A Study of Lung Clearance After Hypertonic Saline Delivery Using the tPAD Device

Cystic Fibrosis (CF) lung disease is caused by dehydration of airway secretions that leads to
mucus adhesion, infection and airways inflammation. A simple means to restore hydration to CF
airway surfaces is to inhale hypertonic (3-7% NaCl) saline, which osmotically draws water
onto the airway surface. Rehydration of the lubricant layer of the airway surface liquid
facilitates mucociliary clearance (MCC) and therefore the removal of inhaled infectious
agents. Recent studies have described (1) the short term (two weeks) beneficial effects of
inhaled hypertonic saline (HS) four times daily on pulmonary function, MCC, and quality of
life and (2) the long term (one year) benefits of inhaled HS twice daily on lung function and
pulmonary exacerbation frequency. Consequently, inhaled HS is now used by ~55% of patients
with CF nationwide. Due to the large number of medications that CF patients use on a daily
basis in conjunction with airway clearance techniques, there is a high treatment burden that
results in decreased quality of life.

Both the Cystic Fibrosis Foundation and leading CF clinicians support the idea that the use
of hypertonic saline is now a standard of care. The investigators believe the use of a
specialized transnasal Pulmonary Aerosol Delivery (tPAD) device for administration of HS will
improve on that standard of care by reducing the treatment burden during CF patients' waking
hours, ensuring greater compliance and potentially improving the efficacy and tolerability of
inhaled HS.

A previous deposition study with the tPAD, in six healthy adult subjects, demonstrated ~38%
of the 7% HS aerosol emitted from the nasal cannula is deposited in the adult lungs, with no
acute safety or tolerability issues (Parion Sciences Protocol PS-D100-102; Scott Donaldson,
PI). This deposition efficiency matched that of the Pari LC Star used via the oral route,
which was used as a standard of practice comparator. However, 7% HS nebulization by the tPAD
resulted in a more peripheral deposition of the aerosol than the Pari LC Star comparator.

Previously, it has been shown that administration of 5 mL of 7% HS QID by the Pari LC Star
leads to a significant improvement in the lung function in CF patients. The investigators
estimate that this dosing regimen deposits ~400 mg of NaCl per day but requires four ~18
minute administrations (deposition rate = 5.8 mg/min). Although HS is generally well
tolerated in the CF population, intolerance does occur and is largely related to the rate of
NaCl delivery to the oropharynx and airway surfaces. As nebulizer devices capable of
administering aerosols through a nasal cannula are not currently available, Parion Sciences
has designed a customized nebulizer spacer that entrains the aerosol from an approved and
marketed Aerogen Aeroneb Pro vibrating mesh nebulizer into a nasal cannula without
significant "rain out" or dripping from the cannula. The tPAD system being utilized has an
output rate of ~50 ul/min, and so emits ~3.5 mg/min of NaCl and deposits ~1.3 mg/min in the
lung (38% deposition efficiency). If used overnight for 8 hours, the investigators estimate
that 640 mg NaCl will be deposited in the lung. Therefore, the investigators project that
this novel administration system has the capacity to deliver approximately 50% greater mass
of NaCl to the lung when used overnight, compared to 4 times a day treatment with a standard
oral nebulizer, thereby potentially increasing efficacy. However, because the lung deposition
rate is less than 25% that of the standard oral nebulizer, the investigators anticipate that
the tPAD will also be better tolerated and will eliminate the need for daytime HS treatments.
In this study, the investigators will explore the safety, tolerability and effect on
mucociliary and absorptive clearance rates of a 7% HS solution administered continuously
overnight via the transnasal route.

The tPAD is a non-significant risk device which is composed of a 510K approved Aerogen
Aeroneb Pro vibrating mesh nebulizer with a custom nebulization chamber that allows for
connection of a standard nasal cannula. Protocol PS-D201 is funded by NIH Grant
2R44HL110502-02 "Hypertonic Saline for Cystic Fibrosis".

Inclusion Criteria:

- Has a diagnosis of CF via standard criteria

- Is aged 18 years or older

- Is capable of providing written informed consent in English to participate in the
study.

- Has a forced expiratory volume in 1 second (FEV1) >= 40% and < 110% predicted normal
for age, gender, and height at Screening.

- Has a body mass index (BMI) < 30 kg/m2

- Can tolerate cessation of treatment with HS for 72 hours and rhDNase for 24 hours
prior to each treatment visit until discharge from Visits 2 and 3.

- Can tolerate cessation of treatment with long-acting beta-agonists (LABAs) for 12
hours and short-acting beta-agonists (SABAs) for 6 hours prior to radioaerosol
administration for each MCC measurement and at least until discharge from Visits 2 and
3

- Is on a stable medication regimen for at least 28 days before start of dosing and can
continue such regimen for duration of study

- Tolerates the 30 minute administration of 7% HS by the tPAD device at screening
without subjective intolerance, oxyhemoglobin desaturation, or significant change in
spirometry (>10% reduction from pre-dose value in FEV1, measured 30 minutes after
completion of the aerosol administration)

Exclusion Criteria:

- Has evidence of an acute upper or lower respiratory infection or clinically
significant illness at screening or within 28 days prior to the start of dosing

- Required an acute intervention with antibiotics (oral, inhaled, or IV) or systemic
corticosteroids within the last 28 days for a respiratory illness

- Has a history of intolerance to a beta-agonist or hypertonic saline

- Has evidence of significant nasal obstruction that impairs the ability to breathe
through the nose

- Has a clinical diagnosis of sleep apnea

- Has current symptoms of allergic rhinitis

- Is unable to maintain a stable dosage regimen of any concomitant medication throughout
the duration of the trial.

- Has participated in a clinical drug or investigational device trial within the past 28
days

- Has a history of positive test for Burkholderia cepacia

- Has a present history of any clinically significant and uncontrolled neurologic,
gastrointestinal, renal, hepatic, cardiovascular (including hyper/hypotension and
tachy/bradycardia), psychological, pulmonary, metabolic, endocrine, or hematological
disorder or disease, or any other major disorder or disease, in the opinion of the
investigator

- Has a history of smoking within the last 12 months

- Is known to be pregnant, has a positive urine pregnancy test or is nursing (female
subjects only)

- Should not participate in the study, in the opinion of the Principal or Clinical
investigator