Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele
Autor: | Middleton, P. G., Mall, M. A., Drevinek, P., Lands, L. C., Mckone, E. F., Polineni, D., Ramsey, B. W., Taylor-Cousar, J. L., Tullis, E., Vermeulen, F., Marigowda, G., Mckee, C. M., Moskowitz, S. M., Nair, N., Savage, J., Simard, C., Tian, S., Waltz, D., Xuan, F., Rowe, S. M., Jain, R., Magazzu, G. |
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Přispěvatelé: | Clinical sciences, Physiotherapy, Human Physiology and Anatomy, Pediatrics |
Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Male
Adolescent Adult Aminophenols Benzodioxoles Child Chloride Channel Agonists Chlorides Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Double-Blind Method Drug Combinations Female Forced Expiratory Volume Genotype Humans Indoles Pyrazoles Pyridines Pyrrolidines Quinolones Sweat Young Adult Mutation 030204 cardiovascular system & hematology medicine.disease_cause Gastroenterology Cystic fibrosis Ivacaftor chemistry.chemical_compound 0302 clinical medicine 030212 general & internal medicine biology Lumacaftor General Medicine Cystic fibrosis transmembrane conductance regulator medicine.drug congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Article 03 medical and health sciences Internal medicine medicine Allele business.industry Potentiator medicine.disease chemistry biology.protein business |
Zdroj: | N Engl J Med |
Popis: | BACKGROUND: 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. METHODS: 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. RESULTS: 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 |
Databáze: | OpenAIRE |
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