Changes in Area under curve for glucose
    End point description
    Changes in Area under curve for glucose from Baseline to 12 weeks
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Linagliptin Placebo
    Number of subjects analysed
    20
    23
    Units: mg/dL
        arithmetic mean (standard deviation)
    -1135 ( 2619 )
    481 ( 3185 )
    No statistical analyses for this end point

    Secondary: Change in Area under curve for free fatty acids

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    End point title
    		 Change in Area under curve for free fatty acids
    End point description
    Change in Area under curve for free fatty acids from baseline to 12 weeks
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Linagliptin Placebo
    Number of subjects analysed
    20
    23
    Units: µmol/L
        arithmetic mean (standard deviation)
    2 ( 28.4 )
    -3.1 ( 18.3 )
    No statistical analyses for this end point

    Secondary: Changes in Area under curve for insulin

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    End point title
    		 Changes in Area under curve for insulin
    End point description
    changes in Area under curve for insulin from baseline to 12 weeks
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Linagliptin Placebo
    Number of subjects analysed
    20
    23
    Units: mU/L
        arithmetic mean (standard deviation)
    249 ( 4766 )
    40 ( 6357 )
    No statistical analyses for this end point

    Secondary: Changes in Area under curve for c-peptide

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    End point title
    		 Changes in Area under curve for c-peptide
    End point description
    Changes in Area under curve for c-peptide from Baseline to 12 weeks
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Linagliptin Placebo
    Number of subjects analysed
    20
    23
    Units: mg/dL
        arithmetic mean (standard deviation)
    -3 ( 161 )
    -34 ( 211 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Linagliptin
    Reporting group description
    		 Verum Group

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group

    Serious adverse events
    		 Linagliptin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 23 (4.35%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Coordination abnormal
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Prolapse
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Borrelia infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Linagliptin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 20 (15.00%)
    3 / 23 (13.04%)
    Vascular disorders
    Intermittent claudication
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    Cardiac disorders
    Hypotension
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    Nervous system disorders
    Pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0
    General disorders and administration site conditions
    Nausea
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Aug 2013
    Combination of Screening and Baseline Visits
    22 Oct 2013
    Inclusion criterion (max age changed from 75 to 80 years)
    30 Apr 2014
    Exclusion criteria: HbA1c <6.0% (42mmol/mol) instead of HbA1c <6.5 (48mmol/mol)
    24 Oct 2014
    Storage of blood samples in the Biobank (Medical University of Graz)

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29773079
    http://www.ncbi.nlm.nih.gov/pubmed/27733180
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