Ethicare (Germany)

Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric patients with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) in five participating European countries. Children were treated for 8 weeks with ODMTs according to an age-appropriate dosing schedule. The primary objective was to describe PK parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (t-max)) of enalapril and its active metabolite enalaprilat. Of 102 patients, 89 patients (n = 26, DCM; n = 63 CHD) were included in the primary PK endpoint analysis. Rate and extent of enalapril and its active metabolite enalaprilat were described and etiology and age could be identified as potential PK modifying factors. The dosing schedule appeared to be tolerated well and did not result in any significant drug-related serious adverse events. The PK analysis and the lack of severe safety events supports the applied age-appropriate dosing schedule for the enalapril ODMTs.

BackgroundRecurrent Aphthous stomatitis (RAS) is a prevalent ulcerative and painful disorder of the oral cavity with unknown etiology and for which no efficient treatment is currently available.The present study aimed to evaluate the safety and the efficacy of AphtoFix®, a new mouth ulcer cream that was developed to help treat RAS. Prior to launching the product on the market, two initial safety assessment studies were performed.Subjects and methodsIn a first study, the in vitro biocompatibility of AphtoFix® was evaluated on reconstructed human gingival tissue models according to ISO guidelines 10993. In a second study, the tolerability of AphtoFix® was evaluated in 20 subjects during a 4-weeks daily application in the mouth. The third study investigated both the safety and efficacy of AphtoFix® treatment on 19 patients suffering from RAS. This study was done in compliance with the Helsinki Declaration.ResultsThe results of in vitro biocompatibility study showed that AphtoFix® mouth ulcer cream did not induce any detectable cytotoxicity and irritation. These observations were confirmed in the 4 weeks tolerability study where no undesired of adverse reactions were noticed. The results of the post-market clinical efficacy study demonstrated a clear reduction in ulcer size from baseline after 3 days treatment (p < 0.05). Pain intensity reduction was also observed in all subjects.ConclusionThe application of AphtoFix® did not induce any undesired skin or mucosa reactions. These initial findings demonstrate that AphtoFix® is safe and efficient in reducing ulcer size and decreasing the pain intensity induced by ulcers.Trial registrationClinical trial Registry India Nr. CTRI201408004918, Date of registration: 22/08/2014Electronic supplementary materialThe online version of this article (doi:10.1186/s12903-016-0177-0) contains supplementary material, which is available to authorized users.

BackgroundThe LENA (Labeling of Enalapril from Neonates up to Adolescents) project has been initiated to improve the healthcare of children with heart failure by an enalapril orodispersible mini-tablet. The LENA consortium combines academic clinical research centers, SMEs (small and medium-sized enterprises) and a patient/parent advocacy organization. The objective of the project requires to comply with respective GxP regulations like Good Manufacturing Practice (GMP), Good Clinical (Laboratory) Practice (GCP/“GCLP”1) and Good Vigilance Practice (GVP). The project team is comprised of sub-teams experienced in paediatric clinical practice, medicines development, clinical research and project management, but not all team members work in an appropriate quality framework. Aim: To establish a well-documented, efficient quality system applying a new approach for ensuring quality in all trial aspects by combining existing organization-related quality system elements of the project partners with newly developed SOPs and overarching, integrating trial-specific elements to ensure a reliable quality environment for the LENA Phase I clinical trial.MethodsBased on the network-structure of the project organization, a strategy based on a team approach with joint responsibilities for the quality conduct of the project was pursuit, forming a QM Team consisting of the project leader, the leaders for pharmaceutical and clinical development and an external quality expert. The team compiled a quality manual and an organizational chart displaying the sub-teams and their responsibilities. Another responsibility of the team is the integration of existing SOPs and Work Instructions as well as the creation of procedures at the project level and furthermore the verification of appropriate qualification of all staff involved in the project through CVs, job descriptions and training records.ResultsFor the Phase I study, a thorough analysis of all existing relevant SOPs and Work Instructions, forms and other quality elements was performed, uncovered trial-related processes were identified and a work plan was established to fill the gaps with the smallest possible number of newly developed organization-related SOPs/Work Instructions and by preparing trial-specific process manuals. Demonstration of the trial team members was ensured by completing documentation concerning CVs, job description and training records. Among the sub-teams, the GCLP environment of the bioanalytical laboratory was started from scratch and could adequately support the LENA Phase I study by “GCLP” quality work and sample logistics.ConclusionThe consortiums approach enabled the preparation of a comprehensive, reliable GxP compliant quality system within a short timeframe and with the limited resources of a publicly funded project.1 “GCLP” is used as acronym for a quality system established in compliance with “Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples” (EMA/INS/GCP/532137/2010; 28 February 2012)The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).