In patients with cystic fibrosis (CF) with relatively well-preserved pulmonary function being treated with elexacaftor plus tezacaftor plus ivacaftor (ETI), discontinuation of daily hypertonic saline or dornase alfa for 6 weeks was not associated with clinically meaningful differences in pulmonary function. This was among study findings published in The Lancet Respiratory Medicine.
In an effort to find ways to simplify the considerable treatment burden experienced by patients with CF, investigators sought to assess the effects of stopping the use of nebulized hypertonic saline or dornase alfa in individuals using ETI, a CF transmembrane conductance regulator (CFTR) modulator that is considered to be a highly effective treatment for patients with CF.
The SIMPLIFY study (ClinicalTrials.gov identifier: NCT04378153) comprised 2 parallel, multicenter, open-label, randomized, controlled, noninferiority trials at 88 participating clinics across the US in the Cystic Fibrosis Therapeutics Development Network. Conducted between August 25, 2020, and May 25, 2022, the trial randomly assigned participants to receive either hypertonic saline in 1 of the trials or dornase alfa in the other trial.
Individuals with CF who had been taking ETI and either or both mucoactive therapies (ie, ≥3% hypertonic saline or dornase alfa) for at least 90 days were eligible for the study, provided that they met the following criteria: 12 to 17 years of age with a percent predicted forced expiratory volume in 1 second (ppFEV1) of at least 70%; or at least18 years of age with a ppFEV1 of at least 60%.
The primary objective of each trial was to evaluate whether discontinuing hypertonic saline or dornase alfa was noninferior to continuing therapy. The primary study outcome was 6-week mean absolute change in ppFEV1. Secondary objectives assessed the safety of discontinuing treatment, as measured by comparing adverse event (AE) rates between the groups and percentages of participants who changed their assigned treatment regimen. Secondary outcomes included 6-week change in lung clearance index at 2.5% of the starting gas concentration, which was measured by nitrogen multiple breath washout (MBW) among a subcohort that was enrolled at 27 participating sites.
Overall, 672 participants were evaluated for eligibility across 1021 screening visits, which resulted in 847 total random assignments across both studies among 594 unique participants. A subset that comprised 43% (253 of 594) of participants being treated with both hypertonic saline and dornase alfa participated in both of the trials. Upon completion of the screening period, all eligible participants were randomly assigned to either discontinue (n=184 in the hypertonic saline trial and n=240 in the dornase alfa trial) or continue (n=186 in the hypertonic saline trial and n=237 in the dornase alfa trial) therapy in each trial.
Results of the study showed that participants across both trials had an average ppFEV1 of 96.9%. In the per-protocol population of the hypertonic saline trial, the absolute change in ppFEV1 from baseline to week 6 was -0.19% (n=133; 95% CI, -0.85 to 0.48) in the discontinuation group vs 0.14% (n=140; 95% CI, -0.51 to 0.78) in the continuation group, indicating a between-group difference of -0.32% (95% CI, -1.25 to 0.60). In the per-protocol population of the dornase alfa trial, a mean 6-week change of 0.18% (n=199; 95% CI, -0.38 to 0.74) was seen in the discontinuation group vs -0.16% (n=193; 95% CI, -0.73 to 0.41) in the continuation group, indicating a between-group difference of 0.35% (95% CI, -0.45 to 1.14). Thus, noninferiority was established in both trials.
Adverse event rates were low in all groups, with “[no] substantial safety concerns were identified,” said study authors, who nevertheless noted that those discontinuing inhaled therapies had slightly higher AE rates than who continued these therapies. Moreover, AEs were more likely in those with worse lung function.
Limitations of the current include: an inability to mask study participants, particularly with respect to inhaled therapies with visible features and distinctive taste; and the higher baseline ppFEV1 and much lower rates of acute pulmonary exacerbations among study participants compared with study participants in previous trials of hypertonic saline and dornase alfa.
“In summary,” the study authors concluded, “the results of SIMPLIFY indicate that,
among a study population of adolescents and adults with cystic fibrosis who have good lung function and are established on ETI, clinically meaningful reduction in pulmonary function did not occur with short-term discontinuation of daily use of inhaled medications that work on downstream manifestations of CFTR dysfunction in the airway, specifically hypertonic saline and dornase alfa.” Such results may be useful for informing shared decision making “for many people with cystic fibrosis benefiting from CFTR restorative therapies now and in the future.”
Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Mayer-Hamblett N, Ratjen F, Russell R, et al; SIMPLIFY Study Group. Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials. Lancet Respir Med. Published online November 4, 2022. doi:10.1016/S2213-2600(22)00434-9