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    Clinical Trial Results:
    Perfusion by Arterial Spin labelling following Single dose Tadalafil In Small vessel disease

    Summary
    EudraCT number
    		 2015-001235-20
    Trial protocol
    		 GB  
    Global end of trial date
    25 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jun 2022
    First version publication date
    03 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    14.0189
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02450253
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    St George's University of London
    Sponsor organisation address
    Cranmer Terrace, London, United Kingdom,
    Public contact
    Atticus Hainsworth , St George's University of London, 44 02087253516, ahainswo@sgul.ac.uk
    Scientific contact
    Atticus Hainsworth , St George's University of London, 44 02087253516, ahainswo@sgul.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
    13 Oct 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does Tadalafil increase blood flow in deep brain tissue?
    Protection of trial subjects
    N/A
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 65
    Worldwide total number of subjects
    65
    EEA total number of subjects
    0
    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)
    32
    From 65 to 84 years
    32
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 65 assessed for eligibility, 65 randomised

    Pre-assignment
    Screening details
    		 65 assessed for eligibility, 65 randomised

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1
    Arm description
    		 Allocated to tadalafil at Visit 1, placebo at Visit 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tadalafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20mg

    Arm title
    		 Group 2
    Arm description
    		 Allocated to placebo at Visit 1, tadalafil at Visit 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tadalafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20mg

    Number of subjects in period 1
    		Group 1 Group 2
    Started
    35
    30
    Completed
    31
    24
    Not completed
    4
    6
         Physician decision
    1
    3
         Consent withdrawn by subject
    3
    3

    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
    		 65 65
    Age categorical
    Units: Subjects
        Adults (18-90years)
    		 65 65
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.7 ± 8.7 -
    Gender categorical
    Units: Subjects
        Female
    		 19 19
        Male
    		 46 46
    MoCA score
    Scoring in MoCA ranges from0 to 30, with a score of 26 or higher indicating normal cognitive ability. These cores have been adjusted for educational level (+1 if the participant had 12 or more years of education).
    Units: Score
        arithmetic mean (standard deviation)
    		 25.4 ± 3.4 -
    Time from stroke to consent
    Units: Months
        arithmetic mean (standard deviation)
    		 16 ± 17.6 -
    Systolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 145 ± 16.6 -

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Allocated to tadalafil at Visit 1, placebo at Visit 2

    Reporting group title
    Group 2
    Reporting group description
    		 Allocated to placebo at Visit 1, tadalafil at Visit 2

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received placebo

    Subject analysis set title
    Tadalafil
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received Tadalafil

    Primary: Changes in Deep gray matter CBF

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    End point title
    		 Changes in Deep gray matter CBF [1]
    End point description
    End point type
    Primary
    End point timeframe
    All MRI data were acquired from brain scans performed on a Tuesday or Thursday, pre-dosing scans between the hours of 10:00 a.m. and 12:00 p.m., and post-dosing scans from 2:00 p.m. to 5:00 p.m.
    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: Please see attached link for the publication
    End point values
    		 Placebo Tadalafil
    Number of subjects analysed
    53 [2]
    53 [3]
    Units: ml/min/100g
        arithmetic mean (confidence interval 95%)
    1.75 (0.74 to 2.76)
    1.79 (0.71 to 2.88)
    Notes
    [2] - completed the arm
    [3] - completed the arm
    No statistical analyses for this end point

    Primary: Changes in Normal appearing white matter CBF

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    End point title
    		 Changes in Normal appearing white matter CBF [4]
    End point description
    End point type
    Primary
    End point timeframe
    All MRI data were acquired from brain scans performed on a Tuesday or Thursday, pre-dosing scans between the hours of 10:00 a.m. and 12:00 p.m., and post-dosing scans from 2:00 p.m. to 5:00 p.m.
    Notes
    [4] - 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: Please see attached link for the publication
    End point values
    		 Placebo Tadalafil
    Number of subjects analysed
    53
    53
    Units: ml/min/100g
        arithmetic mean (confidence interval 95%)
    0.8 (0.14 to 1.47)
    1.15 (0.49 to 1.80)
    No statistical analyses for this end point

    Primary: Changes in White matter hyperintensities

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    End point title
    		 Changes in White matter hyperintensities [5]
    End point description
    End point type
    Primary
    End point timeframe
    All MRI data were acquired from brain scans performed on a Tuesday or Thursday, pre-dosing scans between the hours of 10:00 a.m. and 12:00 p.m., and post-dosing scans from 2:00 p.m. to 5:00 p.m.
    Notes
    [5] - 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: Please see attached link for the publication
    End point values
    		 Placebo Tadalafil
    Number of subjects analysed
    53
    53
    Units: ml/min/100g
        arithmetic mean (confidence interval 95%)
    0.82 (0.48 to 1.12)
    1.29 (0.21 to 2.38)
    No statistical analyses for this end point

    Secondary: Changes in Total gray matter CBF

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    End point title
    		 Changes in Total gray matter CBF
    End point description
    End point type
    Secondary
    End point timeframe
    All MRI data were acquired from brain scans performed on a Tuesday or Thursday, pre-dosing scans between the hours of 10:00 a.m. and 12:00 p.m., and post-dosing scans from 2:00 p.m. to 5:00 p.m.
    End point values
    		 Placebo Tadalafil
    Number of subjects analysed
    53
    53
    Units: ml/min/100g
        arithmetic mean (confidence interval 95%)
    2.05 (0.93 to 3.17)
    2.54 (1.48 to 3.61)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    2 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 DAIDS
    Dictionary version
    2.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Tadalafil
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Tadalafil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Tadalafil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 65 (12.31%)
    3 / 65 (4.62%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Faint, light headed
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    Panic attack
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Left knee pain
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Infections and infestations
    Cold and sore throat
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Chest infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Sep 2015
    Move Cognitive testing from V1 to V0 and amend Statistician details
    09 Nov 2015
    Adjust MRI acquisition timings Eligibility criteria adjusted to allow lower age limit 50 and lower CrCl 30ml/min
    10 Mar 2016
    PIC sites added Eligibility criteria adjusted & FBC sample added
    05 Jul 2017
    SiMPD V3 May 2017 to include expiration date change following manufacture of 2nd IMP batch Protocol v5 22nd May 2017 to include corrections throughout and clarification of AE reporting frame To also include notification to MHRA of changes brought about by SA02 in regards to inclusion criteria
    02 Aug 2017
    Increase Sample size from 54 to 90
    06 Sep 2017
    Update PIS and ICF following SmPC review (DSUR#2 preparation) with rare reports of sudden hearing loss and Visual Disturbances

    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.
    See final report appendix for limitations

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35135037
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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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