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    Clinical Trial Results:
    Early prospective therapy trial to delay renal failure in children with Alport syndrome.

    Summary
    EudraCT number
    		 2010-024300-10
    Trial protocol
    		 DE  
    Global end of trial date
    25 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 May 2020
    First version publication date
    27 May 2020
    Other versions
    Summary report(s)
    		 ALPORT_Summary report_V01_20200319

    Trial information

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    Trial identification
    Sponsor protocol code
    00814
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01485978
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsmedizin der Georg-August-Universität Göttingen
    Sponsor organisation address
    Robert-Koch-Straße 40, Göttingen, Germany, 37075
    Public contact
    Study centre-UMG, University Medical Center Goettingen (UMG), +49 55139171347, sz-umg.sponsor-qm@med.uni-goettingen.de
    Scientific contact
    Abt. Nephrologie und Rheumatologie, University Medical Center Goettingen, +49 5513966331, gross.oliver@med.uni-goettingen.de
    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
    19 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    to determine the safety and efficacy of the ACEi ramipril in delaying disease progression in patients with early stages of Alport Syndrome, in a setting of multi-centre, randomised, placebo-controlled, patient- and investigator-blind trial.
    Protection of trial subjects
    Medications affecting blood pressure and immune-suppressants were avoided in the randomized arm of this study. Non-steroidal anti-inflammatory drugs (NSAID) were allowed to be administered for no more than 1 week e.g., for the treatment of an acute injury. For randomised patients treated in a double blind fashion, emergency codes were available to the investigator. A code, which revealed the treatment group for a specific study patient, was opened during the study only if the choice of treatment depends on the study subject’s therapy assignment or if the patient progresses to the next disease level.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 66
    Worldwide total number of subjects
    66
    EEA total number of subjects
    66
    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)
    46
    Adolescents (12-17 years)
    20
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period: 3.5 years First patient in: 07.05.2012 Last patient in: 30.09.2015

    Pre-assignment
    Screening details
    		 not apllicable.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ramipril (randomized)
    Arm description
    		 For patients randomised to receive ramipril, the dose of ramipril will be up-titrated over a period of 12 months from 1 to 6 mg/m2 or until the individual maximum tolerated dose (MTD) is reached.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramipril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage of ramipril in patients <18 years will be calculated using the Mosteller formula for the calculation of the body surface area (m2). For paediatric patients, the maximum daily dose of ramipril will be 6 mg/m2. For adults, the maximum daily dose of ramipril will be 10 mg. The same number of tablets will be administered for placebo treatment.

    Investigational medicinal product name
    Ramipril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage of ramipril in patients <18 years will be calculated using the Mosteller formula for the calculation of the body surface area (m2). For paediatric patients, the maximum daily dose of ramipril will be 6 mg/m2. For adults, the maximum daily dose of ramipril will be 10 mg. The same number of tablets will be administered for placebo treatment.

    Arm title
    		 Placebo (randomized)
    Arm description
    		 For patients randomised to receive ramipril, the dose of ramipril will be up-titrated over a period of 12 months from 1 to 6 mg/m2 or until the individual maximum tolerated dose (MTD) is reached. Patients randomised to receive placebo will take the same number of tablets. The individual MTD should be held throughout the study. Placebo tablets are identical in appearance to the study medication but do not contain the active ingredient.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage of ramipril in patients <18 years will be calculated using the Mosteller formula for the calculation of the body surface area (m2). For paediatric patients, the maximum daily dose of ramipril will be 6 mg/m2. For adults, the maximum daily dose of ramipril will be 10 mg. For all patients, there will be an initial up-titration phase for ramipril. The same number of tablets will be administered for placebo treatment.

    Arm title
    		 Ramipril (open label)
    Arm description
    		 Patients may be treated open label with ramipril, including previously treated as well as un-treated patients who, or whose parents/legal guardian refuse randomisation after eligibility is confirmed. All patients will undergo study-specific procedures according to the study schedule without regard to treatment/ randomisation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramipril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage of ramipril in patients <18 years will be calculated using the Mosteller formula for the calculation of the body surface area (m2). For paediatric patients, the maximum daily dose of ramipril will be 6 mg/m2. For adults, the maximum daily dose of ramipril will be 10 mg. For all patients, there will be an initial up-titration phase for ramipril.

    Number of subjects in period 1
    		Ramipril (randomized) Placebo (randomized) Ramipril (open label)
    Started
    12
    10
    44
    Completed
    12
    10
    44

    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
    		 66 66
    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)
    		 46 46
        Adolescents (12-17 years)
    		 20 20
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 64 64

    End points

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    End points reporting groups
    Reporting group title
    Ramipril (randomized)
    Reporting group description
    		 For patients randomised to receive ramipril, the dose of ramipril will be up-titrated over a period of 12 months from 1 to 6 mg/m2 or until the individual maximum tolerated dose (MTD) is reached.

    Reporting group title
    Placebo (randomized)
    Reporting group description
    		 For patients randomised to receive ramipril, the dose of ramipril will be up-titrated over a period of 12 months from 1 to 6 mg/m2 or until the individual maximum tolerated dose (MTD) is reached. Patients randomised to receive placebo will take the same number of tablets. The individual MTD should be held throughout the study. Placebo tablets are identical in appearance to the study medication but do not contain the active ingredient.

    Reporting group title
    Ramipril (open label)
    Reporting group description
    		 Patients may be treated open label with ramipril, including previously treated as well as un-treated patients who, or whose parents/legal guardian refuse randomisation after eligibility is confirmed. All patients will undergo study-specific procedures according to the study schedule without regard to treatment/ randomisation.

    Primary: Safety - adverse events before disease progression

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    End point title
    		 Safety - adverse events before disease progression
    End point description
    End point type
    Primary
    End point timeframe
    Time before disease progression varies from 0.41 to 5.1 years.
    End point values
    		 Ramipril (randomized) Placebo (randomized) Ramipril (open label)
    Number of subjects analysed
    11
    9
    42
    Units: Adverse events before disease progressio
    289
    176
    0
    Statistical analysis title
    		 Safety - adverse events before disease progression
    Comparison groups
    Ramipril (randomized) v Placebo (randomized)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.98
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.53

    Primary: Efficacy - disease progression

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    End point title
    		 Efficacy - disease progression
    End point description
    End point type
    Primary
    End point timeframe
    Observation period until final examination after 6 years.
    End point values
    		 Ramipril (randomized) Placebo (randomized) Ramipril (open label)
    Number of subjects analysed
    11
    9
    42
    Units: Disease progression
    3
    5
    17
    Statistical analysis title
    		 Efficacy - time before disease progression
    Comparison groups
    Ramipril (randomized) v Placebo (randomized)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Weibull regression
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 2.2

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events were recorded during the full study period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICD-10
    Dictionary version
    2019
    Frequency threshold for reporting non-serious adverse events: 5%
    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: Information about Adverse events can be found under End point section

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2012
    Amendement due to changes in the summary of product characterisitcs of the investigetional product.
    20 Mar 2013
    Update of Protocol (new version 3.0 dated 18.02.2013) due to changes in storage conditions of investigational product.
    15 Jul 2014
    Update of protocol (new version 4.0 dated 06.06.2014) due to adjustment of randomization ratio and changes in the maunfacturing process of the investigational product (verum).
    14 Jul 2015
    Update of protocol (new version 5.0 dated 12.06.2015) due to extension of shelf-life of the placebo and extension of recruitment period.
    20 Apr 2017
    Update of Protocol (new version 6.0 dated 30.03.2017) due to changes in destruction of medication, permitted concomitant medication and AE-documentation. Furthermore the unblinding process is described in more detail.

    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
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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
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