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    Clinical Trial Results:
    Effects of Linagliptin on active GLP-1 concentrations in subjects with renal impairment

    Summary
    EudraCT number
    		 2013-000364-28
    Trial protocol
    		 DE  
    Global end of trial date
    22 Apr 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    00/0594-LINARI
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01903070
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Profil Institut für Stoffwechselforschung GmbH
    Sponsor organisation address
    Hellersbergstr. 9, Neuss, Germany, 41460
    Public contact
    RA, Profil Institut für Stoffwechselforschung GmbH, +49 21314018145, regulatory@profil.com
    Scientific contact
    RA, Profil Institut für Stoffwechselforschung GmbH, +49 21314018145, regulatory@profil.com
    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
    07 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To quantify differences in GLP-1 concentrations following glucose challenge between subjects with T2DM with or without renal impairment before and after linagliptin therapy
    Protection of trial subjects
    To further decrease the risk for hypoglycemia during the study, subjects will be asked to assess their plasma glucose at least 3x/day during the intensification of the treatment and to immediately report any change in hypoglycemia or hyperglycemia occurrence. The dose of insulin can be adapted during the course of the study as judged by the investigator in order to avoid hypo- or hyperglycemia.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Jul 2013
    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
    Germany: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment occured in three trial centres in Germany

    Pre-assignment
    Screening details
    		 In total, 115 subjects were screened and 31 subjects were included in the trial (15 subjects with normal renal function and 16 subjects with impaired renal function) and randomised to one of the two possible test visit sequences. A total of 30 subjects completed the trial.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1st arm
    Arm description
    		 normal renal function: glomerular filtration rate [GFR] > 90 mL/min
    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
    TRAJENTA® (linagliptin) 5 mg tablets; 1 tablet/day for 9 to max 12 days in total.

    Arm title
    		 2nd arm
    Arm description
    		 impaired renal function (glomerular filtration rate [GFR] < 60 mL/min)
    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
    TRAJENTA® (linagliptin) 5 mg tablets; 1 tablet/day for 9 to max 12 days in total.

    Number of subjects in period 1
    		1st arm 2nd arm
    Started
    15
    16
    Completed
    15
    15
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1st arm
    Reporting group description
    		 normal renal function: glomerular filtration rate [GFR] > 90 mL/min

    Reporting group title
    2nd arm
    Reporting group description
    		 impaired renal function (glomerular filtration rate [GFR] < 60 mL/min)

    Reporting group values
    		 1st arm 2nd arm Total
    Number of subjects
    		 15 16 31
    Age categorical
    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)
    		 12 9 21
        From 65-84 years
    		 3 7 10
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 56.0 (46 to 74) 64.0 (54 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 1 7 8
        Male
    		 14 9 23
    Ethnic group
    Units: Subjects
        Caucasian
    		 14 16 30
        Tunisian
    		 1 0 1
    Weight
    Units: kg
        arithmetic mean (full range (min-max))
    		 93.97 (72.9 to 137.8) 98.72 (75.0 to 133.9) -

    End points

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    End points reporting groups
    Reporting group title
    1st arm
    Reporting group description
    		 normal renal function: glomerular filtration rate [GFR] > 90 mL/min

    Reporting group title
    2nd arm
    Reporting group description
    		 impaired renal function (glomerular filtration rate [GFR] < 60 mL/min)

    Subject analysis set title
    Efficacy analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The analysis of pharmacodynamic endpoints was based on the Pharmacodynamic Analysis Set including the 31 randomised subjects.

    Primary: Change in active GLP-1 concentrations after oral glucose ingestion after linagliptin treatment compared between groups

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    End point title
    		 Change in active GLP-1 concentrations after oral glucose ingestion after linagliptin treatment compared between groups
    End point description
    End point type
    Primary
    End point timeframe
    0-240min
    End point values
    		 1st arm 2nd arm
    Number of subjects analysed
    15
    15
    Units: pmol*h/L
        median (full range (min-max))
    6.16 (-1.9 to 13.5)
    6.05 (-2.6 to 16.6)
    Statistical analysis title
    		 Primary Endpoint
    Statistical analysis description
    Statistical Analysis of ΔAUCIntact GLP-1,OGTT,0-240min, change in active (intact) GLP-1 concentrations during an OGTT from Day 0/1 to Day 9/10 between the two groups (with vs. without renal impairment)
    Comparison groups
    1st arm v 2nd arm
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall trial
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Normal Renal Function
    Reporting group description
    		 -

    Reporting group title
    Renal Impairment
    Reporting group description
    		 -

    Serious adverse events
    		 Normal Renal Function Renal Impairment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
    Additional description: This was a non-treatment emergent SAE (hepatocellular carcinoma) reported in Subject 306 (renal impairment) with start date 50 days before first planned linagliptin treatment.
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         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: 5%
    Non-serious adverse events
    		 Normal Renal Function Renal Impairment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 15 (26.67%)
    6 / 15 (40.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nervous system disorders
    Concussion
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    2 / 15 (13.33%)
    3 / 15 (20.00%)
         occurrences all number
    2
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Hunger
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Hiccups
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Nervousness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Groin pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 May 2013
    The possibility of pancreatitis due to exposure to Linagliptinin very rare cases was added in the benefit-risk assessment. Details for contraceptive measures for female subjects were added to the inclusion criteria.
    09 Apr 2015
    Due to recruitment problems some in- and exclusion criteria were slighlty adapted.

    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
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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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