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    Clinical Trial Results:
    A randomised, doublet blinded, placebo controlled cross-over study of Allopurinols effect to prevent loss of kidney function in type 1 diabetes

    Summary
    EudraCT number
    		 2014-001786-26
    Trial protocol
    		 DK  
    Global end of trial date
    12 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Jan 2018
    First version publication date
    31 Jan 2018
    Other versions
    Summary report(s)
    		 Summary of MIKAL study

    Trial information

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    Trial identification
    Sponsor protocol code
    3004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Steno Diabetes Center
    Sponsor organisation address
    Niels Steensensvej 2-6, Gentofte, Denmark, 2820
    Public contact
    Diabetes complications research , Steno Diabetes Center, +45 30912975, sascha.maria.pilemann-lyberg@regionh.dk
    Scientific contact
    Diabetes complications research , Steno Diabetes Center, +45 30912975, sascha.maria.pilemann-lyberg@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
    07 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether lowering serum uric acid by means of allopurinol early in the course of kidney disease may be effective in slowing the decline of renal function in T1D patients.
    Protection of trial subjects
    Blood samples for HbA1c, white blood count, electrolytes, hemoglobin and skin assessment was used to monitor any side effects or distress of the subjects.
    Background therapy
    		 Insulin treatment and RAAS blockers
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    21
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 30 Subjects with type 1 diabetes (WHO criteria), uric acid ≥ 0.26 mmol/l, persistent albuminuria (UACR: urine albumin creatinine ratio ≥30 mg/g in at least 2 out of 3 consecutive morning spot urine samples) and CKD-EPI-eGFR ≥ 40 ml/min/1.73m2. Recruitment started September 2014 and ended January 2016.

    Pre-assignment
    Screening details
    		 64 subjects were screened and 34 failed screening due to low uric acid level, low eGFR or not albuminuric.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo treatment period
    Arm description
    		 Subjects were treated with placebo for 60 days either as there first treatment or after a 4 week wash out period after the first treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg per day

    Arm title
    		 Active treatment with allopurinol
    Arm description
    		 Subjects either started active treatment as there first treatment or after a 4 week wash out period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Allopurinol "DAK"
    Investigational medicinal product code
    M04AA01
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg per day

    Number of subjects in period 1
    		Placebo treatment period Active treatment with allopurinol
    Started
    15
    15
    Cr51-EDTA-GFR
    15
    12
    Completed
    15
    12
    Not completed
    0
    3
         Adverse event, non-fatal
    -
    3
    Period 2
    Period 2 title
    Treatment period 2
    Is this the baseline period?
    		 No
    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
    		 Active treatment with allopurinol
    Arm description
    		 Subjects enter active treatment after 4 weeks of wash out
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Allopurinol "DAK"
    Investigational medicinal product code
    M04AA01
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg pr day

    Arm title
    		 Placebo treatment period
    Arm description
    		 Subjects started placebo treatment after a 4 week period wash out
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg pr. day

    Number of subjects in period 2
    		Active treatment with allopurinol Placebo treatment period
    Started
    15
    12
    Cr51-EDTA-GFR
    14
    12
    Completed
    14
    12
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Placebo treatment period
    Reporting group description
    		 Subjects were treated with placebo for 60 days either as there first treatment or after a 4 week wash out period after the first treatment.

    Reporting group title
    Active treatment with allopurinol
    Reporting group description
    		 Subjects either started active treatment as there first treatment or after a 4 week wash out period.
    Reporting group title
    Active treatment with allopurinol
    Reporting group description
    		 Subjects enter active treatment after 4 weeks of wash out

    Reporting group title
    Placebo treatment period
    Reporting group description
    		 Subjects started placebo treatment after a 4 week period wash out

    Subject analysis set title
    paired t test
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    First the data was subjected to analysis to confirm that there is no carry-over effect and when this was confirmed the to treatment arms "allopurinol" and "placebo" was compared with a paired ttest.

    Primary: change in albuminuria

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    End point title
    		 change in albuminuria
    End point description
    End point type
    Primary
    End point timeframe
    Albuminuria was measured at the last day of treatment (after 60 days of treatment with either Allopurinol or placebo).
    End point values
    		 Placebo treatment period Active treatment with allopurinol Active treatment with allopurinol Placebo treatment period paired t test
    Number of subjects analysed
    15
    11
    14
    10
    25
    Units: mg/24h
        median (standard deviation)
    403 ± 611
    523 ± 495
    403 ± 853
    351 ± 240
    456 ± 707
    Statistical analysis title
    		 Paired ttest
    Statistical analysis description
    Paired ttest was used to compare treatment periods allopurinol vs. placebo
    Comparison groups
    Placebo treatment period v Active treatment with allopurinol
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: changes in Cr51-EDTA-GFR

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    End point title
    		 changes in Cr51-EDTA-GFR
    End point description
    End point type
    Secondary
    End point timeframe
    Cr51-EDTA-GFR was measured at the last treatment day (after 60 days of treatment with either Allopurinol or placebo)
    End point values
    		 Placebo treatment period Active treatment with allopurinol Active treatment with allopurinol Placebo treatment period paired t test
    Number of subjects analysed
    15
    12
    14
    12
    26
    Units: ml/min/1.73m2
        median (standard deviation)
    69 ± 20
    79 ± 21
    70 ± 19
    75 ± 22
    74 ± 20
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    4 subjects experienced adverse event. All adverse events occurred after initiation study medication and was assed by a doctor immediately after the subject reported the adverse event.
    Adverse event reporting additional description
    2 had gastrointestinal discomfort, 2 had universal skin rash
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Skin Rash
    Reporting group description
    		 Universal skin rash after initiating study medication

    Reporting group title
    Gastroentestinal discomfort
    Reporting group description
    		 -

    Reporting group title
    irregular heart rythm
    Reporting group description
    		 -

    Serious adverse events
    		 Skin Rash Gastroentestinal discomfort irregular heart rythm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    irregular heart rhythm
    Additional description: one had irregular heart rhythm but was known with this previously and was without study medication when it occurred.
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Skin Rash Gastroentestinal discomfort irregular heart rythm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    Gastrointestinal disorders
    gastroentestinal discomfort
    Additional description: Two experienced gastrointestinal discomfort.
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    2
    0
    Skin and subcutaneous tissue disorders
    Universal rash
    Additional description: two subjects experienced universal skin rash after intiating study medicantion. Was gone after stopping with study medication.
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    2
    0

    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.
    The treatment period was to short to show an effect on the end point.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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