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Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis

This study has been completed.
Information provided by (Responsible Party):
Pharmaxis Identifier:
First received: April 28, 2008
Last updated: March 29, 2016
Last verified: March 2016

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.

Condition Intervention Phase
Drug: Inhaled mannitol
Drug: Matched control
Phase 3

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

Resource links provided by NLM:

Further study details as provided by Pharmaxis:

Primary Outcome Measures:
  • Rate of Graded Pulmonary Exacerbations [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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

Secondary Outcome Measures:
  • Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Antibiotic Use Prescribed for Treated Pulmonary Exacerbations [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Time to First Graded Exacerbation [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Duration of Graded Exacerbations [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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

  • Sputum Volume [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    24 hour sputum weight, measured at baseline, week 6, week 16, week 28, week 40, week 52

  • Daytime Sleepiness Scores [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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

  • Lung Function - Change in FEV1 (Forced Expiratory Volume in One Second) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
  • Lung Function - Change in FVC (Forced Vital Capacity) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
  • Lung Function - Change in FEV1/FVC [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    FEV1 expressed as a ratio of FVC. Endpoint is expressed as a percentage ie FEV1/FVC*100

  • Lung Function - Change in FEF25-75 (Forced Expiratory Flow Rate Averaged Over 25th -75th Percentile of FVC) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
  • Safety Profile - Sputum Microbiology [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    sputum microbiology assessed as the presence of abnormal flora in sputum sample taken at any post baseline visit

  • Safety Profile - Clinical Chemistry [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    Clinical chemistry was assessed as clinically significant abnormal liver function test and clinically significant abnormal urea/electrolyte test at any point post baseline.

  • Safety Profile - Hematology [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    hematology assessed as clinically significant abnormal FBC (Full Blood count) at any point post baseline.

  • • (Exploratory) Number of Hospitalizations Due to Pulmonary Exacerbations [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    Mean rate of hospitalisations (number/year) summarised and analysed to take account of differing follow-up times.

Other Outcome Measures:
  • Health Related Costs of Treating Patients With Bronchiectasis [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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)

  • Health Status and Utility Scores [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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)

  • Health Related Quality of Life (HRQL) and Quality Adjusted Life Years (QALYs) by Treatment Group Using Utility Scores From the Health Utilities Index Questionnaire [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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).

  • Cost Effectiveness of Treating Patients With Bronchiectasis With Inhaled Mannitol [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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).

Enrollment: 485
Study Start Date: November 2009
Study Completion Date: January 2014
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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


Ages Eligible for Study:   18 Years to 85 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00669331

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Sponsors and Collaborators
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
  More Information

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Pharmaxis Identifier: NCT00669331     History of Changes
Other Study ID Numbers: DPM-B-305 
Study First Received: April 28, 2008
Results First Received: November 22, 2015
Last Updated: March 29, 2016
Health Authority: United States: Food and Drug Administration
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Australia: Department of Health and Ageing Therapeutic Goods Administration
Germany: Federal Institute for Drugs and Medical Devices
United Kingdom: Medicines and Healthcare Products Regulatory Agency
New Zealand: Medsafe
Belgium: Federal Agency for Medicinal Products and Health Products
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Chile: Instituto de Salud Pública de Chile

Keywords provided by Pharmaxis:
randomized clinical trial

Additional relevant MeSH terms:
Bronchial Diseases
Respiratory Tract Diseases
Diuretics, Osmotic
Natriuretic Agents
Physiological Effects of Drugs processed this record on October 21, 2016