VO2max as an exercise tolerance endpoint in people with cystic fibrosis: Lessons from a lumacaf tor/ivacaf tor trial

Background: The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied. Methods: We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants >= 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VO2max) during cardiopulmonary exercise testing (CPET) at Week 24. The key secondary endpoint was relative change from baseline in exercise duration during CPET at Week 24. Other secondary endpoints included changes in other indices of exercise tolerance and changes in CF assessments; safety and tolerability were assessed as an endpoint. Results: Seventy participants were randomized to receive lumacaftor/ivacaftor (n = 34) or placebo (n = 36). The least-squares mean difference for lumacaftor/ivacaftor versus placebo in relative change in VO2max from baseline at Week 24 was -3.2% (95% CI: -9.2, 2.9; P=0.3021); the least-squares mean difference in relative change from baseline in exercise duration at Week 24 was -3.2% (95% CI: -8.0, 1.6). Safety results were consistent with the known lumacaftor/ivacaftor safety profile. Conclusions: Definitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results; however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. (C) 2020 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.

Automated summary

This study investigated the impact of lumacaftor/ivacaftor on exercise tolerance in individuals with cystic fibrosis, with results suggesting that definitive conclusions cannot be drawn at this time. However, multicenter studies using CPET show promise for reliable assessments of exercise tolerance in this population.