Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis

• antibiotic use for pulmonary exacerbations [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• To show a significant difference in Quality of Life as measured by the St. Georges Respiratory Questionnaire (SGRQ), in patients with bronchiectasis using inhaled mannitol as the intervention and control as the comparator. [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]

• To show a significant difference in Quality of Life as measured by the St. Georges Respiratory Questionnaire (SGRQ) in patients with bronchiectasis treated with inhaled mannitol compared to placebo control [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• • To show a significant difference in antibiotic use prescribed for treated pulmonary exacerbations in patients with bronchiectasis treated with inhaled mannitol compared to placebo control. [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• • To show a significant improvement in other graded exacerbation parameters (time to first exacerbation and duration of exacerbation) in patients with bronchiectasis treated with inhaled mannitol compared to placebo control [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• • To show a significant difference in sputum volume in patients with bronchiectasis treated with inhaled mannitol compared to placebo control [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• • To show a significant difference in daytime sleepiness scores in patients with bronchiectasis treated with inhaled mannitol compared to placebo control [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• • To show a significant difference in lung function (FEV1, FVC, FEV1/FVC, FEF25-75 values) in patients with bronchiectasis treated with inhaled mannitol compared to placebo control [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• • To monitor the safety profile of inhaled mannitol compared to placebo control in subjects with bronchiectasis by investigating adverse events, airway reactivity, hematology, clinical chemistry, sputum microbiology and vital signs [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
• To compare health related costs of treating patients with bronchiectasis with inhaled mannitol and placebo control [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• To compare health status and utility scores in patients treated with inhaled mannitol compared to placebo control [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• To investigate health related quality of life (HRQL) and quality adjusted life years (QALYs) by treatment group using utility scores from the Health Utilities Index Questionnaire [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• To investigate cost effectiveness of treating patients with bronchiectasis with inhaled mannitol [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• • (Exploratory) To investigate number of hospitalizations due to pulmonary exacerbations in patients with bronchiectasis treated with inhaled mannitol compared to placebo control [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]

• pulmonary exacerbations [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• sputum volume [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• exercise tolerance [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• lung function [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• adverse events, blood chemistry, sputum microbiology, [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]

No gold standard therapy exists for clearing mucus from the airways of patients with bronchiectasis. While rhDNase has a proven place in the treatment of CF, it failed to improve FEV1 in a short-term non-CF bronchiectasis study and has been shown to be detrimental after 6 months therapy in non CF bronchiectasis, moreover it has no proven effect on mucociliary clearance. Hypertonic saline has been shown to have a comparable mode of action to inhaled mannitol, but has yet to be examined as a long term treatment option in bronchiectasis.

The purpose of this study is to examine the efficacy and safety of 52 weeks treatment with inhaled mannitol in subjects with non-cystic fibrosis bronchiectasis. Previous studies with inhaled mannitol have demonstrated improvement in mucociliary clearance; mucus rehydration; improvement in quality of life and respiratory symptoms in patients with bronchiectasis and pulmonary function in cystic fibrosis. The results of this current study in combination with a recently completed 3 month study seek to confirm these early findings and to extend the evidence to support its use as a mucoactive therapy in subjects with bronchiectasis.

We hypothesize that mannitol will improve the overall health and hygiene of the lung through regular and effective clearing of the mucus load. As a consequence of the reduction in mucus load and inflammatory process, the frequency of bronchiectasis related pulmonary exacerbations and the need for exacerbation related antibiotic treatment should fall. Days in hospital and community health care costs are expected to change in line with improvements in respiratory health.

Finally, we plan to demonstrate that inhaled mannitol is safe and well tolerated over a 52 week period. We will test these hypotheses using 400 mg mannitol twice daily against control.

• Drug: Inhaled mannitol
  400mg BD for 52 weeks
• Drug: matched control
  10 capsules twice a day for 52 weeks

• Experimental: 1
  Inhaled mannitol
  Intervention: Drug: Inhaled mannitol
• Placebo Comparator: 2
  matched control given in same regimen as inhaled mannitol
  Intervention: Drug: matched control

• Daviskas E, Anderson SD, Eberl S, Chan HK, Bautovich G. Inhalation of dry powder mannitol improves clearance of mucus in patients with bronchiectasis. Am J Respir Crit Care Med. 1999 Jun;159(6):1843-8.
• Daviskas E, Anderson SD, Eberl S, Young IH. Effect of increasing doses of mannitol on mucus clearance in patients with bronchiectasis. Eur Respir J. 2008 Apr;31(4):765-72. Epub 2007 Dec 5.
• Daviskas E, Anderson SD, Young IH. Inhaled mannitol changes the sputum properties in asthmatics with mucus hypersecretion. Respirology. 2007 Sep;12(5):683-91.
• Daviskas E, Anderson SD. Hyperosmolar agents and clearance of mucus in the diseased airway. J Aerosol Med. 2006 Spring;19(1):100-9. Review.
• Daviskas E, Anderson SD, Gomes K, Briffa P, Cochrane B, Chan HK, Young IH, Rubin BK. Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: effect on lung function, health status and sputum. Respirology. 2005 Jan;10(1):46-56.
• Daviskas E, Robinson M, Anderson SD, Bye PT. Osmotic stimuli increase clearance of mucus in patients with mucociliary dysfunction. J Aerosol Med. 2002 Fall;15(3):331-41. Review.
• Daviskas E, Anderson SD, Eberl S, Chan HK, Young IH. The 24-h effect of mannitol on the clearance of mucus in patients with bronchiectasis. Chest. 2001 Feb;119(2):414-21.

Inclusion Criteria

1. Have given written informed consent to participate in this study in accordance with local regulations
2. Have documented evidence of confirmed diagnosis of (non-cystic fibrosis) bronchiectasis by CT, HRCT or bronchogram
3. Be aged 18 - 85 years inclusive, male and female
4. Have FEV1 ≥ 40% and ≤85% predicted* and ≥1.0L (*according to NHANES III predicted tables)measured at V0A
5. Clinician documented history of at least 2 pulmonary exacerbations, each requiring antibiotic therapy, in the last 12 months prior to Visit 0A and a total of at least 4 in the last 2 years prior to Visit 0A
6. Have a total SGRQ score of ≥30 at Visit 0B
7. Have a production of ≥10g of sputum at Visit 0B Have reported chronic sputum production of ≥1 tablespoon (15mL) per day on the majority of days in the 3 months prior to Visit 0A
8. Be able to perform all the techniques necessary to measure lung function
9. Have FEV1 ≥40% predicted* and ≥1.0L (*according to NHANES III 1999 predicted tables) measured at V0B (Baseline result prior to MTT administration)

Exclusion Criteria

1. Be investigators, site personnel directly affiliated with this study, or their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biologically or legally adopted.
2. Have bronchiectasis as a consequence of cystic fibrosis or focal endobronchial lesion or otherwise curable causes (e.g. foreign body aspiration)
3. Be considered "terminally ill" or listed for transplantation
4. Be using hypertonic saline in the 14 days prior to commencing Visit 0B or thereafter at any time during the study
5. Have previously used inhaled mannitol (Bronchitol) for more than a day
6. Have had a significant episode of hemoptysis (>60 mL) in the previous 6 months
7. Have had rescue antibiotics in the 4 weeks prior to V0B (chronic background antibiotic therapy accepted)
8. Have smoked within the last 3 months and must not smoke during their participation in the study
9. Have had a myocardial infarction in the three months prior to Visit 0A
10. Have had a cerebral vascular accident in the three months prior to Visit 0A
11. Have had major ocular surgery in the three months prior to Visit 0A
12. Have had major abdominal, chest or brain surgery in the three months prior to Visit 0A
13. Have a known cerebral, aortic or abdominal aneurysm
14. Have actively treated Mycobacterium tuberculosis
15. Have actively treated or unstable nontuberculous mycobacterial infection or be under consideration for NTM treatment in the next 12 months
16. Have unstable ABPA requiring steroid therapy (≤5mg dose oral steroids in stable ABPA accepted)
17. Have end stage interstitial lung disease
18. Have active malignancy including melanoma (other skin carcinomas exempted). Remissions from any malignancy ≥2 years also exempted
19. Be breast feeding or pregnant, or plan to become pregnant while in the study
20. Be using an unreliable form of contraception (female subjects at risk of pregnancy only)
21. Be participating in another investigational drug study, parallel to, or within 4 weeks of Visit 0A
22. Have a known intolerance to mannitol or β2-agonists
23. Have uncontrolled hypertension - e.g. for adults: systolic BP > 190 and or diastolic BP > 100
24. Subject has a condition or is in a situation which in the Investigator's opinion may put the subject at significant risk, may confound results or may interfere significantly with the patient's participation in the study
25. Have previously been screen failed for the study (exceptions - see section 3.3.2 Eligibility Criteria - Rescreening)