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    The EU Clinical Trials Register currently displays   43974   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2016-004433-24
    Sponsor's Protocol Code Number:59498
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-02-22
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2016-004433-24
    A.3Full title of the trial
    ACE inhibition in Fontan patients: its effect on body fluid regulation.
    ACE remmers bij Fontan patienten en het effect op vloeistof verplaatsingen binnen het lichaam.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of the effect from ACE inhibition on body fluid regulation in children with a Fontan circulation (a circulation in which it lacks a heart chamber that pumps the blood througt the lung circulation).

    Evaluatie van het effect van ACE-remmers op de regulatie van lichaamsvocht bij kinderen met een Fontan circulatie (een circulatie waarbij de hartkamer mist die bloed door de longcirculatie pompt).
    A.3.2Name or abbreviated title of the trial where available
    Evaluation of ACE inhibition in Fontan patients (SAFE)
    Evaluatie van ACE remmers in Fontan patiënten (SAFE)
    A.4.1Sponsor's protocol code number59498
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLeids Universitair Medisch Centrum
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLeids Universitair Medisch Centrum
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeids Universitair Medisch Centrum
    B.5.2Functional name of contact pointDr. A.D.J. ten Harkel
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 ZA Leiden
    B.5.4Telephone number00310715262833
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Renitec: Enalapril
    D. of the Marketing Authorisation holderSandoz bv, Ratiopharm Nederland BV and Teva Nederland bv
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with univentricular hearts palliated by the Fontan procedure
    Patienten met een univentriculaire hartcirculatie die zijn ontlast met een Fontan procedure
    E.1.1.1Medical condition in easily understood language
    Patients with a functional one chamber heart who have now a Fontan circulation, which means venous return from the system circulation is directly connected tot the arterial circulation form the lungs.
    Patiënten met één functionele hartkamer die nu een Fontan circulatie hebben, wat betekent dat de veneuze retour van de systeemcirculatie direct op de arteriele circulatie van de longen is aangesloten.
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.
    Om Fontan patiënten 3 maanden te behandelen met de ACE remmer enalapril en dit te vergelijken met een set van cardiovasculaire metingen voor en na de behandeling om zo het effect van enalapril op het cardiovasculaire systeem bij Fontan patiënten te kunnen onderzoeken.
    E.2.2Secondary objectives of the trial
    -To assess autonomic parasympathetic and sympathetic function as well as vascular function in a population of patients with univentricular hearts palliated by the Fontan procedure and compare it with the results in healthy subjects.
    -To assess the effects of central fluid depletion by means of a passive head-up-tilt test and central fluid loading by passive leg raising on cardiac output, aortic distensibility and hepatic venous blood flow patterns in a group of patients with a Fontan circulation and compare it with the results in healthy controls.
    -To correlate the above mentioned results with the results of a symptom limited maximal exercise test.
    -To study the effect of a reversible fluid challenge and fluid depletion on cardiovascular parameters before and after a period of enalapril treatment in order to study changes in fluid susceptibility in Fontan patients.
    - Om autonome parasympathische en sympathische functie als ook vasculaire functie te beoordelen in een populatie van patiënten met een univentriculair hart ontlast door een Fontan procedure en dit te kunnen vergelijken met resultaten bij gezonde kinderen.
    - Om het effect van depletie van centraal vocht, middels een passieve kieptafel test, en toename van centraal vocht, middels passief benen omhoog houden, op hartminuutvolume, distensibiliteit van de aorta en hepatisch veneuze bloedstroompatronen in een groep patiënten met een Fontan circulatie en dit te vergelijken met gezonde kinderen.
    - Om al het bovenstaande met resultaten te correleren met resultaten van een symptoom limiterende maximale inspanningstest.
    - Om het effect van een reversibele vocht test en vocht depletie te onderzoeken op cardiovasculaire parameters voor en na een periode van behandeling met enalapril om zo de vatbaarheid van verandering van vocht te kunnen onderzoek in Fontan patiënten.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Fontan patiënts
    Patiënts from 8 until 18 years old
    Fontan patiënten
    Patiënten van 8 tot 18 jaar oud
    E.4Principal exclusion criteria
    Fontan patients who already use enalapril
    Fontan patiënten die reeds enalapril gebruiken
    E.5 End points
    E.5.1Primary end point(s)
    - Echocardiography: 2D imaging, color Doppler and pulse wave velocity measurements of inflow and outflow through the cardiac valves. Tissue Doppler imaging as well as speckle tracking strain of wall movement. Hepatic venous blood flow patterns and superior caval venous (Glenn) flow patterns.
    - Cardiopulmonary Exercise Stress Testing: Maximal oxygen consumption, VE/VCO2 relationship and the measurement of the Oxygen Uptake Efficiency Slope (OUES).
    - Blood Sampling: Electrolytes (Na and K), kidney function (Creatinin and Urea), liver function (ASAT, ALAT, alkalic fosfatase, gamma globulin and bilirubin levels), albumin and NT-pro BNP levels.
    - 24-hour monitoring of electrocardiography and impedance cardiography: heart rate, heart rate variability, stroke volume, pre ejection period and respiratory sinus arrhythmia.
    - Aortic stiffness: pulse wave velocity of the aorta, augmentation index and central blood pressure
    - Outcome of passive leg raising: aortic pulse wave velocity, cardiac output and hepatic venous blood flow, cardiac autonomic tone (heart rate variability, pre ejection period and respiratory sinus arrhythmia) and cerebral blood flow.
    - Outcome of head up tilt table testing: aortic pulse wave velocity, cardiac output and hepatic venous blood flow, cardiac autonomic tone (heart rate variability, pre ejection period and respiratory sinus arrhythmia), cerebral blood flow and continuous blood pressure measurement.
    - Echocardiografie: 2D beeldvorming, kleuren Doppler en metingen van polsgolfsnelheid van instroom en uitstroom door de cardiale kleppen. Beeldvorming middels tissue Doppler als ook speckle tracking strain van wandbewegingen. Bloedstroompatronen door de superior vena cava (Glenn) en door levervenen.
    - Inspanningstest: Maximale zuurstof verbruik, VE/CO2 relatie en de meting van de zuurstof opname efficiëntie curve (Oxygen Uptake Efficiency Slope (OUES)).
    - Bloedtest: Elektrolyten (Na en K), nierfunctie (creatinine en ureum), leverfunctie (ASAT,ALAt, alkalisch fosfatase, gamma globuline en bilirubine), albumine en NT-pro BNP levels.
    - 24-uurs monitoring van elektrocardiogram en impedantiemeting: hartslag, variabiliteit hartslag, slagvolume, pre-ejectie periode en ademhaling- sinus aritmie.
    - Vaatwandstijfheid aorta: polsgolfsnelheid van de aorta, augmentatie-index en centrale bloeddruk.
    - Uitkomst van passief benen omhoog houden: polsgolfsnelheid aorta, hartminuutvolume en veneuze bloedstroom in de lever, cardiale autonome tonus (variabiliteit hartslag, pre-ejectie periode en ademhalings- sinus aritmie) en cerebrale bloedstroom.
    - Uitkomst van staande kieptafeltest: polsgolfsnelheid aorta, hartminuutvolume en veneuze bloedstroom in de lever, cardiale autonome tonus (variabiliteit hartslag, pre-ejectie periode en ademhalings- sinus aritmie), cerebrale bloedstroom en continue bloeddrukmeting.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After three months of start Enalapril endpoints will be measured.
    Al these endpoints wil be measured at ones in the healthy person group.
    Na drie maanden va start Enalapril zullen al eindpunten gemeten worden.
    Al dexe eindpunten zullen éénmaal gemeten worden in de groep van gezonde personen.
    E.5.2Secondary end point(s)
    There ar no secondary end points
    Er zijn geen secundaire uitkomstmaten
    E.5.2.1Timepoint(s) of evaluation of this end point
    There ar no secondary end points
    Er zijn geen secundaire uitkomstmaten
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E. trial design description
    Longitudinale interventie studie en een cross-sectionele studie
    Longitudinal intervention study and a cross-sectional study
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 92
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F. of subjects for this age range: 32
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 60
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    Children from 8 until 18 years old
    Kinderen van 8 tot 18 jaar oud
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state92
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After treatment, patiënts can decide with their own pediatric cardiologist if they want to continue treatment or not.
    Na de behandeling kunnen patiënten met hun eigen kindercardioloog beslissen of ze door gaan met de behandeling of niet.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-02-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-17
    P. End of Trial
    P.End of Trial StatusCompleted
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