CLEAR Trial: Hypertonic Saline and Carbocisteine Do Not Reduce Exacerbations in Non-CF Bronchiectasis

Mucoactive therapy is variably recommended for bronchiectasis due to limited high-quality evidence. The CLEAR trial randomized 288 adults with CT-confirmed, non-CF bronchiectasis, frequent prior exacerbations, and daily sputum to standard care plus: 6% hypertonic saline, carbocisteine (750 mg TID ×8 weeks then BID), both, or standard care alone, in an open-label 2×2 factorial design across 20 UK sites. The prespecified co-primary comparisons were “hypertonic saline vs no hypertonic saline” and “carbocisteine vs no carbocisteine.” The primary endpoint was the number of fully adjudicated pulmonary exacerbations over 52 weeks, with key secondary outcomes including disease-specific HRQoL, time to next exacerbation, and safety.

Results. No treatment interaction was found. Mean fully adjudicated exacerbations/52 weeks were 0.76 with hypertonic saline vs 0.98 without (adjusted difference −0.25; 95% CI −0.57 to 0.07; P=0.12) and 0.86 with carbocisteine vs 0.90 without (adjusted difference −0.04; 95% CI −0.36 to 0.28; P=0.81). Secondary outcomes (QoL-B, SGRQ, EQ-5D-5L, time to next exacerbation, antibiotic days, lung function) were similar between groups.

Safety. Overall adverse events (AEs) and serious AEs were comparable across groups; GI AEs were more frequent with carbocisteine. Investigators attributed more AE events to trial drugs in the active-therapy groups, but without clear serious-harm signals.

Implications for practice. In adults with bronchiectasis and daily sputum production receiving guideline-based airway-clearance care, adding 6% hypertonic saline or carbocisteine did not reduce exacerbations over 1 year. Given the added treatment burden and GI AEs with carbocisteine, routine use of these two mucoactives for exacerbation prevention should be reconsidered; decisions may pivot toward patient-specific goals (e.g., symptomatic sputum management) pending future trials with other mucoactives or phenotyped subgroups.

#Bronchiectasis #RespiratoryMedicine #MucoactiveTherapies #ClinicalTrials #NEJM

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