Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR.
Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del-CFTR, but it has not been assessed in younger patients.



In this open-label phase III trial, we evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis who were homozygous for F508del-CFTR.



Patients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications.



Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug-related adverse events: elevated liver transaminases, n = 1; rash, n = 1). No safety concerns were associated with spirometry. No significant changes in percent predicted FEV1were observed (change from baseline at Week 24, +2.5 percentage points; 95% confidence interval [CI], -0.2 to 5.2; P = 0.0671). At Week 24, significant improvements from baseline were observed in sweat chloride (-24.8 mmol/L; 95% CI, -29.1 to -20.5; P < 0.0001), body mass index z score (+0.15; 95% CI, 0.08 to 0.22; P < 0.0001), Cystic Fibrosis Questionnaire-Revised respiratory domain score (+5.4; 95% CI, 1.4 to 9.4; P = 0.0085), and lung clearance index based on lung volume turnover required to reach 2.5% of starting N2concentration (-0.88; 95% CI, -1.40 to -0.37; P = 0.0018).



Lumacaftor/ivacaftor was well tolerated in this young population; no new safety concerns were identified. Improvements in lung clearance index, sweat chloride, nutritional status, and health-related quality of life were observed after 24 weeks of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT01897233).
1 Department of Pediatrics, Stanford University, Palo Alto, California.
Carlos E
CE
Milla
2 Pediatric Respiratory Medicine, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Felix
F
Ratjen
3 Vertex Pharmaceuticals Incorporated, Boston, Massachusetts.
Gautham
G
Marigowda
3 Vertex Pharmaceuticals Incorporated, Boston, Massachusetts.
Fang
F
Liu
3 Vertex Pharmaceuticals Incorporated, Boston, Massachusetts.
David
D
Waltz
4 Pulmonary and Sleep Medicine, Seattle Children's Hospital, Seattle, Washington; and.|5 Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.
Margaret
M
Rosenfeld
D000627:Aminophenols / Q000627:therapeutic use*; D000631:Aminopyridines / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000627:therapeutic use*; D002648:Child; D003550:Cystic Fibrosis / Q000188:drug therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004359:Drug Therapy, Combination; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D015363:Quinolones / Q000627:therapeutic use*; D016896:Treatment Outcome
D000627:Aminophenols; D000631:Aminopyridines; D052117:Benzodioxoles; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor; C569105:lumacaftor
cystic fibrosis transmembrane conductance regulator protein; ivacaftor; lumacaftor; lung clearance index; sweat test