Human Lung Regional Ventilation Defect Severity Measured by Fluorine-19 Gas MRI
Phase: PHASE1
Conditions: COPD
Sponsor: Hal C Charles

 
This document contains confidential information belonging to Duke. Except as otherwise agreed 
to in writing, by accepting or reviewing this document, you agree to hold this information in 
confidence and not to disclose it to others (except where required by applicable law) or to use it 
for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, 
Duke should be promptly notified.  
 
 
 
 
 
PROTOCOL NAME Human Lung Regional Ventilation Defect Severity Measured by 
Fluorine-19 Gas MRI  
 
 
PROTOCOL NUMBER DIAL1001004 
 
 
PROTOCOL VERSION    7.0 
 
 
PROTOCOL VERSION DATE 07Jun2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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GENERAL INFORMATION 
 
 
Name and address of the Principal Investigator of the study (Note: Dr. Moon is Co-PI on 
the IND but is an investigator on the R01) 
 
Hal Cecil Charles, PhD 
 
Richard Moon, MD 
Duke University Medical Center 
Duke University Medical Center 
Duke Image Analysis Laboratory 
Department of Anesthesiology 
Department of Radiology 
 
5676 HAFS Bldg. 
2424 Erwin Rd                                   DUMC Box 3094 
Hock plz Suite 301                             Durham, NC 27710 
DUMC Box 2702 
 
 
(919) 684-8762   
Durham, NC 27710 
 
 
richard.moon@duke.edu 
(919) 684-7921 
 
 
  
cecil.charles@duke.edu 
  
Name and title of the sub-investigators responsible for the trial with address and phone 
number(s)   
 
Bastiaan Driehuys, PhD                     Neil Macintyre, MD 
Associate Professor                            Professor 
Duke University Medical Center       Duke University Medical Center 
Department of Radiology-General     Department of Medicine of pulmonary 
161I Bryan Research                          7451 Hospital North. 
DUMC Box 3302                               DUMC Box 3911 
Durham NC 27710                             Durham NC 27710 
(919) 684-7786 
 
 
(919) 681-2720 
bastiaan.driehuys@duke.edu  
macin001@mc.duke.edu 
 
Holman Page McAdams, MD           Brian Soher 
Professor                                           Assistant Professor 
Duke University Medical Center      Duke University Medical Center  
Department of Radiology-Chest       Department of Radiology- General  
 2523 Hospital South                         North 1812B 
DUMC Box 3808                              DUMC Box 3808                       
Durham NC 27710                            Durham NC  27710 
(919) 684-7652                                 (919)                                                      
                                                           
  
  
 
 
 
 
 
 

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Name, title, address and telephone number(s) of the Statistician for the trial 
 
Kingshuk Roy Choudhury 
Associate Professor 
Duke University Medical Center 
Department of Radiology-General 
2424 Erwin Rd Hock plz Suite 302 
Durham NC  27705 
kingshuk.roy.choudhury@duke.edu 
 
Name, title, address and telephone number(s) of the Data Manager for the trial 
 
Hal Cecil Charles  
Associate Professor  
Duke University Medical Center 
Department of Radiology-General 
2424 Erwin Rd Hock plz Suite 301 
DUMC Box 2702 
Durham NC 27710 
 
 
Name and addresses of the clinical laboratories and/or other institutions involved in the 
trial 
DUKE UNIVERSITY MEDICAL CENTER 
DEPARTMENT OF RADIOLOGY 
DUMC BOX 3808 
1800 HOSPITAL NORTH  
DURHAM NC  27710 
  
DRUG SHIPMENT ADDRESS: 
CENTER FOR ADVANCED MR 
DEVELOPMENT (CAMRD) 
DUKE UNIVERSITY MEDICAL CENTER 
DEPARTMENT OF RADIOLOGY  
ROOM 1839, MRI DEPARTMENT  
DURHAM NC 27710 
DUKE UNIVERSITY HEALTH SYSTEMS  
CLINICAL LABORATORIES- DUH SITE 
1312 DAVISON BUILDING, BOX 3712 
DURHAM NC 27710 
DUKE UNIVERSITY HEALTH SYSTEM  
CLINICAL LABORATORIES- FRANKLIN 
SITE 
4425 BEN FRANKLIN BLVD 
DURHAM NC  27710 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1 Background ............................................................................................................................. 1 
1.1 
Investigational Agent ...................................................................................................................................................... 1 
1.2 
Preclinical Data .................................................................................................................................................................. 1 
1.3 
Risk/Benefits ...................................................................................................................................................................... 1 
1.3.1 
Potential Risks ................................................................................................................................................................ 1 
1.3.2 
Protection Against Risk .............................................................................................................................................. 2 
1.3.3 
MRI Risk ........................................................................................................................................................................... 3 
1.3.4 
Computed Tomography (CT) ................................................................................................................................... 3 
1.4 
Dose Rationale.................................................................................................................................................................... 4 
1.5 
Trial Design .......................................................................................................................................................................... 4 
1.6 
Literature .............................................................................................................................................................................. 4 
2 
Trial Objectives ................................................................................................................. 5 
3 
Trial Design ....................................................................................................................... 5 
3.1 
Primary Study Aims/Secondary Aims ................................................................................................................... 6 
3.2 
Trial Treatment .................................................................................................................................................................... 6 
3.3 
Duration .................................................................................................................................................................................. 6 
3.3.1 
Screening (V0) ................................................................................................................................................................ 6 
3.3.2 
Visit 1: MRI ..................................................................................................................................................................... 7 
3.3.3 
Twenty-four Hour Follow-up ................................................................................................................................... 7 
3.4 
Product Accountability ..................................................................................................................................................... 8 
3.5 
Data Identification .............................................................................................................................................................. 9 
4 
Selection of Subjects and Withdrawal/Discontinuation ................................................... 9 
4.1 
Inclusion/Exclusion Criteria for Subjects with COPD ........................................................................................ 9 
4.2 
Inclusion/Exclusion Criteria for Normal Subjects ............................................................................................. 10 
4.3 
Subject Withdrawal and/or discontinuation.......................................................................................................... 10 
4.4 
Treatment of Subjects .................................................................................................................................................... 11 
4.4.1 
MRI................................................................................................................................................................................... 11 
4.4.2 
High Resolution Computerized Tomography ................................................................................................. 11 
4.5 
Concomitant Medication .............................................................................................................................................. 11 
5 
Assessment of Efficacy .................................................................................................... 13 
5.1 
Efficacy Parameters ........................................................................................................................................................ 13 
5.2 
Adverse Event Reporting ............................................................................................................................................. 13 
5.3 
Definitions .......................................................................................................................................................................... 13 
5.3.1 
Adverse Events ............................................................................................................................................................ 13 
5.3.2 
Serious and Unexpected Adverse Events.......................................................................................................... 14 
5.4 
Adverse Event Follow-up............................................................................................................................................. 14 
6 
Statistical Plan ................................................................................................................. 15 
6.1 
Statistical Methods and Subject Population for Analysis ............................................................................... 15 
6.2 
Termination Criteria ....................................................................................................................................................... 16 
7 
Direct Access to Source Data/Documentation ................................................................ 16 
8 
Quality Control and Quality Assurance ......................................................................... 16 
9 
Ethical Considerations .................................................................................................... 16 
9.1 
Institutional Review Board .......................................................................................................................................... 16 

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9.2 
Ethical Conduct of the Trial ........................................................................................................................................ 16 
9.3 
Subject Information and Consent .............................................................................................................................. 16 
10 
Data Handling and Record Keeping ........................................................................... 17 
10.1 
Data Management .......................................................................................................................................................... 17 
10.2 
Data Storage ..................................................................................................................................................................... 17 
10.3 
Record Retention ........................................................................................................................................................... 17 
11 
Publication Plan........................................................................................................... 18 
12 
Reference ..................................................................................................................... 19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
(e.g.) 
 
CAMRD  
Center for Advanced MR Development 
 
CRF 
 
Case Report Form 
 
COPD  
Chronic Obstruction Pulmonary Disease 
 
CFR 
 
Code of Federal Regulations 
 
CT 
 
Computed Tomography 
 
DIAL  
Duke Image Analysis Laboratory 
 
DSMC  
Data Safety and Monitoring Committee 
 
DUMC 
Duke University Medical Center  
 
FDA  
Food and Drug Administration 
 
GCP 
 
Good Clinical Practice 
 
GOLD  
Global Obstructive Lung Disease  
 
ICH 
 
International Conference on Harmonization 
 
IRB 
 
Institutional Review Board 
 
MRI 
 
 Magnetic Resonance Imaging 
 
PFP 
 
Perfluoropropane gas 
 
PFT 
 
Pulmonary Function Test  
 
SF6 
 
Sulfur Hexafluoride 
 
SQUID  
Scalable Query Utility and Image Database 

Methods Study – PFP  
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This document contains confidential information belonging to Duke. Except as otherwise agreed 
to in writing, by accepting or reviewing this document, you agree to hold this information in 
confidence and not to disclose it to others (except where required by applicable law) or to use it 
for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, 
Duke should be promptly notified.  
 
1 Background 
1.1 Investigational Agent 
 
Perfluoropropane gas (PFP or C3F8) (Air Liquide, DMF #16400) 
1.2 Preclinical Data 
 
Various laboratories around the world have successfully used PFx gas mixtures to image 
morphology and function in animal lungs in vivo and in ex-vivo human lungs. Likely the first 
use of PFx gases in an animal study was in 1984 (20) where perfluoromethane mixed with 
oxygen was compared to Xenon ventilation CT studies in dogs. There was little additional 
activity in the field until 1998 when Kuethe’s group demonstrated the use of perfluoroethane 
mixed with oxygen to image rat lungs using 19F MRI and respiratory triggered imaging (13). 
Two years later Schreiber’s group demonstrated ‘breath-hold’ imaging of the lungs of ventilated 
pigs using SF6 and ‘ultrafast’ MRI (24). The same group evaluated dynamic imaging including 
wash-in/washout kinetics of pulmonary ventilation in 2001, again in ventilated pigs (23). 
Kauczor reviewed various strategies for lung ventilation assessment using MRI in 2002 and cited 
six animal studies using PFx gases for such purposes (11). Jacob et al. demonstrated imaging of 
ventilation and diffusion in diseased and healthy excised human lungs as well as in 7 excised 
canine lungs using perfluoroethane (9). Perez-Sanchez et al. used SF6 to create diffusion-
weighted images in anesthetized rats as well as calculated apparent diffusion constant (ADC) 
maps in 2005 (18). The same group demonstrated the impact of pressure and air-SF6 
composition on ADC maps in rats in 2005 (21). Schreiber’s group demonstrated sub-second SF6 
images in pigs in 2006 as well as static 3D and dynamic wash-in images (26). Conradi et al. 
expanded on previous work and evaluated hyperpolarized 3He in humans as well as PFx gases in 
excised healthy and emphysematous human lung using perfluoroethane and perfluoropropane 
(4). Most recently Schreiber’s group has compared MRI of inhaled SF6 with respiratory gas 
analysis in anesthetized pigs and found correlations adequate for lung function analysis (22). 
1.3 Risk/Benefits 
 
There likely will be no direct benefits to the subjects, other than increased understanding 
of their COPD. There will be not direct benefits to the subjects without lung disease. The 
benefits resulting from this research includes a better understanding of COPD structure/function 
relationships and how these relate to clinical trajectories and therapeutic responses. This should 
translate into better-targeted therapies and more focused clinical trial designs. 
1.3.1 Potential Risks 
1. Pain and/or hematoma formation may occur at blood sampling site. This is not a serious 
complication. 
2. Dizziness during blood sampling may occur. 
3. Spirometry may exacerbate bronchospasm, but in our laboratory this has not been a 

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serious problem. 
4. Ionizing radiation exposure from HRCT 
5. The risks of participating in the MRI component of the study are considered minimal. 
MRI is a non-invasive imaging modality that involves no ionizing radiation. At the time 
of recruitment/consenting and again before the MRI session, all subjects will complete a 
standard questionnaire to screen for contraindications to MRI imaging (e.g. presence of 
metal in the eye). 
6. The primary risk of the perfluorinated gases would be asphyxiation if breathed without 
oxygen present. This risk is minimized by obtaining the medical grade agents premixed 
with oxygen and with certificates of analysis. Further, as described in the preliminary 
data and research methods the source gas oxygen level is tested in the source gasbag prior 
to the study (510k cleared Oxygraf system) and the subject’s oxygen saturation is 
monitored with pulse oximetry before, during and after the MRI. Any abnormal drop in 
oxygen saturation based on absolute levels (SpO2 < 90%) or levels observed relative to 
room air breath-hold maneuvers OR any indication of a problem will the source gas 
would cause termination of the procedure. In addition, the gas is delivered via a 
disposable mask with spirometer filters to isolate the subject from the gas delivery 
system. Further, we monitor inhaled and exhaled flow with MR compatible 
pneumotachometers (510k cleared). 
1.3.2 Protection Against Risk 
1. Pain and/or hematoma formation may occur at the blood drawing site. We have 
experienced coordinators and pulmonary function technologists certified in both arterial 
and venous blood sampling. 
2. Dizziness during blood sampling may occur. Subjects will be supine during blood 
sampling to avoid this problem. 
3. Spirometry may exacerbate bronchospasm, but in our laboratory this has not been a 
serious problem.  
4. Subjects will stay on their prescribed oxygen levels while participating in the study. 
Please note, this includes all the imaging components (CT and MRI)   
5. HRCT will be performed in accordance with all Duke Department of Radiology 
procedures to minimize unnecessary ionizing radiation. The risks of the delivered 
radiation (increased cancer risk) is described out in the required consent language and 
compared to other risks of everyday life (refer to section 1.3.4). 
6. All data will be maintained in secured files within the Duke Research site or in the 
SQUID research image management system. 
7. Subjects will be monitored as follows during the imaging procedures: (a) monitoring of 
SpO2 before during and after the examination (any SpO2 levels < 90% will cause the 
study to be terminated (b) monitoring of exhaled oxygen (%) and CO2 (%) using a laser 
based capnograph. Further, we monitor inhaled and exhaled flow with MR compatible 
pneumotachometers (510k cleared). 
8. Duke University has formal education and certification procedures regarding research 
ethics (www.irb.mc.duke.edu/certification.htm). All research personnel will complete 
these in full before entry into the protocol; the nature and risks of the study will be 
reviewed with each subject.  
9. Each subject will be given the opportunity to read the consent form and ask questions. 

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After all questions by the study subject are answered, and before any protocol specified 
procedures are initiated, each subject will sign and date the consent form. A copy of the 
signed consent will be provided to the subject 
1.3.3 MRI Risk  
MRI uses a magnet and radio waves to make diagnostic medical images of the body. There have 
been no ill effects reported from exposure to the magnetism or radio waves used in this test. 
However, it is possible that harmful effects could be recognized in the future. A known risk is 
that the magnet could attract certain kinds of metal. Therefore, The technologist will carefully 
ask the subject about metal within the subject’s body (this includes certain dyes found in tattoos). 
If there is any question about potentially hazardous metal within the subject’s body, we will be 
excluding the subject from participation in this research study. We will also keep the exam room 
locked so that no one carrying metal objects can enter while the subject is in the scanner. 
 
The study involves entering a large room in which a magnet is present. The subject will be 
placed on a narrow bed and then slid into a small tunnel approximately 6 feet in length and 25 
inches in diameter. The subject will be asked to lie still for about one hour on this bed. The 
subject will hear a loud machine-like noise. The subject may be asked to have a harmless 
monitoring device applied during the study. During the study, the subject can have voice contact 
and physical contact with someone in attendance if you desire. 
1.3.4 Computed Tomography (CT)  
CT is a way to make x-ray images of the inside of the body. The CT scanner is a doughnut-
shaped machine that uses x-rays to create computer pictures that show structures inside your 
body more clearly than regular x-ray pictures. During the procedure, a technologist will take the 
subject into the CT scan room where the subject will lie down on the table (usually on the 
subject’s back) inside of the CT machine. The subject should get comfortable because it is very 
important the subject does not move during certain parts of the test. CT examinations differ 
depending on the part of your body being studied. For example, if your abdomen is being 
studied, a series of pictures will be taken from your lower chest to your lower pelvis. During the 
study, the subject will be asked to hold their breath so that the pictures will not be blurred. The 
machine will make some noise, and the table will move during the scan. Also, the subject may 
receive signals from the technologist or from the machine about their breathing. 
 
If the subject is taking part in this research, the subject will have one or more medical imaging 
studies that use radiation. The tests or treatments the subject will have include lung CT scan 
(inhale/exhale). The radiation dose from this research is about 4 millisievert. To give subject an 
idea about how much radiation will get, we will make a comparison with an every-day situation. 
Everyone receives a small amount of unavoidable radiation each year. Some of this radiation 
comes from space and some from naturally occurring radioactive forms of water and minerals. 
This research gives your body the equivalent of about 1 extra year’s worth of this natural 
radiation. The radiation dose we have discussed is what you will receive from this study only, 
and does not include any exposure you may have received or will receive from other tests. 
 

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A possible health problem seen with radiation exposure is the development of cancer later in life. 
This extra cancer risk is higher at younger ages and for girls and women. The extra lifetime risk 
of dying of a fatal cancer due to the radiation exposure from this research may range from about 
one in 8,000 to about one in 3,000. At such low radiation exposures, scientists disagree about the 
amount of risk. These estimates are very uncertain, and there may be no extra risk at all. 
 
We can compare this possible extra cancer risk to other risks (over a lifetime) that everyone is 
subject to in everyday life. For example, the chances of a person dying of cancer with no extra 
radiation exposure are about one in 4. The chances of dying in a car crash are about one in 82, 
and the chances of being killed by a car while crossing the street are about one in 730. 
1.4 Dose Rationale  
 
Each subject will receive PFP as a contrast agent to visualize the airway and alveolar 
spaces in their lungs using magnetic resonance imaging of inert gas/oxygen mixtures.  
1.5 Trial Design 
An open label study in 250 subjects over five years. We are planning 130 subjects with 
COPD (varies stages of GOLD I-IV) and 120 normal subjects (non-smokers, ex smokers and 
current smokers with normal PFT’s).  
1.6 Literature 
 
Gas trapping by HRCT 
Air trapping can be detected by CT (14) (11) at suspended or full expiration with straightforward 
analysis of the image density in the lung field usually by counting pixels below a threshold 
value, e.g. <-856 in the COPDGene protocol. Air trapping using HRCT has been shown in recent 
work associated with the COPDGene project to be perhaps the only clinical phenotype to 
identify the several genotypes of COPD (http://www.copdgene.org/ats-abstracts-2010) (17) (7). 
We will focus on measuring such trapping in Aim 1.1 as well as washout using temporal 
measures of PFx image intensity in Aim 1. 
 
Preliminary Studies 
1. IND and Mixed Gases from Air Liquide/Scott Medical Products 
Before the initiation of these studies we received a full FDA safety review and obtained 
IND 104,917 (Evaluation of Regional Ventilation in Normal Subjects and Subjects with Airway 
and Lung Disorders Using 19F Magnetic Resonance Imaging of Inert Perfluorinated Gases 
mixed with Oxygen (SF6, and PFP): A Phase 1 Study). We provided this information to our IRB 
in support of local approval of the protocol. Our shipments of gas mixtures have undergone 
microbial limit testing under USP <1111>, USP <61> and USP <62> as required by the FDA 
Note that these gases are supplied at low pressure to insure that the dense gas component remains 
in the gaseous state. Example calculations follow: The gas mixture is formulated to have a ‘dew 
point’ of 0°C, i.e. it will not ‘condense’ above 0°C. The vapor pressure of PFP at 0°C is 60.41 
psi. In order to determine the overall pressure of the mixture we divide the vapor pressure by the 
concentration in the mix to get the corresponding mix pressure (at 0°C). Then multiply by 
294/273 (°Kelvin to °C conversion) to find the pressure at 21°C/70°F (assumed room 
temperature). So, for 79% PFP mix, it is: 60.41 / 0.79 = 76.46 psia @ 0°C x 294/273 = 82.35 

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psia @ 21°C - 14.7 = 67.65 psig @ 21C. 
 
 
 
2. Initial Human Images and Physiological Monitoring 
We have initiated a proof of concept study under IND 104,917 and with local IRB approval 
(Evaluation of Regional Ventilation in Normal Subjects and Subjects with Airway and Lung 
Disorders Using 19F Magnetic Resonance Imaging of Inert Perfluorinated Gases mixed with 
Oxygen (PFP): A Phase 1 Study). We have consented 44 subjects minus one withdrawal, 
screened 43 subjects in the study with the characteristics described in Table 1 and scanned 30 
subjects (reasons for non scanning of subjects: 1 voluntary withdrawal prior to any study 
participation, 5 body habitus (too obese), 4 screen fails, 4 MRI contraindications).   
Disease Status  
Number of Subjects Screened 
(F/M) 
Normal  
13 (5/8) 
COPD  
11(7/4) 
COPD, Emphysema  
4 (1/3) 
COPD Emphysema, Asthma, Small Airway 
Disease 
1(1/0) 
COPD Asthma, Small Airway Disease  
1 (1/0) 
Asthma  
2 (2/0) 
Asthma, small airway Disease 
2 (2/0) 
Cystic Fibrosis  
5 (4/1)* all with lung transplant 
Lung Transplant  
2 (1/1) 
Small Airway Disease  
1 (1/0) 
Unknown Etiology  
1 (0/1) 
Total  
43 (25/18) 
Table 1: Disease profiles of screened subjects in the phase 1 proof of concept study 
2 Trial Objectives 
The proposed study will determine regional qualitative and quantitative lung function 
information in the context of the clinical trajectory of COPD defined by the cross sectional 
cohort components. Due to the long time-frame of this disease we are using a modified case 
control design that allows a cross-sectional evaluation of the proposed measures in aims 1-2 to 
identify putative markers that could later be tested as prognostic factors in longitudinal studies. 
In the case of these PFx/oxygen mixtures, the availability of multi-liter quantities allows for 
wash-in/wash-out image acquisition and analysis allowing direct measures of gas trapping in a 
manner not easily achieved with any existing modality.  
3 Trial Design 
 
The central hypothesis and current observation is that PFx gases 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: 

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3.1 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 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. 
 
3.2 Trial Treatment 
Each subject will receive PFP gas as a contrast agent to visualize the airway and alveolar 
spaces in their lungs using magnetic resonance imaging of inert gas/oxygen mixtures.  The 
subjects will receive the gas by breathing normoxic mixtures of the gas using a 6500 V2 
Disposable oral-nasal mask and a standard Douglas Bag system. No additional drug products, 
investigational or otherwise will be provided in this study. The subject will be monitored with a 
MRI compatible pulse oximeter as well as exhaled % oxygen and carbon dioxide.  
3.3 Duration 
3.3.1 Screening (V0)  
1. Obtaining Informed Consent from each subject   
2. History and Physical exam. The history will focus on onset of symptoms, co-morbidities, 
and smoking/occupational/environmental history. Also included:  
a. An assessment of patterns of exacerbations (mild = use of oral antibiotics and/or 
steroids for an acute change in respiratory status; moderate = hospital admission 
for a change in respiratory status; severe = requirement for mechanical ventilation 
for a change in respiratory status). 
b. A measurement of the body mass index (BMI). 
c. A medication history (oral steroids, chronic bronchodilator use, oxygen use) with 
an emphasis on whether adherence was adequate. 
d. Assessment of gastro-esophageal reflux disease (10) 
e. Epworth Sleepiness Scale as a marker of sleep disordered breathing 

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f. Estimate of daily physical activity (25) 
3. Pulmonary function tests will include spirometry, plethysmographic lung volumes, and 
corrected carbon monoxide diffusing capacity (DLCO). All procedures will be done in 
accordance with ATS/ERS standards (3) (15) (17). 
4. High resolution computerized scans of the chest (HRCT). Emphysema scores will be 
calculated per COPD Gene protocol (7). We will also explore novel approaches to 
quantifying airway structures (5) (16) 
5. A six-minute walk test with monitoring of pulse oximetry and heart rate will be 
conducted in accordance with ATS standards (1) 
6. Vital Signs will be measured and recorded (temperature, heart rate, blood pressure and 
respiratory rate) 
7. Pulse oximetry will be measured and recorded.  
8. Weight and height will be recorded.   
9. Quality of Life (QOL) will be assessed using the St George self-administered instrument 
10. A serum pregnancy test will also be performed in women with child bearing potential.  
  
MRI will be collected at the study visit 1 after the screening visit. Where possible the screening 
visit (V0) and MRI visit (V1) will be accomplished on the same day for the convenience of the 
subject. In all cases, the MRI will be followed-up immediately following the MRI procedure for 
any adverse events. Finally, all subjects will be contacted 24 hours post-MRI by phone for 
follow-up regarding any adverse events. 
 
3.3.2 Visit 1: MRI 
Visit 1 will include a rescreening for MRI safety by the MR Technologist, (if not performed at 
screening), the MRI exam, Vital signs (temperature, heart rate, blood pressure, respiratory rate 
and pulse oximetry) will be collected at pre and post imaging examination. A urine pregnancy 
test will be performed on female of child-bearing potential if the screening serum test was given 
48 or more hours earlier.  They must have a negative result to further participate in the study.   
 
 Additionally, subjects will be carefully observed for any signs of hypoxia before, during, and 
after the MRI exam using pulse oximetry. Any SpO2 reading < 90% will result in termination of 
the study. 
Subjects will stay on their prescribed oxygen treatment, while participating in the study. Please 
note, this includes both imaging components (CT and MRI)  
 
3.3.3 Twenty-four Hour Follow-up  
Twenty-four hours post V1 (and subsequent imaging visits) the subjects will be contacted by 
phone and questioned regarding any post MRI adverse events.  (Refer to Table 2 for the 
scheduled of events.) 
 
 
 
 
 
 
 

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Table 2: Scheduled of Events  
                          
3.4 Product Accountability 
In accordance with ICH, we will have proper documentation with regards to product 
accountability. The documentation will include the following information: the gas type, dates 
(e.g. order, receive, certification and expiration), ALHCH Lot (or Cylinder #), and ALHACH 
park #.  
Protocol Activities 
Screening 
(V0) 
Study 
Visit 
(V1) 
Follow Up 
(24 hours by 
phone) 
Informed Consent 
X 
 
 
General Medical History 
X 
 
 
Physical Exam 
X 
 
 
HRCT 1 
X 
 
 
Weight and Height 
X 
 
 
Concomitant Medication 
X 
 
 
Pregnancy Test (serum and urine) 2 
X 
 
 
Quality of Life Assessment  
X 
 
 
MRI Screening Form 
X 
X 
 
Vital Signs Assessment  
X 
X 
 
Pulse oximetry 
X 
X 
 
Six Minute Walk Test 
X 
 
 
Thermally Polarized Gas MRI 
 
X 
 
Pulmonary Function Test  
X 
 
 
Adverse Event Assessment 
 
X 
X 
1 depending on scheduling, the HRCT will be performed at screening (V0) or 
between screening (V0) – study visit (V1) 
 
 
 
2 Females of child–bearing potential who had a blood pregnancy tests 
performed, will have a urine pregnancy test if blood test was given 48 or more 
hours earlier   
 
 
 
 
 
 

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The Cylinder # (ALHCH lot) and gas type will be included on each subject’s CRF for product 
accountability purpose.  
 
3.5 Data Identification 
According to ICH and FDA guidance, the following data will be considered source and will be 
recorded directly into each subject’s CRFs.  
• Screening (V0) 
o Informed Consent date  
o General Medical History 
o Physical Exam  
o Weight/Height 
o Concomitant Medications 
o Quality of Life Assessment  
o Vital Signs  
o Pulse Oximetry  
o 6 Minutes Walk  
o PFT First section  
• Study Visit (V1) 
o Vital Signs (pre and post imaging) 
o Pulse Oximetry (pre and post imaging) 
o For Women of child bearing potential  
o Date of the results of the pregnancy test  
o Adverse Events (post imaging)  
• 24hr Follow up phone call  
o Adverse Event  
o Follow-up  
The following data will be considered source but will not be recorded directly into each subject’s 
CRFs.  This data will likely be found in the subject’s research folder (paper) and/or electric 
medical record.  
o Informed Consent 
o For Women of child bearing potential 
o Result of pregnancy test 
o MRI screening Form 
o HRCT reading   
o PFT Testing results    
The CRFs, the MR/HRCT images and PFT testing results will serve as source documents for this 
study. 
4 Selection of Subjects and Withdrawal/Discontinuation 
4.1 Inclusion/Exclusion Criteria for Subjects with COPD   
Inclusion criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 

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trial 
1. Outpatients of either gender, age > 18. 
2. Willing and able to give informed consent and adhere to visit/protocol schedules. 
(Consent must be given before any study procedures are performed.) 
3. Women of childbearing potential must have a negative serum pregnancy test. This will 
be confirmed before participation in this investigational protocol. 
4. Clinical diagnosis of COPD confirmed by Spirometry demonstrating FEV1/FVC 
<0.70. 
 
Exclusion criteria 
Subjects presenting with any of the following will not be included in the trial: 
1. Abuse of alcohol or illicit substances. 
2. Medical conditions, which, in the opinion of the investigator, will significantly affect 
five-year survival. 
3. 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. 
4. Conditions that will prohibit MRI scanning (metal in eye, claustrophobia, inability to lie 
supine, renal insufficiency with eGFR < 60 mL/min/1.73 m2) 
4.2 Inclusion/Exclusion Criteria for Normal Subjects 
Inclusion criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
trial 
1. Outpatients of either gender, age > 18. 
2. Willing and able to give informed consent and adhere to visit/protocol schedules. 
(Consent must be given before any study procedures are performed.) 
3. Women of childbearing potential must have a negative serum pregnancy test. This will be 
confirmed before participation in this investigational protocol. 
4. Normal PFT determined by spirometry. 
5. Non-smoker, ex-smoker, or current smoker. 
 
Exclusion criteria 
1. Abuse of alcohol or illicit substances. 
2. Conditions that will prohibit MRI scanning (metal in eye, claustrophobia, inability to lie 
supine). 
4.3 Subject Withdrawal and/or discontinuation   
 
The reason for a subject discontinuing from the trial will be recorded in the CRF.  A 
discontinuation occurs when an enrolled subject ceases participation in the study, regardless of 
the circumstances, prior to completion of the protocol.  The investigator must determine the 
primary reason for discontinuation.  
 
When a discontinuation is due to a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below. 
 
 

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4.4 Treatment of Subjects 
4.4.1  MRI  
At the study visit (V1), MRI ‘studies’ will be performed using the same MR scanner (a 
3.0-Tesla (T) TRIO MRI system (Siemens Medical Systems)).  Lung morphology and function 
will be acquired using conventional 1H MRI followed by 19F MRI with a gaseous contrast agent 
mixed with oxygen for the 19F MRI study.  For both series the subject will lie down in a supine 
position on the magnet bed inside a transmitter and receive (T/R) coil for imaging of the human 
torso. 
 
For the gas mixture, the inert medical grade perfluorinated gas (PFP) will be present at 
79% combined with 21% medical grade oxygen.  The agents will be supplied in aluminum 
cylinders (MR compatible) at pressures to prevent phase change of the perfluorinated component 
to the liquid phase.  For example, in an 8 inch by 52-inch aluminum cylinder, the same format 
cylinder of the 79% PFP/21% oxygen mixture will contain 137 liters of the mixture. 
 
Subjects will rest in a supine position for breathing in normal air, and then switch to PFP 
by a passive Douglas bag system with 35 mm tubing with remote pneumatic switching between 
room air and PFP and MRI compatible pneumotachometers to allow flow rate and gas volume 
determinations. The subjects are monitored with an MRI compatible pulse oximeter as well as 
exhaled % oxygen and carbon dioxide. The subjects will then exit the MRI suite. 
4.4.2 High Resolution Computerized Tomography  
Chest CT Scan will be performed to assess for emphysema and airway disease in all 
subjects. An inspiratory chest CT scan will be performed with a radiation dose of 200 mAs in 
order to provide thorough assessment of small airway wall thickness and emphysema. An 
expiratory chest CT scan will be performed of lower dose (50 mA) to assess for air trapping. 
4.5 Concomitant Medication 
 
There will be no restriction on participation based on medication use. The following 
concomitant medication will be recorded.  
 
• Beta Adrenergic agents 
• Non-selective agents 
o 
Alprenolol 
o 
Oxprenolol 
o 
Carteolol 
o 
Penbutolol 
o 
Levobunolol 
o 
Pindolol 
o 
Mepindolol 
o 
Propranolol 
o 
Metipranolol 
o 
Sotalol 
o 
Nadolol 
o 
Timolol 
 
• β1-Selective agents 
o 
Acebutolol 
o 
Atenolol 
o 
Betaxolol 
o 
Bisoprolol 

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o 
Metoprolol 
o 
Nebivolol 
o 
Amosulalol 
o 
Landiolol 
o 
Tilisolol 
 
 
• Mixed α1/β-adrenergic antagonists 
o 
Arotinolol 
o 
Carvedilol 
o 
Celiprolol 
o 
Labetalol 
 
• Quaternary ammonium compound 
o 
Ipratropium   
o 
Tiotropium 
 
• Inhaled Brochodilators 
o 
Albuterol 
o 
Formoterol 
o 
Arformoterol 
o 
Levabuterol 
o 
Metaproterenol 
o 
Pirbuterol 
o 
Salmeterol 
o 
Fenoterol 
o 
Terbutaline 
 
 
• Inhaled corticosteroids 
o 
Beclomethasone 
o 
Budesondie 
o 
Ciclesonide 
o 
Flunisolide 
o 
Fluticasone Propionate 
o 
Monetasone Furoate 
o 
Triamcinolon 
 
 
• Leukotriene blockers 
o 
Montelukast 
o 
Zafirlukast 
o 
Zileutol 
 
 
• Inhaled Combos 
o 
Albuterol and pratropium 
Inhalation  
o 
Fluticasone Propionate 
and Salmeterol 
o 
Budesonide and 
Formoterol 
o 
Formoterol and 
Mometasone 
 
• Mast Cell Blocker 
o 
Chromolyn  
 
 
• Bronchodilator  
o 
Oxtiphylline 
o 
Theophylline 
 
• Oral Steroids 
o 
Prednisone 
o 
Methyl-prednisolone 
o 
Prednisolone  
 
 
 

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• Phosphodiesterase type 4 (PDE-4) 
o 
Roflumilast 
 
 
• Medical Gas 
o Oxygen 
 
5 Assessment of Efficacy 
5.1 Efficacy Parameters 
 
All of the protocols in this proposal will be approved by our Institutional Review Board 
and reviewed periodically (every 6-12 months).  In addition, a local Data Safety and Monitoring 
Committee (DSMC) will be established. The committee members will be pulmonologists and 
radiologists with knowledge of COPD, imaging techniques and clinical research procedures. The 
frequency of monitoring depends on the progress of the study and will range between 3 and 12 
months.  Any adverse event will be reported to the IRB and DSMC, and serious adverse events 
will be reported within 24 hours.  An annual progress report (or more frequently, if requested) 
will be submitted to the IRB and DSMC. 
5.2 Adverse Event Reporting 
Any adverse event will be reported to the IRB and DSMC, and any other regulatory agents, 
and serious adverse events will be reported within 24 hours. An annual progress report (or more 
frequently, if requested) will be submitted to the IRB, DSMC and any other regulatory agents.  
 
Significant morbidity and mortality are anticipated in these study subjects due to the nature of 
the disease. Deaths, exacerbations of COPD, and hospitalizations for any cause are outcome 
measures of the trial and will not be reported as adverse events.  These outcomes will be 
monitored by the DSMC.  In accordance with policies of the NIH, other serious events, including 
severe injuries and new diagnosis of potentially fatal or disabling medical conditions will be 
reported as serious adverse events of the study to the local IRB, the DSMC, and the NIH.  The 
clinical investigator(s) will terminate the study immediately if the occurrence of serious adverse 
events that suggests unacceptable risk to the health of the subjects.  All observed or volunteered 
adverse events, regardless of suspected causal relationship to the study procedure(s), will be 
recorded on the adverse events page(s) of the CRF’s or worksheets.  Events involving adverse 
experiences occurring during the study procedure(s) will be recorded.   
5.3 Definitions 
5.3.1 Adverse Events  
 Adverse event is any untoward medical occurrence in a clinical investigation by a subject 
who has been administered a product or medical device; the event need not necessarily have a 
causal relationship with the study procedures. Adverse events include the following:  
• All suspected procedure-related adverse events.  
• Apparently unrelated illnesses, including the worsening of a preexisting illness (see fifth 
bullet, below, regarding preexisting conditions).  

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• Injury or accidents. Note that if a medical condition is known to have caused the injury or 
accident (e.g., a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) should be reported as 2 separate adverse events.  If an accident results in a 
subsequent adverse event (e.g., hip fracture secondary to the fall), both the accident and 
the subsequent event should be recorded in the adverse event CRF.  
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation unless they are associated with an already 
reported adverse event.  A test or an examination that is repeated to check a possible 
abnormality does not constitute an adverse event.  
• Preexisting condition (i.e., a disorder present before the adverse event reporting period 
started and noted on the pretreatment medical history/physical examination form) should 
not be reported as an adverse event unless the condition worsens or episodes increase in 
frequency during the adverse event reporting period.  
 
5.3.2  Serious and Unexpected Adverse Events  
A serious adverse event is any untoward medical occurrence that:  
• Results in death;  
• Is life-threatening (i.e., puts the patient or clinical investigation subject at immediate risk 
of death; but not an event that, had it been more severe, might have created a risk of 
death);  
• Requires inpatient hospitalization or prolongation of existing hospitalization;  
• Results in persistent or significant disability/incapacity;  
• Results in congenital anomaly/birth defect.  
 
Medical and scientific judgment should be exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately life threatening 
and/or result in death or hospitalization. However, if it is determined that the event may 
jeopardize the patient and may require intervention to prevent one of the other outcomes listed in 
the definition above, the important medical event should be reported as serious.  
 
An unexpected adverse event is any adverse drug experience, the specificity or severity of 
which is not consistent with the current investigator brochure; or, if an investigator brochure is 
not required or available, the specificity or severity of which is not consistent with the risk 
information described in the general investigational plan or elsewhere in the study documents.  
In this case, “expected” does not include events that are anticipated based on pharmacological 
properties. 
5.4 Adverse Event Follow-up 
 
The investigator will document all directly observed adverse events and all adverse 
events spontaneously reported by the trial subject.  In addition, each trial subject will be 
questioned about adverse events by phone at 24 hours post imaging.  The question asked will be 
“Since your MRI examination, have you had any health problems?” 

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6 Statistical Plan 
6.1 Statistical Methods and Subject Population for Analysis  
We have three main methods to employ to characterize of clinical phenotypes using MR 
Imaging bases features.  
 
One method is to estimate with reasonable precision the mean and standard deviation 
ventilation parameters from 19F gas imaging. So with 250 (5 groups) subjects we should be able 
using a t-test (or ANOVA) to detect a variation in defect volume of approximately 6% in the 
smallest sample (N = 26/group, GOLD III/IV) (alpha 0.05 and 90% power) and 5% in the 
reference groups (N=40/group). [Statmate Ver 2, GraphPad Software (La Jolla, Ca)]. 
 
Further, we wish to evaluate the diagnostic/prognostic ability of the MRI parameters to 
provide distinction among current ‘phenotypes’ and perhaps extend better discrimination with 
the MRI parameters from study aims.  We will also use statistical modeling for this project to 
correlate the features obtained from the gas-probe MR imaging-based measures with one or more 
of the clinical assessment measures recorded in Aim 1.2, to better characterize disease 
phenotypes and identify the most promising prognostic indicators. 
 
In a similar context, a recent study has shown such promise for certain CT imaging-based 
features (7). Thus, if the role of MR imaging-based measures can be established in a similar 
fashion then, associated with a link £, is some MR-defined variable Z which can define a 
biomarker, risk factor or phenotype R, resulting in the general linkage statement of 
R←£→GOLD+MRI. The makeup of this biomarker would contain information obtained from 
one or more measures Aims 1, 1.1 and 2 as well as other clinical status information X (as 
codified in the GOLD score or more generally some combination of the demographic, 
physiological and past history information, (Aim 1.2). This biomarker would then provide a 
more rapid and efficient means for deciding treatment strategies. We will examine the 
diagnostic/phenotyping ability of the MR imaging-based features (Aims 1 and 2) in terms of 
their ability to predict existing clinical phenotypes (GOLD) characterized and other clinical 
features (Aim 1.2). For this purpose, we will divide the predictors into two categories: a) clinical 
assessments features (Xa1, Xa2,…, Xak), obtained from existing clinical, physiologic, and 
HRCT imaging, measured under Specific Aims 1.1 and 1.2; b) features obtained from MR 
imaging (Xb1, Xb2,…, Xbl), identified under Aims 1 and 2. A generalized linear model of the 
form [1] will be fitted using the method of maximum likelihood: 
 
g(Yt) = βa0 + βa1Xa1 + …+ βakXak + ε [1] 
 
The predictability of this model will be calculated using the Akaike Information Criterion 
(AIC) statistic (2), which balances the quality of fit (likelihood) against model complexity (8). 
Selection of the optimal subset of predictors will be achieved via a search over predictor space to 
identify the subset that maximizes the AIC statistic. 

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6.2 Termination Criteria  
Premature termination of this clinical trial may occur because of a regulatory authority 
decision, change in opinion of the IRB, or at the discretion of the FDA.  DUMC also reserves the 
right to discontinue the trial prior to inclusion of the intended number of subjects, but intends 
only to exercise this right for valid scientific or administrative reasons.  
 
After such a decision, the investigator must contact all participating subjects within 4 weeks.  
All trial materials must be collected and all CRFs completed to the greatest extent possible 
7 Direct Access to Source Data/Documentation 
During trial conduct, DIAL will conduct periodic monitoring to ensure that the protocol and 
GCP are being followed.  DIAL staff will review source documents to confirm that the data 
recorded on CRFs is accurate.  The investigator and institution will allow DIAL staff and 
appropriate regulatory authorities direct access to source documents to perform this verification.   
8 Quality Control and Quality Assurance 
The trial site (Duke) may be subject to review by IRB and/or to quality assurance audits 
performed by Duke, and/or to inspection by appropriate regulatory authorities from the US.  It is 
important that the investigator(s) and their relevant personnel are available during these 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.  
9 Ethical Considerations 
9.1 Institutional Review Board  
It is the responsibility of the investigator to obtain prospective approval of the trial 
protocol, protocol amendments, informed consent forms, and other relevant documents, e.g., 
advertisements, if applicable, from the IRB.  All correspondence with the IRB should be retained 
in the Investigator file. Copies of IRB approvals should be retained at Duke.  
 
The only circumstance in which an amendment may be initiated prior to IRB approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects consistent 
with applicable regulations.  In that event, the investigator must notify the IRB in writing in a 
time frame consistent with Duke policy and applicable regulations 
9.2  Ethical Conduct of the Trial  
The trial will be performed in accordance with the protocol, ICH, GCP guidelines, and 
applicable local regulatory requirements and federal laws.  
9.3  Subject Information and Consent  
The informed consent form must be approved by the Duke IRB and must be in compliance 
with ICH, GCP, local regulatory requirements, and federal laws.  The investigator must ensure 
that each trial subject is fully informed about the nature and objectives of the trial and possible 
risks associated with participation.  The investigator will obtain written informed consent from 

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each subject subject's before any study-specific activity is performed.  The informed consent 
form used in this trial, and any changes made during the course of the trial, must be 
prospectively approved by the IRB before use.  Additionally, the FDA will be notified of any 
changes prior to implementation as appropriate.  The investigator will retain a copy of each 
subject’s signed consent form.  
 
The subjects will be asked to provide contact information for their primary care (or other 
physician) so that they can be notified if any potentially clinically relevant findings are obtained 
from standard clinical procedure (e.g HRCT or PFT’s).  This contact information will be kept in 
the subjects research record. 
10 Data Handling and Record Keeping 
 
As used in this protocol, the term CRF should be understood to refer to either a paper form 
or an electronic data record or both, depending on the data collection method used in this trial.  A 
CRF is required and should be completed for each included subject. The completed original 
CRFs are the sole property of Duke and should not be made available in any form to third 
parties, except for authorized representatives of Duke or appropriate regulatory authorities, 
without written permission from Duke.  
 
It is the investigator’s responsibility to ensure completion and to review and approve all 
CRFs. CRFs must be electronic signed by the investigator or by an authorized staff member.  
These signatures serve to attest that the information contained on the CRFs is true.  At all times, 
the investigator has final personal responsibility for the accuracy and authenticity of all clinical 
and laboratory data entered on the CRFs.  
 
The CRFs, the MR and HRCT images and PFTs testing results will serve as source 
documents for this study.  
10.1 Data Management  
All patient data will be collected on a dedicated and encrypted Duke University server. The 
data entry system will check for out-of-range and other implausible data entries and immediately 
prompt the study coordinator to confirm or correct the entry. All patient data files will be de-
identified. 
10.2  Data Storage 
All MRI images are stored in DIAL for QA/QC and image analysis; CAMRD will be 
notified of cases of unacceptable image quality to enable the rescheduling of scans accordingly. 
Subjects can be rescanned a maximum of one (1) time. The data will be de-identified and stored 
in the research image management system SQUID, a research image management system in 
DIAL. 
10.3  Record Retention  
As required by law and to enable evaluations and/or audits from regulatory authorities, the 
investigator agrees to keep records, including the identity of all participating subjects (i.e., 
sufficient information to link records to identity), all original signed informed consent forms, 

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copies of all CRFs, other source documents, and detailed records of treatment disposition.  The 
investigator according to International Conference on Harmonization (ICH), or federal, and local 
regulations should retain the records, whichever is longer.  
 
If the investigator relocates, retires, or for any reason withdraws from the trial, the trial 
records must be transferred to an acceptable designee, such as another investigator at Duke.  The 
investigator must obtain Duke’s written permission before disposing of any records, even if 
retention requirements have been met. 
 
11 Publication Plan 
 
The conditions regulating dissemination of the information derived from this clinical trial 
are compliant with existing Duke policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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