Clearance in Primary Ciliary Dyskinesia

Evaluating Non-ciliary Mechanisms of Airway Clearance in Muco-obstructive Lung Disease

Understanding mechanisms of mucus clearance from the airways may lead to treatments in muco-obstructive lung conditions. Mucociliary clearance (MCC) scans are a way to measure the rate at which a person's lungs can clear inhaled particles. Through a single-arm pilot study in participants with primary ciliary dyskinesia (PCD), the investigators will evaluate the effect of exercise as a way to increase clearance through a mechanism called gas liquid transport (GLT) where the faster flow of air through the lungs during exercise is able to clear more particles. The investigators will repeat MCC measures with exercise after administering hypertonic saline (HS) to evaluate the effects of mucus hydration on both GLT and cough clearance (CC).

Aim 1. To quantify non-ciliary, non-cough mechanisms of mucus clearance (i.e., GLT) in PCD through an MCC protocol that introduces a standardized exercise intervention after isotope delivery.

Aim 2. To evaluate whether exercise-induced GLT and/or CC are responsive to hydrator intervention, using a short acting bronchodilator with 7% HS prior to isotope delivery followed by MCC with exercise intervention.

The investigators will perform an open label, single-arm interventional pilot study with all participants undergoing the interventions (exercise, and exercise with HS pretreatment) and serving as their own control to evaluate the effects of exercise on non-ciliary mucus clearance mechanisms in PCD to better identify role of GLT and CC. The investigators will also evaluate the effect of pretreatment with HS on GLT (if present) and CC, to determine if these mechanisms of mucus clearance are modifiable by future therapies in PCD and other muco-obstructive lung diseases.

Patients will be asked to attend a total of 3 study visits: screening visit 1 (V1), baseline exercise MCC (visit 2 (V2) or visit 3 (V3)), and HS pretreatment MCC (V2 or V3). Patients will be randomized to perform their baseline exercise MCC scan first or their HS pretreatment MCC scan first to minimize introduction of bias. The time between V1 and V2 will be 3 days to 28 days to allow for flexibility of scheduling, but participants already prescribed HS will be required to undergo a washout period of at least 3 days. V3 will take place at least 3 days after V2 to allow for remaining MCC isotope washout. At V1, tolerability and change in airway caliber in response to HS will be assessed by symptom assessment and spirometry, along with the performance of an exercise assessment to inform the exercise protocol in V2 and V3. From the baseline exercise MCC visit, the primary outcome of Whole Lung Total GLT will be measured. Through comparing the data from the exercise MCC visit and the HS pretreatment MCC visit, change in Whole Lung Total GLT and CC will be determined.

Inclusion Criteria:

• 18 years old or older
• Diagnosis of PCD with supporting genetics
• Lung function with forced expiratory volume in 1 second (FEV1) percent predicted >30%
• Ability to exercise for 20 minutes (Exercise Assessment performed at screening visit)

Exclusion Criteria:

• Intolerance to 7% HS
• Failure of HS tolerance test (HSTT) at visit 1 (V1), defined as a decline of 10% in FEV1 from baseline pre-bronchodilator (BD) FEV1 after 7% HS
• Intolerance to levalbuterol
• Exercise-induced asthma
• Complex congenital heart disease or other exercise limitation
• Lung transplantation or listed for lung transplantation
• History of lung resection of the lung analyzed by MCC (depending on situs status)
• Pregnancy or unwillingness to use approved birth control during study period
• Recent hemoptysis (>60 ml in the last 3 months)
• Pulmonary exacerbation in preceding 4 weeks
• Change in pulmonary therapies within preceding 4 weeks
• Resting or exertional O2 requirement (nocturnal acceptable)
• Tobacco / smoking history (any within last year, and >10 pack year history in past)
• More than 2 chest computed tomography (CT) scans in the past year or a combination of procedures believed to have exposed the lungs to >150 millisieverts (mSv), including from other research studies
• Participation in another interventional trial within 30 days