A Safety and Efficacy Trial of Inhaled Mannitol in Adult Cystic Fibrosis Subjects

Study Overview
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Brief Summary
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This trial aims to provide prospective evidence of the safety and efficacy of mannitol 400 mg b.i.d. in subjects aged 18 years and above. We hypothesize that inhaled mannitol 400 mg b.i.d. will increase the mean change from baseline FEV1 (mL) compared to control over the 26-week treatment period in adult subjects with cystic fibrosis. Any improvement in FEV1 is considered clinically meaningful, however, this trial has set a threshold of 80 mL for the purposes of determining an appropriate sample size for statistical power while retaining trial feasibility in an orphan disease population

Detailed Description
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This is a double-blind, randomized, parallel arm, controlled, multicenter, and interventional clinical trial. Potential subjects will sign the informed consent form (ICF) and be assessed for eligibility. After satisfying all inclusion & exclusion criteria, subjects will be given a mannitol tolerance test (MTT). Those subjects that pass the MTT will be randomized to receive inhaled mannitol (400 mg b.i.d.) or control b.i.d. for a period of 26-weeks.

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

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Inhaled mannitol
* Drug: Placebo Comparator: Arm B - Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have given written informed consent to participate in this trial 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 at least 18 years old; Have FEV1 > 40 % and < 90% predicted (using NHanes III [1]); Be able to perform all the techniques necessary to measure lung function; Be adherent with maintenance therapies (antibiotics and or rhDNase), if used, for at least 80% of the time in the two weeks prior to visit 1 and If rhDNase and/or maintenance antibiotic are being used treatment must have been established at least 1 month prior to screening (Visit 0). The subject should remain on the rhDNase and / or maintenance antibiotics for the duration of the trial. The subject should not commence treatment with rhDNase or maintenance antibiotics during the trial Exclusion Criteria: Be investigators, site personnel directly affiliated with this trial, 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 maintenance nebulized hypertonic saline in the 2 weeks prior to visit 1; Have had a significant episode of hemoptysis (> 60 mL) in the three months prior to Visit 0; Have had a myocardial infarction in the three months prior to Visit 0; Have had a cerebral vascular accident in the three months prior to Visit 0; Have had major ocular surgery in the three months prior to Visit 0; Have had major abdominal, chest or brain surgery in the three months prior to Visit 0; Have a known cerebral, aortic or abdominal aneurysm; Be breast feeding or pregnant, or plan to become pregnant while in the trial; Be using an unreliable form of contraception (female subjects at risk of pregnancy only); Be participating in another investigative drug trial, parallel to, or within 4 weeks of screening (Visit 0); Have a known allergy to mannitol; Be using non-selective oral beta blockers; Have uncontrolled hypertension -i.e. 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 subject's participation in the trial;or Have a failed or incomplete MTT at trial entry (as evaluated in Section 8.1.1.1). The subject must not commence treatment with rhDNase or maintenance antibiotics during the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Experimental arm A<br>Active treatment. Inhaled Mannitol | Drug: Inhaled mannitol<br>* Inhaled mannitol 400 mg BD for 26 weeks<br>|
| Placebo Comparator: Arm B - Control<br>Arm B | Drug: Placebo Comparator: Arm B - Control<br>* Placebo Comparator: Arm B - Control BD for 26 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4). | 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. Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF). | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period | To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control for improving lung function as measured by mean change from baseline forced vital capacity (FVC) (mL) over the 26-week treatment period in adult subjects with cystic fibrosis (CF). The mean absolute change from baseline FVC (mL) over 26 weeks 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 change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks). Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF). | 26 weeks |