1. Lumacaftor/ivacaftor in people with cystic fibrosis with an A455E–CFTR mutation
- Author
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C. Kors van der Ent, Renske van der Meer, Sylvia F. Boj, Robert G.J. Vries, Harry G.M. Heijerman, Peter van Mourik, Paul K. Audhya, Jamie R Doyle, Jeffrey M. Beekman, Zheng Jason Yuan, N. Kinnman, and Gitte Berkers
- Subjects
Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Adolescent ,Cystic Fibrosis ,Aminopyridines ,Cystic Fibrosis Transmembrane Conductance Regulator ,Quinolones ,Aminophenols ,Placebo ,Cystic fibrosis ,Gastroenterology ,Ivacaftor ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,medicine ,Organoid ,Clinical endpoint ,Humans ,Benzodioxoles ,Cross-Over Studies ,business.industry ,Lumacaftor ,Area under the curve ,Middle Aged ,medicine.disease ,Crossover study ,Drug Combinations ,030104 developmental biology ,030228 respiratory system ,chemistry ,Mutation ,Pediatrics, Perinatology and Child Health ,Female ,sense organs ,business ,medicine.drug - Abstract
Background Previous in vitro organoid data showed A455E–CFTR, a rare CFTR mutation with 4.1% prevalence in the Netherlands, responds to lumacaftor/ivacaftor (LUM/IVA). We explored LUM/IVA's clinical efficacy in people with CF and ≥1 A455E–CFTR mutation. Methods Participants aged ≥12 years were randomized to 1 of 2 treatment sequences (LUM/IVA→placebo or placebo→LUM/IVA) with an 8–week washout period between. Primary endpoint was absolute change in ppFEV1 from study baseline through 8 weeks. Additional endpoints were change in sweat chloride concentration (SwCl) and CFQ–R respiratory domain score. Correlations between organoid–based measurements and clinical endpoints were investigated. Results Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV1 from study baseline through Week 8 showed a treatment difference of 0.1 percentage points (95% CI, –2.5 to 2.7; P = 0.928) between LUM/IVA (within–group mean change, 2.7) and placebo (within–group mean change, 2.6). The mean absolute change in SwCl concentration from study baseline through Week 8 showed a treatment difference of –7.8 mmol/L between LUM/IVA and placebo (P = 0.004), while the absolute change in CFQ–R respiratory domain score showed a treatment difference of 3.5 between LUM/IVA and placebo (P = 0.469). The in vitro organoid–based assay demonstrated a concentration–dependent swelling increase with LUM/IVA. Exploratory correlation analyses between organoid swelling and ppFEV1 and SwCl outcomes showed correlation coefficients of 0.49 and –0.11, respectively. Conclusions In this exploratory study, LUM/IVA elicited an in vitro response in organoid swelling and in vivo response in SwCl in participants with CF and ≥1 A455E–CFTR mutation. The primary endpoint (ppFEV1) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331).
- Published
- 2021