Chest
Volume 144, Issue 1, July 2013, Pages 215-225
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Original Research
Bronchiectasis
Phase 3 Randomized Study of the Efficacy and Safety of Inhaled Dry Powder Mannitol for the Symptomatic Treatment of Non-Cystic Fibrosis Bronchiectasis

https://doi.org/10.1378/chest.12-1763Get rights and content

Background

Inhaled dry powder mannitol enhanced mucus clearance and improved quality of life over 2 weeks in non-cystic fibrosis bronchiectasis. This study's objective was to investigate the efficacy and safety of dry powder mannitol over 12 weeks.

Methods

Patients with bronchiectasis confirmed by high-resolution CT (HRCT) scan, aged 15 to 80 years, with FEV1 ≥ 50% predicted and ≥ 1 L participated in a randomized, placebo-controlled, double-blind study. Patients with a negative mannitol provocation test were randomized to inhale 320 mg mannitol (n = 231) or placebo (n = 112) bid for 12 weeks. To further assess safety, the same mannitol dose/frequency was administered to a patient subset in an open-label extension over 52 weeks. Primary end points were changes from baseline at 12 weeks in 24-h sputum weight and St. George's Respiratory Questionnaire (SGRQ) score.

Results

There was a significant difference of 4.3 g in terms of change in sputum weight over 12 weeks (95% CI, 1.64-7.00; P = .002) between mannitol and placebo; however, this was largely driven by a decrease in sputum weight in the placebo group. This was associated, in turn, with more antibiotic use in the placebo group (50 of 112 [45%]) than in the inhaled mannitol group (85 of 231 [37%]). There was no statistical difference between the groups (P = .304) in total SGRQ score (mannitol, −3.4 points [95% CI, −4.81 to −1.94] vs placebo, −2.1 points [95% CI, −4.12 to −0.09]). In a subgroup study (n = 82), patients receiving mannitol showed less small airway mucus plugging on HRCT scan at 12 weeks compared with patients receiving placebo (P = .048). Compliance rates were high, and mannitol was well tolerated with adverse events similar to those of placebo.

Conclusion

Because the difference in sputum weights appears to be associated with increased antibiotic use in the placebo group, a larger controlled study is now required to investigate the long-term mannitol effect on pulmonary exacerbations and antibiotic use.

Section snippets

Subjects

Table 1 lists the inclusion and exclusion criteria for study patients recruited from 22 sites, approved by the relevant ethics committees in Australia, New Zealand, and the United Kingdom (e-Appendix 1).

Treatment and Materials

Dry powder mannitol (Bronchitol; Pharmaxis) was supplied in 40-mg capsules. Placebo capsules (10 mg) (Roquette) consisted of nonrespirable (approximately 70 μm) United States Pharmacopeia/British Pharmacopoeia good manufacturing practice crystalline mannitol.

Mannitol and placebo were

Patient Disposition and Baseline Demographics

Patient disposition, ITT, and OLE safety populations are described in Figure 1. There were no statistically significant differences in patient demographics, baseline spirometry, or airway function between the groups (Table 3, e-Table 1). Similar numbers of patients in each group (46.4% mannitol; 43.7% placebo) were having regular physiotherapy to clear their secretions.

Sputum Weight

The change from baseline in the 24-h sputum weight after 12 weeks of treatment was significantly different between the mannitol

Discussion

Although bronchiectasis is a major contributor to chronic respiratory morbidity and mortality,2, 6 clinically relevant end points have not been established firmly with regulatory authorities. Consequently, a number of established and exploratory assessments were included in our study, to examine the efficacy of mannitol. However, because the problems in bronchiectasis arise from poor clearance of mucus and consequently poor health, and mannitol is known to facilitate mucus clearance,18 our

Conclusion

Mannitol inhaled bid for 12 weeks in patients with mild-to-moderate bronchiectasis led to a significant difference in expectorated sputum. In a substudy of patients having CT scans, there was a reduction in mucus plugging. Despite improvements in quality of life from baseline, these failed to reach statistical significance compared with placebo. Mannitol therapy was safe and well tolerated for over 3 to 12 months. A large 12-month study is underway to further investigate the effect of mannitol

Acknowledgments

Author contributions: Dr Charlton is the guarantor of the paper and takes responsibility for the integrity of the work as a whole, from inception to published article.

Dr Bilton: contributed to the interpretation of the data, writing of the manuscript, approval of the final version, and final submission of the manuscript for publication.

Dr Daviskas: contributed to the interpretation of the data, writing of the manuscript, and approval of the final version.

Dr Anderson: contributed to the

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    Funding/Support: This study was funded by Pharmaxis Ltd.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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