Orodispersible Minitablets of Enalapril in Children With Heart Failure Due to Dilated Cardiomyopathy (LENA-WP08)

Paediatric clinical trial in 50 children, from 1 month to less than 12 years of age, suffering from heart failure due to dilated cardiomyopathy, 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; Dilated Cardiomyopathy
• 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 up to Adolescents) project: 50 children with heart failure due to dilated cardiomyopathy (LENA-Work Package (WP) 08 Trial) and 50 children with heart failure due to congenital heart disease (LENA-WP09 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 WP08 Trial children between 1 month and less than 12 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 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 protocol a target dose similar to the adult target dose (20 mg of 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 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 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 7843692; Email: iklingmann@pharmaplex.be

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna
    • Contact: Christoph Male, Prof,MD,PhD; Phone Number: + 43 1 40400 32320; Email: christoph.male@meduniwien.ac.at
    • 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
• 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: Michiel Dalinghaus, MD,PhD; Phone Number: +3110-7040704; Email: 'Michiel Dalinghaus' <m.dalinghaus@erasmusmc.nl>
    • Contact: Tjitske van der Zanden; Phone Number: +3110-7040704; Email: t.vanderzanden@erasmusmc.nl
    • Principal Investigator: Michiel Dalinghaus, MD,PhD
    • Sub-Investigator: Marijke Van der Meulen, MD,PjD
  • Utrecht, Netherlands, 3584 CX
    • Wilhelmina Children's Hospital, University Medical Center Utrecht
    • Contact: J.M.P. J. Breur, MD,PhD; Phone Number: + 31 8875 540 02; Email: h.breur@umcutrecht.nl
    • Principal Investigator: J.M.P. J. Breur, MD,PhD
• Serbia
  • Belgrade, Serbia, 11129
    • Univerzitetska Dečja Klinika
    • 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
    • Principal Investigator: Ida Jovanovic, Prof,MD,PhD
• 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 year to 9 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients presenting with heart failure with signs of left ventricular (LV) systolic dysfunction who are eligible to receive ACE-Inhibitors in addition to standard therapy (e.g., digitalis and diuretics) can be enrolled into this trial. Patients who previously presented with LV systolic dysfunction and who have already been treated with ACE-Inhibitors, and currently still have an indication for the use of an ACE-Inhibitor can be switched to an equivalent starting dose of enalapril ODMT.

Patients fulfilling the following inclusion criteria can be enrolled

• Age 1 month to less than 12 years.
• Male and female patients.
• Diagnosis of dilated cardiomyopathy presenting with LV end-diastolic dimension > P95 and/or LV shortening fraction (SF) < 25%
• Subjects may be naïve to ACE-Inhibitor.
• Subjects already on ACE-Inhibitor willing to switch to enalapril Orodispersible Minitablets.
• Written informed consent from parent(s)/legal representative 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:

• Severe heart failure and/or end stage heart failure precluding introduction or continuation of ACE-Inhibitor.
• Too low blood pressure, e.g. ˂P5
• Restrictive and hypertrophic cardiomyopathies.
• Obstructive valvular disease (peak echocardiographic gradient more than 30 mm Hg).
• 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-Inhibitor.

• Concomitant 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; Weight-dependent dose titration and long-term treatment scheme with enalapril ODMTs of 0.25 mg and 1 mg strength; 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 bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 years); descriptive pharmacokinetic investigation	0 hours to 12 hours
Maximum Concentration (Cmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure	Maximum Concentration (Cmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 years); descriptive pharmacokinetic investigation	0 hours to 12 hours
Time to Maximum Concentration (Tmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure	Time to Maximum Concentration (Tmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 years); descriptive pharmacokinetic investigation	0 hours to 12 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets	AUC of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy in the age subsets 1 month to less than 1 year and 1 year to less than 12 years; descriptive pharmacokinetic investigation	0 hours to 12 hours
Cmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets	Cmax of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy in the age subsets 1 month to less than 1 year and 1 year to less than 12 years; descriptive pharmacokinetic investigation	0 hours to 12 hours
Tmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets	Tmax of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy in the age subsets 1 month to less than 1 year and 1 year to less than 12 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 (day 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 (day 14, 28, 42) up to Last Visit after 8 (day 56)
Aldosterone	Aldosterone as marker of the renin-angiotensin-aldosterone system at every 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 (day 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 (day 14, 28, 42) up to Last Visit (day 56)
Brain natriuretic peptides (BNP)	Brain natriuretic peptides measurement as indicator of disease severity measured at every visit up to the end of treatment at 8 weeks	At Screening Visit and then pre-dose at each Titration Visit and Study Control Visit (day 14, 28, 42), at Last Visit (day 56)
Acceptability of the ODMTs	Acceptability assessment according to an age-appropriate scale	Assessment time points: at Initial Dose, at one Study Control Visit (at days 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, at one Study Control Visit (at days 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), over 2 hours after all other Titration Visits, pre-dose at all Study Control Visits (at days 14, 28 and 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)
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

Collaborators and Investigators

• Sponsor: Ethicare GmbH
• Investigators: Study Chair: Michiel Dalinghaus, MD, PhD, Sophia Children's Hospital Erasmus MC Rotterdam; Principal Investigator: J.M.P. J. Breur, MD, PhD, Wilhelmina Children's Hosptial University Medical Center Utrecht; 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 London; Principal Investigator: András Szatmári, Prof,MD,PhD, Hungarian Paediatric Heart Institute, 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 3, 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: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Cardiomegaly; Laminopathies; Heart Failure; Cardiomyopathies; Cardiomyopathy, Dilated; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Enalaprilat; Enalapril
• Other Study ID Numbers: 2015-602295-01; 2015-002335-17 (EudraCT Number)

Plan for Individual participant data (IPD)

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