Clinical Evaluation of Primary Sampling Scatter Correction for Chest Tomosynthesis
Phase: NA
Conditions: Pulmonary Nodule, Solitary, Pulmonary Nodule, Multiple
Sponsor: UNC Lineberger Comprehensive Cancer Center

LCCC  1822: Clinical Evaluation of Primary Sampling Scatter Correction for Chest 
Tomosynthesis 
 
 
NCT#: NCT04076696 
Document Version Date: December 12, 2021 

LINEBERGER COMPREHENSIVE CANCER CENTER 
Imaging Protocol Template 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 February 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC  1822: Clinical Evaluation of Primary Sampling Scatter Correction for Chest 
Tomosynthesis 
 
 
 
Principal Investigator 
Ertan Pamuklar, MD 
Department of Radiology 
CB#7510,  
Chapel Hill, NC 27599  
919-966-2990 phone  
Email: ertan_pamuklar@med.unc.edu 
 
Co-Investigator(s) 
Yueh Lee, MD, PhD 
Department of Radiology  
 
M. Patricia Rivera, MD 
Department of Medicine 
 
Biostatistician  
Donglin Zeng, PhD 
Biostatistics 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
 
Funding Source: NCI Pending 
 
 
Version Date: January 21, 2021 

LINEBERGER COMPREHENSIVE CANCER CENTER 
Imaging Protocol Template 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 February 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC1822:  Clinical Evaluation of Primary Sampling Scatter Correction for Chest 
Tomosynthesis  
 
 
Principal Investigator 
Ertan Pamuklar, MD 
Department of Radiology 
CB#7510,  
Chapel Hill, NC 27599  
919-966-2990 phone  
Email: ertan_pamuklar@med.unc.edu 
 
 
 
 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal regulations 
and ICH guidelines. 
 
Principal Investigator (PI) Name: Ertan Pamuklar, MD 
 
PI Signature: ___________________ 
 
Date:____________________ 
 
Date of Protocol: January 21, 2021 
 
 
 
 

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TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ..................................................................3 
1.1 
Study Synopsis ......................................................................................................3 
1.2 
Lung Cancer and Screening ..................................................................................3 
1.3 
Chest Tomosynthesis.............................................................................................3 
1.4 
Chest Tomosynthesis for Lung Cancer Screening ................................................4 
1.5 
Rationale................................................................................................................5 
2.0 
STUDY OBJECTIVES ...........................................................................................5 
2.1 
Primary Objectives ................................................................................................5 
2.2 
Secondary Objectives ............................................................................................5 
2.3 
Primary Endpoint ..................................................................................................5 
3.0 
PATIENT ELIGIBILITY ......................................................................................5 
3.1 
Inclusion Criteria ...................................................................................................5 
3.2 
Exclusion Criteria ..................................................................................................5 
4.0 
STUDY PLAN .........................................................................................................6 
4.1 
STUDY SCHEMA ................................................................................................6 
4.2 
Duration of the Study ............................................................................................6 
4.3 
Study Procedures ...................................................................................................7 
4.4 
Time and Events Table ..........................................................................................8 
5.0 
INVESTIGATIONAL DEVICE ............................................................................8 
5.1 
Investigational Device Description .......................................................................8 
5.2 
Expected Risks ....................................................................................................10 
6.0 
UNANTICIPATED CONCERNS (DEVICES) ..................................................11 

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6.2 
Data and Safety Monitoring Plan ........................................................................12 
7.0 
STATISTICAL CONSIDERATIONS ................................................................13 
7.1 
Study Design/Study Endpoints ...........................................................................13 
7.2 
Sample Size and Accrual.....................................................................................13 
7.3 
Data Analysis Plans .............................................................................................13 
7.4 
Data Management ...............................................................................................13 
7.5 
Teaching File .......................................................................................................14 
8.0 
STUDY MANAGEMENT ....................................................................................14 
8.1 
Institutional Review Board (IRB) Approval and Consent ..................................14 
8.2 
Registration Procedures.......................................................................................14 
8.3 
Adherence to the Protocol ...................................................................................14 
8.4 
Amendments to the Protocol ...............................................................................16 
8.5 
Record Retention .................................................................................................16 
8.6 
Obligations of Investigators ................................................................................16 
9.0 
REFERENCES ......................................................................................................17 
10.0 APPENDICES .......................................................................................................19 
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This is a study that will evaluate the utility of a scatter reduction technique in reducing 
dose and increasing the sensitivity of stationary digital chest tomosynthesis (s-DCT) in 
the detection of lung lesions. Digital tomosynthesis is an imaging modality that produces 
3D sectional information using x-ray projections acquired over a limited scanning angle.  
Scatter is known to be the primary source of image degradation in x-ray based imaging.  
 
We have developed an approach that measures scatter through a low dose (3% of the 
conventional scan) scatter measurement technique. Preliminary studies have shown that 
scatter reduction in DCT can significantly improve quality.  We plan to characterize the 
reader confidence in lung nodule detection in our scatter corrected chest tomosynthesis 
imaging approach as compared to our conventional chest tomosynthesis.  
 
Fifty (50) patients who have undergone a clinical non-contrast CT with lung nodules will 
be asked to have an s-DCT (scan) within 4 weeks (+/- 2 week) of their clinical CT with 
no intervening procedures or therapies (i.e. biopsy of lung nodules). We will then 
perform a reader study to evaluate the radiologist reader confidence in images generated 
from the scatter reduction technique versus more conventional chest tomosynthesis 
imaging. 
1.2 
Lung Cancer and Screening 
Lung cancer continues to be the leading cause of cancer deaths in the world. Over 
200,000 new cases of lung cancer were identified in 2010 in the US, and lung cancer 
death exceeds the total estimated deaths from breast, prostate and colon combined. 
Conventional chest radiographs are known to perform poorly in screening and 
identification of small stage I cancers due to the small lesion size and poor conspicuity. 
The low dose-CT based National Lung Screening Trial was published in 2011, and 
demonstrated that there was an overall 20% reduction in lung cancer mortality in the low 
dose CT screening group in patients at high risk of lung cancer as compared to 
conventional radiographs.  Low dose CT was estimated to provide 1.5 mSv, at roughly 20 
to 30 mAs for an average sized patient. Conventional chest CT is estimated to be 
approximately 8 mSv. This lower dose results in a lower radiation risk to patients. 
1.3 
Chest Tomosynthesis 
Digital chest tomosynthesis (DCT) is a three-dimensional imaging technique that 
provides reconstruction planes from a limited-angle series of projection images. Clinical 
tomosynthesis applications include chest imaging [3-10], angiography [11], joints 
imaging [12], dental imaging [13], and breast imaging[3, 14, 15]. Compared to 
conventional chest radiography, DCT results in improved visibility of normal structures 
such as vessels, airway and spine. By reducing visual clutter from overlying normal 
anatomy, it also enhances detection of small lung nodules[2]. DCT has better resolution 
than CT in the plane of the image (but worse resolution in the depth direction) at a 
significantly lower radiation dose and cost [2].  In the current commercial systems, the 
projection images are collected by mechanically moving a single x-ray source to different 

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viewing angles, as illustrated in Figure 1.  Two DCT systems are currently commercially 
available, the GE VolumeRAD and Shimadzu RADspeed. In the GE VolumeRAD [16, 
17] system, the x-ray generator is mounted on a crane moving vertically with a variable 
source-to-detector distance of 180cm. A typical tomosynthesis scan includes 61 
projections over 30° in 10 seconds 
1.4 
Chest Tomosynthesis for Lung Cancer Screening 
A number of groups have explored the use of DCT for the screening and the 
identification of pulmonary nodules. The key attraction of DCT is that it exposes patients 
to lower doses of radiation than CT. As shown in Table 1, in terms of dose, DCT is 
typically 10 to 50 times lower than CT, and 3 to 5 times lower than 2D chest radiography 
(CR). In terms of diagnostic sensitivity and accuracy DCT is significantly better than CR, 
and is approaching that of CT. The reported effectiveness, as measured by sensitivity, of 
the GE system, as measured by the AUC (Area under Curve) using CT as the gold 
standard, varies from 0.73 to 0.96. [1] [18] [19]. The reported variation in AUC is 
partially attributed to patient motion during the scan. A recent study by Kim et al shows 
that when no respiratory motion artifacts are present, the detection performance of DCT 
for nodules (4–10 mm) is significantly better than that of CR; whereas there is not a 
significant difference in cases with motion artifacts. Using the Shimadzu RADspeed, 
which has a scanning time of 5s, Yamada et al reported AUC as high as 0.93 [20]. These 
results indicate that reducing image blurring due to respiratory motion is critical for 
improving the diagnostic accuracy of DCT. Patients with diseases of the lung, such as 
COPD or emphysema are severely compromised in their ability to hold their breaths for 
an extended period of time and consistently on command. Because of the long travel 
distance (~1m), heavy weight of the x-ray generator, and the precision required, further 
reduction of the scanning time is difficult even if the x-ray source can produce sufficient 
flux. 
 
Table 1: Comparison of dose, scan time, diagnostic accuracy between CT, CR, DCT, 
and the UNC stationary DCT systems.  
 
CT  
CR 
GE DCT 
Shimadzu 
DCT 
UNC s-
DCT 
Dose (mSv) 
3~10 
0.02~0.06 
0.06~0.2 
0.2 
~0.2 
Dose (mAs) 
130-300 
~1 
3-15 
3 
3 
Scan time (s) 
~2s  
< 1s 
10s 
5s 
2s 
Coverage 
(deg) 
360  
0  
30 
40 
20 ~ 40 
# of views 
~1000 
1 
60 
74 
60 
AUC 
1.0 
0.7~0.77 
0.73~0.96[1]  
0.93[20] 
TBD 
AUC with 
motion  
without 
motion 
 
 
0.73[19] 
0.85 [19] 
 
 

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1.5 
Rationale 
The proposed research, if successfully implemented, will result in a low-dose, low-cost, 
and highly effective method for screening of lung nodules, which may result in earlier 
treatment of patients with early stage lung cancer. Using the scatter corrected s-DCT 
system the imaging dose for a full tomosynthesis scan is expected to be only 10% of that 
from a low-dose CT, and half of a conventional tomosynthesis scan. Beyond lung cancer 
screening, the low-dose and sensitive 3D lung imaging modality will likely to find 
applications in areas such as monitoring of pediatric cystic fibrosis patients where 
reduction of imaging dose is critical.  
 
The proposed study is a close collaboration between 2 clinical researchers (Lee, 
MD/PhD, Ertan Pamkular, MD) utilizing the technology invented by two basic scientists 
(Otto Zhou, PhD, and Jianping Lu, PhD) at UNC. It leverages the resources from several 
ongoing R&D programs in our lab on new imaging and radiotherapy devices based on the 
CNT x-ray source array technology, including the stationary digital breast 
tomosynthesis[25, 26] and microbeam radiation therapy systems[27] that are also 
invented by our team.   We believe the success of this pilot project will lead to a larger 
scale multidisciplinary project to translate the low-dose stationary digital chest 
tomosynthesis technology to a clinically viable modality for lung cancer screening.  
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
Evaluate the reader confidence in the evaluation of s-DCT image with and without PSSC 
scatter correction.   
2.2 
Secondary Objectives  
The sensitivity of the scatter corrected s-DCT system to conventional s-DCT in the 
detection of lung nodules.  
2.3 
Primary Endpoint 
The reader confidence in the interpretation of scatter corrected s-DCT images to 
conventional s-DCT images  
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
3.1.1 Patients with a known lung lesion(s) 
3.1.2 Patients having undergone a chest CT  
3.1.3 Patients 18 years of age and older 
3.1.4 Patients able to provide informed consent   
3.2 
Exclusion Criteria 

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3.2.1 Patients unable to provide consent 
3.2.2 Patients who may not fit on a 35 x 35 detector (BMI > 35). 
3.2.3 Planned procedures or therapies during study (in between SOC scans and study 
scan on s-DCT) (biopsy or excision of lung lesion) 
3.2.4 Institutionalized patient (prisoner or nursing home patient) 
4.0 
STUDY PLAN 
4.1 
STUDY SCHEMA 
This is a one arm study of 50 patients with one or more lung nodules who have had 
standard imaging (chest CT) who consent to undergo an experimental scatter correction 
s-DCT to characterize the number and extent of lung nodules.  This experimental scan 
will be compared with CT to define the sensitivity of lung nodule detection among this 
group.  The CT scan is used as the gold standard to assess for the presence of a nodule 
and will be interpreted by consensus to identify the target nodule for each case. 
 
 
4.2 
Duration of the Study 
It is anticipated that the total study duration encompassing recruitment, enrollment, and 
data analysis will take approximately 1 year.  Patient participation will last approximately 
1 to 3 weeks.   
Patient  has had 
standard of care 
imaging
Recruited from 
MTOP clinic
Consent
s-DCT
(within x weeks 
of SOC imaging)
Reader Study 
(once all data are 
collected)

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4.3 
Study Procedures 
4.3.1 Enrollment/Recruitment 
We will review upcoming clinical chest CT studies for lung nodule follow-up.  We will 
ask patients to participate in this study to evaluate the utility of the scatter reduction 
approach for stationary digital chest tomosynthesis (s-DCT) machine, using the standard 
of care chest CT for comparison.  
 
Once a patient has been identified, or we have collaborated with the treating clinic 
regarding the eligibility of a subject, the patient will be approached by a coordinator from 
Radiology to assess interest in participation. The coordinator will either go to the treating 
clinic, or will call the patient at home.  
 
If the patient is interested in participation, he/she will be consented either then (in their 
treatment clinic) or when he/she arrives to have his/her s-DCT, but prior to any study 
procedures. Review of the consent will take place in the privacy of an exam room, or 
when possible, a sample consent will be sent to the patient via email prior to arriving for 
the scan to allow for ample review. 
4.3.2 Research Imaging 
4.3.2.1 Imaging Procedures 
The study scan, s-DCT and correction scan, will be performed within two weeks of 
his/her clinical evaluations by chest CT and x-ray. The study scan may be done within 2 
weeks prior or two weeks following standard of care imaging. There cannot be any 
intervening therapies or procedures (i.e. biopsy or excision of lesions) done in between 
the SOC imaging and the s-DCT.  
 
All patients will have a breath held s-DCT scan in an anterior-posterior direction. Images 
will be reconstructed off-line and transferred for review on conventional PACS 
workstations. Images will be reviewed by radiologists. 
4.3.3 Reader Study  
Three thoracic imaging specialty radiologists will be asked to separately evaluate the two 
sets of s-DCT images in a paired reader study. The radiologists will be presented with 
deidentified images from one modality (either with or without PSSC correction), then 
asked to identify the lesion and then determine a likelihood of malignancy based on the 
overall image set.  A likelihood of malignancy score (1 to 10) will be initially assigned by 
the reader. The reader will then be given the deidentified images from the second 
modality, and their relative confidence in interpretation of the first modality as compared 
to the second will be evaluated on a 7 point scale. A washout period of four weeks will be 
provided and the images reviewed in reverse. Confidence scores in the evaluation of lung 
lesions, locations and involved structures will also be assessed. The CT scan is used as 
the gold standard to assess for the presence of a nodule and will be interpreted by 
consensus to identify the target nodule for each case. 
 

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4.4 
Time and Events Table 
              
 
 
 
 
 
 
 
 
 
 
5.0 
INVESTIGATIONAL DEVICE 
5.1 
Investigational Device Description 
We recently demonstrated a high-speed, and low-dose stationary digital tomosynthesis 
system (s-DCT) for 3D lung imaging[21].   The system is based on the carbon nanotube 
(CNT) x-ray source array technology invented by our team at UNC[22-24]. Instead of 
mechanically moving a large x-generator to different viewing angles for the projection 
images, s-DCT generates the images by electronically and sequentially activating the 
individual x-ray sources inside spatially distributed CNT x-ray source array without 
moving the source, detector or the patient.  Our initial trial of lung nodule detection 
resulted in mixed results, with reasonable, but not sufficiently accurate identification of 
smaller lung nodules. One of the critical limitations is the reduction in image quality due 
to x-ray scatter, inherent in all x-ray based imaging systems.  
 
As shown in Figure 1, the clinical test ready prototype device has already been 
constructed by retrofitting a commercial mobile digital radiography system with a 
dedicated CNT x-ray source array (XinRay Systems Inc., NC).  A flat panel detector 
(Varian Inc., CA) is placed underneath the patient. An external collimator is connected to 
the source array to confine the x-ray radiation only to the region of interests to minimize 
the radiation to the patient and the staff.  
 
 
 
Baseline 
 
Within 2 weeks of baseline SOC imaging 
Screening 
X 
Informed 
Consent 
X 
SOC 
imaging 
X 
 
Research 
Scan 
 
X 

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Figure 1:  A photograph of the stationary digital chest tomosynthesis imaging 
system with a CNT x-ray source array.  
 
In all x-ray imaging approaches, the detector measures both the photons that have passed 
directly through an object (primary photons) and those that are scattered by the object 
(scattered photons). Unfortunately, only the primary photons are useful for imaging in 
conventional diagnostic imaging. The presence of scattered photons is a major source of 
image degradation and extra dose to the patient. Scatter also increases as the imaging 
subject thickness increases. The scatter-to-primary ratio (SPR) in mammography can 
vary from 30% to 150%. In chest radiography the SPR can vary from 100% to 500%. 
Conventional radiography systems use anti-scatter grids placed in front of the detector to 
block some of the scattered photons from reaching the detector. Unfortunately, the grids 
also block significant portion of primary beam, and thus a large increase in dose (up to 
500%) is required to obtain the same exposure to the detector. Analytical approaches to 
reduce scatter, such as Monte Carlo simulations and using peripheral field for modeling 
are generally time consuming and inaccurate. The slot-scan method, though effective, is 
very slow and impractical for clinical applications.  
 
 
We have extended our system by developing a scatter correction technique that can be 
applied to all of x-ray imaging, but is particularly useful in tomosynthesis scanning. Our 
approach is to estimate scatter by placing a large plate with holes that allow a small 
fraction (3%) of the primary beam to pass, which generates a patient specific scatter map. 
This scatter map can then be subtracted from the diagnostic scan. 
 
Preliminary thoracic phantom and large animal imaging results have demonstrated the 
feasibility of our approach (Figure 2). Furthermore, by accurately estimating scatter, we 

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can also potentially reduce the dose of primary diagnostic scan.  Our proposed 
implementation of the scatter reduction plate is in Figure 3.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The research images will not be interpreted or analyzed for clinical decisions related to 
the patient.  As such, this study will request that the IRB make a determination that this 
study is no greater than minimal risk. This study meets all the requirements for an NSR 
determination including: 
• The device will not be implanted. 
• The device is not intended to support or sustain human life. 
• The device is not being used of substantial importance in diagnosing, 
curing, mitigating, or treating disease. 
• The device does not present a potential for serious risk to health, safety, or 
welfare of a subject. 
5.2 
Expected Risks 
This research protocol presents minimal risk to participants, investigators and study 
personnel. The radiation dose from the device about 10% of the dose comparing to a low-
dose CT. Hardware, though experimental, is built on an FDA approved system. The 
components that will physically have contact with the patient will be a part of the original 
 
 
Figure 2: Chest tomosynthesis image slice from a respiratory 
gated acquisition of a 30 kg normal pig model without (left) and 
with (right) scatter correction performed with the PSSC 
approach.  
Figure 1: CAD drawing of the PSSC device 
designed to be implanted with s-DCT system 
which swings in front and away from the patient 
during the study. The PSSC can be rapidly 
moved in and out of the field to minimize the 
breath hold and patient imaging time.  

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FDA approved device. Only the x-ray source has been modified. All x-ray and electrical 
interlocks will be maintained.  Prior to implementation, this study will be reviewed by the 
Radiation Safety Committee.  
6.0 
UNANTICIPATED CONCERNS (DEVICES) 
6.1.1 Unanticipated Adverse Device Effect (UADE) 
The investigational device exemption (IDE) regulations define an unanticipated 
adverse device effect (UADE) as “any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects” 
(21 CFR 812.3(s)). 
6.1.2 Unanticipated Problems (UP) 
As defined by UNC’s IRB, unanticipated problems involving risks to study 
subjects refers to any incident, experience, or outcome that: 
• Is unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied; 
• Is related or possibly related to a subject’s participation in the research; 
and  
• Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) related 
to the research than was previously known or recognized. 
6.1.3 Reporting 
6.1.4 UADEs 
UADEs must be reported by the clinical investigator to the sponsor and the 
reviewing IRB, as described below:  
 
For this device study, investigators are required to submit a report of a UADE to 
the FDA, the manufacturer of the device and the UNC IRB as soon as possible, 
but in no event later than 10 working days after the investigator first learns of the 
event (§ 812.150(a)(1)), using the MedWatch Form 3500A.   Sponsors  must 
immediately conduct an evaluation of a UADE and must report the results of the 
evaluation to FDA, the UNC IRB, and participating investigators within 10 
working days after the sponsor first receives notice of the effect (§§ 812.46(b), 
812.150(b)(1)).  
 

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For this device study, we will submit a report of a UADE to the manufacturer and 
the IRB as soon as possible, but no later than 10 working days after the 
investigators first learn of the event. 
6.1.5 UP 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the Study Coordinator using the IRB’s web-
based reporting system.   
 
Any unanticipated problem that occurs during the conduct of this study and that 
meets at least the first two criteria listed in section 8.2 must be reported to the 
UNC IRB using the IRB’s web-based reporting system.   
6.2 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the Data and Safety Monitoring Committee 
(DSMC).  
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as protocol nurses, clinical research associates, regulatory 
associates, data managers, biostatisticians, and any other relevant personnel the 
principal investigators may deem appropriate.  At these meetings, the research 
team will discuss all issues relevant to study progress, including enrollment, 
safety, regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight (Office of Human Research Ethics (OHRE) 
Biomedical IRB, the Oncology Protocol Review Committee (PRC) or the North 
Carolina TraCS Institute Data and Safety Monitoring Board (DSMB).   
 
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review 
based on risk and complexity as determined by the UNC Protocol Review 
Committee.  The UNC PI will be responsible for submitting the following 
information for review: 1) safety and accrual data including the number of study 
participants treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report.  
Findings of the DSMC review will be disseminated by memo to the UNC PI, 
PRC, and the UNC IRB and DSMB.   

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7.0 
STATISTICAL CONSIDERATIONS 
7.1 
Study Design/Study Endpoints 
This is a nonrandomized, single-center, observational study.  The purpose and 
endpoint of this study is to compare, in a radiologist reader study, the reader 
preference of the s-DCT scatter corrected images as compared to uncorrected s-
DCT images.  
 
Fifty (50) patients undergoing a clinical non-contrast CT for their lung nodules 
will be asked to have this procedure (scan) within 4 weeks of their clinical CT, 
with no intervening procedures or therapies involving the lung lesion (ie, excision 
or biopsy).  
7.2 
Sample Size and Accrual 
Assuming 50 cases are available for the comparison, and the standard deviation of 
the average reader score to be 2 (the range of the score is from +3 to -3), we will 
have at least 80% power to detect 0.7 confidence score of using scatter correction 
over without correction. In the data analysis, we will fit a linear mixed effect 
model with the confidence score as the outcome and a constant intercept. The 
working correlation matrix among readers is assumed to be compound symmetry. 
We will estimate grand mean from this model and test whether the mean 
confidence score is different from zero.   
7.3 
Data Analysis Plans 
The study will be performed as a reader confidence study. For each comparison, 
the average confidence scores and the corresponding standard deviations will be 
reported. Furthermore, to test whether the mean confidence score is larger than 
zero, a linear mixed effect will be used to analyze data, where the outcome 
variable is the confidence scores collected in this study and only a grand mean 
parameter is in the independent list. Additionally, a random intercept is used in 
the model to account for the correlation among readers when reading the images 
from the same patient.  The Wald’s test based on model fit will be used to test 
whether the grand mean parameter is larger zero. When the p-value from this test 
is less than 0.05, it will be concluded that there exists significant evidence that 
readers have more confidence with the s-DCT scatter corrected modality 
compared to the conventional s-DCT.  
 
The reader preference study form (including both primary and secondary 
evaluations) is located in the Appendix. 
7.4 
Data Management 
The non-contrast chest CT, s-DCT, and SC s-DCT, if available, that are obtained of 
all eligible enrolled subjects will be de-identified for inclusion in the readers study. 
Copies of the clinical report forms as well as the de-identified images described in 
the preceding will be submitted for each case to the Study Coordinators for 
maintaining the study record and entering the data into a spreadsheet in preparation 

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for the reader study. 
  
As an investigator initiated study, this trial will also be audited by the Lineberger 
Cancer Center audit committee every six or twelve months, depending on the 
participation of affiliate sites. 
7.5 
Teaching File 
After completion of the study, the de-identified study images will be developed 
into a teaching file by the PI. It will be used by the PI to educate radiologists in 
evaluating and interpreting s-DCT imaging. 
8.0 
STUDY MANAGEMENT 
8.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
8.2 
Registration Procedures 
Study participants will be registered into OnCore®, a web based clinical research 
platform by one of the Study Coordinators. 
8.3 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   

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8.3.1 Emergency Modifications 
UNC investigators may implement a deviation from, or a change of, the protocol 
to eliminate an immediate hazard(s) to trial subjects without prior UNC’s 
IRB/IEC approval/favorable opinion.   
 
For any such emergency modification implemented, an IRB modification form 
must be completed by UNC Research Personnel within five (5) business days of 
making the change.   
8.3.2 Single Subject Exceptions 
Eligibility single subject exceptions are not permitted for Lineberger 
Comprehensive Cancer Center Investigator Initiated Trials under any 
circumstances. Other types of single subject exceptions may be allowed if proper 
regulatory review has been completed in accordance with Lineberger 
Comprehensive Cancer Center’s Single Subject Exceptions Policy. Other Protocol 
Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
Protocol Deviations: UNC personnel will record the deviation in OnCore®, and 
report to any sponsor or data and safety monitoring committee in accordance with 
their policies.  Deviations should be summarized and reported to the IRB at the 
time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.   

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Unanticipated Problems: 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the study team using the IRB’s web-based 
reporting system.   
8.4 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC.  It should also 
be noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be 
required.   
 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.  
8.5 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
8.6 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study participants.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 

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9.0 
REFERENCES 
1. 
Marshall, H.M., et al., Digital tomosynthesis for the detection and management of 
pulmonary nodules. Lung Cancer Management, 2013. 2(1): p. 5-7. 
2. 
Dobbins, J.T.a.M., H. P., Chest tomosynthesis: technical principles and clinical update. 
European journal of radiology, 2009. 72: p. 244-51. 
3. 
J.T. Dobbins and D.J. Godfrey, Digital X-ray tomosynthesis: current state of the art and 
clinical potential. Phys. Med. Biol., 2003. 48: p. 65-106  
4. 
Dobbins, J.T., Matrix Inversion Tomosynthesis improvements in longitudinal x-ray slice 
imaging, 1990, Duke University: United States. 
5. 
J.T. Dobbins, A.O. Powell, and Y.K. Weaver, Matrix inversion tomosynthesis: Initial image 
reconstructions. Abstract Summaries of the RSNA, 1987. 165(P): p. 333. 
6. 
R.J. Warp, D.J. Godfrey, and J.T. Dobbins, Applications of matrix inverse tomosynthesis. 
Proc. SPIE, 2000. 3977: p. 376-383  
7. 
D.J. Godfrey, R.J. Warp, and J.T. Dobbins, Optimization of matrix inverse tomosynthesis. 
Proc. SPIE, 2001. 4320: p. 696-704  
8. 
D.J. Godfrey, A. Rader, and J.T. Dobbins, Practical strategies for the clinical 
implementation of matrix inversion tomosynthesis. Proc. SPIE, 2003. 5030: p. 379-390  
9. 
D.J. Godfrey, H.P. McAdams, and J.T. Dobbins, Optimization of the Matrix Inversion 
Tomosynthesis (MITS) impulse response and modulation transfer function characteristics 
for chest imaging. Med. Phys. 33, 2006. 3: p. 655-667  
10. 
S. Sone, et al., Image processing in the digital tomosynthesis for pulmonary imaging. Eur. 
Radiol, 1995. 5: p. 96-101  
11. 
G.M. Stiel, et al., Digital flashing tomosynthesis: A promising technique for 
angiocardiographic screening. IEEE Trans. Med. Imag, 1993. 12(2): p. 314-321  
12. 
J. Duryea, J.T. Dobbins, and J.A. Lynch, Digital tomosynthesis of hand joints for arthritis 
assessment. Med. Phys., 2003. 30: p. 325-333  
13. 
C. Badea, Z. Kolitsi, and N. Pallikarakis, A 3D imaging system for dental imaging based 
on digital tomosynthesis and cone beam CT. Proc. of the International Federation for 
Medical and Biological Engineering 2001. 2: p. 739-741  
14. 
S.P. Poplack, et al., Digital breast tomosynthesis: intial experience in 98 women with 
abormal digital screening mammography. AJR, 2007. 189: p. 616. 
15. 
Baorui Ren, et al., A new generation FFDM / tomosynthesis fusion system with selenium 
detector. Medical Imaging 2010, Proc of SPIE 2010. 76220B-2. 

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CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
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18 
16. 
Vikgren, J., et al., Comparison of chest tomosynthesis and chest radiography for detection 
of pulmonary nodules: human observer study of clinical cases. Radiology, 2008. 249: p. 
1034–1041. 
17. 
Bath, M., et al., “Effective dose to patients from chest examinations with tomosynthesis.,” 
Radiation protection dosimetry, 2010. 139: p. 158. 
18. 
Kim, E.Y., et al., Pulmonary mycobacterial disease: diagnostic performance of low-dose 
digital tomosynthesis as compared with chest radiography. Radiology, 2010. 257(1): p. 
269-77. 
19. 
Kim, S.M., et al., Digital tomosynthesis of the thorax: the influence of respiratory motion 
artifacts on lung nodule detection. Acta Radiol, 2013. 
20. 
Yamada, Y., et al., Fast scanning tomosynthesis for the detection of pulmonary nodules: 
diagnostic performance compared with chest radiography, using multidetector-row 
computed tomography as the reference. Invest Radiol, 2011. 46(8): p. 471-7. 
21. 
Jing Shan, et al., Stationary chest tomosynthesis using a CNT x-ray source array. Proc. 
SPIE, Medical Imaging, 2013. 8668: p. 86680E. 
22. 
O. Zhou and J.P. Lu, New x-ray generating mechanism using electron field emission 
cathode, U.S. Patent 6,553,096. 
23. 
Otto Zhou and X. Calderon-Colon, Carbon nanotube based field emission x-ray 
technology, in Carbon Nanotube and Related Field Emitters: Fundamentals and 
Applications, Y. Saito, Editor. 2010, Wiley. 
24. 
Modern x-ray technology: another look inside, in The Economist, July 302009. 
25. 
X. Qian, et al., High resolution stationary digital breast tomosynthesis using distributed 
carbon nanotube x-ray source array. Medical Physics, 2012. 39(4). 
26. 
Otto Zhou, et al., US 7,751,528, Stationary x-ray digital breast tomosynthesis systems and 
related methods. 
27. 
O. Zhou and S. Chang, U.S. patent appliation, "Compact Microbeam Radiation Therapy 
Systems and Methods for Cancer Treatment and Research", 2009. 
28. 
Yueh Z. Lee, et al., Prospective Respiratory Gated Carbon Nanotube Micro Computed 
Tomography. Acad Radiol, 2011. 18(8): p. 588. 
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Guohua Cao, et al., Prospective-gated cardiac micro-CT imaging of free-breathing mice 
using carbon nanotube field emission x-ray. Medical Physics, 2010. 
 
 
 
 

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19 
10.0 APPENDICES 
Scatter Corrected versus Uncorrected s-DCT  
Reader Study 
 
Study #_____  
 
 
 
 
 
 
 
Reader # ______ 
Date __________ 
1. Confidence in the presence of a lesion: 
 
1 
2 
3 
4 
5 
Definitely no  
lesion 
Probably no  
lesion 
unequivocal 
Probably 
 pulmonary 
 lesion 
Definitely 
 pulmonary  
lesion 
 
If the confidence rating is 3 or greater (3, 4 or 5) 
 
Lesion location (mark on figure):  
 
Lesion size (measured in the coronal plane):  
 
Presence of calcifications:    Y / N 
 
Comparing both modalities: 
 
2. Scatter Corrected s-DCT versus Uncorrected: Shape/Morphology 
-3 
-2 
-1 
0 
+1 
+2 
+3 
significantly less  
confident in the  
Chest Tomo 
 representation 
less confident in 
 the CHEST  
TOMO  
representation 
slightly less 
 confident in the  
CHEST TOMO 
 representation 
have the same  
confidence 
 in the CHEST  
TOMO 
slightly more  
confident in the  
CHEST TOMO  
representation 
more confident  
in the CHEST 
 TOMO  
representation 
significantly more 
 confident in the  
CHEST TOMO  
representation 
 
2.  Scatter Corrected s-DCT versus Uncorrected: Calcifications 
-3 
-2 
-1 
0 
+1 
+2 
+3 
significantly less 
 confident in the 
 CHEST TOMO 
 representation 
less confident in 
 the CHEST  
TOMO 
 representation 
slightly less 
 confident in the  
CHEST TOMO  
representation 
have the same  
confidence 
 in the CHEST 
 TOMO 
slightly more  
confident in the 
 CHEST TOMO  
representation 
more confident 
 in the CHEST  
TOMO  
representation 
significantly more  
confident in the  
CHEST TOMO 
 representation 
 
3.  Scatter Corrected s-DCT versus Uncorrected: architectural distortion 
-3 
-2 
-1 
0 
+1 
+2 
+3 
significantly less 
confident in the 
 CHEST TOMO 
 representation 
less confident in 
 the CHEST  
TOMO 
 representation 
slightly less  
confident in the  
CHEST TOMO 
 representation 
have the same 
 confidence 
 in the CHEST 
 TOMO 
slightly more 
 confident in the 
 CHEST TOMO 
 representation 
more confident 
 in the CHEST 
 TOMO  
representation 
significantly more 
 confident in the 
 CHEST TOMO 
 representation