Title: Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 study

Ratjen, F. et al.


What You Need to Know:

In patients with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR), treatment with lumacaftor and ivacaftor significantly improved lung function compared to placebo.

Trial Design:

  • Double-blind, placebo-controlled, multicenter, phase 3 study evaluated the safety and efficacy of treatment with lumacaftor plus ivacaftor in cystic fibrosis patients homozygous for F508del-CFTR
  • Inclusion criteria: 6-11 years old, ≥15 kg, predicted forced expiratory volume in 1s (FEV1) ≥70%, lung clearance index2.5 (LCl2.5) ≥7.5 at screening, F508del-CFTR mutation on both alleles
  • Patients were randomized (1:1) to receive 200mg lumacaftor + 250mg ivacaftor administered every 12 hours or placebo over 24 weeks
  • Primary endpoint: mean absolute change in LCl2.5 during treatment
  • Secondary endpoints: “average absolute change in sweat chloride concentration from baseline at day 15 and week 4, absolute change in BMI [body mass index] from baseline at week 24, and average absolute change in CFQ-R [Cystic Fibrosis Questionnaire-Revised] respiratory domain score from baseline study visit up to and including week 24”

Key Outcomes:

  • 103 patients received ≥1 dose of lumacaftor, 101 patients received ≥1 dose of ivacaftor
  • Least squares mean difference of -1.09 units (95% CI: -1.43, -0.75; P<0.0001) for lumacaftor + ivacaftor vs placebo when assessing the average absolute change in LCl2.5 (primary endpoint)
  • Least squares mean difference when comparing lumacaftor + ivacaftor vs placebo for sweat chloride concentration assessment was -20.8 mmol/L (95% CI: -23.4, -18.2; average absolute change at day 15/week 4; P<0.0001) and 2.4 (95% CI: 0.4, 4.4; P=0.0182) for the absolute change in percent predicted FEV1 assessment
  • 96% of patients (196/204) reported experiencing an adverse event (severity: 42% mild, 48% moderate)
  • 3% of patients receiving lumacaftor + ivacaftor discontinued treatment due to adverse events vs 2% of placebo patients
  • 13% of lumacaftor + ivacaftor patients reported experiencing a serious adverse event vs 11% of placebo patients