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Safety, tolerability of combination therapy sustained in children with cystic fibrosis

Combination therapy with lumacaftor/ivacaftor was safe and well tolerated for up to 120 weeks in children aged 6 to 11 years with the F508del-CFTR mutation for cystic fibrosis, according to results of an open-label, extension study.

“The safety of lumacaftor-ivacaftor therapy over longer than 24 weeks has not been explored previously in children with cystic fibrosis homozygous for the F508del-CFTR mutation who began treatment between ages 6 and 11 years,” Mark A. Chilvers, MD, investigator at BC Children’s Hospital Research Institute and clinical associate professor, division of respiratory medicine, department of pediatrics at the University of British Columbia in Vancouver, Canada, and colleagues wrote in The Lancet Respiratory Medicine.

Healio previously reported data from 24 weeks in this population.

The phase 3, open-label, multicenter extension study was conducted at 61 clinics worldwide and included 239 children with cystic fibrosis homozygous for the F508del-CFTR mutation who were pooled from three parent studies. Those who received lumacaftor/ivacaftor (Orkambi, Vertex Pharmaceuticals) or placebo in the parent studies were administered lumacaftor/ivacaftor for up to 96 weeks (n = 143; mean age, 8.9 years; 42% boys). Those who received combination therapy in the parent studies received up to 120 weeks of lumacaftor/ivacaftor (n = 96; mean age, 9 years; 42% boys). Participants aged 6 to 11 years at baseline of the parent study received lumacaftor (200 mg) and ivacaftor (250 mg) orally once every 12 hours; those aged 12 years and older received lumacaftor (400 mg) and ivacaftor (250 mg) orally once every 12 hours.

The primary outcome was safety and tolerability of combination therapy in children receiving at least one dose of the study drug. Secondary outcomes included change from baseline lung clearance index, sweat chloride concentration, BMI and Cystic Fibrosis Questionnaire-Revised respiratory domain score.

Ninety percent of children enrolled in the study completed 96 weeks of lumacaftor/ivacaftor treatment. Adverse events were observed in 99% of children; 21% had mild events and 62% had moderate events. Overall, there was a low rate of adverse events that led to treatment discontinuation. Cough (65%) and pulmonary exacerbation (49%) were the most common adverse events reported. Other adverse events observed were consistent with the currently known safety profile of lumacaftor/ivacaftor combination therapy in older children and adults, according to the researchers. No new safety concerns emerged in the long term.

The researchers also reported improvements in the least squares mean absolute change in lung function among children in the placebo-to-treatment group (–0.86; 95% CI, –1.33 to –0.38) and treatment-to-treatment group (–0.85; 95% CI, –1.25 to –0.45) that were consistent with improvements observed in the parent studies. These improvements were generally maintained throughout the extension study, according to the researchers.

“The results showed that lumacaftor/ivacaftor treatment was well tolerated for up to 12 weeks and led to multisystem clinical benefits,” the researchers wrote. “These data support the long-term use of lumacaftor-ivacaftor in treating the underlying cause of cystic fibrosis in children aged 6 years or older homozygous for the F508del-CFTR mutation.”


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