Novel Therapies for Muco-Obstructive Lung Diseases: Testing the Transnasal Pulmonary Delivery Device in COPD/CB Subjects

The beneficial effects of inhaled HS in CF patients (cystic fibrosis) have been well
established. Concerns over safety and intolerability in patients with COPD/CB, based in part
upon experiences with ultrasonic delivery devices, have limited interest in further
exploring this therapeutic option. Although our clinical data suggests that HS delivered via
jet nebulizer is generally well tolerated in patients with COPD/CB, our pre-clinical data
suggests that cell shrinkage, the release of proinflammatory cytokines (i.e. IL-8), and
transient cilia stasis is dependent upon the rate of aerosol delivery.

Slow/continuous delivery may avoid most/all of these detrimental effects while promoting an
even greater cumulative ASL (airway surface liquid) volume increase. To translate these data
into a feasible treatment strategy, a comfortable, quiet delivery device that can be used
for long time periods (i.e. overnight) was developed to slowly deliver HS via a nasal
cannula device while avoiding aerosol rain-out in the device's tubing. Use of a
computational model (MPPD: Multiple-Path Particle Dosimetry V2.0) predicts that this device,
which generates a 2 um MMAD aerosol particle, will achieve -5-8% lung deposition. When tuned
to an output of ~0.033 ml/min, 8 hours of use is predicted to deposit a minimum of 140 mg of
NaCI onto airway surfaces. This compares favorably to the estimated mass delivered via jet
nebulizer in the clinically successful study of HS in CF (110 mg/day, assuming 19.75%
deposition fraction with the Pari LC PLUS).

The proposed study is a single site, randomized, open label, cross-over trial designed to
measure the tolerability and effect on mucociliary clearance following 7% HS delivered via
tPAD for eight hours overnight to COPD/CB subjects. Comparison will be to measurements made
following no treatment during an overnight stay. COPD/CB subjects meeting inclusion and
exclusion criteria will be enrolled in the study. All study procedures will be conducted in
the Clinical Translational Research Center (CTRC) at UNC Hospitals and the EPA building on
Mason Farm Rd on the UNC Hospitals campus.

Inclusion Criteria:

Subjects who meet the following criteria will be eligible for study participation:

1. Subjects aged 40 to 80 years (inclusive), and with a body mass index (BMI) < 35 kg/m2

2. Female subjects must be non-pregnant and must be either not sexually active,
post-menopausal, surgically sterilized, or agree to use an appropriate
"double-barrier" method (such as a diaphragm and condom); or, must currently be using
a prescribed transdermal, injection, implant, or oral contraceptive during study
participation

3. Subjects who are in their baseline state of health, as determined by a medical
history and examination

4. Subjects who have normal lung function with a FEV1 of 30% - 80% predicted and a
FEV1/FVC <70%

5. Subjects who are capable of providing written informed consent in English to
participate in the study

6. Produces sputum two days per week or more, on average.

7. History of smoking cigarettes ≥ 10 pack years.

Exclusion Criteria:

Subjects will be excluded from the study according to the following criteria:

1. Subjects who use oxygen continuously or require it at night.

2. Subjects with an FEV1 < 30% or > 80% or an FEV1/FVC of ≥70% at screening.

3. Subjects who chronically require > 10mg per day of prednisone (or equivalent
corticosteroid dose).

4. Subjects with a concomitant presence of congestive heart failure, active coronary
syndromes, or other disease that in the opinion of the investigator would increase
the risk resulting from participation.

5. Subjects with a recent change in respiratory medications, including new antibiotic or
systemic corticosteroid interventions within the last 4 weeks.

6. Subjects with a history of intolerance or hypersensitivity to hypertonic saline or
short acting inhaled beta agonists.

7. Subjects with significant bronchoreactivity by examination or PFT testing that, in
the opinion of the investigator, would increase the risk of HS use.

8. Subjects who have had radiation exposure within the 12 months prior to study
participation that would cause them to exceed Federal Regulations by participating in
this study.

9. Subjects with symptomatically active, chronic or acute rhinosinusitis, or other nasal
abnormality that could interfere with aerosol delivery or impact subject safety.

10. Subjects with a positive pregnancy test or who are nursing.

11. Subjects who have been diagnosed with obstructive sleep apnea.

12. Subjects who, in the opinion of the Principal Investigator, should not participate in
the study.