Ivacaftor in Infants Aged 4 to <12 Months with Cystic Fibrosis and a Gating Mutation. Results of a Two-Part Phase 3 Clinical Trial

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months. Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations. Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B. Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event (n = 10 [58.8%]). Five infants (part A, n = 1 [8.3%]; part B, n = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved. Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations. Clinical trial registered with clinicaltrials.gov (NCT02725567).