A Novel Method to Detect Pulmonary Thromboembolic Events With Non-Contrast 4DCT
Phase: NA
Conditions: Pulmonary Thromboembolisms, Pulmonary Embolism
Sponsor: Thomas Guerrero

 
Study protocol with statistical analysis plan 
 
Official Title: A Novel Method to Detect Pulmonary Thromboembolic Events with Non-Contrast 4DCT 
 
NCT number: 03183063 
 
Document Date: March 29, 2018 
 
 

IRB NUMBER: 2017-018 
IRB APPROVAL DATE: 04/19/2018 
March 29, 2018 
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A Novel Method to Detect Pulmonary Thromboembolic Events with Non-Contrast 4DCT 
 
 
 
 
 
 
 
 
Eligibility Check 
 
1.0 
Introduction 
2.0 
Objectives 
3.0 
Eligibility Recruitment & Selection 
4.0 
Study Evaluations 
5.0 
Criteria for Study Removal 
6.0 
Registration Procedures 
7.0 
Statistical Considerations 
8.0 
Potential Risks 
9.0 
Long Term Goals 
10.0 
Data Monitoring & Adverse Event Reporting 
11.0 
Data Confidentiality Plan 
12.0 
References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 Introduction 
Acute Pulmonary Embolism 
Deep vein thrombosis (DVT) occurs when a blood clot forms in a deep vein, typically in the lower 
extremities. Pulmonary embolism (PE) occurs when a DVT clot (or fragment) breaks free and 
travels through the heart to the pulmonary arteries and lodges in an artery causing complete or 
partial obstruction. Together DVT and PE comprise venous thromboembolism (VTE), a major 
public health problem in the United States (USA). VTE is the third leading cause of cardiovascular 
death (1), is estimated to result in 5% to 10% of all hospital death (2), and the third most common 
cause of preventable hospital death in patients recovering from surgery (3). Using the 2007-9 
National Hospital Discharge Survey data, 548,000 hospitalizations were for VTE and of those 
278,000 were for acute PE (4). The annual cost of VTE to the US healthcare system is $7-10 
billion for newly diagnosed, medically treated VTE cases (5). PE is associated with a high short- 
term mortality, requiring a timely and accurate diagnosis for the initiation of antithrombotic therapy. 
PE is difficult to diagnose on presentation due to the non-specific signs and symptoms for this 
condition such as cough, shortness of breath, hypoxia, tachycardia, and hemoptysis. 
Computed Tomography Angiography 
Pulmonary computed tomography angiography (CTA) is the gold standard for the detection of 
pulmonary emboli (PE) (6), however, radiation exposure and complications related to 
administering intravenous contrast prohibit universal applicability (7). CTA can detect acute PE 
with a sensitivity of 90 percent and specificity of 95 percent when combined with CT venography 
(8, 9). In those who are medically ineligible for CTA, ventilation-perfusion (V/Q) single photon 
emission computed tomography (SPECT) imaging is commonly acquired to detect PE (10, 11). 
However, SPECT imaging acquisitions requires transporting the patient to the nuclear medicine 
clinic, a prolonged acquisition period compared with CTA, and in many hospitals SPECT imaging 
is not available on weekends or evenings. In this study we will investigate an alternative method 
to obtain ventilation and perfusion images from respiratory gated non-contrast CT (commonly 
called 4DCT) that can be performed in the Emergency Department. 
99mTc-MAA SPECT Imaging 
Wagner reported the first use of radiolabeled macroaggregates of albumin (MAA) imaged with 
planar scintigraphy for the detection of pulmonary emboli (PE) causing vascular occlusion (12). 
MAA is composed of particles ranging in size from 10 to 150 µm that are trapped in the pulmonary 
microvasculature on their first pass after intravenous injection. Their distribution remains fixed 
with a biological half-life of 11 h and is dependent on the conditions at the time of injection. 99mTc- 
labelled MAA (99mTc-MAA) imaged with single photon emission computed tomography (SPECT) 
is considered the standard method for the quantitative determination of pulmonary perfusion (13). 
Alternative pulmonary perfusion imaging methods include positron emission tomography imaging 
following administration of 68Ga-labeled particles or after bolus injection of 13N-N2 (14). Magnetic 
resonance imaging (MRI) with contrast agents have been utilized experimentally to image the 
pulmonary vasculature and tissue perfusion (15). Quantification of SPECT images requires 
correction of the acquired data for attenuation and scatter (16, 17). One approach is to utilize 
spatially correlated CT images to determine the attenuation correction, which has lead to the 
development of SPECT-CT scanners (18). The low-dose CT can be utilized to evaluate the lung 
airway architecture, lung parenchyma, and pleural space in conjunction with the registered 
perfusion images rivaling CTA in sensitivity and specificity (19). 
Variation in Pulmonary Perfusion with Breathing 
In a recent study using 99mTc-MAA SPECT imaging, the difference in distribution due to injection 
at maximum inspiration versus maximum expiration breath-hold was measured (20). Each subject 
received SPECT imaging after injection of 99mTc-MAA in either maximum inspiration or expiration. 
There was a posterior displacement of the activity centroid in each lung between the expiration 

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Figure 1. Lung mass difference across 4D 
CT. The total mass of the lung parenchyma 
(HU < –250) for each patient (p1-3) was 
calculated within the manual segmented lungs 
from the CT values and equation. Note there 
are difference between the three patients’ data 
in amplitude and average value. 
and inspiration images. In another study of normal volunteers MRI perfusion imaging obtained at 
either maximum inspiration or expiration breath-holds revealed higher perfusion at expiration (15). 
In a study comparing CT attenuation with SPECT perfusion defects, patients were found to have 
hypo-attenuated pulmonary regions corresponding to regions with decreased perfusion in 57% of 
acute pulmonary emboli and 88% of chronic emboli cases (21). In the same study hyper- 
attenuated regions were found to correspond to regions with hyperperfusion. A method to 
measure pulmonary perfusion based on subtraction digital fluoroscopy without contrast has been 
reported (22). In that study subtraction images were generated between chest projection images 
at systole and diastole generating an image representing the perfusion difference. These 
perfusion projection images were correlated with 99mTc-MAA scintigraphy. Thus, changes in the 
amount and distribution of pulmonary perfusion throughout the respiratory cycle can be expected 
and these changes may be apparent on dynamic CT. 
Imaging Pulmonary Perfusion Defects with 4DCT 
Simon (23) described a technique to calculate the change in fractional content of air within 
pulmonary tissue between anatomically matched CT regions based on a simple model that 
assumes the density changes were solely due to air content (see appendix A in (24)). We 
successfully applied that model to inhale & exhale breath-hold CT image pairs (25) as well as 
4DCT images (24, 26) to create ventilation images. However, the amount of blood in the thorax 
and lungs varies with the respiratory cycle increasing with inspiration during normal breathing (27) 
and decreasing with inspiration with positive pressure ventilation (28). Thus violating the 
assumption of the model. We found a cyclic variation in the apparent weight of the lung on 4DCT 
(see figure 1 below (26)) and others have reported respiratory induced variations in pulmonary 
perfusion of the lung on magnetic resonance imaging (MRI) (29). The pulmonary density changes 
found on 4DCT thus result from both changes in air and blood content. 
4DCT derived ventilation images can also be inferred from the respiratory motion induced local 
tissue volume changes (24) independent of the 
4DCT density values. The Jacobian determinant 
of the deformation field, calculated from the DIR 
result of images depicting different respiratory 
phases of the lungs, is used to estimate the local 
volume changes or ventilation (24, 30). There is 
a discrepancy between the density based and the 
Jacobian based ventilation images suggesting a 
method to extract respiratory induced blood mass 
change from 4DCT images. We hypothesize the 
respiratory induced blood mass change will only 
occur within perfused lung regions. Each 4DCT 
image set contains information representing the 
density change resulting from both ventilation 
and respiratory induced blood mass changes. 
Extracting both ventilation and a perfusion-like 
image from the 4DCT image intensities, referred 
to as Hounsfield Units (HU), is our goal. However, 
novel image processing methods are required to 
extract this information. 
We found a cyclic variation in the apparent mass 
of the pulmonary parenchyma (Figure 1) (26). We hypothesize this variation is due to changes in 
pulmonary perfusion from the respiratory-induced variation in cardiac output (20, 31, 32). We 

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hypothesize 
this 
respiratory 
induced blood mass change will 
allow 
the 
identification 
of 
hypoperfused lung regions. As 
a preliminary study we created 
4DCT RIBMC images from 
cases with hypoxia induced 
vasoconstriction, patients with 
malignant airway obstruction. 
The resulting images visually 
compare well with SPECT 
99mTc-MacroAggregates 
of 
Albumin 
(MAA) 
perfusion 
images (Figure 2). However, in 
these cases there are matched 
ventilation and perfusion 
defects due to malignant airway obstruction. It is unknown if this process works to detect perfusion 
defects due to pulmonary emboli, where perfusion is obstructed and ventilation normal. 
With spontaneous tidal breathing, venous 
return to the right atrium increases with the 
decrease in intrathoracic pressure (33) 
and as a consequence pulmonary arterial 
blood flow to the lungs increases (34). With 
positive pressure ventilation the opposite 
occurs, 
positive-pressure 
inspiration 
decreases the pressure gradient for 
venous return, which decreases venous 
blood flow, RV stroke volume, and 
consequently cardiac output (33). We 
expect the decrease in lung mass, or 
pulmonary blood, with normal expiration to 
become an increase in lung mass with 
positive pressure ventilation as shown in 
Figure 3 at the right. 
In this study, patients found to have new 
segmental, lobar or greater perfusion 
defects, will be imaged with 99mTc-MAA 
SPECT/CT 
and 
4DCT 
to 
compare 
perfusion with RIBMC defects. 
Figure 2. 4DCT RIBMC v. SPECT 99mTc-MAA Perfusion. A 
coronal section is shown from a 4DCT derived RIBMC images for 
a patient with malignant airway stenosis (Left). The corresponding 
99mTc-MAA SPECT coronal section is shown (Right). The cold spot 
in the RIBMC image coincides with the perfusion defect in the 
SPECT perfusion image. 
Figure 3. Effect of Positive Pressure Ventilation. . 
Hypothetical 
expected 
changes 
to 
previously 
mentioned trends in blood mass observed with 
spontaneous breathing if the patients are scanned 
during positive pressure ventilation, such as BPAP. 

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Hypothesis: Thromboembolic pulmonary perfusion defects on 99mTc-MAA SPECT/CT will 
coincide with 4DCT RIBMC defect regions. 
Summary & Significance 
This is a prospective imaging trial of 20 patients with segmental or lobar pulmonary emboli on 
CTA. Each will receive 99mTc-MAA SPECT/CT and 4DCT imaging on the same day. Respiratory 
induced blood mass change (RIBMC) images will be derived from the 4DCT image and 
quantitatively compared with the SPECT perfusion images. A 5 patient cohort (cohort 2) to test 
effect of respiratory pressure on RIBMC was added. A 124 patient cohort (cohort 3) to test the 
sensitivity & specificity of RIBMC was added. Illustrated in Figure 4 below. 
 
Figure 4. Study design. 15 patients (cohort 1) found to have segmental or lobar pulmonary emboli on CTA 
will be recruited for this study. All enrolled subjects will receive 99mTc-MAA SPECT/CT and 4DCT imaging. 
The 4DCT acquisitions will be performed at a single setting to evaluate reproducibility, prior to the 
SPECT/CT imaging. The primary end-point will be the identification and spatial correspondence of 
pulmonary perfusion defects on the 99mTc-MAA SPECT/CT and 4DCT derived RIBMC images. All imaging 
will be performed on the same day. An additional 5 patients (cohort 2) with the same criteria will be recruited. 
Each will receive 99mTc-MAA SPECT/CT imaging as before. They will also receive two 4DCT acquisitions, 
one with normal breathing and the other with positive pressure breathing using BPAP. 62 patients (cohort 
3) found to have PE on CTA and 62 patients negative for PE will be recruited for this study. All enrolled 
subjects will receive a single 4DCT image acquisition. The 4DCT acquisitions will be performed within 48 
hours of the CTA. 
2.0 
Objectives 
2.1 
The primary objective of this study is to test if 4DCT derived RIBMC images can 
detect segmental or lobar pulmonary perfusion detects. 
2.2 
A secondary objective is to evaluate the reproducibility and variability of RIBMC 
images on repeat imaging. 
2.3 
To evaluate the pulmonary blood volume response to positive pressure ventilation 
versus spontaneous breathing. 
2.4 
The primary objective of cohort 3 is to assess the sensitivity and specificity of 
contrast-free 4DCT functional imaging for detection of pulmonary emboli. 
3.0 
ELIGIBILITY, RECRUITMENT, AND SELECTION 
Patients with CTA proven segmental of lobar pulmonary emboli will be recruited for this 
study. Subjects will not be excluded based on age, gender, gender identity, sexual 
orientation, economic status, race or ethnicity. 

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3.1 
One cohort of 15 patients and another of 5 patients (20 patients total) with CTA 
proven segmental of lobar pulmonary emboli will be consented for the study 
and registered on the protocol. Patients may have started anti-coagulation 
therapy prior to enrolling. 
3.1.1 
Inclusion Criteria 
3.1.1.1  Patients with segmental of lobar pulmonary emboli on 
CTA identified within past 48 hours. 
3.1.1.2 May have initiated anticoagulation therapy. 
3.1.1.3 Patients must sign informed consent to enter this study. 
3.1.1.4 Documented not pregnant if child-bearing age woman. 
3.1.2 
Exclusion Criteria 
3.1.2.1  Patients unable to tolerate two 15-minute (4DCT) and one 
30- minute imaging sessions (SPECT/CT) in the same day. 
3.1.2.2 Unable to sign informed consent due to cognitive impairment 
or health status. 
3.1.2.3  Patients who are unstable from a respiratory status requiring 
ICU care. 
3.1.2.4 Patients who receive tissue plasminogen activator. 
3.1.3 
Patients who are <18 years old. 
3.2 
One cohort of 124 patients who present to the Emergency Center with suspected 
pulmonary emboli. We will recruit patients 62 positive and 62 negative for 
pulmonary emboli on CTA. 
3.2.1 
Inclusion Criteria 
3.2.1.1  Patients who are scheduled to receive, or who have 
received, CTA for suspected pulmonary emboli within past 48 
hours. 
3.2.1.2 May have initiated anticoagulation or tissue plasminogen therapy. 
3.2.1.3 Patients must sign informed consent to enter this study. 
3.2.1.4 Documented not pregnant if child-bearing age woman. 
3.2.2 
Exclusion Criteria 
3.2.2.1 Patients unable to tolerate one 15-minute (4DCT). 
3.2.2.2 Unable to sign informed consent due to cognitive impairment 
or health status.Patients who are <18 years old. 
4.0 
STUDY EVALUATIONS 
Study patients will receive 4DCT imaging after signing consent, followed by 99mTc-MAA 
SPECT/CT, and a second 4DCT imaging session. 
4.1 
4DCT ACQUISITIONS*. The patients will be imaged lying supine and flat on the 
scanner bed with their arms above their head. On a multislice CT scanner, CT 
images will be obtained through the entire lung during resting tidal breathing while 
the patient’s respiration is monitored with an external device for respiratory 
gating using the standard over-sampled spiral 4DCT acquisition method (35, 36). 
The 4DCT acquisition will be acquired in duplicate at standard low dose. 
4.2 
4DCT ACQUISITIONS W/ BPAP. The patients will be fitted with a face mask 
covering mouth and nose. The expiratory positive airway pressure (ePAP) will be 
set to 4 cm H2O and inspiratory positive airway pressure (iPAP) to 12 cm H2O. A 
4DCT will acquired as described in the previous section. The patients will undergo 
BPAP for <10 minutes. Upon completion of the scan the patients will resume 
normal breathing of room air. 
4.3 
99mTc-MAA SPECT/CT ACQUISITIONS*. The patients will undergo 99mTc-MAA 
SPECT/CT pulmonary perfusion imaging in the nuclear medicine clinic using the 

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standard clinical procedure under the supervision of a Beaumont nuclear medicine 
physician. This will include SPECT/CT imaging using 99mTc-labeled macro- 
aggregated albumin (99mTc-MAA), an FDA approved radiopharmaceutical in 
routine clinical use at Beaumont. The dose and administration will be prescribed 
by the nuclear medicine physician. A CT will be acquired for attenuation correction 
and image registration purposes and is a standard part of this procedure. The 
patients will be imaged supine with arms above their head. This scan will be 
performed on the same day as the 4D CT scans. 
*If any incidental findings are noted, that have not been previously reported, the 
researcher will discuss these with the patient’s treating clinical physician who will 
determine appropriate follow up. 
5.0 
CRITERIA FOR STUDY REMOVAL 
5.1 
Unacceptable adverse event (at the discretion of the treating physician). 
5.2 
Patients unable to tolerate imaging sessions (1 hour total). 
5.3 
Patient choice (patients can withdraw from the study at any time, for any reason). 
5.4 
Patients who’s image quality does not meet criteria for primary endpoint analysis 
due to imaging techniques, scanner settings, patient movement, etc… 
6.0 
REGISTRATION PROCEDURES 
6.1 
Informed consent is required prior to participation in this study. The study 
coordinator will inform potential subjects about the study opportunity and ask if 
they would like to participate. If the patient is interested, they will be given an 
opportunity to read the informed consent and authorization document specific to 
the study and ask questions of the study coordinator. The patient will be informed 
about: 1) the rationale for the study; 2) the logistics of the study; 3) the risks of the 
study; 4) how the data will be used. Consent will be obtained by the study 
coordinator. The patient will be given a copy of the consent, and asked to sign 
another copy for our records. 
6.2 
Patients will be registered for the study after pretreatment evaluation is completed 
and eligibility criteria are met. 
6.3 
The principal investigator and all key personnel have completed NIH approved 
institutional and HIPAA training in the conduct of medical research studies 
 
7.0 
STATISTICAL CONSIDERATIONS 
Spatial overlap between hypoperfused regions of interest (ROIs) on SPECT perfusion 
(standard) and deficit ROIs on RIBMC will be assessed using Dice similarity coefficient 
(DSC) (37). A priori, we expect a DSC of approximately 0.7 between RIBMC and SPECT 
ROIs. Indication of larger overlap is desirable for RIBMC validation. Thus, we require a 
DSC of at least 0.85 (38) and base our sample size calculations on this degree of 
improvement over a priori expectations. With three experts delineating ROIs on RIBMC 
and SPECT images, we will calculate an average (n = 3 experts) DSC per patient. Sample 
size considerations are based on a t-test for the mean DSC. Castillo et al. (39) provide a 
working DSC standard deviation of ~0.2, leading to a standard deviation of 0.11 (=0.2/√3) for a 
mean DSC based on three experts. Assuming a significance level of .05, power of 95%, 
and standard deviation of 0.11, we find that 15 patients are required to detect a mean 
DSC of at least 0.85. 
Cohort 3. The objective of this study is to collect and process the image data necessary to 
assess the sensitivity and specificity of our CT Functional Imaging (CT-FI) diagnostic 
test, consisting of RIBMC and 4DCT-Ventilation, as well as perform receiver operator  
 

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characteristic (ROC) analysis. We will conduct a prospective imaging study of 124 patients 
who present to the Emergency Department with clinical concern for PE and who 
subsequently undergo chest CTA for further evaluation. 
For each case, an expert reader will determine if functional deficits exist within CT-V and 
RIMBC. The patient will be classified as PE positive if the reader confirms the presence 
of two or more mismatched segmental or subsegmental defects between CT-V and 
RIBMC images, and negative otherwise. This CT-FI binary classification indicator will be 
acquired for each patient. Sensitivity and specificity will be computed with respect to the 
known (CTA defined) PE diagnosis. A score of 1 (low) to 5 (high) will be assigned to each 
defect for the ROC evaluation. 
Because PE status of the subjects will be known a priori, we may use the statistical theory for 
estimating a single proportion to determine the sample size needed to estimate the 
sensitivity or specificity of the CT-FI diagnostic test. Assuming that the sensitivity will be 
(at least) approximately 80%, we can estimate the true sensitivity with a margin of error of 
10% (percentage points) with 95% confidence based on a sample size of 62 positive PE 
cases. Similarly, the specificity can be estimated with 62 negative PE controls. Concerning 
the ROC analysis, to determine the sample size needed to detect an "Area under the ROC 
Curve" (AUC) greater than 50%, it is not necessary to have a prevalence value for PE 
(since PE status is known a priori). To detect an AUC of at least 70% with Type I error of 
1%, power 95% and a 1:1 ratio of cases:controls we require at least 60 cases and 60 
controls (40). Our study is designed to exceed the minimal sample size requirements. 
 
8.0 
POTENTIAL RISKS 
The patients recruited for enrollment in this study will consist of patients who were found 
to have pulmonary emboli on diagnostic CTA. Their participation in this study will consist 
of 99mTc-MAA SPECT/CT imaging once and 4DCT imaging twice. The total dose per 
patient for this study is estimated at 44.2 mSv. This dose is less than the Radiation Safety 
Committee guidelines of 50 mSv per year from research. 
8.1 
SPECT/CT tests. The patients recruited to this study will have 99mTc-MAA 
SPECT/CT imaging at study entry. No changes are made to the clinical SPECT/CT 
imaging techniques specified by this study. A SPECT/CT imaging may cause a 
feeling of claustrophobia while lying in the scanner. The scanner is open at both 
ends and an open dialogue with doctors and staff will be maintained to minimize 
this risk. SPECT/CT imaging utilizes ionizing radiation. The radiation dose will be 
approximately 4.2 mSv. The radioactive isotope 99mTc-MAA has a half-life of 6.0 
hours due to physical decay along with a biological clearance. 
8.2 
4DCT test. The major risk from the two 4DCT scans is from the radiation. Each 
4DCT scan will deliver approximately 10-20 mSv to the patient. Erring on the high 
side of this range, this will befor a total of 40 mSv. 
 
9.0 
LONG TERM GOALS 
This study investigates the use of 4DCT, an imaging study that can be 
rapidly performed in the emergency department without the need 
for contrast, in the evaluation of PE. 
9.1 
If successful, this strategy may be tested in further prospective studies in patients 
who have an unknown PE status. 
9.2 
4DCT RIBMC images may provides a means to detect pulmonary perfusion 
defects rapidly, at low radiation dose, and in patients who cannot receive 
intravenous contrast. 

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9.3 
Determine the sensitivity and specificity of 4DCT RIBMC images to detect 
pulmonary emboli. 
 
10.0 
DATA MONITORING & ADVERSE EVENT REPORTING 
10.1 
Data Monitoring. The Data and Safety Monitoring Plan (DSMP) is established to 
ensure the safety of research participants and the integrity of the study data.. The 
study staff (PI, Co-Investigators, research nursing, etc.) are responsible for 
collecting and recording all clinical data. As these results are collected, all 
toxicities and adverse events will be identified, graded for severity and assigned 
causality, reported to the required entities, and compiled for periodic review. After 
assigning causality, the PI will decide the course of action for the study 
participant. The PI will evaluate all adverse events (AE) and determine whether 
the AE affects the risk/benefit ratio of the study and whether modifications to the 
protocol or informed consent form are required. 
10.2 
Image Quality Evaluation: Images will be computed in Radiation Oncology within 
2-3 days of 4DCT acquisition. The investigators will perform QA of the images 
directly after computation. If the imaging is not evaluable, the investigator will 
inform the research staff and an additional patient will be acquired. 
10.3 
Toxicity Grading. The Common Terminology Criteria for Adverse Events version 
4.0 
will 
be 
used 
to 
grade 
all 
(CTCAE 
v4.0; 
available 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
treatment-related adverse events. All patient encounter or treatment areas should 
have access to a copy of these criteria. 
10.4 
Adverse Events. All AE’s (or unanticipated events) must be reported to the 
Protocol PI. All serious adverse events, defined as grade 4 or 5 toxicity, will be 
reported to the Beaumont Health System’s IRB (institutional review board) of 
according to institutional reporting guidelines and using institutional reporting 
forms. Reports of serious adverse events will be delivered to Clinical Research 
Compliance and will be submitted to the U.S. Food and Drug Administration by the 
safety coordinator according to 21CFR 312.32. 
10.5 
AE Reporting. The following AEs experienced by patients accrued to this protocol 
and attributable to the protocol treatment (definitely, probably, or possibly related) 
should be reported. 
10.5.1 Death on study. 
10.5.2 Hospitalization or prolongation of hospitalization on study 
10.5.3 Life-threatening event 
10.5.4 Persistent or significant disability or incapacity 
 
11.0 
DATA CONFIDENTIALITY PLAN 
11.1 
All patient-reported outcome, laboratory, radiographic, and clinical data gathered 
in this protocol will be stored in a password-protected database. All patient 
information will be handled using anonymous identifiers. Linkage to patient identity 
is only possible after accessing a password-protected database. Access to the 
database is only available to individuals directly involved in the study. Information 
gathered for this study will not be reused or disclosed to any other person or entity, 
or for other research. Once the research has been completed, identifiers will be 
retained for as long as is required by law and by institutional regulations, and at 
that point will be destroyed. 
 
 

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12.0 
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