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    Clinical Trial Results:
    Effects of Linagliptin in Addition to Empagliflozin on Islet Cell Physiology and Metabolic Control in Patients with Type 2 Diabetes Mellitus on Stable Metformin Treatment

    Summary
    EudraCT number
    		 2014-004895-48
    Trial protocol
    		 DE  
    Global end of trial date
    09 Dec 2015

    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
    EMLIN-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02401880
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Profil Institut für Stoffwechselforschung GmbH
    Sponsor organisation address
    Hellersbergstr. 9, Neuss, Germany, 41460
    Public contact
    Dr. Christoph Kapitza, Profil Institut für Stoffwechselforschung GmbH, +49 21314018157, regulatory@profil.com
    Scientific contact
    Dr. Christoph Kapitza, Profil Institut für Stoffwechselforschung GmbH, +49 21314018157, christoph.kapitza@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
    08 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Change in glucagon release during liquid meal test (LMT) from Visit 3 (V3) to Visit 4 (V4) between the two treatment groups (linagliptin vs. Placebo)
    Protection of trial subjects
    Empagliflozin and linagliptin were shown to increase the risk of hypoglycaemia when used in combination with sulfonylureas and/or insulin. Use of sulfonylureas and insulin is excluded in this trial. Empagliflozin and linagliptin even in triple combination with metformin were shown to be associated with only a minor risk of hypoglycaemia which was comparable to placebo treatment. Moreover study participants will be educated on possible symptoms of low blood glucose levels, and will be equipped with a glucose meter and test stripes for blood glucose self- measurement. Treatment with empagliflozin might increase the risk of urogenital infections. Patients will be informed about urogenital hygiene provisions as well as about symptoms of urogenital infections and will be instructed to contact the study site in case of any suspicious symptoms. Treatment with empagliflozin might increase the risk of hypovolemic blood pressure reactions. Patients with low blood pressure values or orthostatic symptoms will be excluded from the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 May 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
    Germany: 44
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    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)
    18
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recrutiment occurred in two trial sites

    Pre-assignment
    Screening details
    		 In total, 83 subjects were screened and 44 subjects were included in the trial. Of the 44 subjects, 43 subjects completed the trial, whereas 1 subject withdrew consent at Visit 4 after the LMT but before the clamp.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1st arm - Empa/Lina
    Arm description
    		 Empagliflozin / Linagliptin treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    34 days, 5 mg milligram(s)/day

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    68 days, 25 mg milligram(s)/day

    Arm title
    		 2nd arm - Empa/Placebo
    Arm description
    		 Empagliflozin / Placebo treatment
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    68 days, 25 mg milligram(s)/day

    Number of subjects in period 1
    		1st arm - Empa/Lina 2nd arm - Empa/Placebo
    Started
    22
    22
    Completed
    22
    21
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 44 44
    Age categorical
    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)
    		 18 18
        From 65-84 years
    		 26 26
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 63.8 (42 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 40 40

    End points

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    End points reporting groups
    Reporting group title
    1st arm - Empa/Lina
    Reporting group description
    		 Empagliflozin / Linagliptin treatment

    Reporting group title
    2nd arm - Empa/Placebo
    Reporting group description
    		 Empagliflozin / Placebo treatment

    Primary: Treatment Comparison for AUCGlucagon,0-180min

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    End point title
    		 Treatment Comparison for AUCGlucagon,0-180min
    End point description
    End point type
    Primary
    End point timeframe
    0-180 min
    End point values
    		 1st arm - Empa/Lina 2nd arm - Empa/Placebo
    Number of subjects analysed
    22
    22
    Units: pmol*h/L
        least squares mean (confidence interval 95%)
    -19.60 (-27.33 to -11.87)
    -4.84 (-12.57 to 2.89)
    Statistical analysis title
    		 Treatment Comparison (Linagliptin Versus Placebo)
    Comparison groups
    1st arm - Empa/Lina v 2nd arm - Empa/Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0103
    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
    18.1
    Reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Serious adverse events
    		 Overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 44 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 44 (25.00%)
    Surgical and medical procedures
    Toe operation
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    General disorders and administration site conditions
    Hyperhidrosis
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Thirst
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Genital candidiasis
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Phimosis
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 44 (4.55%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Investigations
    Red blood cells urine positive
         subjects affected / exposed
    2 / 44 (4.55%)
         occurrences all number
    2
    Cardiac disorders
    Syncope
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Gastrointestinal disorders
    Bowel movement irregularity
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    4 / 44 (9.09%)
         occurrences all number
    4
    Faeces hard
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    4 / 44 (9.09%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1

    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.
    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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