Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis

Bronchiectasis Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00669331
• Other study ID #: DPM-B-305
• Status: Completed
• Phase: Phase 3
• First received: April 28, 2008
• Last updated: January 12, 2014
• Start date: November 2009
• Est. completion date: January 2014

Study information

• Verified date: January 2014
• Source: Pharmaxis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustralia: Department of Health and Ageing Therapeutic Goods AdministrationGermany: Federal Institute for Drugs and Medical DevicesUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyNew Zealand: MedsafeBelgium: Federal Agency for Medicinal Products and Health ProductsNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Chile: Instituto de Salud Pública de Chile
• Study type: Interventional

Clinical Trial 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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 485
• Est. completion date: January 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 85 Years

Eligibility

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 ß2-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)

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bronchiectasis

Intervention

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

Locations

Country	Name	City	State
Argentina	Hospital Interzonal General de Agudos "Dr Jose Penna"	Bahia Bianca	Provinica de Buenos Aires
Argentina	Atención Integral en Reumatología (AIR)	Buenos Aires
Argentina	Centro Médico Dra. De Salvo	Ciudad Autonoma de Buenos Aires
Argentina	Instituto Argentino de Investigación Neurológica	Ciudad Autónoma de Buenos Aires	Ciudad Autónoma de Buenos Aires,
Argentina	Hospital Privado - Centro Medico de Cordoba	Cordoba	Provincia de Cordoba
Argentina	Centro Privado de Medicina Respiratoria	Entre Rios	Paraná Entre Ríos
Argentina	Hospital Zonal Especializado en Agudos y Cronicos "Dr Antonio A. Cetrangolo	Florida Partido de Vicente López	Provincia de Buenos Aires
Argentina	Corporacion medica de General San Martin	Mathew 4071	San Martin Provincia de Buenos Aires
Argentina	Insares	Mendoza	Provincia de Mendoza
Argentina	Centro Respiratorio Quilmes	Quilmes	Provincia de Buenos Aires
Argentina	Clinica del Torax	Rosario	Provincia de Santa Fe
Argentina	Instituto Cardiovascular de Rosario	Rosario	Provincia de Santa Fe
Argentina	Sanatorio Parque	Rosario	Provincia de Santa Fe
Argentina	Investigaciones en Patologias Respiratorias	San Miguel de Tucumán	Provincia de Tucumán
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	The Prince Charles Hospital	Chermside	Queensland
Australia	Repatriation General Hospital	Daws Park	South Australia
Australia	St Vincent's Hospital	Fitzroy	Victoria
Australia	Western Hospital	Footscray	Victoria
Australia	The Rooms of Dr C Steinfort	Geelong	Victoria
Australia	Woolcock Institute of Medical Research	Glebe	New South Wales
Australia	St George Hospital	Kogarah	New South Wales
Australia	Royal Melbourne Hospital	Melbourne	Victoria
Australia	The Queen Elizabeth Hospital	Woodville	South Australia
Belgium	Cliniques Universitaires St. Luc (UCL) - Department of Pulmonology	Brussels
Belgium	ULB Hopital Erasme - Department of Pneumology	Brussels
Belgium	UZ Leuven (University Hospital Leuven) - Depatment of Pulmonary Medicine	Leuven
Chile	Pontificia Universidad Catolica de Chile	Santiago de Chile	Santiago
Chile	Universidad de Chile	Santiago de Chile	Santiago
Chile	Hospital Regional de Talca	Talca
Germany	Lungen und Bronchialheikunde	Bonn	Nordrhein-Westfalen
Germany	IKF Pneumologie GmbH and Co KG	Frankfurt	Hessen
Germany	Medizinische Hochschule Hannover Klinik für Pneumologie	Hannover	Niedersachsen
Germany	Pneumologisch Studienzentrum	Leipzig	Sachsen
Netherlands	Medisch Centrum Alkmaar - Department of Pulmonary Medicine	Alkmaar	Alkmaar AM
Netherlands	Atrium MC -Department of Pulmonary Diseases	Heerlen
Netherlands	Medisch Centrum Leeuwarden (MCL) - Department of Pulmonology	Leeuwarden	Leeuwarden AD
New Zealand	Middlemore Hospital	Auckland
New Zealand	Green Lane Clinical Centre	Greenlane	Auckland
New Zealand	Waikato Hospital	Hamilton
United Kingdom	Aberdeen Royal Infirmary	Aberdeen
United Kingdom	Belfast City Hospital	Belfast
United Kingdom	Birmingam Queen Elizabeth Hospital	Birmingham	West Midlands
United Kingdom	Llandough Hospital	Cardiff	Vale of Glamorgan
United Kingdom	West Wales General Hospital	Carmarthen	Carmarthenshire
United Kingdom	Ashford & St Peters Hospital	Chertsey	Surrey
United Kingdom	Castle Hill Hospital	Cottingham	East Yorkshire
United Kingdom	Royal Derby Hospital	Derby	Derbyshire
United Kingdom	Royal Devon and Exeter Hospital	Exeter	Devon
United Kingdom	Churchill Hospital	Headington	Oxfordshire
United Kingdom	Glenfield Hospital	Leicester	Leicestershire
United Kingdom	University Hospital Aintree	Liverpool
United Kingdom	Royal Brompton Hospital	London
United Kingdom	Freeman Hospital	Newcastle-upon-Tyne
United Kingdom	North Tyneside General Hospital	North Shields
United Kingdom	Nottingham City Hospital	Nottingham	Nottinghamshire
United Kingdom	Sheffield Northern General Hospital	Sheffield	South Yorkshire
United Kingdom	Royal Shrewsbury Hospital	Shrewsbury	Shropshire
United Kingdom	Southampton General Hospital	Southampton
United Kingdom	Stafford Hospital	Stafford	Staffordshire
United Kingdom	University Hospital of North Tees	Stockton	Teeside
United Kingdom	Torbay Hospital	Torquay	Devon
United Kingdom	Wolverhampton New Cross Hospital	Wolverhampton	West Midlands
United Kingdom	Wrexham Maelor Hospital	Wrexham
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Saint Luke's Hospital	Chesterfield	Missouri
United States	The University of Chicago Hospitals	Chicago	Illinois
United States	National Jewish Medical and Research Center	Denver	Colorado
United States	University of Connecticut Health Center, Pulmonary Division	Farmington	Connecticut
United States	University of Miami	Miami	Florida
United States	Winthrop University Hospital	Mineola	New York
United States	Research Associates of New York	New York	New York
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvania Medical Center	Philadelphia	Pennsylvania
United States	The Oregon Clinic, PC/Pulmonary Division	Portland	Oregon
United States	Pulmonary Associates of Richmond, Inc	Richmond	Virginia
United States	Allergy and Critical Care Medicine Pulmonary Clinical Research Unit	Rochester	Minnesota
United States	Alamo Clinical Research Associates	San Antonio	Texas
United States	Chest Medicine Clinical Services, LLC	Skokie	Illinois
United States	South Carolina Pharmaceutical Research	Spartanburg	South Carolina
United States	Pulmonary and Allergy Associates	Summit	New Jersey
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	Florida Pulmonary Research	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Pharmaxis

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Chile,  Germany,  Netherlands,  New Zealand,  United Kingdom, 

References & Publications (7)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Daviskas E, Anderson SD, Young IH. Inhaled mannitol changes the sputum properties in asthmatics with mucus hypersecretion. Respirology. 2007 Sep;12(5):683-91. — View Citation

Daviskas E, Anderson SD. Hyperosmolar agents and clearance of mucus in the diseased airway. J Aerosol Med. 2006 Spring;19(1):100-9. Review. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	• To show a significant difference in the rates of graded pulmonary exacerbations, in patients with bronchiectasis treated with inhaled mannitol compared to placebo control		52 weeks	No
Secondary	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		52 weeks	No
Secondary	• 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.		52 weeks	No
Secondary	• 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		52 weeks	No
Secondary	• To show a significant difference in sputum volume in patients with bronchiectasis treated with inhaled mannitol compared to placebo control		52 weeks	No
Secondary	• To show a significant difference in daytime sleepiness scores in patients with bronchiectasis treated with inhaled mannitol compared to placebo control		52 weeks	No
Secondary	• 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		52 weeks	No
Secondary	• 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		52 weeks	Yes
Secondary	To compare health related costs of treating patients with bronchiectasis with inhaled mannitol and placebo control		52 weeks	No
Secondary	To compare health status and utility scores in patients treated with inhaled mannitol compared to placebo control		52 weeks	No
Secondary	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		52 weeks	No
Secondary	To investigate cost effectiveness of treating patients with bronchiectasis with inhaled mannitol		52 weeks	No
Secondary	• (Exploratory) To investigate number of hospitalizations due to pulmonary exacerbations in patients with bronchiectasis treated with inhaled mannitol compared to placebo control		52 weeks	No