Imaging Regional Lung Defect Severity

Recently, The Center for Disease Control and Prevention (CDC) announced that chronic
obstructive pulmonary disease (COPD) had escalated to the 3rd leading cause of death in this
country. John Walsh (President, COPD Foundation) remarked that "It's unacceptable that COPD
has gone from the fourth leading cause to the third twelve years sooner than what was
originally projected. This wakeup call intensifies our declaration of war on COPD and points
to the importance of improved awareness, prevention, detection and treatment to decrease the
burden of COPD". Although there have been significant advances in care, the COPD epidemic
persists, leading to approximately 137,082 deaths/yr. in the US alone. COPD represents the
only disease in the top ten causes of death that has consistently increased in frequency over
the past 4 decades only showing a slight decrease (~4%) in the preliminary data for deaths in
2009 recently released. The economic burden of COPD in the US in 2010 is estimated at 29.5
billion dollars in direct costs (an increase of 63% from 2002) and another 20.5 billion in
productivity loss. Consequently COPD represents one of the largest uncontrolled disease
epidemics in the U.S.; it currently includes 15-20 million diagnosed cases with perhaps a
similar number undiagnosed. In the U.S., there are approximately 90 million current or former
smokers thus; a huge population is at risk of developing COPD.

COPD is defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as a
disease state characterized by airflow limitation that is not fully reversible. There is
clear recognition that COPD includes both emphysema and small airway disease; however, there
is little appreciation of how to identify COPD early - before there is significant airflow
obstruction and clinical impairment.

It has long been appreciated that better characterization of pulmonary disease requires
assessing the lung regionally. To this end computed tomography (CT) is gaining prominence by
distinguishing airways-predominant vs. emphysema-predominant COPD. CT can also add functional
information regarding perfusion or ventilation, but concern is increasing regarding radiation
dose and increased cancer risk. The introduction of 3-Helium (3He) MRI enables longitudinal
and sensitive imaging of ventilation, while adding contrast like the apparent diffusion
coefficient (ADC) to reveal emphysema. Unfortunately the world supply of 3He is miniscule,
and 3He ADC has failed to measure disease progression. Thus, attention has turned to
129-Xenon (129Xe) MRI and the Duke group has now shown clinical 129Xe MRI with similar
quality to 3He, including ADC contrast. Ultimately, however, the dissemination of the
hyperpolarization technology required to acquire these scans remains problematic and acts as
a hindrance in using it in clinical trials. Consequently another imaging biomarker is
required, and hence perfluoropropane/oxygen mixtures are being considered.

To treat patients, or to develop new therapies for a disease, requires the ability to
phenotype the condition, monitor progression/response, and to do so non-invasively and
longitudinally. Improved measurements will be critical to drive progress in treating chronic
diseases such as COPD that affect over 15 million US patients, but progress slowly and
respond to therapy slowly. Clinical trials of treatments of lung airway disease often require
very large numbers of subjects due to the limited sensitivity of global ventilation
assessment or other clinical measures (e.g. number of exacerbations per year).

The question of regional ventilation in disorders such as COPD is becoming increasingly
important. An editorial in the New England Journal of Medicine (NEJM) addressed the concerns
of using changes in Forced Expiratory Volume in 1 second (FEV1) as an endpoint in treatment
trials. The comments were related to the Understanding Potential Long-Term Impacts on
Function with Tiotropium trial (tiotropium vs. placebo (UPLIFT). In this study, reported in
the same issue, patients using standard respiratory medications (except inhaled
anticholinergic drugs) were randomized to their existing treatment with either tiotropium or
placebo and followed for a 4-year period. While the treatment group using tiotropium had
improvements in lung function, quality of life (QOL) and fewer exacerbations in the 4-year
study, there was no significant change in the rate of decline in FEV1 either before of after
bronchodilator administration. In a separate study called Towards a Revolution in COPD Health
(TORCH), trial patients were randomized to a combination treatment (fluticasone and
salmeterol), each of the agents alone or placebo. TORCH patients were followed for a 3-year
period where the primary outcome was death from any cause. The reduction in mortality did not
reach statistical validity although there were benefits in secondary outcomes (e.g. frequency
of exacerbations, spirometric values). The difference in FEV1 for the dual agent arm versus
placebo was 0.092 liters (95% confidence interval (CI) 0.075 - 0.108, p<0.001) although the
mean baseline FEV1 for the treated and placebo group was 1.24 and 1.26 liters respectively
yielding a 7% difference in the FEV1, a difference not generally considered clinically
relevant. The dominant question in the editorial and one facing studies of COPD is the
heterogeneity of the disorder and the current lack of a good diagnostic tool for
stratification/screening of potential subjects for a treatment study. Potentially
radiographic or non-radiographic imaging may become a tool to assist in such screenings or
even serve as an endpoint. Avoiding such failures requires developing measurements with
greater sensitivity and specificity.

Clearly, COPD is a major health issue in this country and current treatment strategies are
limited. The limits of global pulmonary function testing are recognized as a stumbling block
in the development and evaluation of new therapeutic tools for these diseases. These new
imaging biomarkers (PFx's) for evaluation of regional ventilation should be an important step
in decreasing the impact of these diseases in the US and perhaps worldwide.

The central hypothesis and current observation is that PFx gases, when used as contrast
agents, provide functional images of the lung airways including important regional
ventilation information such as ventilation defect severity and gas trapping. We will test
the central hypothesis and accomplish the overall objective by addressing the following
specific aims:

Primary Study Aims/Secondary Aims Aim 1: Determine quantitative measures of lung ventilation
performance in terms of direct measures of gas trapping measured during washout of the
perfluorinated gas mixture.

Sub-aim 1.1: Compare gas trapping from AIM 1 with air trapping by high-resolution computed
tomography (HRCT) using conventional analysis procedures.

Sub-aim 1.2: We will accomplish this aim (as well as Aim 2) in a well-characterized cohort of
subjects with COPD and subjects with normal global pulmonary function tests (non-, ex- and
current smokers). This cohort will provide the basis for the cross sectional evaluation of
the imaging markers in all aims with respect to disease severity (e.g. GOLD status) and risk
factors (e.g. smoking)

Aim 2: Determine ventilation defect severity by comparing regional gas signal during wash-in
of the perfluorinated gas mixture to steady state in the same cohort.

The outcomes of the work proposed in the aims is expected to demonstrate a novel quantitative
approach for ventilation defect and gas trapping evaluation of regional lung function in
humans that would be easily deployed for multi-center studies. It should also provide a set
of biomarkers that could better inform evaluation of new treatments.

In each of these 250 subjects, after obtaining informed consent, an array of clinical,
physiologic, imaging, and disease impact data will be collected on dedicated computerized
case report forms. The goal is to categorize the disease from structural, functional, and
clinical perspectives. The specific data to be collected have been shown in multiple studies
to be useful in describing clinical phenotypes and helped characterize subjects. They can
predict functional status and can also demonstrate and predict responders to various
therapeutic interventions.

COPD Subjects: All subjects will be adults (age >18) with spirometrically confirmed COPD
(GOLD stages I-IV) recruited from the greater Durham, North Carolina community. We
anticipate 52% female and 14% minority based on community demographics and previous COPD
study recruitment (see below). No subject will be excluded from the study on the basis of
gender or ethnicity. Female subjects of childbearing potential will undergo pregnancy
testing at study entry, and before each procedure. Informed consent will be obtained before
a subject begins any study.

Definition of COPD: We will define COPD in accordance with the World Health Organization
definition as a lung disease characterized by chronic obstruction of lung airflow that
interferes with normal breathing and is not fully reversible. Furthermore, we will classify
COPD severity using post bronchodilator GOLD spirometry criteria:

forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 0.70 and Mild
(GOLD I): FEV1 >80% predicted Moderate (GOLD II): FEV1 50-80% predicted Severe (GOLD III):
FEV1 30-50% predicted Very Severe (GOLD IV): FEV1 <30% predicted

Inclusion criteria,

- Outpatients of either gender, age > 18.

- Willing and able to give informed consent and adhere to visit/protocol schedules.
(Consent must be given before any study procedures are performed.)

- Women of childbearing potential must have a negative serum pregnancy test. This will
be confirmed before participation in this investigational protocol.

- Clinical diagnosis of COPD confirmed by spirometry demonstrating FEV1/FVC < 0.70

Exclusion criteria

- Recent exacerbation (within 30 days) defined by the need for antibiotics and/or
systemic steroids

- Abuse of alcohol or illicit substances

- Medical conditions, which, in the opinion of the investigator, will significantly
affect five-year survival.

- Medical or psychological conditions which, in the opinion of the investigator, might
create undue risk to the subject or interfere with the subject's ability to comply
with the protocol requirements

- Conditions that will prohibit MRI scanning (metal in eye, claustrophobia, inability to
lie supine, renal insufficiency with epidermal growth factor receptor (eGFR) < 60
mL/min/1.73 m2)

Continued therapy with the patient's prescribed COPD regimen will be permitted. Similarly,
all other prescribed medications will be allowed.

Normal Subjects: All subjects will be adults (age >18) with normal pulmonary function tests
(spirometrically confirmed) recruited from the greater Durham, North Carolina community. We
anticipate 52% female and 14% minority based on community demographics (see below). No
subject will be excluded from the study on the basis of gender or ethnicity. Female
subjects of childbearing potential will undergo pregnancy testing at study entry, and
before each procedure. Informed consent will be obtained before a subject begins any study.

Inclusion criteria,

- Outpatients of either gender, age > 18.

- Willing and able to give informed consent and adhere to visit/protocol schedules.
(Consent must be given before any study procedures are performed.)

- Women of childbearing potential must have a negative serum pregnancy test. This will
be confirmed before participation in this investigational protocol.

- Normal pulmonary function testing (PFT) determined by spirometry.

Exclusion criteria

- Abuse of alcohol or illicit substances

- Conditions that will prohibit MRI scanning (metal in eye, claustrophobia, inability to
lie supine)