Work package 9: Orodispersible Minitablets of Enalapril in Neonates, Infants and Toddlers with Heart Failure due to Congenital Heart Disease (ENACHD)
Work package leader
Participants in the Clinical Trial
Description of the work package
In work package 9 we are performing a prospective, open-label, multicentre, PK and PD study of orodispersible minitablets of enalapril in paediatric patients, including neonates and infants with CHD and HF before and after surgery. The study will be conducted according to the highest ethical standards and following GCP in accredited European centres and will be coordinated by Prof. Dr. Milica Bajcetic.
The study will primarily determine the lowest possible paediatric age at which enalapril can be used and contribute to increasing the number of paediatric patients in whom the novel drug formulation can be used safely. The results will provide detailed information relating to PK and safety of orodispersible minitablets of enalapril in this population of paediatric patients. Addtitional efficacy parameters will be assessed in an exploratory manner.
The study execution will require 18 months for recruitment followed by 8 weeks of treatment. A preliminary feasibility assessment in the study centres has determined that recruitment of the required number of patients will be achieved by the clinical partners involved. These centres have been involved in many previous international studies involving paediatric patients with CHD and HF. The staff in each of these sites is experienced in clinical investigations of drugs in paediatric patients with cardiovascular pathology.
The primary endpoint is the pharmacokinetic and the safety of enalapril and enalaprilat (bridging study). Secondary endpoints are pharmacodynamic markers of RAAS and BNPs, and acceptability of the novel formulation. All other criteria are the same as in work package 8, the Dilated Cardiomyopathy Bridging Study.
The tasks included in our work package 9 are described below:
- Setting up of Clinical Trial: The study protocol will be designed in collaboration with all participants and will provide background information and rationale, study objectives, investigational plan including study design, and study population (inclusion and exclusion criteria). This task will be performed in a collaborative fashion between work package 6 on Statistics and Data Management, work package 7, the Clinical Study on Bioavailability and Food Effect in Healthy Adults and this work package 8. Furthermore, the protocol will contain all information about the investigational product (e.g. drug preparation, administration, and storage) based on information from work package 2 on Pharmaceutical Development. Finally, the efficacy, pharmacokinetics and safety assessment will be defined in the protocol in collaboration with work package 5 on Pharmacokinetics and Modelling & Simulation, work package 6 and work package 7.
- The ethical and regulatory documentation: Documentation for the Institutional Review Board/Independent Ethics Committee (IRB/IEC) including informed consent, patient assent and information for patients will be adapted in the local language based on the documents provided by work package 6 Statistics and Data Management and work package 11 on Ethics & Dissemination to Parents, Patients, and Society. Additionally, documentation for ALIMS, the Serbian drug agency, for registration of the drug investigation and for the Serbian Ministry of Health for permission to export blood samples will be prepared by local investigators.
- Recruitment of patients fulfilling the inclusion criteria: The aim is to enrol 50 patients with CHD and HF over a 20-month period. Centres will recruit patients meeting all inclusion criteria after inform consent from patients/parents has been obtained. Patients eligible for inclusion in the study are paediatric patients with HF due to large left-to-right shunts, regurgitant valvular lesions or complex congenital heart disease before transcatheter or surgical intervention and paediatric patients with postoperative HF or residual lesions due to valvular regurgitations. Premature neonates (<36 weeks of gestation) and patients with DCM as well as patients with aortic obstructive disease are excluded from the study.
- Education: Investigators will be trained in practical application of Good Clinical Practice (GCP) and innovative site approaches in collaboration with work package 12 on Education of Scientific and Clinical Community and work package 4 on Clinical Trial Management, Pharmacovigilance and Safety.
- Perform clinical observations and blood sample withdrawal: Plasma sampling will be performed for will be sent or stored according to guidelines determined in work package 5 on Pharmacokinetic and Modelling & Simulation.
The following pharmacokinetics parameters will be measured and calculated: Tmax, Cmax, Ct, AUC, t½, Cl and Vss. Furthermore, the following PD parameters will be estimated by local investigators: clinical symptoms (Ross, NYHA classification), echocardiography parameters and PD markers of RAAS and BNPs. These assessments will be performed in collaboration with WP05.
Assessment of safety is the duty and responsibility of the local investigator. Safety will be evaluated mainly by recorded AEs and ADRs and will also include standardized clinical and laboratory safety assessments according to drug class-specific AEs, compliance adherence, and acceptability of the novel formulation. This task will be performed in collaboration with work package 8 and work package 10.
- Monitor and report progress of study, including safety reporting:
This task pertains to recruitment numbers. The day-to-day management of the patients will be done by the local clinical team, all data collection, monitoring and trial interventions will be done or facilitated by the research fellows, nurses or physicians involved in the LENA project. This task includes data entry into the CRF by site personnel, follow up interactions with the Central Trial Management Unit to address queries, and interactions with safety monitoring personnel. Total numbers of enrolled patients will be enumerated on a six-monthly basis and according to the study protocol. Regular progress reports will be provided to the Central Trial Management Unit in work package 4.
- Data collection and transfer (CRF). Data collection and transfer of forms to the database will be performed in timely manner, ideally on a daily basis. This will be done in work package 6 and monitored by work package 4.
- Report the study outcome: A final report on recruitment at all clinical sites and a final clinical study Report summarising primary and secondary outcomes will be provided. This task requires statistical analysis by the Data Management Unit, compilation of a final trial report and dissemination of results through publications in peer-reviewed medical journals.