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    Clinical Trial Results:
    Acute effects of Sodium-glucose coTRansporter-2 inhibition on renal OxygeNation and AUTonomic function in type 1 diabetes

    Summary
    EudraCT number
    		 2019-004557-92
    Trial protocol
    		 DK  
    Global end of trial date
    23 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jul 2021
    First version publication date
    26 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    H-19052662
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04193566
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Steno Diabetes Center Copenhagen
    Sponsor organisation address
    niels steensens vej 2, Gentofte, Denmark, 2820
    Public contact
    Jens Christian Laursen, Steno Diabetes Center Copenhagen, 0045 30913252, jens.christian.laursen.01@regionh.dk
    Scientific contact
    Jens Christian Laursen, Steno Diabetes Center Copenhagen, 0045 30913252, jens.christian.laursen.01@regionh.dk
    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
    22 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim of the study is to assess the acute effects of SGLT2 inhibition on parameters reflecting oxygenation and oxygen consumption of the human kidney in persons with type 1 diabetes.
    Protection of trial subjects
    Patient risks and management of complications The risk was considered very little with treatment with two single doses of 50 mg, even if these doses are larger than usually applied daily doses (10 mg per day), as side effects have not been observed with this or higher doses (up to 500 mg as single dose). After longer periods of using dapagliflozin, the following side-effects have been observed: Hypoglycemia, hypotension, elevated hematocrite, dyslipidemia, back pain, dizziness, skin rash, urinary tract infection, vulvovaginitis and dehydration. Very rare incidents of ketoacidosis have been observed. If the mentioned side-effects against all expectations should occur, it is common for them, that they are transient or simple to manage with standard treatment methods. Blood sampling by arterial puncture and venous puncture can cause a short pain, a small risk of hematoma and a minimal infection risk at the puncture site. Arterial puncture is also associated with a minimal risk of arteriospasm, nerve damage, fainting and thrombosis (25). The most feared complication is irreversible ischemic damage distally for the thrombosis-site. This will only happen if revascularization is not achieved before six hours after the vascular occlusion. Due to access to nearby vascular surgery, irreversible ischemic damage is not considered a realistic ultimate consequence of potentially occurring thromboses during the present study. Usually there is no discomfort associated with MRI scans. Short-term transient side-effects can be experienced: Slight increase in body temperature (< 0.6 °C), touch sensations, dizziness, nausea and taste of metal. Besides this, it can feel claustrophobic to lie in the scanner. No complications or side-effects occurred with any of the study participants.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2020
    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
    Denmark: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    10
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 15 patients with type 1 diabetes were recruited from Steno Diabetes Center Copenhagen.

    Pre-assignment
    Screening details
    		 Information about civil registration number, phone number, address, diagnosis of T1D and historic levels of urine albumin on outpatients at Steno Diabetes Center Copenhagen is provided by the treatment-responsible doctor and passed on to the study investigator for recruitment.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Dapagliflozin
    Arm description
    		 Forxiga®, dapagliflozin 10 mg film-coated tablets. The intervention is a single dose of 50 mg. For further information please refer to: https://www.ema.europa.eu/en/documents/product-information/forxiga-epar-product-information_en.pdf.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Forxiga
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in the active arm will be treated with dapagliflozin 50 mg once on site for visit 2 and once at home on the evening before visit 3.

    Arm title
    		 Placebo
    Arm description
    		 The composition equals the composition of Forxiga® – just with the active ingredient omitted. Active drug and placebo are similar in appearance and smell.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The composition equals the composition of Forxiga® – just with the active ingredient omitted. Active drug and placebo are similar in appearance and smell.

    Number of subjects in period 1
    		Dapagliflozin Placebo
    Started
    15
    15
    Completed
    15
    15

    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
    		 15 15
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 10 10
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58 ± 14 -
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 10 10

    End points

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    End points reporting groups
    Reporting group title
    Dapagliflozin
    Reporting group description
    		 Forxiga®, dapagliflozin 10 mg film-coated tablets. The intervention is a single dose of 50 mg. For further information please refer to: https://www.ema.europa.eu/en/documents/product-information/forxiga-epar-product-information_en.pdf.

    Reporting group title
    Placebo
    Reporting group description
    		 The composition equals the composition of Forxiga® – just with the active ingredient omitted. Active drug and placebo are similar in appearance and smell.

    Primary: Change from 0 to 6 hours in renal cortical oxygenation

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    End point title
    		 Change from 0 to 6 hours in renal cortical oxygenation
    End point description
    End point type
    Primary
    End point timeframe
    Change from 0 to 6 hours
    End point values
    		 Dapagliflozin Placebo
    Number of subjects analysed
    15
    15
    Units: second^-1
        least squares mean (standard error)
    -1.1 ± 0.7
    1.3 ± 0.7
    Statistical analysis title
    		 Difference in change from 0 to 6 hours
    Comparison groups
    Dapagliflozin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.012 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 -0.6
    Notes
    [1] - Calculated with the use of a repeated-measures analysis including terms for treatment, randomisation-sequence, day of visit, blood glucose, time of measurement and interaction between time of measurement and treatment. A low R2* corresponds to a high oxygenation. P-values for comparisons of changes from baseline between dapagliflozin and placebo.
    [2] - The least squares mean changes in renal cortical R2* from baseline to six hours were for dapagliflozin -1·1 (SEM 0·7) s-1 and for placebo +1·3 (0·7) s-1 resulting in a difference between interventions of -2·3 s-1 (95% CI -4·0 to -0·6); p=0·012

    Primary: Change from 0 to 3 hours in renal cortical oxygenation

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    End point title
    		 Change from 0 to 3 hours in renal cortical oxygenation
    End point description
    The primary outcome was change in renal oxygenation (R2*) measured with quantitative MRI on a 3-T Philips Achieva scanner.
    End point type
    Primary
    End point timeframe
    Time Frame: From baseline to +3 hours from intervention
    End point values
    		 Dapagliflozin Placebo
    Number of subjects analysed
    15
    15
    Units: second^-1
        least squares mean (standard error)
    0.3 ± 0.6
    0.6 ± 0.6
    Statistical analysis title
    		 Difference in change from 0 to 3 hours
    Comparison groups
    Dapagliflozin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.673
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9

    Primary: 3-hour change in renal medullary oxygenation

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    End point title
    		 3-hour change in renal medullary oxygenation
    End point description
    End point type
    Primary
    End point timeframe
    change from 0 to 3 hours
    End point values
    		 Dapagliflozin Placebo
    Number of subjects analysed
    15
    15
    Units: second^-1
        least squares mean (standard error)
    1.4 ± 0.7
    0.7 ± 0.8
    Statistical analysis title
    		 Difference in change from 0 to 3 hours
    Comparison groups
    Dapagliflozin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.588
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 2.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7

    Primary: 6-hour change in renal medullary perfusion

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    End point title
    		 6-hour change in renal medullary perfusion
    End point description
    End point type
    Primary
    End point timeframe
    change from 0 to 6 hours
    End point values
    		 Dapagliflozin Placebo
    Number of subjects analysed
    15
    15
    Units: second^-1
        least squares mean (standard error)
    -0.2 ± 0.8
    1.2 ± 0.6
    Statistical analysis title
    		 Difference in change from 0 to 6 hours
    Comparison groups
    Dapagliflozin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.162
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1

    Secondary: 6-hour change in renal cortical perfusion

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    End point title
    		 6-hour change in renal cortical perfusion
    End point description
    the unit is ml/100g/minute
    End point type
    Secondary
    End point timeframe
    Change from 0 to 6 hours in renal cortical perfusion
    End point values
    		 Dapagliflozin Placebo
    Number of subjects analysed
    15
    15
    Units: second^-1
        least squares mean (standard error)
    5.1 ± 13.3
    8.6 ± 11.2
    Statistical analysis title
    		 Difference in change from 0 to 6 hours
    Comparison groups
    Dapagliflozin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.822
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.7
         upper limit
    		 28.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    15.1

    Secondary: 3-hour change in renal cortical perfusion

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    End point title
    		 3-hour change in renal cortical perfusion
    End point description
    the unit is ml/100g/minute
    End point type
    Secondary
    End point timeframe
    change from 0 to 3 hours
    End point values
    		 Dapagliflozin Placebo
    Number of subjects analysed
    15
    15
    Units: second^-1
        least squares mean (standard error)
    -11.8 ± 10.3
    -5.7 ± 8.8
    Statistical analysis title
    		 Difference in change from 0 to 3 hours
    Comparison groups
    Dapagliflozin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.53
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27
         upper limit
    		 13.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.7

    Secondary: 6-hour change in renal medullary perfusion

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    End point title
    		 6-hour change in renal medullary perfusion
    End point description
    End point type
    Secondary
    End point timeframe
    change from 0 to 6 hours
    End point values
    		 Dapagliflozin Placebo
    Number of subjects analysed
    15
    15
    Units: ml/100g/minute
        least squares mean (standard error)
    0.2 ± 3.0
    3.4 ± 3.9
    Statistical analysis title
    		 Difference in change from 0 to 6 hours
    Comparison groups
    Dapagliflozin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.441
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.7
         upper limit
    		 5.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    4

    Secondary: 3-hour change in renal medullary oxygenation

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    End point title
    		 3-hour change in renal medullary oxygenation
    End point description
    End point type
    Secondary
    End point timeframe
    change from 0 to 3 hours
    End point values
    		 Dapagliflozin Placebo
    Number of subjects analysed
    15
    15
    Units: ml/100g/minute
        least squares mean (standard error)
    -2.0 ± 2.3
    -0.2 ± 4.8
    Statistical analysis title
    		 Difference in change from 0 to 3 hours
    Comparison groups
    Dapagliflozin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.717
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.1
         upper limit
    		 8.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.8

    Secondary: 3-hour change in renal artery blood flow

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    End point title
    		 3-hour change in renal artery blood flow
    End point description
    End point type
    Secondary
    End point timeframe
    change from 0 to 3 hours
    End point values
    		 Dapagliflozin Placebo
    Number of subjects analysed
    15
    15
    Units: ml/minute
        least squares mean (standard error)
    -30 ± 15
    -2 ± 8
    Statistical analysis title
    		 Difference in change from 0 to 3 hours
    Comparison groups
    Dapagliflozin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.135
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -64
         upper limit
    		 10
    Variability estimate
    Standard error of the mean
    Dispersion value
    17

    Secondary: 6-hour change in renal artery blood flow

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    End point title
    		 6-hour change in renal artery blood flow
    End point description
    End point type
    Secondary
    End point timeframe
    change from 0 to 6 hours
    End point values
    		 Dapagliflozin Placebo
    Number of subjects analysed
    15
    15
    Units: ml/minute
        least squares mean (standard error)
    -3 ± 14
    16 ± 12
    Statistical analysis title
    		 Difference in change from 0 to 6 hours
    Comparison groups
    Dapagliflozin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.237
    Method
    		 Mixed models analysis
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54
         upper limit
    		 15
    Variability estimate
    Standard error of the mean
    Dispersion value
    16

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    between February 3, 2020 and October 23, 2020
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Dapagliflozin
    Reporting group description
    		 -

    Serious adverse events
    		 Dapagliflozin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Dapagliflozin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: I confirm that there were no non-serious adverse events in this mechanistic acute effect study with a single dose of 50 mg dapagliflozin.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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