Mucoactives Found to Have Little Benefit for Bronchiectasis

A new study has found that neither hypertonic saline nor carbocisteine significantly reduced the mean incidence of pulmonary exacerbations in people with bronchiectasis over 52 weeks.1

“Some current guidelines recommend mucoactive drugs plus airway clearance to enhance sputum expectoration in bronchiectasis. However, these guidelines rely on a 2014 systematic review that showed limited effectiveness of mucolytics for bronchiectasis on the basis of low-quality evidence from 4 trials,” study investigator Judy M. Bradley, PhD, Wellcome–Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom, and colleagues wrote.1

The study followed an open-label, randomized, 2-by-2 factorial trial design and was conducted at 20 sites in the United Kingdom, enrolling participants with non–cystic fibrosis bronchiectasis who had frequent pulmonary exacerbations and daily sputum production. It excluded current smokers and people who had recently received mucoactive treatments. All participants (n = 288) received standard care as well as either hypertonic saline (the hypertonic-saline group), hypertonic saline and carbocisteine (the combination group), or carbocisteine (the carbocisteine group), or standard care alone. Investigators primarily compared pulmonary exacerbations over a 52-week period between hypertonic saline and no hypertonic saline and between carbocisteine and no carbocisteine. Key secondary outcomes included scores on disease-specific health-related quality-of-life (QoL) assessments, time to next pulmonary exacerbation, and safety.

Bradley and colleagues found no treatment interactions. They found that the mean number of adjudicated fully qualifying pulmonary exacerbations over the 52-week period was 0.76 (95% CI, 0.58-0.95) with hypertonic saline as compared with 0.98 (95% CI, 0.78-1.19) with no hypertonic saline (adjusted between-group difference, −0.25 [95% CI, −0.57 to 0.07; P = .12]) and 0.86 (95% CI, 0.66-1.06) with carbocisteine as compared with 0.90 (95% CI, 0.70-1.09) with no carbocisteine (adjusted between-group difference, −0.04 [95% CI, −0.36 to 0.28; P = .81]). Groups had similar scores on QoL assessments, and times to next pulmonary exacerbations.

The incidence of serious adverse events (AEs) were similar between those who received hypertonic saline (17 events in 16 participants) and those who did not (22 events in 19 participants; relative risk, 0.8 [95% CI, 0.4-1.5]; P = .53), as well as between those who received hypertonic saline (274 events in 100 participants) and those who did not (238 events in 94 participants; relative risk, 1.0 [95% CI, 0.9-1.2]; P = .68). A total of 69 AEs in 43 participants who received hypertonic saline and 22 AEs in 15 participants who did not were determined by the investigators to be related to a trial drug. Participants that received a mucoactive drug had a greater incidence of respiratory, thoracic, and mediastinal and gastrointestinal disorders. Findings were also similar between carbocisteine and no carbocisteine groups.

“How should clinicians respond to this groundbreaking trial? The results shown convincingly that neither hypertonic saline nor carbocisteine should be prescribed routinely for continuous daily use across the broad spectrum of patients who have symptomatic bronchiectasis. However, we caution against abandoning airway mucoactive therapy altogether on the basis of this 1 trial,” John Hansen-Flaschen, MD, and Gregory Tino, MD, both from the Perelman School of Medicine, University of Pennsylvania, Philadelphia, wrote in a related editorial about the new findings.2

Bradley and colleagues noted that while their findings suggest that proposed physiological effects of mucoactives do not translate to clinical benefit for patients, similar safety profiles suggest they may not cause substantial harm, but there nonetheless remain associated costs and treatment burdens that are important to consider in the absence of real benefits.1

The study comes with several limitations. Mucoactive agents can improve sputum viscosity but do not directly move secretions from distal to central airways, making their timing before airway-clearance maneuvers crucial. Although participants were advised to maintain or learn airway-clearance routines, adherence, timing, and technique were not objectively measured, potentially affecting outcomes. Additionally, patients with the most advanced bronchiectasis were not analyzed separately, leaving uncertainty about responses in those with greater disease burden or during exacerbations. Finally, as carbocisteine has distinct pharmacologic properties, its limited efficacy should not be extrapolated to other mucoactive agents with different mechanisms of action.

“Until further evidence is available, we recommend continuing to use airway clearance selectively for patients with bronchiectasis and chronic or acute chest congestion who are motivated to actively engage in their therapy. The choice of clearance method and use of an adjunctive mucoactive agent should be individualized on the basis of clinician assessment and patient-reported experience with airway clearance,” Hansen-Flaschen and Tino wrote.2

Notably, the treatment landscape of bronchiectasis recently expanded with the United States Food and Drug Administration (FDA) approval of Insmed's brensocatib in August 2025 under the name Brinsupri, marking the first approval of a disease-modifying therapy for non-cystic fibrosis bronchiectasis.3

References

1. Bradley JM, O'Neill B, McAuley DF, et al. Hypertonic Saline or Carbocisteine in Bronchiectasis. N Engl J Med. Published online September 28, 2025. doi:10.1056/NEJMoa2510095

2. Hansen-Flaschen J, Tino G. Time to Reconsider Mucoactive Agents for Airway Clearance. N Engl J Med. Published online September 28, 2025. doi:10.1056/NEJMe2512146

3. Johnson. FDA Approves First Bronchiectasis Therapy, Brensocatib, for Ages 12 and Up. HCPLive. Article. August 12, 2025. https://www.hcplive.com/view/fda-approves-first-bronchiectasis-therapy-brensocatib-12-up