In Vivo Imaging of Destructive Processes in Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Sponsor: Columbia University

 
 
 
 
 
 
Lung Imaging of Apoptosis in Chronic Obstructive 
Pulmonary Disease (COPD) 
NCT02978144 
IRB approval date: 01/14/2025 
 
 

BACKGROUND 
 
Study Purpose and Rationale: 
Current imaging modalities in lung disease primarily focus on the evaluation of end 
organ damage and destruction (1). While molecular imaging approaches have been developed in 
oncology (2-5) and in the assessment of cardiovascular disease (6, 7), the utility of such an 
approach in lung disease is not yet established. The development of methods to image cellular 
processes and targets related to disease pathogenesis will allow an evaluation over the time 
course of disease and provides information as a potential biomarker of disease activity and 
response to therapy. Chronic obstructive pulmonary disease (COPD) is a major cause of 
disability and death worldwide and is a progressive lung condition in which tobacco smoke and 
other stimuli trigger inflammation, production of destructive enzymes and programmed cellular 
death within the lung (8). Although inflammation can be seen in smokers without COPD, both 
apoptosis and MMP production are not seen at an increased rate in smokers without COPD (9-
12), with the rate of apoptosis correlating with emphysema severity (12). Collaborative studies 
have successfully developed an imaging approach specifically targeting apoptosis in a pre-
clinical model of emphysema (13). These data provide the first evidence of our ability to 
visualize in vivo with molecular imaging an ongoing cellular process consistent with lung 
destruction in an animal model of smoke exposure. Molecular imaging offers the advantage of 
relatively small molecular size probes that can clear from the blood pool and cross capillaries to 
access receptors or protein antigenic binding sites within tissue, allowing non-invasive functional 
measurements of disease. This probe (AxV-128/Tc) has already undergone Phase 1 clinical 
testing for tracer kinetics and radiodosimetry in Canada (12 healthy volunteers, 6 men and 6 
women) and the safety profile has been established (see attachment from Advanced 
Accelerators). We propose to advance into patients this imaging approach with the goal of 
detecting alterations in pulmonary apoptosis in various stages of COPD. A correlation of known 
biomarkers with apoptosis imaging will also be assessed. If successful, these imaging techniques 
will greatly advance the field of pulmonology with clinical imaging modalities to non-invasively 
assess response to therapies and to potentially guide in prognostication. 
 
 

Study Design: 
This will be a prospective study examining the use of 99mTc-Annexin V-128 (AxV-
128/Tc) SPECT/CT technology in the imaging and functional assessment of the lung of patients 
with COPD, healthy volunteer smokers without COPD and healthy volunteer subjects without 
smoking history. 
 
STUDY PROTOCOL 
 
We will study patients with and without lung disease (COPD) and compare AxV-128/Tc 
SPECT-CT scans. To test the hypothesis that AxV-128/Tc SPECT-CT scanning can detect 
apoptosis in patients with COPD, we will perform a case control study in patients with varying 
severity of COPD. There will be four groups of subjects: -Patients with moderate COPD: GOLD 
Stage II, FEV1/FVC < 0.7 and FEV1 50-79% predicted -Patients with severe COPD: GOLD 
Stage III-IV, FEV1/FVC < 0.7 and FEV1 < 50% predicted -Healthy controls who are currently 
smoking (> 10 pack years) with normal spirometry (FEV1 > 80% and FEV1/FVC > 70%) -
Healthy controls who never smoked (less than 100 lifetime cigarettes) with normal spirometry 
(FEV1 > 80% and FEV1/FVC > 70%) The subjects will undergo spirometry (lung function tests) 
and blood and urine samples will be drawn prior to undergoing SPECT Scan. The spirometry 
will ascertain the severity of COPD and blood and urine samples will allow us to measure 
markers of lung injury as well as cotinine to confirm the smoking status of the subject. Blood 
samples will be also stored for analysis of biomarkers and possible future DNA and RNA 
analysis. 
Study population: We will study 16 patients with COPD (8 patients with GOLD Stage 2 
disease, 8 patients with GOLD Stage 3-4 disease) and 8 healthy volunteer smokers without 
COPD, and 8 healthy volunteer subjects without smoking history or lung disease to compare 
AxV-128/Tc SPECT-CT scans in smokers, patients with COPD, and normal control patients.  
Recruitment: The patient population will be drawn from the Center for LAM and Rare 
Lung Diseases, Jo-Ann F. LeBuhn Center for Chest Disease and the Price Family Center for 
Comprehensive Chest Care and will be stratified by severity of disease. Recruitment of healthy 
volunteers will be performed with advertisements in Columbia University’s “recruitme” website, 
and flyers throughout the medical center. In order to be eligible, patients with COPD must have a 

forced expiratory volume in one second (FEV1) less than 80% of predicted for age and height, 
and bronchodilatory reversibility of less than 15% or 200 ml with airflow obstruction evidenced 
by an FEV1/Forced Vital Capacity (FVC) ratio of 70% and FEV1 > 80% of predicted for age 
and height. 
Study Procedures: After obtaining informed consent, the subjects will undergo: 
Pulmonary Function Testing: pre- and post-bronchodilator spirometry, lung volume and 
DLCO measurements. 
Urine sample: urinalysis and smoking status will be confirmed by urine cotinine level.  
Pregnancy Test: If participant is a woman of child-bearing potential, a urine pregnancy 
test may be performed to ensure study eligibility. Pregnant women may not participate in this 
research study as risk of technetium to an embryo or unborn fetus may exist. Women of 
childbearing potential include all women except those whose menstrual periods have not 
occurred for more than one year after menopause (change of life) or those who have had 
sterilization surgery (tubes tied) or hysterectomy (removal of uterus or womb).For women whose 
menstrual period started less than 4 weeks prior to the study date, a urine dip stick pregnancy test 
will be performed prior to study drug administration. 
Blood sample: Serum biomarkers including leukocyte count, fibrinogen and CRP will be 
obtained for correlation of these serum biomarkers for COPD exacerbation risk with lung 
apoptosis-targeted imaging. In addition, apoptotic endothelial microparticles 
(CD42bCD62E+/CD42bCD31+) will be assessed in order to obtain a direct comparison between 
imaging signal (%ID) and alternate markers of apoptosis that can be obtained non-invasively. 
Repeat PFTs after initial imaging in order to determine the ability of AxV-128/Tc imaging 
to predict later lung function decline.  
SPECT/CT imaging: Vials of AxV-128 provided by AAA will be shipped to Nuclear 
Diagnostics, a satellite pharmacy that serves Columbia University Medical Center Nuclear 
Medicine. Nuclear Diagnostics will label AxV-128 with 99mTc and deliver pre-calibrated doses 
by time of injection to the CUMC Nuclear Medicine Department. Each dose will be injected 
intravenously by a Medical Doctor (i.e., PI, co-investigators) and if unavailable a certified 
Nuclear Medicine Technologist (NMT) or Registered Nurse (RN). The injected dose is between 
8-10mCi and never more than 10mCi as stated in the IND. Radiation is measured before and 
residual after injection. 

Scans will be performed on Siemen’s Symbia T hybrid SPECT/CT (16 slice) scanner in 
the Nuclear Medicine department. A chest CT scan will be performed with breath hold at the 
clinical dose using a standard diagnostic CT imaging acquisition protocol. Immediately 
following the CT acquisition, a SPECT will be performed with a FOV set for the chest from 
lower neck to upper abdomen. Standard CT acquisition protocols will be used. 
Vitals: Vitals will be obtained at two time points: before injection of tracer/blood draw 
and after the SPECT/CT imaging has been performed. Vital signs indicate the status of a person's 
life-sustaining functions including: Blood pressure, Heart rate and oxygen saturation rate. These 
measures will be recorded for safety purposes only. 
Medical History: Medical history including diagnoses and current medications taken will 
be collected during the study visit. Participants are encouraged, but not required to provide 
outside medical documentation confirming COPD or Alpha-1 diagnosis or any recent Pulmonary 
Function Testing, blood work and imaging done clinically. Study investigators will review any 
outside medical documentation and determine if any study procedures may be substituted for 
outside clinical records as to not burden participants repeating exams already done clinically. 
Follow up calls: One of the study team members will conduct follow up phone calls at 
24-72hours, 1 month and 6 months post imaging. These calls will be done for safety purposes 
only and will only take 1-2 minutes. Information collected includes any reporting of side effects 
and any medical diagnosis or medication changes. 
Reproducibility (Short and Long Term): In order to document short term reproducibility 
of the imaging method and give an assessment of a meaningful change of signal in a patient, up 
to 10 of the subjects with COPD (from either the moderate or severe COPD groups) will undergo 
repeat AxV-128/Tc SPECT/CT scans within one week of the original scan. Patients will not 
undergo repeat imaging if there has been a significant change in their clinical status including a 
COPD exacerbation pulmonary infection, or CHF exacerbation. Repeat imaging will only be 
performed on patients with COPD as it is anticipated based upon literature documenting that 
never smokers have negligible levels of apoptosis within the lung. The Phase I data of AxV-
128/Tc with normal subjects also demonstrated less than 5% ID lung uptake. Smokers without 
disease will be excluded from this reproducibility study as smoking may be variable from day to 
day and may alter signal results. 

In addition, long term changes in this imaging method will be assessed on subjects with 
COPD with an additional AxV-128/Tc SPECT-CT scan and same procedures listed above. The 
follow up visit may be done without an additional AxV-128/Tc SPECT-CT scan and same 
procedures listed above. Please note that only a SUBSET of subjects will undergo 1 year or 1 
week repeat scan. One year follow up visits are approximate 1 year +/- 8 months. This is to 
compensate for coordinating contacting participant and scheduling visits around their most 
convenient time. 
Imaging and data analysis: Mean ± SD for values for uptake of AxV-128/Tc for 
individual lobes and for lungs will be determined for each COPD group and compared using 
unpaired t-test for values with Gaussian distribution and Mann-Whitney (Wilcoxon rank) test for 
continuous variables without normal distribution. Gaussian distribution will be determined using 
the Kolmogorov-Smirnov test. We have included moderate, severe and very severe COPD 
patients assuming that the signal will increase with the severity of COPD. We could therefore 
establish an exposure-response relationship between severity of COPD (on a non-linear scale) 
and signal. This assumption is based upon our work establishing a correlation between COPD 
severity and apoptotic index in the lung (12). Mean ± SD for values for volumes and Hounsfield 
units will also be compared among the same groups. We will also assess tracer uptake 
normalized for lung volumes. In the emphysema patients we are measuring a signal coming from 
living (and dying) tissue that is interspersed in air. In the more severe cases of COPD, the lung 
tissue takes up less volume within the lungs and the air forms greater percent of each lobe. We 
will attempt to account for these changes by normalization for Hounsfield units. In addition 
values for %ID tracer uptake will be correlated with values for PA:A ratio. For the serial 
reproducibility studies, the values for whole lungs and lobes from the two studies will be 
analyzed for agreement using Bland-Altman analysis. 
Incidental finding of clinical significance: Potential incidental findings of clinical 
significance that may be discovered during imaging procedure may include tumors, hematomas, 
infectious complications such as abscesses and vascular abnormalities among others.. The 
following procedures pertain to the finding of incidental findings (IF) that may occur during the 
imaging of the subjects. The images will be read by a radiologist credentialed by the Department 
of Radiology as soon as possible but no later than two weeks following receipt of the image. 
Imaging will only take place at Columbia University Medical Center. If the credentialed 

radiologist will find an IF with clinical significance this will be recorded in the research record 
and the subject will notified by the PI who is a critical care physician either in person or by 
phone followed by a letter or email. 
If an IF has been reported we will notify the IRB during the next review about the 
number of Required Review Images, a list of the subject study numbers, the type of scan, the 
date of the scan, a description of the IF of Clinical Significance, the date of communication with 
the subject and the outcome, if known.  
 
Eligibility Criteria 
Inclusion Criteria: 
1. Males and females age 45-80 years  
2. Able and willing to comply with the study procedures 
3. Gold class II COPD or greater  
4. Healthy Smoker  
5. Healthy non-smoker  
6. Lie flat for 30 minutes 
 
Exclusion Criteria:  
1. Current Malignancy  
2. Bronchiectasis  
3. Recent COPD exacerbation (less than 1 month)  
4. Recent pulmonary infection (less than 1 month)  
5. Asthma or other significant lung disease  
6. Pregnancy or lactation  
7. Claustrophobia or inability to lie still in a supine position  
 
 
 
 
 
 

RESEARCH AIMS & ABSTRACTS 
 
Research Question(s)/Hypothesis(es): 
We hypothesize that there will be an increased AxV-128/Tc signal in the lungs of patients 
with COPD as compared to control patients. This signal is hypothesized to be higher in patients 
with more severe COPD. 
Scientific Abstract: 
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death and is 
characterized by clinical symptoms and spirometry. Additional measures for diagnosis can be 
taken using imaging modalities such as CT. However, the evaluation of lung destruction in 
COPD is limited by the inability to visualize the activation of pathological processes since 
imaging modalities are only able to evaluate end-organ damage. In this proposal, we aim to 
assess a molecular imaging probe targeting apoptosis, a cellular process known to be pathogenic 
in COPD. Apoptosis, a process of programmed cellular death, correlates with COPD severity and 
is not seen in the normal adult lung. In the past several years we have demonstrated the 
successful ability of AxV-128/Tc to detect apoptosis in vivo in a rabbit smoke exposure 
emphysema model. Additionally, Phase 1 studies have demonstrated safety of this agent in 
healthy patients. Therefore, we will bring AxV-128/Tc forward as a probe to image the apoptotic 
disease process of the lung in patients with COPD. We will determine if the imaging signal 
correlates with serum biomarkers of apoptosis and inflammation. It is our hypothesis that AxV-
128/99mTc imaging will show increased uptake in the lungs of patients with COPD, and that this 
signal intensity will correlate with accepted markers of apoptosis and inflammation. If 
successful, such an approach will be a powerful tool to potentially predict disease progression 
after diagnosis, identify patients at risk for disease exacerbation related lung function decline, 
and monitor response to disease targeted therapy. The total effective dose from the combined 
SPECT and CT scans is 6.71 mSv. This effective dose is below what a patient receives during a 
standard 2 dose rest and stress cardiac nuclear imaging study and well within the range of current 
clinical nuclear imaging tests. The exact long term risk for development of cancer from 
diagnostic radiological procedures is currently under debate but all imaging procedures in this 
study are aimed to keep total radiation burden ALARA (As Low As Reasonably Achievable). 
 

STATISTICAL PROCEDURES 
 
Serum biomarkers of inflammation and levels of apoptotic endothelial microparticles will 
be correlated with % injected dose of radiotracer on SPECT-CT imaging results. Up to ten 
patients with COPD will undergo a second SPECT-CT scan within 1 week of the first 
baseline/visit#1 scan in order to determine the short-term reproducibility of the signal and to 
determine what would be a meaningful change in signal. Patients must be clinically unchanged 
in the intervening week. A subset of COPD diagnosed subjects will undergo a repeat scan after 1 
year of the baseline/visit#1 scan; this will include repeat SPECT-CT, pulmonary function testing, 
blood and urine testing. The purpose of the repeat imaging to determine (1) the ability of the 
initial scan to determine later lung function decline and (2) if change in signal over a 1 year time 
point is associated with meaningful clinical change. In addition, we will compare SPECT-CT 
signal (percent injected dose, %ID) as a primary endpoint, apoptotic endothelial microparticles 
and serum biomarkers of inflammation in patients with COPD, smoking history without COPD, 
and healthy non-smoking control participants. There is no human data of AxV-128/Tc SPECT-
CT imaging in lung disease that would allow us to determine an appropriate sample size for this 
study. We will therefore base this on our rabbit studies (13) which found a %ID of approximately 
0.645 +/- 0.427 % in animals without and 2.0 +/- 0.589 % in animals with smoke exposure with 
a common standard deviation of (0.63+0.589) / 2 = 0.508 %. We will need 5 patients per group 
to achieve a power of 80% and a confidence level of 99%. We will recruit 8 subjects who never 
smoked and are without lung disease, 8 patients who were smokers without lung disease, and 16 
patients with COPD (8 with GOLD Stage 2 disease and 8 with Gold Stage 3-4 disease). Eight 
patients per group will give us sufficient power even when compensating for increases in 
variability in human subjects. 
 
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