Some patients with cystic fibrosis may be able to stop mucoactive therapies

Discontinuing hypertonic saline or dornase alfa for 6 weeks did not appear to have a negative effect on pulmonary function among patients with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor, according to study results.

“Clinicians and people with cystic fibrosis (CF) should work together to make individualized decisions with available evidence from SIMPLIFY and forthcoming studies regarding the continuance of chronic hypertonic saline or dornase alfa in the setting of elexacaftor/tezacaftor/ivacaftor [ETI; Trikafta, Vertex Pharmaceuticals] use,” Nicole Mayer-Hamblett, PhD, professor of pediatrics in the division of pulmonary and sleep medicine at the University of Washington School of Medicine and co-executive director of the Cystic Fibrosis Therapeutics Development Network Coordinating Center, and colleagues wrote. “It is reasonable to hypothesize that people with cystic fibrosis on potent modulator drug therapy might still benefit from inhaled dornase alfa and hypertonic saline when having increased respiratory symptoms or as part of a regimen to address acute pulmonary exacerbations.”

In SIMPLIFY, two parallel, multicenter, open-label, randomized, controlled, non-inferiority trials published in The Lancet Respiratory Medicine, Mayer-Hamblett and colleagues evaluated 594 patients with CF on the CF transmembrane conductance (CFTR) modulator ETI from Aug. 25, 2020, to May 25, 2022, to determine if there was a clinically meaningful difference between discontinuing and continuing nebulized hypertonic saline or dornase alfa (Pulmozyme, Genentech) therapies in an effort to reduce the treatment burden for this patient population.

All patients had a percent predicted FEV₁ (ppFEV₁) of 70% or more (for age 12-17 years) or a ppFEV₁ of 60% or more (for age 18 years).

Given that some patients were receiving both mucoactive therapies, SIMPLIFY included 847 total random assignments, with 370 patients assigned to the hypertonic saline trial and 477 to the dornase alfa trial. In each trial, researchers then randomly assigned patients 1:1 to either continue their therapy (taken at least once daily) or discontinue their therapy for 6 weeks.

Change in ppFEV₁ over the study period in the per-protocol group (n = 273 in hypertonic saline trial; n = 392 in dornase alfa trial) served as the study’s primary endpoint, with a noninferiority margin set at –3%.

Average ppFEV₁ at baseline was 96.9% across groups.

Based on absolute 6-week ppFEV₁ changes, both trials demonstrated that discontinuing treatment was noninferior to continuing treatment.

Specifically, in the hypertonic saline trial, there was a –0.32% (95% CI, 1.25 to 0.6) between-group difference between those who discontinued treatment (n = 133; change in ppFEV₁ = –0.19%; 95% CI, –0.85 to 0.48) and those who continued treatment (n = 140; change in ppFEV₁ = 0.14%; 95% CI, –0.51 to 0.78).

Similarly, there was a 0.35% (95% CI, –0.45 to 1.14) between-group difference in the dornase alfa trial between discontinuation of treatment (n = 199; change in ppFEV₁ = 0.18%, 95% CI, –0.38 to 0.74) and continuation of treatment (n = 193; change in ppFEV₁ = –0.16%, 95% CI, –0.73 to 0.41).

These findings persisted in the intention-to-treat population and across patient subgroups.

Discontinuing these therapies also did not result in meaningful changes in lung clearance index at 2.5% of the starting gas concentration in a subcohort of patients, results showed.

Further, researchers found that a greater percentage of patients who discontinued therapy experienced at least one adverse event in the hypertonic saline group (34.8% vs. 23.7%) and the dornase alfa group (37.1% vs. 23.2%) compared with continuing the respective therapies. Researchers noted that most of these were respiratory adverse events.

Lastly, researchers noted that patient reported changes in Chronic Respiratory Infection Symptom Score and Cystic Fibrosis Questionnaire-Revised Respiratory Domain Score did not differ between treatment groups in either trial over the study period.

“These results provide an opportunity to re-evaluate daily treatment requirements, wherein long-standing use of some inhaled medications might not be required to maintain pulmonary function in individuals receiving drugs known to substantially improve CFTR function and respiratory health,” Mayer-Hamblett and colleagues wrote. “When interpreting the results of SIMPLIFY, it is important to recognize the average and range of baseline lung function of study participants and to appreciate the 6-week observational timeframe focused primarily on changes in lung function.”