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    Clinical Trial Results:
    A 28-day randomised, placebo-controlled, double-blind parallel group phase IIa trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of once daily oral doses of 2.5 mg, 10 mg, and 25 mg empagliflozin as adjunctive to insulin in patients with type 1 diabetes mellitus (EASE-1)

    Summary
    EudraCT number
    		 2011-004354-25
    Trial protocol
    		 DE   AT  
    Global end of trial date
    20 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    17 Apr 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1245.78
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01969747
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim Pharma GmbH & Co. KG
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co. KG, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co. KG, 001 8002430127, clintriage.rdg@boehringer-ingelheim.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
    10 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety, tolerability, PK and PD of once daily oral doses of 2.5 mg, 10 mg, and 25 mg of empagliflozin in patients with T1DM as adjunctive therapy to insulin. To assess the impact of empagliflozin on 24 h urinary glucose excretion (UGE) after seven days of administration compared to placebo and add-on to a stable insulin background therapy in patients with T1DM In the second part of the treatment period (Day 8 to 28), when each patient’s background insulin was to be adjusted to achieve optimal glycaemic control: To gain experience in the need for such adjustments and to provide adjustment recommendations for subsequent trials
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
    Background therapy
    		 Subjects were on multiple daily injections (MDI) of insulin background medication: From Day 1 up to the morning of Day 8 all subjects were required to keep their algorithm of background insulin as stable as possible; from Day 8 until end of treatment (Day 28) each subject’s algorithm of background insulin was adjusted freely to achieve optimal glycaemic control.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Nov 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
    Austria: 60
    Country: Number of subjects enrolled
    Germany: 51
    Worldwide total number of subjects
    111
    EEA total number of subjects
    111
    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)
    111
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subject) met all strictly implemented inclusion/exclusion criteria. Subjects were not randomised to trial treatment if any one of the specific entry criteria were violated.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablet; oral administration once daily for 28 days; background therapy: MDI insulin
    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 tablets matching empagliflozin 2.5, 10 and 25 mg; administered oral once daily.

    Arm title
    		 Empagliflozin 2.5 mg
    Arm description
    		 Empagliflozin 2.5 mg tablet; oral administration once daily for 28 days; background therapy: MDI insulin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin 2.5 mg tablet; administered oral once daily

    Arm title
    		 Empagliflozin 10 mg
    Arm description
    		 Empagliflozin 10 mg tablet; oral administration once daily for 28 days; background therapy: MDI insulin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin 10 mg tablet; administered oral once daily

    Arm title
    		 Empagliflozin 25 mg
    Arm description
    		 Empagliflozin 25 mg tablet; oral administration once daily for 28 days; background therapy: MDI insulin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin 25 mg tablet; administered oral once daily

    Number of subjects in period 1 [1]
    		Placebo Empagliflozin 2.5 mg Empagliflozin 10 mg Empagliflozin 25 mg
    Started
    19
    19
    19
    18
    Completed
    19
    19
    19
    18
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics and subject disposition data are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet; oral administration once daily for 28 days; background therapy: MDI insulin

    Reporting group title
    Empagliflozin 2.5 mg
    Reporting group description
    		 Empagliflozin 2.5 mg tablet; oral administration once daily for 28 days; background therapy: MDI insulin

    Reporting group title
    Empagliflozin 10 mg
    Reporting group description
    		 Empagliflozin 10 mg tablet; oral administration once daily for 28 days; background therapy: MDI insulin

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Empagliflozin 25 mg tablet; oral administration once daily for 28 days; background therapy: MDI insulin

    Reporting group values
    		 Placebo Empagliflozin 2.5 mg Empagliflozin 10 mg Empagliflozin 25 mg Total
    Number of subjects
    		 19 19 19 18 75
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.5 ( 10.6 ) 41.9 ( 12.4 ) 39.6 ( 11.6 ) 41.9 ( 9.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 4 4 8 22
        Male
    		 13 15 15 10 53

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet; oral administration once daily for 28 days; background therapy: MDI insulin

    Reporting group title
    Empagliflozin 2.5 mg
    Reporting group description
    		 Empagliflozin 2.5 mg tablet; oral administration once daily for 28 days; background therapy: MDI insulin

    Reporting group title
    Empagliflozin 10 mg
    Reporting group description
    		 Empagliflozin 10 mg tablet; oral administration once daily for 28 days; background therapy: MDI insulin

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Empagliflozin 25 mg tablet; oral administration once daily for 28 days; background therapy: MDI insulin

    Primary: Change From Baseline in 24 h UGE (g/24 h) at Day 7

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    End point title
    		 Change From Baseline in 24 h UGE (g/24 h) at Day 7
    End point description
    Change from baseline in urinary glucose excretion (UGE) (g/24h) after seven days of treatment. The term 'baseline' refers to the last observation prior to the first intake of any randomised study drug (Day -1). The treatment effect was estimated on the basis of the least square mean treatment difference at Day 7 extracted from the primary analysis model. The primary endpoint is an exploratory endpoint. Full analysis set (FAS): all patients randomised, treated with at least one dose of study drug, had a baseline UGE (g/24 h) and a UGE (g/24 h) on Day 1 or Day 7. The last observation carried forward (LOCF) approach was used as the primary method of imputation for missing data.
    End point type
    Primary
    End point timeframe
    Baseline (Day -1) and 7 days after first drug administration (Day 7)
    End point values
    		 Placebo Empagliflozin 2.5 mg Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    19 [1]
    19 [2]
    19 [3]
    18 [4]
    Units: g/24h
        arithmetic mean (standard error)
    -3.56 ( 4.27 )
    72.45 ( 7.01 )
    103.33 ( 6.68 )
    101.79 ( 6.51 )
    Notes
    [1] - FAS
    [2] - FAS
    [3] - FAS
    [4] - FAS
    Statistical analysis title
    		 Comparison of Empagliflozin 2.5 mg and Placebo
    Statistical analysis description
    The model includes baseline urine glucose excretion as linear covariate(s) and treatment as fixed effect(s). The adjusted mean difference is calculated as the adjusted mean of 'Empagliflozin 2.5 mg' minus the adjusted mean of 'Placebo'.
    Comparison groups
    Empagliflozin 2.5 mg v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    76.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 58.6
         upper limit
    		 93.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.77
    Statistical analysis title
    		 Comparison of Empagliflozin 10 mg and Placebo
    Statistical analysis description
    The model includes baseline urine glucose excretion as linear covariate(s) and treatment as fixed effect(s). The adjusted mean difference is calculated as the adjusted mean of 'Empagliflozin 10 mg' minus the adjusted mean of 'Placebo'.
    Comparison groups
    Empagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    106.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 88.73
         upper limit
    		 124.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.85
    Statistical analysis title
    		 Comparison of Empagliflozin 25 mg and Placebo
    Statistical analysis description
    The model includes baseline urine glucose excretion as linear covariate(s) and treatment as fixed effect(s). The adjusted mean difference is calculated as the adjusted mean of 'Empagliflozin 25 mg' minus the adjusted mean of 'Placebo'.
    Comparison groups
    Empagliflozin 25 mg v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    104.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 86.88
         upper limit
    		 122.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.99

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first drug administration until 7 days after last drug administration (Day 35)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet; oral administration once daily

    Reporting group title
    2.5 mg Empagliflozin
    Reporting group description
    		 2.5 mg Empagliflozin tablet; oral administration once daily

    Reporting group title
    10 mg Empagliflozin
    Reporting group description
    		 10 mg Empagliflozin tablet; oral administration once daily

    Reporting group title
    25 mg Empagliflozin
    Reporting group description
    		 25 mg Empagliflozin tablet; oral administration once daily

    Serious adverse events
    		 Placebo 2.5 mg Empagliflozin 10 mg Empagliflozin 25 mg Empagliflozin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo 2.5 mg Empagliflozin 10 mg Empagliflozin 25 mg Empagliflozin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 19 (94.74%)
    17 / 19 (89.47%)
    15 / 19 (78.95%)
    18 / 18 (100.00%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Phlebitis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    1
    Thrombophlebitis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    3 / 19 (15.79%)
    0 / 19 (0.00%)
    2 / 19 (10.53%)
    6 / 18 (33.33%)
         occurrences all number
    3
    0
    5
    6
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash erythematous
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    2 / 19 (10.53%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Back pain
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 19 (26.32%)
    2 / 19 (10.53%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    5
    2
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    17 / 19 (89.47%)
    16 / 19 (84.21%)
    13 / 19 (68.42%)
    17 / 18 (94.44%)
         occurrences all number
    64
    62
    47
    66
    Polydipsia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    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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