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

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.

Inclusion Criteria:

1. Have given written informed consent to participate in this trial in accordance with
local regulations;

2. 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);

3. Be aged at least 18 years old;

4. Have FEV1 > 40 % and < 90% predicted (using NHanes III [1]);

5. Be able to perform all the techniques necessary to measure lung function;

6. 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

7. 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:

1. 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;

2. Be considered "terminally ill" or eligible for lung transplantation;

3. Have had a lung transplant;

4. Be using maintenance nebulized hypertonic saline in the 2 weeks prior to visit 1;

5. Have had a significant episode of hemoptysis (> 60 mL) in the three months prior to
Visit 0;

6. Have had a myocardial infarction in the three months prior to Visit 0;

7. Have had a cerebral vascular accident in the three months prior to Visit 0;

8. Have had major ocular surgery in the three months prior to Visit 0;

9. Have had major abdominal, chest or brain surgery in the three months prior to Visit 0;

10. Have a known cerebral, aortic or abdominal aneurysm;

11. Be breast feeding or pregnant, or plan to become pregnant while in the trial;

12. Be using an unreliable form of contraception (female subjects at risk of pregnancy
only);

13. Be participating in another investigative drug trial, parallel to, or within 4 weeks
of screening (Visit 0);

14. Have a known allergy to mannitol;

15. Be using non-selective oral beta blockers;

16. Have uncontrolled hypertension -i.e. systolic BP > 190 and / or diastolic BP > 100;

17. 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

18. Have a failed or incomplete MTT at trial entry (as evaluated in Section 8.1.1.1).

19. The subject must not commence treatment with rhDNase or maintenance antibiotics during
the trial.