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    Clinical Trial Results:
    Preventing cognitive decline and dementia from cerebral small vessel disease

    Summary
    EudraCT number
    		 2015-001953-33
    Trial protocol
    		 GB  
    Global end of trial date
    31 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions
    Summary report(s)
    		 Fronteirs paper
    EClinical Medicine paper

    Trial information

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    Trial identification
    Sponsor protocol code
    PrevSVD-2015
    Additional study identifiers
    ISRCTN number
    		 ISRCTN12580546
    US NCT number
    		 NCT02481323
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Alzheimer's Society: 252 (AS-PG-14-033)
    Sponsors
    Sponsor organisation name
    University of Edinburgh
    Sponsor organisation address
    Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Trial Manager (Kirsten Shuler), University of Edinburgh, 44 131 465 9599, joanna.wardlaw@ed.ac.uk
    Scientific contact
    Prof Joanna Wadlaw, University of Edinburgh, 44 131 465 9599, joanna.wardlaw@ed.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
    17 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We propose to do a small clinical trial to test how well Cilostazol and ISMN are tolerated by lacunar stroke patients when given individually or in combination, at increasing doses. We will monitor symptoms like headache, heart thumping, dizziness, bruising, other brain and leg symptoms, to see how patients find taking the drugs.
    Protection of trial subjects
    Participants take trial medication for 11 weeks. The dose is increased, in weekly increments over two to three weeks as tolerated, sustained until eight weeks post-randomization, then decreased gradually over two weeks and stopped. The escalating dose is designed to reduce potential adverse effects following initiation of cilostazol and is standard for ISMN. Gradual dose reduction aims to prevent large hemodynamic changes on cessation of medication
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Nov 2015
    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: 57
    Worldwide total number of subjects
    57
    EEA total number of subjects
    57
    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)
    27
    From 65 to 84 years
    27
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 57
    Number of subjects completed
    		 57

    Period 1
    Period 1 title
    treatment phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    To maintain blinding of participants, prior to the start of the trial, the Investigational Supplies Group (ISG), an independent arm of the Research and Development Office, NHS Lothian, removed study medications from their original blister packs and placed them in bottles labelled‘ Drug A’ or ‘Drug B’, a process which was approved by the Medicines and Healthcare Regulatory Agency.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 cilostazol
    Arm description
    		 cilostazol alone, 50 mg twice daily, increasing to 100 mg twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    cilostazol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50mg twice daily increasing to 100mg twice daily

    Arm title
    		 ISMN
    Arm description
    		 ISMN alone, 25 mg once daily increasing to 25 mg twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Isosorbide Mononitrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25mg od increasing to 25mg bd

    Arm title
    		 both, immediate start
    Arm description
    		 Cilostazol and ISMN combined, started immediately, ISMN given first
    Arm type
    		 Experimental

    Investigational medicinal product name
    cilostazol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50mg twice daily increasing to 100mg twice daily

    Investigational medicinal product name
    Isosorbide Mononitrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25mg od increasing to 25mg bd

    Arm title
    		 both, delayed
    Arm description
    		 cilostazol and ISMN combined, start delayed for three weeks, cilostazol given first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    cilostazol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50mg twice daily increasing to 100mg twice daily

    Investigational medicinal product name
    Isosorbide Mononitrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25mg od increasing to 25mg bd

    Number of subjects in period 1
    		cilostazol ISMN both, immediate start both, delayed
    Started
    13
    15
    14
    15
    Completed
    13
    15
    14
    14
    Not completed
    0
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    treatment phase
    Reporting group description
    		 -

    Reporting group values
    		 treatment phase Total
    Number of subjects
    		 57 57
    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)
    		 66.1 ( 11.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 18 18
        Male
    		 39 39
    Subject analysis sets

    Subject analysis set title
    analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    one patient withdrew from study

    Subject analysis sets values
    		 analysis set
    Number of subjects
    56
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.1 ( 11.1 )
    Gender categorical
    Units: Subjects
        Female
    999
        Male
    999

    End points

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    End points reporting groups
    Reporting group title
    cilostazol
    Reporting group description
    		 cilostazol alone, 50 mg twice daily, increasing to 100 mg twice daily

    Reporting group title
    ISMN
    Reporting group description
    		 ISMN alone, 25 mg once daily increasing to 25 mg twice daily

    Reporting group title
    both, immediate start
    Reporting group description
    		 Cilostazol and ISMN combined, started immediately, ISMN given first

    Reporting group title
    both, delayed
    Reporting group description
    		 cilostazol and ISMN combined, start delayed for three weeks, cilostazol given first.

    Subject analysis set title
    analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    one patient withdrew from study

    Primary: proportion of patients reaching target dose

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    End point title
    		 proportion of patients reaching target dose
    End point description
    The primary outcome was the proportion of participants achieving target dose by the end of the eight-week trial period, assessed by structured questionnaire
    End point type
    Primary
    End point timeframe
    8 weeks from randomisation
    End point values
    		 cilostazol ISMN both, immediate start both, delayed analysis set
    Number of subjects analysed
    13
    15
    14
    14
    56
    Units: persons reaching target dose
    3
    8
    5
    5
    21
    Statistical analysis title
    		 SAP
    Statistical analysis description
    provided in the study protocol at https://doi.org/10.1177/1747493017731947
    Comparison groups
    ISMN v both, immediate start v cilostazol v both, delayed
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05 [2]
    Method
    		 difference in proportions
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 14.46
    Variability estimate
    Standard deviation
    Notes
    [1] - safety and tolerability
    [2] - ... in proportion reaching target dose

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    baseline, treatment phase
    Adverse event reporting additional description
    patient self report at weekly FU
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 physician self compl
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 1.8%
    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: Symptoms were common without trial medication. In the week prior to randomisation, the following symptoms were experienced: headache 30%; palpitations 20%; dizziness 40%; loose stools 30%; nausea 15%; dyspepsia 45%; bruising 20%; bleeding from mucous membranes 15%; and rash 9%. Following drug initiation, there was a slight increase in headache, palpitations, dizziness, loose stools, nausea, followed by a return to baseline levels with continued trial drug (Fig. 3; Table 2; Supplementary Fig. S3)

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31317131
    http://www.ncbi.nlm.nih.gov/pubmed/31333572
    http://www.ncbi.nlm.nih.gov/pubmed/28906205
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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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