• Citer

Ataluren for the treatment of nonsense-mutation cystic fibrosis: A randomised, double-blind, placebo-controlled phase 3 trial

par Kerem, Eitan;Wilschanski, Michael;Konstan, Michael M.W.;Deboeck, Kris;Accurso, Frank F.J.;Sermet-Gaudelus, Isabelle;Elborn, Stuart J.S.;Melotti, Paola;Bronsveld, Inez;Fajac, Isabelle;Malfroot, Anne;Rosenbluth, Daniel D.B.;Walker, Patricia P.A.;McColley, Susanna S.A.;Knoop, Christiane ;Quattrucci, Serena;Rietschel, Ernst;Zeitlin, Pamela P.L.;Barth, Jay;Elfring, Gary G.L.;Welch, Ellen E.M.;Branstrom, Arthur;Spiegel, Robert R.J.;Peltz, Stuart S.W.;Ajayi, Temitayo;Rowe, Steven S.M.
Référence The Lancet Respiratory Medicine, 2, 7, page (539-547)
Publication Publié, 2014

Article révisé par les pairs

• Accès en ligne
• Détails
• Contenu
• Statistiques

Résumé :

Background: Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis. Methods: This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s [FEV1] ≥40% and ≤90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV1. The primary endpoint was relative change in percent-predicted FEV1 from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205. Findings: Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV1 did not differ significantly between ataluren and placebo at week 48 (-2·5% vs -5·5%; difference 3·0% [95% CI -0·8 to 6·3]; p=0·12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0·77 [95% CI 0·57-1·05]; p=0·0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5·7% difference (95% CI 1·5-10·1) in relative change from baseline in percent-predicted FEV1 between the ataluren and placebo groups at week 48 (-0·7% [-4·0 to 2·1] vs -6·4% [-9·8 to -3·7]; nominal p=0·0082), and fewer pulmonary exacerbations in the ataluern group (1·42 events [0·9-1·9] vs 2·18 events [1·6-2·7]; rate ratio 0·60 [0·42-0·86]; nominal p=0·0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group. Interpretation: Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin. Funding: PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health. © 2014 Elsevier Ltd.