Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis

NCT00669331 | Completed Phase 3 Results DMC

• 1 other identifier: DPM-B-305
• Study Type: interventional
• Target: 485
• Locations: 9 countries
• Sites: 83

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.

Conditions

Bronchiectasis

Keywords

randomized clinical trial; mannitol; mucoactive

Outcome Measures

Primary Outcomes (1)

• Rate of Graded Pulmonary Exacerbations

  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

  52 weeks

Secondary Outcomes (14)

• Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score

  52 weeks

• Antibiotic Use Prescribed for Treated Pulmonary Exacerbations

  52 weeks

• Time to First Graded Exacerbation

  52 weeks

• Duration of Graded Exacerbations

  52 weeks

• Sputum Volume

  52 weeks

Other Outcomes (4)

• Health Related Costs of Treating Patients With Bronchiectasis

  52 weeks

• Health Status and Utility Scores

  52 weeks

• 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

Study Arms (2)

Mannitol

EXPERIMENTAL

Inhaled mannitol 400mg

Drug: Inhaled mannitol

Control

PLACEBO COMPARATOR

Matched control - inhaled mannitol 50mg

Drug: Matched control

Interventions

Inhaled mannitol DRUG

400mg dose of Mannitol BD (twice a day) for 52 weeks

Mannitol

Matched control DRUG

50mg dose of Mannitol BD (twice a day) for 52 weeks

Control

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have given written informed consent to participate in this study in accordance with local regulations
• Have documented evidence of confirmed diagnosis of (non-cystic fibrosis) bronchiectasis by computed tomography (CT), High resolution computed tomography (HRCT) or bronchogram
• Be aged 18 - 85 years inclusive, male and female
• 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)
• 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
• Have a total SGRQ (St George's respiratory questionnaire) score of ≥30 at Visit 0B (V0B)
• 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
• Be able to perform all the techniques necessary to measure lung function
• 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)

You may not qualify if:

• 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.
• Have bronchiectasis as a consequence of cystic fibrosis or focal endobronchial lesion or otherwise curable causes (e.g. foreign body aspiration)
• Be considered "terminally ill" or listed for transplantation
• Be using hypertonic saline in the 14 days prior to commencing Visit 0B or thereafter at any time during the study
• Have previously used inhaled mannitol (Bronchitol) for more than a day
• Have had a significant episode of hemoptysis (\>60 mL) in the previous 6 months
• Have had rescue antibiotics in the 4 weeks prior to V0B (chronic background antibiotic therapy accepted)
• Have smoked within the last 3 months and must not smoke during their participation in the study
• Have had a myocardial infarction in the three months prior to Visit 0A
• Have had a cerebral vascular accident in the three months prior to Visit 0A
• Have had major ocular surgery in the three months prior to Visit 0A
• Have had major abdominal, chest or brain surgery in the three months prior to Visit 0A
• Have a known cerebral, aortic or abdominal aneurysm
• Have actively treated Mycobacterium tuberculosis
• Have actively treated or unstable nontuberculous mycobacterial (NTM)infection or be under consideration for NTM treatment in the next 12 months

Sponsors & Collaborators

• Syntara: lead

Study Sites (83)

National Jewish Medical and Research Center

Denver, Colorado, 80206, United States

Location

University of Connecticut Health Center, Pulmonary Division

Farmington, Connecticut, 06030-1321, United States

Location

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Florida Pulmonary Research

Winter Park, Florida, 32789, United States

Location

The University of Chicago Hospitals

Chicago, Illinois, 60637, United States

Location

Chest Medicine Clinical Services, LLC

Skokie, Illinois, 60076, United States

Location

Allergy and Critical Care Medicine Pulmonary Clinical Research Unit

Rochester, Minnesota, 55905, United States

Location

Saint Luke's Hospital

Chesterfield, Missouri, 63017, United States

Location

Pulmonary and Allergy Associates

Summit, New Jersey, 07901, United States

Location

Winthrop University Hospital

Mineola, New York, 11501, United States

Location

Research Associates of New York

New York, New York, 10028, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27514, United States

Location

The Oregon Clinic, PC/Pulmonary Division

Portland, Oregon, 97220, United States

Location

University of Pennsylvania Medical Center

Philadelphia, Pennsylvania, 19104, United States

Location

Temple University Hospital

Philadelphia, Pennsylvania, 19140, United States

Location

South Carolina Pharmaceutical Research

Spartanburg, South Carolina, 29303, United States

Location

Alamo Clinical Research Associates

San Antonio, Texas, 78212, United States

Location

Pulmonary Associates of Richmond, Inc

Richmond, Virginia, 23225, United States

Location

Hospital Zonal Especializado en Agudos y Cronicos "Dr Antonio A. Cetrangolo

Florida Partido de Vicente López, Buenos Aires, B1602DOH, Argentina

Location

Centro Respiratorio Quilmes

Quilmes, Buenos Aires, B1878FNR, Argentina

Location

Instituto Argentino de Investigación Neurológica

Buenos Aires, Buenos Aires F.D., C1015ABR, Argentina

Location

Hospital Privado - Centro Medico de Cordoba

Córdoba, Córdoba Province, X5016KEH, Argentina

Location

Insares

Mendoza, Mendoza Province, M5500CCG, Argentina

Location

Centro Privado de Medicina Respiratoria

Entre Ríos, Paraná Entre Ríos, E3100BHK, Argentina

Location

Hospital Interzonal General de Agudos "Dr Jose Penna"

Bahia Bianca, Provinica de Buenos Aires, B8001DDU, Argentina

Location

Corporacion medica de General San Martin

Matheu, San Martin Provincia de Buenos Aires, B1650CSQ, Argentina

Location

Clinica del Torax

Rosario, Santa Fe Province, S2000DBS, Argentina

Location

Instituto Cardiovascular de Rosario

Rosario, Santa Fe Province, S2000DSR, Argentina

Location

Sanatorio Parque

Rosario, Santa Fe Province, S2000KZD, Argentina

Location

Investigaciones en Patologias Respiratorias

San Miguel de Tucumán, Tucumán Province, T4000IAR, Argentina

Location

Centro Médico Dra. De Salvo

Buenos Aires, CP1426ABO, Argentina

Location

Atención Integral en Reumatología (AIR)

Buenos Aires, CP1426, Argentina

Location

Woolcock Institute of Medical Research

Glebe, New South Wales, 2037, Australia

Location

St George Hospital

Kogarah, New South Wales, 2217, Australia

Location

The Prince Charles Hospital

Chermside, Queensland, 4032, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Repatriation General Hospital

Daws Park, South Australia, 5041, Australia

Location

The Queen Elizabeth Hospital

Woodville, South Australia, 5011, Australia

Location

St Vincent's Hospital

Fitzroy, Victoria, 3065, Australia

Location

Western Hospital

Footscray, Victoria, 3011, Australia

Location

The Rooms of Dr C Steinfort

Geelong, Victoria, 3220, Australia

Location

Royal Melbourne Hospital

Melbourne, Victoria, 3050, Australia

Location

ULB Hopital Erasme - Department of Pneumology

Brussels, Brussels Capital, B-1070, Belgium

Location

Cliniques Universitaires St. Luc (UCL) - Department of Pulmonology

Brussels, Brussels Capital, B-1200, Belgium

Location

UZ Leuven (University Hospital Leuven) - Depatment of Pulmonary Medicine

Leuven, Leuven, B-3000, Belgium

Location

Pontificia Universidad Catolica de Chile

Santiago, Santiago Metropolitan, Chile

Location

Universidad de Chile

Santiago, Santiago Metropolitan, Chile

Location

Hospital Regional de Talca

Talca, Talca, 1990, Chile

Location

IKF Pneumologie GmbH and Co KG

Frankfurt am Main, Hesse, 60596, Germany

Location

Medizinische Hochschule Hannover Klinik für Pneumologie

Hanover, Lower Saxony, 30625, Germany

Location

Lungen und Bronchialheikunde

Bonn, North Rhine-Westphalia, 53123, Germany

Location

Pneumologisch Studienzentrum

Leipzig, Saxony, 4357, Germany

Location

Medisch Centrum Alkmaar - Department of Pulmonary Medicine

Alkmaar, Alkmaar AM, 1800, Netherlands

Location

Atrium MC -Department of Pulmonary Diseases

Heerlen, Heerlen, 6419, Netherlands

Location

Medisch Centrum Leeuwarden (MCL) - Department of Pulmonology

Leeuwarden, Leeuwarden AD, 8934, Netherlands

Location

Middlemore Hospital

Auckland, Auckland, 1640, New Zealand

Location

Green Lane Clinical Centre

Greenlane, Auckland, 1051, New Zealand

Location

Waikato Hospital

Hamilton, 3240, New Zealand

Location

West Wales General Hospital

Carmarthen, Carmarthenshire, SA31 2AF, United Kingdom

Location

Royal Derby Hospital

Derby, Derbyshire, DE22 3NE, United Kingdom

Location

Royal Devon and Exeter Hospital

Exeter, Devon, EX2 5DW, United Kingdom

Location

Torbay Hospital

Torquay, Devon, TQ2 7AA, United Kingdom

Location

Castle Hill Hospital

Cottingham, East Yorkshire, HU16 5JQ, United Kingdom

Location

Glenfield Hospital

Leicester, Leicestershire, LE3 9QP, United Kingdom

Location

Nottingham City Hospital

Nottingham, Nottinghamshire, NG5 1PB, United Kingdom

Location

Churchill Hospital

Headington, Oxfordshire, OX3 7LJ, United Kingdom

Location

Royal Shrewsbury Hospital

Shrewsbury, Shropshire, SY3 8XQ, United Kingdom

Location

Sheffield Northern General Hospital

Sheffield, South Yorkshire, S5 7AU, United Kingdom

Location

Stafford Hospital

Stafford, Staffordshire, ST16 3SA, United Kingdom

Location

Ashford & St Peters Hospital

Chertsey, Surrey, KT16 0PZ, United Kingdom

Location

University Hospital of North Tees

Stockton, Teeside, TS19 8PE, United Kingdom

Location

Llandough Hospital

Cardiff, Vale of Glamorgan, CF64 2XX, United Kingdom

Location

Birmingam Queen Elizabeth Hospital

Birmingham, West Midlands, B15 2TH, United Kingdom

Location

Wolverhampton New Cross Hospital

Wolverhampton, West Midlands, WV10 0QP, United Kingdom

Location

Aberdeen Royal Infirmary

Aberdeen, AB25 22N, United Kingdom

Location

Belfast City Hospital

Belfast, BT9 7AB, United Kingdom

Location

University Hospital Aintree

Liverpool, L9 7AL, United Kingdom

Location

Royal Brompton Hospital

London, SW3 6NP, United Kingdom

Location

Freeman Hospital

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

North Tyneside General Hospital

North Shields, NE29 8NH, United Kingdom

Location

Southampton General Hospital

Southampton, SO16 6YD, United Kingdom

Location

Wrexham Maelor Hospital

Wrexham, LL13 7TD, United Kingdom

Location

Related Publications (8)

• 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.

  PMID: 10351929 BACKGROUND

• 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.

  PMID: 18057051 BACKGROUND

• 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.

  PMID: 17875056 BACKGROUND

• 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.

  PMID: 16551221 BACKGROUND

• 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.

  PMID: 15691238 BACKGROUND

• 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.

  PMID: 12396422 BACKGROUND

• 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.

  PMID: 11171717 BACKGROUND

• 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.

  PMID: 25246664 DERIVED

MeSH Terms

Conditions

Bronchiectasis

Interventions

Case-Control Studies

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Epidemiologic Studies; Epidemiologic Study Characteristics; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Limitations and Caveats

Relatively few studies in this area -ideal choice of endpoints not well-defined. No widely accepted exacerbation definition. Relies on patients' accurate \& timely symptom reporting.Unclear event end-dates may impact on counting of subsequent events.

Results Point of Contact

• Title: Dr Brett Charlton, Medical Director
• Organization: Pharmaxis Ltd

brett.charlton@pharmaxis.com.au

+61 2 94547210

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 28, 2008
• First Posted: April 30, 2008
• Study Start: November 1, 2009
• Primary Completion: January 1, 2014
• Study Completion: January 1, 2014
• Last Updated: April 29, 2016
• Results First Posted: April 29, 2016

Record last verified: 2016-03

Locations

DE (4); CL (3); NL (3); AR (14); NZ (3); GB (24); AU (10); US (19); BE (3)