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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT00669331




Registration number
NCT00669331
Ethics application status
Date submitted
28/04/2008
Date registered
30/04/2008
Date last updated
29/04/2016

Titles & IDs
Public title
Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis
Scientific 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.
Secondary ID [1] 0 0
DPM-B-305
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bronchiectasis 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Inhaled mannitol
Treatment: Drugs - Matched control

Experimental: Mannitol - Inhaled mannitol 400mg

Placebo comparator: Control - Matched control - inhaled mannitol 50mg


Treatment: Drugs: Inhaled mannitol
400mg dose of Mannitol BD (twice a day) for 52 weeks

Treatment: Drugs: Matched control
50mg dose of Mannitol BD (twice a day) for 52 weeks
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Rate of Graded Pulmonary Exacerbations
Timepoint [1] 0 0
52 weeks
Secondary outcome [1] 0 0
Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score
Timepoint [1] 0 0
52 weeks
Secondary outcome [2] 0 0
Antibiotic Use Prescribed for Treated Pulmonary Exacerbations
Timepoint [2] 0 0
52 weeks
Secondary outcome [3] 0 0
Time to First Graded Exacerbation
Timepoint [3] 0 0
52 weeks
Secondary outcome [4] 0 0
Duration of Graded Exacerbations
Timepoint [4] 0 0
52 weeks
Secondary outcome [5] 0 0
Sputum Volume
Timepoint [5] 0 0
52 weeks
Secondary outcome [6] 0 0
Daytime Sleepiness Scores
Timepoint [6] 0 0
52 weeks
Secondary outcome [7] 0 0
Lung Function - Change in FEV1 (Forced Expiratory Volume in One Second)
Timepoint [7] 0 0
52 weeks
Secondary outcome [8] 0 0
Lung Function - Change in FVC (Forced Vital Capacity)
Timepoint [8] 0 0
52 weeks
Secondary outcome [9] 0 0
Lung Function - Change in FEV1/FVC
Timepoint [9] 0 0
52 weeks
Secondary outcome [10] 0 0
Lung Function - Change in FEF25-75 (Forced Expiratory Flow Rate Averaged Over 25th -75th Percentile of FVC)
Timepoint [10] 0 0
52 weeks
Secondary outcome [11] 0 0
Safety Profile - Sputum Microbiology
Timepoint [11] 0 0
52 weeks
Secondary outcome [12] 0 0
Safety Profile - Clinical Chemistry
Timepoint [12] 0 0
52 weeks
Secondary outcome [13] 0 0
Safety Profile - Hematology
Timepoint [13] 0 0
52 weeks
Secondary outcome [14] 0 0
• (Exploratory) Number of Hospitalizations Due to Pulmonary Exacerbations
Timepoint [14] 0 0
52 weeks

Eligibility
Key inclusion criteria
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 computed tomography (CT), High resolution computed tomography (HRCT) or bronchogram
3. Be aged 18 - 85 years inclusive, male and female
4. Have FEV1 (Forced expiratory volume in one second) = 40% and =85% predicted* and =1.0L (*according to NHANES III predicted tables) measured at Visit 0A (V0A)
5. Clinician documented history of at least 2 pulmonary exacerbations, each requiring antibiotic therapy, in the last 12 months prior to Visit 0A (V0A) and a total of at least 4 in the last 2 years prior to Visit 0A
6. Have a total SGRQ (St George's respiratory questionnaire) score of =30 at Visit 0B (V0B)
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 (Mannitol Tolerance Test) administration)
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 (NTM)infection or be under consideration for NTM treatment in the next 12 months
16. Have unstable Allergic bronchopulmonary aspergillosis (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 ß2-agonists
23. Have uncontrolled hypertension - e.g. for adults: systolic blood pressure (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)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/11/2009
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/01/2014
Sample size
Target
Accrual to date
Final
485
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 0 0
Woolcock Institute of Medical Research - Glebe
Recruitment hospital [2] 0 0
St George Hospital - Kogarah
Recruitment hospital [3] 0 0
The Prince Charles Hospital - Chermside
Recruitment hospital [4] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [5] 0 0
Repatriation General Hospital - Daws Park
Recruitment hospital [6] 0 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [7] 0 0
St Vincent's Hospital - Fitzroy
Recruitment hospital [8] 0 0
Western Hospital - Footscray
Recruitment hospital [9] 0 0
The Rooms of Dr C Steinfort - Geelong
Recruitment hospital [10] 0 0
Royal Melbourne Hospital - Melbourne
Recruitment postcode(s) [1] 0 0
2037 - Glebe
Recruitment postcode(s) [2] 0 0
2217 - Kogarah
Recruitment postcode(s) [3] 0 0
4032 - Chermside
Recruitment postcode(s) [4] 0 0
5000 - Adelaide
Recruitment postcode(s) [5] 0 0
5041 - Daws Park
Recruitment postcode(s) [6] 0 0
5011 - Woodville
Recruitment postcode(s) [7] 0 0
3065 - Fitzroy
Recruitment postcode(s) [8] 0 0
3011 - Footscray
Recruitment postcode(s) [9] 0 0
3220 - Geelong
Recruitment postcode(s) [10] 0 0
3050 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
Connecticut
Country [3] 0 0
United States of America
State/province [3] 0 0
District of Columbia
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Minnesota
Country [7] 0 0
United States of America
State/province [7] 0 0
Missouri
Country [8] 0 0
United States of America
State/province [8] 0 0
New Jersey
Country [9] 0 0
United States of America
State/province [9] 0 0
New York
Country [10] 0 0
United States of America
State/province [10] 0 0
North Carolina
Country [11] 0 0
United States of America
State/province [11] 0 0
Oregon
Country [12] 0 0
United States of America
State/province [12] 0 0
Pennsylvania
Country [13] 0 0
United States of America
State/province [13] 0 0
South Carolina
Country [14] 0 0
United States of America
State/province [14] 0 0
Texas
Country [15] 0 0
United States of America
State/province [15] 0 0
Virginia
Country [16] 0 0
Argentina
State/province [16] 0 0
Ciudad Autónoma de Buenos Aires,
Country [17] 0 0
Argentina
State/province [17] 0 0
Paraná Entre Ríos
Country [18] 0 0
Argentina
State/province [18] 0 0
Provincia de Buenos Aires
Country [19] 0 0
Argentina
State/province [19] 0 0
Provincia de Cordoba
Country [20] 0 0
Argentina
State/province [20] 0 0
Provincia de Mendoza
Country [21] 0 0
Argentina
State/province [21] 0 0
Provincia de Santa Fe
Country [22] 0 0
Argentina
State/province [22] 0 0
Provincia de Tucumán
Country [23] 0 0
Argentina
State/province [23] 0 0
Provinica de Buenos Aires
Country [24] 0 0
Argentina
State/province [24] 0 0
San Martin Provincia de Buenos Aires
Country [25] 0 0
Argentina
State/province [25] 0 0
Buenos Aires
Country [26] 0 0
Argentina
State/province [26] 0 0
Ciudad Autonoma de Buenos Aires
Country [27] 0 0
Belgium
State/province [27] 0 0
Brussels
Country [28] 0 0
Belgium
State/province [28] 0 0
Leuven
Country [29] 0 0
Chile
State/province [29] 0 0
Santiago
Country [30] 0 0
Chile
State/province [30] 0 0
Talca
Country [31] 0 0
Germany
State/province [31] 0 0
Hessen
Country [32] 0 0
Germany
State/province [32] 0 0
Niedersachsen
Country [33] 0 0
Germany
State/province [33] 0 0
Nordrhein-Westfalen
Country [34] 0 0
Germany
State/province [34] 0 0
Sachsen
Country [35] 0 0
Netherlands
State/province [35] 0 0
Alkmaar AM
Country [36] 0 0
Netherlands
State/province [36] 0 0
Leeuwarden AD
Country [37] 0 0
Netherlands
State/province [37] 0 0
Heerlen
Country [38] 0 0
New Zealand
State/province [38] 0 0
Auckland
Country [39] 0 0
New Zealand
State/province [39] 0 0
Hamilton
Country [40] 0 0
United Kingdom
State/province [40] 0 0
Carmarthenshire
Country [41] 0 0
United Kingdom
State/province [41] 0 0
Derbyshire
Country [42] 0 0
United Kingdom
State/province [42] 0 0
Devon
Country [43] 0 0
United Kingdom
State/province [43] 0 0
East Yorkshire
Country [44] 0 0
United Kingdom
State/province [44] 0 0
Leicestershire
Country [45] 0 0
United Kingdom
State/province [45] 0 0
Nottinghamshire
Country [46] 0 0
United Kingdom
State/province [46] 0 0
Oxfordshire
Country [47] 0 0
United Kingdom
State/province [47] 0 0
Shropshire
Country [48] 0 0
United Kingdom
State/province [48] 0 0
South Yorkshire
Country [49] 0 0
United Kingdom
State/province [49] 0 0
Staffordshire
Country [50] 0 0
United Kingdom
State/province [50] 0 0
Surrey
Country [51] 0 0
United Kingdom
State/province [51] 0 0
Teeside
Country [52] 0 0
United Kingdom
State/province [52] 0 0
Vale of Glamorgan
Country [53] 0 0
United Kingdom
State/province [53] 0 0
West Midlands
Country [54] 0 0
United Kingdom
State/province [54] 0 0
Aberdeen
Country [55] 0 0
United Kingdom
State/province [55] 0 0
Belfast
Country [56] 0 0
United Kingdom
State/province [56] 0 0
Liverpool
Country [57] 0 0
United Kingdom
State/province [57] 0 0
London
Country [58] 0 0
United Kingdom
State/province [58] 0 0
Newcastle-upon-Tyne
Country [59] 0 0
United Kingdom
State/province [59] 0 0
North Shields
Country [60] 0 0
United Kingdom
State/province [60] 0 0
Southampton
Country [61] 0 0
United Kingdom
State/province [61] 0 0
Wrexham

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Syntara
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/study/NCT00669331
Trial related presentations / publications
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. doi: 10.1164/ajrccm.159.6.9809074.
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. doi: 10.1183/09031936.00119707. 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. doi: 10.1111/j.1440-1843.2007.01107.x.
Daviskas E, Anderson SD. Hyperosmolar agents and clearance of mucus in the diseased airway. J Aerosol Med. 2006 Spring;19(1):100-9. doi: 10.1089/jam.2006.19.100.
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. doi: 10.1111/j.1440-1843.2005.00659.x.
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. doi: 10.1089/089426802760292681.
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. doi: 10.1378/chest.119.2.414.
Bilton D, Tino G, Barker AF, Chambers DC, De Soyza A, Dupont LJ, O'Dochartaigh C, van Haren EH, Vidal LO, Welte T, Fox HG, Wu J, Charlton B; B-305 Study Investigators. Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial. Thorax. 2014 Dec;69(12):1073-9. doi: 10.1136/thoraxjnl-2014-205587. Epub 2014 Sep 21.
Public notes

Contacts
Principal investigator
Name 0 0
Diana Bilton, MD
Address 0 0
Brompton Hospital London UK
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT00669331