A phase III multicenter, randomized, parallel, controlled, double blind study to investigate the safety and efficacy of inhaled mannitol over 12 months in the treatment of bronchiectasis.

Bronchiectasis is a chronic lung condition in which damage to the airways
causes abnormal dilation of one or more bronchi, leading to pooling of mucus in
affected areas. Patients with bronchiectasis usually have cough and abnormal
sputum production, some have wheeze and breathlessness. Undue tiredness and
fatigue are often reported by patients with bronchiectasis. The increased
production of mucus together with impairment of the mucociliary system leads to
mucus accumulation, cough, sputum production and recurrent infections. Patients
with mucociliary dysfunction are usually treated on a daily basis with physical
treatment like postural drainage to help clear excessive secretions and also
with pharmacological agents. However, the physico-chemical properties of the
secretions from these patients are such that the currently available
pharmacological and physical interventions are not very effective.
Inhaled dry powder mannitol is an osmotic agent that was first shown to
increase mucociliary clearance in asthmatic and healthy subjects who have
normal mucociliary clearance at baseline. It has been shown that a single
inhalation of mannitol increases the clearance of mucus both acutely and over
24 hours in patients with bronchiectasis, and acutely in patients with cystic
fibrosis. Clinical outcome studies have shown that inhaled mannitol over 2
weeks improves health related quality of life10 respiratory symptoms and
fatigue, and respiratory symptoms, and daytime sleepiness11 in bronchiectasis
patients. In addition, sputum collected from patients 1 hour post mannitol was
shown to have physical changes that benefit mucus transport.

2.1.1 Primary Objective:
To evaluate the difference in the rates of graded pulmonary exacerbations in
patients with bronchiectasis treated with inhaled mannitol compared with
placebo control

2.1.2 Secondary Objectives:
Efficacy
To evaluate the difference in Quality of Life as measured by the St. Georges
Respiratory Questionnaire (SGRQ) in patients with bronchiectasis treated with
inhaled mannitol compared with placebo control
To evaluate the difference in antibiotic use prescribed for treated pulmonary
exacerbations in patients with bronchiectasis treated with inhaled mannitol
compared with placebo control. Such antibiotic use parameters to be analyzed
will include number of discrete courses; days on antibiotics; and time to
antibiotic need.
To evaluate the difference in other graded exacerbation parameters (time to
first exacerbation and duration of exacerbation) in patients with
bronchiectasis treated with inhaled mannitol compared with placebo control
To evaluate the difference in sputum volume in patients with bronchiectasis
treated with inhaled mannitol compared with placebo control
To evaluate the difference in daytime sleepiness scores in patients with
bronchiectasis treated with inhaled mannitol compared with placebo control
To evaluate the difference in lung function (FEV1, FVC, FEV1/FVC, FEF25-75
values) in patients with bronchiectasis treated with inhaled mannitol compared
with placebo control (Exploratory)
To investigate the difference in number of hospitalizations due to pulmonary
exacerbations in patients with bronchiectasis treated with inhaled mannitol
compared with placebo control

Safety
To monitor the safety profile of inhaled mannitol compared with placebo control
in subjects with bronchiectasis by investigating adverse events, airway
reactivity, hematology, clinical chemistry, sputum microbiology and vital signs

Costs, Health Status, Utilities and Cost Effectiveness
To compare health related costs of treating patients with bronchiectasis with
inhaled mannitol and placebo control
To compare health status and utility scores in patients treated with inhaled
mannitol compared with placebo control
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
To investigate cost effectiveness of treating patients with bronchiectasis with
inhaled mannitol

This is a double-blind, randomized, parallel group, controlled, multi-center,
interventional clinical trial in subjects with non-CF bronchiectasis.
Eligibility will be determined at Visit 0A & Visit 0B, and baseline assessments
captured at Visit 0B prior to the mannitol tolerance test (MTT). Subjects must
have a negative MTT result to be randomized. Randomized subjects will receive
for 52 weeks, 400 mg BID inhaled mannitol or placebo control, in a ratio of
1:1. All subjects will be followed for 4 weeks following cessation of the
intervention arm.

Dose: 400mg inhaled mannitol BID or placebo control BID

See protocol: Time and Events schedule, p89 and section 'Known potential risks
and benifits to human subjects', p16.