Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial

Abstract

Rationale Bronchiectasis is characterised by excessive production of mucus and pulmonary exacerbations. Inhaled osmotic agents may enhance mucociliary clearance, but few long-term clinical trials have been conducted. Objectives To determine the impact of inhaled mannitol on exacerbation rates in patients with non-cystic fibrosis (CF) bronchiectasis. Secondary endpoints included time to first exacerbation, duration of exacerbations, antibiotic use for exacerbations and quality of life (QOL) (St George's Respiratory Questionnaire, SGRQ). Methods Patients with non-CF bronchiectasis and a history of chronic excess production of sputum and ≥2 pulmonary exacerbations in the previous 12 months were randomised (1:1) to 52 weeks treatment with inhaled mannitol 400 mg or low-dose mannitol control twice a day. Patients were 18-85 years of age, baseline FEV 1 ≥40% and ≤85% predicted and a baseline SGRQ score ≥30. Main results 461 patients (233 in the mannitol and 228 in the control arm) were treated. Baseline demographics were similar in the two arms. The exacerbation rate was not significantly reduced on mannitol (rate ratio 0.92, p=0.31). However, time to first exacerbation was increased on mannitol (HR 0.78, p=0.022). SGRQ score was improved on mannitol compared with low-dose mannitol control (−2.4 units, p=0.046). Adverse events were similar between groups. Conclusions Mannitol 400 mg inhaled twice daily for 12 months in patients with clinically significant bronchiectasis did not significantly reduce exacerbation rates. There were statistically significant improvements in time to first exacerbation and QOL. Mannitol therapy was safe and well tolerated. Trial registration number NCT00669331.

Management of bronchiectasis in adults

“…The study failed to meet its primary end-point, with a rate ratio for exacerbations of 0.92 (95% CI 0.78-1.08; p=0.3). Among secondary endpoints there was an increase in time to next exacerbation and a small improvement in SGRQ with mannitol treatment [56]. Therefore, despite two large trials the role of mannitol in bronchiectasis treatment remains unclear.…”

“…Therefore a further trial was conducted focussing on exacerbations. This study randomised 233 patients to 400 mg inhaled mannitol or control mannitol for 52 weeks [56]. The population was tightly defined, requiring two exacerbations in the previous year, FEV1 between 40 and 85% predicted and a baseline SGRQ score of ⩾30 points [56].…”

RESPIRE: breathing new life into bronchiectasis

“…This is only achievable with clearer precision medicine approaches for the disease which in turn is reliant on a better mechanistic understanding of its pathology and progression. For instance, several failed clinical trials in bronchiectasis including recombinant DNAase and inhaled dry powder mannitol, both effective therapies in cystic fibrosis (CF), did not translate [13,14]. This illustrates that while the bronchiectasis appears anatomically similar to that in CF, pathophysiological differences exist and probably extend across different aetiologies.…”

Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis

“…The authors concluded however, that therapy needed to be continuous to maintain efficacy [23]. Other recent trials of therapies aiming to reduce exacerbations, such as the non-antibiotic mucoactive inhaled mannitol [24,25], or nebulized antibiotics such as colistin [26], and aztreonam lysine [27] all failed to show significant benefits in their primary end points. This may reflect the choice of end point(s) or the prerequisite study population rather than a true lack of efficacy.…”