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dc.contributor.authorRowe, Steven M.
dc.contributor.authorDaines, Cori
dc.contributor.authorRingshausen, Felix C.
dc.contributor.authorKerem, Eitan
dc.contributor.authorWilson, John
dc.contributor.authorTullis, Elizabeth
dc.contributor.authorNair, Nitin
dc.contributor.authorSimard, Christopher
dc.contributor.authorHan, Linda
dc.contributor.authorIngenito, Edward P.
dc.contributor.authorMcKee, Charlotte
dc.contributor.authorLekstrom-Himes, Julie
dc.contributor.authorDavies, Jane C.
dc.date.accessioned2017-12-21T17:09:44Z
dc.date.available2017-12-21T17:09:44Z
dc.date.issued2017-11-23
dc.identifier.citationTezacaftor–Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis 2017, 377 (21):2024 New England Journal of Medicineen
dc.identifier.issn0028-4793
dc.identifier.issn1533-4406
dc.identifier.doi10.1056/NEJMoa1709847
dc.identifier.urihttp://hdl.handle.net/10150/626280
dc.description.abstractBACKGROUND Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR. METHODS We conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to one of six sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor-ivacaftor, ivacaftor mono-therapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period. RESULTS The number of analyzed intervention periods was 162 for tezacaftor-ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor-ivacaftor and 4.7 percentage points for ivacaftor alone (P<0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor-ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%). CONCLUSIONS CFTR modulator therapy with tezacaftor-ivacaftor or ivacaftor alone was efficacious in patients with cystic fibrosis who were heterozygous for the Phe508del deletion and a CFTR residual-function mutation.
dc.description.sponsorshipVertex Pharmaceuticals; NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust; Imperial College London; Cystic Fibrosis Foundation Therapeutics Development Network; National Institutes of Health [P30DK072482, R35HL135816, U54TR001005]en
dc.language.isoenen
dc.publisherMASSACHUSETTS MEDICAL SOCen
dc.relation.urlhttp://www.nejm.org/doi/10.1056/NEJMoa1709847en
dc.rightsCopyright © 2017 Massachusetts Medical Society.en
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.titleTezacaftor–Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosisen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Arizona Resp Ctren
dc.identifier.journalNew England Journal of Medicineen
dc.description.note6 month embargo; published online: 3 Nov 2017.en
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
refterms.dateFOA2018-05-03T00:00:00Z
html.description.abstractBACKGROUND Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR. METHODS We conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to one of six sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor-ivacaftor, ivacaftor mono-therapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period. RESULTS The number of analyzed intervention periods was 162 for tezacaftor-ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor-ivacaftor and 4.7 percentage points for ivacaftor alone (P<0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor-ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%). CONCLUSIONS CFTR modulator therapy with tezacaftor-ivacaftor or ivacaftor alone was efficacious in patients with cystic fibrosis who were heterozygous for the Phe508del deletion and a CFTR residual-function mutation.


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