Targeting Pulmonary Perfusion in Alpha-1 Antitrypsin Deficiency

The aim of this study is to test whether aspirin improves endothelial function in alpha-1 antitrypsin deficiency-associated lung disease, measured by pulmonary microvascular blood flow on magnetic resonance imaging (MRI) and with apoptotic endothelial microparticles.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease; Emphysema; Alpha-1 Antitrypsin Deficiency
• Intervention / Treatment: Drug: Aspirin; Drug: Placebo; Other: Withdrawal from alpha1 antitrypsin replacement therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Aspirin first then placebo; Aspirin 81mg for 2 weeks followed by a washout period and then placebo for 2 weeks	Drug: Aspirin; 81mg aspirin taken once per day in the morning; Drug: Placebo; placebo taken once per day in the morning; Other: Withdrawal from alpha1 antitrypsin replacement therapy; 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.
Placebo Comparator: Placebo first then aspirin; Placebo for 2 weeks followed by a washout period and then aspirin 81mg for 2 weeks	Drug: Aspirin; 81mg aspirin taken once per day in the morning; Drug: Placebo; placebo taken once per day in the morning; Other: Withdrawal from alpha1 antitrypsin replacement therapy; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary Microvascular Blood Flow, Mean	Pulmonary microvascular blood flow is measured on contrast-enhanced MRI, limited to blood flow in the 2cm periphery of the lung	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelial Microparticles	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.	2 weeks
Endothelial Microparticles	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.	5 weeks
Pulmonary Microvascular Blood Flow, Mean	Pulmonary microvascular blood flow is measured on contrast-enhanced MRI in the peripheral 2cm of the lung.	5 weeks

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Alpha-1 Foundation; Stony Wold-Herbert Fund, Inc.
• Investigators: Principal Investigator: Carrie Aaron, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): October 1, 2020

Study Registration Dates

• First Submitted: December 22, 2016
• First Submitted That Met QC Criteria: December 30, 2016
• First Posted (Estimate): January 4, 2017

Study Record Updates

• Last Update Posted (Actual): February 17, 2021
• Last Update Submitted That Met QC Criteria: January 28, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Emphysema; chronic obstructive pulmonary disease; alpha-1 antitrypsin deficiency
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Liver Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Emphysema; Alpha 1-Antitrypsin Deficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Protease Inhibitors; Serine Proteinase Inhibitors; Trypsin Inhibitors; Aspirin; Alpha 1-Antitrypsin; Protein C Inhibitor
• Other Study ID Numbers: AAAP9855

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No