Long Term Administration of Inhaled Mannitol in Cystic Fibrosis

Study Overview
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Brief Summary
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The purpose of this study is to examine the efficacy and safety of 26 weeks treatment with inhaled mannitol in subjects with cystic fibrosis. Previous studies have demonstrated improvements in lung function, mucociliary clearance, changes in physical properties of mucus, 24 hour sputum weight and quality of life. The results of this study are to further investigate and confirm these findings in addition to examine the effect on antibiotic use and chest infections. It is hypothesised that inhaled mannitol will have beneficial effects compared to a control treatment. An open label phase of 26 weeks duration will follow the blinded 26 week phase. During the open label phase all subjects will receive active treatment.

Official Title
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Long Term Administration of Inhaled Mannitol in Cystic Fibrosis- A Safety and Efficacy Study

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: inhaled mannitol
* Drug: Placebo comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have given written informed consent to participate in this study in accordance with local regulations Have a confirmed diagnosis of cystic fibrosis (positive sweat chloride value ≥ 60 mEq/L) and/or genotype with two identifiable mutations consistent with CF, accompanied by one or more clinical features consistent with the CF phenotype) Be aged > 6 years old Have FEV1 >40 % and < 90% predicted Be able to perform all the techniques necessary to measure lung function Exclusion Criteria: 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. Be considered terminally ill or eligible for lung transplantation Have had a lung transplant Be using nebulized hypertonic saline in the 4 weeks prior to visit 1 Have had a significant episode of hemoptysis (>60 mL) in the three months prior to enrolment Have had a myocardial infarction in the three months prior to enrolment Have had a cerebral vascular accident in the three months prior to enrolment Have had major ocular surgery in the three months prior to enrolment Have had major abdominal, chest or brain surgery in the three months prior to enrolment Have a known cerebral, aortic or abdominal aneurysm Be breast feeding or pregnant, or plan to become pregnant while in the study Be using an unreliable form of contraception (female subjects at risk of pregnancy only) Be participating in another investigative drug study, parallel to, or within 4 weeks of visit 0 Have a known allergy to mannitol Be using beta blockers Have uncontrolled hypertension - systolic BP > 190 and / or diastolic BP > 100 Have a condition or be 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 Be 'Mannitol Tolerance Test positive' -

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>active treatment | Drug: inhaled mannitol<br>* 400 mg BD for 26 + 26 weeks<br>|
| Placebo Comparator: B<br> | Drug: Placebo comparator<br>* BD for 26 weeks followed by 26 weeks of inhaled mannitol in the open label phase<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Absolute FEV1 From Baseline Over 26 Weeks | Change from baseline in forced expiratory volume at one second (FEV1) averaged over 26 weeks (measured at 6,14 and 26 weeks) The mean absolute change from baseline FEV1 (mL) over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach.Least square means presented are for the average change over the 6, 14, and 26 week visits. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FEV1 From Baseline Over 26 Weeks - Dornase Users | In the subset of dornase users, the mean absolute change from baseline FEV1 (mL) averaged over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the average change over the 6, 14, and 26 week visits. Change from baseline over 26 weeks (measured at 6,14, 26 weeks) in subset of dornase users | 26 weeks | 
| Rate of Protocol Defined Pulmonary Exacerbations (PDPE) | Exacerbations treated with IV antibiotics and with at least 4 signs and symptoms according to Fuchs criteria (1994). Summary table presents the number with 0, 1,2 and 3 PDPEs during the 26 week treatment period. | 26 weeks | 
| Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs) | The number of hospitalisations is summarised and then the rate per person is analysed. | 26 weeks | 
| Antibiotic Use Associated With PDPEs | Number of courses per person in the 26 week period is summarised and then the rate per person analysed. | 26 weeks | 
| Absolute Change in FEV1 Percent Predicted at 26 Weeks | Change from baseline at 26 weeks in FEV1 percent predicted with BOCF for those with missing values at week 26 | 26 weeks | 
| Change in FVC (mL) Across 26 Weeks | Change from baseline in forced vital capacity (FVC) across 26 weeks (measured at 6,14 and 26 weeks) | 26 weeks | 
| Change From Baseline FEF25-75 (mL/s) Over 26 Weeks | Change from baseline in forced expiratory flow at 25-75% of forced vital capacity (FEF25-75) (mL/s) averaged over 26 weeks (measured at 6,14 and 26 weeks) The mean absolute change from baseline over 26 weeks (measured at week 6, 14 and 26) was compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the average change over the 6, 14, and 26 week visits. | 26 weeks | 
| Sputum Weight at Baseline in Response to First Dose of Treatment | Sputum was collected during and for 30 minutes following the administration of the first dose of study treatment. | up to 30 mins after first dose of trial treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cystic fibrosis, mannitol, mucoactive