Ivacaftor in People with Cystic Fibrosis and a → or Residual Function Mutation.

Ivacaftor's clinical effects in the residual function mutations and warrant further characterization. To evaluate ivacaftor's effect in people with cystic fibrosis aged ≥6 years with or residual function mutations and to explore the correlation between ivacaftor-induced organoid-based cystic fibrosis transmembrane conductance regulator function measurements and clinical response to ivacaftor. Participants were randomized (1:1) in this placebo-controlled crossover study; each treatment sequence included two 8-week treatments with an 8-week washout period. The primary endpoint was absolute change in lung clearance index from baseline through Week 8. Additional endpoints included lung function, patient-reported outcomes, and intestinal organoid-based measurements of ivacaftor-induced cystic fibrosis transmembrane conductance regulator function. Of 38 participants, 37 completed the study. The primary endpoint was met; the Bayesian posterior probability of improvement in lung clearance index with ivacaftor versus placebo was >99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor's known safety profile. Dose-dependent swelling was observed in 23 of 25 viable organoid cultures with ivacaftor treatment. Correlations between ivacaftor-induced organoid swelling and clinical endpoints were negligible to low. In people with cystic fibrosis aged ≥6 years with a or mutation, ivacaftor treatment improved clinical endpoints compared with placebo; however, there was no correlation between organoid swelling and change in clinical endpoints. The organoid assay may assist in identification of ivacaftor-responsive mutations but in this study did not predict magnitude of clinical benefit for individual people with cystic fibrosis with these two mutations.Clinical trial registered with ClinicalTrials.gov (NCT03068312).