In this study, we focused on the short-term effects of LUM/IVA. Longer-term studies of LUM/IVA are likely required to demonstrate effects on exercise capacity, particularly as exercise limitation in CF is complex and often related to peripheral muscle dysfunction and not ventilatory constraints, except in individuals with more advanced lung disease [
6‐
8]. In support of this, participants who had an increase in their endurance time in our study experienced less leg discomfort but there was no relationship with changes in dyspnea. While an improvement in exercise time during an incremental exercise test was noted in a placebo controlled, cross-over study evaluating IVA in individuals with at least one copy of the G551D mutation treated for a similar period of 28 days, there was no difference in peak work rate or VO
2 [
9]. The clinical importance of a change in cycle time during an incremental exercise protocol with no change in peak work rate or VO
2 is unclear. This study differed in design as we used a constant work rate protocol, which is considered to be a more sensitive and clinically relevant way of assessing exercise performance compared to incremental exercise protocols [
10]. Nevertheless, the lack of change in peak VO
2 in the setting of relatively large improvements in ppFEV
1 in this previous study supports the notion that ventilatory limitation is likely not the sole driver of exercise limitation in CF. Therefore, other factors such as muscle dysfunction and deconditioning likely play more important roles. We did not evaluate muscle function in this study but there was no significant difference in self-reported physical activity levels based on the IPAQ-LF between baseline and 1-month post LUM/IVA initiation. In a longer-term study by Savi et al. evaluating the effects of LUM/IVA in 3 adults treated for at least 2 years, there was an increase in physical activity measurements and oxygen uptake values at anaerobic threshold and peak exercise on symptom-limited incremental exercise testing [
11]. The precise physiological mechanisms underlying these improvements with LUM/IVA requires further investigation.
There are some limitations to this study that should be acknowledged. Firstly, recruitment was less than anticipated due to lack of public reimbursement for LUM/IVA. Secondly, this study was not placebo-controlled and therefore we cannot exclude a placebo effect for participants who reported less leg discomfort with exercise following initiation of LUM/IVA. Thirdly, physical exercise and performance of physiotherapy prior to and during the study were not controlled for and could have influenced exercise performance. While we did not capture details on physiotherapy before and after introduction of LUM/IVA, we did not observe a difference in physical activity levels. Finally, to reduce the burden related to frequent study visits, we did not include a familiarization visit for our constant work rate exercise test. While a learning effect could have contributed, at least in part, to the improvement in endurance time for some individuals, a learning effect was not observed in a prior study involving CF patients following repeated cycle ergometer exercise testing [
12].
In conclusion, 1 month of LUM/IVA did not lead to an overall increase in endurance time or modify exertional dyspnea or leg discomfort ratings. However, there was a trend toward less leg discomfort at submaximal exercise, which correlated with increased endurance time. Given the importance of peripheral muscle dysfunction on exercise limitation in CF, the direct or indirect effects of CFTR modulators on muscle function should be evaluated in future studies.