Clinical trial NCT00669331: Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bronchiectasis
Keywords: randomized clinical trial
mannitol
mucoactive
Lead sponsor: Syntara
Sponsor class: INDUSTRY
First posted: 2008-04-30
Enrollment: 485
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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)

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 β2-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)

Primary outcomes:
measure: Rate of Graded Pulmonary Exacerbations
timeFrame: 52 weeks
Secondary outcomes:
measure: Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score
timeFrame: 52 weeks
measure: Antibiotic Use Prescribed for Treated Pulmonary Exacerbations
timeFrame: 52 weeks
measure: Time to First Graded Exacerbation
timeFrame: 52 weeks
measure: Duration of Graded Exacerbations
timeFrame: 52 weeks
measure: Sputum Volume
timeFrame: 52 weeks
measure: Daytime Sleepiness Scores
timeFrame: 52 weeks
measure: Lung Function - Change in FEV1 (Forced Expiratory Volume in One Second)
timeFrame: 52 weeks
measure: Lung Function - Change in FVC (Forced Vital Capacity)
timeFrame: 52 weeks
measure: Lung Function - Change in FEV1/FVC
timeFrame: 52 weeks
measure: Lung Function - Change in FEF25-75 (Forced Expiratory Flow Rate Averaged Over 25th -75th Percentile of FVC)
timeFrame: 52 weeks
measure: Safety Profile - Sputum Microbiology
timeFrame: 52 weeks
measure: Safety Profile - Clinical Chemistry
timeFrame: 52 weeks
measure: Safety Profile - Hematology
timeFrame: 52 weeks
measure: • (Exploratory) Number of Hospitalizations Due to Pulmonary Exacerbations
timeFrame: 52 weeks
Other outcomes:
measure: Health Related Costs of Treating Patients With Bronchiectasis
timeFrame: 52 weeks
measure: Health Status and Utility Scores
timeFrame: 52 weeks
measure: Health Related Quality of Life (HRQL) and Quality Adjusted Life Years (QALYs) by Treatment Group Using Utility Scores From the Health Utilities Index Questionnaire
timeFrame: 52 weeks
measure: Cost Effectiveness of Treating Patients With Bronchiectasis With Inhaled Mannitol
timeFrame: 52 weeks
Locations:
city: Denver
country: United States
facility: National Jewish Medical and Research Center
state: Colorado
city: Farmington
country: United States
facility: University of Connecticut Health Center, Pulmonary Division
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Winter Park
country: United States
facility: Florida Pulmonary Research
state: Florida
city: Chicago
country: United States
facility: The University of Chicago Hospitals
state: Illinois
city: Skokie
country: United States
facility: Chest Medicine Clinical Services, LLC
state: Illinois
city: Rochester
country: United States
facility: Allergy and Critical Care Medicine Pulmonary Clinical Research Unit
state: Minnesota
city: Chesterfield
country: United States
facility: Saint Luke's Hospital
state: Missouri
city: Summit
country: United States
facility: Pulmonary and Allergy Associates
state: New Jersey
city: Mineola
country: United States
facility: Winthrop University Hospital
state: New York
city: New York
country: United States
facility: Research Associates of New York
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Portland
country: United States
facility: The Oregon Clinic, PC/Pulmonary Division
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Spartanburg
country: United States
facility: South Carolina Pharmaceutical Research
state: South Carolina
city: San Antonio
country: United States
facility: Alamo Clinical Research Associates
state: Texas
city: Richmond
country: United States
facility: Pulmonary Associates of Richmond, Inc
state: Virginia
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: Instituto Argentino de Investigación Neurológica
state: Ciudad Autónoma de Buenos Aires,
city: Entre Rios
country: Argentina
facility: Centro Privado de Medicina Respiratoria
state: Paraná Entre Ríos
city: Florida Partido de Vicente López
country: Argentina
facility: Hospital Zonal Especializado en Agudos y Cronicos "Dr Antonio A. Cetrangolo
state: Provincia de Buenos Aires
city: Quilmes
country: Argentina
facility: Centro Respiratorio Quilmes
state: Provincia de Buenos Aires
city: Cordoba
country: Argentina
facility: Hospital Privado - Centro Medico de Cordoba
state: Provincia de Cordoba
city: Mendoza
country: Argentina
facility: Insares
state: Provincia de Mendoza
city: Rosario
country: Argentina
facility: Clinica del Torax
state: Provincia de Santa Fe
city: Rosario
country: Argentina
facility: Instituto Cardiovascular de Rosario
state: Provincia de Santa Fe
city: Rosario
country: Argentina
facility: Sanatorio Parque
state: Provincia de Santa Fe
city: San Miguel de Tucumán
country: Argentina
facility: Investigaciones en Patologias Respiratorias
state: Provincia de Tucumán
city: Bahia Bianca
country: Argentina
facility: Hospital Interzonal General de Agudos "Dr Jose Penna"
state: Provinica de Buenos Aires
city: Mathew 4071
country: Argentina
facility: Corporacion medica de General San Martin
state: San Martin Provincia de Buenos Aires
city: Buenos Aires
country: Argentina
facility: Atención Integral en Reumatología (AIR)
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Centro Médico Dra. De Salvo
city: Glebe
country: Australia
facility: Woolcock Institute of Medical Research
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Chermside
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Daws Park
country: Australia
facility: Repatriation General Hospital
state: South Australia
city: Woodville
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Fitzroy
country: Australia
facility: St Vincent's Hospital
state: Victoria
city: Footscray
country: Australia
facility: Western Hospital
state: Victoria
city: Geelong
country: Australia
facility: The Rooms of Dr C Steinfort
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Brussels
country: Belgium
facility: ULB Hopital Erasme - Department of Pneumology
city: Brussels
country: Belgium
facility: Cliniques Universitaires St. Luc (UCL) - Department of Pulmonology
city: Leuven
country: Belgium
facility: UZ Leuven (University Hospital Leuven) - Depatment of Pulmonary Medicine
city: Santiago de Chile
country: Chile
facility: Pontificia Universidad Catolica de Chile
state: Santiago
city: Santiago de Chile
country: Chile
facility: Universidad de Chile
state: Santiago
city: Talca
country: Chile
facility: Hospital Regional de Talca
city: Frankfurt
country: Germany
facility: IKF Pneumologie GmbH and Co KG
state: Hessen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover Klinik für Pneumologie
state: Niedersachsen
city: Bonn
country: Germany
facility: Lungen und Bronchialheikunde
state: Nordrhein-Westfalen
city: Leipzig
country: Germany
facility: Pneumologisch Studienzentrum
state: Sachsen
city: Alkmaar
country: Netherlands
facility: Medisch Centrum Alkmaar - Department of Pulmonary Medicine
state: Alkmaar AM
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden (MCL) - Department of Pulmonology
state: Leeuwarden AD
city: Heerlen
country: Netherlands
facility: Atrium MC -Department of Pulmonary Diseases
city: Greenlane
country: New Zealand
facility: Green Lane Clinical Centre
state: Auckland
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Carmarthen
country: United Kingdom
facility: West Wales General Hospital
state: Carmarthenshire
city: Derby
country: United Kingdom
facility: Royal Derby Hospital
state: Derbyshire
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: Devon
city: Torquay
country: United Kingdom
facility: Torbay Hospital
state: Devon
city: Cottingham
country: United Kingdom
facility: Castle Hill Hospital
state: East Yorkshire
city: Leicester
country: United Kingdom
facility: Glenfield Hospital
state: Leicestershire
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
state: Nottinghamshire
city: Headington
country: United Kingdom
facility: Churchill Hospital
state: Oxfordshire
city: Shrewsbury
country: United Kingdom
facility: Royal Shrewsbury Hospital
state: Shropshire
city: Sheffield
country: United Kingdom
facility: Sheffield Northern General Hospital
state: South Yorkshire
city: Stafford
country: United Kingdom
facility: Stafford Hospital
state: Staffordshire
city: Chertsey
country: United Kingdom
facility: Ashford & St Peters Hospital
state: Surrey
city: Stockton
country: United Kingdom
facility: University Hospital of North Tees
state: Teeside
city: Cardiff
country: United Kingdom
facility: Llandough Hospital
state: Vale of Glamorgan
city: Birmingham
country: United Kingdom
facility: Birmingam Queen Elizabeth Hospital
state: West Midlands
city: Wolverhampton
country: United Kingdom
facility: Wolverhampton New Cross Hospital
state: West Midlands
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Liverpool
country: United Kingdom
facility: University Hospital Aintree
city: London
country: United Kingdom
facility: Royal Brompton Hospital
city: Newcastle-upon-Tyne
country: United Kingdom
facility: Freeman Hospital
city: North Shields
country: United Kingdom
facility: North Tyneside General Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Wrexham
country: United Kingdom
facility: Wrexham Maelor Hospital
Study officials:
affiliation: Brompton Hospital London UK
name: Diana Bilton, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania Medical Centre, Philadelphia
name: Greg Tino, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Oregon Health Sciences University, Portland Oregon
name: Alan Barker, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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. doi: 10.1183/09031936.00119707. Epub 2007 Dec 5.
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. doi: 10.1111/j.1440-1843.2007.01107.x.
citation: 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.
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. doi: 10.1111/j.1440-1843.2005.00659.x.
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. doi: 10.1089/089426802760292681.
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. doi: 10.1378/chest.119.2.414.
citation: 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.