Alpha-1 Antitrypsin Deficiency, Chronic Obstructive Pulmonary Disease, Emphysema
Conditions
Keywords
alpha-1 antitrypsin deficiency, Emphysema, chronic obstructive pulmonary disease
Brief summary
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.
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.
Interventions
DRUGAspirin
81mg aspirin taken once per day in the morning
DRUGPlacebo
placebo taken once per day in the morning
OTHERWithdrawal 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.
Sponsors
Alpha-1 Foundation
Stony Wold-Herbert Fund, Inc.
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Pulmonary Microvascular Blood Flow, Mean | 5 weeks | Pulmonary microvascular blood flow is measured on contrast-enhanced MRI in the peripheral 2cm of the lung. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Baseline characteristics reported for all 15 participants in the crossover study. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment 1 | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 55.6 years STANDARD_DEVIATION 7.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| FEV1/FVC ratio | 44.0 percent STANDARD_DEVIATION 13 |
| Percent emphysema, -950 HU | 21.2 percent STANDARD_DEVIATION 9.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 10 Participants |
| Smoking status Former smoker | 9 Participants |
| Smoking status Never smoker | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 15 |
| other Total, other adverse events | 0 / 14 | 1 / 15 |
| serious Total, serious adverse events | 0 / 14 | 0 / 15 |
Outcome results
Primary
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
Time frame: 2 weeks
Population: Due to errors in acquisition of MRI, a number of participants had uninterpretable scans. 13 participants had MRIs interpretable for PMBF on placebo, and 7 on aspirin. Altogether, there were 6 participants with paired results from the two scans.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Pulmonary Microvascular Blood Flow, Mean | 36.9 mL blood/minute per 100mL lung | Standard Deviation 13 |
| Placebo | Pulmonary Microvascular Blood Flow, Mean | 35.1 mL blood/minute per 100mL lung | Standard Deviation 15.4 |
Comparison: The null hypothesis is that there is no difference between measures on aspirin and placebo.p-value: 0.692t-test, 2 sided
Secondary
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.
Time frame: 2 weeks
Population: Due to lab closure and technician availability, only the first 3 participants had EMPs measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aspirin | Endothelial Microparticles | CD31+ | 749.0 EMPs/uL | Standard Deviation 231.1 |
| Aspirin | Endothelial Microparticles | CD62+ | 1357.3 EMPs/uL | Standard Deviation 469.6 |
| Aspirin | Endothelial Microparticles | Annexin V, CD31+ | 145.0 EMPs/uL | Standard Deviation 62.8 |
| Placebo | Endothelial Microparticles | CD31+ | 821.5 EMPs/uL | Standard Deviation 3.5 |
| Placebo | Endothelial Microparticles | CD62+ | 596 EMPs/uL | Standard Deviation 287.1 |
| Placebo | Endothelial Microparticles | Annexin V, CD31+ | 317.0 EMPs/uL | Standard Deviation 210.7 |
Secondary
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.
Time frame: 5 weeks
Population: Only 2 participants had EMPs measured on placebo and 2 off AAT replacement therapy, only 1 participant had EMPs measured at both time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aspirin | Endothelial Microparticles | Annexin V, CD31+ | 146.0 EMPs/uL | Standard Deviation 186.7 |
| Aspirin | Endothelial Microparticles | CD31+ | 996.0 EMPs/uL | Standard Deviation 408.7 |
| Aspirin | Endothelial Microparticles | CD62+ | 3681.5 EMPs/uL | Standard Deviation 3806.4 |
| Placebo | Endothelial Microparticles | CD31+ | 821.5 EMPs/uL | Standard Deviation 3.5 |
| Placebo | Endothelial Microparticles | CD62+ | 596.0 EMPs/uL | Standard Deviation 287.1 |
| Placebo | Endothelial Microparticles | Annexin V, CD31+ | 317.0 EMPs/uL | Standard Deviation 210.7 |
Secondary
Pulmonary Microvascular Blood Flow, Mean
Pulmonary microvascular blood flow is measured on contrast-enhanced MRI in the peripheral 2cm of the lung.
Time frame: 5 weeks
Population: 2 participants who completed the withdrawal phase had MRIs interpretable for PMBF on placebo and off AAT replacement therapy, data for the other 2 participants was uninterpretable for at least 1 of the 2 scans.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Pulmonary Microvascular Blood Flow, Mean | 35.5 mL blood/minute per 100mL lung | Standard Deviation 2.6 |
| Placebo | Pulmonary Microvascular Blood Flow, Mean | 35.1 mL blood/minute per 100mL lung | Standard Deviation 11 |