Wrist Fracture Evaluation With a Desktop Orthopedic Tomosynthesis System
Phase: NA
Conditions: Fracture
Sponsor: University of North Carolina, Chapel Hill

Wrist Fracture Evaluation with a Desktop Orthopedic Tomosynthesis System 
 
 
NCT#: NCT03993691 
Document Version Date: November 18, 2020 

Wrist Fracture Evaluation with Tomo-E 
 
CONFIDENTIAL 
PI: Nissman 
 
UNIVERSITY OF NORTH CAROLINA 
November 18, 2020 
Page 1 of 23 
 
 
 
Wrist Fracture Evaluation with a Desktop Orthopedic Tomosynthesis System 
Short Title: Wrist Fracture Evaluation with Tomo-E 
 
Drug or Device Name(s): Tomo-E 
Sponsor: The University of North Carolina  
Protocol Date: November 18, 2020 
Amendment 1 Date: 
Amendment 2 Date:  
Amendment 3 Date: 
Amendment 4 Date:  
 
 
 
 
 
 
 
 
Study Principal Investigator: Daniel Nissman, MD, MPH, MSEE 
Biostatistician: Donglin Zeng, PhD 
 
Department of Radiology 
Campus Box 7510 
Chapel Hill, NC 27599-7510 
Phone 919-846-7675 
email: daniel_nissman@med.unc.edu 
 
 

Wrist Fracture Evaluation with Tomo-E 
 
CONFIDENTIAL 
PI: Nissman 
 
UNIVERSITY OF NORTH CAROLINA 
November 18, 2020 
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PROTOCOL TITLE:  
Wrist Fracture Evaluation with a Desktop Orthopedic 
Tomosynthesis System   
Short Title:  
Wrist Fracture Evaluation with Tomo-E 
 
 
 
Lead Investigator: 
Daniel Nissman, MD, MPH, MSEE 
 University of North Carolina at Chapel Hill 
Protocol Version: 1.0  
Version Date: January 1, 2019 
 
 
 
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 Name:  
 
 
 
 
 
 
 
 
Principal Investigator Signature:   
 
 
 
 
 
 
Date:   
 
 
 
 
 
 
 
 
 
 
 
 
 

Wrist Fracture Evaluation with Tomo-E 
 
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UNIVERSITY OF NORTH CAROLINA 
November 18, 2020 
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TABLE OF CONTENTS 
Table of Contents ................................................................................................................... 3 
Abbreviations and Definitions of Terms .............................................................................. 5 
Protocol Synopsis ................................................................................................................... 6 
PRIMARY OBJECTIVE ................................................................................................................................................ 6 
SECONDARY OBJECTIVES ........................................................................................................................................ 6 
INCLUSION CRITERIA ................................................................................................................................................ 7 
EXCLUSION CRITERIA ............................................................................................................................................... 7 
1. BACKGROUND AND RATIONALE ............................................................................................................. 9 
1.1 
INTRODUCTION ........................................................................................................................................... 10 
1.2 
EXTREMITY TOMOSYNTHESIS .................................................................................................................... 10 
1.3 
NON-CLINICAL AND CLINICAL STUDY FINDINGS ...................................................................................... 11 
2. STUDY OBJECTIVES .................................................................................................................................... 13 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................. 13 
2.2 
SECONDARY OBJECTIVES ......................................................................................................................... 13 
3. INVESTIGATIONAL PLAN ........................................................................................................................... 13 
3.1 
STUDY DESIGN ........................................................................................................................................... 13 
3.2 
STUDY DURATION, ENROLLMENT AND NUMBER OF SUBJECTS ............................................................... 13 
3.3 
STUDY POPULATION .................................................................................................................................. 13 
3.3.1 
INCLUSION CRITERIA ............................................................................................................................. 13 
3.3.2 
EXCLUSION CRITERIA ............................................................................................................................ 14 
4.1 
SCREENING/BASELINE VISIT PROCEDURES .............................................................................................. 14 
4.2 
RESEARCH IMAGING PROCEDURE ............................................................................................................ 14 
4.3 
MEDICAL RECORD ABSTRACTION ............................................................................................................. 15 
4.4 
READER STUDY ......................................................................................................................................... 15 
4.5 
VARIABLES OF INTEREST........................................................................................................................... 15 
5. STATISTICAL CONSIDERATION .............................................................................................................. 16 
5.1 
PRIMARY ENDPOINT .................................................................................................................................. 16 
5.2 
SECONDARY ENDPOINT ............................................................................................................................. 16 
5.3 
STATISTICAL METHODS ............................................................................................................................. 16 
5.4 
SAMPLE SIZE AND POWER ........................................................................................................................ 17 
5.5 
INTERIM ANALYSIS ..................................................................................................................................... 17 
6. SAFETY MANAGEMENT.............................................................................................................................. 17 
6.1 
UNANTICIPATED ADVERSE DEVICE EFFECT (UADE) .............................................................................. 17 
6.2 
UNANTICIPATED PROBLEMS (UP)............................................................................................................. 17 
6.3 
REPORTING ................................................................................................................................................ 18 
6.3.1 
UADES .................................................................................................................................................. 18 
6.3.2 
UP .......................................................................................................................................................... 18 
6.3.3 
DATA AND SAFETY MONITORING PLAN ................................................................................................ 18 
7. STUDY MANAGEMENT ................................................................................................................................ 19 
7.1 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT .......................................................... 19 
7.2 
REGISTRATION PROCEDURES ................................................................................................................... 19 
7.3 
DATA MANAGEMENT AND MONITORING/AUDITING .................................................................................. 19 
7.4 
ADHERENCE TO THE PROTOCOL ............................................................................................................... 20 
7.5 
EMERGENCY MODIFICATIONS.................................................................................................................... 20 

Wrist Fracture Evaluation with Tomo-E 
 
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November 18, 2020 
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7.6 
PROTOCOL DEVIATIONS/VIOLATIONS ....................................................................................................... 20 
7.7 
AMENDMENTS TO THE PROTOCOL ............................................................................................................ 21 
7.8 
RECORD RETENTION ................................................................................................................................. 21 
7.9 
OBLIGATIONS OF INVESTIGATORS............................................................................................................. 21 
7.10 
CONFLICT OF INTEREST ............................................................................................................................. 21 
8. PLANS FOR PUBLICATION ........................................................................................................................ 22 
9. REFERENCES ................................................................................................................................................. 22 
10. APPENDIX ........................................................................................................................................................ 23 
10.1 
APPENDIX A: READER STUDY DATA COLLECTION FORM ....................................................................... 23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Wrist Fracture Evaluation with Tomo-E 
 
CONFIDENTIAL 
PI: Nissman 
 
UNIVERSITY OF NORTH CAROLINA 
November 18, 2020 
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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
 
Abbreviation 
Definition 
CNT 
Carbon Nanotube 
Tomo-E 
Extremity Tomosynthesis System 
MSK 
Musculoskeletal 
PACS 
Picture Archiving and Communication System 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Wrist Fracture Evaluation with Tomo-E 
 
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PI: Nissman 
 
UNIVERSITY OF NORTH CAROLINA 
November 18, 2020 
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PROTOCOL SYNOPSIS 
 
Study Title 
Wrist Fracture Evaluation with a Desktop Orthopedic 
Tomosynthesis System   
Funder 
The University of North Carolina (NC TraCS Institute) 
Clinical Phase 
Pilot Study 
Study Rationale 
Tomosynthesis is a quasi-3D imaging modality that uses a 
series of limited-angle projection images to produce a 3D 
representation of the object. It provides depth information and 
removes structural overlaps at significantly reduced radiation 
dose and cost compared to CT. It is now widely used clinically 
for breast cancer detection with significantly higher sensitivity 
and accuracy compared to digital mammography. The value 
of tomosynthesis for orthopedic imaging has also been 
demonstrated. 
Study Objective(s) 
Primary Objective 
The primary objective is to compare (using a reader study) 
the sensitivity of Tomo-E compared to radiography of the wrist 
in detecting wrist fractures. 
Secondary Objectives 
Specificity 
The secondary aim is to determine the specificity of Tomo-E 
compared to radiography of the wrist in detecting wrist 
fractures.   
Reader Confidence 
To compare radiologist confidence of Tomo-E compared to 
wrist radiography for the evaluation of: 
• Articular surfaces  
• Cortical surface of the bones 
• Joint spaces 
• Soft tissue structures 
• Subarticular structures 
Area Under the Curve (AUC) Comparison  
To compare the area under the curve (AUC) for Tomo-E 
compared to wrist radiography for fracture detection. 

Wrist Fracture Evaluation with Tomo-E 
 
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UNIVERSITY OF NORTH CAROLINA 
November 18, 2020 
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Investigational Device 
 
This study will be an evaluation of a compact extremity 
tomosynthesis (“Tomo-E”) device to provide 3D imaging at 
the price and radiation dose of 2D radiography at the point-of-
care in orthopedic and radiology clinics.  Compared to the 
current standard practice, 2D radiography, Tomo-E offers 
increased sensitivity and specificity resulting in better 
diagnostic accuracy without increasing the radiation dose to 
the patient or cost to the healthcare system. Successful 
implementation of the technology will reduce misdiagnosis 
and overtreatment, and reduce the use of CT scans.   
Study Design 
 
This is a prospective, one arm, single center study of 50 that 
have undergone radiographic imaging of wrist for presumed 
or known scaphoid, wrist or distal radius fractures to 
demonstrate Tomo-E’s clinical utility for diagnosis of wrist 
injury.  
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
• Age 18 or older 
• Undergone radiographic imaging of wrist for presumed or 
known scaphoid, wrist or distal radius fractures within 2 
weeks or are scheduled to undergo such imaging. 
• Able to provide informed consent 
 
Exclusion Criteria 
• Patients with an intervening surgical procedure 
performed prior to study imaging. 
• Institutionalized subject (prisoner or nursing home 
patient) 
Number Of Subjects  
 
A total of 50 participants will be consecutively recruited from 
individuals that have recently undergone radiographic imaging 
of wrist for presumed or known scaphoid, wrist or distal radius 
fractures.   
Study Duration 
Subjects will be followed for 2 months after initial imaging with 
the Tomo-E device.  
Statistical And 
Analytic Plan 
We will perform sensitivity, specificity and area under the 
curve (AUC) analysis of the imaging modalities based on 
radiologist reader studies. We will also perform reader 
confidence studies in evaluation of imaging characteristics 
relevant to wrist pain imaging.  
The primary outcome of interest is the sensitivity of Tomo-E is 
defined as the ability of readers (radiologists) to detect wrist 

Wrist Fracture Evaluation with Tomo-E 
 
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PI: Nissman 
 
UNIVERSITY OF NORTH CAROLINA 
November 18, 2020 
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fractures in patients. This will be determined by performing a 
reader study with radiologists.  Using these results, we can 
determine the mean confidence score of radiologist readers 
using the new device as compared to the competing modality. 
We will also test the primary null hypothesis that the 
difference between the two mean confidence scores is zero in 
the target population. 
For the confidence study, 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-effects model 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 Tomo-E modality compared to the other 
modality. The estimated mean confidence score is given by 
the grand mean parameter and its 95% confidence interval 
will be reported.  We anticipate that it would be meaningful to 
detect a mean confidence score of greater than 1 between 
the modalities. 
DATA AND SAFETY 
MONITORING PLAN 
The Principal Investigator will provide continuous monitoring 
of patient safety in this trial with periodic reporting to an 
independent Medical Monitor. The medical monitor will review 
any reported Unanticipated Adverse Device Effects after 
patients 5, 25, and 50. 
 
 
 

Wrist Fracture Evaluation with Tomo-E 
 
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1. BACKGROUND AND RATIONALE 
Trauma to the extremities such wrist, ankle, limb is very common and affects all 
population groups. It constitutes a significant public health issue. Standard radiography 
remains the basic imaging tool. However, as a 2-dimensional (2D) imaging modality it 
lacks sensitivity and specificity. Misdiagnosis rates are known to be high, especially for 
non-displaced fractures of the scaphoid and talus as well as erosions due to rheumatoid 
arthritis [1-3].  Misdiagnosis leads to over treatment and unnecessary loss of 
productivity and quality of life including 6-12 weeks in a cast.  Missed fractures can 
result in a chronic, non-healing fracture that may require surgical fixation and early 
arthritis of the joint. From a physician perspective, a missed diagnosis can result in a 
lawsuit and an expensive settlement/penalty.  
Computed tomography (CT) offers high resolution and excellent visualization of bone 
and joint morphology, and Magnetic Resonance Imaging (MRI) delivers soft tissue and 
cartilage visibility. However, cost, space and workflow related issues make them 
prohibitive for small orthopedic clinics.  Although the radiation dose of a CT scan has 
been reduced considerably in recent years, it is still significantly higher than a regular 
radiograph. The whole-body scanners also have difficulties in imaging patients in 
portable and weight-bearing conditions. Dedicated extremity CT scanners (Figure 1) 
have been commercialized recently in an attempt to address the current deficiency. 
They still suffer from higher cost and at such have a limited installation base. 
c
 
 
Figure 1: Top: illustration of common a common 
cause of scaphoid fracture (left), which was not 
revealed by 2D x-rau (middle), but clearly resolved 
by tomosynthesis (right). Bottom: A commercial 
extremity CT (left) and a tomosynthesis scanner 
(right) 
 

Wrist Fracture Evaluation with Tomo-E 
 
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UNIVERSITY OF NORTH CAROLINA 
November 18, 2020 
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1.1 
Introduction 
Tomosynthesis is a quasi-3D imaging modality that uses a series of limited-angle 
projection images to produce a 3D representation of the object [4]. It provides depth 
information and removes structural overlaps at significantly reduced radiation dose and 
cost compared to CT. It is now widely used clinically for breast cancer detection with 
significantly higher sensitivity and accuracy compared to digital mammography. The 
value of tomosynthesis for orthopedic imaging has also been demonstrated [1, 2, 5]. 
1.2 
Extremity Tomosynthesis 
This study will be an evaluation of a compact extremity tomosynthesis (“Tomo-E”) 
device to provide 3D imaging at the price and radiation dose of 2D radiography at the 
point-of-care in orthopedic and radiology clinics.  Compared to the current standard 
practice, 2D radiography, Tomo-E offers increased sensitivity and specificity resulting in 
better diagnostic accuracy without increasing the radiation dose to the patient or cost to 
the healthcare system. Successful implementation of the technology will reduce 
misdiagnosis and overtreatment, and reduce the use of CT scans.  The device is 
enabled by the unique UNC-invented carbon nanotube (CNT) x-ray source array [6] and 
stationary tomosynthesis technologies [7]. 
This will be carried out using an existing and re-configurable imaging set-up (Figure 4), 
and an iterative image reconstruction algorithm developed in-house, which has been 
utilized in our preliminary studies using cadaveric hands.  The device will be modified to 
meet the safety standards for patient imaging and will be characterized and tested. 
 
 
 
 
Figure 2: Top: An illustration of the Tomo-E 
device with a CNT x-ray source array (left). A 
photo of the experimental set-up to be used in 

Wrist Fracture Evaluation with Tomo-E 
 
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UNIVERSITY OF NORTH CAROLINA 
November 18, 2020 
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this study (right). Bottom: Reconstructed 
tomosynthesis images of a hand phantom at 
different depth. The images were collected 
using the experimental set-up shown above 
 
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. 
 
1.3 
Non-Clinical and Clinical Study Findings 
Two dimensional radiography is the most commonly used diagnostic tool for orthopedic 
examinations. Although its low accuracy is well known, it remains the most cost 
effective screening tool. Tomosynthesis is gaining clinical acceptance as a low-dose 
modality that increases diagnostic sensitivity compared to 2D radiography while using 
significantly lower radiation dose compared to 3D.  
Current commercial approaches: Commercial tomosynthesis scanners collect the 
projection images needed for reconstruction by mechanically moving a large single-
beam x-ray tube mounted on a motorized arm across a long distance while taking the x-
ray exposures (Figure 1). Because of the tube motion blurring its spatial sensitivity and 
consequently the detection sensitivity are lower than what the modality can intrinsically 
provide (Figure 1). Furthermore, the device is expensive (~$150K), and requires a 
dedicated imaging room. The technology has not made a significant inroad to 
orthopedic clinics.  
Our innovation: Tomo-E is a compact and stationary device that utilizes a distributed 
CNT x-ray source array that will be specially designed for extremity imaging to collect all 
the projection views without any mechanical motion, as illustrated in Figure 2.   X-ray 
exposure is synchronized with a high frame-rate x-ray detector, which is controlled via 
dedicated control electronics. The entire device is packaged in radiation shielding and 
will be operated at the point-of-care (Figure 3). The projection images are processed by 
a fast iterative tomosynthesis reconstruction algorithm developed at UNC. The 
reconstructed images are generated in the DICOM format and can be viewed in 
standard clinical PACS systems. Imaging can be performed with the patient either 

Wrist Fracture Evaluation with Tomo-E 
 
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November 18, 2020 
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sitting in the examination chair or with the patient standing in the load-bearing situation 
(Figure 3).  
Figure 3: Photos illustrating the proposed 
compact Tomo-E device for quasi-3D 
extremity imaging (The photo on the right is 
a commercial 2D radiography machine. 
Tomo-E is expected to have a similar 
dimension)  
 
Compared to 2D radiography this quasi-3D method offers higher diagnostic accuracy to 
allow physicians to make better treatment decisions, prevent unnecessary patient 
casting, and reduces the use high-dose/cost MRI or CT imaging. Compared to 
commercial tomosynthesis systems, Tomo-E will be the world’s first compact 3D 
orthopedic imaging system that can be used as point-of-care, is low cost, and offers 
higher spatial resolution. 
 
Figure 4: Left: a FDA approved CNT x-ray 
based digital mobile x-ray radiography 
system on display at RSAN 2017. Right: a 
schematic showing a CNT x-ray source 
array 
 
Preliminary studies using phantoms and cadaveric tissue have been performed to 
optimize the system configuration for orthopedic imaging. Figure 2 shows an example 
of the reconstructed tomosynthesis images of a cadaveric hand obtained from this 

Wrist Fracture Evaluation with Tomo-E 
 
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UNIVERSITY OF NORTH CAROLINA 
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device. Utilizing a set of 25 cadaveric hands (Draeger, MD), we have established the 
geometry, dose parameters and image resolution necessary to provide diagnostic 
quality wrist radiographs through a reader study with musculoskeletal radiologists.  
2. STUDY OBJECTIVES 
The aim of this one-year study is to demonstrate Tomo-E’s clinical utility for diagnosis of 
wrist fractures.   
2.1 
Primary Objective 
The primary objective is to compare (using a reader study) the sensitivity of Tomo-E 
compared to radiography of the wrist in detecting wrist fractures. 
2.2 
Secondary Objectives 
2.2.1 Specificity 
The secondary aim is to determine the specificity of Tomo-E compared to radiography 
of the wrist in detecting wrist fractures.   
2.2.2 Reader Confidence 
To compare radiologist confidence of Tomo-E compared to wrist radiography for the 
evaluation of: 
• Articular surfaces  
• Cortical surface of the bones 
• Joint spaces 
• Soft tissue structures 
• Subarticular structures 
 
2.2.3 Area Under the Curve (AUC) Comparison  
To compare the area under the curve (AUC) for Tomo-E compared to wrist radiography 
for fracture detection. 
3. INVESTIGATIONAL PLAN  
3.1 
Study Design 
This is a prospective, one arm, single center study of 50 that have undergone 
radiographic imaging of wrist for presumed or known scaphoid, wrist or distal radius 
fractures to demonstrate Tomo-E’s clinical utility for diagnosis of wrist injury.   
3.2 
Study Duration, Enrollment and Number of Subjects 
We will include a total of 50 participants in this trial.  These subjects will be followed for 
2 months after initial imaging with the Tomo-E device.  
3.3 
Study Population 
3.3.1 Inclusion Criteria 
3.3.1.1 
Age 18 or older 

Wrist Fracture Evaluation with Tomo-E 
 
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UNIVERSITY OF NORTH CAROLINA 
November 18, 2020 
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3.3.1.2 
Undergone radiographic imaging of wrist for presumed or known scaphoid, 
wrist or distal radius fractures within 2 weeks or are scheduled to undergo such 
imaging. 
3.3.1.3 
Able to provide informed consent 
 
3.3.2 Exclusion Criteria 
3.3.2.1 
Patients with an intervening surgical procedure performed prior to study 
imaging. 
3.3.2.2 
Institutionalized subject (prisoner or nursing home patient) 
 
4. STUDY PROCEDURES 
A patient study focusing on wrist injury will be carried out by comparing Tomo-E with 
conventional 2D radiographs obtained from a clinical device at UNC Radiology or 
Orthopedic clinics. Fifty patients who have wrist injuries and have been imaged by 
conventional 2D radiography at UNC orthopedic clinic (at the Ambulatory Care Center) 
or Urgent Care will be recruited and be imaged using the Tomo-E device which will be 
installed in our clinical imaging space in the Marsico Hall, located approximately 200 
yards away. We will recruit subjects ages 18 and above to evaluate the device in the 
adult population. The images will be compared and evaluated by 3 experienced 
musculoskeletal radiologists from UNC. Clinical outcome reviewed up to 2 months after 
initial imaging will serve as the clinical standard for the presence of fracture.  
4.1 
Screening/Baseline Visit procedures 
A total of 50 participants will be enrolled to this study. The 50 study subjects will be 
consecutively recruited from individuals that have recently undergone radiographic 
imaging of wrist for presumed or known scaphoid, wrist or distal radius fractures.  
Eligible patients will be identified by research staff review in coordination with the UNC 
Radiology Clinic.   
Once a patient has been referred, the patient will be approached by a coordinator from 
Radiology to assess interest in participation.  
All eligible participants who agree to participate in the study will be asked to come to 
their scheduled appointment thirty minutes early to complete the informed consent 
process.  For patients who have already undergone their clinical imaging, they will be 
scheduled to return to UNC for the study visit. 
Review of the consent will take place in the privacy of an exam room, or when possible, 
a sample consent form will be sent to the patient via email prior to the patient’s visit to 
allow for ample review.   
4.2 
Research Imaging Procedure 
Participants who consent for the study will be escorted by the research coordinator to 
the dedicated study room for the imaging exam.  

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The patient will have the Tomo-E scan performed in a similar manner as conventional 
wrist radiography.  The research technologist will assist in positioning the wrist in the 
tomosynthesis unit. Once positioned, the total scan time is approximately 15 seconds. 
The length of time for the positioning and examination of a subject’s wrist may vary but 
it is expected that the entire imaging procedure will take about 5-10 min, including 
positioning time. 
4.3 
Medical Record Abstraction 
Participants’ medical record will be reviewed for 2 months following their initial research 
imaging to meet the primary and secondary aims.  
4.4 
Reader Study 
Upon completion of all study image data collection, a reader study will be performed 
with three MSK fellowship trained radiologists. All images will be reconstructed with our 
fast-reconstruction algorithm and presented on 3MP viewing monitors with PACS 
viewing software with conventional zoom/pan/window and level tools.  The readers will 
not be blinded whether the images are from Tomo-E. 
Each radiologist will be randomly presented with either the patient’s diagnostic 
radiographs or tomosynthesis study in a random order. They will be asked to review the 
scan for the presence of a fracture, and comment on location (specific bone) and 
fracture type. They will be asked their confidence rating on a scale of 0 to 100%.  
A washout period of four weeks will be utilized so that the radiologists will have 
“forgotten” their initial interpretations. At this timepoint, the other modality for each 
patient will be randomly presented. Diagnostic accuracy will be defined by the presence 
of a fracture as defined by the clinical diagnosis by the attending orthopedic surgeon at 
2 months post imaging during the patients’ routine clinical care, such as cast placement, 
surgery, or follow-up imaging. Sensitivity and specificity to the presence of fractures will 
be estimated and evaluated between the modalities. 
The order that imaging modalities will be presented will be randomly assigned using a 
computational software in collaboration with the study biostatistician.  This 
randomization schedule will be created prior to the beginning of the reader study and 
will not be shared with any of the readers. 
4.5 
Variables of Interest 
Primary Variables of Interest: 
• Presence of fracture based on imaging (T/F) 
• Confidence in interpretation of image set (0 to 100%) 
Secondary Variables of Interest 
• Reader confidence in articular surface evaluation (1-5) 
• Reader confidence in Cortical surface evaluation (1-5) 
• Reader confidence in Joint Space evaluation (1-5) 

Wrist Fracture Evaluation with Tomo-E 
 
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• Reader confidence in Soft tissue Structures evaluation (1-5) 
• Reader confidence in Subarticular structure evaluation (1-5) 
5. STATISTICAL CONSIDERATION    
5.1 
Primary Endpoint 
The sensitivity of Tomo-E is defined as the ability of readers (radiologists) to detect wrist 
fractures in patients.   Diagnostic accuracy will be defined by the presence of a fracture 
as defined clinically by the attending orthopedic surgeon at 2 months post imaging. 
5.2 
Secondary Endpoint 
The specificity of Tomo-E is defined as the ability to distinguish between individuals that 
do not have a wrist fracture.  Diagnostic accuracy will be defined by the presence of a 
fracture as defined clinically by the attending orthopedic surgeon at 2 months post 
imaging. 
5.3 
Statistical Methods 
A total of 50 participants will be recruited for this study.  Three radiologists will be 
recruited to conduct the reader study.   
We will perform sensitivity, specificity and area under the curve (AUC) analysis of the 
imaging modalities based on radiologist reader studies. We will also perform reader 
confidence studies in evaluation of imaging characteristics relevant to wrist pain 
imaging.  
The primary outcome of interest is the sensitivity of Tomo-E is defined as the ability of 
readers (radiologists) to detect wrist fractures in patients. This will be determined by 
performing a reader study with radiologists.  Using these results, we can determine the 
mean confidence score of radiologist readers using the new device as compared to the 
competing modality. We will also test the primary null hypothesis that the difference 
between the two mean confidence scores is zero in the target population. 
For the confidence study, 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-effects model 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 Tomo-E modality compared to the other modality. The 
estimated mean confidence score is given by the grand mean parameter and its 95% 
confidence interval will be reported.  We anticipate that it would be meaningful to detect 
a mean confidence score of greater than 1 between the modalities. 

Wrist Fracture Evaluation with Tomo-E 
 
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For the primary and secondary objective, we will estimate the sensitivity and specificity 
for a pre-specified cutoff of review scores to detect wrist fracture. Generalized 
estimating equation will be used to produce such estimates, where diagnosis outcomes 
from readers are treated as clustered data and a compound symmetry working 
covariance matrix is used. Normal distributions will be used to construct 95% 
confidence intervals. Bootstrap method may be used when the normality assumption is 
of concern. For the AUC analysis, the same estimating procedures will be used to 
obtain the sensitivity and specificity when varying cutoff scores then the AUC will be 
calculated using the trapezoidal rule. The confidence of the AUC will be obtained from 
bootstrap method. 
For the confidence study, we expect no missing data or drop out. For any missed data 
during the reader study, we will question the reader to collect the data.  The only 
primary hypothesis test is whether the mean confidence score is zero with a 
significance level of 0.05. There is no need to adjust multiple tests.  All hypothesis tests 
that are observed to be not statistically significant will be reported as being inconclusive. 
5.4 
Sample Size and Power 
A typical sensitivity of radiographs for wrist fractures is approximately 65%[5] We 
estimate that our sensitivity using the Tomo-E system will be approximately 80%. Thus 
we will need 50 patients to detect this difference, assuming a prevalence of 
approximately 33% in our test population and with 3 readers, that we will have 70% 
power to detect differences between the two modalities.   
5.5 
Interim Analysis 
Interim analyses will not be conducted. 
6. SAFETY MANAGEMENT 
6.1 
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)). 
6.2 
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; 

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• 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. 
6.3 
Reporting 
6.3.1 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 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)).  
For this device study, we will submit a report of a UADE to the IRB as soon as possible, 
but no later than 10 working days after the investigators first learn of the event. 
6.3.2 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 7.2 must be reported to the UNC IRB using 
the IRB’s web-based reporting system.   
6.3.3 Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in this trial 
with periodic reporting to an independent Medical Monitor. The medical monitor will 
review any reported Unanticipated Adverse Device Effects after patients 5, 25, and 50. 
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 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 Scientific 
Review Committee (SRC), the Office of Clinical Trials (OCT), or the North Carolina 
TraCS Institute Data and Safety Monitoring Board (DSMB).   

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The PI will be responsible for submitting the following information for review by the 
independent medical monitor: 1) safety and accrual data including the number of study 
participants imaged; 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 medical monitor review will be disseminated by memo.   
7. STUDY MANAGEMENT 
7.1 
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.  
7.2 
Registration Procedures 
Study participants will be registered into CRMS, a web based clinical research platform 
by one of the Study Coordinators. 
7.3 
Data Management and Monitoring/Auditing 
The wrist radiograph and Tomo-E scan that are obtained of all eligible enrolled subjects 
will be de-identified for inclusion in the appropriate 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 REDCap in preparation for the reader study. 
Information regarding why a data value is missing will be documented in the study 
database in REDCap. 

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7.4 
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.   
7.5 
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.   
7.6 
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 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 according to the UNC IRB 
reporting requirements. 
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.   
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.   

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7.7 
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.  
7.8 
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. 
7.9 
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. 
7.10 Conflict of Interest 
Any investigator who has a conflict of interest (COI) with this study as defined by the 
policies of the University of North Carolina will have the conflict reviewed by a properly 
constituted Conflict of Interest Review Committee with a committee-sanctioned conflict 
management plan that has been reviewed and approved by the IRB prior to 
participation in this study.  All University of North Carolina investigators will follow the 
University conflict of interest policy. 

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8. PLANS FOR PUBLICATION 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the sponsor for the purposes of 
performing the study, will be published or passed on to any third party without the 
consent of the study sponsor. Any investigator involved with this study will be obligated 
to provide the sponsor with complete test results and all data derived from the study. 
9. REFERENCES  
1. 
Aoki, T., et al., Tomosynthesis of the Wrist and Hand in Patients With Rheumatoid 
Arthritis: Comparison With Radiography and MRI. AJR, 2014. 202: p. 386. 
2. 
Geijer M, Börjesson AM, and G. JH, Clinical utility of tomosynthesis in suspected 
scaphoid fracture. A pilot study. Skelet Radiol, 2011. 40: p. 863. 
3. 
Van Tassel DC and Owens BD, Incidence estimates and demographics of 
scaphoid fracture in the U.S. population. J Hand Surg Am, 2010. 35: p. 1242. 
4. 
Dobbins III, J.T. and D.J. Godfrey, Digital x-ray tomosynthesis: current state of the 
art and clinical potential. Physics in medicine and biology, 2003. 48(19): p. R65. 
5. 
Marie-Alexia Ottenin, et al., Evaluation of the Diagnostic Performance of 
Tomosynthesis in Fractures of the Wrist. AJR 2012. 198: p. 180. 
6. 
Lei Zhang, et al., Carbon Nanotube Based Field Emission X-ray Technology, in 
Handbook of X-ray Imaging: Physics and Technology, P. Russo, Editor. 2018, 
CRC Press. 
7. 
Otto Zhou, et al., US 7,751,528, Stationary x-ray digital breast tomosynthesis 
systems and related methods. 
8. 
J. Zhang, et al., A stationary scanning x-ray source based on carbon nanotube 
field emitters. Appl. Phys. Lett., 2005. 86: p. 184104. 
9. 
O. Zhou and J.P. Lu, New x-ray generating mechanism using electron field 
emission cathode, U.S. Patent 6,553,096. 
10. 
Modern x-ray technology: another look inside, in The Economist, July 30. 2009. 
11. 
Guang Yang, et al. Stationary digital breast tomosynthesis system  with a multi-
beam field emission x-ray source array. in SPIE proceeding on Medical Imaging. 
2008. 
12. 
Qian, X., et al., High resolution stationary digital breast tomosynthesis using 
distributed carbon nanotube x-ray source array. Medical Physics, 2012. 39(4): p. 
2090. 
13. 
Jing Shan, et al., Stationary chest tomosynthesis using a carbon nanotube X-ray 
source array: a feasibility study. Physics in Medicine and Biology, 2015. 60(81). 
14. 
Otto Zhou, et al., US 9,782,136, INTRAORAL TOMOSYNTHESIS SYSTEMS, 
METHODS, AND COMPUTER READABLE MEDIA FOR DENTAL IMAGING. 
2017. 
15. 
Shan, J., et al., Stationary intra-oral digital tomosynthesis using a carbon nanotube 
X-ray source array. Dentomaxillofacial Radiology. 0(0): p. 20150098. 
 
 
 
 

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10. APPENDIX 
10.1 Appendix A: Reader Study Data Collection Form 
 
Subject ID:   
 
 
 
 
 
 
Reader: 
 
 
 
 
 
Date:  
 
 
Overall Assessment: 
Is there a fracture? 
If yes, which bone?  
Overall confidence in presence of a fracture (0-100)   
% 
 
Please indicate your overall confidence for each of the items below. 
 
Very Poor 
Poor 
Fair 
Good 
Excellent 
Articular 
Surfaces 
 
 
 
 
 
Cortical 
Surfaces of 
Bones 
 
 
 
 
 
Joint 
Spaces 
 
 
 
 
 
Soft Tissue 
Structures 
 
 
 
 
 
Subarticular 
Structures