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SHR Neuro Cancer Cardio Lipid Metab Microb

Middleton, PG; Mall, MA; Dřevínek, P; Lands, LC; McKone, EF; Polineni, D; Ramsey, BW; Taylor-Cousar, JL; Tullis, E; Vermeulen, F; Marigowda, G; McKee, CM; Moskowitz, SM; Nair, N; Savage, J; Simard, C; Tian, S; Waltz, D; Xuan, F; Rowe, SM; Jain, R; VX17-445-102 Study Group.
Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.
N Engl J Med. 2019; 381(19): 1809-1819. Doi: 10.1056/NEJMoa1908639 [OPEN ACCESS]
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Abstract:: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV₁) at week 4. A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV₁ that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.). Copyright © 2019 Massachusetts Medical Society.
Find related publications in this database (using NLM MeSH Indexing): Adolescent -; Adult -; Aminophenols - administration & dosage; Aminophenols - adverse effects; Benzodioxoles - administration & dosage; Benzodioxoles - adverse effects; Child -; Chloride Channel Agonists - administration & dosage; Chloride Channel Agonists - adverse effects; Chlorides - analysis; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cystic Fibrosis - physiopathology; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Double-Blind Method -; Drug Combinations -; Female -; Forced Expiratory Volume -; Genotype -; Humans -; Indoles - administration & dosage; Indoles - adverse effects; Male -; Mutation -; Pyrazoles - administration & dosage; Pyrazoles - adverse effects; Pyridines - administration & dosage; Pyridines - adverse effects; Pyrrolidines - administration & dosage; Pyrrolidines - adverse effects; Quinolones - administration & dosage; Quinolones - adverse effects; Sweat - chemistry; Young Adult -