Effect of Hypertonic Saline on Mucus Clearance in Children Ages 5-12 With Cystic Fibrosis

Our current understanding of the pathogenesis of CF lung disease stems from data that
demonstrate the presence of airway surface liquid (ASL) dehydration in CF. ASL dehydration
in CF is caused by defective chloride secretion through the cystic fibrosis transmembrane
regulator (CFTR) and increased sodium reabsorption through the epithelial sodium channel
(ENaC). ASL dehydration, in turn, interferes with the mucociliary clearance apparatus,
causing a breach in a critical line of lung host defense. A number of novel therapeutics
are now being developed to address this basic defect of disease, including the use of
inhaled hypertonic saline.

Previous work demonstrated that inhaled hypertonic saline (HS) reduces exacerbation
frequency and improves lung function in patients with clinically apparent lung disease. A
number of issues revolving around the use of HS in CF remain unresolved. First, the typical
patients enrolled in previous studies were adults (mean age = 26 yrs) with established lung
disease (mean FEV1=78%). Despite our hypothesis that HS should positively affect MCC in
preserved/normal airways, a common view of HS is that it benefits CF patients by inducing
cough and transiently promoting the clearance of thick CF secretions. It has been
questioned, therefore, whether HS will benefit patients who are younger and have mild (or
undetectable) lung disease and potentially normal (though unmeasured) rates of MCC. Second,
it is unclear whether the substantial beneficial effects of HS in CF were achieved because
of a long (>4 hours) duration of action or in spite of an extremely short (~45 minutes)
duration of action (the traditional view based upon experiments in normal epithelia). This
issue is important, as it relates to the development and dosing of hydrator therapies that
may have different pharmacodynamic profiles. Certainly, if twice daily dosing of a short
acting compound is sufficient to provide significant clinical benefit, it would reduce the
challenge of drug discovery for CF and ease the treatment burden imposed upon patients. The
study of HS in CF provides us an opportunity to address this issue.

The hypothesis being tested is that HS will rehydrate CF airway secretions, producing a
sustained acceleration in MCC in young children with CF, regardless of whether a measurable
mucus clearance defect exists at this relatively early stage of disease. We predict a
substantial acceleration of MCC will reduce the exacerbation rate in young children with CF.
In addition, with the growing number of treatment modalities that are prescribed to
patients with CF, adherence to complex and time consuming medical regimens becomes
increasingly problematic and important. We therefore, wish to test an improved drug
delivery platform for HS- the eFlow (Pari Pharma) vibrating mesh nebulizer, which has the
potential to reduce treatment times, improve compliance, and increase treatment efficacy.

Inclusion Criteria:

- Gender: Females or Males. If the subject is female and of childbearing potential
(first menses has occurred), she must have a documented negative pregnancy test at
screening and prior to each mucociliary clearance study. Those of childbearing
potential must be abstinent or using an acceptable method of birth control (i.e. an
Intrauterine Contraceptive Device with a failure rate of <1%, hormonal contraceptives
or a barrier method).

- Age: 5-12 years, inclusive

- Diagnosis: Cystic fibrosis documented by a compatible clinical presentation and
sweat chloride > 60 mEq/l or 2 disease causing CFTR mutations.

- Severity of the Disease: Suitable patients will have mild lung disease, as defined
by:

- Pulmonary Function: Each patient must have an FEV1 of greater than or equal to
60% of predicted at the screening visit.

- Hemoglobin saturation: Patients must have an oxygen saturation of >92% on room
air as determined by pulse oximetry at the screening visit.

- Informed consent - The patient and a parent or legally authorized guardian must agree
to the subject's participation in the study by signing and dating the informed
consent/assent forms after the nature of the study has been fully explained and all
questions have been satisfactorily answered.

Exclusion Criteria:

- Unstable or asthmatic lung disease: As defined by a change in medical regimen during
the preceding 2 weeks; an FEV1 15% below recent (within 6 months) clinical
measurements. Patients with a history of co-existent asthma, as manifested by
wheezing and significant bronchoreactivity (>15% increase in FEV1 with
bronchodilator), will also be excluded.

- Other medication usage: Patients unable or unwilling to be withdrawn from hypertonic
saline therapy for two weeks prior to Visit 1 (baseline MCC visit). Patients using
Pulmozyme will be permitted to participate in this trial. Patients on chronic,
cycling antibiotics will be required to have completed at least 2 full cycles of the
prescribed antibiotic prior to enrollment and should not cycle on or off this therapy
during the treatment period of the study.

- Spirometry Performance: Those subjects who are unable to perform acceptable,
reproducible spirometry will be excluded from this study.

- Drug allergy: A history of allergy or intolerance to any of the study medications,
including albuterol or hypertonic saline.

- Have received an investigational drug or therapy during the preceding 30 days.

- Have had radiation exposure within the past year that would cause them to exceed
Federal Regulations by participating in this study.