Conditions: Alpha-1 Antitrypsin Deficiency Emphysema Chronic Obstructive Pulmonary Disease
Keywords: alpha-1 antitrypsin deficiency Emphysema chronic obstructive pulmonary disease
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 15
Healthy volunteers: no

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.

Arms:
arm 1: Aspirin 81mg for 2 weeks followed by a washout period and then placebo for 2 weeks arm 2: Placebo for 2 weeks followed by a washout period and then aspirin 81mg for 2 weeks

Interventions: intervention 1: Aspirin intervention 2: Placebo intervention 3: Withdrawal from alpha1 antitrypsin replacement therapy
Intervention descriptions: intervention 1: 81mg aspirin taken once per day in the morning intervention 2: placebo taken once per day in the morning intervention 3: 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.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
Study Protocol for 
 
 
Targeting Pulmonary Perfusion in  
Alpha-1 Antitrypsin Deficiency 
NCT03008915 
 
 
 
 
IRB# AAAP9855 
Version 1.6 
April 11, 2017 
 
 
Columbia University Medical Center 
622 West 168th Street, PH 9E Room 105 
New York, NY  10032 
 
 
 
 
 
 
Principal Investigator: Carrie Aaron, MD   
Tel: 212-305-8114 
Email: cp2346@columbia.edu 
 
Study Coordinator: Casandra Almonte 
Tel: 212-342-4162 
Email: ca2344@columbia.edu 
 
 
Funding Source: Alpha-1 Foundation 
 


 
 
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Table of Contents 
1.  Study Purpose and Rationale ..................................................................................................... 3 
2.  Study Design .............................................................................................................................. 4 
3.  Statistical Procedures ................................................................................................................. 7 
4.  Recruitment and Consent ........................................................................................................... 7 
5.  Study Procedures ....................................................................................................................... 8 
6.  Results Reporting ....................................................................................................................... 9 
7.  Potential Risks ......................................................................................................................... 10 
a. Interventions ........................................................................................................................................ 10 
b. Study Procedures ................................................................................................................................ 11 
8.  Potential Benefits ..................................................................................................................... 13 
9.  Data Safety and Monitoring Plan  ............................................................................................ 13 
10.  Privacy and Data Security ...................................................................................................... 13 
11.  References .............................................................................................................................. 14 
 
 


 
 
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1.  Study Purpose and Rationale 
 
The purpose of the Alpha-1 Foundation-funded study “Targeting Pulmonary Perfusion in 
Alpha-1 Antitrypsin Deficiency” is to determine whether pulmonary vascular changes in alpha-1 
antitrypsin (AAT) associated chronic obstructive pulmonary disease (COPD) are modified by 
either aspirin use or AAT replacement therapy.  
 
COPD and emphysema cause significant morbidity and mortality in patients with AAT 
deficiency (AATD).1,2 Emphysema is defined as airspace enlargement and alveolar wall 
destruction,3 whereas COPD is defined by spirometric airflow limitation. AAT has been 
associated with lower lobe emphysema, which often occurs before airflow limitation. 
Emphysema on CT has been associated with impaired cardiac function,4 increased dyspnea,5 and 
increased all-cause mortality in those with and without COPD6,7 AAT augmentation is the only 
medication to target emphysema, and it is a weekly intravenous therapy that is costly and 
burdensome to the patient. AAT replacement was FDA-approved based on its ability to re-
establish normal levels of AAT in the lung, and the only clinical endpoint with high quality 
positive results was a reduction in emphysema progression.8-11  
 
Platelets are involved in many vascular diseases and when activated have been shown to 
cause microvascular dysfunction.12-14 Platelets are activated by von Willebrand factor (vWF)15 
and in chronic vascular inflammation.16 As pulmonary capillaries are integral to alveolar 
structure, platelets may also be involved in the pathogenesis of emphysema. In fact, human 
genome-wide17 and DNA methylation association studies18 of COPD have found associations for 
platelet-related genes including serotonin receptor 4 (HTR4), vWF (VWF), and its platelet 
receptor glycoprotein 1bα (GP1BA). Moreover, the serine proteases neutrophil elastase and 
cathepsin G, both inhibited by AAT, increase platelet activation.19-22 In animal studies activated 
platelets form aggregates in the pulmonary microvasculature23,24 and cause vasoconstriction.25,26 
Finally, the addition of platelet factor 4, which is released by activated platelets, increased 
emphysema in an animal model of neutrophil elastase-induced emphysema.27  
 
Human studies also suggest a relationship between platelet activation and COPD. Two 
small studies found that platelet activation was associated with COPD and hypoxemia.28,29 A 
larger study of COPD hospitalizations found that thrombocytosis was associated with greater 1-
year mortality, which was reduced in those on aspirin.30 In the Multi-Ethnic Study of 
Atherosclerosis (MESA) Lung Study (AAAE9235) we found that progression of percent 
emphysema on computed tomography (CT) was more rapid in those with higher vWF (P=0.05) 
and slower among participants taking aspirin compared to those not (P=0.008). In summary, 
platelet activation has been associated with COPD in humans, and aspirin may reduce mortality 
in COPD and predict slower progression of emphysema; however, whether aspirin improves 
pulmonary microvascular blood flow in COPD or AATD is unknown. 
 
Endothelial cell perturbation and reduced pulmonary blood flow may be relevant to the 
pathogenesis of emphysema31,32 and important in AATD. AAT has been shown to attenuate 
endothelial apoptosis in animal models of emphysema.33,34 We examined the endothelial 
hypothesis of emphysema in the MESA COPD Study (AAAD6395), a case-control study of 
COPD, in which we found pulmonary microvascular blood flow on contrast-enhanced magnetic 
resonance imaging (MRI) to be inversely associated with CT percent emphysema and COPD 
stage, and associated with CD31+ endothelial microparticles (EMPs), which reflect endothelial 
apoptosis.35,37 In the Alpha-1 Foundation-funded study “Pulmonary Vascular Damage in Alpha-1 
Antitrypsin Deficiency”, which followed the MESA COPD protocol, we found greater CD31+ 
EMPs in AATD compared to MESA COPD cases and controls, and a non-significant reduction 
in pulmonary microvascular blood flow in AATD compared to controls. Importantly, those with 


 
 
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AATD on AAT augmentation had lower CD31+ EMPs and a trend toward greater pulmonary 
microvascular blood flow compared to those not on AAT therapy. These findings demonstrate 
increased endothelial damage in AATD compared to non-AATD COPD and suggest 
amelioration of endothelial damage by AAT augmentation; however whether AAT augmentation 
reduces CD31+ EMPs and improves pulmonary microvascular blood flow is unknown. 
 
Therefore, we propose to accrue 15 subjects with PiZZ AATD-associated lung disease 
who are on AAT augmentation therapy into a study protocol that includes: 1) a Phase IIa cross-
over randomized controlled trial (RCT) of aspirin vs. placebo and 2) a withdrawal study with a 
follow-up visit off AAT augmentation therapy in order to test the following hypotheses: 
1) 
Randomization to aspirin 81mg daily increases pulmonary microvascular blood flow on 
MRI and improves secondary endpoints compared to placebo in participants with AATD-
associated lung disease receiving standard care (including AAT augmentation therapy). 
2)     CD31+ EMPs will be lower and secondary endpoints will be improved when participants 
are on AAT augmentation therapy compared to off AAT augmentation therapy, while 
receiving other standard medical treatment. 
Successful completion of these aims would demonstrate that aspirin and AAT augmentation 
therapy improve pulmonary microvascular blood flow and reduce CD31+ EMPs in AATD-
related lung disease, would support future studies evaluating aspirin in emphysema in AAT, 
demonstrate additional benefits of AAT augmentation, and support the use of pulmonary MRI 
and EMPs as outcomes for clinical trials in COPD. 
 
 
2.  Study Design  
 
a. The proposed study is a single-center Phase IIa randomized cross-over study and 
withdrawal study. 
 
b. The study will accrue 15 subjects and enroll up to 20. 
 
c. Inclusion criteria: 
i. 
Alpha-1 antitrypsin deficiency (PiZZ genotype)  
ii. 
40 years of age or older  
iii. 
Evidence of emphysema on CT scan as read by a Radiologist 
iv. 
On intravenous alpha-1 antitrypsin replacement therapy 
 
d. Exclusion criteria: 
i. 
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; 
ii. 
Immunosuppression by use of medications (including oral prednisone) or medical 
condition (organ transplantation or actively-treated malignancy), including 
autoimmune conditions that require immunomodulatory treatment (e.g. anti-TNF 
agents);  
iii. 
Known atrial fibrillation or left ventricular (LV) systolic heart failure;  
iv. 
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; 


 
 
5 
v. 
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. GFR will be calculated using 
the MDRD equation based on the most recent laboratory sample available (within 
the last 30 days required). If one is not available at the time of MRI a point-of-care 
Creatinine will be run and this value will be used instead of the laboratory sample; 
vi. 
Frequent exacerbations of respiratory symptoms (two or more in the last year); and 
vii. 
Exacerbation of respiratory symptoms within the previous 6 weeks, such as that 
requiring hospitalization, oral prednisone or antibiotics to control symptoms. 
 
 
Figure 1. Study Design 
 
 
 
 
 
 
Table 1: Study Components 
 
Visit #: 
 1 
2 
3 
4 
Exam component 
Screening 
visit 
After  
treatment 1 
After  
treatment 2 
Off AAT  
augmentation 
Anthropometry 
X 
X 
X 
X 
Blood pressure 
 
X 
X 
X 
Questionnaires 
X 
X 
X 
X 
Phlebotomy 
 
 
 
 
Endothelial microparticles 
 
X 
X 
X 
Creatinine, CBC 
X 
X 
X 
X 
Platelet activation 
 
X 
X 
X 
Alpha-1 antitrypsin level 
 
X 
X 
X 
Urine specimen 
 
X 
X 
X 
Spirometry, pre- and post-bronchodilator 
X 
X 
X 
X 
Diffusing capacity 
X 
X 
X 
X 
Pulse oximetry 
X 
X 
X 
X 
Six minute walk test 
 
X 
X 
X 
Non-contrast chest CT 
X 
 
 
 
Cardiopulmonary MRI 
 
 
 
 
   Pulmonary microvascular blood flow 
   RV, LV, cardiac output 
 
X 
X 
X 
X 
X 
X 


 
 
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e. Endpoints 
i. 
Aspirin RCT 
(1) Primary endpoint: pulmonary microvascular blood flow 
(2) Secondary endpoints:  
a. Pulmonary perfusion: pulmonary microvascular blood volume, pulmonary 
microvascular transit time, and above measures of pulmonary perfusion in 
areas of emphysema on chest CT  
b. CD31+ endothelial microparticles (reflecting endothelial apoptosis), CD62+ 
endothelial microparticles (reflecting endothelial activation) 
c. Spirometry: post-bronchodilator FEV1 and FEV1/FVC 
d. Pulse oximetry 
e. Diffusing capacity 
f. Six minute walk test 
g. Alpha-1 antitrypsin level 
h. Cardiac MRI: LV EDV, RV EDV, LV SV, cardiac output 
i. Questionnaire: MMRC dyspnea scale, COPD Assessment Test 
 
ii. 
Alpha1 Augmentation Withdrawal Study 
(1) Primary endpoint: CD31+ endothelial microparticles (reflecting endothelial 
apoptosis) 
(2) Secondary endpoints: 
a. CD62+ endothelial microparticles (reflecting endothelial activation), platelet 
microparticles (reflecting platelet activation) 
b. Pulmonary perfusion: pulmonary microvascular blood flow, pulmonary 
microvascular blood volume, pulmonary microvascular transit time, and 
above measures of pulmonary perfusion in areas of emphysema on chest CT 
c. Spirometry: post-bronchodilator FEV1 and FEV1/FVC 
d. Pulse oximetry 
e. Diffusing capacity 
f. Six minute walk test 
g. Markers of platelet activation: beta-thromboglobulin, platelet factor 4, 
thromboxane B2, von Willebrand factor 
h. Cardiac MRI: LV EDV, RV EDV, LV SV, cardiac output 
i. Questionnaire: MMRC dyspnea scale, COPD Assessment Test 
 
f. Subjects will undergo telephone pre-screening before Visit 1. At Visit 1 they will be 
consented, after which a platelet count and creatinine will be drawn to confirm eligibility. 
Participants will then complete questionnaires, perform spirometry, diffusing capacity 
and pulse oximetry. Eligible patients will then be randomized as to the order of 
intervention vs. placebo and will undergo non-contrast chest CT. Randomization will be 
stratified by smoking status with full concealment of allocation; subjects and the 
investigative team will be blinded as to treatment assignment. The intervention will be 
81mg aspirin and a matched placebo, each taken once per day in the morning. Each 
treatment will last approximately 2 weeks (Figure 1, previous page) with Visits 2 and 3 
occurring at the end of treatment 1 and 2, respectively. Each treatment may be continued 
for up to 18 days, if needed, to coordinate scheduling of the participant visit and 
procedures. There will be a 2-week washout period between the treatments, and the total 
length of the randomized protocol will be approximately 6 weeks. The CU Research 


 
 
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Pharmacy will dispense study medications. During the study period, subjects will be 
asked to continue the same medication regimen and avoid using over-the-counter aspirin 
and other non-steroidal anti-inflammatory drugs. 
 
g. Timing with respect to AAT infusions: We will recruit subjects who are on AAT 
augmentation therapy, and the timing of study visits will be coordinated with their 
weekly dosing of AAT to minimize differences between study visits other than the 
intervention. We will schedule patient visits on days 1-3 post-infusion in order to study 
the effects of peak AAT levels.  
  
h. Withdrawal of AAT augmentation therapy:  
Subjects will be asked to stop AAT augmentation therapy for approximately 5 weeks and 
return for Visit 4. Withdrawal of AAT for 5 weeks (a maximum of 5.5 weeks) will allow 
AAT levels to drop briefly to those seen in the absence of AAT augmentation.  
     
 
3.  Statistical Procedures 
 
a. Data analysis: Data analysis will be performed primarily by the PI at Columbia 
University. The primary analysis will use paired t-tests to compare pulmonary 
microvascular blood flow on aspirin compared to placebo, and CD31+ EMPs on AAT 
augmentation therapy compared to off augmentation following the intention-to-treat 
principle. Similar analyses will be performed for secondary endpoints. Exploratory 
analyses will also evaluate for different effects in subgroups by smoking status, COPD 
severity, use of supplemental oxygen, and by severity of reduction in DLCO and will 
evaluate for period and carryover effects. Approaches to missing data will include: 1) 
minimization through short study duration and efforts to retain 100% of participants for 3 
months and 2) sensitivity analyses using a variety of imputed values (worst-case scenario, 
baseline observation carried forward, last observation carried forward). 
 
b. Statistical power:  Power was estimated for a paired t-test to compare an individual’s 
pulmonary microvascular blood flow before and after the intervention. For 15 subjects 
with power of 80% and α=0.05, we will be able to detect a minimally significant 
difference of 0.30 log CD31+ EMPs (1.2 SDs of the difference in log CD31+ EMPs for 
those on replacement and not), and a minimally significant difference of 48.4 mL 
blood/min*100mL lung (1.6 times the SD of the difference in pulmonary microvascular 
blood flow [PMBF] for those on replacement and not). Power will be adequate for CD31+ 
EMPs and moderate for PMBF. As power was derived from a cross-sectional analysis, 
this is a conservative estimate and we expect that power will be improved when 
comparing changes within an individual. 
 
 
4.  Recruitment and Consent 
 
a. Recruitment:  Participants will be recruited from multiple sources. First, we will recruit 
among the 30 participants who previously enrolled in the Alpha-1 extension of the 
MESA COPD Study over the telephone (AAAD6395). All of these participants agreed to 
be contacted for future research purposes on their consent forms. Second, we will email, 


 
 
8 
call, meet in person with, or mail flyers to pulmonologists within the recruitment region 
who see patients with alpha-1 antitrypsin deficiency to ask them to refer any patients who 
might be interested. The flyer may also be posted on the pulmonary and lung transplant 
floors of Presbyterian Hospital at Columbia University. Third, we will distribute study 
information through AlphaNet, a network for Alpha-1 patients that is affiliated with the 
Alpha-1 Foundation (see attached recruitment materials). Fourth, we will utilize the 
Alpha1 Research Registry (run out of the Medical University of South Carolina), who 
maintains a database of approximately 5,000 persons with alpha-1 antitrypsin deficiency 
and can send study information to a subset who meet our basic eligibility criteria and live 
in the geographic region. Fifth, we will contact leaders of support groups for alpha-1 
antitrypsin deficiency in the recruitment region to consider presenting material about our 
study at their meetings, allowing us to present the material, or distributing recruitment 
materials to their list-serve via email. The recruitment region includes NY, NJ, CT, PA, 
DE and MA. 
 
Interested persons will be contacted directly by telephone to discuss the study (following 
the attached script). The interviewer will then administer a Screening Questionnaire to 
check inclusion and exclusion criteria, and determine willingness to participate. 
 
For persons who are screened over the telephone but found to be ineligible for the study, 
we will keep record of their name, telephone number and Screening Questionnaire for the 
duration of the study in a locked cabinet in the study coordinator’s office. The rationale 
for this is 1) to ensure that we do not contact the same person twice, and 2) in the event 
that we change eligibility criteria, we would be able to contact the appropriate persons for 
potential inclusion in the study. We will send an information sheet to those who are 
screened but ineligible to inform them that they were contacted for this study. 
 
b. Informed Consent: Each participant will go through the process of informed consent (and 
signature documentation of this) with the PI, Dr. Aaron. Informed consent includes 
consent to be randomized to take the study drug and placebo in either order, holding their 
home augmentation therapy for approximately 5 weeks, and return for three study visits. 
Prior to initiation of the study, the consent form will be approved by the IRB. The 
alternative to participating in the study is not participating in the study, or participating in 
part of the study as it is entirely voluntary. If subjects wish to withdraw from the study, 
we will request to perform measurements at the time of drop out if the subject is 
amenable.  
5.  Study Procedures  
 
The study will consist of the following components, as outlined in Table 1 (next page): 
1. 
Anthropometric measurements. Height and weight will be measured to the nearest 0.1cm 
and 0.5kg with a scale and stadiometer at visits 1-4.  
2. 
Blood pressure. Resting blood pressure is measured at visits 1-4 in the right arm after 5 
minutes in the seated position with the automated Dinamap Monitor Pro 100. Three readings 
are taken and the 2nd and 3rd readings are averaged for use in analyses. 
3. 
Questionnaires. Questionnaires will be administered to all study participants at visits 1-4 
including respiratory symptoms, smoking habits, medication use, occupation, and health 
information.  


 
 
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4. 
Phlebotomy. A blood sample will be collected at visit 1 to confirm eligibility. Fasting blood 
samples will be collected at visits 2-4 to measure EMPs, creatinine, complete blood count, 
measures of platelet activation, and alpha-1 antitrypsin level. The total amount  
to be drawn will be no more than 45mL. A 10mL syringe will be transported immediately 
for EMP analysis. A second blood sample may be collected during visits 2, 3 and 4 for a 
point-of-care Creatinine, if the laboratory measurement is not resulted at the time of MRI. 
5. 
Urine specimen. Approximately 1 cup of urine will be collected at visits 2-4, this is for 
storage for potential future measurement of platelet activation. 
6. 
Spirometry. At visits 1-4 pre and post-bronchodilator spirometry will be performed 
according to American Thoracic Society (ATS) guidelines. Testing will be performed before 
and 15 minutes after administration of 2 puffs of albuterol (180 mcg) from a metered dose 
inhaler.  
7. 
Diffusing capacity. This non-invasive test is similar to spirometry, but involves less effort. 
All participants will undergo single breath DLCO at visits 1-4.  
8. 
Pulse oximetry, or oxygen saturation. Resting oxygen saturation (off supplemental oxygen 
for 5 minutes, if used) will be measured non-invasively with a pulse-oximeter at visits 1-4.  
9. 
Six minute walk test. The 6MWT will be conducted on an established course according to 
ATS standards by a certified and trained technician with continuous non-invasive 
monitoring (e.g. oxygen saturation). 
10. CT scan. The CT scan will be performed using a GE 64 multi-detector computed 
tomography (MDCT) scanner at visit 1. The protocol comprises a full scan of the chest 
following instructions for a very deep breath. The purpose of this test is to measure the full 
lung and lung segments and regions, and the total pulmonary vasculature volume. At the end 
of the study, participants will be asked to breathe out and hold it for a few seconds to be able 
to take an expiratory phase scan. The estimated effective radiation exposure for the 
inspiratory and expiratory scans is 6.5 mSv total. Women age 40-55 years will have a urine 
pregnancy test performed prior to CT and MRI scanning.   
11. Magnetic Resonance Scanning on MRI scanners. The MRI exam will be performed at visits 
2-4. Before having the MRI exam, participants will be asked questions about their medical 
history and any contraindications to MRI. The MRI will be a pulmonary angiography with 
the administration of gadolinium to visualize the pulmonary vascular bed. For this exam, the 
participant will lie on a table inside the MRI for about 30 minutes and will wear a facemask 
delivering supplemental oxygen at 8 L/min to reverse pulmonary hypoxic vasoconstriction. 
Gadolinium contrast will be injected into the antecubital vein through an 18-20 gauge IV. 
The type of gadolinium will be gadoterate meglumine (a macrocyclic agent, Dotarem), and 
the dose per scan will be 0.03 mmol/kg (0.06 ml/kg). The scanning will be at Functional 
Residual Capacity (FRC), which is the volume of air left in the lungs after a normal, passive 
exhalation. Participants will be asked to breathe out to a resting phase, and will be asked to 
practice achieving and holding their breath during the expiration phase. 
12. Storage of Blood and urine. Blood and urine from visits 2-4 will be stored at Columbia and 
at University of Vermont, identified only by study ID and following standard procedures. It 
will be accessible only to study investigators and, if the participant approves, outside 
investigators with IRB approval. Blood and urine will be kept indefinitely. 
 
 
6.  Results Reporting 
a. Clinically relevant results (spirometry, CT scan report, LV mass and ejection fraction and 
Class A and B incidental findings and, if highly abnormal, blood pressure and blood test 


 
 
10 
results) will be provided to participants and if they allow it, to their physicians.  
 
b. Incidental Findings. Images will be reviewed within 2 weeks as follows: all CT scans are 
acquired on clinical scanners and enter into the clinical workflow and are read by a 
credentialed Radiologist as part of clinical work and a clinical report is produced; all 
cardiac MRI and pulmonary perfusion sequences will be reviewed by a credentialed 
Radiologist and a safety read will be produced for incidental findings. When medically 
significant incidental findings occur the Reporting of Incidental Findings in Research 
Form will be submitted to the IRB. 
 
c. Typical incidental findings include nodules and signs of low-grade infection, rarely 
cancer, LV hypertrophy and low ejection fraction. Clinical reports are sent out and, 
additionally, the PI calls participants in the case of incidental findings in a timeframe 
consistent with the severity of the incidental finding. 
 
 
7.  Potential Risks 
a. Interventions 
i. 
Aspirin 81 mg daily x 2 weeks. Aspirin is a commonly used over-the-counter 
medication that is generally regarded as safe. The most common adverse effects of 
aspirin are minor bleeding and gastrointestinal upset. Serious adverse effects are rare, 
but include intracranial and gastrointestinal hemorrhage. The increased attributable 
risk of intracranial hemorrhage for daily aspirin use (most at 81 mg, some at 325 mg 
dose) was 0.4 events per 1000 person-years, and attributable risk of gastrointestinal 
hemorrhage due to peptic ulcer disease was 2 events per 1000 persons-years.36 Renal 
function can be transiently reduced with aspirin, as with any nonsteroidal anti-
inflammatory drug, but this is rare in the absence of chronic kidney disease.37 In 
AATD there is no documented increase in adverse effects of aspirin. However, those 
with cirrhosis or liver failure should avoid aspirin due to increased risk of variceal 
bleed38 and acute kidney injury.37 Aspirin will be administered for at least 2 weeks, 
and may be continued for up to 18 days if needed to coordinate scheduling for the 
participant and Visit 2 or 3 procedures. 
ii. 
Placebo daily x 2 weeks. There are no risks of the placebo medication. Participants 
will be asked not to take aspirin and other nonsteroidal anti-inflammatory drugs 
during the study period, but are able to take Tylenol if needed. We plan to exclude 
subjects who take aspirin prescribed by a physician, minimizing the potential risk of 
withholding a participant’s usual medication. Placebo will be administered for at least 
2 weeks, and may be continued for up to 18 days if needed to coordinate scheduling 
for the participant and Visit 2 or 3 procedures. 
iii. 
Stopping alpha-1 antitrypsin replacement therapy. Participants will be asked to stop 
AAT replacement therapy for 5 weeks, so that AAT levels drop to levels seen in the 
absence of AAT replacement. AAT replacement therapy may be withheld for up to 40 
days if needed to coordinate scheduling for the participant and Visit 4 procedures. 
AAT replacement therapy is the standard of care for AATD in the U.S. and was 
FDA-approved because it was shown to restore AAT in the lung to normal levels.39 
Further evidence for its use is based mostly on observational data: an alpha-1 registry 
study compiling 5 years of data found a lower mortality in those on augmentation 
compared to those not, and a slower decline in FEV1 in those with poor lung function 


 
 
11 
on augmentation therapy compared to those not on augmentation therapy;40 a meta-
analysis of randomized and non-randomized studies found a slower rate of FEV1 
decline in those with initial FEV1 between 30-65% predicted who were on 
augmentation therapy compared to those not on therapy;41 and a retrospective study 
found lower exacerbation rates and less severe exacerbations in subjects when they 
were on augmentation therapy compared to when they were not on augmentation 
therapy.42 A few RCTs have also found a borderline reduction in the progression of 
CT emphysema in those on AAT augmentation compared to those not,8-10 with one 
meeting statistical significance.11 One of these RCTs evaluated exacerbations in 77 
participants over 2 years, they found the overall exacerbation rate to be similar among 
the two groups, however a post-hoc analysis found a reduction in severe 
exacerbations (those requiring hospitalization) in those on augmentation therapy.9  
In summary, there is no data to suggest that short term withdrawal of AAT 
augmentation will lead to a clinical change or exacerbation. The participants in this 
study will miss approximately 4 doses of AAT augmentation over approximately 5 
weeks (5.5 weeks maximum), this is 1/24 of the 2-year duration of the RCT 
mentioned above and there would be little change in emphysema or exacerbation 
rates expected to occur during this interval. However, we will mitigate the potential 
risk of increased exacerbations during this short withdrawal period by excluding 
participants who have experienced frequent exacerbations (2 or more exacerbations in 
the last year).  
 
b. Study Procedures 
i. Anthropometry, blood pressure and pulse oximetry. There are no direct risks or 
discomforts from participation in the anthropometry, blood pressure or pulse 
oximetry to measure oxygen saturation.  
ii. Questionnaires. There is minimal risk related to questionnaires, this involves the 
social-psychological risk from the inadvertent disclosure of confidential medical 
information. We guard against this by maintaining study information identified by 
study number only in a filing system separate from the name and address files. 
iii. Phlebotomy. The risks associated with blood collection are minimal and include the 
potential to feel a little pain or get a bruise at the place where the blood is drawn. It is 
possible, but not likely, that there may be swelling or bleeding at the site. A second 
blood collection (for point-of-care Creatinine in MRI) will be avoided if possible by 
collecting a blood sample at the time of IV placement. 
iv. Urine specimen. Minimal risk. 
v. Spirometry. Spirometry is non-invasive and involves minimal risks. Spirometry can 
induce shortness of breath, coughing or chest tightness, and may cause the participant 
to feel lightheaded. Albuterol will be given as part of the pulmonary function testing. 
Albuterol is a commercially available, FDA-approved drug. The common side effects 
associated with albuterol are transient mild tachycardia, tremulousness and 
nervousness. 
vi. Six minute walking test (6MWT). The 6MWT may cause a participant to experience 
shortness of breath or chest tightness while doing the test. Treatment will be available 
if this occurs. There is a very small risk of abnormally high or low blood pressure, 
fainting, abnormally slow, fast or irregular heartbeat, and heart attack. We will 
minimize this risk by excluding higher risk participants (those with resting heart rate 


 
 
12 
below 50 or above 110 beats per minute, chest pain within the last 4 weeks, or 
new/worsening chest pain, shortness of breath or fainting within the last 8 weeks). 
vii. CT Scan. MDCT involves exposure to low doses of x-ray radiation. The estimated 
effective radiation dose that an average sized participant will receive from the MDCT 
will be approximately 6.5 mSv, which is the radiation dose that everyone receives in 
about 2.1 years of background radiation in the greater New York City area.  
viii. MRI Scanning. The MRI procedures do not expose participants to ionizing radiation. 
All subjects will be screened to exclude those with contraindications to MR, 
including those with pacemakers, aneurysm clips, cochlear implants or other 
implanted electronic devices. Subjects with a history of occupational exposure to 
small metallic projectiles will be further evaluated with orbital radiographs as needed. 
There is also a psychological risk if an individual becomes claustrophobic while 
inside the MRI machine. Claustrophobic episodes may be traumatic to the patient, 
however it resolves after removal from the scanner and usually does not have any 
known lasting effects. We minimize this risk by excluding subjects with a known 
history of severe claustrophobia. Subjects will be in direct verbal contact with the 
MRI operator at all times and MRI examinations will be terminated at any time upon 
the request of the subject. The MRI scanner areas at the sites are equipped with 
standard emergency equipment for a hospital-based MRI center.  
ix. Gadolinium (contrast agent). There is a risk of allergic reaction after the gadolinium 
injection; with less than one in 300,000 chances that this will severe. Metallic taste in 
the mouth, tingling in the arm, nausea, or headache occurs in less than 1% (less than 1 
in 100) people. Insertion of the needle may also cause minor pain, bruising and/or 
infection at the site. Participants with chronic renal insufficiency (estimated 
glomerular filtration rate [eGFR] < 45 mL/min/1.73 m2) will be excluded to eliminate 
the risk of nephrogenic systemic fibrosis. Gadolinium has recently been reported to 
persist in the brain; the significance of this finding is unknown and there is no 
reported harm. Persistance of a gadolinium signal in the brain has been reported to be 
associated with renal failure, linear gadolinium agents compared to macrocyclic 
agents, and cumulative dose.43,44 We will guard against this potential harm by using a 
macrocyclic agent (gadoterate meglumine, Dotarem). The macrocyclic agents are not 
reported to persist in the brain,45,46 and we use a very low dose so that our cumulative 
study dose of 0.09 mmol/kg is less than the clinical dose for 1 scan of 0.1 mmol/kg. 
We will also exclude those who have received gadolinium agents within the past 6 
months. 
x. Supplemental Oxygen During MRI. There is a risk that supplemental oxygen via non-
rebreather mask (at 8 L/min, with an FiO2 of 50-60%) will lead to retention of carbon 
dioxide, as it reverses hypoxic pulmonary vasoconstriction. If this occurs it could 
cause somnolence, confusion and decreased respiratory rate. We will mitigate this 
risk in five ways: 1) participants with current use of supplemental oxygen, history of 
intubation for COPD exacerbation, history of being a “retainer” (high carbon dioxide 
levels in the blood), or history of becoming drowsy or confused when given too much 
oxygen will not receive supplemental oxygen; instead they will undergo MRI using 
the rate of oxygen used at home, if prescribed; 2) respiratory rate and pattern will be 
monitored by the MRI technician during the MRI; 3) verbal communication will be 
maintained with the participant while they are in the MRI scanner; 4) a physician will 
be present during oxygen administration for the first MRI, and for subsequent MRIs a 
registered nurse (certified in advanced cardiac life support) will be in the vicinity 


 
 
13 
during oxygen administration; and 5) emergency equipment will be immediately 
available in case the participant’s respiratory rate drops. If there is any change in 
mental status or respiratory rate, supplemental oxygen will be discontinued 
immediately, and not used for the subsequent visits.  
xi. Findings on Imaging. The imaging may reveal incidental findings that require further 
testing or interventions that may be harmful, costly or cause distress. Please note that 
all CT and MRI scans are read by board-certified radiologists; the former get a 
clinical read, the latter, a safety read. In the event of incidental findings, the PI will 
contact the participant and their physician, if desired by the participant. If the 
participant does not have a physician, we will refer then to an appropriate clinic for 
follow-up. At the time an incidental finding of clinical significance is reported to the 
PI, the PI will provide the IRB with image numbers, study subject numbers, type of 
scan, date of scan, description of the incidental finding of clinical significance, date of 
communication with the patient and outcome, if it is known. 
 
8.  Potential Benefits 
 
a.  Benefits to society 
The information learned from this study may benefit the alpha-1 community, as it will 
increase scientific knowledge about changes in the pulmonary vasculature in lung disease 
related to AATD. Benefits also include that it may further our understanding of how 
emphysema occurs in lung disease related to alpha-1 antitrypsin deficiency, potentially 
leading to new treatments, and will explore intermediate endpoints for the only specific 
alpha-1 targeted therapy, AAT augmentation. As emphysema is also prominent in some 
subtypes of COPD, there would also be potential benefit to the larger population of 
individuals with, or at risk for, COPD. 
 
b.  Benefits to the individual 
The imaging may reveal subclinical findings that may lead to interventions that are 
beneficial to some participants. In particular, results of the National Lung Cancer 
Screening Study suggest that screening current and former smokers with CT scanning 
reduces both lung cancer-specific and all-cause mortality 
 
 
9.  Data Safety and Monitoring Plan - please see separate document. 
 
 
10.  Privacy and Data Security 
All data will be treated confidentially. Discussions of informed consent and all study-related 
matters will take place in a private room. Personal, identifiable information such as name, 
date of birth, consent form and contact information will be kept in a locked file cabinet 
located in the study coordinator’s locked office, along with the code linking to study ID. Data 
analysis will occur at Columbia University only by the PI and co-investigators. The analysis 
datasets will consist of coded data, which can only be linked back to the participant by the 
code in the study coordinator’s office, will be kept on our institution’s clinical trials server 
which is password protected, encrypted and accessible only to those involved in the study, 
and on endpoint devices which will be encrypted and password protected. Questionnaires and 
study records will be identified by study ID only. 


 
 
14 
 
Data that will be transmitted include:  
• Spirometry data - to the Spirometry Reading Center, John Hankinson 
• CT images - to University of Iowa, the MESA COPD CT Reading Center 
• Pulmonary perfusion on MRI - to Hannover Medical School, Hannover, Germany 
 
Transmitted data will always be secure. Data transmitted to and from the Spirometry Reading 
Center will be identified only by study ID, acrostic and date of test; it will not be personally 
identifiable. Data will be sent to Iowa and Hannover using the secure data sharing portal 
DatAnywhere (file size up to 2 GB) or a SFTP (files over 2 GB). Although these are secure 
means of sharing data, we will safeguard the data by using only acrostic and study ID to 
identify study subjects and the data will not include any of the 18 HIPAA identifiers. Data 
will not be transmitted to these sites until IRB/ethics approval is obtained. 
 
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