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Rationale: In a prior study, lumacaftor/ivacaftor treatment (≤28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function.Objectives: To evaluate an optimized lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR.Methods: Patients aged 18 years or older with a confirmed CF diagnosis and percent predicted FEV1 (ppFEV1) of 40 to 90 were randomized to lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Primary outcomes were change in ppFEV1 at Day 56 and safety. Other disease markers were evaluated.Measurements and Main Results: Of 126 patients, 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs. 14.3% and 14.5% vs. 6.3%, respectively). Mean (SD) ppFEV1 values at baseline were 62.9 (14.3) in the active treatment group and 60.1 (14.0) in the placebo group. Absolute changes in ppFEV1 (least squares mean [SE]) at Day 56 were -0.6 (0.8) percentage points in the active treatment group and -1.2 (0.8) percentage points in the placebo group (P = 0.60). CF respiratory symptom scores in the active treatment group improved by a mean of 5.7 points versus a decrease of -0.8 in the placebo group (P < 0.01). No changes in body mass index occurred. Changes from baseline in sweat chloride (least squares mean [SE]) at Day 56 were -11.8 (1.3) mmol/L in the active treatment group and -0.8 (1.2) mmol/L in the placebo group (P < 0.0001).Conclusions: Sweat chloride and respiratory symptom scores improved with lumacaftor/ivacaftor, though no meaningful benefit was seen in ppFEV1 or body mass index in patients heterozygous for F508del-CFTR. Clinical trial registered with www.clinicaltrials.gov (NCT01225211). [ABSTRACT FROM AUTHOR]

Background: The cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, ivacaftor, was first approved for people with CF and the G551D CFTR mutation. This study describes the long-term clinical effectiveness of ivacaftor in this population., Methods: We conducted a multicenter, prospective, longitudinal, observational study of people with CF ages ≥6 years with at least one copy of the G551D CFTR mutation. Measurements of lung function, growth, quality of life, and sweat chloride were performed after ivacaftor initiation (baseline, 1 month, 3 months, 6 months, and annually thereafter until 5.5 years)., Results: Ninety-six participants were enrolled, with 81% completing all study measures through 5.5 years. This cohort experienced significant improvements in percent predicted forced expiratory volume in 1 second (ppFEV1) of 4.8 [2.6, 7.1] (p < 0.001) at 1.5 years, that diminished to 0.8 [-2.0, 3.6] (p = 0.57) at 5.5 years. Adults experienced larger improvements in ppFEV1 (7.4 [3.6, 11.3], p < 0.001 at 1.5 years and 4.3 [0.6, 8.1], p = 0.02 at 5.5 years) than children (2.8 [0.1, 5.6], p = 0.04 at 1.5 years and -2.0 [-5.9, 2.0], p = 0.32 at 5.5 years). Rate of lung function decline for the overall study cohort from 1 month after ivacaftor initiation through 5.5 years was estimated to be -1.22 pp/year [-1.70, -0.73]. Significant improvements in growth, quality of life measures, sweat chloride, Pseudomonas aeruginosa detection, and pulmonary exacerbation rates requiring antimicrobial therapy persisted through five years of therapy., Conclusions: These findings demonstrate the long-term benefits and disease modifying effects of ivacaftor in children and adults with CF and the G551D mutation., Competing Interests: Declaration of Competing Interest SMR and MJ serve as investigators and/or consultants on the design and conduct of CF clinical trials to Vertex Pharmaceuticals, the manufacturer of ivacaftor. A.P. declares a previous (within 36 months) equity interest in AbbVie, Inc. All other authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Rationale: The association between CFTR genotype, sweat chloride and mortality has been inconsistent, but no previous analyses have examined the association stratified by individual genotypes., Objectives: To evaluate the genotype-specific association between sweat chloride and mortality., Methods: The CFF Patient Registry was assessed and included all patients in the registry between 1996 and 2012 with at least one F508del allele. We excluded patients without a documented genotype or plausible sweat chloride level. The primary outcome was time to mortality during the observation period. We examined 15 genotypes using the three most prevalent alleles in each of 5 classes. We compared subgroups of sweat chloride using Kaplan-Meier curves, log-rank tests, and multivariable Cox PH models. The overall predictive value of sweat chloride on mortality was assessed using area under the receiver operating characteristic curves., Measurements and Main Results: 18,893 subjects met inclusion criteria. Sweat chloride distribution was similar across genotypes in patients with class 1 mutations, but was significantly different across genotypes in mutation classes 2-5. The R117H/F508del genotype patients demonstrated an association between sweat chloride and mortality (HR: 1.32 for every 10mmol/L increase in sweat chloride [95% CI 1.12-1.54]. There were also significant associations in patients with F508del/F508del, I507del/F508del, G551D/F508del and 2789+5G→A/F508del genotypes, though the clinical relevance for these genotypes is unclear., Conclusions: There is significant variability in sweat chloride distribution across CFTR class 2-5 genotypes. The relationship between sweat chloride and mortality varies by genotype with a relatively strong relationship in R117H/F508del patients., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)