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.

• Aspirin (Drug): 81mg aspirin taken once per day in the morning
• Placebo (Drug): placebo taken once per day in the morning
• Withdrawal from alpha1 antitrypsin replacement therapy (Other): After the completion of the randomization to aspirin and placebo, participants who are on alpha1 replacement therapy are asked to withhold their usual alpha1 antitrypsin replacement therapy for 5 weeks. This is not randomized.

Primary outcomes

• Pulmonary Microvascular Blood Flow, Mean [2 weeks]: Pulmonary microvascular blood flow is measured on contrast-enhanced MRI, limited to blood flow in the 2cm periphery of the lung

Secondary outcomes

• Endothelial Microparticles [2 weeks]: Endothelial microparticles (EMPs) are vesicles shed from endothelial plasma membranes into the circulation in response to endothelial cell perturbation. CD31+ is a measure of apoptotic endothelial microparticles, CD62+ (P-selectin) is a measure of endothelial activation, and Annexin V/CD31+ is a more specific marker of endothelial cell apoptosis.
• Endothelial Microparticles [5 weeks]: Endothelial microparticles (EMPs) are vesicles shed from endothelial plasma membranes into the circulation in response to endothelial cell perturbation. CD31+ is a measure of apoptotic endothelial microparticles, CD62+ (P-selectin) is a measure of endothelial activation, and Annexin V/CD31+ is a more specific marker of endothelial cell apoptosis.
• Pulmonary Microvascular Blood Flow, Mean [5 weeks]: Pulmonary microvascular blood flow is measured on contrast-enhanced MRI in the peripheral 2cm of the lung.

Sex: All, ages: 40 Years to any

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.

Participant flow

Outcome results

• Pulmonary Microvascular Blood Flow, Mean (Primary), Mean, mL blood/minute per 100mL lung: Aspirin 36.9 +/- 13.0; Placebo 35.1 +/- 15.4 (p 0.692)
• Endothelial Microparticles (Secondary), Mean, EMPs/uL: Aspirin 749.0 +/- 231.1; Placebo 821.5 +/- 3.5
• Endothelial Microparticles (Secondary), Mean, EMPs/uL: Off Alpha-1 Replacement Therapy 996.0 +/- 408.7; Placebo 821.5 +/- 3.5
• Pulmonary Microvascular Blood Flow, Mean (Secondary), Mean, mL blood/minute per 100mL lung: Off Alpha-1 Replacement Therapy 35.5 +/- 2.6; Placebo 35.1 +/- 11.0

Adverse events

Time frame: During the course of the study, typically this was 6 weeks, but up to 11 weeks for those also withheld their alpha-1 antitrypsin replacement therapy.

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2017-04-11)

• Carrie Aaron, MD, Principal investigator, Columbia University