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

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.

Study Overview

• Status: Unknown
• Conditions: Heart Failure; Congenital Heart Disease
• Intervention / Treatment: Drug: Enalapril Orodispersible Minitablet

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.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Stephanie Laeer, Prof,MD,PhD; Phone Number: +49 211 8110740; Email: stephanie.laeer@uni-duesseldorf.de
• Study Contact Backup: Name: Ingrid Klingmann, MD,PhD; Phone Number: +32 2 784 36 93; Email: iklingmann@pharmaplex.be

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Enalapril ODMT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the Curve (AUC) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure	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	0 hours to 12 hours
Maximum Concentration (Cmax) of enalapril and its active metabolite	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	0 hours to 12 hours
Time to Maximum Concentration (Tmax) of enalapril and its active metabolite	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	0 hours to 12 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients experiencing rehospitalisation due to heart failure	Number of patients experiencing rehospitalisation due to heart failure including the need for heart transplantation or the institution of mechanical circulatory support	During 8 weeks of treatment
Death due to worsening of the underlying disease	Death due to worsening of the underlying disease	During 8 weeks of treatment
AUC of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure	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	0 hours to 12 hours
Cmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure	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	0 hours to 12 hours
Tmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure	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	0 hours to 12 hours
Renin	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	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	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	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	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	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	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	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)
Brain natriuretic peptides (BNPs).	Brain natriuretic peptides measurement as indicator of disease severity at every visit up to end of treatment at 8 weeks	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)
Acceptability of the ODMTs	Acceptability assessment according to an age-appropriate scale	Assessment time points: at Initial Dose Visit, at one Study Control Visit (day 14, 28 or 42), at Last Visit (day 56)
Palatability of the ODMTs	Palatability assessment according to an age-appropriate scale	Assessment time points: at Initial Dose Visit, at one Study Control Visit (day 14, 28 or 42), at Last Visit (day 56)
Blood pressure	Safety monitoring parameter to decide on next dose prescription level	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)
Serum potassium	Renal monitoring parameter to decide on next dose prescription level	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)
Blood urea nitrogen (BUN)	Renal monitoring parameter to decide on next dose prescription level	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)
Creatinine	Renal monitoring parameter to decide on next dose prescription level	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)
Micro-albuminuria	Renal monitoring parameter to decide on next dose prescription level	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)
Shortening Fraction	Shortening Fraction in echocardiography	Assessment time points: at Screening Visit and at Last Visit (day 56)

Collaborators and Investigators

• Sponsor: Ethicare GmbH
• Investigators: Principal Investigator: Ida Jovanovic, Prof,MD,PhD, Univerzitetska Dečja Klinika Belgrade; 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; Study Chair: Milica Bajcetic, 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: András Szatmári, Prof,MD,PhD, Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology Budapest

Publications and helpful links

Helpful Links

• FP7-funded "LENA" project, Grant Agreement 602295

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Anticipated): June 1, 2017
• Study Completion (Anticipated): June 1, 2017

Study Registration Dates

• First Submitted: January 4, 2016
• First Submitted That Met QC Criteria: January 8, 2016
• First Posted (Estimate): January 12, 2016

Study Record Updates

• Last Update Posted (Estimate): January 12, 2016
• Last Update Submitted That Met QC Criteria: January 8, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Failure; Heart Diseases; Heart Defects, Congenital; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Enalaprilat; Enalapril
• Other Study ID Numbers: 2015-602295-02; 2015-002396-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Serious Adverse Event information