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Orodispersible Minitablets of Enalapril in Young Children With Heart Failure Due to Congenital Heart Disease (LENA-WP09)

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ClinicalTrials.gov Identifier: NCT02652741
Recruitment Status : Unknown
Verified January 2016 by Ethicare GmbH.
Recruitment status was:  Not yet recruiting
First Posted : January 12, 2016
Last Update Posted : January 12, 2016
Sponsor:
Information provided by (Responsible Party):
Ethicare GmbH

Brief Summary:
Paediatric clinical trial in 50 children, from newborn to less than 6 years of age, suffering from heart failure due to congenital heart disease, to obtain paediatric pharmacokinetic and pharmacodynamic data of enalapril and its active metabolite enalaprilat while treated for 8 weeks with enalapril in form of Orodispersible Minitablets (ODMTs), to describe the dose exposure in this patient population.

Condition or disease Intervention/treatment Phase
Heart Failure Congenital Heart Disease Drug: Enalapril Orodispersible Minitablet Phase 2 Phase 3

Detailed Description:

This clinical trial is one of three clinical trials of the European Commission (FP7)-funded "LENA" (Labeling of Enalapril from Neonates to Adolescents) project: 50 children with heart failure due to congenital heart disease (LENA-Work Package (WP)09 Trial), and 50 children with heart failure due to dilated cardiomyopathy (LENA-WP08 Trial) get treated with an optimal dose of enalapril ODMTs for up to 8 weeks after thorough, individualised titration and get invited to join the 10 months Safety Follow-up Study (LENA-WP10 Trial).

In this WP09 Trial children from age of newborn to less than 6 years, naive to enalapril treatment or switched from an Angiotensin-Converting-Enzyme (ACE)-Inhibitor pre-treatment, receive an Initial Dose to investigate the reaction over 8 hours before a decision on the first dose level is made. Always up to 7 days later a next higher dose is given at the hospital, the patient is supervised for 4 and then always 2 hours before a decision on the prescribed dose for the next dosing period is made. In this study a target dose similar to the adult target dose (20 mg enalapril in a 70 year old adult result in 0.282 mg/kg/day enalapril) is defined. Enalapril ODMTs of 0.25 mg and 1 mg strength are available to allow for an individual dose titration scheme.

Weight-dependently, pharmacokinetic (PK) and pharmacodynamic (PD) data are collected once in a full PK/PD day over 12, respectively 6 hours, and single PK/PD samples at each Dose Titration Visit and each bi-weekly Study Control Visit until the Last Visit after 8 weeks of treatment. Blood pressure and renal monitoring is performed at each visit before deciding on the dose level for the next treatment period.

Pharmacogenomics and metabolomics exploratory studies are added as a sub-study to better understand the underlying disease, its progression as well as the impact of the ACE-inhibition on cardiac outcome and renal function.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Orodispersible Minitablets of Enalapril in Young Children With Heart Failure Due to Congenital Heart Disease
Study Start Date : January 2016
Estimated Primary Completion Date : June 2017
Estimated Study Completion Date : June 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Drug administration
Enalapril Orodispersible Minitablet (ODMT), 0.25 mg or 1 mg, administered 1x/day or 2x/day for up to 8 weeks
Drug: Enalapril Orodispersible Minitablet
8-weeks treatment, open, uncontrolled, PK/PD, acceptability and palatability assessments and safety assessments after Enalapril intake in form of 0.25 mg or 1 mg ODMTs
Other Name: Enalapril ODMT




Primary Outcome Measures :
  1. Area under the Curve (AUC) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure [ Time Frame: 0 hours to 12 hours ]
    Area under the Curve (AUC) of enalapril and enalaprilat are measured at first dose or at any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease (newborn to less than 6 years); descriptive pharmacokinetic investigation

  2. Maximum Concentration (Cmax) of enalapril and its active metabolite [ Time Frame: 0 hours to 12 hours ]
    Maximum Concentration (Cmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease (newborn to less than 6 years); descriptive pharmacokinetic investigation

  3. Time to Maximum Concentration (Tmax) of enalapril and its active metabolite [ Time Frame: 0 hours to 12 hours ]
    Time to Maximum Concentration (Tmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease (newborn to less than 6 years); descriptive pharmacokinetic investigation


Secondary Outcome Measures :
  1. AUC of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure [ Time Frame: 0 hours to 12 hours ]
    AUC of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease in the age su-sets newborn to less than 1 year and 1 to less than 6 years; descriptive pharmacokinetic investigation

  2. Cmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure [ Time Frame: 0 hours to 12 hours ]
    Cmax of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease in the age su-sets newborn to less than 1 year and 1 to less than 6 years; descriptive pharmacokinetic investigation

  3. Tmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure [ Time Frame: 0 hours to 12 hours ]
    Tmax of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease in the age su-sets newborn to less than 1 year and 1 to less than 6 years; descriptive pharmacokinetic investigation

  4. Renin [ Time Frame: Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56) ]
    Renin as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation

  5. Angiotensin 1 [ Time Frame: Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56) ]
    Angiotensin 1 as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation

  6. Aldosterone [ Time Frame: Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56) ]
    Aldosterone as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation

  7. Plasma Renin Activity [ Time Frame: Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56) ]
    Plasma Renin Activity as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation

  8. Brain natriuretic peptides (BNPs). [ Time Frame: At Screening Visit and then pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56) ]
    Brain natriuretic peptides measurement as indicator of disease severity at every visit up to end of treatment at 8 weeks

  9. Acceptability of the ODMTs [ Time Frame: Assessment time points: at Initial Dose Visit, at one Study Control Visit (day 14, 28 or 42), at Last Visit (day 56) ]
    Acceptability assessment according to an age-appropriate scale

  10. Palatability of the ODMTs [ Time Frame: Assessment time points: at Initial Dose Visit, at one Study Control Visit (day 14, 28 or 42), at Last Visit (day 56) ]
    Palatability assessment according to an age-appropriate scale

  11. Blood pressure [ Time Frame: Pre-dose at each Visit, over 8 hours at Initial Dose Visit, over 4 hours at First Titration Visit (day 3 to 7), for 2 hours after all following Titration Visits, pre-dose at all Study Control Visits (day 14, 28, 42), at last Visit (day 56) ]
    Safety monitoring parameter to decide on next dose prescription level

  12. Serum potassium [ Time Frame: Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56) ]
    Renal monitoring parameter to decide on next dose prescription level

  13. Blood urea nitrogen (BUN) [ Time Frame: Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56) ]
    Renal monitoring parameter to decide on next dose prescription level

  14. Creatinine [ Time Frame: Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56) ]
    Renal monitoring parameter to decide on next dose prescription level

  15. Micro-albuminuria [ Time Frame: Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56) ]
    Renal monitoring parameter to decide on next dose prescription level

  16. Shortening Fraction [ Time Frame: Assessment time points: at Screening Visit and at Last Visit (day 56) ]
    Shortening Fraction in echocardiography

  17. Number of patients experiencing rehospitalisation due to heart failure [ Time Frame: During 8 weeks of treatment ]
    Number of patients experiencing rehospitalisation due to heart failure including the need for heart transplantation or the institution of mechanical circulatory support

  18. Death due to worsening of the underlying disease [ Time Frame: During 8 weeks of treatment ]
    Death due to worsening of the underlying disease



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 5 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients fulfilling the following Inclusion Criteria can be enrolled:

  • Age from birth to less than 6 years.
  • Male and female patients.
  • Weight greater than 2.5 kg.
  • Diagnosis of heart failure due to congenital heart disease requiring after-load reduction by drug therapy.
  • Subjects may be naïve to ACE-Inhibitors.
  • Subjects already on ACE-Inhibitors willing to switch to enalapril Orodispersible Minitablets.
  • Patient and/or parent(s)/legal representative provided written informed consent and assent from the patient according to national legislation and as far as achievable from the child.

Exclusion Criteria:

Patients fulfilling any of the following Exclusion Criteria cannot be enrolled into this trial:

  • Neonates if born < 37 weeks of gestation.
  • Severe heart failure and/or end stage heart failure precluding introduction or continuation of ACE-Inhibitor.
  • Too low blood pressure, e.g. ˂P5
  • Uncorrected primary obstructive valvular disease, or significant systemic ventricular outflow obstruction, dilated restrictive or hypertrophic cardiomyopathy.
  • Uncorrected severe peripheral stenosis of large arteries including severe coarctation of the aorta.
  • Severe renal impairment with serum creatinine >2x Upper Limit of Normal (ULN) (according to the hospital's test methodology)
  • History of angioedema.
  • Hypersensitivity to ACE-Inhibitors.
  • Concommitant medication:

    • Dual ACE-Inhibitor therapy
    • Renin inhibitors
    • Angiotensin II antagonists
    • Non-Steroidal Anti-Inflammatory Drugs (including ibuprofen) except for aspirin and paracetamol
  • Already enrolled in an interventional trial with an investigational drug, unless no interference with the current study can be shown.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02652741


Contacts
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Contact: Stephanie Laeer, Prof,MD,PhD +49 211 8110740 stephanie.laeer@uni-duesseldorf.de
Contact: Ingrid Klingmann, MD,PhD +32 2 784 36 93 iklingmann@pharmaplex.be

Locations
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Austria
Medical University of Vienna Not yet recruiting
Vienna, Austria, 1090
Contact: Christoph Male, MD,PhD    + 43 1 40400 32320    christoph.male@meduniwien.ac.at   
Contact: Vanessa Swoboda, MD    + 43 1 40400 32320    v.swoboda@live.at   
Principal Investigator: Christoph Male, Prof,MD,PhD         
Sub-Investigator: Vanessa Swoboda, MD         
Hungary
Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology Not yet recruiting
Budapest, Hungary, 1095
Contact: Andras Szatmari, Prof,MD,PhD    +36 1 215 1220    szatmari@kardio.hu   
Contact: Laszlo Ablonczy, MD    +36 1 215 1220    ablonczyl@gmail.com   
Principal Investigator: Andras Szatmari, Prof,MD,Phd         
Sub-Investigator: Laszlo Ablonczy, MD         
Netherlands
Sophia Children's Hospital, Erasmus MC Not yet recruiting
Rotterdam, Netherlands, 3015 CN
Contact: Michiel Dalinghaus, MD,PhD    +3110-7040704    m.dalinghaus@erasmusmc.nl   
Contact: Tjitske van der Zanden    +3110-7040704    t.vanderzanden@erasmusmc.nl   
Sub-Investigator: Marijke Van der Meulen, MD,PhD         
Wilhelmina Children's Hospital, University Medical Center Utrecht Not yet recruiting
Utrecht, Netherlands, 3584 CX
Contact: J.M.P. Breur J. Breur, MD,PhD    + 31 8875 540 02    h.breur@umcutrecht.nl   
Principal Investigator: J.M.P. J. Breur, MD,PhD         
Serbia
Univerzitetska Dečja Klinika Not yet recruiting
Belgrade, Serbia, 11129
Contact: Milica Bajcetic, Prof,MD,PhD    38 1112060716    milica.bajcetic@udk.bg.ac.rs   
Contact: Ida Jovanovic, Prof,MD,PhD    38 1112060716    idaj@rcub.bg.ac.rs   
Principal Investigator: Ida Jovanovic, Prof,MD,PhD         
United Kingdom
Great Ormond Street Hospital for Children NHS Trust Not yet recruiting
London, United Kingdom, WC1N 3JH
Contact: Michael Burch, Prof,MD,PhD    +44 020 7405 9200    michael.burch@gosh.nhs.uk   
Principal Investigator: Michael Burch, Prof,MD,PhD         
Sponsors and Collaborators
Ethicare GmbH
Investigators
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Study Chair: Milica Bajcetic, Prof,MD,PhD Univerzitetska Dečja Klinika Belgrade
Principal Investigator: Ida Jovanovic, Prof,MD,PhD Univerzitetska Dečja Klinika Belgrade
Principal Investigator: Michiel Dalinghaus, MD,PhD Sophia Children's Hospital, Erasmus MC Rotterdam
Principal Investigator: J.M.P. J Breur, MD,PhD Wilhelmina Children's Hospital, University Medical Center Utrecht
Principal Investigator: Christoph Male, Prof,MD,PhD Medical University of Vienna
Principal Investigator: Michael Burch, Prof,MD,PhD Great Ormond Street Hospital for Children NHS Trust London
Principal Investigator: András Szatmári, Prof,MD,PhD Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology Budapest

Additional Information:
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Responsible Party: Ethicare GmbH
ClinicalTrials.gov Identifier: NCT02652741     History of Changes
Other Study ID Numbers: 2015-602295-02
2015-002396-18 ( EudraCT Number )
First Posted: January 12, 2016    Key Record Dates
Last Update Posted: January 12, 2016
Last Verified: January 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Serious Adverse Event information

Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Heart Defects, Congenital
Cardiovascular Diseases
Congenital Abnormalities
Cardiovascular Abnormalities
Enalapril
Enalaprilat
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents