Work package 10: Clinical Safety Study with Longer Observation
Work package leader
Participants in the Clinical Trial
Description of the work package
The long-term observational study entitled "Follow-up Safety Trial in Children with Chronic Heart Failure Therapy Receiving Orodispersible Minitablets of Enalapril" will be performed by the clinical partners also involved in work package 8 and work package 9.
Dr. S.N. de Wildt, paediatric clinical pharmacologist, Erasmus University Medical Center–Sophia Children’s Hospital, Rotterdam, the Netherlands will lead the study as Principal Investigator.
Our work package 10 includes tasks like protocol development, set up and conduct of a observational, prospective, open-label, multicentre safety study in infants, children and adolescents (age range 0-18 years) receiving chronic heart failure therapy with enalapril to evaluate the safety of continued use of orodispersible minitablets of enalapril in paediatric populations respecting the international ethical and regulatory standards.
- 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.
- Our Objectives:
- To demonstrate the safety of continued use of orodispersible minitablets of enalapril in paediatric populations
- To describe compliance, adherence and acceptability of orodispersable minitablets of enalapril
- To explore effcicacy of orodispersable minitablets of enalapril
- Trial design: A observational, prospective, open-label, multicentre safety study in infants, children and adolescents (age range 0-18 years) receiving chronic heart failure therapy with enalapril to evaluate the safety of continued use of orodispersible minitablets of enalapril in paediatric populations.
- Enrollment: Maximum enrolment is the number of patients from WP08 and WP09 (~100). Assuming that 70% of patients are enrolled, adverse events with a frequency <4% can be detected. The observation period will cover 6 months.
- Trial Population are all patients from studies in work package 8 and work package 9.
- Intervention: In this roll-over safety study, the final dose of the pharmacokinetic studies in work package 8 and work package 9 will be continued, unless adverse events necessitate down-titration of the dose.
The dose in the pharmacokinetic studies is determined as follows: A starting dose of 0.1 mg/kg (assuming a minimum neonatal weight of 2.5kg, this will be one single orodispersible minitablet of 0.25mg)–to be increased by 0.1 mg/kg/day every 7 days up to a maximum of 0.5 mg/kg/day–will be verified by modeling and simulation prior to the study. The duration of treatment in each individual patient will be 8 weeks.
- Main trial parameters/endpoints:
- Primary endpoint: Number of any adverse event of enalapril (clinical and/or laboratory parameters), including blood pressure, heart rate, renal function.
- Secondary endpoints: Compliance, adherence, and acceptability of the novel formulation orodispersible minitablets during prolonged use; PK of orodispersible minitablets enalapril; Exploratory efficacy data (BNPs, PD markers of RAAS, echocardiography, death, progression to transplant list or transplantation.