title: Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del-CFTR.
abstract: BACKGROUND
  In a prior study, lumacaftor/ivacaftor treatment (≤28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function.
  
  
  OBJECTIVE
  To evaluate an optimized lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR.
  
  
  METHODS
  Patients aged 18 years or older with a confirmed CF diagnosis and percent predicted FEV1(ppFEV1) of 40 to 90 were randomized to lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Primary outcomes were change in ppFEV1at Day 56 and safety. Other disease markers were evaluated.
  
  
  RESULTS
  Of 126 patients, 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs. 14.3% and 14.5% vs. 6.3%, respectively). Mean (SD) ppFEV1values at baseline were 62.9 (14.3) in the active treatment group and 60.1 (14.0) in the placebo group. Absolute changes in ppFEV1(least squares mean [SE]) at Day 56 were -0.6 (0.8) percentage points in the active treatment group and -1.2 (0.8) percentage points in the placebo group (P = 0.60). CF respiratory symptom scores in the active treatment group improved by a mean of 5.7 points versus a decrease of -0.8 in the placebo group (P < 0.01). No changes in body mass index occurred. Changes from baseline in sweat chloride (least squares mean [SE]) at Day 56 were -11.8 (1.3) mmol/L in the active treatment group and -0.8 (1.2) mmol/L in the placebo group (P < 0.0001).
  
  
  CONCLUSIONS
  Sweat chloride and respiratory symptom scores improved with lumacaftor/ivacaftor, though no meaningful benefit was seen in ppFEV1or body mass index in patients heterozygous for F508del-CFTR. Clinical trial registered with www.clinicaltrials.gov (NCT01225211).
authors.affiliation: 1 Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Steven M
authors.identifier: http://orcid.org/0000-0001-9045-0133
authors.initials: SM
authors.lastname: Rowe
authors.affiliation: 2 Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Susanna A
authors.initials: SA
authors.lastname: McColley
authors.affiliation: 3 Faculty of Medicine, Children's Hospital, University of Cologne, Cologne, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Rietschel
authors.affiliation: 4 Vertex Pharmaceuticals Incorporated, Boston, Massachusetts.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Li
authors.affiliation: 5 The Prince Charles Hospital and QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Bell
authors.affiliation: 6 Case Western Reserve University School of Medicine and Rainbow Babies and Children's Hospital, Cleveland, Ohio; and.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Konstan
authors.affiliation: 4 Vertex Pharmaceuticals Incorporated, Boston, Massachusetts.
authors.forename: Gautham
authors.initials: G
authors.lastname: Marigowda
authors.affiliation: 4 Vertex Pharmaceuticals Incorporated, Boston, Massachusetts.
authors.forename: David
authors.identifier: http://orcid.org/0000-0003-4132-6018
authors.initials: D
authors.lastname: Waltz
authors.affiliation: 7 Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Boyle
mesh_terms: D000293:Adolescent; D000328:Adult; D000627:Aminophenols / Q000009:adverse effects / Q000627:therapeutic use*; D000631:Aminopyridines / Q000009:adverse effects / Q000627:therapeutic use*; D001315:Australia; D052117:Benzodioxoles / Q000009:adverse effects / Q000627:therapeutic use*; D015992:Body Mass Index; D002712:Chlorides / Q000032:analysis*; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015363:Quinolones / Q000009:adverse effects / Q000627:therapeutic use*; D013542:Sweat / Q000737:chemistry*; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D000627:Aminophenols; D000631:Aminopyridines; D052117:Benzodioxoles; C505032:CFTR protein, human; D002712:Chlorides; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor; C569105:lumacaftor
keywords: adverse events; percent predicted forced expiratory volume in 1 second; sweat chloride