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    Clinical Trial Results:
    A multi-center, randomized, double-blind, parallel-group dose-finding study to assess the effect of 3 doses of LIK066 compared to placebo or empagliflozin in type 2 diabetes mellitus patients with heart failure

    Summary
    EudraCT number
    		 2016-003084-19
    Trial protocol
    		 AT   GB   DE   CZ   DK   NO   NL   HU   ES   BE   BG   PL   HR   IT  
    Global end of trial date
    06 Jun 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Jul 2019
    First version publication date
    15 May 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Clarification of previously reported data.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLIK066B2204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03152552
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, Novartis.email@novartis.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
    06 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the dose-response signal and assess the dose-response relationship of LIK066 2.5mg, 10mg, and 50mg qd as measured by the change from baseline (BL) in NT-proBNP relative to placebo after 12 weeks of treatment in T2DM patients with HF.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jul 2017
    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
    Argentina: 11
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Croatia: 8
    Country: Number of subjects enrolled
    Czech Republic: 11
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    South Africa: 1
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    124
    EEA total number of subjects
    87
    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)
    40
    From 65 to 84 years
    81
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were randomized in a 1:1:2:2:2 ratio to one of 5 regimens (LIK066 2.5mg, 10mg, 50 mg, EMPA 25mg, Pbo) at Visit 201 (randomization) with a plan to be treated for 36 weeks.

    Pre-assignment
    Screening details
    		 A placebo run-in period (Epoch 2) running up to 2 weeks before randomization was used to assess eligibility

    Period 1
    Period 1 title
    Treatment Period 1 (12 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LIK066 2.5mg
    Arm description
    		 LIK066 2.5mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    LIK066
    Investigational medicinal product code
    LIK066
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LIK066 2.5mg qd at bedtime

    Arm title
    		 LIK066 10mg
    Arm description
    		 LIk066 10mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    LIK066
    Investigational medicinal product code
    LIK066
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LIK066 10mg qd at bedtime

    Arm title
    		 LIK066 50mg
    Arm description
    		 LIK066 50mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    LIK066
    Investigational medicinal product code
    LIK066
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LIK066 50mg qd at bedtime

    Arm title
    		 EMPA 25mg
    Arm description
    		 Empagliflozin 25 mg once daily
    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
    Empagliflozin (up-titrated from 10mg qd to 25mg qd after 2 weeks); in the morning

    Arm title
    		 Placebo
    Arm description
    		 LIK066 matching placebo and empagliflozin matching placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo LIK066
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo LIK066 at bedtime/Placebo Empagliflozin in the morning

    Number of subjects in period 1
    		LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Started
    15
    16
    30
    30
    33
    Full Analysis Set (FAS)
    15
    16
    30
    30
    33
    Completed
    7
    5
    10
    10
    12
    Not completed
    8
    11
    20
    20
    21
         Adverse event, serious fatal
    -
    1
    -
    -
    1
         Protocol deviation
    -
    1
    -
    -
    -
         Study terminated by sponsor
    8
    9
    19
    19
    20
         Lost to follow-up
    -
    -
    1
    -
    -
         Subject/guardian decision
    -
    -
    -
    1
    -
    Period 2
    Period 2 title
    Treatment Period 2 (24 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LIK066 2.5mg
    Arm description
    		 LIK066 2.5mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    LIK066
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LIK066 2.5mg qd at bedtime

    Arm title
    		 LIK066 10mg
    Arm description
    		 LIk066 10mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    LIK066
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LIK066 10mg qd at bedtime

    Arm title
    		 LIK066 50mg
    Arm description
    		 LIK066 50mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    LIK066
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LIK066 50mg qd at bedtime

    Arm title
    		 EMPA 25mg
    Arm description
    		 Empagliflozin 25 mg once daily
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Intratumoral use, Oral use
    Dosage and administration details
    Empagliflozin (up-titrated from 10mg qd to 25mg qd after 2 weeks); in the morning

    Arm title
    		 Placebo
    Arm description
    		 LIK066 matching placebo and empagliflozin matching placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo LIK066
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo LIK066 at bedtime/Placebo Empagliflozin in the morning

    Number of subjects in period 2 [1]
    		LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Started
    7
    5
    9
    9
    11
    Completed
    1
    0
    0
    0
    0
    Not completed
    6
    5
    9
    9
    11
         Study terminated by sponsor
    6
    5
    9
    9
    11
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all patients who completed Period 1 went into period 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LIK066 2.5mg
    Reporting group description
    		 LIK066 2.5mg once daily

    Reporting group title
    LIK066 10mg
    Reporting group description
    		 LIk066 10mg once daily

    Reporting group title
    LIK066 50mg
    Reporting group description
    		 LIK066 50mg once daily

    Reporting group title
    EMPA 25mg
    Reporting group description
    		 Empagliflozin 25 mg once daily

    Reporting group title
    Placebo
    Reporting group description
    		 LIK066 matching placebo and empagliflozin matching placebo

    Reporting group values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo Total
    Number of subjects
    		 15 16 30 30 33 124
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 5 2 13 10 10 40
        From 65-84 years
    		 10 14 16 20 21 81
        85 years and over
    		 0 0 1 0 2 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 68.2 ( 7.10 ) 69.8 ( 9.69 ) 65.8 ( 9.08 ) 68.6 ( 7.89 ) 67.8 ( 10.93 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 1 4 6 10 14 35
        Male
    		 14 12 24 20 19 89
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 14 14 28 28 29 113
        Black
    		 0 0 0 0 1 1
        Asian
    		 1 2 2 1 3 9
        Other
    		 0 0 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    LIK066 2.5mg
    Reporting group description
    		 LIK066 2.5mg once daily

    Reporting group title
    LIK066 10mg
    Reporting group description
    		 LIk066 10mg once daily

    Reporting group title
    LIK066 50mg
    Reporting group description
    		 LIK066 50mg once daily

    Reporting group title
    EMPA 25mg
    Reporting group description
    		 Empagliflozin 25 mg once daily

    Reporting group title
    Placebo
    Reporting group description
    		 LIK066 matching placebo and empagliflozin matching placebo
    Reporting group title
    LIK066 2.5mg
    Reporting group description
    		 LIK066 2.5mg once daily

    Reporting group title
    LIK066 10mg
    Reporting group description
    		 LIk066 10mg once daily

    Reporting group title
    LIK066 50mg
    Reporting group description
    		 LIK066 50mg once daily

    Reporting group title
    EMPA 25mg
    Reporting group description
    		 Empagliflozin 25 mg once daily

    Reporting group title
    Placebo
    Reporting group description
    		 LIK066 matching placebo and empagliflozin matching placebo

    Primary: Change from Baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) at Week 12

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    End point title
    		 Change from Baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) at Week 12 [1] [2]
    End point description
    Evaluation of NT-proBNP was performed by a central laboratory. For Change from baseline, Geometric mean is the geometric mean of the endpoint to baseline ratio. Pre-planned statistical analysis was not performed for this primary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not done for this arm.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was not done for this arm.
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg Placebo
    Number of subjects analysed
    15
    16
    30
    33
    Units: ratio
    geometric mean (confidence interval 95%)
        Change from BL at Week 12(n=9, 8,12,16)
    0.8 (0.5 to 1.2)
    0.6 (0.2 to 1.7)
    0.8 (0.7 to 1.1)
    1.1 (0.8 to 1.6)
    No statistical analyses for this end point

    Secondary: Change from Baseline in glycated hemoglobin (HbA1c) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in glycated hemoglobin (HbA1c) at Weeks 12 and 36
    End point description
    HbA1c was measured from a blood sample and analyzed using a National Glycohemoglobin Standardization Program (NGSP) certified method at a central laboratory. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    15
    16
    30
    30
    33
    Units: Percentage (%)
    arithmetic mean (standard deviation)
        Baseline(n=15,16,30,30,33)
    8.26 ( 0.684 )
    7.51 ( 0.642 )
    7.82 ( 0.795 )
    7.92 ( 0.863 )
    8.12 ( 0.886 )
        Change from BL at Week 12(n=9,8,12,14,18)
    -0.29 ( 0.836 )
    -0.01 ( 0.508 )
    -0.58 ( 0.335 )
    -0.44 ( 1.176 )
    -0.04 ( 0.913 )
        Change from BL at Week 36(n=3,0,1,0,3)
    0.13 ( 0.961 )
    0.00 ( 0.00 )
    -0.60 ( 999 )
    0.00 ( 0.00 )
    -1.83 ( 0.321 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Plasma Glucose (FPG) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose (FPG) at Weeks 12 and 36
    End point description
    FPG was measured from a blood sample after an overnight fast; patients were not allowed to eat or drink anything (except water) for at least 8 h before each study visit. Samples were analyzed at a central laboratory. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    15
    16
    30
    30
    33
    Units: millimoles per litre (mmol/L)
    arithmetic mean (standard deviation)
        Baseline(n=15,14,29,28,30)
    10.076 ( 3.1466 )
    9.581 ( 3.2087 )
    9.105 ( 2.8418 )
    9.231 ( 3.0525 )
    8.921 ( 2.3119 )
        Change from BL at Week 12(n=8,6,12,13,15)
    -1.021 ( 1.0368 )
    -2.041 ( 4.9772 )
    -0.426 ( 2.1451 )
    -1.303 ( 2.4386 )
    -1.187 ( 3.9653 )
        Change from BL at Week 36(n=3,0,1,0,3)
    0.392 ( 1.1119 )
    0.00 ( 0.00 )
    -1.200 ( 999 )
    0.00 ( 0.00 )
    -4.733 ( 0.3055 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Weight at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Body Weight at Weeks 12 and 36
    End point description
    Body weight was measured to the nearest 0.1 kg on a calibrated scale (weight and bio-impedance measurements), provided by the sponsor. Exceptionally (e.g. if the body weight exceeded the limits of the provided scale) sites were allowed to use another scale for weight measurement as available, but during the study the same scale was to be used for the same patient. The measurement was performed with the study patient in underwear and without shoes. Indoor clothing was also acceptable, but measurements were to be done consistently (either with underwear or with indoor clothing) throughout the study. Voiding before weight measurement was required. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    15
    16
    30
    30
    33
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        Baseline(n=15,16,30,30,33)
    100.16 ( 19.331 )
    92.29 ( 18.010 )
    96.32 ( 19.746 )
    93.35 ( 22.906 )
    90.30 ( 17.998 )
        Change from BL at Week 12(n=9,8,13,14,18)
    -0.78 ( 2.734 )
    -1.83 ( 1.402 )
    -2.15 ( 2.397 )
    -2.25 ( 1.894 )
    -0.34 ( 2.115 )
        Change from BL at Week 36(n=3,0,1,0,3)
    -2.21 ( 1.586 )
    0.00 ( 0.00 )
    -3.90 ( 999 )
    0.00 ( 0.00 )
    0.47 ( 6.158 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Composition assessed by bio-impedance (Total Body Fat Mass) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Body Composition assessed by bio-impedance (Total Body Fat Mass) at Weeks 12 and 36
    End point description
    Body composition was measured in all patients using bio-impedance, except in patients where it was contra-indicated, e.g. those using an implantable cardioverter-defibrillator. Body composition parameters were assessed as available for the different models of calibrated bio-impedance scales. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    15
    16
    30
    30
    33
    Units: Percentage of body fat mass
    arithmetic mean (standard deviation)
        Baseline (n = 12, 13, 27, 23, 28)
    28.40 ( 10.388 )
    35.55 ( 8.003 )
    34.79 ( 9.263 )
    34.36 ( 9.299 )
    36.49 ( 9.217 )
        Wk 12 Chge from BL (n=6,7,11,12,15)
    -0.77 ( 2.276 )
    -1.51 ( 5.048 )
    -0.32 ( 4.675 )
    1.63 ( 3.639 )
    -1.77 ( 7.812 )
        Wk 36 Chge from BL (n=2,0,1,0,2)
    2.25 ( 1.485 )
    0.00 ( 0.00 )
    0.20 ( 999 )
    0.00 ( 0.00 )
    6.70 ( 20.082 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Composition assessed by bio-impedance (Visceral Fat Level) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Body Composition assessed by bio-impedance (Visceral Fat Level) at Weeks 12 and 36
    End point description
    Body composition was measured in all patients using bio-impedance, except in patients where it was contra-indicated, e.g. those using an implantable cardioverter-defibrillator. Body composition parameters were assessed as available for the different models of calibrated bio-impedance scales. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. Visceral fat levels were measured by Omron device. Levels ranged from 1 - 30 and are relative (not absolute) values.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    15
    16
    30
    30
    33
    Units: Level
    arithmetic mean (standard deviation)
        Baseline (n = 13, 13, 27, 23, 26)
    18.077 ( 6.1164 )
    19.077 ( 5.8944 )
    17.796 ( 6.2553 )
    16.348 ( 6.4499 )
    15.538 ( 4.5540 )
        Wk 12 Chge from BL (n=7,7,11,12,15)
    -2.429 ( 4.6853 )
    -2.857 ( 3.8914 )
    -0.436 ( 4.6877 )
    -0.417 ( 1.3114 )
    -3.200 ( 4.7988 )
        Wk 36 Chge from BL (n=2,0,1,0,2)
    0.000 ( 1.4142 )
    999 ( 999 )
    0.000 ( 999 )
    999 ( 999 )
    3.500 ( 7.7782 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Composition assessed by bio-impedance (Lean Body Mass) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Body Composition assessed by bio-impedance (Lean Body Mass) at Weeks 12 and 36
    End point description
    Body composition was measured in all patients using bio-impedance, except in patients where it was contra-indicated, e.g. those using an implantable cardioverter-defibrillator. Body composition parameters were assessed as available for the different models of calibrated bio-impedance scales. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    15
    16
    30
    30
    33
    Units: Percentage of body fat mass
    arithmetic mean (standard deviation)
        Baseline (n = 12, 12, 26, 23, 25)
    33.03 ( 4.682 )
    38.39 ( 20.028 )
    28.28 ( 4.221 )
    40.83 ( 62.377 )
    30.94 ( 12.419 )
        Wk 12 Chge from BL (n=6,6,10,12,14)
    -2.32 ( 7.063 )
    -2.32 ( 5.774 )
    -0.24 ( 2.022 )
    -0.68 ( 2.454 )
    1.64 ( 4.584 )
        Wk 36 Chge from BL (n=2,0,1,0,2)
    -0.85 ( 1.344 )
    999 ( 999 )
    -0.30 ( 999 )
    999 ( 999 )
    -5.35 ( 13.223 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Composition assessed by DXA (Total Body Fat Mass) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Body Composition assessed by DXA (Total Body Fat Mass) at Weeks 12 and 36
    End point description
    A whole body DXA scan was performed to assess Total Body Fat Mass (Whole Body Minus Head Hologic, Whole Body Minus Head Lunar). DXA data were transferred to a central reading vendor for independent review and analysis. Only descriptive statistics done.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    1
    0 [3]
    4
    4
    1
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        BL Whole Body Minus Head Hologic(n=1,0,0,1,1)
    35.970 ( 999 )
    ( )
    0.00 ( 0.00 )
    18.870 ( 999 )
    27.550 ( 999 )
        Wk 12 Whole Body - Hd Hologic Chge BL(n=1,0,0,0,1)
    -0.310 ( 999 )
    ( )
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    -4.280 ( 999 )
        Wk 36 Whole Body - Hd Hologic Chge BL(n=1,0,0,0,1)
    -3.800 ( 999 )
    ( )
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    -5.590 ( 999 )
        BL Whole Body Minus Head Lunar(n=0,0,3,2,0)
    0.00 ( 0.00 )
    ( )
    29.350 ( 4.9403 )
    37.455 ( 6.0175 )
    0.00 ( 0.00 )
        Wk 12 Whole Body - Hd Lunar Chge BL(n=0,0,1,1,0)
    0.00 ( 0.00 )
    ( )
    -1.260 ( 999 )
    1.190 ( 999 )
    0.00 ( 0.00 )
        Wk 36 Whole Body - Hd Lunar Chge BL(n=0,0,0,0,0)
    0.00 ( 0.00 )
    ( )
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    Notes
    [3] - Subject discontinued before time point
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Composition assessed by DXA (Visceral Fat Mass) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Body Composition assessed by DXA (Visceral Fat Mass) at Weeks 12 and 36
    End point description
    A whole body DXA scan was performed to assess Visceral Fat Mass (Whole Body Minus Head Hologic, Whole Body Minus Head Lunar). DXA data were transferred to a central reading vendor for independent review and analysis. Only descriptive statistics done.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    1
    0 [4]
    4
    4
    1
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        BL Whole Body Minus Head Hologic(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Wk 12 Whole Body - Hd Hologic Chge BL(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Wk 36 Whole Body - Hd Hologic Chge BL(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        BL Whole Body Minus Head Lunar(n=0,0,0,0,0)9
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Wk 12 Whole Body - Hd Lunar Chge BL(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Wk 36 Whole Body - Hd Lunar Chge BL(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    Notes
    [4] - Subject discontinued before time point
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Composition assessed by DXA (Lean Body Mass) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Body Composition assessed by DXA (Lean Body Mass) at Weeks 12 and 36
    End point description
    A whole body DXA scan was performed to assess Lean Body Mass (Whole Body Minus Head Hologic, Whole Body Minus Head Lunar). DXA data were transferred to a central reading vendor for independent review and analysis. Only descriptive statistics done.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    1
    0 [5]
    4
    4
    1
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        BL Whole Body Minus Head Hologic(n=1,0,0,1,1)
    29.490 ( 999 )
    ( )
    999 ( 999 )
    38.990 ( 999 )
    58.400 ( 999 )
        Wk 12 Whole Body - Hd Hologic Chge BL(n=1,0,0,0,1)
    -1.910 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    4.980 ( 999 )
        Wk 36 Whole Body - Hd Hologic Chge BL(n=1,0,0,0,1)
    0.860 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    1.700 ( 999 )
        BL Whole Body Minus Head Lunar(n=0,0,3,2,0)
    999 ( 999 )
    ( )
    48.220 ( 13.0748 )
    59.335 ( 4.1224 )
    999 ( 999 )
        Wk 12 Whole Body - Hd Lunar Chge BL(n=0,0,1,1,0)
    999 ( 999 )
    ( )
    -1.290 ( 999 )
    -2.960 ( 999 )
    999 ( 999 )
        Wk 36 Whole Body - Hd Lunar Chge BL(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    Notes
    [5] - Subject discontinued before time point
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Composition assessed by DXA (Total Body Water) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Body Composition assessed by DXA (Total Body Water) at Weeks 12 and 36
    End point description
    A whole body DXA scan was performed to assess Total Body Water (Whole Body Minus Head Hologic, Whole Body Minus Head Lunar). DXA data were transferred to a central reading vendor for independent review and analysis. Only descriptive statistics done.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    1
    0 [6]
    4
    4
    1
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        BL Whole Body Minus Head Hologic(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Wk 12 Whole Body - Hd Hologic Chge BL(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Wk 36 Whole Body - Hd Hologic Chge BL(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        BL Whole Body Minus Head Lunar(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Wk 12 Whole Body - Hd Lunar Chge BL(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Wk 36 Whole Body - Hd Lunar Chge BL(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    Notes
    [6] - Subject discontinued before time point
    No statistical analyses for this end point

    Secondary: Change from Baseline in sitting Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in sitting Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Weeks 12 and 36
    End point description
    Three sitting BP measurements were performed. At each visit, sitting BP was derived as the mean of three readings of the sitting SBP/DBP at that visit. Pre-planned statistical analyses were not performed for these secondary endpoints due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    15
    16
    30
    30
    33
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline SBP(n=15,16,30,30,33)
    132.20 ( 7.992 )
    133.94 ( 15.575 )
    129.17 ( 12.811 )
    130.64 ( 14.918 )
    128.10 ( 12.467 )
        SBP Change from BL at Week 12(n=9,8,13,14,18)
    5.15 ( 13.485 )
    0.17 ( 15.373 )
    -9.54 ( 16.884 )
    -6.98 ( 15.031 )
    -2.85 ( 11.967 )
        SBP Change from BL at Week 36(n=3,0,1,0,3)
    13.78 ( 17.900 )
    999 ( 999 )
    -4.00 ( 999 )
    999 ( 999 )
    0.00 ( 8.627 )
        Baseline DBP(n=15,16,30,30,33)
    78.67 ( 9.665 )
    77.56 ( 8.961 )
    75.70 ( 9.520 )
    76.47 ( 7.853 )
    72.73 ( 10.603 )
        DBP Change from BL at Week 12(n=9,8,13,14,18)
    -2.00 ( 6.582 )
    4.50 ( 12.746 )
    -4.46 ( 11.238 )
    -1.81 ( 10.421 )
    -2.00 ( 8.596 )
        DBP Change from BL at Week 36(n=3,0,1,0,3)
    1.12 ( 3.975 )
    999 ( 999 )
    3.66 ( 999 )
    999 ( 999 )
    -0.44 ( 8.517 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Lipid Profile (Triglycerides (TG)) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Fasting Lipid Profile (Triglycerides (TG)) at Weeks 12 and 36
    End point description
    TG was measured on blood samples obtained after an overnight fast and analyzed at a central laboratory. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    15
    16
    30
    30
    33
    Units: percent change
    arithmetic mean (standard deviation)
        % Change from BL at Week 12(n=9,6,12,13,15)
    -1.623 ( 35.2838 )
    19.089 ( 31.4798 )
    9.878 ( 30.3065 )
    8.865 ( 35.0872 )
    -2.979 ( 25.1049 )
        % Change from BL at Week 36(n=3,0,1,0,3)
    4.324 ( 31.4438 )
    999 ( 999 )
    14.286 ( 999 )
    999 ( 999 )
    -1.111 ( 18.3586 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Lipid Profile (Lipoproteins) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Fasting Lipid Profile (Lipoproteins) at Weeks 12 and 36
    End point description
    Lipoproteins (High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) Cholesterol) were measured on blood samples obtained after an overnight fast and analyzed at a central laboratory. Pre-planned statistical analysis were not performed for these secondary endpoints due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    15
    16
    30
    30
    33
    Units: percent change
    arithmetic mean (standard deviation)
        HDL % Change from BL at Week 12(n=9,8,7,12,12)
    9.33 ( 16.735 )
    -10.54 ( 20.590 )
    0.26 ( 9.772 )
    2.18 ( 12.179 )
    -0.67 ( 13.322 )
        HDL % Change from BL at Week 36(n=3,0,1,0,2)
    10.70 ( 16.257 )
    999 ( 999 )
    0.00 ( 999 )
    999 ( 999 )
    35.00 ( 49.497 )
        LDL % Change from BL at Week 12(n=9,8,7,12,12)
    22.02 ( 35.466 )
    2.62 ( 17.525 )
    16.40 ( 36.928 )
    22.24 ( 35.145 )
    -1.59 ( 31.970 )
        LDL % Change from BL at Week 36(n=3,0,1,0,2)
    22.73 ( 31.690 )
    999 ( 999 )
    -3.57 ( 999 )
    999 ( 999 )
    0.22 ( 13.163 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Lipid Profile (Total Cholesterol) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Fasting Lipid Profile (Total Cholesterol) at Weeks 12 and 36
    End point description
    Total Cholesterol was measured on blood samples obtained after an overnight fast and analyzed at a central laboratory. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    15
    16
    30
    30
    33
    Units: percent change
    arithmetic mean (standard deviation)
        % Change from BL at Week 12(n=9,8,7,12,12)
    9.69 ( 23.892 )
    -2.66 ( 13.202 )
    6.32 ( 22.667 )
    10.83 ( 11.330 )
    1.46 ( 16.741 )
        % Change from BL at Week 36(n=3,0,1,0,2)
    14.72 ( 13.147 )
    999 ( 999 )
    2.04 ( 999 )
    999 ( 999 )
    10.27 ( 28.326 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in High sensitive C-reactive protein (hsCRP) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in High sensitive C-reactive protein (hsCRP) at Weeks 12 and 36
    End point description
    hs-CRP is an inflammation biomarker. For Change from baseline, Geometric mean is the geometric mean of the endpoint to baseline ratio. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    15
    16
    30
    30
    33
    Units: milligram per litre (mg/L)
    geometric mean (confidence interval 95%)
        Baseline(n=9,13,20,24,22)
    4.477 (1.114 to 18.001)
    2.970 (1.617 to 5.453)
    2.531 (1.424 to 4.500)
    3.932 (2.582 to 5.988)
    3.373 (1.773 to 6.417)
        Change from BL at Week 12(n=7,7,7,11,10)
    0.543 (0.086 to 3.446)
    0.722 (0.157 to 3.321)
    1.997 (0.758 to 5.263)
    0.714 (0.353 to 1.443)
    1.018 (0.661 to 1.566)
        Change from BL at Week 36(n=3,0,1,0,3)
    0.953 (0.221 to 4.112)
    0.00 (0.00 to 0.00)
    0.620 (0 to 999)
    0.00 (0.00 to 0.00)
    0.578 (0.172 to 1.945)
    No statistical analyses for this end point

    Secondary: Change from Baseline in 24 hour Urinary Glucose Excretion (UGE) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in 24 hour Urinary Glucose Excretion (UGE) at Weeks 12 and 36
    End point description
    UGE was measured from a 24h urine collection from about 25% of randomized patients and analyzed at a central laboratory. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    3
    11
    7
    12
    16
    Units: millimoles per 24 hours (mmol/24h)
    arithmetic mean (standard deviation)
        Baseline(n=2,6,3,9,11)
    102.325 ( 135.1635 )
    27.343 ( 36.4044 )
    3.590 ( 3.8192 )
    2.510 ( 3.6456 )
    91.535 ( 201.7728 )
        Change from BL at Week 12(n=2,2,1,2,5)
    256.245 ( 129.0682 )
    346.360 ( 107.3671 )
    305.110 ( 999 )
    254.270 ( 198.8243 )
    84.778 ( 222.6565 )
        Change from BL at Week 36 (n=0,0,0,0,0)
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in 24 hour Sodium Excretion at Weeks 12 and 36

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    End point title
    		 Change from Baseline in 24 hour Sodium Excretion at Weeks 12 and 36
    End point description
    Sodium excretion was measured from a 24h urine collection from about 25% of randomized patients and analyzed at a central laboratory. Only descriptive statistics were done.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    3
    11
    7
    12
    16
    Units: millimoles per 24 hours (mmol/24h)
    arithmetic mean (standard deviation)
        Baseline(n=2,7,6,9,13)
    160.3 ( 148.14 )
    209.9 ( 99.86 )
    167.4 ( 71.62 )
    186.4 ( 98.03 )
    195.4 ( 125.07 )
        Change from BL at Week 12(n=2,2,2,2,7)
    -38.5 ( 86.69 )
    45.6 ( 40.52 )
    -42.6 ( 28.50 )
    82.3 ( 98.29 )
    -43.9 ( 112.48 )
        Change from BL at Week 36 (n=0,0,0,0,0)
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Left Atrial Size at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Left Atrial Size at Weeks 12 and 36 [7]
    End point description
    A limited two-dimensional and Doppler ECHO examination was performed to assess ECHO parameters. The images were sent to a central reading vendor for independent review and analysis. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was not done for this arm.
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg Placebo
    Number of subjects analysed
    15
    16
    30
    33
    Units: milliliter per square meter (mL/m^2)
    arithmetic mean (standard deviation)
        Baseline (n = 13,16, 28, 30)
    46.608 ( 17.6085 )
    57.088 ( 22.1322 )
    41.446 ( 13.6345 )
    42.783 ( 16.3363 )
        Change from BL at Week 12 (n = 3, 4, 7, 11)
    -1.167 ( 14.8123 )
    0.075 ( 6.7884 )
    2.700 ( 7.2155 )
    -1.045 ( 11.0223 )
        Change from BL at Week 36 (n=3,0,1,3)
    16.333 ( 20.9194 )
    999 ( 999 )
    0.300 ( 999 )
    5.100 ( 6.2960 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Left Atrial Volume at Weeks 12 and 36

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    End point title
    		 Change from baseline in Left Atrial Volume at Weeks 12 and 36 [8]
    End point description
    A limited two-dimensional and Doppler ECHO examination was performed to assess ECHO parameters. The images were sent to a central reading vendor for independent review and analysis.Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was not done for this arm.
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg Placebo
    Number of subjects analysed
    15
    16
    30
    33
    Units: milliliter (mL)
    arithmetic mean (standard deviation)
        Baseline (n=14,16,29,30)
    91.457 ( 37.8730 )
    115.869 ( 45.1660 )
    86.083 ( 30.3583 )
    86.120 ( 33.9823 )
        Change from BL at Week 12 (n=5,4,8,11)
    12.360 ( 42.7067 )
    0.225 ( 15.4157 )
    7.725 ( 16.9351 )
    -3.591 ( 22.8382 )
        Change from BL at Week 36(n=3,0,1,3)
    34.800 ( 51.0409 )
    999 ( 999 )
    -0.900 ( 999 )
    11.333 ( 12.7892 )
    No statistical analyses for this end point

    Secondary: Nunmber of subjects with New York Heart Association (NYHA) class I, II, II or IV

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    End point title
    		 Nunmber of subjects with New York Heart Association (NYHA) class I, II, II or IV [9]
    End point description
    The NYHA Functional Classification classifies patients' heart failure according to the severity of their symptoms. The classification is as follows: Class I: no limitation of physical activity, ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath); Class II: slight limitation to physical activity, comfortable at rest, ordinary physical activity results in fatigue, palpitation or dyspnea; Class III: marked limitation of physical activity, comfortable at rest, less than ordinary activity causes fatigue, palpitation or dyspnea; Class IV: unable to carry on any physical activity without discomfort, symptoms of heart failure at rest, if any physical activity is undertaken, discomfort increases. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was not done for this arm.
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg Placebo
    Number of subjects analysed
    15
    16
    30
    33
    Units: Subjects
        Baseline (n=15,16,30,33)|Class I
    0
    0
    0
    0
        Week 12 (n=9,8,13,18)|Class I
    13
    14
    26
    25
        Week 36 (n=3,0,1,3)|Class I
    2
    2
    3
    8
        Baseline (n=15,16,30,33)|Class II
    0
    0
    1
    0
        Week 12 (n=9,8,13,18)|Class II
    1
    1
    1
    1
        Week 36 (n=3,0,1,3)|Class II
    6
    6
    10
    13
        Baseline (n=15,16,30,33)|Class III
    2
    1
    2
    4
        Week 12 (n=9,8,13,18)|Class III
    0
    0
    0
    0
        Week 36 (n=3,0,1,3)|Class III
    0
    0
    0
    0
        Baseline (n=15,16,30,33)|Class IV
    3
    0
    1
    3
        Week 12 (n=9,8,13,18)|Class IV
    0
    0
    0
    0
        Week 36 (n=3,0,1,3)|Class IV
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with change from Baseline in New York Heart Association (NYHA) Class at Week 12 and 36

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    End point title
    		 Number of subjects with change from Baseline in New York Heart Association (NYHA) Class at Week 12 and 36 [10]
    End point description
    The change from BL in NYHA class at a given visit is a three-category ordinal variable (improved/unchanged/worsened) with the following definition: 1. Improved, if NYHA class decreases at least one level from BL; 2. Unchanged, if NYHA class is unchanged from BL; 3. Worsened, if NYHA class increases at least one level from BL. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Week 12, Week 36
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was not done for this arm.
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg Placebo
    Number of subjects analysed
    15
    16
    30
    33
    Units: Subjects
        Week 12 (n=9,8,13,18)|Improved
    1
    1
    1
    4
        Week 36 (n=3,0,1,3)|Improved
    8
    7
    12
    13
        Week 12 (n=9,8,13,18)|Unchanged
    0
    0
    0
    1
        Week 36 (n=3,0,1,3)|Unchanged
    0
    0
    0
    0
        Week 12 (n=9,8,13,18)|Worsened
    3
    0
    1
    3
        Week 36 (n=3,0,1,3)|Worsened
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) at Week 36

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    End point title
    		 Change from Baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) at Week 36 [11]
    End point description
    Evaluation of NT-proBNP was performed by a central laboratory. For Change from baseline, Geometric mean is the geometric mean of the endpoint to baseline ratio. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 36
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was not done for this arm.
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg Placebo
    Number of subjects analysed
    15
    16
    30
    33
    Units: ratio
    geometric mean (confidence interval 95%)
        Change from BL at Week 36(n=3,0,1,3)
    0.7 (0.4 to 1.4)
    0.00 (0.00 to 0.00)
    1.3 (0 to 999)
    1.0 (0.5 to 1.8)
    No statistical analyses for this end point

    Secondary: Change from Baseline in 24 hour urinary calcium excretion at Weeks 12 and 36

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    End point title
    		 Change from Baseline in 24 hour urinary calcium excretion at Weeks 12 and 36
    End point description
    Urinary calcium excretion was measured from a 24h urine collection from about 25% of randomized patients and analyzed at a central laboratory. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    3
    11
    7
    12
    16
    Units: millimoles per day (mmol/d)
    arithmetic mean (standard deviation)
        Baseline(n=1,5,5,7,9)
    1.60 ( 999 )
    3.54 ( 1.540 )
    2.04 ( 1.146 )
    3.36 ( 1.896 )
    6.07 ( 5.427 )
        Change from BL at Week 12(n=1,1,2,1,5)
    1.40 ( 999 )
    3.80 ( 999 )
    0.10 ( 0.566 )
    0.60 ( 999 )
    -0.49 ( 3.202 )
        Change from BL at Week 36(n=0,0,0,0,0)
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: 24 hour urinary phosphate excretion at Weeks 12 and 36

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    End point title
    		 24 hour urinary phosphate excretion at Weeks 12 and 36
    End point description
    Urinary phosphate excretion was measured from a 24h urine collection from about 25% of randomized patients and analyzed at a central laboratory. Only descriptive statistics were done.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    3
    11
    7
    12
    16
    Units: millimoles per day (mmol/d)
    arithmetic mean (standard deviation)
        Baseline(n=2,5,6,7,12)
    184.95 ( 69.650 )
    263.24 ( 33.864 )
    184.32 ( 116.065 )
    155.27 ( 45.636 )
    215.20 ( 102.259 )
        Change from BL at Week 12(n=2,2,2,1,6)
    55.35 ( 25.809 )
    19.25 ( 55.225 )
    -125.95 ( 105.571 )
    5.30 ( 999 )
    26.07 ( 142.536 )
        Change from BL at Week 36(n=0,0,0,0,0)
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Bone Mineral Density (BMD) at Weeks 12 and 36

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    End point title
    		 Change from Baseline in Bone Mineral Density (BMD) at Weeks 12 and 36
    End point description
    To evaluate bone mineral density as assessed by bone mineral content after 12 weeks and after 36 weeks of treatment. Only descriptive statistics were done.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36
    End point values
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Number of subjects analysed
    1
    0 [12]
    4
    4
    1
    Units: grams (g)
    arithmetic mean (standard deviation)
        BL Whole Body Minus Head Hologic(n=1,0,0,1,1)
    1633.710 ( 999 )
    ( )
    999 ( 999 )
    1991.270 ( 999 )
    2435.000 ( 999 )
        Wk 12 Whole Body - Hd Hologic Chge BL(n=1,0,0,0,1)
    -13.250 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    -3.340 ( 999 )
        Wk 36 Whole Body - Hd Hologic Chge BL(n=1,0,0,0,1)
    -58.220 ( 999 )
    ( )
    999 ( 999 )
    999 ( 999 )
    64.620 ( 999 )
        BL Whole Body Minus Head, Lunar N=0,0,3,2,0)
    999 ( 999 )
    ( )
    2167.063 ( 550.9181 )
    2723.345 ( 74.6493 )
    999 ( 9999 )
        Wk 12 Whole Body - Hd Lunar Chge BL(n=0,0,1,1,0)
    999 ( 999 )
    ( )
    -78.750 ( 999 )
    37.350 ( 999 )
    999 ( 999 )
        Wk 36 Whole Body - Hd Lunar Chge BL(n=0,0,0,0,0)
    999 ( 999 )
    ( )
    999 ( 999 )
    999 ( 9999 )
    999 ( 999 )
    Notes
    [12] - Subject discontinued before time point
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent AEs are represented for the double-blind period (i.e., starting from randomization to the end of the double-blind period). Total duration of the double-blind period was planned to be approximately 36 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    LIK066 2.5mg
    Reporting group description
    		 LIK066 2.5mg

    Reporting group title
    LIK066 10mg
    Reporting group description
    		 LIK066 10mg

    Reporting group title
    LIK066 50mg
    Reporting group description
    		 LIK066 50mg

    Reporting group title
    EMPA 25mg
    Reporting group description
    		 EMPA 25mg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 16 (12.50%)
    3 / 30 (10.00%)
    5 / 30 (16.67%)
    3 / 33 (9.09%)
         number of deaths (all causes)
    0
    1
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral vascular occlusion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cardiac death
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Infections and infestations
    Diarrhoea infectious
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LIK066 2.5mg LIK066 10mg LIK066 50mg EMPA 25mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 15 (46.67%)
    6 / 16 (37.50%)
    8 / 30 (26.67%)
    12 / 30 (40.00%)
    9 / 33 (27.27%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 16 (0.00%)
    2 / 30 (6.67%)
    3 / 30 (10.00%)
    1 / 33 (3.03%)
         occurrences all number
    3
    0
    2
    3
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Thirst
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    1
    0
    1
    Cough
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Investigations
    Heart rate irregular
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Liver function test increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    2
    1
    Nervous system disorders
    Dysaesthesia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    1
    0
    4
    2
    2
    Enteritis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Infections and infestations
    Breast abscess
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Genital infection fungal
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    2 / 33 (6.06%)
         occurrences all number
    0
    1
    1
    1
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 16 (6.25%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    0
    0
    1
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Fluid retention
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    0
    1
    2
    Hypoglycaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 16 (12.50%)
    2 / 30 (6.67%)
    3 / 30 (10.00%)
    2 / 33 (6.06%)
         occurrences all number
    15
    7
    2
    7
    5
    Hypokalaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2017
    Amendment 1 introduced the following changes: - The protocol was amended to add a newly identified risk (lower limb amputation) observed with the SGLT-2 inhibitor canagliflozin, and preventive measures were provided. - The inclusion criterion for NT-proBNP was lowered from >400 to >300 pg/mL. When designing the study protocol, a NT-proBNP value of >400 pg/mL was selected to make a patient eligible for the study. This was based on the experience and results from the PARAMOUNT study, which included patients with chronic HF and preserved left ventricular ejection fraction (LVEF). Based on more recent guidelines defining patients with preserved LVEF by NT-proBNP >125 pg/mL, the NT-proBNP value to qualify patients for this study was changed to >300 pg/mL, as this cut-off has a robust predictive value to identify chronic HF patients with preserved LVEF. - In addition, the inclusion criterion for serum potassium was changed from ≤ 5.2 mM to ≤ 5.3 mM to be in line with the reference range used by the Central laboratory in this study. - The HbA1c inclusion criterion was modified from 7.0% - 10.0% to 6.5% - 10.0% to allow for exploration of LIK066 effects in the group of patients with HbA1c 6.5% - 7.0%.
    04 Feb 2018
    Amendment 2 introduced the following changes: - The protocol was amended to provide the option for patients to be pre-screened for certain laboratory parameters (NT-proBNP, HbA1c, eGFR, serum potassium) assessed by the central laboratory before patients entered the study at screening (Visit 1). This measure was expected to significantly decrease the number of screen failure patients which reduces the burden on many patients, who otherwise had to undergo the full range of screening assessments but did not qualify for the study. - Other changes included adjustments and/or clarifications for several technical and logistical procedures, such as for body weight, bio-impedance and echocardiography assessments.

    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.
    Due to early discontinuation of the study, the analysis of efficacy was done on the available data (mostly for Epoch 3 (double-blind period 1) only). Because of the small sample sizes the interpretation of the results remained limited.
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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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