Targeting Pulmonary Perfusion in Alpha-1 Antitrypsin Deficiency

• Sponsor: Columbia University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03008915
• Collaborator: Alpha-1 Foundation (Other), Stony Wold-Herbert Fund, Inc. (Other)
• Enrollment: 15
• Location: 1
• Arms: 2
• Actual Duration (Months): 45
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Alpha-1 Antitrypsin Deficiency; Emphysema; Chronic Obstructive Pulmonary Disease	Drug: Aspirin; Drug: Placebo; Other: Withdrawal from alpha1 antitrypsin replacement therapy	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Targeting Pulmonary Perfusion in Alpha-1 Antitrypsin Deficiency
• Actual Study Start Date: Jan 1, 2017
• Actual Primary Completion Date: Jul 1, 2018
• Actual Study Completion Date: Oct 1, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. Pulmonary Microvascular Blood Flow, Mean [5 weeks]

   Pulmonary microvascular blood flow is measured on contrast-enhanced MRI in the peripheral 2cm of the lung.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Columbia University	New York	New York	United States	10032

Sponsors and Collaborators

• Columbia University
• Alpha-1 Foundation
• Stony Wold-Herbert Fund, Inc.

Investigators

• Principal Investigator: Carrie Aaron, MD, Columbia University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 11, 2017

More Information

Publications

None provided.

• Responsible Party: Carrie Aaron, Assistant Professor of Medicine, Columbia University
• ClinicalTrials.gov Identifier: NCT03008915
• Other Study ID Numbers: AAAP9855
• First Posted: Jan 4, 2017
• Last Update Posted: Feb 17, 2021
• Last Verified: Jan 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Carrie Aaron, Assistant Professor of Medicine, Columbia University: alpha-1 antitrypsin deficiency; Emphysema; chronic obstructive pulmonary disease
• Additional relevant MeSH terms: Alpha 1-Antitrypsin Deficiency; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Emphysema; Aspirin; Alpha 1-Antitrypsin; Protein C Inhibitor

Study Results

Participant Flow

Arm/Group Title	Aspirin First, Then Placebo	Placebo First, Then Aspirin
Arm/Group Description	Aspirin 81mg for 2 weeks followed by a washout period and then placebo for 2 weeks Aspirin: 81mg aspirin taken once per day in the morning Placebo: placebo taken once per day in the morning 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 for 2 weeks followed by a washout period and then aspirin 81mg for 2 weeks Aspirin: 81mg aspirin taken once per day in the morning Placebo: placebo taken once per day in the morning 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.
Period Title: Treatment 1
STARTED	8	7
COMPLETED	8	6
NOT COMPLETED	0	1
Period Title: Treatment 1
STARTED	8	6
COMPLETED	8	6
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Overall Study
Arm/Group Description	Baseline characteristics reported for all 15 participants in the crossover study.
Overall Participants	15
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.6 (7.9)
Sex: Female, Male (Count of Participants)
Female	5 33.3%
Male	10 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	15 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	15 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	15 100%
Smoking status (Count of Participants)
Former smoker	9 60%
Never smoker	6 40%
FEV1/FVC ratio (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	44.0 (13.0)
Percent emphysema, -950 HU (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	21.2 (9.8)

Outcome Measures

1. Primary Outcome

Title	Pulmonary Microvascular Blood Flow, Mean
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aspirin	Placebo
Arm/Group Description	Assessment on aspirin 81mg for 2 weeks.	Assessment on placebo for 2 weeks.
Measure Participants	6	6
Mean (Standard Deviation) [mL blood/minute per 100mL lung]	36.9 (13.0)	35.1 (15.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments	The null hypothesis is that there is no difference between measures on aspirin and placebo.
	Type of Statistical Test	Other
	Comments	Paired t-test for participants with measures on both aspirin and placebo.
Statistical Test of Hypothesis	p-Value	0.692
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Endothelial Microparticles
Description	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

Outcome Measure Data

Analysis Population Description

Due to lab closure and technician availability, only the first 3 participants had EMPs measured.

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	Assessment on aspirin 81mg for 2 weeks.	Assessment on placebo for 2 weeks.
Measure Participants	3	2
CD31+	749.0 (231.1)	821.5 (3.5)
CD62+	1357.3 (469.6)	596 (287.1)
Annexin V, CD31+	145.0 (62.8)	317.0 (210.7)

3. Secondary Outcome

Title	Endothelial Microparticles
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Off Alpha-1 Replacement Therapy	Placebo
Arm/Group Description	Assessment after 5 weeks off alpha-1 replacement therapy	Assessment on placebo for 2 weeks.
Measure Participants	2	2
CD31+	996.0 (408.7)	821.5 (3.5)
CD62+	3681.5 (3806.4)	596.0 (287.1)
Annexin V, CD31+	146.0 (186.7)	317.0 (210.7)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Off Alpha-1 Replacement Therapy	Placebo
Arm/Group Description	Assessment after 5 weeks off alpha-1 replacement therapy	Assessment on placebo for 2 weeks.
Measure Participants	2	13
Mean (Standard Deviation) [mL blood/minute per 100mL lung]	35.5 (2.6)	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.
Arm/Group Title	Aspirin		Placebo
Arm/Group Description	Assessment on aspirin 81mg for 2 weeks.		Assessment on placebo for 2 weeks.
All Cause Mortality
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/15 (0%)
Serious Adverse Events
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		1/15 (6.7%)
Vascular disorders
Syncope	0/14 (0%)	0	1/15 (6.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.