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    Clinical Trial Results:
    Kidney Fat in Type 2 Diabetes & Diabetic Kidney Disease and the Effects of Ezetimibe: A Cross-Sectional Study and Randomized, Placebo-Controlled Trial

    Summary
    EudraCT number
    		 2020-001155-40
    Trial protocol
    		 DK  
    Global end of trial date
    12 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Aug 2023
    First version publication date
    21 Aug 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    16032020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT16032020
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Steno Diabetes Center Copenhagen
    Sponsor organisation address
    Borgmester Ib Juuls Vej 83, Herlev, Denmark, 2730
    Public contact
    Professor Peter Rossing, Complications Research, Steno Diabetes Center Copenhagen, 0045 3091 3383, peter.rossing@regionh.dk
    Scientific contact
    Professor Peter Rossing, Complications Research, Steno Diabetes Center Copenhagen, 30913383 3091 3383, peter.rossing@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
    25 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether ezetimibe reduces albuminuria and kidney parenchymal fat content in individuals with type 2 diabetes and non-severe chronic kidney disease in a randomized, double-blinded, placebo-controlled intervention study in around 60 individuals. Also to compare, in a cross-sectional study, the kidney parenchymal fat content between controls (planned n=30), individuals with type 2 diabetes and no chronic kidney disease (planned n=30) and individuals with type 2 diabetes and non-severe chronic kidney disease. Results only reported here for intervention study.
    Protection of trial subjects
    Study conducted in compliance with the Good Clinical Practice standard, Declaration of Helsinki and Danish Data Protection Act. Potocol was approved by the Capital Region’s Scientific Ethics Committee (jr.nr. H-20021349) and the Danish Medicines Agency (jr.nr. 2020033463). External monitoring was conducted by the Good Clinical Practice-unit affiliated with the University of Copenhagen. All participants gave written informed consent. Appropriate safety laboratory analyses and screening and precautions for MRI scans were carried out.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 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: 115
    Worldwide total number of subjects
    115
    EEA total number of subjects
    115
    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)
    48
    From 65 to 84 years
    67
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants with T2D were recruited by letter of invitation to relevant candidates attending Steno Diabetes Center Copenhagen

    Pre-assignment
    Screening details
    		 Main eligibility criteria were: T2D (WHO-criteria), persistent urine albumin creatine ratio (UACR) ≥ 30mg/g, estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2, age 40-80 years and absence of contraindication to MRI. CKD primarily ascribed to other causes than diabetes was an exclusion criterium.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ezetimibe
    Arm description
    		 Ezetimibe group
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily for 16 weeks

    Arm title
    		 Placebo
    Arm description
    		 Placebo group
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily for 16 weeks

    Number of subjects in period 1 [1]
    		Ezetimibe Placebo
    Started
    25
    24
    Completed
    25
    24
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: We aimed to screen and enroll 120 subjects for this "DiaKiDZ" study encompassing both an intervention study and a cross-sectional study. Only 60 were to be enrolled for the intervention study. Only results from intervention study (where 57 subjects ended up being enrolled) are reported here.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention period
    Reporting group description
    		 -

    Reporting group values
    		 Intervention period Total
    Number of subjects
    		 49 49
    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)
    		 17 17
        From 65-84 years
    		 32 32
        85 years and over
    		 0 0
    Age continuous
    Age
    Units: years
        arithmetic mean (standard deviation)
    		 67 ± 7 -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 41 41
    Sodium-glucose cotransporter-2 inhibitor
    Units: Subjects
        Yes
    		 34 34
        No
    		 15 15
    Glucagon-like peptide-1 receptor agonist
    Units: Subjects
        Yes
    		 33 33
        No
    		 16 16
    BMI
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 31 ± 4 -
    Waist circmference
    Waist circumference
    Units: cm
        arithmetic mean (standard deviation)
    		 114 ± 110 -
    Diabetes duration
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 19 (12 to 26) -
    Urine albumin creatinine ratio
    Units: mg/g
        geometric mean (inter-quartile range (Q1-Q3))
    		 95 (41 to 297) -
    Estimated glomerular filtration rate
    Units: ml/min/1.73m2
        arithmetic mean (standard deviation)
    		 76 ± 22 -
    HbA1c, IFCC
    Units: mmol/mol
        arithmetic mean (standard deviation)
    		 57 ± 10 -
    Total cholesterol
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 3.6 ± 0.7 -
    plasma triglyceride
    Units: mmol/l
        median (inter-quartile range (Q1-Q3))
    		 1.76 (1.13 to 2.90) -

    End points

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    End points reporting groups
    Reporting group title
    Ezetimibe
    Reporting group description
    		 Ezetimibe group

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group

    Primary: Change in urine albumine creatinine ratio

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    End point title
    		 Change in urine albumine creatinine ratio
    End point description
    End-of-treatment urine albumin creatinine ratio
    End point type
    Primary
    End point timeframe
    16 weeks
    End point values
    		 Ezetimibe Placebo
    Number of subjects analysed
    25
    24
    Units: mg/g
        geometric mean (inter-quartile range (Q1-Q3))
    140 (49 to 213)
    67 (34 to 148)
    Statistical analysis title
    		 Relative change in urine albumine creatinine ratio
    Statistical analysis description
    Effect (β) of ezetimibe relative to placebo on urine albumine creatinine ratio
    Comparison groups
    Ezetimibe v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.83
    Method
    		 Regression, Linear
    Parameter type
    		 Least squares mean
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.31
    Notes
    [1] - Change (β) in urine albumin creatinine ratio with ezetimibe relative to placebo. β: regression coefficient (back-transformed) from a multiple linear regression model with (log-transformed) end-of-treatment urine albumin creatinine ratio as dependent variable and treatment group (ezetimibe or placebo) and (log-transformed) baseline urine albumin creatinine ratio as independent variables.

    Secondary: Change in kidney parenchyma fat content

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    End point title
    		 Change in kidney parenchyma fat content
    End point description
    End-of-treatment kidney parenchyma fat content
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 Ezetimibe Placebo
    Number of subjects analysed
    22
    19
    Units: percent
        geometric mean (inter-quartile range (Q1-Q3))
    0.6 (0.4 to 1.2)
    1.0 (0.4 to 2.0)
    Statistical analysis title
    		 Relative change in kidney parenchyma fat content
    Statistical analysis description
    Effect of ezetimibe relative to placebo on kidney parenchyma fat content
    Comparison groups
    Ezetimibe v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.12
    Method
    		 Regression, Linear
    Parameter type
    		 Least squares mean
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.14
    Notes
    [2] - Change in kidney parenchyma fat content from baseline to end-of-treatment for ezetimibe relative to placebo (β). β: regression coefficient (back-transformed) from a multiple linear regression model with (log-transformed) end-of-treatment kidney parenchyma fat content as dependent variable and treatment group (ezetimibe or placebo) and (log-transformed) baseline kidney parenchyma fat content as independent variables.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Enrolment to end-of-treatment (approx. 19 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    Ezetimibe group
    Reporting group description
    		 -

    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Serious adverse events
    		 Ezetimibe group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 24 (4.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Peripheral artery stenosis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Subdural haematoma
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal disorders
    Haemorrhoidal haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Ezetimibe group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 25 (28.00%)
    11 / 24 (45.83%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Change in stool or flatulence
         subjects affected / exposed
    6 / 25 (24.00%)
    6 / 24 (25.00%)
         occurrences all number
    6
    6
    Dyspepsia or reflux
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 24 (12.50%)
         occurrences all number
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2021
    Addition in Protocol of “MR estimate (by Dixon’s method) of kidney parenchymal fat fraction” to secondary endpoints in both cross-sectional and intervention part of study. In cross-secional part of study, previous other secondary endpoints have been delegated to tertiary endpoints. Addition in Protocol of “Images are also obtained to estimate fat fraction in the kidney parenchyma by Dixon’s method.” in the description of the Kidney MR examination. In this description the duration of the MR examination has also been changed from 20-30 minutes to 40-60 minutes and the duration of fasting before the examination has been shortened to 4 hours (from 6 hours). Change in Participation Information of duration of study visit with MR examination to 60 minutes and addition of 4 hours fasting from food and 2 hours fasting from liquid before examination. Change in Protocol and Participant Information in inclusion criteria to “Age ≥ 40 and ≤ 80 years” from “Age ≥ 40 and ≤ 75 years” Removal of following inclusion criterion for intervention group: “LDL above 1,5mmol/L at screening” End of study postponed to 31/12/2021 from 30-06-2021

    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/37278273
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