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    Clinical Trial Results:
    Effect of Tadalafil on cerebral large arteries in stroke patients.

    Summary
    EudraCT number
    		 2016-000896-26
    Trial protocol
    		 DK  
    Global end of trial date
    04 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 May 2020
    First version publication date
    09 May 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ETLAS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02801032
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Herlev Gentofte Hospital
    Sponsor organisation address
    Borgmester Ib Juuls Vej 1, Herlev, Denmark, 2730
    Public contact
    Christina Rostrup Kruuse, Herlev Gentofte Hospital, 45 38681233, christina.rostrup.kruuse@regionh.dk
    Scientific contact
    Christina Rostrup Kruuse, Herlev Gentofte Hospital, 45 38681233, christina.rostrup.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
    29 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to investigate the effect of the phosphodiesterase-5-inhibitor (PDE-5-inhibitor) tadalafil on blood flow velocity in the cerebral large arteries and cortical brain oxygenation in patients with former lacunar stroke caused by small vessel diseases.
    Protection of trial subjects
    During the trial days, trial participants were monitored thoroughly with heart rate and blood pressure. They were asked how they felt every hour during the trial days and if they experienced any side effects. After the trial days, they were asked to complete a side effect form and then hand it in to the investigator. They were also given a phone number to the Department of Neurology, Herlev Gentofte Hospital (sponsor) which they could call to if they experienced any side effects or had any other trouble. If the participants experienced pain or distress during the trial days, we talked about it and tried to accomodate their wishes to see if we could minimize pain.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2016
    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
    Denmark: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    8
    From 65 to 84 years
    11
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients were recruited from the Department of Neurology, Herlev Gentofte Hospital, Denmark. Patients were recruited year 2016 and 2017.

    Pre-assignment
    Screening details
    		 Evaluation by a doctor.

    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
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Medication were packed in opaque capsuels by the pharmacy. The investigator and subjects were blinded from treatment. Data were analyzed in a blidend fashion. Unbliding was done after data had been analyzed.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Tadalafil
    Arm description
    		 Crossover trial. Tadalafil (20 mg) was given as a single dose during trial day one or two. Placebo was given on the other trial day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tadalafil
    Investigational medicinal product code
    Other name
    Cialis
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage: 20 mg. Use: Oral use. Single dose tadalafil was given on either trial day one or two.

    Arm title
    		 Placebo
    Arm description
    		 Crossover trial. Placebo was given as a single dose during trial day one or two. Tadalafil was given on the other trial day.
    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
    Dosage: placebo Administration details: Oral use Single dose placebo was given on either trial day one or two.

    Number of subjects in period 1
    		Tadalafil Placebo
    Started
    20
    20
    Completed
    19
    20
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 In this crossover trial, 20 subjects were recruited.

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 8 8
        From 65-84 years
    		 11 11
        85 years and over
    		 1 1
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 17 17

    End points

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    End points reporting groups
    Reporting group title
    Tadalafil
    Reporting group description
    		 Crossover trial. Tadalafil (20 mg) was given as a single dose during trial day one or two. Placebo was given on the other trial day.

    Reporting group title
    Placebo
    Reporting group description
    		 Crossover trial. Placebo was given as a single dose during trial day one or two. Tadalafil was given on the other trial day.

    Subject analysis set title
    Tadalafil - baseline
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Tadalafil baseline

    Subject analysis set title
    Tadalafil - 30 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Tadalafil group at 30 minutes

    Subject analysis set title
    Tadalafil - 60 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Tadalafil group at 60 minutes

    Subject analysis set title
    Tadalafil - 90 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Tadalafil group at 90 minutes

    Subject analysis set title
    Tadalafil - 120 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Tadalafil group at 120 minutes

    Subject analysis set title
    Tadalafil - 150 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Tadalafil group at 150 minutes

    Subject analysis set title
    Tadalafil - 180 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Tadalafil group at 180 minutes

    Subject analysis set title
    Placebo - baseline
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo group at baseline

    Subject analysis set title
    Placebo - 30 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo group at 30 minutes

    Subject analysis set title
    Placebo - 60 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo group at 60 minutes

    Subject analysis set title
    Placebo - 90 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo group at 90 minutes

    Subject analysis set title
    Placebo - 120 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo group at 120 minutes

    Subject analysis set title
    Placebo - 150 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo group at 150 minutes

    Subject analysis set title
    Placebo - 180 minutes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo group at 180 minutes

    Primary: Transcranial Doppler

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    End point title
    		 Transcranial Doppler
    End point description
    Changes in mean blood flow velocity in the middle cerebral artery before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Primary
    End point timeframe
    We performed TCD measurements twice at baseline and after 30, 60, 90, 120, 150, and 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 30 minutes Tadalafil - 60 minutes Tadalafil - 90 minutes Tadalafil - 120 minutes Tadalafil - 150 minutes Tadalafil - 180 minutes Placebo - baseline Placebo - 30 minutes Placebo - 60 minutes Placebo - 90 minutes Placebo - 120 minutes Placebo - 150 minutes Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    19
    20
    20
    20
    20
    20
    20
    20
    Units: cm/sec
        arithmetic mean (standard deviation)
    57.8 ± 10.8
    57.8 ± 10.4
    57.4 ± 10.1
    58.0 ± 11.7
    59.2 ± 12.7
    59.2 ± 12.7
    58.4 ± 12.0
    57.1 ± 11.1
    59.3 ± 12.7
    58.7 ± 13.2
    59.6 ± 14.7
    59.9 ± 12.9
    59.8 ± 13.2
    59.7 ± 13.8
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 30 minutes v Tadalafil - 60 minutes v Tadalafil - 90 minutes v Tadalafil - 120 minutes v Tadalafil - 150 minutes v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 30 minutes v Placebo - 60 minutes v Placebo - 90 minutes v Placebo - 120 minutes v Placebo - 150 minutes v Placebo - 180 minutes
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - We performed a repeated measurement analysis of variance (ANOVA).
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 30 minutes v Tadalafil - 60 minutes v Tadalafil - 90 minutes v Tadalafil - 120 minutes v Tadalafil - 150 minutes v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 30 minutes v Placebo - 60 minutes v Placebo - 90 minutes v Placebo - 120 minutes v Placebo - 150 minutes v Placebo - 180 minutes
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - We performed a paired sample T-test when ANOVA detected a significant difference.

    Primary: Near infrared spectroscopy

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    End point title
    		 Near infrared spectroscopy
    End point description
    Changes in cortical blood oxygen saturation before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Primary
    End point timeframe
    We performed NIRS measurements at baseline and after 30, 60, 90, 120, 150, and 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 30 minutes Tadalafil - 60 minutes Tadalafil - 90 minutes Tadalafil - 120 minutes Tadalafil - 150 minutes Tadalafil - 180 minutes Placebo - baseline Placebo - 30 minutes Placebo - 60 minutes Placebo - 90 minutes Placebo - 120 minutes Placebo - 150 minutes Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    19
    20
    20
    20
    20
    20
    20
    20
    Units: percent
        arithmetic mean (standard deviation)
    66.8 ± 8.8
    66.7 ± 8.0
    66.6 ± 8.7
    67.2 ± 8.4
    67.8 ± 8.5
    67.9 ± 9.0
    66.8 ± 9.0
    67.2 ± 7.7
    68.1 ± 8.2
    68.1 ± 7.8
    67.9 ± 7.4
    68.1 ± 7.0
    68.0 ± 7.8
    67.7 ± 8.1
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 30 minutes v Tadalafil - 60 minutes v Tadalafil - 90 minutes v Tadalafil - 120 minutes v Tadalafil - 150 minutes v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 30 minutes v Placebo - 60 minutes v Placebo - 90 minutes v Placebo - 120 minutes v Placebo - 150 minutes v Placebo - 180 minutes
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [3] - We performed a repeated measurement analysis of variance (ANOVA).
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 30 minutes v Tadalafil - 60 minutes v Tadalafil - 90 minutes v Tadalafil - 120 minutes v Tadalafil - 150 minutes v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 30 minutes v Placebo - 60 minutes v Placebo - 90 minutes v Placebo - 120 minutes v Placebo - 150 minutes v Placebo - 180 minutes
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [4] - We performed a paired sample T-test when ANOVA detected a significant difference.

    Secondary: Blood pressure - systolic

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    End point title
    		 Blood pressure - systolic
    End point description
    Changes in blood pressure before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    We performed blood pressure measurements twice at baseline and after 60, 120, and 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 60 minutes Tadalafil - 120 minutes Tadalafil - 180 minutes Placebo - baseline Placebo - 60 minutes Placebo - 120 minutes Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    19
    19
    20
    20
    20
    20
    Units: mmHg
        arithmetic mean (standard deviation)
    145.3 ± 16.9
    136.4 ± 17.4
    141.7 ± 20.0
    140.5 ± 14.5
    146.3 ± 22.1
    142.5 ± 18.4
    143.8 ± 17.5
    147.1 ± 18.3
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 60 minutes v Tadalafil - 120 minutes v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 60 minutes v Placebo - 120 minutes v Placebo - 180 minutes
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [5] - We performed a repeated measurment analysis of variance (ANOVA).
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 60 minutes v Tadalafil - 120 minutes v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 60 minutes v Placebo - 120 minutes v Placebo - 180 minutes
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [6] - We performed a paired sample T-test when ANOVA detected a significant difference.

    Secondary: Blood pressure - diastolic

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    End point title
    		 Blood pressure - diastolic
    End point description
    Changes in blood pressure before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    We performed blood pressure measurements twice at baseline and after 60, 120, and 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 60 minutes Tadalafil - 120 minutes Tadalafil - 180 minutes Placebo - baseline Placebo - 60 minutes Placebo - 120 minutes Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    19
    19
    20
    20
    20
    20
    Units: mmHg
        arithmetic mean (standard deviation)
    83.6 ± 9.1
    78.5 ± 9.6
    78.7 ± 10.2
    78.4 ± 10.2
    79.0 ± 8.8
    80.3 ± 10.5
    79.5 ± 9.0
    82.0 ± 8.1
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 60 minutes v Tadalafil - 120 minutes v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 60 minutes v Placebo - 120 minutes v Placebo - 180 minutes
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [7] - We performed a repeated measurement analysis of variance (ANOVA).
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 60 minutes v Tadalafil - 120 minutes v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 60 minutes v Placebo - 120 minutes v Placebo - 180 minutes
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [8] - We performed a paired sample T-test when ANOVA detected a significant difference.

    Secondary: Heart rate

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    End point title
    		 Heart rate
    End point description
    Changes in heart rate before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    We performed heart rate measurements twice at baseline and after 60, 120, and 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 60 minutes Tadalafil - 120 minutes Tadalafil - 180 minutes Placebo - baseline Placebo - 60 minutes Placebo - 120 minutes Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    19
    19
    20
    20
    20
    20
    Units: bpm
        arithmetic mean (standard deviation)
    61.2 ± 11.8
    59.1 ± 9.8
    57.7 ± 9.2
    57.1 ± 9.2
    63.5 ± 11.7
    60.7 ± 10.4
    58.2 ± 9.9
    60.1 ± 9.9
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 60 minutes v Tadalafil - 120 minutes v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 60 minutes v Placebo - 120 minutes v Placebo - 180 minutes
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [9] - We performed a repeated measurement analysis of variance (ANOVA).

    Secondary: EndoPAT - RHI

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    End point title
    		 EndoPAT - RHI
    End point description
    Changes in regional hyperemia index before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    We performed EndoPAT measurements at baseline and after 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 180 minutes Placebo - baseline Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    20
    20
    Units: no unit
        arithmetic mean (standard deviation)
    2.4 ± 0.8
    2.6 ± 0.8
    2.4 ± 0.8
    2.6 ± 0.7
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 180 minutes
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [10] - We performed a paired sample T-test.

    Secondary: EndoPat - AI

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    End point title
    		 EndoPat - AI
    End point description
    Changes in EndoPAT - augmentation index before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    We performed EndoPAT measurements at baseline and after 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 180 minutes Placebo - baseline Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    20
    20
    Units: no unit
        arithmetic mean (standard deviation)
    25.2 ± 19.1
    29.0 ± 21.1
    21.2 ± 14.3
    28.1 ± 23.8
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 180 minutes
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [11] - We performed a paired sample T-test.

    Secondary: EndoPAT - AI@75

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    End point title
    		 EndoPAT - AI@75
    End point description
    Changes in EndoPAT - augmentation index standardized to a heart rate of 75 before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    We performed EndoPAT measurements at baseline and after 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 180 minutes Placebo - baseline Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    20
    20
    Units: no unit
        arithmetic mean (standard deviation)
    15.9 ± 17.5
    18.9 ± 19.3
    13.6 ± 12.0
    19.8 ± 21.0
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - 180 minutes v Tadalafil - baseline v Placebo - baseline v Placebo - 180 minutes
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [12] - We performed a paired sample T-test.

    Secondary: Blood sample - E-selectin

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    End point title
    		 Blood sample - E-selectin
    End point description
    Changes in biomarker concentration before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at baseline and after 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 180 minutes Placebo - baseline Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    20
    20
    Units: pg/ml
        arithmetic mean (standard deviation)
    4619.2 ± 207.2
    4764.5 ± 2566.5
    4836.1 ± 2383.2
    4489.6 ± 2938.2
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 180 minutes
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [13] - We performed a paired sample T-test.

    Secondary: Blood sample - TNF-alpha

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    End point title
    		 Blood sample - TNF-alpha
    End point description
    Changes in biomarker concentration before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at baseline and after 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 180 minutes Placebo - baseline Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    20
    20
    Units: pg/ml
        arithmetic mean (standard deviation)
    2.13 ± 0.72
    2.05 ± 0.85
    2.12 ± 0.90
    2.52 ± 1.76
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 180 minutes
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [14] - We performed a paired sample T-test.

    Secondary: Blood sample - IL-6

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    End point title
    		 Blood sample - IL-6
    End point description
    Changes in biomarker concentration before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at baseline and after 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 180 minutes Placebo - baseline Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    20
    20
    Units: pg/ml
        arithmetic mean (standard deviation)
    0.94 ± 0.38
    2.21 ± 3.35
    1.05 ± 0.55
    4.52 ± 7.95
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 180 minutes
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [15] - We performed a paired sample T-test.

    Secondary: Blood sample - IL1-beta

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    End point title
    		 Blood sample - IL1-beta
    End point description
    Changes in biomarker concentration before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at baseline and after 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 180 minutes Placebo - baseline Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    20
    20
    Units: pg/ml
        arithmetic mean (standard deviation)
    0.16 ± 0.12
    0.04 ± 0.02
    0.10 ± 0.06
    0.20 ± 0.11
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 180 minutes
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [16] - We performed a paired sample T-test.

    Secondary: Blood sample - VCAM1

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    End point title
    		 Blood sample - VCAM1
    End point description
    Changes in biomarker concentration before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at baseline and after 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 180 minutes Placebo - baseline Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    20
    20
    Units: pg/ml
        arithmetic mean (standard deviation)
    624348.39 ± 231467.28
    797138.04 ± 245361.56
    777176.51 ± 297499.83
    718597.67 ± 379344.50
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 180 minutes
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [17] - We performed a paired sample T-test.

    Secondary: Blood sample - ICAM1

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    End point title
    		 Blood sample - ICAM1
    End point description
    Changes in biomarker concentration before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at baseline and after 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 180 minutes Placebo - baseline Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    20
    20
    Units: pg/ml
        arithmetic mean (standard deviation)
    354852.44 ± 154885.50
    476033.98 ± 169334.63
    459055.08 ± 195422.13
    402261.70 ± 190472.98
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - 180 minutes v Placebo - baseline v Placebo - 180 minutes v Tadalafil - baseline
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [18] - We performed a paired sample T-test.

    Secondary: Blood sample - VEGF

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    End point title
    		 Blood sample - VEGF
    End point description
    Changes in biomarker concentration before and after tadalafil/placebo for each subject were calculated and then further used for statistical analysis. Here, results are shown as the mean value and standard deviation for both groups at the different timepoints.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at baseline and after 180 minutes post-medication.
    End point values
    		 Tadalafil - baseline Tadalafil - 180 minutes Placebo - baseline Placebo - 180 minutes
    Number of subjects analysed
    19
    19
    20
    20
    Units: pg/ml
        arithmetic mean (standard deviation)
    21.88 ± 8.24
    26.927 ± 8.85
    23.82 ± 9.99
    30.14 ± 8.39
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Total number of subjects: 19 in tadalafil and 20 in placebo.
    Comparison groups
    Tadalafil - baseline v Tadalafil - 180 minutes v Placebo - baseline v Placebo - 180 minutes
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [19] - We performed a paired sample T-test.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the whole trial period.
    Adverse event reporting additional description
    Questionare given to the subjects. Subjects were asked to note all adverse events for three days after the trial days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Events not coded
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    Tadalafil
    Reporting group description
    		 Crossover trial. Tadalafil (20 mg) was given as a single dose during trial day one or two. Placebo was given on the other trial day.

    Reporting group title
    Placebo
    Reporting group description
    		 Crossover trial. Placebo was given as a single dose during trial day one or two. Tadalafil was given on the other trial day.

    Serious adverse events
    		 Tadalafil Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 20 (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
    		 Tadalafil Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 19 (26.32%)
    6 / 20 (30.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Ear and labyrinth disorders
    Dizziness
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Social circumstances
    Sleep deficit
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Fatigue
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2

    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
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