Abstract
Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6-11 years with cystic fibrosis (CF) and one or more F508del-CFTR alleles. Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial. Methods: In this phase 3, two-part (part A and part B), open-label extension study, children aged ⩾6 years with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received elx 100mg once daily tez 50mg once daily iva 75mg every 12hours whereas children weighing 30kg received elx 200mg once daily tez 100mg once daily iva 150mg every 12hours adult dose. the 96-week analysis of part a of this extension study is reported here. measurements and main results: sixty-four children f mf genotypes n=" 36;" f f genotype n=" 28)" were enrolled and received one or more doses of elx tez iva. mean sd period of exposure to elx tez iva was 93.9 11.1 weeks. the primary endpoint was safety and tolerability. adverse events and serious adverse events were consistent with common manifestations of cf disease. overall exposure-adjusted rates of adverse events andserious adverse events 407.74 and 4.72 events per 100 patient-years were lower than in the parent study 987.04and8.68 events per 100 patient-years. one child 1.6 had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. from parent study baseline at week 96 of this extension study the mean percent predicted fev1 increased 11.295 confidence interval ci 8.3 to 14.2 percentage points sweat chloride concentration decreased -62.3 95 ci -65.9 to -58.8 mmol l cystic fibrosis questionnaire-revised respiratory domain score increased 13.3 95 ci 11.4 to 15.1 points and lung clearance index 2.5 decreased -2.00 95 ci -2.45 to -1.55 units. increases in growth parameters were also observed. the estimated pulmonary exacerbation rate per 48weeks was 0.04. the annualized rate of change in percent predicted fev1 was 0.51 95 ci -0.73 to 1.75 percentage points per year. conclusions: elx tez iva continued to be generally safe and well tolerated in children aged 6years through an additional 96weeks of treatment. improvements in lung function respiratory symptoms and cftr function observed in the parent study were maintained. these results demonstrate the favorable long-term safety profile and durable clinical benefits of elx tez iva in this pediatric population. clinical trial registered with www.clinicaltrials.gov nct04183790.>
