Orodispersible Minitablets of Enalapril in Children With Heart Failure Due to Dilated Cardiomyopathy

Ethicare GmbH50 enrolled

Overview

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.

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

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Heart Failure Dilated Cardiomyopathy

Interventions

Enalapril Orodispersible MinitabletDRUG

Weight-dependent dose titration and long-term treatment scheme with enalapril ODMTs of 0.25 mg and 1 mg strength

Eligibility

Sex: ALLMin age: 1 MonthMax age: 11 Years

Medical Language ↔ Plain English

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.

Locations (6)

Medical University of Vienna

Vienna, Austria

Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology

Budapest, Hungary

Sophia Children's Hospital, Erasmus MC

Rotterdam, Netherlands

Wilhelmina Children's Hospital, University Medical Center Utrecht

Utrecht, Netherlands

Outcomes

Primary Outcomes

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

Time frame: 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

Time frame: 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

Time frame: 0 hours to 12 hours

Secondary Outcomes

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

Time frame: 0 hours to 12 hours

Central Contacts

Stephanie Laeer, Prof,MD,PhD

CONTACT

+49 211 8110740 Stephanie.Laeer@uni-duesseldorf.de

Ingrid Klingmann, MD, PhD

CONTACT

+32 2 7843692 iklingmann@pharmaplex.be

Data from ClinicalTrials.gov

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