Bronchiectasis
Conditions
Keywords
randomized clinical trial, mannitol, mucoactive
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.
Interventions
DRUGInhaled mannitol
400mg dose of Mannitol BD (twice a day) for 52 weeks
DRUGMatched control
50mg dose of Mannitol BD (twice a day) for 52 weeks
Sponsors
Syntara
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Graded Pulmonary Exacerbations | 52 weeks | 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
| Measure | Time frame | Description |
|---|---|---|
| Daytime Sleepiness Scores | 52 weeks | 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 |
| Safety Profile - Sputum Microbiology | 52 weeks | sputum microbiology assessed as the presence of abnormal flora in sputum sample taken at any post baseline visit |
| Safety Profile - Clinical Chemistry | 52 weeks | 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 | 52 weeks | hematology assessed as clinically significant abnormal FBC (Full Blood count) at any point post baseline. |
| • (Exploratory) Number of Hospitalizations Due to Pulmonary Exacerbations | 52 weeks | Mean rate of hospitalisations (number/year) summarised and analysed to take account of differing follow-up times. |
| Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | 52 weeks | 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 | 52 weeks | 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 | 52 weeks | 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 | 52 weeks | 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 | 52 weeks | 24 hour sputum weight, measured at baseline, week 6, week 16, week 28, week 40, week 52 |
| 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 | 52 weeks | 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) | 52 weeks | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 52 weeks | 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). |
| Health Status and Utility Scores | 52 weeks | 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 Costs of Treating Patients With Bronchiectasis | 52 weeks | 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) |
Countries
Argentina, Australia, Belgium, Chile, Germany, Netherlands, New Zealand, United Kingdom, United States
Participant flow
Pre-assignment details
Prior to randomisation, subjects underwent a Mannitol Tolerance Test (MTT) - only those who passed the MTT were eligible to be randomised. 581 patients in total underwent the MTT
Participants by arm
| Arm | Count |
|---|---|
| Mannitol Inhaled mannitol
Inhaled mannitol: 400mg BD for 52 weeks | 233 |
| Control Matched control: Inhaled mannitol 50mg BD for 52 weeks | 228 |
| Total | 461 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Blinded Treatment Period | Adverse Event | 16 | 10 |
| Blinded Treatment Period | Death | 0 | 2 |
| Blinded Treatment Period | Lost to Follow-up | 3 | 2 |
| Blinded Treatment Period | Physician Decision | 3 | 3 |
| Blinded Treatment Period | Protocol Violation | 1 | 1 |
| Blinded Treatment Period | Unable/unwilling to comply w trial reqs | 2 | 2 |
| Blinded Treatment Period | Withdrawal by Subject | 17 | 19 |
| Randomisation to First Dose | Adverse Event | 1 | 0 |
| Randomisation to First Dose | Death | 1 | 0 |
| Randomisation to First Dose | Lost to Follow-up | 2 | 0 |
| Randomisation to First Dose | Protocol Violation | 1 | 0 |
| Randomisation to First Dose | Randomised in error | 3 | 10 |
| Randomisation to First Dose | Sponsor decision | 0 | 1 |
| Randomisation to First Dose | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Mannitol | Control | Total |
|---|---|---|---|
| Age, Continuous | 59.30 years STANDARD_DEVIATION 14.06 | 60.26 years STANDARD_DEVIATION 13.02 | 59.77 years STANDARD_DEVIATION 13.55 |
| Baseline % of Predicted FEV1 <60% | 101 participants | 107 participants | 208 participants |
| Baseline % of Predicted FEV1 >=60% | 132 participants | 121 participants | 253 participants |
| Baseline Pulmonary Exacerbation rate | 3.20 events/year STANDARD_DEVIATION 1.38 | 3.25 events/year STANDARD_DEVIATION 1.4 | 3.22 events/year STANDARD_DEVIATION 1.39 |
| Extent of Bronchiectasis Both (Diffuse and Focal) | 23 participants | 37 participants | 60 participants |
| Extent of Bronchiectasis Diffuse | 133 participants | 118 participants | 251 participants |
| Extent of Bronchiectasis Focal | 77 participants | 73 participants | 150 participants |
| Sex: Female, Male Female | 147 Participants | 142 Participants | 289 Participants |
| Sex: Female, Male Male | 86 Participants | 86 Participants | 172 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 215 / 233 | 214 / 228 |
| serious Total, serious adverse events | 43 / 233 | 51 / 228 |
Outcome results
Primary
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
Time frame: 52 weeks
Population: Randomised and Treated (referred to as the ITT population in this trial)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mannitol | Rate of Graded Pulmonary Exacerbations | Raw rate | 1.95 GPE events per year |
| Mannitol | Rate of Graded Pulmonary Exacerbations | Rate from negative binomial model | 1.69 GPE events per year |
| Control | Rate of Graded Pulmonary Exacerbations | Raw rate | 2.10 GPE events per year |
| Control | Rate of Graded Pulmonary Exacerbations | Rate from negative binomial model | 1.84 GPE events per year |
p-value: 0.311595% CI: [0.78, 1.08]Negative binomial regression model
Secondary
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.
Time frame: 52 weeks
Population: Randomised and treated (referred to as ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mannitol | Antibiotic Use Prescribed for Treated Pulmonary Exacerbations | 1.9 events/year |
| Control | Antibiotic Use Prescribed for Treated Pulmonary Exacerbations | 2.1 events/year |
p-value: 0.275495% CI: [0.77, 1.08]Negative binomial regression model
Secondary
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
Time frame: 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mannitol | Daytime Sleepiness Scores | Baseline | 7.23 units on a scale | Standard Deviation 4.85 |
| Mannitol | Daytime Sleepiness Scores | Week 6 | 6.07 units on a scale | Standard Deviation 4.78 |
| Mannitol | Daytime Sleepiness Scores | Week 16 | 6.21 units on a scale | Standard Deviation 5.1 |
| Mannitol | Daytime Sleepiness Scores | Week 28 | 6.05 units on a scale | Standard Deviation 4.73 |
| Mannitol | Daytime Sleepiness Scores | Week 40 | 6.32 units on a scale | Standard Deviation 5.1 |
| Mannitol | Daytime Sleepiness Scores | Week 52 | 6.09 units on a scale | Standard Deviation 4.98 |
| Control | Daytime Sleepiness Scores | Week 40 | 6.33 units on a scale | Standard Deviation 4.83 |
| Control | Daytime Sleepiness Scores | Baseline | 6.89 units on a scale | Standard Deviation 4.89 |
| Control | Daytime Sleepiness Scores | Week 28 | 6.57 units on a scale | Standard Deviation 4.82 |
| Control | Daytime Sleepiness Scores | Week 6 | 6.87 units on a scale | Standard Deviation 4.74 |
| Control | Daytime Sleepiness Scores | Week 52 | 6.34 units on a scale | Standard Deviation 5.02 |
| Control | Daytime Sleepiness Scores | Week 16 | 6.50 units on a scale | Standard Deviation 4.86 |
p-value: 0.115995% CI: [-0.99, 0.11]Mixed Models Analysis
Secondary
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
Time frame: 52 weeks
Population: Randomised and treated
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Mannitol | Duration of Graded Exacerbations | 31.49 Days with GPE |
| Control | Duration of Graded Exacerbations | 35.74 Days with GPE |
Comparison: Analysed using a negative binomial model with treatment, region and baseline pulmonary exacerbation rate as predictors, and with log of follow-up time as the offset variablep-value: 0.360295% CI: [0.67, 1.16]Negative binomial model
Secondary
• (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.
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Mannitol | • (Exploratory) Number of Hospitalizations Due to Pulmonary Exacerbations | 0.12 hospitalisations/year |
| Control | • (Exploratory) Number of Hospitalizations Due to Pulmonary Exacerbations | 0.20 hospitalisations/year |
p-value: 0.092895% CI: [0.34, 1.09]Negative binomial regression
Secondary
Lung Function - Change in FEF25-75 (Forced Expiratory Flow Rate Averaged Over 25th -75th Percentile of FVC)
Time frame: 52 weeks
Population: Randomised and treated with at least one post-baseline spirometry assessment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mannitol | Lung Function - Change in FEF25-75 (Forced Expiratory Flow Rate Averaged Over 25th -75th Percentile of FVC) | -18.21 mL/s |
| Control | Lung Function - Change in FEF25-75 (Forced Expiratory Flow Rate Averaged Over 25th -75th Percentile of FVC) | -3.40 mL/s |
Secondary
Lung Function - Change in FEV1 (Forced Expiratory Volume in One Second)
Time frame: 52 weeks
Population: Randomised and treated with at least one post-baseline spirometry assessment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mannitol | Lung Function - Change in FEV1 (Forced Expiratory Volume in One Second) | 2.36 mL |
| Control | Lung Function - Change in FEV1 (Forced Expiratory Volume in One Second) | -5.20 mL |
p-value: 0.667795% CI: [-27.01, 42.13]Mixed Models Analysis
Secondary
Lung Function - Change in FEV1/FVC
FEV1 expressed as a ratio of FVC. Endpoint is expressed as a percentage ie FEV1/FVC\*100
Time frame: 52 weeks
Population: Randomised and treated with at least one post-baseline spirometry assessment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mannitol | Lung Function - Change in FEV1/FVC | -0.08 ratio (expressed as a %) |
| Control | Lung Function - Change in FEV1/FVC | 0.09 ratio (expressed as a %) |
Secondary
Lung Function - Change in FVC (Forced Vital Capacity)
Time frame: 52 weeks
Population: Randomised and treated with at least one post-baseline spirometry assessment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mannitol | Lung Function - Change in FVC (Forced Vital Capacity) | 0.15 mL |
| Control | Lung Function - Change in FVC (Forced Vital Capacity) | -15.70 mL |
Secondary
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.
Time frame: 52 weeks
Population: Randomised and treated with one or more post-baseline SGRQ data available
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mannitol | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Baseline | 52.98 units on a scale | Standard Deviation 14.64 |
| Mannitol | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Week 6 | 44.09 units on a scale | Standard Deviation 17.49 |
| Mannitol | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Week 16 | 40.67 units on a scale | Standard Deviation 19.07 |
| Mannitol | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Week 28 | 41.45 units on a scale | Standard Deviation 18.58 |
| Mannitol | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Week 40 | 40.39 units on a scale | Standard Deviation 18.86 |
| Mannitol | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Week 52 | 41.43 units on a scale | Standard Deviation 19.6 |
| Control | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Week 40 | 43.51 units on a scale | Standard Deviation 19.96 |
| Control | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Baseline | 52.22 units on a scale | Standard Deviation 14.71 |
| Control | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Week 28 | 43.46 units on a scale | Standard Deviation 19.05 |
| Control | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Week 6 | 44.55 units on a scale | Standard Deviation 18.49 |
| Control | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Week 52 | 42.25 units on a scale | Standard Deviation 19.5 |
| Control | Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score | Week 16 | 44.23 units on a scale | Standard Deviation 19.89 |
p-value: 0.045795% CI: [-4.76, -0.05]Mixed model repeated measures analysis
Secondary
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.
Time frame: 52 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mannitol | Safety Profile - Clinical Chemistry | Subjects with Clin sig liver funtion tests at wk52 | 2 participants |
| Mannitol | Safety Profile - Clinical Chemistry | Subjects with clin sig urea/electrolyte test wk52 | 3 participants |
| Control | Safety Profile - Clinical Chemistry | Subjects with Clin sig liver funtion tests at wk52 | 0 participants |
| Control | Safety Profile - Clinical Chemistry | Subjects with clin sig urea/electrolyte test wk52 | 0 participants |
Secondary
Safety Profile - Hematology
hematology assessed as clinically significant abnormal FBC (Full Blood count) at any point post baseline.
Time frame: 52 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mannitol | Safety Profile - Hematology | 13 participants |
| Control | Safety Profile - Hematology | 5 participants |
Secondary
Safety Profile - Sputum Microbiology
sputum microbiology assessed as the presence of abnormal flora in sputum sample taken at any post baseline visit
Time frame: 52 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mannitol | Safety Profile - Sputum Microbiology | 81 participants |
| Control | Safety Profile - Sputum Microbiology | 81 participants |
Secondary
Sputum Volume
24 hour sputum weight, measured at baseline, week 6, week 16, week 28, week 40, week 52
Time frame: 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mannitol | Sputum Volume | Baseline | 28.88 g | Standard Deviation 18.71 |
| Mannitol | Sputum Volume | Week 6 | 24.97 g | Standard Deviation 23.17 |
| Mannitol | Sputum Volume | Week 16 | 23.69 g | Standard Deviation 22.09 |
| Mannitol | Sputum Volume | Week 28 | 22.92 g | Standard Deviation 25.66 |
| Mannitol | Sputum Volume | Week 40 | 21.56 g | Standard Deviation 21.58 |
| Mannitol | Sputum Volume | Week 52 | 20.54 g | Standard Deviation 24.07 |
| Control | Sputum Volume | Week 40 | 18.17 g | Standard Deviation 16.67 |
| Control | Sputum Volume | Baseline | 28.96 g | Standard Deviation 19.92 |
| Control | Sputum Volume | Week 28 | 18.88 g | Standard Deviation 17.83 |
| Control | Sputum Volume | Week 6 | 22.82 g | Standard Deviation 20.06 |
| Control | Sputum Volume | Week 52 | 18.33 g | Standard Deviation 16 |
| Control | Sputum Volume | Week 16 | 20.25 g | Standard Deviation 16.99 |
p-value: 0.035595% CI: [0.19, 5.33]Mixed Models Analysis
Secondary
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.
Time frame: 52 weeks
Population: Randomised and treated
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mannitol | Time to First Graded Exacerbation | 5.4 months |
| Control | Time to First Graded Exacerbation | 4.1 months |
p-value: 0.021895% CI: [0.63, 0.96]Regression, Cox
Other Pre-specified
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).
Time frame: 52 weeks
Population: Not collected. As the primary objective of this study did not reach statistical significance, cost effectiveness data were not collected.
Other Pre-specified
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)
Time frame: 52 weeks
Population: No data were collected. Since the primary objective was not significant in this study, further exploration of health economic endpoints was not done.
Other Pre-specified
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).
Time frame: 52 weeks
Population: No data were collected for this assessment. As the primary objective of this study did not reach statistical significance, HRQL and QALYs were not derived.
Other Pre-specified
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)
Time frame: 52 weeks
Population: No data were collected. As the primary objective of this study did not reach statistical significance, health status and utility scores were not derived.