Targeting Pulmonary Perfusion in Alpha-1 Antitrypsin Deficiency

Emphysema is a common type of lung disease in patients with alpha-1 antitrypsin deficiency
(AATD). Emphysema refers to destruction of the fine network of air spaces and blood vessels
in the lung, and results in what looks like "holes" in the lung. Emphysema is associated with
an increased risk of death but currently no medications, except for replacement of alpha-1
antitrypsin (AAT), have been shown to treat emphysema.

The study plans to enroll subjects with alpha-1 antitrypsin deficiency-associated lung
disease (PiZZ phenotype) to perform a cross-over randomized controlled trial (RCT) of aspirin
compared to placebo to test the hypotheses that aspirin is effective in improving blood flow
in the lungs and reducing damage to the endothelial cells. Subjects will be randomized to
receive aspirin or placebo for 2 weeks. There will be a 2-week washout period, then the
participant will be crossed over to receive the other treatment (those who received aspirin
first will receive the placebo and those who received the placebo first will receive
aspirin).

Participants who are on alpha-1 replacement therapy who have had fewer than 2 exacerbations
in the last year will be asked whether they are interested in a withdrawal study. For this
second part of the study, eligible and willing participants will be asked to stop their
alpha-1 replacement therapy for 5 weeks and come in for a 4th study visit. This will allow
AAT levels to drop briefly to those seen in the absence of AAT augmentation.

Inclusion Criteria:

- Alpha-1 antitrypsin deficiency (PiZZ genotype)

- 40 years of age or older

- Evidence of emphysema on CT scan as read by a Radiologist

Exclusion Criteria:

- Platelet count < 150,000/dL, history of intracranial hemorrhage or severe GI bleed,
use of systemic anticoagulant, physician prescribed use of antiplatelet drug
(including aspirin and P2Y12 receptor inhibitors), or known severe liver disease

- Immunosuppression by use of medications (including oral prednisone), or those with
immunomodulatory disease (organ transplantation, autoimmune conditions or
actively-treated malignancy)

- Known atrial fibrillation or left ventricular (LV) systolic heart failure

- Contraindication to MRI, including pregnancy, weight > 300 lbs (due to weight limits
of the machine), those with pacemakers, aneurysm clips, cochlear implants or other
implanted electronic devices, or severe claustrophobia;

- Chronic renal insufficiency (estimated GFR < 45 L/min/1.73 m2 or self report) due to
slightly increased risk of nephrogenic systemic fibrosis from gadolinium
administration and aspirin-related renal insufficiency

- Exacerbation of respiratory symptoms within the previous 6 weeks, such as that
requiring hospitalization, oral prednisone or antibiotics to control symptoms.