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    Clinical Trial Results:
    ACE inhibition in Fontan patients: its effect on body fluid regulation.

    Summary
    EudraCT number
    		 2016-004433-24
    Trial protocol
    		 NL  
    Global end of trial date
    17 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Nov 2021
    First version publication date
    27 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    59498
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Netherlands Trial Register: NL6415
    Sponsors
    Sponsor organisation name
    Leiden Universitair Medisch Centrum
    Sponsor organisation address
    Albinusdreef 2, Leiden, Netherlands,
    Public contact
    Dr. A.D.J. ten Harkel, Leids Universitair Medisch Centrum, 0031 0715262833, A.D.J.ten_Harkel@lumc.nl
    Scientific contact
    Dr. A.D.J. ten Harkel, Leids Universitair Medisch Centrum, 0031 0715262833, A.D.J.ten_Harkel@lumc.nl
    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
    12 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To treat Fontan patients for 3 months with the ACE inhibitor enalapril and compare a set of cardiovascular measurements before and after treatment in order to study its effect on the cardiovascular system in Fontan patients.
    Protection of trial subjects
    The examinations included in this study are low-impact and are not harmful to health. Most of the examinations are also well known by the patients as they are part of the regular checks. During the study, pain and distress were tried to be minimized, trial subjects could watch videos of their choice during the tilt table test, and a crème could be used to relieve the pain of blood sampling. There is a risk of falling of the tilting table, but this risk is minimized by properly securing the trial subjects to the table and always having a second person present during the tests. Furthermore, there is a risk of side effect from enalapril. During the entire study, trial subjects could easily contact the researchers, if side effects occurred, the dosage could easily be reduced or discontinued. Finally, trial subjects could leave the study at any time.
    Background therapy
    		 Although survival of Fontan patients has improved, life expectancy is still less than normal, and many patients suffer from morbidities. Exercise performance, diastolic and systolic ventricular function are already reduced at a young age. Because severe diastolic and systolic dysfunction may not be present yet, both functions deteriorate over time in these patients, which may eventually result in heart failure. Enalapril, an angiotensin converting enzyme (ACE) inhibitor, has shown to be effective in reducing mortality in patients with a biventricular heart and mild to severe symptomatic heart failure. Therefore, ACE inhibition became the cornerstone of therapeutic interventions in patients with systolic heart failure. The effectiveness of ACE inhibition has been ascribed to its effect on various cardiovascular and pulmonary parameters, including systemic vascular resistance, cardiac autonomic tone, aortic pulse wave velocity (a surrogate of aortic stiffness) and lung function. However, the role of afterload reduction in Fontan patients for heart failure therapy is controversial. Many centers prescribe enalapril on a routine base for patients with a Fontan circulation and preserved ventricular function, while other centers have considerable doubt about its effectiveness as the systemic circulation in Fontan patients is highly preload dependent. In a small study no effect of enalapril on exercise capacity in Fontan patients has been found. There are yet no studies available that investigate the effect of ACE inhibition on various cardiovascular parameters in patients with a Fontan circulation. Studying the effects of short-term ACE-inhibition on several cardiovascular parameters will provide new insights on the effects of afterload reduction in Fontan patients.
    Evidence for comparator
    		 We did not compare different therapies, we compared the parameters of patients before treatment at baseline with parameters after three months of enalapril treatment.
    Actual start date of recruitment
    10 Apr 2017
    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
    Netherlands: 71
    Worldwide total number of subjects
    71
    EEA total number of subjects
    71
    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)
    20
    Adolescents (12-17 years)
    51
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients and healthy controls were recruited from July 2017 to October 2019. Fontan patients from 8 to 18 years old who were operated at the Leiden University Medical Center were recruited. Healthy controls with a similar age were recruited through advertising in local schools.

    Pre-assignment
    Screening details
    		 Patients with pre-existent ACE inhibitor use, systolic ventricular dysfunction and those unable to exercise were excluded. A total of 74 Fontan patients were eligible for inclusion of which 36 agreed to participate. 35 healthy controls were included.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Enalapril treatment baseline
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Renitec:Enalapril
    Investigational medicinal product code
    CPMP/3175/03
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Initial enalapril dosage was 5 mg/day and was titrated, as tolerated, to the target dose of 0.5 mg/kg/day or a maximum of 20 mg/day. Enalapril dosage was titrated by blood pressure measured weekly for at least 2 weeks after initiation of treatment.

    Number of subjects in period 1 [1]
    		Enalapril treatment baseline
    Started
    30
    Completed
    28
    Not completed
    2
         Consent withdrawn by subject
    1
         Not completed because of non-compliance
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: It is correct that the numbers are not the same. 71 subjects were included, 36 Fontan patients and 35 controls. From the 36 Fontan patient 30 patients started with treatment.
    Period 2
    Period 2 title
    End of trial
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Enalapril treatment Follow-up
    Arm description
    		 Follow-up
    Arm type
    		 Follow-up

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Enalapril treatment Follow-up
    Started
    28
    Completed
    28

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enalapril treatment baseline
    Reporting group description
    		 -

    Reporting group values
    		 Enalapril treatment baseline Total
    Number of subjects
    		 30 30
    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)
    		 4 4
        Adolescents (12-17 years)
    		 26 26
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 14.0 (12.9 to 16.7) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 20 20
    Main ventricle
    Units: Subjects
        Left
    		 15 15
        Right
    		 12 12
        Undifferentiated
    		 3 3
    Fenestration
    Units: Subjects
        Open at time of study
    		 1 1
        Closed at time of study (naturally or by device)
    		 27 27
        No fenestration
    		 2 2
    Type Fontan tunnel
    Units: Subjects
        TCPC-EC
    		 30 30
        TCPC-LT
    		 0 0
        APC
    		 0 0
    Age at Glenn operation
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 0.50 (0.38 to 0.77) -
    Age at Fontan operation
    Units: Years
        arithmetic mean (standard deviation)
    		 3.11 ± 0.64 -
    Subject analysis sets

    Subject analysis set title
    All Fontan patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Baseline

    Subject analysis set title
    Healthy controls
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Baseline

    Subject analysis set title
    Fontan patient completed enalapril study baseline
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    From the 36 patients, 6 patients only participated in the baseline measurements, therefore 30 patients were enrolled in the enalapril part of the study. During the study 1 patient withdrew at the request of parents and 1 patient was excluded for further analysis because of medication noncompliance.

    Subject analysis sets values
    		 All Fontan patients Healthy controls Fontan patient completed enalapril study baseline
    Number of subjects
    36
    35
    28
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    6
    14
    3
        Adolescents (12-17 years)
    30
    21
    25
        Adults (18-64 years)
    0
    0
    0
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    14.0 (12.7 to 16.6)
    12.8 (11.1 to 15.5)
    13.9 (13.0 to 16.7)
    Gender categorical
    Units: Subjects
        Female
    13
    17
    10
        Male
    23
    18
    18
    Main ventricle
    Units: Subjects
        Left
    21
    35
    13
        Right
    12
    0
    12
        Undifferentiated
    3
    0
    3
    Fenestration
    Units: Subjects
        Open at time of study
    1
    0
    1
        Closed at time of study (naturally or by device)
    32
    0
    25
        No fenestration
    3
    0
    2
    Type Fontan tunnel
    Units: Subjects
        TCPC-EC
    36
    0
    28
        TCPC-LT
    0
    0
    0
        APC
    0
    0
    0
    Age at Glenn operation
    Units: Years
        median (inter-quartile range (Q1-Q3))
    0.52 (0.38 to 0.79)
    0.5 (0.37 to 0.75)
    Age at Fontan operation
    Units: Years
        arithmetic mean (standard deviation)
    3.19 ± 0.65
    - ± -
    3.10 ± 0.60

    End points

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    End points reporting groups
    Reporting group title
    Enalapril treatment baseline
    Reporting group description
    		 -
    Reporting group title
    Enalapril treatment Follow-up
    Reporting group description
    		 Follow-up

    Subject analysis set title
    All Fontan patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Baseline

    Subject analysis set title
    Healthy controls
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Baseline

    Subject analysis set title
    Fontan patient completed enalapril study baseline
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    From the 36 patients, 6 patients only participated in the baseline measurements, therefore 30 patients were enrolled in the enalapril part of the study. During the study 1 patient withdrew at the request of parents and 1 patient was excluded for further analysis because of medication noncompliance.

    Primary: Maximal oxygen consumption

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    End point title
    		 Maximal oxygen consumption
    End point description
    End point type
    Primary
    End point timeframe
    Measurements from baseline were compared with measurements acquired after a 3 month treatment period with enalapril.
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up
    Number of subjects analysed
    25
    25
    Units: ml/kg/min
        arithmetic mean (standard deviation)
    26.2 ± 4.7
    26.7 ± 6.5
    Statistical analysis title
    		 Maximal oxygen consumotion
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.691
    Method
    		 Paired-sample T-test
    Confidence interval

    Primary: Heart rate variability RSA

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    End point title
    		 Heart rate variability RSA
    End point description
    End point type
    Primary
    End point timeframe
    Main analysis: Baseline vs 3 months of treatment Sub-analysis: Baseline Fontan patients vs controls
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    21
    21
    28
    34
    Units: ms
        median (inter-quartile range (Q1-Q3))
    81.5 (42.2 to 111.1)
    66.7 (35.7 to 88.2)
    68.7 (26.1 to 110.3)
    84.5 (54.7 to 123.5)
    Statistical analysis title
    		 RSA treatment arm
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    42
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.476
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - 21 patients were compared in pairs
    Statistical analysis title
    		 RSA subanalysis
    Statistical analysis description
    Sub analysis between Fontan patients and healthy controls
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    62
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.104
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Pre-ejection period

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    End point title
    		 Pre-ejection period
    End point description
    End point type
    Primary
    End point timeframe
    Main analysis: Baseline vs 3 months of enalapril treatment Sub analysis: Baseline measures Fontan patients vs healthy controls
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    21
    21
    28
    34
    Units: ms
        arithmetic mean (standard deviation)
    123.7 ± 17.8
    127.5 ± 3.9
    122.4 ± 17.6
    81.3 ± 15.9
    Statistical analysis title
    		 PEP treatment arm
    Comparison groups
    Enalapril treatment Follow-up v Enalapril treatment baseline
    Number of subjects included in analysis
    42
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence [2]
    P-value
    		 = 0.141
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.88
         upper limit
    		 1.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.45
    Notes
    [2] - 21 patients before and after treatment were analyzes pair wise
    Statistical analysis title
    		 PEP subanalysis
    Statistical analysis description
    Comparing all Fontan patients with healthy controls
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    62
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    41.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 32.5
         upper limit
    		 49.7
    Variability estimate
    Standard deviation
    Dispersion value
    4.29

    Primary: Passive leg raising Cardiac index

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    End point title
    		 Passive leg raising Cardiac index
    End point description
    End point type
    Primary
    End point timeframe
    Main analysis: difference between cardiac index from baseline to passive leg compared between baseline and after 3 months of treatment Subanalsysis: Difference in cardiac index change between all fontan patients and healthy controls
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    16
    16
    21
    34
    Units: Percentage
        arithmetic mean (standard deviation)
    0.62 ± 16.8
    -6.20 ± 8.4
    -1.17 ± 15.9
    -3.34 ± 16.6
    Statistical analysis title
    		 Subanalysis
    Statistical analysis description
    Comparison of change of cardiac index from baseline to passive leg raising between fontan patients and controls
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    55
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.52
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 10.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.18
    Statistical analysis title
    		 PLR CI Enalapril anaysis
    Statistical analysis description
    Comparing the difference in cardiac index form baseline lying to passive leg in patients before and after a three month enalapril treatment.
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    32
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.06
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.34
         upper limit
    		 14
    Variability estimate
    Standard deviation
    Dispersion value
    3.36

    Primary: Passive leg raising cardiac autonomic tone RSA

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    End point title
    		 Passive leg raising cardiac autonomic tone RSA
    End point description
    End point type
    Primary
    End point timeframe
    Main comparison: Difference in RSA from baseline lying to passive leg raising in patient before and after three months of treatment with enalapril
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    21
    21
    28
    34
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    0.59 (-10.3 to 22.9)
    -4.59 (-17.9 to 11.7)
    1.05 (-10.6 to 22.3)
    1.64 (-15.0 to 14.9)
    Statistical analysis title
    		 Main comparison RSA enalapril treatment
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    42
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.149
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Subanalysis PLR RSA
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    62
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.777
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Head up tilt test cardiac index percentage change

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    End point title
    		 Head up tilt test cardiac index percentage change
    End point description
    End point type
    Primary
    End point timeframe
    Main comparison: Percentage difference from baseline lying to head up tilt testing in patients before and after three months of treatment Sub analysis: the percentage difference in CI between Fontan patients at baseline and healthy controls
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    15
    15
    20
    32
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    -6.69 (-18.2 to 2.43)
    -20.51 (-27.6 to -6.8)
    -9.69 (-18.3 to -4.6)
    -17.95 (-24.6 to -3.1)
    Statistical analysis title
    		 HUT CI Enalapril
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.027
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 HUT CI subanalysis
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    52
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.221
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Head up tilt test Cardiac index absolute

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    End point title
    		 Head up tilt test Cardiac index absolute
    End point description
    End point type
    Primary
    End point timeframe
    Cardiac index at HUT before an after treatment with enalapril
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up
    Number of subjects analysed
    15
    15
    Units: L/min/m2
        arithmetic mean (standard deviation)
    2.99 ± 0.49
    2.83 ± 0.69
    Statistical analysis title
    		 HUT CI enalapril absolute
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.153
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11

    Primary: Head up tilt test cardiac autonomic tone RSA

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    End point title
    		 Head up tilt test cardiac autonomic tone RSA
    End point description
    End point type
    Primary
    End point timeframe
    Main parameter: Perc. difference of RSA from supine rest to head up tilt before and after three months of treatment Sub analysis: Perc difference between fontan patients at baseline and healthy controls
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    21
    21
    27
    32
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    -44.0 (-65.5 to -12.3)
    -34.3 (-61.9 to -8.6)
    -44.0 (-62.7 to -25.7)
    -47.0 (-54.3 to -31.8)
    Statistical analysis title
    		 HUT RSA treatment
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    42
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.903
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 HUT RSA subanalysis
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    59
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.843
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Head up tilt test cardiac autonomic tone PEP

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    End point title
    		 Head up tilt test cardiac autonomic tone PEP
    End point description
    End point type
    Primary
    End point timeframe
    Main analysis: Perc. difference of PEP from supine rest to head up tilt test in patients before and after thee months of treatment Sub analysis: Perc. difference between Fontan patients at baseline and healthy controls
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    21
    21
    27
    32
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    6.8 (-0.2 to 19.5)
    5.6 (-1.3 to 20.0)
    6.9 (0.3 to 16.9)
    31.6 (16.0 to 61.1)
    Statistical analysis title
    		 HUT PEP enalapril
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    42
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.131
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Subanalysis HUT PEP
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    59
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Passive leg raising cardiac autonomic tone PEP

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    End point title
    		 Passive leg raising cardiac autonomic tone PEP
    End point description
    End point type
    Primary
    End point timeframe
    Main analysis: Perc. change in PEP from supine rest to PLR in patients before and after three months of treatment with enalapril
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    20
    20
    27
    34
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    -1.6 (-2.9 to 1.0)
    -0.9 (-2.2 to 1.9)
    -1.48 (-3.0 to 0.9)
    -1.1 (-3.1 to 0.7)
    Statistical analysis title
    		 Sub analysis PLR PEP
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    61
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.717
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 PLR PEP treatment
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    40
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.433
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Systolic Global longitudinal strain

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    End point title
    		 Systolic Global longitudinal strain
    End point description
    End point type
    Secondary
    End point timeframe
    Main: Baseline versus three moths of treatment with enalapril Sub analysis: All Fontan patients vs healthy controls
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    23
    23
    29
    33
    Units: Percentage
        arithmetic mean (standard deviation)
    15.3 ± 3.5
    14.6 ± 3.1
    15.3 ± 3.2
    16.6 ± 2.4
    Statistical analysis title
    		 Global longitudinal strain enalapril
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    46
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.139
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 1.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47
    Statistical analysis title
    		 Global longitnudinal strain sub analysis
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    62
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.062
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 0.07
    Variability estimate
    Standard deviation
    Dispersion value
    0.71

    Secondary: Systolic function TDI value free wall

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    End point title
    		 Systolic function TDI value free wall
    End point description
    End point type
    Secondary
    End point timeframe
    Main: Baseline vs three months of treatment with enalapril Sub analysis: All Fontan patients vs health controls
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    27
    27
    36
    33
    Units: m/s
        arithmetic mean (standard deviation)
    0.056 ± 0.01
    0.055 ± 0.01
    0.058 ± 0.02
    0.106 ± 0.03
    Statistical analysis title
    		 TDI S free wall enalapril
    Comparison groups
    Enalapril treatment Follow-up v Enalapril treatment baseline
    Number of subjects included in analysis
    54
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.78
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.001
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.004
         upper limit
    		 0.006
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.002
    Statistical analysis title
    		 TDI S free wall sub analysis
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    69
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.059
         upper limit
    		 -0.038
    Variability estimate
    Standard deviation
    Dispersion value
    0.005

    Secondary: Systolic function TDI IVS

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    End point title
    		 Systolic function TDI IVS
    End point description
    End point type
    Secondary
    End point timeframe
    Main: Baseline vs three months of enalapril treatment Sub analysis: All Fontan patients vs healthy controls
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    23
    23
    32
    34
    Units: m/s
        median (inter-quartile range (Q1-Q3))
    0.043 (0.03 to 0.05)
    0.043 (0.04 to 0.05)
    0.043 (0.03 to 0.05)
    0.080 (0.07 to 0.08)
    Statistical analysis title
    		 TDi S IVS Enalapril
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    46
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.875
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 TDI S IVS sub analsyis
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    66
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Diastolic E/A

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    End point title
    		 Diastolic E/A
    End point description
    End point type
    Secondary
    End point timeframe
    Main: Baseline vs three months of treatment with enalapril in Fontan patients Sub analysis: Baseline all Fontan patients vs healthy controls.
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    24
    24
    36
    35
    Units: Not applicable
        median (inter-quartile range (Q1-Q3))
    1.43 (1.1 to 1.9)
    1.51 (1.2 to 1.9)
    1.43 (1.1 to 2.1)
    2.32 (2.0 to 2.7)
    Statistical analysis title
    		 Diastolic E/A Sub analysis
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    71
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Diastolic E/A Enalapril
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    48
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.361
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Diastolic E/E'

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    End point title
    		 Diastolic E/E'
    End point description
    End point type
    Secondary
    End point timeframe
    Main: Baseline vs three months of treatment with enalapril in Fontan patients Sub analysis: Baseline all Fontan patients vs healthy controls.
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    24
    24
    36
    34
    Units: Not applicable
        median (inter-quartile range (Q1-Q3))
    8.79 (6.7 to 11.9)
    7.70 (7.3 to 11.7)
    8.51 (6.49 to 12.5)
    5.71 (5.1 to 7.1)
    Statistical analysis title
    		 Diastolic E/E Enalapril
    Comparison groups
    Enalapril treatment Follow-up v Enalapril treatment baseline
    Number of subjects included in analysis
    48
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.864
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Diastolic E/E subanalysis
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    70
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Submaximal exercise VE/VCO2

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    End point title
    		 Submaximal exercise VE/VCO2
    End point description
    End point type
    Secondary
    End point timeframe
    Main: Baseline vs three months of treatment with enalapril in Fontan patients
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up
    Number of subjects analysed
    28
    28
    Units: Not applicable
        median (inter-quartile range (Q1-Q3))
    36.1 (32.6 to 40.8)
    38.1 (34.1 to 42.5)
    Statistical analysis title
    		 Submaximal exercise VE/VCO2
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    56
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.133
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Submaximal exercise OUES/kg

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    End point title
    		 Submaximal exercise OUES/kg
    End point description
    End point type
    Secondary
    End point timeframe
    Main: Baseline vs three months of treatment with enalapril in Fontan patients
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up
    Number of subjects analysed
    28
    28
    Units: Not apllicable
        arithmetic mean (standard deviation)
    27.2 ± 6.0
    26.9 ± 6.5
    Statistical analysis title
    		 Submaximal exercise OUES/kg
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    56
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.706
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Blood NT-pro BNP

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    End point title
    		 Blood NT-pro BNP
    End point description
    End point type
    Secondary
    End point timeframe
    Main: Baseline vs three months of treatment with enalapril in Fontan patients
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up
    Number of subjects analysed
    28
    28
    Units: ng/L
        median (inter-quartile range (Q1-Q3))
    80.2 (48.4 to 146.8)
    71.5 (42.1 to 136.4)
    Statistical analysis title
    		 Blood NT Pro BNP Enalapril
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    56
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.036
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Aortic stiffnes PWVao

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    End point title
    		 Aortic stiffnes PWVao
    End point description
    End point type
    Secondary
    End point timeframe
    Main: Baseline vs three months of treatment with enalapril in Fontan patients Sub analysis: Baseline all Fontan patients vs healthy controls.
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    22
    22
    31
    34
    Units: m/s
        arithmetic mean (standard deviation)
    5.3 ± 0.9
    5.2 ± 1.2
    5.5 ± 1.1
    4.7 ± 0.6
    Statistical analysis title
    		 Aortic stiffness PWVao Enalapril
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.535
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 0.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19
    Statistical analysis title
    		 Aortic stiffness PWVao Sub analysis
    Comparison groups
    Healthy controls v All Fontan patients
    Number of subjects included in analysis
    65
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.32
    Variability estimate
    Standard deviation
    Dispersion value
    0.22

    Secondary: Aortic stiffness AIXao

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    End point title
    		 Aortic stiffness AIXao
    End point description
    End point type
    Secondary
    End point timeframe
    Main: Baseline vs three months of treatment with enalapril in Fontan patients Sub analysis: Baseline all Fontan patients vs healthy controls.
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    22
    22
    31
    34
    Units: Percentage
        arithmetic mean (standard deviation)
    19.4 ± 9.7
    17.0 ± 9.8
    17.5 ± 9.9
    11.2 ± 7.8
    Statistical analysis title
    		 Aortic stiffness AIXao Sub analysis
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    65
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.006
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.85
         upper limit
    		 10.7
    Variability estimate
    Standard deviation
    Dispersion value
    2.2
    Statistical analysis title
    		 Aortic stiffness AIXao Enalapril
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.062
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 4.98
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.2

    Secondary: Central systolic blood pressure

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    End point title
    		 Central systolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Main: Baseline vs three months of treatment with enalapril in Fontan patients Sub analysis: Baseline all Fontan patients vs healthy controls.
    End point values
    		 Enalapril treatment baseline Enalapril treatment Follow-up All Fontan patients Healthy controls
    Number of subjects analysed
    22
    22
    34
    35
    Units: mmHg
        arithmetic mean (standard deviation)
    109.9 ± 9.6
    104.3 ± 9.2
    118.8 ± 9.1
    108.9 ± 8.6
    Statistical analysis title
    		 Central systolic blood pressure Enalapril
    Comparison groups
    Enalapril treatment baseline v Enalapril treatment Follow-up
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.003
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.1
         upper limit
    		 9.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.67
    Statistical analysis title
    		 Central systolic blood pressure Sub analysis
    Comparison groups
    All Fontan patients v Healthy controls
    Number of subjects included in analysis
    69
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.6
         upper limit
    		 14.1
    Variability estimate
    Standard deviation
    Dispersion value
    2.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First patient started with enalapril 19-09-2017 and last patient ended the study with enalapril on 21-10-2019
    Adverse event reporting additional description
    Enalapril was titrated during the first weeks, if systolic blood pressure fell >20%, or if patients experienced side effects, dosage was lowered. Renal function was checked after 4-5 weeks. At baseline, during the titration period and at follow-up, patients were asked about side effects.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 METC / CCMO
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    Enalapril treatment
    Reporting group description
    		 All Fontan patients who were treated with enalapril correctly. 30 patients were enrolled study and started with enalapril treatment. During the study 1 patient withdrew at the request of parents after a few weeks and 1 patient was excluded for further analysis because of medication noncompliance.

    Serious adverse events
    		 Enalapril treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Enalapril treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 30 (43.33%)
    Cardiac disorders
    Decrease >20% blood pressure
    Additional description: Enalapril was titrated on blood pressure, when it fell >20% dosage was lowered, in all patients who experienced the blood pressure drop, blood pressure recovered with lowering the dosage and all patients completed the study with a lower dosage.
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    6
    Syncope
    Additional description: Two patients experienced syncope, after lowering the dosage it did not occurred again and both patients completed the study.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Dizziness postural
    Additional description: 3 patients experienced dizziness, in 2 patients it was related with enalapril and the dosage was lowered and it did not occur again. For he third patients it happened during a hot summer, after advise of extra fluid intake it did not happen again.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Palpitations
    Additional description: One patients, already known with palpitations before the study, experienced palpitations during the titration period, the dosage was not raised per protocol and the subject completed the study.
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Lower saturation, tired, cough
    Additional description: 1 patient catched a cold cough during the study and due to the infection he was tired and had lower saturations, on parents request the patients stopped with the study.
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jan 2019
    An substantial amendment was done as: - We decided that healthy subjects did not had to do the exercise tests since sufficient reference values are already known in children to be able to compare the outcome values of the Fontan patients. - The diary used for the 24-hour VU-AMS measurement had not been submitted as a separated document at the firs submission. Therefore we added that at the amendment. - An example letter to the general practitioner about the participation of study patients was missing in the study file, we added that in the amendment. - In view of the changes of the privacy law in Europe, the trial subject information forms were adapted accordingly.

    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.
    Small sample size despite many eligible patients. Nonetheless, this is the largest prospective study of enalapril in Fontan patients yet, and the power to conclude that enalapril has no beneficial effect was enhanced by lower-than-expected variance.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34375703
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