Clinical trial NCT02652741: Orodispersible Minitablets of Enalapril in Young Children With Heart Failure Due to Congenital Heart Disease
Official title: Orodispersible Minitablets of Enalapril in Young Children With Heart Failure Due to Congenital Heart Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Heart Failure
Congenital Heart Disease
Lead sponsor: Ethicare GmbH
Sponsor class: INDUSTRY
First posted: 2016-01-12
Enrollment: 50
Sex: ALL
Minimum age (years): 1
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Area under the Curve (AUC) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure
timeFrame: 0 hours to 12 hours
measure: Maximum Concentration (Cmax) of enalapril and its active metabolite
timeFrame: 0 hours to 12 hours
measure: Time to Maximum Concentration (Tmax) of enalapril and its active metabolite
timeFrame: 0 hours to 12 hours
Secondary outcomes:
measure: AUC of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure
timeFrame: 0 hours to 12 hours
measure: Cmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure
timeFrame: 0 hours to 12 hours
measure: Tmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure
timeFrame: 0 hours to 12 hours
measure: Renin
timeFrame: 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)
measure: Angiotensin 1
timeFrame: 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)
measure: Aldosterone
timeFrame: 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)
measure: Plasma Renin Activity
timeFrame: 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)
measure: Brain natriuretic peptides (BNPs).
timeFrame: 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)
measure: Acceptability of the ODMTs
timeFrame: Assessment time points: at Initial Dose Visit, at one Study Control Visit (day 14, 28 or 42), at Last Visit (day 56)
measure: Palatability of the ODMTs
timeFrame: Assessment time points: at Initial Dose Visit, at one Study Control Visit (day 14, 28 or 42), at Last Visit (day 56)
measure: Blood pressure
timeFrame: 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)
measure: Serum potassium
timeFrame: 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)
measure: Blood urea nitrogen (BUN)
timeFrame: 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)
measure: Creatinine
timeFrame: 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)
measure: Micro-albuminuria
timeFrame: 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)
measure: Shortening Fraction
timeFrame: Assessment time points: at Screening Visit and at Last Visit (day 56)
measure: Number of patients experiencing rehospitalisation due to heart failure
timeFrame: During 8 weeks of treatment
measure: Death due to worsening of the underlying disease
timeFrame: During 8 weeks of treatment
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Budapest
country: Hungary
facility: Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology
city: Rotterdam
country: Netherlands
facility: Sophia Children's Hospital, Erasmus MC
city: Utrecht
country: Netherlands
facility: Wilhelmina Children's Hospital, University Medical Center Utrecht
city: Belgrade
country: Serbia
facility: Univerzitetska Dečja Klinika
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Trust
Study officials:
affiliation: Univerzitetska Dečja Klinika Belgrade
name: Milica Bajcetic, Prof,MD,PhD
role: STUDY_CHAIR
affiliation: Univerzitetska Dečja Klinika Belgrade
name: Ida Jovanovic, Prof,MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sophia Children's Hospital, Erasmus MC Rotterdam
name: Michiel Dalinghaus, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wilhelmina Children's Hospital, University Medical Center Utrecht
name: J.M.P. J Breur, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of Vienna
name: Christoph Male, Prof,MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Great Ormond Street Hospital for Children NHS Trust London
name: Michael Burch, Prof,MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology Budapest
name: András Szatmári, Prof,MD,PhD
role: PRINCIPAL_INVESTIGATOR
References: