Durability of Hypertonic Saline for Enhancing Mucociliary Clearance in Cystic Fibrosis
Durability of Hypertonic Saline for Enhancing Mucociliary Clearance in Cystic Fibrosis
Direct measurement of mucociliary and cough clearance (MCC/CC) has been used as a biomarker
 in cystic fibrosis (CF). Additional knowledge of the performance of this biomarker is needed
 to inform exploratory clinical trial design in support of programs to develop new inhaled
 therapies for CF. We hypothesize that MCC/CC measurements can be used to determine the
 durability of action of agents like hypertonic saline (HS) which increase epithelial lining
 fluid height.
A reduction in epithelial lining fluid height in cystic fibrosis (CF) as a consequence of
 decreased function of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride
 channel and related increased activity of the Epithelial sodium (Na) Channel (ENaC) results
 in impaired mucociliary clearance (MCC), mucus stasis, inflammation, infection, and
 ultimately progressive bronchiectasis. Inhalation of hypertonic saline (HS), through a direct
 osmotic effect on the airways, results in an increase in epithelial lining fluid height in
 vitro and an increase in MCC in vivo as measured following inhalation of a radiotracer with
 gamma scintigraphy (Sood, et al 2003). MCC as a biomarker is being validated in the clinic,
 as administration of inhaled hypertonic saline (HS) to cystic fibrosis patients results in
 short- and medium-term improvements in MCC (Donaldson, et al 2006), while long-term
 administration of HS is associated with improvements in the registration endpoints of lung
 function and pulmonary exacerbations (Elkins, et al 2006). Based in large part on these
 studies, HS has gained acceptance in the CF community, with estimates of up to 50% of
 patients being treated with this therapy. MCC/CC is thus an excellent choice as a Proof of
 Concept endpoint for exploratory clinical studies of ENaC modulators. Prior clinical
 experience with the ENaC blocker amiloride, which improves MCC acutely in healthy volunteers
 (Sood, et al 2003) but failed to improve lung function in long-term studies in CF (Pons, et
 al 2000), suggests that durable ENaC modulation will be required for clinical success. It is
 believed that modulation of ENaC for a period of at least 4 hours will be required to achieve
 the necessary durability. This durability should also enable twice daily dosing. For
 comparison we need to know the effectiveness of HS over this same period. Thus, this study is
 intended to assess 1) the duration of action out to 4 hours for inhaled hypertonic saline
 (7%) in adult CF patients and 2) the variability of MCC/CC measurements with and without HS
 treatment. These assessments at UNC will be compared to similar measures at Johns Hopkins
 University (JHU) for Novartis to determine the feasibility for future multicenter studies
 using MCC/CC as a primary endpoint.
Inclusion Criteria:

 -  Gender: Male or female (non-pregnant, non-lactating)

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

 -  Severity of Disease:

 1. Must have FEV1 of greater than or equal to 50% of predicted at the screening
 visit.

 2. Must have an oxygen saturation of >92% on room air as determined by pulse
 oximetry at the screening visit.

 -  Patient or legally authorized representative agrees to the patient/individual's
 participation in the study by signing and dating the informed consent form after the
 nature of the study has been fully explained and all questions have been
 satisfactorily answered.

 Exclusion Criteria:

 -  Unstable 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; or a
 significant new finding on chest radiograph (pneumothorax, lobar/segmental collapse)
 not considered a part of the usual, chronic progression of CF lung disease.

 -  Patients unable or unwilling to be withdrawn from hypertonic saline therapy, dornase
 alfa, or N-acetylcysteine 3 days prior to and for the duration of each Baseline and
 Treatment Period will be excluded.

 -  Patients unable to withhold use of long-acting bronchodilators (i.e., Salmeterol,
 Advair, Formoterol), anti-cholinergics, and vest therapy 12 hours prior to and for the
 duration of each treatment period.

 -  Patients unable to withhold short-acting bronchodilator 6 hours prior to and for the
 duration of each treatment period except as prescribed by the study protocol.

 -  Patients that have received an investigational drug or therapy during the preceding 30
 days.

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