Rosenfeld M, et al. - Researchers assessed ivacaftor treatment in children aged 12 to <24 months who have cystic fibrosis and specific CFTR mutations. Children aged 12 to <24 months generally safely well-tolerated ivacaftor for up to 24 weeks. It was associated with rapid and sustained reductions in sweat chloride concentrations. It led to improvements in biomarkers of pancreatic function suggesting its role in the preservation of exocrine pancreatic function if started early. In infants younger than 12 months, the study is continuing.

Methods

• A phase 3, single-arm, two-part, multicentre study (the ARRIVAL study) was performed.
• Children (aged 12 to <24 months) with confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele could participate in one or both parts of the study.
• Every 12 h, researchers administered 50 mg (bodyweight 7 to <14 kg) or 75 mg (bodyweight ≥14 to <25 kg) ivacaftor orally to the children.
• In study part A, ivacaftor was given for 3 days plus one morning to the children.
• In study part B, 24 weeks of treatment was provided to the children.
• They enrolled children into part A at seven sites in Australia (one site), the UK (one), and the USA (five) and into part B at 13 sites in Australia (two sites), Canada (one), the UK (three), and the USA (seven).
• Pharmacokinetics (part A) and safety (parts A and B) in children who received at least one dose of ivacaftor were included as primary endpoints.
• In part B, pharmacokinetics in children who received at least one dose of ivacaftor and absolute change from baseline in sweat chloride concentration were assessed as secondary endpoints.

Results

• From Aug 25, 2016 to Nov 1, 2017, researchers enrolled children aged 12 to <24 months.
• In part A, 7 children were enrolled; five, of these, received 50 mg and two received 75 mg ivacaftor.
• Treatment was completed by all.
• In this work, 50 mg ivacaftor was administered to 19 children enrolled in part B; these children included one child from part A.
• Of these, 18 completed treatment (one withdrew because of difficulty with blood draws).
• At least one dose of ivacaftor was taken by all children.
• Children aged 2 to <6 years and adults demostrated similar exposure as per pharmacokinetic analysis.
• Because of adverse events or safety findings, no children discontinued.
• Treatment-emergent adverse events were noted in three (43%) of seven children in part A; all of which were mild and deemed not to be or unlikely to be related to ivacaftor.
• Treatment-emergent adverse events had been reported in 18 (95%) of 19 children by 24 weeks in part B; of which most were mild or moderate and the most frequent was cough (14 [74%] children).
• Four serious adverse events were noted in 2 children in part B: one had constipation (possibly related to ivacaftor), distal intestinal obstruction syndrome, and eczema herpeticum, and one had persistent cough, all needing hospital admission.
• In five (28%) of 18 children, aspartate or alanine aminotransferase concentrations rose to more than three times the upper limit of normal (to more than eight times in two children with concurrent infections).
• Findings revealed the mean absolute change from baseline in sweat chloride concentration at week 24 of -73·5 (SD 17·5) mmol/L.
• At baseline and at week 24, growth parameters for age were normal.
• From baseline, increase in concentrations of faecal elastase-1 and decrease in concentrations of immunoreactive trypsinogen were noted at week 24.
• Raised mean serum lipase and amylase were noted at baseline; after initiation of treatment these rapidly decreased.