Pulmonary endpoints in clinical trials for children with cystic fibrosis under two years of age.

Cystic fibrosis is a lifelong progressive disease in which lung disease is the main prognostic factor, where starting early treatment is crucial for improving long-term outcomes. Therefore, new treatment should be available as early as possible. However, choosing appropriate and feasible clinical trial endpoints in children under 2 years of age presents significant challenges. Most studies in this age group have extrapolated pulmonary efficacy from older age groups, focusing on safety, pharmacokinetics, and biomarker response. As lung health is near normal in infants, demonstrating absence of pulmonary decline requires large sample sizes and extended study duration, which may not be feasible for standard regulatory trials. To address this gap, the European Cystic Fibrosis Society Clinical Trials Network developed a consensus document evaluating direct pulmonary endpoints for therapeutic pulmonary studies in this young age group. The pulmonary endpoints evaluated include multiple-breath washout (MBW); chest computed tomography (CT); chest magnetic resonance imaging (MRI); airway infection and inflammation. Relevant literature, pitfalls, practice guidelines, and recommendations are presented. None of the pulmonary endpoints evaluated are currently suitable to serve as a primary efficacy endpoint in children below 2 years of age, as this will require large numbers and long follow-up. For clinical trials in infants with CF, pharmacokinetics, pharmacodynamics, safety and tolerability should remain the primary endpoints, with pulmonary endpoints as secondary or exploratory outcomes. Post authorization studies are essential to evaluate long-term pulmonary benefits, including MBW, structural lung assessment (e.g. CT and MRI), and markers of pulmonary inflammation to fully understand the impact of early therapy initiation in this young population.