title: Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST).
abstract: BACKGROUND
  Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, is approved for the treatment of patients with cystic fibrosis aged 6 years or older with Gly551Asp-CFTR. We assessed the safety and efficacy of ivacaftor during 96 weeks of PERSIST in patients with cystic fibrosis who completed a previous 48-week, placebo-controlled trial of the drug (STRIVE or ENVISION).
  
  
  METHODS
  In this phase 3, open-label extension study, patients received ivacaftor 150 mg every 12 h in addition to their prescribed cystic fibrosis therapies. Patients who received placebo in their previous study initiated ivacaftor in this extension study. Patients were eligible if they had a Gly551Asp-CFTR mutation on at least one allele. The primary objective was to assess the long-term safety profile of ivacaftor as assessed by adverse events, clinical laboratory assessments, electrocardiograms, vital signs, and physical examination; secondary measures included change in forced expiratory volume in one second (FEV1), weight, and pulmonary exacerbations. This study is registered with ClinicalTrials.gov, number NCT01117012 and EudraCT, number 2009-012997-11.
  
  
  RESULTS
  Between July 8, 2010, and April 8, 2013, 144 adolescents/adults (≥12 years) from STRIVE and 48 children (6-11 years) from ENVISION were enrolled. Across both trials, 38 (20%) patients had a serious adverse event during the first 48 weeks and 44 (23%) during the subsequent 48 weeks. Two adults (1%) and one child (<1%) discontinued because of adverse events. The most common adverse events were pulmonary exacerbation, cough, and upper respiratory tract infection. Patients previously treated with ivacaftor had sustained improvements in FEV1, weight, and rate of pulmonary exacerbations for up to 144 weeks of treatment. Among adolescents/adults and children who previously received ivacaftor, absolute change in FEV1 at week 96 (144 weeks ivacaftor) was 9·4 and 10·3 % points and absolute increase in weight was 4·1 kg and 14·8 kg, respectively. For adolescents/adults only, the pulmonary exacerbation rate remained suppressed compared with that of patients who received placebo in the placebo-controlled study.
  
  
  CONCLUSIONS
  At 144 weeks of treatment, ivacaftor was well tolerated, with no new safety concerns. Ivacaftor also provided durable effects for 144 weeks in patients who had received active treatment in the placebo-controlled study. Those patients who previously received placebo had improvements comparable to those of patients treated with ivacaftor in the placebo-controlled study.
  
  
  BACKGROUND
  Vertex Pharmaceuticals Inc.
authors.affiliation: St Vincent's University Hospital, Dublin, Ireland; University College Dublin School of Medicine, Dublin, Ireland. Electronic address: e.mckone@svuh.ie.
authors.forename: Edward F
authors.initials: EF
authors.lastname: McKone
authors.affiliation: State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: Drucy
authors.initials: D
authors.lastname: Borowitz
authors.affiliation: University Hospital Motol and 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Drevinek
authors.affiliation: Hauner Children's Hospital, Munich, Germany; Ludwig Maximillians University, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
authors.affiliation: Case Western Reserve University School of Medicine and Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Konstan
authors.affiliation: Royal Children's Hospital and Queensland Children's Medical Research Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Wainwright
authors.affiliation: Division of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada.
authors.forename: Felix
authors.initials: F
authors.lastname: Ratjen
authors.affiliation: Assistance Publique Hôpitaux de Paris, INSERM U 1151 Université Paris Sorbonne, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sermet-Gaudelus
authors.affiliation: Cork University Hospital, University College Cork, Ireland.
authors.forename: Barry
authors.initials: B
authors.lastname: Plant
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, CF Centre, Université Paris 7, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Munck
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Gilmartin
authors.affiliation: Royal Brompton Hospital, London, UK.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Davies
mesh_terms: D000293:Adolescent; D000328:Adult; D000627:Aminophenols / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D003371:Cough / Q000139:chemically induced*; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D009154:Mutation; D015363:Quinolones / Q000009:adverse effects* / Q000627:therapeutic use; D012141:Respiratory Tract Infections / Q000139:chemically induced*; D013997:Time Factors; D015430:Weight Gain / Q000187:drug effects; D055815:Young Adult
chemical_list: D000627:Aminophenols; C505032:CFTR protein, human; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor