Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis
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 cystic fibrosis (CF), it failed to improve Forced expiratory volume in one second (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 (BD) against control.
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||: A Phase III Multicenter, Randomized, Parallel Group, Controlled, Double Blind Study to Investigate the Safety and Efficacy of Inhaled Mannitol Over 12 Months in the Treatment of Bronchiectasis.|
- Rate of Graded Pulmonary Exacerbations [ Time Frame: 52 weeks ]A graded pulmonary exacerbation was defined as a worsening in signs and symptoms requiring a change in treatment (Center for Drug Evaluation and Research (CDER), 2007). Grade I was required 3 main signs and symptoms, Grade II 2 main signs and symptoms and Grade III 1 main and one or more minor signs and symptoms. Main signs and symptoms were increased cough, sputum volume or sputum purulence. Minor were upper respiratory tract infection, fever, increased wheezing, increased dyspnea, increase in respiratory rate, increase in cardiac frequency of >20%, and increased malaise, fatigue or lethargy. Rate is defined as the number of all GPE events observed in one treatment year
- Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score [ Time Frame: 52 weeks ]The SGRQ was collected at baseline, week 6, week 16, week 28, week 40 and week 52. Change in total score was calculated from baseline. Total scores are a weighted sum across all questions. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. Higher scores indicate lower quality of life. Outcome data table gives the raw mean total score at each visit.
- Antibiotic Use Prescribed for Treated Pulmonary Exacerbations [ Time Frame: 52 weeks ]Rate of antibiotic treated graded pulmonary exacerbations, using the same definition of a graded pulmonary exacerbation as the primary endpoint. A graded pulmonary exacerbation was considered to be anti-biotic treated if use of oral, IV or inhaled antibiotic use was recorded related to the GPE event.
- Time to First Graded Exacerbation [ Time Frame: 52 weeks ]Time to first graded exacerbation is defined as the duration (in months) from the randomisation date to the start of the first reported graded PE during the on-treatment period. Patients without reported graded PE event will be censored at the last participation.
- Duration of Graded Exacerbations [ Time Frame: 52 weeks ]Duration of graded exacerbations is defined as the number of days with graded PE within one treatment year. Mean days estimated via negative binomial model with treatment, region and baseline pulmonary exacerbation rate as predictors, with log of follow-up time as the offset variable
- Sputum Volume [ Time Frame: 52 weeks ]24 hour sputum weight, measured at baseline, week 6, week 16, week 28, week 40, week 52
- Daytime Sleepiness Scores [ Time Frame: 52 weeks ]Epworth Sleepiness Scale (ESS) score was calculated as the sum of scores for each of eight individual questions, such that a total score of zero represents no daytime sleepiness, and a total score of 24 represents the maximum degree of daytime sleepiness. Measured at baseline, 6 weeks, 16 weeks, 28 weeks, 40 weeks, 52 weeks
- Lung Function - Change in FEV1 (Forced Expiratory Volume in One Second) [ Time Frame: 52 weeks ]
- Lung Function - Change in FVC (Forced Vital Capacity) [ Time Frame: 52 weeks ]
- Lung Function - Change in FEV1/FVC [ Time Frame: 52 weeks ]FEV1 expressed as a ratio of FVC. Endpoint is expressed as a percentage ie FEV1/FVC*100
- Lung Function - Change in FEF25-75 (Forced Expiratory Flow Rate Averaged Over 25th -75th Percentile of FVC) [ Time Frame: 52 weeks ]
- Safety Profile - Sputum Microbiology [ Time Frame: 52 weeks ]sputum microbiology assessed as the presence of abnormal flora in sputum sample taken at any post baseline visit
- Safety Profile - Clinical Chemistry [ Time Frame: 52 weeks ]Clinical chemistry was assessed as clinically significant abnormal liver function test and clinically significant abnormal urea/electrolyte test at any point post baseline.
- Safety Profile - Hematology [ Time Frame: 52 weeks ]hematology assessed as clinically significant abnormal FBC (Full Blood count) at any point post baseline.
- • (Exploratory) Number of Hospitalizations Due to Pulmonary Exacerbations [ Time Frame: 52 weeks ]Mean rate of hospitalisations (number/year) summarised and analysed to take account of differing follow-up times.
- Health Related Costs of Treating Patients With Bronchiectasis [ Time Frame: 52 weeks ]In the presence of a significant primary endpoint, these data were intended to be derived using the trial data together with external information (Note as the primary objective of this study did not reach statistical significance, health related costs were not assessed)
- Health Status and Utility Scores [ Time Frame: 52 weeks ]In the presence of a significant primary endpoint, these data were intended to be derived from the trial data and external information (Note as the primary objective of this study did not reach statistical significance, differences in health status and utility scores were not assessed)
- 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 ]In the presence of a significant primary endpoint, these data were intended to be derived using the trial data and external information (Note as the primary objective of this study did not reach statistical significance, HRQL and QALYs were not collected).
- Cost Effectiveness of Treating Patients With Bronchiectasis With Inhaled Mannitol [ Time Frame: 52 weeks ]In the presence of a significant primary endpoint, these data were intended to be derived using the trial data and external information (Note as the primary objective of this study did not reach statistical significance, cost effectiveness was not collected).
|Study Start Date:||November 2009|
|Study Completion Date:||January 2014|
|Primary Completion Date:||January 2014 (Final data collection date for primary outcome measure)|
Inhaled mannitol 400mg
Drug: Inhaled mannitol
400mg dose of Mannitol BD (twice a day) for 52 weeks
Placebo Comparator: Control
Matched control - inhaled mannitol 50mg
Drug: Matched control
50mg dose of Mannitol BD (twice a day) for 52 weeks
Please refer to this study by its ClinicalTrials.gov identifier: NCT00669331
Show 83 Study Locations
|Principal Investigator:||Diana Bilton, MD||Brompton Hospital London UK|
|Principal Investigator:||Greg Tino, MD||University of Pennsylvania Medical Centre, Philadelphia|
|Principal Investigator:||Alan Barker, MD||Oregon Health Sciences University, Portland Oregon|