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Abstract
Several placebo-controlled trials have been recently published evaluating novel therapies targeting the defective CFTR protein. This systematic review examines the clinical efficacy and safety of CFTR modulators in individuals with cystic fibrosis (CF) with specific genetic mutations. Online sources were searched for placebo-controlled, parallel-design clinical trials investigating CFTR modulators from January 1, 2005 to March 31, 2018. The primary outcome of interest was FEV1% predicted (ppFEV1). Fourteen RCTs met our eligibility criteria. The largest improvement in ppFEV1 favouring treatment was observed for ivacaftor (IVA) in G551D individuals (≥6 years old). Both tezacaftor-ivacaftor (TEZ-IVA) and lumacaftor-ivacaftor (LUM-IVA) also improved ppFEV1 in F508del homozygous individuals but there was increased reporting of respiratory adverse events with LUM-IVA compared to placebo. IVA also significantly improved ppFEV1 in a sub-group of individuals ≥18 years old with an R117H mutation. No significant improvements in ppFEV1 were observed for IVA, LUM, or TEZ in F508del homozygous individuals, LUM or LUM-IVA in F508del heterozygous individuals, or ataluren in individuals with a nonsense mutation. Significant improvements in ppFEV1 and other clinical outcomes were observed for IVA in G551D individuals, TEV-IVA and LUM-IVA in F508del homozygous individuals, and IVA in adults with a R117H mutation.
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1 The University of Sydney, School of Medicine, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X)
2 University of British Columbia, School of Population and Public Health, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830)
3 University of British Columbia, Division of Respiratory Medicine, Department of Pediatrics, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830)
4 University of Calgary, Division of Respirology, Department of Medicine, Alberta, Canada (GRID:grid.22072.35) (ISNI:0000 0004 1936 7697)
5 University of British Columbia, Centre for Heart Lung Innovation, St. Paul’s Hospital, Department of Medicine, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830)