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    Clinical Trial Results:
    Renal and Cardiovascular Effects of SGLT2 inhibition in combination with loop diuretics in diabetic patients with chronic heart failure.

    Summary
    EudraCT number
    		 2016-003968-39
    Trial protocol
    		 GB  
    Global end of trial date
    09 Jan 2019

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

    Trial information

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    Trial identification
    Sponsor protocol code
    2015CA02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03226457
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sponsor Reference: 2015CA02, REC: Regional Ethics Committee Reference: 16/ES/0137
    Sponsors
    Sponsor organisation name
    University of Dundee & Tayside Health Board
    Sponsor organisation address
    George Pirie Way, Dundee, United Kingdom, DD1 9SY
    Public contact
    Professor Jacob George , University of Dundee & Tayside Health Board Tayside Medical Science Centre, Ninewells Hospital, 01382 383204, J.George@dundee.ac.uk
    Scientific contact
    Professor Jacob George , University of Dundee & Tayside Health Board Tayside Medical Science Centre, Ninewells Hospital, 01382 383204, J.George@dundee.ac.uk
    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
    01 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective will be to assess whether empagliflozin (SGLT2 Inhibitor) can augment the effects of loop diuretics in diabetic patients with mild congestive heart failure with left ventricular systolic dysfunction (LVSD), as measured by urinary volume.
    Protection of trial subjects
    Participants were recruited had both Type 2 Diabetes (T2D) and Heart Failure (HF). Whilst this co-morbidity can often lead to fraility, the inclusion/exclusion criteria ensured that participants with stable T2D and HF were recruited. Participants were eligible if they were: • Aged 18 to 80 years with previously diagnosed Type 2 Diabetes Mellitus. • Diagnosed with NYHA Functional class II-III HF with prior echocardiographic evidence of LVSD. • On stable doses of furosemide, or alternative loop diuretic for at least one month. • Type 2 Diabetes • eGFR ≥ 45 ml/min. • Had stable HF symptoms for at least three months prior to consent • On stable HF therapy for at least three months prior to consent • Had not been hospitalised for HF for at least three months prior to consent. • Women of childbearing potential* (WoCBP) agreed to take precautions to avoid pregnancy throughout the trial and for 4 weeks after intake of the last dose. Participants will be excluded if they had: • A diagnosis of chronic liver disease and/or liver enzymes that are twice the upper limit of normal • Systolic BP of <95mmHg at screening visit. • HbA1c < 6.0% • Participants on thiazide diuretics. • Participants receiving renal dialysis • Participants who had previously had an episode of diabetic ketoacidosis. • Participants with type 1 diabetes mellitus • Malignancy (receiving active treatment) or other life threatening disease. • Pregnant or lactating women • Participants with difficulty in micturition e.g. severe prostate enlargement • Allergy to any SGLT2 inhibitor or lactose or galactose intolerance • Past or current treatment with any SGLT2 inhibitor • Participants who have participated in any other clinical interventional trial of an investigational medicinal product within 30 days. • Participants who are unable to give informed consent • Any other reason considered by the physician to be inappropriate for inclusion.
    Background therapy
    		 Participants recruited were on HF medications (except for thiazide diuretics) and could be on T2D medications or have diet-controlled T2D.
    Evidence for comparator
    		 The landmark EMPA-REG outcome study reported a striking 35% relative risk reduction in HF hospitalisations with empagliflozin providing supportive evidence for the beneficial effects of SGLT2 inhibition in the setting of chronic HF. The early separation curves on the Kaplan-Meier graphs and the effect on HF hospitalisations has led to the hypothesis that this outcome is seen due to a diuretic effect of SGLT2 inhibition. Data on the effect of SGLT2 inhibitor use with diuretics are limited, but given the relative frequency of both HF and T2D they are likely to be prescribed concurrently. The RECEDE-CHF trial sets out to explore this in more detail.
    Actual start date of recruitment
    30 Nov 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
    United Kingdom: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    5
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A high drop out rate was factored into the power calculations due to the high intensity of the patient visits. A minimum of 22 participants was required to meet the power calculations. There were no patient drop outs and 23 patients were recruited and completed participation in the trial.

    Pre-assignment
    Screening details
    		 At the screening visit, following informed consent, an initial medical history and clinical examination was performed and concomitant medication will be recorded. Participants had bloods taken for safety analysis and vital signs will be checked to confirm eligibility prior to enrolment.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Participants were randomised to either empagliflozin 25mg/ placebo or placebo/empagliflozin 25 mg in a double blind fashion. The double blind medication (empagliflozin or placebo) was prepared, packaged and labelled by Tayside Pharmaceuticals. The Clinical Trials Pharmacy, Ninewells Hospital were provided with a copy of the randomisation allocation for the purposes of 24 hour emergency unblinding.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Placebo arm, one tablet once a day for 6 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, one tablet once a day

    Arm title
    		 Empagliflozin 25 mg
    Arm description
    		 Empagliflozin 25 mg, one tablet once a day for 6 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin 25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin 25 mg once daily, oral administration

    Number of subjects in period 1
    		Placebo Empagliflozin 25 mg
    Started
    23
    23
    Completed
    23
    23

    Baseline characteristics

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

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 23 23
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.8 ( 5.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 17 17

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm, one tablet once a day for 6 weeks

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Empagliflozin 25 mg, one tablet once a day for 6 weeks

    Primary: Change in 24 hour urine volume from baseline to day 3

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    End point title
    		 Change in 24 hour urine volume from baseline to day 3
    End point description
    End point type
    Primary
    End point timeframe
    Change in 24 hour urine volume from baseline to day 3
    End point values
    		 Placebo Empagliflozin 25 mg
    Number of subjects analysed
    23
    23
    Units: millilitres
        least squares mean (confidence interval 95%)
    -117.65 (-348.78 to 113.49)
    425.16 (118.26 to 662.07)
    Statistical analysis title
    		 Change in 24 hour urine volume from baseline to D3
    Comparison groups
    Placebo v Empagliflozin 25 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [1]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - Mean difference from placebo 549.30 mls (151.42 to 947.17; 95% CI), p value < 0.004

    Primary: Change in 24 hour urine volume from baseline to week 6

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    End point title
    		 Change in 24 hour urine volume from baseline to week 6
    End point description
    End point type
    Primary
    End point timeframe
    Change in 24 hour urine volume from baseline to week 6
    End point values
    		 Placebo Empagliflozin 25 mg
    Number of subjects analysed
    23
    23
    Units: millilitre(s)
        least squares mean (confidence interval 95%)
    -117.65 (-348.78 to 113.49)
    425.16 (188.26 to 662.07)
    Statistical analysis title
    		 Change in 24h urinary volume from baseline to wk6
    Comparison groups
    Placebo v Empagliflozin 25 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change in 24 hour urinary sodium at week 6 from baseline

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    End point title
    		 Change in 24 hour urinary sodium at week 6 from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Change in 24 hour urinary sodium at week 6 from baseline
    End point values
    		 Placebo Empagliflozin 25 mg
    Number of subjects analysed
    23
    23
    Units: millimole(s)/litre
        least squares mean (confidence interval 95%)
    0.42 (-10.26 to 11.10)
    -7.99 (-18.7 to 2.69)
    Statistical analysis title
    		 Change in 24 hour urinary sodium at week 6
    Comparison groups
    Placebo v Empagliflozin 25 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.81
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change in serum creatinine at week 6 from baseline

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    End point title
    		 Change in serum creatinine at week 6 from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Change in serum creatinine at week 6 from baseline
    End point values
    		 Placebo Empagliflozin 25 mg
    Number of subjects analysed
    23
    23
    Units: millimole(s)/litre
        least squares mean (confidence interval 95%)
    -10.81 (-19.2 to -2.44)
    -0.44 (-8.82 to 7.94)
    Statistical analysis title
    		 Change in serum creatinine at week 6 from baseline
    Comparison groups
    Placebo v Empagliflozin 25 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.512
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change in urinary Protein:Creatinine Ratio at week 6 from baseline

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    End point title
    		 Change in urinary Protein:Creatinine Ratio at week 6 from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Change in urinary Protein:Creatinine Ratio at week 6 from baseline
    End point values
    		 Placebo Empagliflozin 25 mg
    Number of subjects analysed
    23
    23
    Units: milligram/millimol
        least squares mean (confidence interval 95%)
    -3.05 (-7.05 to 0.97)
    2.26 (-1.75 to 6.28)
    Statistical analysis title
    		 Change in urine PCR from baseline to wk6
    Comparison groups
    Placebo v Empagliflozin 25 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.399
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change in urinary Albumin:Creatinine Ratio at week 6 from baseline

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    End point title
    		 Change in urinary Albumin:Creatinine Ratio at week 6 from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Change in urinary Albumin:Creatinine Ratio at week 6 from baseline
    End point values
    		 Placebo Empagliflozin 25 mg
    Number of subjects analysed
    23
    23
    Units: milligram/millimol
        least squares mean (confidence interval 95%)
    -1.10 (-2.98 to 0.77)
    1.18 (-0.69 to 3.05)
    Statistical analysis title
    		 Change in uACR from baseline to week 6
    Comparison groups
    Placebo v Empagliflozin 25 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.543
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change in cystatin C from baseline to week 6

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    End point title
    		 Change in cystatin C from baseline to week 6
    End point description
    End point type
    Secondary
    End point timeframe
    Change in cystatin C from baseline to week 6
    End point values
    		 Placebo Empagliflozin 25 mg
    Number of subjects analysed
    23
    23
    Units: nanogram/millilitre
        least squares mean (confidence interval 95%)
    22.50 (-91.52 to 136.52)
    31.35 (-80.07 to 142.75)
    Statistical analysis title
    		 Change in cystatin C from baseline to week 6
    Comparison groups
    Placebo v Empagliflozin 25 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.99
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation to the last patient visit (visit 10), which was 4 weeks post discontinuation of investigational medicinal product (both treatment arms and last arm being either empagliflozin 25 mg od or placebo).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm, one tablet once a day for 6 weeks

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Empagliflozin 25 mg, one tablet once a day for 6 weeks

    Serious adverse events
    		 Placebo Empagliflozin 25 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 23 (8.70%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
    Additional description: 2 x cases of Cardiac Failure (congestive), 1 on placebo (after washout period following treatment of empaglilfozin) and 1 on discontinuation of empagliflozin.
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delerium
    Additional description: In relation to sepsis caused by cellulitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Empagliflozin 25 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 23 (39.13%)
    13 / 23 (56.52%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    Vascular disorders
    hypotension
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Thirst
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    Rectal haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    3
    Dysuria
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Pollakiuria
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 23 (13.04%)
         occurrences all number
    0
    3
    Balanitis candida
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    Sinusitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    Gout
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 23 (8.70%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jan 2018
    Participant selection and enrolment: the addition of the Scottish Diabetes Research Network including GoDARTS database. Inclusion criteria was changed from HbA1c in the last 3 months of 6.5% < and <10.0%, to exclusion criteria of HbA1c < 6.0%.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29042392
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