Crossover Trial Determining the Efficacy of Dry Powder Mannitol to Improve Lung Function in Subjects Aged 6-17 Years

A Randomised, Multicentre, Double-blind, Placebo-controlled, Crossover Trial Determining the Efficacy of Dry Powder Mannitol in Improving Lung Function in Subjects With Cystic Fibrosis Aged Six to Seventeen Years

It is hypothesised that inhaled mannitol 400 mg b.d. will lead to a significant improvement in the absolute change in percentage of predicted FEV1 from baseline following eight-weeks of trial treatment compared to treatment with inhaled placebo b.d.

Any improvement in FEV1 is considered clinically meaningful; however, this trial has set a threshold of 3% for the purposes of determining an appropriate sample size for statistical power whilst retaining trial feasibility in an orphan disease population.

Drug Name: Dry powder mannitol for inhalation Phase: 2 Indication: Paediatric and adolescent cystic fibrosis Trial Centres: Multicentre Sponsor: Pharmaxis Limited, 20 Rodborough Road, Frenchs Forest, NSW 2086 Australia Trial Duration: 27 weeks Number of Subjects: 160 Trial Design: Randomised, multicentre, double-blind, placebo-controlled, crossover Primary Objective: To determine the effect of eight weeks of twice-daily treatment with inhaled dry powder mannitol on lung function (FEV1) in subjects with CF who are aged six to seventeen years Dosage and Administration: Trial drug is to be administered via a dry powder inhaler.

• Mannitol 400 mg b.d. for 8 weeks followed by a 8-week washout followed by placebo b.d. for 8 weeks; or
• Placebo b.d. for 8 weeks followed by a 8-week washout followed by mannitol 400 mg b.d. for 8 weeks.

Statistical Methods:

• The primary and secondary efficacy analyses will be based upon a modified Grizzle model for crossover design. Absolute and relative changes from baseline in percentage of predicted FEV1 and FVC will be analysed. The absolute change in percentage of predicted lung function (FEV1 and FVC) will be the primary focus. Changes in FEF25-75 will also be analysed.
• Safety data will be analysed descriptively (listings and summary tables).

Inclusion Criteria: The subject must:

1. Personally provide, or have a legal guardian provide written informed consent to participate in the trial, according to local regulations;
2. rhDNase and maintenance antibiotic use is allowed but treatment must have been established at least 3 months prior to screening. The subject must remain on rhDNase and / or maintenance antibiotics for the duration of the trial. The subject must not commence treatment with rhDNase or maintenance antibiotics during the trial;
3. Have a confirmed diagnosis of cystic fibrosis (sweat test result greater than or equal to 60 mEq/L chloride and/or genotyping showing two identifiable mutations consistent with a diagnosis of cystic fibrosis);
4. Be aged greater than or equal to 6 years and < 18 years;
5. Have a percentage of predicted FEV1 of greater than or equal to 30% and less than or equal to 90% at Screening (Visit 0). Percentage of predicted FEV1 will be calculated using Wang for children aged < 8 years, and using NHanes III for those greater than or equal to 8 years; and
6. Be able to perform all the techniques necessary to measure lung function.

Exclusion Criteria: The subject must NOT:

1. Be using maintenance nebulised hypertonic saline;
2. Be considered "terminally ill"; eligible for lung transplantation, or have received a lung transplant previously;
3. Require home oxygen or assisted ventilation;
4. Have had an episode of massive haemoptysis defined as acute bleeding ≥240 ml in a 24-hour period and/or recurrent bleeding ≥100 ml/day over several days in the three-months prior to Screening (Visit 0);
5. Have a known intolerance to mannitol;
6. Be taking non-selective beta-blockers;
7. In the three months prior to Screening (Visit 0) have had a myocardial infarction; a cerebral vascular accident; major ocular, abdominal, chest or brain surgery;
8. Have a known cerebral, aortic or abdominal aneurysm;
9. Be currently participating in, or have participated in another investigative drug trial within four weeks of Screening (Visit 0);
10. Be pregnant or breastfeeding, or plan to become pregnant whilst in the trial;
11. For females of childbearing potential, be using an unreliable form of contraception, (at the discretion of the investigator);
12. Have any concomitant medical, psychiatric, or social condition that, in the Investigator's opinion, would put the subject at significant risk, may confound the results or may significantly interfere with the subject's participation in the trial; or
13. Have a "failed" or "incomplete" mannitol tolerance test (as described in Section 8.3.1.1).