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    Clinical Trial Results:
    A prospective, randomised, placebo-controlled, double blind, multi-centre study of the effects of Irbesartan on aortic dilatation in Marfan syndrome

    Summary
    EudraCT number
    		 2010-019302-16
    Trial protocol
    		 GB  
    Global end of trial date
    12 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jan 2020
    First version publication date
    16 Jan 2020
    Other versions
    Summary report(s)
    		 AIMS_Publication

    Trial information

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    Trial identification
    Sponsor protocol code
    2010GU001B
    Additional study identifiers
    ISRCTN number
    		 ISRCTN90011794
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Royal Brompton and Harefield NHS Foundation Trust
    Sponsor organisation address
    Sydney Street, London, United Kingdom, SW3 6NP
    Public contact
    Chief Investigator, Bart’s Heart Centre St Bartholomew's Hospital West Smithfield, +44 02037658633, Michael.Mullen@bartshealth.nhs.uk
    Scientific contact
    Chief Investigator, Bart’s Heart Centre St Bartholomew's Hospital West Smithfield, +44 02037658633, Michael.Mullen@bartshealth.nhs.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
    06 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    to determine whether giving patients with Marfan Syndrom treatment with Irbesartan reduces the annual rate of aortic dilatation compared to giving the placebo
    Protection of trial subjects
    The Data Safety and Monitoring Committee reviews interim safety analysis
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Mar 2012
    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
    United Kingdom: 192
    Worldwide total number of subjects
    192
    EEA total number of subjects
    192
    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)
    40
    Adolescents (12-17 years)
    53
    Adults (18-64 years)
    99
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment Period 24 months

    Pre-assignment
    Screening details
    		 Screening visit Date of assessment Unique patient ID no. Patient initials Date of Birth Gender Height Weight Ethnic origin Name of Hospital Concomitant medications SBP/DBP Heart rate ECG taken with detailed 12 leads quantitative measurements Echocardiogram performed and recorded in digital format 75mg open label

    Period 1
    Period 1 title
    baseline
    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
    		 Irbesartan
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Irbesartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg, 150 mg and 300 mg depending on tolerance

    Arm title
    		 Placebo
    Arm description
    		 -
    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
    75 mg, 150 mg and 300 mg

    Number of subjects in period 1
    		Irbesartan Placebo
    Started
    104
    88
    Completed
    104
    88
    Period 2
    Period 2 title
    end of follow-up
    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
    		 Ibesartan
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Irbesartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg, 150 mg, 300 mg

    Arm title
    		 Placebo
    Arm description
    		 -
    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
    75 mg, 150 mg, 300 mg

    Number of subjects in period 2
    		Ibesartan Placebo
    Started
    104
    88
    Completed
    104
    88

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Irbesartan
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Irbesartan Placebo Total
    Number of subjects
    		 104 88 192
    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
        median (inter-quartile range (Q1-Q3))
    		 18 (12 to 28) 18 (12 to 28) -
    Gender categorical
    Units: Subjects
        Female
    		 57 42 99
        Male
    		 47 46 93

    End points

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    End points reporting groups
    Reporting group title
    Irbesartan
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    Ibesartan
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    end of follow-up analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    At the end of follow-up, the data was analysed according to Intention-to-treat using mixed effects models to determine the rate of change in aortic z score, the primary endpoint.

    Primary: the absolute difference in the mean annual rates of aortic root dilatation (measured by echocardiogram)

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    End point title
    		 the absolute difference in the mean annual rates of aortic root dilatation (measured by echocardiogram)
    End point description
    End point type
    Primary
    End point timeframe
    per year measured by echocardiogram
    End point values
    		 Ibesartan Placebo
    Number of subjects analysed
    104
    88
    Units: mm
        number (not applicable)
    104
    88
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    The primary analysis is the comparison of rates of change in aortic root diameter per year between the active Irbesartan and placebo arms of the trial. This will be carried out on the full analysis set based on the intention to treat principle. The mean annual rate of change in aortic root diamenter in each treatment group, together with the absolute difference between these rates ( and its associated p value and 95% CI) will be estimated using a linear mixed effect model for repeated measur
    Comparison groups
    Ibesartan v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 -0.02
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All SAE reported within 24 hours.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Irbesartan
    Reporting group description
    		 -

    Serious adverse events
    		 Irbesartan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Irbesartan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    Vascular disorders
    Headache
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Oct 2010
    1.Changes to the study eligibility criteria, PIS and ICF. 2.Update of site list; Note: This amendment was approved by the REC on 26.10.2010 and MHRA on 08.11.2010.
    25 Jan 2011
    1.New sites added: Hear H, GOST; 2.Change of PI in: Golden Jubilee Hospital and Yorkhill Hospital Glasgow; Note: This amendment was approved by the REC on 25.01.2011. The amendment was not submitted to the MHRA at the time.
    30 Mar 2011
    1.Study label have been revised, V2/ 09.03.2011. Note: This amendment was approved by the MHRA on 30.03.2011.
    13 Oct 2011
    1.To notify changes of PI at: Middlesborough and Newcastle Note: This amendment was approved by the REC 13.10.2011 . The amendment was not submitted to the MHRA at the time.
    26 Oct 2011
    1.Notifying of the temporary halt Note: This amendment was approved by the REC on 15.11.2011 and MHRA on 26.10.2011.
    05 Dec 2011
    1.Following the notification of a Serious Breach, notification of recommencement of the trial. Note: This amendment was approved by the REC on 05.12.2011 and MHRA on 21.12.2011.
    02 Mar 2012
    1.Notification of addition of a new site: South Devon Healthcare NHS FT Note: This amendment was approved by the REC on 02.03.2011.
    12 Mar 2012
    1.Notifying: Parent/ Carer ICF (V3/ 24 Oct 2011) amendment to ensure consistency with the Adult ICF; correction of a typo error to the footer of the Genetics sub study adult ICF (V1/ 26 Feb 2010). Note: This amendment was approved by the REC on 12.03.2012.
    12 Mar 2012
    1.School letter (V1/11 Nov 2011) to explain absenteeism for paediatric patients entering the study. Note: This amendment was approved by the REC on 12.03.2012
    08 Jun 2012
    1.Addition of a new site: Cumberland Infirmary Note: This amendment was approved by the REC on 08.06.2012
    30 Oct 2012
    1.Change of PI at Royal Victoria Hospital Belfast Note: This amendment was approved by the REC on 30.10.2012.
    07 Feb 2013
    1.Add Invitation Reply Form V1/08.01.2013 2.AIMS Wikipedia Text entries 3.Addition of new site: Glenfield Hospital Leicester, PI Aidan Bolger Note: This amendment was approved by the REC on 07.02.2013.
    28 Mar 2013
    1.Change of PI at Southampton, Dr Aisling Carroll Note: This amendment was approved by the REC on 28.03.2013.
    18 Apr 2013
    1.Change of PI AT Heart Hospital London Note: This amendment was approved by the REC on 18.04.2013.
    18 Jun 2013
    1.Poster Note: This amendment was approved by the REC on 18.06.2013
    05 Aug 2013
    1.Web press release V1/23.07.2013 Note: This amendment was submitted to the REC on 05.08.2013.
    22 Oct 2014
    1.Change of PI at Sheffield Hospital Note: This amendment was submitted to the REC on 22.10.2014
    16 Jan 2015
    1.Addition of new site St Barholomew’s Hospital 2.Change of PI at Guy’s and St Thoma’s Hospital Note: This amendment was approved by the REC on 16.01.2015.
    20 Mar 2015
    1.Change of PI at Northern General Hospital Sheffield Note: This amendment was submitted to the REC on 20.03.2015.
    11 May 2015
    1.Suspended recruitment into AIMS study Note: This amendment was approved by the REC on 11.05.2015 and MHRA on 29.05.2015
    02 Feb 2017
    1.Protocol amended 2.SmPC Note: This amendment was approved by the REC 0n 13.01.2017 and MHRA on 07.02.2017

    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
    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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