Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation

Abstract

Rationale: Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation.

Objectives: This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6-11 years with a G551D-CFTR mutation on at least one allele.

Methods: Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies.

Measurements and main results: Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were evident by 2 weeks, and a significant treatment effect was maintained through Week 48. Patients treated with ivacaftor gained, on average, 2.8 kg more than those receiving placebo at Week 48 (P < 0.001). The change from baseline through Week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor was -53.5 mmol/L (P < 0.001) versus placebo. The incidence of adverse events was similar in the two groups.

Conclusions: In patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo. Clinical trial registered with www.clinicaltrials.gov (NCT00909727).

Figure 1.

Patient disposition.

Figure 2.

Absolute changes from baseline in percent of predicted FEV₁ and Cystic Fibrosis Questionnaire-revised (CFQ-R) respiratory domain scores, and absolute sweat chloride concentrations by study group. (A) Absolute mean change from baseline (± SEM) in percent of predicted FEV₁. (B) Absolute mean change from baseline (± SEM) in the CFQ-R respiratory domain score (child questionnaire version). (C) Sweat chloride concentrations (± SEM) from baseline to Week 48. The orange dashed line indicates 60 mmol/L, the recognized diagnostic cut-off. In A, B, and C, estimates are model-based.

Figure 3.

Changes from baseline in weight, and absolute body mass index (BMI)-for-age z scores by study group. (A) Absolute mean change from baseline (± SEM) in weight. (B) Absolute mean (± SEM) BMI-for-age z scores. Z scores are adjusted for normal growth by age and sex and are presented as the standard deviation from the population mean. In A and B, estimates are model-based.