WS05.05 Randomised withdrawal of hypertonic saline in those with lower lung function after receiving elexacaftor/tezacaftor/ivacaftor; a sub-study of the SIMPLIFY Trial

Objectives: SIMPLIFY tested withdrawal of hypertonic saline (HS) or dornase alfa for 6 weeks in PwCF taking ETI and showed non-inferiority (compared with continuing HS or dornase alfa) in both lung function and respiratory symptom scores. Inclusion in either trial required ppFEV1 ≥60%, and the mean ppFEV1 was 97%. A pre-planned lower lung function (LLF) sub-study was conducted to test HS withdrawal in PwCF with ppFEV1 of 40–59%, hypothesizing that continuing HS is superior to discontinuing HS with respect to 6-week change in ppFEV1. Dornase alfa was not tested in the LLF sub-study. Methods: After interim DSMB safety review of the SIMPLIFY primary study, the LLF sub-study began enrolling participants with ppFEV1 40–59% randomized to continue (n = 11) or discontinue (n = 12) HS for 6 weeks. Results: 23 of 120 planned were enrolled at 18 study sites in the US. Mean age was 32.2 years and mean ppFEV1 was 52.4%. The average 6-week change in ppFEV1 in those discontinuing HS was –0.34%, compared with 1.85% in those continuing HS; difference –2.19 (95% CI –4.89, 0.51). Adverse events, pulmonary exacerbations, and need for antibiotics were infrequent and comparable between groups. Conclusions: In this LLF sub-study, individuals taking ETI with ppFEV1 40–59% randomized to discontinue HS for 6 weeks on average demonstrated little reduction in ppFEV1 or associated adverse events. Those randomized to continue HS were similarly stable and had an average ppFEV1 improvement of 1.85%. The sub-study sample size was small, which limits analyses and interpretation of results. Overall stability in those discontinuing HS was similar to the larger study population, which had mean ppFEV1 of 97%. The small improvement in the LLF group continuing HS may suggest ongoing benefit from daily use in people with lower lung function despite ETI use. Additional research would better inform shared decision making regarding daily treatment regimens in those on ETI with low lung function.