Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis

: 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.

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 Overview

• Status: Completed
• Conditions: Bronchiectasis
• Intervention / Treatment: Drug: Inhaled mannitol; Drug: Matched control

• Study Type: Interventional
• Enrollment (Actual): 485
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, CP1426
    • Atencion Integral en Reumatologia (AIR)
  • Ciudad Autonoma de Buenos Aires, Argentina, CP1426ABO
    • Centro Médico Dra. De Salvo
  • Ciudad Autónoma de Buenos Aires,
    • Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires,, Argentina, C1015ABR
      • Instituto Argentino de Investigacion Neurologica
  • Paraná Entre Ríos
    • Entre Rios, Paraná Entre Ríos, Argentina, E3100BHK
      • Centro Privado de Medicina Respiratoria
  • Provincia de Buenos Aires
    • Florida Partido de Vicente López, Provincia de Buenos Aires, Argentina, B1602DOH
      • Hospital Zonal Especializado en Agudos y Cronicos "Dr Antonio A. Cetrangolo
    • Quilmes, Provincia de Buenos Aires, Argentina, B1878FNR
      • Centro Respiratorio Quilmes
  • Provincia de Cordoba
    • Cordoba, Provincia de Cordoba, Argentina, X5016KEH
      • Hospital Privado - Centro Medico de Cordoba
  • Provincia de Mendoza
    • Mendoza, Provincia de Mendoza, Argentina, M5500CCG
      • INSARES
  • Provincia de Santa Fe
    • Rosario, Provincia de Santa Fe, Argentina, S2000DBS
      • Clinica del Tórax
    • Rosario, Provincia de Santa Fe, Argentina, S2000DSR
      • Instituto Cardiovascular de Rosario
    • Rosario, Provincia de Santa Fe, Argentina, S2000KZD
      • Sanatorio Parque
  • Provincia de Tucumán
    • San Miguel de Tucumán, Provincia de Tucumán, Argentina, T4000IAR
      • Investigaciones en Patologias Respiratorias
  • Provinica de Buenos Aires
    • Bahia Bianca, Provinica de Buenos Aires, Argentina, B8001DDU
      • Hospital Interzonal General de Agudos "Dr Jose Penna"
  • San Martin Provincia de Buenos Aires
    • Mathew 4071, San Martin Provincia de Buenos Aires, Argentina, B1650CSQ
      • Corporación Médica de General San Martín
• Australia
  • New South Wales
    • Glebe, New South Wales, Australia, 2037
      • Woolcock Institute of Medical Research
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital
  • Queensland
    • Chermside, Queensland, Australia, 4032
      • The Prince Charles Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
    • Daws Park, South Australia, Australia, 5041
      • Repatriation General Hospital
    • Woodville, South Australia, Australia, 5011
      • The Queen Elizabeth Hospital
  • Victoria
    • Fitzroy, Victoria, Australia, 3065
      • St Vincent's hospital
    • Footscray, Victoria, Australia, 3011
      • Western Hospital
    • Geelong, Victoria, Australia, 3220
      • The Rooms of Dr C Steinfort
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital
• Belgium
  • Brussels, Belgium, B-1070
    • ULB Hopital Erasme - Department of Pneumology
  • Brussels, Belgium, B-1200
    • Cliniques Universitaires St. Luc (UCL) - Department of Pulmonology
  • Leuven, Belgium, B-3000
    • UZ Leuven (University Hospital Leuven) - Depatment of Pulmonary Medicine
• Chile
  • Talca, Chile, 1990
    • Hospital Regional de Talca
  • Santiago
    • Santiago de Chile, Santiago, Chile
      • Pontificia Universidad Catolica de Chile
    • Santiago de Chile, Santiago, Chile
      • Universidad de Chile
• Germany
  • Hessen
    • Frankfurt, Hessen, Germany, 60596
      • IKF Pneumologie GmbH and Co KG
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hannover Klinik für Pneumologie
  • Nordrhein-Westfalen
    • Bonn, Nordrhein-Westfalen, Germany, 53123
      • Lungen und Bronchialheikunde
  • Sachsen
    • Leipzig, Sachsen, Germany, 4357
      • Pneumologisch Studienzentrum
• Netherlands
  • Heerlen, Netherlands, 6419
    • Atrium MC -Department of Pulmonary Diseases
  • Alkmaar AM
    • Alkmaar, Alkmaar AM, Netherlands, 1800
      • Medisch Centrum Alkmaar - Department of Pulmonary Medicine
  • Leeuwarden AD
    • Leeuwarden, Leeuwarden AD, Netherlands, 8934
      • Medisch Centrum Leeuwarden (MCL) - Department of Pulmonology
• New Zealand
  • Auckland, New Zealand, 1640
    • Middlemore Hospital
  • Hamilton, New Zealand, 3240
    • Waikato Hospital
  • Auckland
    • Greenlane, Auckland, New Zealand, 1051
      • Green Lane Clinical Centre
• United Kingdom
  • Aberdeen, United Kingdom, AB25 22N
    • Aberdeen Royal Infirmary
  • Belfast, United Kingdom, BT9 7AB
    • Belfast City Hospital
  • Liverpool, United Kingdom, L9 7AL
    • University Hospital Aintree
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital
  • Newcastle-upon-Tyne, United Kingdom, NE7 7DN
    • Freeman Hospital
  • North Shields, United Kingdom, NE29 8NH
    • North Tyneside General Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital
  • Wrexham, United Kingdom, LL13 7TD
    • Wrexham Maelor Hospital
  • Carmarthenshire
    • Carmarthen, Carmarthenshire, United Kingdom, SA31 2AF
      • West Wales General Hospital
  • Derbyshire
    • Derby, Derbyshire, United Kingdom, DE22 3NE
      • Royal Derby Hospital
  • Devon
    • Exeter, Devon, United Kingdom, EX2 5DW
      • Royal Devon and Exeter Hospital
    • Torquay, Devon, United Kingdom, TQ2 7AA
      • Torbay Hospital
  • East Yorkshire
    • Cottingham, East Yorkshire, United Kingdom, HU16 5JQ
      • Castle Hill Hospital
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE3 9QP
      • Glenfield Hospital
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG5 1PB
      • Nottingham City Hospital
  • Oxfordshire
    • Headington, Oxfordshire, United Kingdom, OX3 7LJ
      • Churchill Hospital
  • Shropshire
    • Shrewsbury, Shropshire, United Kingdom, SY3 8XQ
      • Royal Shrewsbury Hospital
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S5 7AU
      • Sheffield Northern General Hospital
  • Staffordshire
    • Stafford, Staffordshire, United Kingdom, ST16 3SA
      • Stafford Hospital
  • Surrey
    • Chertsey, Surrey, United Kingdom, KT16 0PZ
      • Ashford & St Peters Hospital
  • Teeside
    • Stockton, Teeside, United Kingdom, TS19 8PE
      • University Hospital of North Tees
  • Vale of Glamorgan
    • Cardiff, Vale of Glamorgan, United Kingdom, CF64 2XX
      • LLandough Hospital
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • Birmingam Queen Elizabeth Hospital
    • Wolverhampton, West Midlands, United Kingdom, WV10 0QP
      • Wolverhampton New Cross Hospital
• United States
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Medical and Research Center
  • Connecticut
    • Farmington, Connecticut, United States, 06030-1321
      • University of Connecticut Health Center, Pulmonary Division
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
    • Winter Park, Florida, United States, 32789
      • Florida Pulmonary Research
  • Illinois
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Hospitals
    • Skokie, Illinois, United States, 60076
      • Chest Medicine Clinical Services, LLC
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Allergy and Critical Care Medicine Pulmonary Clinical Research Unit
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • Saint Luke's Hospital
  • New Jersey
    • Summit, New Jersey, United States, 07901
      • Pulmonary and Allergy Associates
  • New York
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New York, New York, United States, 10028
      • Research Associates of New York
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina
  • Oregon
    • Portland, Oregon, United States, 97220
      • The Oregon Clinic, PC/Pulmonary Division
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Medical Center
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • South Carolina Pharmaceutical Research
  • Texas
    • San Antonio, Texas, United States, 78212
      • Alamo Clinical Research Associates
  • Virginia
    • Richmond, Virginia, United States, 23225
      • Pulmonary Associates of Richmond, Inc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mannitol; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score	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.	52 weeks
Antibiotic Use Prescribed for Treated Pulmonary Exacerbations	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.	52 weeks
Time to First Graded Exacerbation	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.	52 weeks
Duration of Graded Exacerbations	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	52 weeks
Sputum Volume	24 hour sputum weight, measured at baseline, week 6, week 16, week 28, week 40, week 52	52 weeks
Daytime Sleepiness Scores	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	52 weeks
Lung Function - Change in FEV1 (Forced Expiratory Volume in One Second)		52 weeks
Lung Function - Change in FVC (Forced Vital Capacity)		52 weeks
Lung Function - Change in FEV1/FVC	FEV1 expressed as a ratio of FVC. Endpoint is expressed as a percentage ie FEV1/FVC*100	52 weeks
Lung Function - Change in FEF25-75 (Forced Expiratory Flow Rate Averaged Over 25th -75th Percentile of FVC)		52 weeks
Safety Profile - Sputum Microbiology	sputum microbiology assessed as the presence of abnormal flora in sputum sample taken at any post baseline visit	52 weeks
Safety Profile - Clinical Chemistry	Clinical chemistry was assessed as clinically significant abnormal liver function test and clinically significant abnormal urea/electrolyte test at any point post baseline.	52 weeks
Safety Profile - Hematology	hematology assessed as clinically significant abnormal FBC (Full Blood count) at any point post baseline.	52 weeks
• (Exploratory) Number of Hospitalizations Due to Pulmonary Exacerbations	Mean rate of hospitalisations (number/year) summarised and analysed to take account of differing follow-up times.	52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health Related Costs of Treating Patients With Bronchiectasis	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)	52 weeks
Health Status and Utility Scores	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)	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	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).	52 weeks
Cost Effectiveness of Treating Patients With Bronchiectasis With Inhaled Mannitol	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).	52 weeks

Collaborators and Investigators

• Sponsor: Pharmaxis
• Investigators: 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

Publications and helpful links

General 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, 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.
• 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, 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, 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.
• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: April 28, 2008
• First Submitted That Met QC Criteria: April 29, 2008
• First Posted (Estimate): April 30, 2008

Study Record Updates

• Last Update Posted (Estimate): April 29, 2016
• Last Update Submitted That Met QC Criteria: March 29, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: mannitol; randomized clinical trial; mucoactive
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Bronchial Diseases; Bronchiectasis; Physiological Effects of Drugs; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Mannitol
• Other Study ID Numbers: DPM-B-305