M W Konstan1, D R VanDevanter2, S M Rowe3, M Wilschanski4, E Kerem4, I Sermet-Gaudelus5, E DiMango6, P Melotti7, J McIntosh8, K De Boeck9. 1. Rainbow Babies and Children's Hospital, Cleveland, OH 44106 USA; Case Western Reserve University School of Medicine, Cleveland, OH 44106 USA. Electronic address: Michael.konstan@case.edu. 2. Case Western Reserve University School of Medicine, Cleveland, OH 44106 USA. 3. Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35249 USA. 4. Center for Cystic Fibrosis, Hadassah Hebrew University Medical Center, Jerusalem, 91240, Israel. 5. Centre de Ressource et de Competence de la Mucoviscidose, Service de Pediatrie Generale, Service de Pneumologie Pediatrique, Service de Radiologie Pediatrique, Centre d'Investigation Clinique Hôpital Necker - Enfants Malades, 75015 Paris, France. 6. Pulmonary, Allergy, and Critical Care Medicine, Columbia University, Department of Medicine, New York, NY 10032 USA. 7. Centro Fibrosi Cistica, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. 8. PTC Therapeutics, South Plainfield, NJ 07080 USA. 9. Pediatric Pulmonology and Infectious Diseases, University Hospital of Leuven, University of Leuven, Belgium.
Abstract
BACKGROUND: Ataluren was developed for potential treatment of nonsense-mutation cystic fibrosis (CF). A previous phase 3 ataluren study failed to meet its primary efficacy endpoint, but post-hoc analyses suggested that aminoglycosides may have interfered with ataluren's action. Thus, this subsequent trial (NCT02139306) was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation CF not receiving aminoglycosides. METHODS: Eligible subjects with nonsense-mutation CF (aged ≥6 years; percent predicted (pp) FEV1 ≥40 and ≤90) from 75 sites in 16 countries were randomly assigned in double-blinded fashion to receive oral ataluren or matching placebo thrice daily for 48 weeks. The primary endpoint was absolute change in average ppFEV1 from baseline to the average of Weeks 40 and 48. FINDINGS: 279 subjects were enrolled; 138 subjects in the ataluren arm and 136 in the placebo arm were evaluable for efficacy. Absolute ppFEV1 change from baseline did not differ significantly between the ataluren and placebo groups at Week 40 (-0.8 vs -1.8) or Week 48 (-1.7 vs -2.4). Average ppFEV1 treatment difference from baseline to Weeks 40 and 48 was 0.6 (95% CI -1.3, 2.5; p = 0.54). Pulmonary exacerbation rate per 48 weeks was not significantly different (ataluren 0.95 vs placebo 1.13; rate ratio p = 0.40). Safety was similar between groups. No life-threatening adverse events or deaths were reported. INTERPRETATION: Neither ppFEV1 change nor pulmonary exacerbation rate over 48 weeks were statistically different between ataluren and placebo groups. Development of a nonsense-mutation CF therapy remains elusive.
BACKGROUND: Ataluren was developed for potential treatment of nonsense-mutation cystic fibrosis (CF). A previous phase 3 ataluren study failed to meet its primary efficacy endpoint, but post-hoc analyses suggested that aminoglycosides may have interfered with ataluren's action. Thus, this subsequent trial (NCT02139306) was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation CF not receiving aminoglycosides. METHODS: Eligible subjects with nonsense-mutation CF (aged ≥6 years; percent predicted (pp) FEV1 ≥40 and ≤90) from 75 sites in 16 countries were randomly assigned in double-blinded fashion to receive oral ataluren or matching placebo thrice daily for 48 weeks. The primary endpoint was absolute change in average ppFEV1 from baseline to the average of Weeks 40 and 48. FINDINGS: 279 subjects were enrolled; 138 subjects in the ataluren arm and 136 in the placebo arm were evaluable for efficacy. Absolute ppFEV1 change from baseline did not differ significantly between the ataluren and placebo groups at Week 40 (-0.8 vs -1.8) or Week 48 (-1.7 vs -2.4). Average ppFEV1 treatment difference from baseline to Weeks 40 and 48 was 0.6 (95% CI -1.3, 2.5; p = 0.54). Pulmonary exacerbation rate per 48 weeks was not significantly different (ataluren 0.95 vs placebo 1.13; rate ratio p = 0.40). Safety was similar between groups. No life-threatening adverse events or deaths were reported. INTERPRETATION: Neither ppFEV1 change nor pulmonary exacerbation rate over 48 weeks were statistically different between ataluren and placebo groups. Development of a nonsense-mutation CF therapy remains elusive.
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