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    Clinical Trial Results:
    A Calcium channel or Angiotensin converting enzyme inhibitor/Angiotensin receptor blocker Regimen to reduce Blood pressure variability in acute ischaemic Stroke (CAARBS): A Feasibility Trial

    Summary
    EudraCT number
    		 2017-002560-41
    Trial protocol
    		 GB  
    Global end of trial date
    31 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Dec 2019
    First version publication date
    03 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0611
    Additional study identifiers
    ISRCTN number
    		 ISRCTN10853487
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Leicester
    Sponsor organisation address
    Leicester General Hospital, Gwendolen Road, Leicester, United Kingdom, LE5 4PW
    Public contact
    Professor Thompson Robinson, University of Leicester, +44 01162523182, tgr2@leicester.ac.uk
    Scientific contact
    Professor Thompson Robinson, University of Leicester, +44 01162523182, tgr2@leicester.ac.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
    20 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In this feasibility study, patient recruitment and reasons for non-eligibility will be recorded. Accordingly, a screening log of all patients referred to the stroke services will be collected, and the reasons for non-inclusion in the study recorded.
    Protection of trial subjects
    Subjects randomised to receive an angiotensin converting enzyme inhibitor or angiotensin receptor blocker had a blood test to monitor their renal function at the first follow-up visit, in line with standard clinical practise.
    Background therapy
    		 Participants in both arms of the trial received standard stroke secondary prevention treatment in addition to the investigational treatment.
    Evidence for comparator
    		 Work exploring the effects of commonly used antihypertensive medications in patients with hypertension has indicated that different classes of antihypertensive medication have different effects on the variability of blood pressure despite having similar impacts on average blood pressure levels. Specifically, blood pressure variability is reduced by calcium channel blockers, but increased by angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Furthermore, these differential effects on blood pressure variability correlate with the risk of stroke seen in patients taking these medications.
    Actual start date of recruitment
    01 Sep 2017
    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: 14
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    3
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment for the trial commenced on 3rd January 2018 and was undertaken at three sites within the UK. The trial closed to recruitment on 31st December 2018.

    Pre-assignment
    Screening details
    		 All patients presenting to stroke services at the involved trial sites (both in-patient and out-patient services at two of the sites and only out-patients at one site) were screened for potential inclusion in the trial.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The trial was open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CCB arm
    Arm description
    		 Patients randomised to this arm were allocated to treatment with a medication from the class dihydropyridine calcium channel blockers, with the specific choice of medication from within that class being at the discretion of the treating physician.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dihydropyridine calcium channel blocker
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administer orally once daily for the duration of the trial. To be started at the introductory dose and titrated up at the first follow-up visit if blood pressure remained above the pre-specified target value.

    Arm title
    		 ACEI/ARB arm
    Arm description
    		 Patients randomised to this arm were allocated to treatment with a medication from the class angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, with the specific choice of medication from within the allocated class being at the discretion of the treating physician.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Angiotensin-converting enzyme inhibitor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily for the duration of the trial. To be commenced at the introductory dose and titrated up at the first follow-up visit if blood pressure was above the pre-specified target value.

    Investigational medicinal product name
    Angiotensin receptor blocker
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily for the duration of the trial. To be commenced at the introductory dose and titrated up at the first follow-up visit if blood pressure was above the pre-specified target value.

    Number of subjects in period 1
    		CCB arm ACEI/ARB arm
    Started
    6
    8
    Completed
    4
    5
    Not completed
    2
    3
         Screening failure
    1
    1
         Consent withdrawn by subject
    1
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CCB arm
    Reporting group description
    		 Patients randomised to this arm were allocated to treatment with a medication from the class dihydropyridine calcium channel blockers, with the specific choice of medication from within that class being at the discretion of the treating physician.

    Reporting group title
    ACEI/ARB arm
    Reporting group description
    		 Patients randomised to this arm were allocated to treatment with a medication from the class angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, with the specific choice of medication from within the allocated class being at the discretion of the treating physician.

    Reporting group values
    		 CCB arm ACEI/ARB arm Total
    Number of subjects
    		 6 8 14
    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
        arithmetic mean (standard deviation)
    		 74.8 ± 4.2 64.9 ± 9.1 -
    Gender categorical
    Units: Subjects
        Female
    		 1 3 4
        Male
    		 4 4 8
        Not recorded
    		 1 1 2
    Ethnicity categorical
    Units: Subjects
        White - British
    		 4 6 10
        White - other
    		 1 1 2
        Not recorded
    		 1 1 2
    Diagnosis categorical
    Units: Subjects
        Stroke
    		 2 4 6
        TIA
    		 3 3 6
        Not recorded
    		 1 1 2
    Smoking status categorical
    Units: Subjects
        Never smoked
    		 2 2 4
        Ex-smoker
    		 3 2 5
        Current smoker
    		 0 3 3
        Not recorded
    		 1 1 2
    Past medical history of hypertension categorical
    Units: Subjects
        Yes
    		 3 1 4
        No
    		 2 6 8
        Not recorded
    		 1 1 2
    Past medical history of diabetes categorical
    Units: Subjects
        Yes
    		 1 0 1
        No
    		 4 7 11
        Not recorded
    		 1 1 2
    Body mass index continuous
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 28.2 ± 4.6 27.1 ± 5.8 -
    Alcohol consumption continuous
    Units: units/week
        median (inter-quartile range (Q1-Q3))
    		 5 (0 to 17) 14 (12 to 38) -
    Mean enhanced clinic SBP continuous
    Units: mmHg
        arithmetic mean (standard deviation)
    		 163.6 ± 17.3 152.7 ± 14.5 -
    Mean enhanced clinic DBP continuous
    Units: mmHg
        arithmetic mean (standard deviation)
    		 81.8 ± 5.9 83.1 ± 6.5 -
    Standard deviation of enhanced clinic SBP continuous
    Units: mmHg
        arithmetic mean (standard deviation)
    		 8.4 ± 5.2 6.8 ± 5.3 -
    Standard deviation of enhanced clinic DBP continuous
    Units: mmHg
        arithmetic mean (standard deviation)
    		 5.6 ± 3.0 6.0 ± 3.4 -
    Coefficient of variation of enhanced clinic SBP continuous
    Units: percent
        arithmetic mean (standard deviation)
    		 4.9 ± 2.6 4.5 ± 3.4 -
    Coefficient of variation of enhanced clinic DBP continuous
    Units: percent
        arithmetic mean (standard deviation)
    		 7.0 ± 3.9 7.2 ± 4.0 -
    Mean beat-to-beat SBP continuous
    Units: mmHg
        arithmetic mean (standard deviation)
    		 156.6 ± 5.7 151.0 ± 11.9 -
    Mean beat-to-beat DBP continuous
    Units: mmHg
        arithmetic mean (standard deviation)
    		 79.8 ± 7.1 82.6 ± 6.1 -
    Standard deviation of beat-to-beat SBP continuous
    Units: mmHg
        arithmetic mean (standard deviation)
    		 9.9 ± 3.9 9.2 ± 5.5 -
    Standard deviation of beat-to-beat DBP continuous
    Units: mmHg
        arithmetic mean (standard deviation)
    		 5.2 ± 2.2 5.1 ± 2.4 -
    Coefficient of variation of beat-to-beat SBP continuous
    Units: percent
        arithmetic mean (standard deviation)
    		 6.3 ± 2.5 6.0 ± 2.6 -
    Coefficient of variation of beat-to-beat DBP continuous
    Units: percent
        arithmetic mean (standard deviation)
    		 6.6 ± 2.6 6.3 ± 3.0 -

    End points

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    End points reporting groups
    Reporting group title
    CCB arm
    Reporting group description
    		 Patients randomised to this arm were allocated to treatment with a medication from the class dihydropyridine calcium channel blockers, with the specific choice of medication from within that class being at the discretion of the treating physician.

    Reporting group title
    ACEI/ARB arm
    Reporting group description
    		 Patients randomised to this arm were allocated to treatment with a medication from the class angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, with the specific choice of medication from within the allocated class being at the discretion of the treating physician.

    Primary: Feasibility of recruitment and retention

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    End point title
    		 Feasibility of recruitment and retention [1]
    End point description
    Firstly, the proportion of patients screened who were eligible for, and agreed to participate in the trial was recorded from the screening logs and is presented in the CONSORT flow diagram. Reasons for ineligibility were also assessed and quantified, and are presented in the accompanying table. Secondly, the rate of retention in the trial was assessed by recording the number of recruited participants who did and did not complete the trial follow-up period.
    End point type
    Primary
    End point timeframe
    The number of patients screened who were recruited to the trial and the number of recruited participants who completed the trial was assessed over the whole trial period (15 months).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As this was a feasibility trial only descriptive analyses were carried out, with no formal statistical testing of any of the primary or secondary end-points.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    6
    8
    Units: Number of participants
        Completed the trial
    4
    5
        Did not complete the trial
    2
    3
    Attachments
    		 CONSORT flow diagram
    Untitled (Filename: Table of reasons for exclusion.docx)
    No statistical analyses for this end point

    Secondary: Compliance with trial treatment

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    End point title
    		 Compliance with trial treatment
    End point description
    Compliance was assessed using a self-report questionnaire. If participants were taking the trial medication >80% of the time then they were considered to be compliant.
    End point type
    Secondary
    End point timeframe
    Compliance with trial treatment was assessed in each participant who completed the three month follow-up period.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    6
    8
    Units: Number of participants
        >80% compliant
    4
    4
        <80% compliant
    0
    1
        Not recorded
    2
    3
    No statistical analyses for this end point

    Secondary: Completion rate of enhanced clinic blood pressure measurements

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    End point title
    		 Completion rate of enhanced clinic blood pressure measurements
    End point description
    End point type
    Secondary
    End point timeframe
    Compliance with trial measurement methods was assessed by recording completion rates of each blood pressure measurement over the three month follow-up period.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    6
    8
    Units: Number of participants
        Complete
    4
    5
        Incomplete
    0
    0
        Not recorded
    2
    3
    No statistical analyses for this end point

    Secondary: Completion rate of beat-to-beat blood pressure measurements

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    End point title
    		 Completion rate of beat-to-beat blood pressure measurements
    End point description
    End point type
    Secondary
    End point timeframe
    Compliance with trial measurement methods was assessed by recording completion rates of each blood pressure measurement over the three month follow-up period.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    6
    8
    Units: Number of participants
        Complete
    4
    3
        Incomplete
    0
    2
        Not recorded
    2
    3
    No statistical analyses for this end point

    Secondary: Standard deviation of enhanced clinic systolic blood pressure variability after three months

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    End point title
    		 Standard deviation of enhanced clinic systolic blood pressure variability after three months
    End point description
    End point type
    Secondary
    End point timeframe
    Blood pressure variability was assessed at three month follow-up.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    4
    5
    Units: mmHg
        arithmetic mean (standard deviation)
    5.1 ± 2.1
    3.9 ± 1.7
    No statistical analyses for this end point

    Secondary: Standard deviation of enhanced clinic diastolic blood pressure variability after three months

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    End point title
    		 Standard deviation of enhanced clinic diastolic blood pressure variability after three months
    End point description
    End point type
    Secondary
    End point timeframe
    Blood pressure variability was assessed at three month follow-up.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    4
    5
    Units: mmHg
        arithmetic mean (standard deviation)
    4.3 ± 2.2
    3.1 ± 1.7
    No statistical analyses for this end point

    Secondary: Coefficient of variation of enhanced clinic systolic blood pressure variability after three months

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    End point title
    		 Coefficient of variation of enhanced clinic systolic blood pressure variability after three months
    End point description
    End point type
    Secondary
    End point timeframe
    Blood pressure variability was assessed at three month follow-up.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    4
    5
    Units: percent
        arithmetic mean (standard deviation)
    4.0 ± 1.7
    3.1 ± 1.5
    No statistical analyses for this end point

    Secondary: Coefficient of variation of enhanced clinic diastolic blood pressure variability after three months

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    End point title
    		 Coefficient of variation of enhanced clinic diastolic blood pressure variability after three months
    End point description
    End point type
    Secondary
    End point timeframe
    Blood pressure variability was assessed at three month follow-up.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    4
    5
    Units: percent
        arithmetic mean (standard deviation)
    5.8 ± 2.7
    4.3 ± 1.6
    No statistical analyses for this end point

    Secondary: Standard deviation of beat-to-beat systolic blood pressure variability after three months

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    End point title
    		 Standard deviation of beat-to-beat systolic blood pressure variability after three months
    End point description
    End point type
    Secondary
    End point timeframe
    Blood pressure variability was assessed at three month follow-up.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    4
    5
    Units: mmHg
        arithmetic mean (standard deviation)
    6.2 ± 3.0
    8.7 ± 5.9
    No statistical analyses for this end point

    Secondary: Standard deviation of beat-to-beat diastolic blood pressure variability after three months

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    End point title
    		 Standard deviation of beat-to-beat diastolic blood pressure variability after three months
    End point description
    End point type
    Secondary
    End point timeframe
    Blood pressure variability was assessed at three month follow-up.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    4
    5
    Units: mmHg
        arithmetic mean (standard deviation)
    2.8 ± 1.4
    3.9 ± 2.7
    No statistical analyses for this end point

    Secondary: Coefficient of variation of beat-to-beat systolic blood pressure variability after three months

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    End point title
    		 Coefficient of variation of beat-to-beat systolic blood pressure variability after three months
    End point description
    End point type
    Secondary
    End point timeframe
    Blood pressure variability was assessed at three month follow-up.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    4
    5
    Units: percent
        arithmetic mean (standard deviation)
    4.5 ± 2.1
    6.0 ± 2.9
    No statistical analyses for this end point

    Secondary: Coefficient of variation of beat-to-beat diastolic blood pressure variability after three months

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    End point title
    		 Coefficient of variation of beat-to-beat diastolic blood pressure variability after three months
    End point description
    End point type
    Secondary
    End point timeframe
    Blood pressure variability was assessed at three month follow-up.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    4
    5
    Units: percent
        arithmetic mean (standard deviation)
    3.8 ± 1.8
    4.9 ± 2.9
    No statistical analyses for this end point

    Other pre-specified: Modified Rankin score at three months

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    End point title
    		 Modified Rankin score at three months
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Functional outcome was assessed using the modified Rankin score at three month follow-up.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    4
    5
    Units: mRS points
        median (inter-quartile range (Q1-Q3))
    0 (0 to 1)
    0 (0 to 1)
    No statistical analyses for this end point

    Other pre-specified: Montreal Cognitive Assessment score at three months

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    End point title
    		 Montreal Cognitive Assessment score at three months
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Cognition was assessed using the Montreal Cognitive Assessment at the three month follow-up visit.
    End point values
    		 CCB arm ACEI/ARB arm
    Number of subjects analysed
    4
    5
    Units: MoCA points
        arithmetic mean (standard deviation)
    23.5 ± 2.7
    23.6 ± 3.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Data on adverse events was collected over the whole three month follow-up period for each participant. Only serious adverse events were reported in this feasibility trial.
    Adverse event reporting additional description
    Data regarding adverse events were collected by research staff initiated questionnaire at each trial follow-up visit. There were no serious adverse events recorded during the trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0.0
    Reporting groups
    Reporting group title
    CCB arm
    Reporting group description
    		 Patients randomised to this arm were allocated to treatment with a medication from the class dihydropyridine calcium channel blockers, with the specific choice of medication from within that class being at the discretion of the treating physician.

    Reporting group title
    ACEI/ARB arm
    Reporting group description
    		 Patients randomised to this arm were allocated to treatment with a medication from the class angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, with the specific choice of medication from within the allocated class being at the discretion of the treating physician.

    Serious adverse events
    		 CCB arm ACEI/ARB arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CCB arm ACEI/ARB arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (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: Only data on serious adverse events was collected in this feasibility trial.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Aug 2018
    A substantial amendment was made to the trial eligibility criteria in order to try and improve recruitment figures. This was done following discussion with the Trial Management Group and Trial Steering Committee based on analysis of screening log data. Specifically, the inclusion criteria which stipulated that patients should be recruited within 72 hours of the qualifying clinical event (i.e. ischaemic stroke or transient ischaemic attack) was altered to allow inclusion of patients up to 7 days following the qualifying clinical event.

    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/30782930
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