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

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.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 2017

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.

Interventions

  • Drug: Enalapril Orodispersible Minitablet
    • Weight-dependent dose titration and long-term treatment scheme with enalapril ODMTs of 0.25 mg and 1 mg strength

Arms, Groups and Cohorts

  • Experimental: Drug administration
    • Enalapril Orodispersible Minitablet (ODMT), 0.25 mg or 1 mg, administered 1x/day or 2x/day for up to 8 weeks

Clinical Trial Outcome Measures

Primary Measures

  • 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 bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 years); descriptive pharmacokinetic investigation
  • Maximum Concentration (Cmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure
    • 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 bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 years); descriptive pharmacokinetic investigation
  • Time to Maximum Concentration (Tmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure
    • 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 bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 years); descriptive pharmacokinetic investigation

Secondary Measures

  • AUC of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets
    • 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 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
  • Cmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets
    • 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 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
  • Tmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets
    • 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 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
  • Renin
    • Time Frame: 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)
    • 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
  • Angiotensin 1
    • Time Frame: 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)
    • 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
  • Aldosterone
    • Time Frame: 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)
    • 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
  • Plasma Renin Activity
    • Time Frame: 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 as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation
  • Brain natriuretic peptides (BNP)
    • Time Frame: At Screening Visit and then pre-dose at each Titration Visit and Study Control Visit (day 14, 28, 42), at Last Visit (day 56)
    • Brain natriuretic peptides measurement as indicator of disease severity measured at every visit up to the end of treatment at 8 weeks
  • Acceptability of the ODMTs
    • Time Frame: Assessment time points: at Initial Dose, at one Study Control Visit (at days 14, 28 or 42), at Last Visit (day 56)
    • Acceptability assessment according to an age-appropriate scale
  • Palatability of the ODMTs
    • Time Frame: Assessment time points: at Initial Dose, at one Study Control Visit (at days 14, 28 or 42), at Last Visit (day 56)
    • Palatability assessment according to an age-appropriate scale
  • 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), 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)
    • Safety monitoring parameter to decide on next dose prescription level
  • 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
  • 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
  • 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
  • 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
  • Shortening fraction
    • Time Frame: Assessment time points: at Screening Visit and at Last Visit (day 56)
    • Shortening Fraction in echocardiography
  • 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
  • Death due to worsening of the underlying disease
    • Time Frame: During 8 weeks of treatment
    • Death due to worsening of the underlying disease

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 1 Month

Maximum Age: 11 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Ethicare GmbH
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Michiel Dalinghaus, MD, PhD, Study Chair, Sophia Children’s Hospital Erasmus MC Rotterdam
    • J.M.P. J. Breur, MD, PhD, Principal Investigator, Wilhelmina Children’s Hosptial University Medical Center Utrecht
    • Ida Jovanovic, Prof,MD,PhD, Principal Investigator, Univerzitetska Decja Klinika Belgrade
    • Christoph Male, Prof, MD,PhD, Principal Investigator, Medical University of Vienna
    • Michael Burch, Prof,MD,PhD, Principal Investigator, Great Ormond Street Hospital for Children London
    • András Szatmári, Prof,MD,PhD, Principal Investigator, Hungarian Paediatric Heart Institute, Göttsegen Gyorgy Hungarian Institute of Cardiology Budapest
  • Overall Contact(s)
    • Stephanie Laeer, Prof,MD,PhD, +49 211 8110740, Stephanie.Laeer@uni-duesseldorf.de

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