Margaret Rosenfeld1, Steve Cunningham2, William T Harris3, Allen Lapey4, Warren E Regelmann5, Gregory S Sawicki6, Kevin W Southern7, Mark Chilvers8, Mark Higgins9, Simon Tian10, Jon Cooke11, Jane C Davies12. 1. Seattle Children's Hospital, 4800 Sand Point Way NE, Seattle, WA 98105, USA. Electronic address: margaret.rosenfeld@seattlechildrens.org. 2. University of Edinburgh Centre for Inflammation Research and NHS Lothian, Edinburgh, UK. Electronic address: steve.cunningham@nhs.net. 3. University of Alabama at Birmingham, 1720 2nd Avenue S, Birmingham, AL 35294, USA. Electronic address: tharris@peds.uab.edu. 4. Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. Electronic address: alapey@mgh.harvard.edu. 5. University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA. Electronic address: regel001@umn.edu. 6. Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: gregory.sawicki@childrens.harvard.edu. 7. University of Liverpool, Liverpool L69 3BX, UK. Electronic address: k.w.southern@liverpool.ac.uk. 8. British Columbia Children's Hospital, 4480 Oak Street, Vancouver, BC V6H 3N1, Canada. Electronic address: mchilvers@cw.bc.ca. 9. Vertex Pharmaceuticals (Europe) Limited, 2 Kingdom Street, London, W2 6BD, UK. Electronic address: mark_higgins@vrtx.com. 10. Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA. Electronic address: simon_tian@vrtx.com. 11. Formerly of Vertex Pharmaceuticals (Europe) Limited, 2 Kingdom Street, London W2 6BD, UK. 12. National Heart & Lung Institute, Imperial College London & Royal Brompton Hospital, London SW3 6LR, UK. Electronic address: j.c.davies@imperial.ac.uk.
Abstract
BACKGROUND: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS: Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS: All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS: Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.
BACKGROUND: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS:Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS: All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS:Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.
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