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    Clinical Trial Results:
    Improving cerebral blood flow and cognition in patient with cerebral small vessel disease. The ETLAS-2 Trial.

    Summary
    EudraCT number
    		 2020-002329-27
    Trial protocol
    		 DK  
    Global end of trial date
    23 Sep 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Nov 2025
    First version publication date
    15 Nov 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ETLAS-2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05173896
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of Neurology, Copenhagen University Hospital - Herlev and Gentofte
    Sponsor organisation address
    Borgmester Ib Juuls Vej 1, Herlev, Denmark, 2730
    Public contact
    Christina Kruuse, Copenhagen University Hospital - Herlev and Gentofte, 0045 38681233, christina.kruuse@regionh.dk
    Scientific contact
    Christina Kruuse, Copenhagen University Hospital - Herlev and Gentofte, 0045 38681233, christina.kruuse@regionh.dk
    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
    22 Aug 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    We aim to investigate the feasibility of daily tadalafil for three months compared to placebo in patients with cerebral small vessel disease and stroke/TIA.
    Protection of trial subjects
    Safety and adverse events were monitored throughout the trial period. Participants had a phone number they could call throughout the day to contact study personnel in case of questions and adverse events.
    Background therapy
    		 All participants received standard care medication.
    Evidence for comparator
    		 Daily dosing with 20 mg tadalafil was tested against daily placebo for three months. Tadalafil is a known vasoactive substance which we wanted to test in a population with cerebral small vessel disease. Impaired vascular reactivity is a characteristic feature of cerebral small vessel disease.
    Actual start date of recruitment
    14 Jun 2022
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 76
    Worldwide total number of subjects
    76
    EEA total number of subjects
    76
    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)
    29
    From 65 to 84 years
    44
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment began on June 14, 2022, and concluded on June 19, 2024. All participants were recruited from the Capital Region of Denmark.

    Pre-assignment
    Screening details
    		 We prescreened patient records of previously admitted patients from the stroke department of four hospitals in the Capital Region of Denmark. Eligible patients were asked for interest and invited to an information and inclusion visit. We prescreened 13 532 patients, of which 255 were asked for interest. We included 76 patients in total.

    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, Monitor, Data analyst, Subject, Carer, Assessor
    Blinding implementation details
    This trial was blinded and placebo-controlled, with a 1:1 allocation between oral daily tadalafil 20 mg or placebo. Randomization was conducted by the Capital Region Pharmacy in Denmark. Tadalafil and placebo were encapsulated in identical opaque capsules and packaged in identical containers, each labeled with a unique identification number. Upon inclusion, participants were assigned a randomization number to ensure blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tadalafil
    Arm description
    		 Daily tadalafil for 3 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tadalafil Stada
    Investigational medicinal product code
    G04BE08
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Tadalafil Stada, 20 mg, administered once daily in the morning, for three months.

    Arm title
    		 Placebo
    Arm description
    		 Daily placebo for 3 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, administered once daily in the morning, for three months.

    Arm title
    		 Excluded before treatment initiation
    Arm description
    		 These participants were all in the placebo group, but they were excluded before treatment initiation due to unexpected MRI contraindications.
    Arm type
    		 Placebo, excluded

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, administered once daily in the morning, for three months.

    Number of subjects in period 1
    		Tadalafil Placebo Excluded before treatment initiation
    Started
    38
    33
    5
    Completed
    33
    33
    0
    Not completed
    5
    0
    5
         Adverse event, non-fatal
    5
    -
    -
         Excluded due to MRI contraindications.
    -
    -
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tadalafil
    Reporting group description
    		 Daily tadalafil for 3 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Daily placebo for 3 months.

    Reporting group title
    Excluded before treatment initiation
    Reporting group description
    		 These participants were all in the placebo group, but they were excluded before treatment initiation due to unexpected MRI contraindications.

    Reporting group values
    		 Tadalafil Placebo Excluded before treatment initiation Total
    Number of subjects
    		 38 33 5 76
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 13 15 1 29
        From 65-84 years
    		 23 17 4 44
        85 years and over
    		 2 1 0 3
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 70 (61 to 75) 65 (60 to 75) 75 (65.5 to 75.5) -
    Gender categorical
    Units: Subjects
        Female
    		 13 7 0 20
        Male
    		 25 26 5 56

    End points

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    End points reporting groups
    Reporting group title
    Tadalafil
    Reporting group description
    		 Daily tadalafil for 3 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Daily placebo for 3 months.

    Reporting group title
    Excluded before treatment initiation
    Reporting group description
    		 These participants were all in the placebo group, but they were excluded before treatment initiation due to unexpected MRI contraindications.

    Primary: Treatment feasibility: Compliance

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    End point title
    		 Treatment feasibility: Compliance [1]
    End point description
    Medication compliance rate ≥90% at the end of the trial (3 months follow-up).
    End point type
    Primary
    End point timeframe
    3 months follow-up.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38
    33
    Units: number of participants
        Compliance ≥90%
    26
    31
        Compliance <90%
    12
    33
    Statistical analysis title
    		 Binary logistic regression analysis
    Statistical analysis description
    Binary logistic regression analysis of compliance rate between groups.
    Comparison groups
    Placebo v Tadalafil
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: Systolic blood pressure

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    End point title
    		 Systolic blood pressure [2]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [3]
    33
    Units: mmHg
    median (inter-quartile range (Q1-Q3))
        Baseline
    144 (137 to 157)
    144 (134 to 154)
        Follow-up
    139 (131 to 156)
    140 (130 to 148)
    Notes
    [3] - 38 at baseline and 33 at follow-up.
    No statistical analyses for this end point

    Secondary: Diastolic blood pressure

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    End point title
    		 Diastolic blood pressure [4]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [5]
    33
    Units: mmHg
    median (inter-quartile range (Q1-Q3))
        Baseline
    85 (78 to 94)
    87 (81 to 94)
        Follow-up
    83 (74 to 88)
    85 (79 to 90)
    Notes
    [5] - 38 at baseline and 33 at follow-up.
    No statistical analyses for this end point

    Secondary: Heart rate

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    End point title
    		 Heart rate [6]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [7]
    33
    Units: bpm
    median (inter-quartile range (Q1-Q3))
        Baseline
    71 (65 to 77)
    73 (64 to 82)
        Follow-up
    72 (65 to 77)
    71 (58 to 75)
    Notes
    [7] - 38 at baseline and 33 at follow-up.
    No statistical analyses for this end point

    Secondary: Montreal Cognitive Assessment (MoCA)

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    End point title
    		 Montreal Cognitive Assessment (MoCA) [8]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [9]
    33
    Units: points
    median (inter-quartile range (Q1-Q3))
        Baseline
    27 (25 to 27)
    27 (26 to 29)
        Follow-up
    26 (24 to 27)
    27 (26 to 29)
    Notes
    [9] - 38 at baseline and 33 at follow-up.
    No statistical analyses for this end point

    Secondary: Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)

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    End point title
    		 Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) [10]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [11]
    33
    Units: points
    median (inter-quartile range (Q1-Q3))
        Baseline
    3.13 (3.00 to 3.42)
    3.06 (3.00 to 3.25)
        Follow-up
    3.13 (3.00 to 3.50)
    3.06 (3.00 to 3.19)
    Notes
    [11] - 38 at baseline and 33 at follow-up.
    No statistical analyses for this end point

    Secondary: Becks Depression Inventory II (BDI-II)

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    End point title
    		 Becks Depression Inventory II (BDI-II) [12]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [13]
    33
    Units: points
    median (inter-quartile range (Q1-Q3))
        Baseline
    5 (2 to 10)
    3 (1 to 11)
        Follow-up
    4 (1 to 8)
    3 (1 to 7)
    Notes
    [13] - 38 at baseline and 33 at follow-up.
    No statistical analyses for this end point

    Secondary: Fatigue Severity Scale (FSS)

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    End point title
    		 Fatigue Severity Scale (FSS) [14]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [15]
    33
    Units: points
    median (inter-quartile range (Q1-Q3))
        Baseline
    3.22 (2.33 to 5.11)
    3.78 (2.56 to 4.78)
        Follow-up
    3.61 (1.89 to 4.72)
    3.11 (1.89 to 4.89)
    Notes
    [15] - 38 at baseline and 33 at follow-up.
    No statistical analyses for this end point

    Secondary: World Health Organization 5 Well-Being Index (WHO-5)

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    End point title
    		 World Health Organization 5 Well-Being Index (WHO-5) [16]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [17]
    33
    Units: points
    median (inter-quartile range (Q1-Q3))
        Baseline
    72 (60 to 80)
    74 (60 to 88)
        Follow-up
    72 (66 to 82)
    80 (64 to 88)
    Notes
    [17] - 38 at baseline and 33 at follow-up.
    No statistical analyses for this end point

    Secondary: MRI: White matter hyperintensity volume

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    End point title
    		 MRI: White matter hyperintensity volume [18]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [19]
    33
    Units: ml
    median (inter-quartile range (Q1-Q3))
        Baseline
    12.6 (4.18 to 29.1)
    6.86 (3.43 to 22.5)
        Follow-up
    9.57 (4.59 to 22.2)
    6.75 (3.45 to 21.2)
    Notes
    [19] - 38 at baseline and 32 at follow-up.
    No statistical analyses for this end point

    Secondary: MRI: Incident DWI lesions

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    End point title
    		 MRI: Incident DWI lesions [20]
    End point description
    Number of DWI lesions and delta value (follow-up - baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [21]
    33
    Units: Number of DWI lesions
        Baseline: DWI lesion - YES
    7
    1
        Baseline: DWI lesion - NO
    31
    32
        Follow-up: DWI lesion - YES
    5
    3
        Follow-up: DWI lesion - NO
    27
    30
        Delta -1
    4
    0
        Delta 0
    26
    31
        Delta 1
    2
    2
    Notes
    [21] - 38 at baseline and 32 at follow-up.
    No statistical analyses for this end point

    Secondary: MRI: Lacunes

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    End point title
    		 MRI: Lacunes [22]
    End point description
    Number of lacunes and delta value (follow-up - baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [23]
    33
    Units: Number of lacunes
    median (inter-quartile range (Q1-Q3))
        Baseline
    2 (1 to 4)
    2 (1 to 4)
        Follow-up
    2 (1 to 5)
    2 (1 to 4)
        Delta
    0 (0 to 1)
    0 (0 to 0)
    Notes
    [23] - 38 at baseline and 32 at follow-up.
    No statistical analyses for this end point

    Secondary: MRI: Microbleeds

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    End point title
    		 MRI: Microbleeds [24]
    End point description
    Number of microbleeds and delta value (follow-up - baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [25]
    33
    Units: Number of microbleeds
    median (inter-quartile range (Q1-Q3))
        Baseline
    1 (0 to 3)
    1 (0 to 5)
        Follow-up
    1 (0 to 4)
    1 (0 to 5)
        Delta
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [25] - 38 at baseline and 32 at follow-up.
    No statistical analyses for this end point

    Secondary: MRI: Cortical superficial siderosis

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    End point title
    		 MRI: Cortical superficial siderosis [26]
    End point description
    Presence of cortical superficial siderosis and delta value (follow-up - baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [27]
    33
    Units: Present or not present
        Baseline: Yes
    1
    1
        Baseline: No
    37
    32
        Follow-up: Yes
    0
    2
        Follow-up: No
    32
    31
        Delta 0
    32
    32
        Delta 1
    0
    1
    Notes
    [27] - 38 at baseline and 32 at follow-up.
    No statistical analyses for this end point

    Secondary: MRI: Central atrophy

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    End point title
    		 MRI: Central atrophy [28]
    End point description
    Central atrophy score and delta value (follow-up - baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [29]
    33
    Units: Scale from 0-2
        Baseline: None
    9
    11
        Baseline: Moderate
    28
    22
        Baseline: Severe
    1
    0
        Follow-up: None
    10
    14
        Follow-up: Moderate
    21
    19
        Follow-up: Severe
    1
    0
        Delta -1
    3
    3
        Delta 0
    26
    30
        Delta 1
    3
    0
    Notes
    [29] - 38 at baseline and 32 at follow-up.
    No statistical analyses for this end point

    Secondary: MRI: Global cortical atrophy scales score

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    End point title
    		 MRI: Global cortical atrophy scales score [30]
    End point description
    Global cortical atrophy scales score and delta value (follow-up - baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [31]
    33
    Units: Scale from 0-3
        Baseline: 0: Normal volume
    8
    7
        Baseline: 1: Opening of sulci
    23
    22
        Baseline: 2: Volume loss of gyri
    7
    4
        Baseline: 3: Knife blade atrophy
    0
    0
        Follow-up: 0: Normal volume
    7
    8
        Follow-up: 1: Opening of sulci
    20
    20
        Follow-up: 2: Volume loss of gyri
    5
    5
        Follow-up: 3: Knife blade atrophy
    0
    0
        Delta -1
    3
    3
        Delta 0
    25
    27
        Delta 1
    4
    3
    Notes
    [31] - 38 at baseline and 32 at follow-up.
    No statistical analyses for this end point

    Secondary: MRI: Periventricular WMH

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    End point title
    		 MRI: Periventricular WMH [32]
    End point description
    Periventricular WMH and delta value (follow-up - baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [33]
    33
    Units: Scale from 0-3
        Baseline: Fazekas 0
    1
    1
        Baseline: Fazekas 1
    14
    17
        Baseline: Fazekas 2
    10
    7
        Baseline: Fazekas 3
    13
    8
        Follow-up: Fazekas 0
    1
    0
        Follow-up: Fazekas 1
    11
    19
        Follow-up: Fazekas 2
    10
    5
        Follow-up: Fazekas 3
    10
    9
        Delta -1
    2
    2
        Delta 0
    28
    28
        Delta 1
    2
    3
    Notes
    [33] - 38 at baseline and 32 at follow-up.
    No statistical analyses for this end point

    Secondary: MRI: Deep WMH

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    End point title
    		 MRI: Deep WMH [34]
    End point description
    Deep WMH and delta value (follow-up - baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [35]
    33
    Units: Scale from 0-3
        Baseline: Fazekas 0
    1
    2
        Baseline: Fazekas 1
    14
    17
        Baseline: Fazekas 2
    10
    8
        Baseline: Fazekas 3
    13
    6
        Follow-up: Fazekas 0
    1
    1
        Follow-up: Fazekas 1
    10
    18
        Follow-up: Fazekas 2
    13
    7
        Follow-up: Fazekas 3
    8
    7
        Delta -1
    2
    0
        Delta 0
    28
    31
        Delta 1
    2
    2
    Notes
    [35] - 38 at baseline and 32 at follow-up.
    No statistical analyses for this end point

    Secondary: MRI: EPVS basal ganglia and centrum semiovale

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    End point title
    		 MRI: EPVS basal ganglia and centrum semiovale [36]
    End point description
    EPVS basal ganglia and centrum semiovale and delta value (follow-up - baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [37]
    33
    Units: Scale from 0-3
        Baseline: No EPVS
    1
    2
        Baseline: 1-10 EPVS (mild)
    20
    24
        Baseline: 11-20 EPVS (moderate)
    11
    6
        Baseline: 21- EPVS (frequent)
    6
    1
        Follow-up: No EPVS
    2
    2
        Follow-up: 1-10 EPVS (mild)
    19
    24
        Follow-up: 11-20 EPVS (moderate)
    6
    5
        Follow-up: 21-40 EPVS (frequent)
    5
    2
        Delta -1
    6
    0
        Delta 0
    25
    32
        Delta 1
    1
    1
    Notes
    [37] - 38 at baseline and 32 at follow-up.
    No statistical analyses for this end point

    Secondary: MRI: EPVS midbrain

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    End point title
    		 MRI: EPVS midbrain [38]
    End point description
    Visible EPVS in the midbrain and delta value (follow-up - baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and follow-up visit (3 months).
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no data for the Arm: Excluded before treatment initiation. These participants were excluded before any intervention and assessment.
    End point values
    		 Tadalafil Placebo
    Number of subjects analysed
    38 [39]
    33
    Units: Visible or not visible
        Baseline: No EPVS visible
    20
    25
        Baseline: EPVS visible
    18
    8
        Follow-up: No EPVS visible
    19
    24
        Follow-up: EPVS visible
    13
    9
        Delta -1
    4
    1
        Delta 0
    26
    30
        Delta 1
    2
    2
    Notes
    [39] - 38 at baseline and 32 at follow-up.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inclusion in the trial to the safety follow-up visit 2 weeks after treatment cessation.
    Adverse event reporting additional description
    Adverse events were registered on a specific adverse events questionnaire. This questionnaire was reviewed during all physical visits and orally during all telephone visits.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    28.1
    Reporting groups
    Reporting group title
    Tadalafil
    Reporting group description
    		 Daily tadalafil for 3 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Daily placebo for 3 months.

    Serious adverse events
    		 Tadalafil Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 33 (0.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Death
    Additional description: Sudden cardiac death.
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Seizure
    Additional description: Required admission at a local hospital for observation.
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
    Additional description: Required admission at a local hospital for observation.
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Cholelithiasis
    Additional description: Required admission at a local hospital for observation.
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chest pain
    Additional description: Muscular chest pain that required admission at a local hospital for investigation and observation.
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Tadalafil Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 38 (65.79%)
    8 / 33 (24.24%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 38 (26.32%)
    5 / 33 (15.15%)
         occurrences all number
    16
    17
    Ear and labyrinth disorders
    Dizziness
         subjects affected / exposed
    7 / 38 (18.42%)
    3 / 33 (9.09%)
         occurrences all number
    25
    5
    Eye disorders
    Eye pain
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 33 (6.06%)
         occurrences all number
    13
    2
    Gastrointestinal disorders
    Reflux gastritis
         subjects affected / exposed
    17 / 38 (44.74%)
    3 / 33 (9.09%)
         occurrences all number
    35
    44
    Abdominal discomfort
         subjects affected / exposed
    10 / 38 (26.32%)
    3 / 33 (9.09%)
         occurrences all number
    23
    3
    Abdominal pain
         subjects affected / exposed
    4 / 38 (10.53%)
    3 / 33 (9.09%)
         occurrences all number
    9
    3
    Diarrhoea
         subjects affected / exposed
    6 / 38 (15.79%)
    0 / 33 (0.00%)
         occurrences all number
    5
    0
    Nausea
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    5 / 38 (13.16%)
    4 / 33 (12.12%)
         occurrences all number
    8
    4
    Dyspnoea
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Flushing
    Additional description: Facial flushing.
         subjects affected / exposed
    6 / 38 (15.79%)
    3 / 33 (9.09%)
         occurrences all number
    36
    3
    Erythema
    Additional description: Local skin reddening and itching.
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Pain
    Additional description: Muscle pain.
         subjects affected / exposed
    13 / 38 (34.21%)
    2 / 33 (6.06%)
         occurrences all number
    28
    13
    Back pain
         subjects affected / exposed
    8 / 38 (21.05%)
    1 / 33 (3.03%)
         occurrences all number
    13
    1

    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.
    Recruitment stopped before reaching the aimed 100 participants due to limited time in the funded trial period. This resulted in a smaller sample size than planned.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/40718899
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    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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