Work package 8: Dilated Cardiomyopathy Bridging Study
Work package leader
Participants in the Clinical Trial
Description of the work package
Our work package 8 will assess the pharmacokinetics of orodispersible minitablets of enalapril as well as the safety of orodispersible minitablets of enalapril as required for completion of the PUMA application by means of a clinical trial according to GCP guidelines and in accordance with the highest ethical standards, in which 50 children with DCM with LV dysfunction will be enrolled within 20 months of the trial.
This Trial will be coordinated by Dr. Michiel Dalinghaus, Paediatric Cardiologist at Erasmus University Medical Center–Sophia Children’s Hospital.
The work package 8 participants are performing a bridging trail on Orodispersible Minitablets of Enalapril in Children with Heart Failure due to Dilated Cardiomyopathy. Thus, this work package 8 includes the protocol development, set up and conduct of a clinical trial to evaluate the pharmacokinetics and pharmacodynamics of orodispersible minitablets of enalapril in pediatric patients respecting the international ethical and regulatory Standards.
- Our rationale: Enalapril is an ACE inhibitor commonly used for cardiac failure in children, although it is not labelled for any condition in patients <20 kg in European countries. Current problems with the use of enalapril in children include: no appropriate formulation and insufficient stability of the liquid soluble formulation for young paediatric patients; insufficient paediatric pharmacokinetic (PK) data for any formulation; insufficient safety data in neonates, infants, and young children; and limited pharmacodynamics (PD) and efficacy data for paediatric cardiological indications.
- The aim of the LENA project is to address these shortcomings and provide a basis for a future PUMA of enalapril by developing an age-appropriate solid oral formulation suitable for all paediatric subsets; generating PK and PD data; collecting data on the safety of enalapril in young paediatric patients; and providing dose recommendations based on PK/PD modelling and bridging from adult data.
- The bridging trial is designed as follows: work package 8 includes a Phase II prospective, open-label, multicentre pharmacokinetic bridging study in infants, children, and adolescents (1 month to 18 years of age) titled “PK and PD of orodispersible minitablets of enalapril in paediatric patients with Dilated Cardiomyopathy". The study execution will require 20 months for recruitment, the active treatment period per participant will be 8 weeks. The total study duration is 22 months.
- Enrollment: 50 children with DCM with LV dysfunction
- Trial population: Children (<18 years) with heart failure secondary to dilated cardiomyopathy, newly presenting or with prior presentation. Subjects may be naïve to ACEI or be switched to orodispersable mini-tablets.
- Intervention: Children participating in this clinical study will start with or be switched to enalapril orodispersable minitablets, for a period of 8 weeks. A starting dose of 0.1 mg/kg (assuming a minimum neonatal weight of 2.5kg, to be increased by 0.1 mg/kg/day every 7 days up to a maximum of 0.5 mg/kg/day
- Main trial parameters/endpoints:
- Primary endpoint: Elucidation of the PK of enalapril and enalaprilat from oro dispersible minitablets (bridging study)
- Secondary endpoints: Clinical efficacy and safety parameters: Brain natriuretic peptides (BNPs) blood pressure, heart rate, renal function, PD markers of RAAS, acceptability of the novel formulation.