Imagio Feasibility Multi-Reader, Multi-Case Study of Optoacoustic Images Versus Imagio Ultrasound to Guide Decision to Biopsy
Phase: NA
Conditions: Breast Cancer
Sponsor: Seno Medical Instruments Inc.

 
 
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Clinical Study Protocol 
Study Title: 
Imagio Feasibility Multi-Reader, Multi-Case Study of Optoacoustic 
Images versus Imagio Ultrasound to Guide Decision to Biopsy 
Study Type: 
Single arm, controlled, blinded, multi-reader, multi-case study 
Study Identifier: 
Reader Study-01 
Study Phase: 
Feasibility 
Study Objective: 
To determine the design and sample size required for the pivotal study  
Indication: 
The Imagio™ breast imaging system is indicated for use by a trained and 
qualified healthcare provider for evaluation of breasts in women who are 
referred for a diagnostic breast work-up (including both palpable and non-
palpable masses), following clinical presentation, mammography, 
diagnostic, screening, or staging methodology.  In ultrasound mode, the 
device can 
be 
used 
to 
assess 
BI-RADS1-6.  For BI-RADS 
3-
5 lesions, the ultrasound mode should be initially used to assess the 
lesion before moving to OA. In Opto-Acoustic (OA) mode, the Imagio™ 
provides information about the central nidus, boundary and peripheral 
zones to assist in the assessment of BI-RADS category and diagnosis of 
the benign or malignant lesion(s) of interest. Using OA and the 
corresponding features of the lesion(s) allows for improved classification 
of the mass of interest as compared to ultrasound alone in BIRADS 3-5 
masses. 
This device is not intended to be used as a replacement for 
mammographic screening or for definitive pathologic diagnosis. 
Sponsor: 
Seno Medical Instruments, Inc. 
Sponsor Contact: 
Shaan Schaeffer, Vice President, Clinical Operations 
Seno Medical Instruments, Inc. 8023 Vantage Dr. 
Suite 1000 
San Antonio, TX 78230  
Phone: 210-615-6501 
E-mail: sschaeffer@senomedical.com 
IDE Approval 
Identifier 
Not Applicable – Non-Significant Risk Study 
 
 

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TABLE OF CONTENTS 
Page 
TABLE OF CONTENTS ............................................................................................................ 3 
List of Abbreviations and Definitions of Terms ..................................................................... 5 
CLINICAL RESEARCH ORGANIZATIONS ............................................................................... 7 
1.  
STUDY OBJECTIVES ....................................................................................................... 8 
1.1 
Primary Objective ....................................................................................................... 8 
1.2 
Secondary Objectives ................................................................................................. 8 
1.3 
Other Objectives ......................................................................................................... 8 
2. 
ENDPOINTS ...................................................................................................................... 8 
2.1 
Primary Endpoint ........................................................................................................ 8 
2.2 
Secondary Endpoints .................................................................................................. 9 
3.  
BACKGROUND AND RATIONALE ..................................................................................10 
4.  
STUDY DESIGN ...............................................................................................................10 
5.  
SELECTION OF READERS .............................................................................................11 
5.1 
Reader Qualification Criteria ......................................................................................11 
5.2 
Reader Training .........................................................................................................12 
6.  
SELECTION OF READER SETS ......................................................................................13 
6.1 
Inclusion Criteria ........................................................................................................13 
6.2 
Exclusion Criteria .......................................................................................................13 
6.3 
Reader Set Selection Procedure................................................................................13 
7.0    
READER STUDY PROCEDURES ................................................................................13 
7.1 
Reader Study Process Work Flow .............................................................................13 
7.2 
Schedule of Reader Sessions ....................................................................................15 
7.3 
Description of Reading Environment ..........................................................................16 
7.4 
Randomization...........................................................................................................16 
7.5 
Blinding......................................................................................................................16 
8.  
SAFETY ASSESSMENTS ................................................................................................17 
9.  
STATISTICAL CONSIDERATIONS ..................................................................................17 
9.1 
General Design Issues ..............................................................................................17 
9.2 
Reader Set Sample Size ...........................................................................................18 

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9.4  
Population Definition ..................................................................................................18 
9.5 
Interim Analyses ........................................................................................................18 
9.6 
Protocol Deviations ....................................................................................................18 
9.7 
Outcomes ..................................................................................................................18 
9.8 
Data Analyses ...........................................................................................................18 
10.  DATA COLLECTION AND QUALITY ASSURANCE ........................................................22 
10.1 
Data Management .....................................................................................................22 
10.2 
Quality Assurance .....................................................................................................22 
10.2.1 
Training ..............................................................................................................22 
10.2.2 
Quality Control ...................................................................................................22 
10.3.4 
Monitoring ..........................................................................................................22 
11.  PARTICIPANT RIGHTS AND CONFIDENTIALITY ..........................................................22 
11.1 
Informed Consent Forms ...........................................................................................22 
11.2 
Participant Confidentiality ..........................................................................................22 
11.3 
Study Discontinuation ................................................................................................22 
12.  PUBLICATION OF RESEARCH FINDINGS .....................................................................23 
13.  REFERENCES ..................................................................................................................23 
14. VERSION HISTORY .........................................................................................................24 
 
 
 

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List of Abbreviations and Definitions of Terms  
ACR 
American College of Radiology  
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUC 
Area Under the Curve 
BI-RADS 
Breast Imaging-Reporting and Data System 
CDU 
Conventional Diagnostic Ultrasound 
eCRF 
Electronic Case Report Form 
EDC  
Electronic Data Capture System 
FDA 
Food and Drug Administration 
GEE 
Generalized Estimating Equations 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITD 
Intention-to-Diagnose 
IUS 
Imagio Internal Ultrasound  
MRMC 
Multi-reader, multi-case 
N/A 
Not Applicable 
NLR 
Negative Likelihood Ratio 
NPV 
Negative Predictive Value 
NSR 
Non-significant Risk 
OA 
Opto-Acoustic 
PDU 
Positive Diagnostic Ultrasound 
PDUNB 
Positive Diagnostic Ultrasound, No Biopsy 
PIONEER  
Abbreviated name of a previous study  (Pivotal study of Imaging with Opto-
acoustics to diagnose breast masses detected by mammography and/or 
clinical findings: A NEw Evaluation Tool for Radiologists) 
PLR 
Positive Likelihood Ratio 
PMA 
Premarket Approval 
POM 
Probability of Malignancy 
PPV 
Positive Predictive Value 
QC 
Quality Control 
ROC 
Receiver Operating Characteristic 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 

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SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
USA 
United States of America 

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STUDY TEAM LEADERS  
Shaan Schaeffer - VP of Clinical Operations 
Philip Lavin PhD, FASA, FRAPS - Chief Biostatistician  
Tom Stavros MD, FACP - Chief Medical Officer 
CLINICAL RESEARCH ORGANIZATIONS 
American College of Radiology Center for Research and Innovation (ACR - CRI) will 
serve as the Imaging Core Lab to conduct the Imagio Feasibility Reader Study. ACR-
CRI is located in Philadelphia, PA 19103. ACR-CRI complies with Good Clinical 
Practices (GCPs) and Title 21 Code of Federal Regulations (CFR) Part 11.  
Boston Biostatistics Research Foundation (BBRF) will provide study design, mass 
sampling, database construction, and data analyses for the Imagio Feasibility Study. 
BBRF is located in Framingham, MA.  
 
 

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1.  
STUDY OBJECTIVES 
1.1 
Primary Objective 
1. To select the effectiveness endpoints and determine the corresponding sample size 
required for the Pivotal study. 
2. To evaluate the gain in Imagio (Imagio Internal Ultrasound [IUS] + Opto-acoustic 
[OA]) specificity versus IUS, controlling for sensitivity 
1.2 
Secondary Objectives 
To evaluate the following overall and for individual readers for IUS versus Imagio (OA+ 
IUS):  
• 
the Imagio (IUS+OA) partial Receiver Operator Characteristic (ROC) Area under the 
Curve (AUC) for 95-99% vs IUS for 95-99% sensitivity 
• 
the sensitivity and specificity for Imagio (IUS+OA) versus IUS according to multiple 
models for readers and masses used for assessing sources of variation 
• 
the Negative Likelihood Ratio (NLR) for IUS versus Imagio (IUS+OA). 
• 
the Imagio (IUS+OA) downgrades and upgrades relative to IUS, separately, for 
benign and malignant masses 
• 
the net gain (new True Positives [TP] + new True Negatives [TN] – new False 
Positives [FP] – new False Negatives [FN]) estimate of Imagio (IUS+OA) versus IUS 
combining benign and malignant masses   
• 
the usage and performance of the SenoGram model for the purposes of determining 
whether it will be adjusted prior to starting the pivotal study  
1.3 
Other Objectives 
To evaluate the following overall and for individual readers for IUS versus Imagio 
(IUS+OA): 
• 
the differentiation between benign versus malignant masses with respect to Imagio 
(IUS+OA) feature scores 
2. 
ENDPOINTS - endpoints to include a separate mammogram analysis 
2.1 
Primary Endpoint 
To evaluate the following overall and for individual readers for IUS versus Imagio 
(IUS+OA):  
• 
the gain in Imagio (IUS+OA) specificity versus IUS for fixed sensitivity (e.g., 98%) 
with specificities interpolated from the respective ROC curve as applicable. 
 

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2.2 
Secondary Endpoints 
To evaluate the following overall and for individual readers for: 
1. the partial ROC AUC corresponding to 95-99% sensitivity with specificities 
extrapolated from the respective Imagio and IUS ROC curves as applicable. 
• 
the observed and model-adjusted specificity and sensitivity   
• 
the Negative Likelihood Ratio (NLR) defined as ((1-sensitivity)/specificity) 
• 
the upgrade and downgrade metrics:  
o the percent correct of downgrades for benign masses from IUS BI-RADS 4a 
to Imagio (IUS+OA) BI-RADS 2-3, and from IUS BI-RADS 3 to Imagio 
(IUS+OA) BI-RADS 2 
o the percent incorrect of upgrades for benign masses from IUS BI-RADS 2-3 
to Imagio (IUS+OA) BI-RADS 4-5 and from IUS BI-RADS 2 to Imagio 
(IUS+OA) BI-RADS 3-4-5 
o the percent of incorrect downgrades for malignant masses from IUS BI-RADS 
4-5 to Imagio (IUS+OA) BI-RADS 2-3; and 
o the percent of correct upgrades for malignant masses from IUS BI-RADS 2-3 
to Imagio (IUS+OA) BI-RADS 4-5. 
2. the Cumulative effect of downgrades and upgrades for combined benign masses and 
malignant masses.    
3. the SenoGram usage: 
• 
Utilization percent reported by the readers 
• 
Sensitivity and specificity discordance with Imagio (IUS+OA) Downgrades and 
upgrades versus Imagio (IUS+OA) and IUS, separately for benign and malignant 
masses 
• 
POM paired differences versus Imagio (IUS+OA) and IUS, separately for benign 
and malignant masses. 
4. the SenoGram performance:  
• 
Sensitivity and specificity compared to sensitivity and specificity estimated from 
cross-validation and hold-out validation. 
• 
Partial AUC for individual users and overall corresponding to 95-99% sensitivity 
• 
Separate assessment of Senogram performance with and without 
mammographic data input. 
2.3 
Exploratory Endpoints 
To evaluate the following overall and for individual readers for IUS versus Imagio 
(IUS+OA): 
• 
Imagio (IUS+OA) feature score distributions for benign versus malignant masses 
 

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3.  
BACKGROUND AND RATIONALE 
The Imagio Feasibility Study is intended to evaluate if a subsequent pivotal study can be 
implemented to test prospective hypotheses for pre-specified effectiveness endpoints 
with an acceptable sample size.  The Feasibility Study will be based on ITD masses 
from the PIONEER Pivotal study to simultaneously reflect the distributions with and 
without mammograms as well as site CDU BI-RADS scores within benign and malignant 
masses as strata. 
4.  
STUDY DESIGN 
This will be a single arm, controlled, blinded, multi-reader, multi-case (MRMC) study 
using a sequential design.  The study will include 5-12 readers depending on 
qualifications and availability. 
Imagio (IUS+OA) Training to be completed prior to any reads taking place.  Read 1 is 
immediately followed by Read 2 within the same read session. 
• 
Read 1 (Control): Mammogram (if available) + History + IUS (stills and videos 
provided), IUS Probability of Malignancy (POM) and BI-RADS scored and the data 
form locked.  
• 
Read 2 (Test): Mammogram (if available) + History + IUS (stills and videos 
provided), and Imagio (IUS+OA) (stills and videos provided).  An interim IUS POM 
and BI-RADS is recorded as well as a combined Imagio (IUS+OA) POM and BI-
RADS Pre and Post SenoGram on separate data forms.    
Read 1 reflects the information available to a radiologist when evaluating standard 
ultrasound images, taking under consideration the mass and patient history and 
assessing mammogram results as available. The History details to be provided are 
summarized under the Blinding section of the protocol. Read 1 (IUS reads) will serve as 
the control representing current clinical practice. Read 2 (IUS+OA) will be considered the 
test read and reflect a pre SenoGram IUS and Imagio (IUS+OA) POM and BI-RADS 
assessment in addition to a post SenoGram IUS and Imagio (IUS +OA) POM and BI-
RADS assessment.  Following the display of the SenoGram within the Post SenoGram 
data form, the IUS and OA feature scores are locked, and the reader is prompted to 
provide a Post SenoGram POM and BI-RADS.  Once the Post SenoGram POM and BI-
RADS are provided, the form is locked.   
A total of 155 complete read sets from the original PIONEER Intention-to Diagnose (ITD) 
population will be randomly selected from within the PIONEER Study.  
• 
Comprising the 155 mass read sets, the first cohort will consist of 75 benign and 45 
malignant masses (reflecting the same 37.5% prevalence of cancer as for the overall 
pivotal ITD population), classified by conventional diagnostic ultrasound (CDU) as BI-
RADS 3 to 5 to be selected at random in proportion to the original assignment 
distribution of BI-RADS classifications among subjects in the PIONEER Study. To 
facilitate the alignment of the PIONEER Pivotal Study data with the Feasibility Study 
data, the mass image set sampling plan will select a proportion with and without 
mammograms depending on availability of the mammograms, separately for benign 
and malignant masses.  Cohort 1 will be used for the effectiveness endpoint 
analyses in support of decision making. The same sampling strategy will be used to 
ensure a comparable proportion of mass image sets as for the PIONEER Pivotal 
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• The second cohort consists of 30 additional malignant masses for which 1 or more 
pivotal study readers scored the mass a false negative during a read from the 
PIONEER study; this will assess if the excess FN rate observed with OA in the 
PIONEER study can be reversed.  
• 
The third cohort will consist of five DCIS, lymphoma, or Phyllodes masses; this will 
assess how these atypical cases will be scored.  Since there are so few of these 
cases, mammogram matching will not be possible.    
This evaluation will further achieve the following: 
1. The incremental contributions of IUS and Imagio (IUS+OA) by assessing the BI-
RADS and POM values at each step in the read order traditionally used in clinical 
practice. 
2. The SenoGram performance versus IUS and versus Imagio (IUS+OA) once IUS + 
OA features are scored with subset evaluation of the effect of presence or absence 
of the mammographic data on Senogram performance. 
The SenoGram is a classification model that predicts the probability that a lesion is 
malignant for a given set of reader-assigned feature scores and other relevant data.  For 
this study, the SenoGram will consist of two components, a user interface and a back-
end computation engine.  The reader will enter feature data into the user interface.  
When all data has been entered, but prior to a final submission of the data, the user 
interface will graphically display the model’s predicted likelihood of malignancy [not to be 
confused with POM].   
 
The SenoGram figure will also display threshold lines that correspond to estimated 
sensitivities of 98%, 98.5%, 99%, and 99.5%, in relationship to the boundaries between 
BI-RADS categories. If the reader changes a feature score, the graphical display will 
automatically update with the revised prediction.  The reader may optionally modify his 
or her BI-RADS and POM assignments based on the SenoGram predication; however, 
there is no requirement to do so.  The use of the SenoGram result in decision making 
will be recorded for each reader for each image mass set evaluated.  The SenoGram is 
trained on cases not selected for any Cohort of this study. 
5.  
SELECTION OF READERS  
5.1 
Reader Qualification Criteria  
• 
Completed residency and are board certified in radiology 
• 
Active breast imager for at least 3 years.  
• 
Readers to meet mammography interpretation requirements per mammography 
Quality Standards ACR (MQSA) for the year prior to study.  
• 
Readers to meet breast imaging ultrasound interpretation requirements per ACR. for 
year prior to study. 
• 
For the clinical study, a willingness to use BI-RADS 4 sub categories 
• 
For the clinical study, the ability to participate and read all masses in both IUS and 
OA/US reader sessions. 

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5.2 
Reader Training 
Imagio (IUS+OA) Training Summary Reader 01 Study  
 
1.     Didactic training module (4 hours) 
a) Fundamentals of OA (Questions and Answers) 
b) OA feature scoring (Questions and Answers) 
c) OA-histologic correlation (Questions and Answers) 
d) OA artifacts and Scan Techniques (Questions and Answers) 
e) IUS feature scoring, including Importance of BI-RADS 4 subcategories, NLR and 
Bayes Theorem (Questions and Answers) 
f) Pivotal Study False Negative and False Positive analysis (Questions and 
Answers) 
g) The SenoGram and How to Use It 
h) Summary (final questions and comments) 
2.    Interactive reading case module (estimate 5 cases per hour, 4-6 hours) 
a) Mixture of benign and malignant enriched to 50% malignant 
b) Mixture of cases with good, average, and below average reader performance – 
will start with easy cases, move to average cases, and finish with most difficult 
cases 
c) Some malignant masses that caused false negative Pivotal study OA reads 
d) Readers will learn to use reading station, draw ROIs, score features, and use the 
OA and combined OA-IUS SenoGrams to predict OA POM and BI-RADS 
category and downgrade 
e) Each case will be read and scored by trainees, and then the Seno instructor will 
review how and why he/she would score the case, and finally review the 
histology and discuss concordance or discordance of OA feature scoring with the 
histology. 
3.   Test Cases - 30 (7.5 hours) 4 cases an hour 
a) Mixture of benign (18) and malignant (12) masses, same prevalence as overall 
Pivotal ITD population 
b) Mixture of easy, average, and difficult cases based upon Pivotal study reads 
c) Some masses that caused false negative pivotal study Imagio (IUS+OA) reads 
4.  Pass / Fail criteria  
Readers reading must pass a proficiency test before starting their study reads.  If this 
is not achieved the first time the reader takes the test, the reader will be given 
targeted remediation training to their deviations and a second opportunity to take the 
test on a different set of test cases. The reader will proceed to read cases whether or 
not they pass the second test. If they fail the second test, remediation will take place 
before they start the study reads.  

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6.  
SELECTION OF READER SETS 
6.1 
Inclusion Criteria  
Reader sets must meet all the following inclusion criteria to be included in this study: 
• 
One analyzable mass per patient  
• 
DCIS, lymphoma, and phyllodes masses to be looked at separately 
• 
BI-RADS 3 and 4a, 4b, 4c and 5 masses as declared by clinical site investigator via 
PIONEER study conventional diagnostic ultrasound (CDU)  
• 
Masses declared to be ITD 
• 
Evaluable mammograms for a percentage of cases 
• 
Patient age, indication and history available 
• 
Evaluable OA and IUS video loops and stills     
6.2 
Exclusion Criteria 
Reader sets must be excluded if any of the following criteria are met: 
• 
Critical missing views for mammogram cases, IUS or OA stills and video that would 
preclude case from being evaluated by readers 
• 
Mammogram, IUS or Imagio (IUS+OA) image quality inadequate due to error in 
labeling or positioning or acquisition technique 
• 
Masses from multiple mass cases incorrectly labeled.  
• 
Reader training cases 
6.3 
Reader Set Selection Procedure  
• 
BBRF will select the mass sampling strategy taking training cases and cohort 
requirements into consideration 
• 
BBRF will prepare the mass read order for Part 2 of the study. 
• 
All image sets will be de-identified. 
7.0    READER STUDY PROCEDURES  
7.1 
Reader Study Process Work Flow 
Figure 1 below illustrates, at a high level, the central reader study process flow. Seno 
Medical will electronically transfer image sets to ACR-CRI. Upon receipt of the images at 
ACR CRI, imaging support staff will upload images to Transfer of Images and Data 
[TRIAD], ACR’s electronic image submission tool.  
The images automatically undergo a de-identification process in TRIADTM, whereby all 
personal identifier DICOM tags in the image metadata are de-identified according to 
TRIADTM’s anonymization profile. If any personal identifiers are burned into exams 
received, ACR CRI staff will remove that by pixel cleaning. ACR-CRI imaging 
technologists will first perform quality control (QC-1) to document an inventory of all 
exams and their attributes.   

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ACR-CRI contracted multiple mass quality control reviewer will assess the image sets 
(QC-2) for inclusion by identifying and labeling Mass 1 on all modalities submitted for a 
given subject case where multiple masses are present. The acceptable image sets from 
the ACR QC (QC-1 and QC-2) process will be approved by BBRF and considered ready 
for central read.  
BBRF will generate the study mass randomization scheme for the study.  
The QC-1 and QC-2 checks will be documented in study specific procedure documents 
and outputs of such checks documented on study specific forms, all of which will be 
archived in an electronic Trial Master File (eTMF) and ACR CRI clinical databases. 
ACR research staff serving as read monitors will be present during read sessions to 
ensure the read sequence is maintained, eCRFs are fully completed by the reader, 
cross-check the assigned read list with completed eCRFs and assist in any workstation-
related questions. The read monitors will relay any issues they cannot resolve to the 
ACR Project Manager for remediation. 
For the Feasibility Reader Study, a manual process of data entry will be performed. In 
order to maximize both workflow efficiency and data integrity, this process will be 
achieved by using the combination of the reader and a read monitor, working together as 
a team.  Both the reader and the read monitor will be trained on the data entry process 
prior to production subject case assessments.  The process of data entry is outlined 
below.  
1. Read monitor calls out the Read ID to be reviewed based on the provided Reader 
Work List.  The reader opens the Subject image case in the image viewing 
workstation. The read monitor opens the Subject eCRF case in the Rave Electronic 
Data Capture (EDC) Database. The reader calls out the Subject ID for the opened 
case as confirmation that it corresponds to the Subject ID opened in the eCRF 
database by the read monitor. 
2.   Reader performs the specified subject’s image review using the designated 
Workstation and following assessment criteria as trained on for this study.   
3. Read monitor prepares to perform data entry for the specified subject. 
4. When the reader is ready to provide the data for data entry, the reader verbally 
notifies the read monitor. 
5. The reader verbally provides the answers to each of the eCRF required field entries. 
6. As the read monitor performs the manual data entry for each of the sequential fields 
directed by the flow of the eCRF, the read monitor verbally calls out their entry which 
is then verbally confirmed (or corrected, as necessary) by the reader. 
7. This process will be repeated until all the appropriate fields for each of the required 
eCRFs are completed. 
The reader electronically signs off on the data for a subject case at the completion of 
his/her review. It is understood that the commitment of a reader’s electronic signature on 
the eCRF signifies that the assessment of the corresponding randomization ID is 
complete and accurate and is an attestation that no changes/edits need to occur.  

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The read monitor should be attuned to reader performance and suggest breaks as 
necessary to avoid reader fatigue.   
As per the image review and data entry workflow described in this Protocol, once a 
subject scan review is completed by a reader, the reader provides their electronic 
signature and the eCRF is ‘locked’, preventing further changes. 
Upon completion of all central read assessments by all readers, ACR-CRI will transfer 
the readers’ results to Seno Medical’s portal. BBRF will have access to the portal for 
purposes of conducting the statistical analyses. 
Figure 1: Reader Study Work Flow 
Reader Study Process Workflow
ACR
Seno Medical
START
Select transfer 
images to ACR
ACR receives 
images
ACR pushes images 
to multiple readers
QC-1: 
image set 
complete?
YES
Provide 
randomization 
scheme
Readers record 
findings in 
Rave / CTMS - 
Senogram
QC-2: 
inclusion / 
exclusion criteria 
met?
NO
Document 
on QC Form
YES
Complete 
QC Form
Systems to be used:
• Rave (CTMS)
• Triad to local database 
(viewer – protocol / modality 
dependent)
• Four databases to support 
randomization scheme 
ACR transfers 
reader results to 
Seno Portal
Reader results 
in Seno Portal 
BBRF accesses 
Seno Portal to 
perform statistical 
analyses 
COMPLETE
Reader Study 
Report
Document 
on QC Form
NO
 
7.2 
Schedule of Reader Sessions 
All reads will include standard reader training on an image viewing workstation, eCRF 
completion, etc.  
 
Imagio (IUS +OA) training and a proficiency test will take place prior to the start of all 
study reads.  
 
 

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7.3 
Description of Reading Environment  
After completion of standard training and Imagio (IUS+OA) training, each of the readers 
will use an image display and electronic data capture workstation to perform image 
analysis, working alongside an ACR Read Monitor, for all reading sessions. Each reader 
and read monitor will be in a designated, private reading room for their use during a 
reading session. Readers will work undistracted so that their attention is focused on an 
accurate interpretation. The workstation desk will have adjustable height for reader 
comfort, the room will be equipped with noise abatement features, diagnostic display 
monitors and moderate illumination. As part of reader training and as documented in the 
confidentiality agreement they sign during the ACR CRI contracting process, readers will 
be aware and monitored to maintain confidentiality on study details and subject images 
reviewed. Access to the reading rooms is controlled and read monitors ensure readers 
do not take any unauthorized material into the reading rooms. 
7.4 
Graphical Interface for BI-RADS Category and POM Rating; 
For the purpose of this study, the Readers will use a graphical interface to indicate their 
assessment of the BI-RADS category and POM rating for IUS and Imagio (IUS+OA) 
modalities (see Figure 2).   
The POM scale is linear for all BI-RADS categories; however, the scale for BI-RADS 3 is 
expanded ten-fold compared to other categories.  This design allows for a finer gradation 
of the malignancy rating for BI-RADS 3 lesions, which in turn provides more data points 
for the ROC curve and enables a better estimation of the partial AUC.    One advantage 
of a graphical metaphor is that it provides an aid to the Reader in converting the BI-
RADS feature lexicon to a numerical POM scale. 
 
Figure 2.  Graphical input of BI-RADS category and POM rating. 
7.5 
Randomization 
 BBRF will generate the randomized study read list. 
 
7.6 
Blinding 
The readers will be blinded to the diagnosis, but the reader will have access to the 
following baseline variables: 
• 
Age 
• 
Indication (reason study was ordered) 
• 
Mass location   
• 
Medical History 
• 
Mammograms (if available) 

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8.  
SAFETY ASSESSMENTS  
Safety assessments are not required as this is a reader study of de-identified Imagio 
(IUS+OA) and IUS images. No patient diagnoses are affected by the reader sets or this 
MRMC study.    
9.  
STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  
BBRF will implement the Feasibility Study sampling plan to represent the PIONEER 
Pivotal Study masses to reflect mammography use and site CDU BI-RADS score.   
BBRF will determine which masses are to be assigned to each cohort; Cohorts 1-3 will 
be the same across all readers.   
The unit of measurement for reader-based outcomes is at the reader-mass level. The 
Feasibility Study will be used to assess if independent readers can conduct pre-specified 
POM evaluations separately for IUS and then for Imagio (IUS+OA) and the Senogram to 
evaluate the primary and secondary effectiveness endpoints.  Pre-specified POM 
evaluations will be performed separately for IUS, Imagio (IUS+OA), and the reader use 
of the SenoGram to evaluate the Imagio (IUS+OA) and SenoGram specificities and 
sensitivities.  
The primary endpoint is to show a specificity advantage for fixed sensitivity; this diffuses 
the tradeoff between FNs and FPs if the FN rate is the same.  These sensitivity and 
specificities will be calculated overall and per reader using generalized estimating 
equations (GEE) and the analysis of variance (ANOVA) modeling as well as for 
observed without adjustment.   
For each endpoint, Imagio will be compared versus IUS; the same analyses will be 
performed for the SenoGram versus IUS and Imagio.   
The specificity advantages will be computed for fixed sensitivity (e.g. 98% target) with 
interpolation or extrapolation used by calculating the specificities and sensitivities from 
the ROC curve as needed.  This same principle will be used to construct the partial ROC 
curves and to compute the area under the ROC curve to correspond to 95-99% 
sensitivity. 
The results from the Feasibility Study will be used to judge if there is sufficient rationale 
to proceed to a pivotal study involving more masses and more readers to support the 
indications for use.  If there is sufficient strength of the data, then the Imagio Feasibility 
Study results will be used to determine the pivotal study sample size.  The effect sizes 
will be assessed to judge if the pivotal study can be conducted with at least 80% power 
for two-sided hypothesis testing with 5% Type I error; this depends on the effect sizes 
achieved for the primary and secondary effectiveness endpoints as well as inter-reader 
variabilities.   
Feasibility Study data will not be used or combined with any subsequent pivotal study 
data, but the same masses used in the Feasibility Study may be used in the subsequent 
pivotal study.   
The Feasibility Study will not test any formal statistical hypotheses but will be used to 
formulate hypotheses to be formally tested in the pivotal study.  

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A move forward decision will be made based on the collective performance of the 
primary and secondary effectiveness endpoints using Cohort 1 (75 benign masses and 
45 malignant masses). Cohort 2 will give separate confidence that training has helped to 
reduce FNs.  Cohorts 1, 2 and 3 will be analyzed separately. 
9.2 
Reader Set Sample Size  
This Imagio Feasibility Study is not powered but should be more than adequate to 
estimate effect sizes to power the subsequent pivotal study.   
Every effort will be made to identify missing reads and to provide readers with the 
opportunity to read all 155 image sets which includes the two additional cohorts:  
• 
Cohort 1: 120 masses (75 benign, 45 malignant) to represent the PIONEER 
study 
• 
Cohort 2: 30 additional malignant masses with FNs 
• 
Cohort 3:  5 DCIS, lymphoma and phyllodes masses.  
All reads will be included in all analyses, consistent with an “intention to diagnose” 
approach.  
9.4  
Population Definition 
The original PIONEER Intention-to-diagnose classification will be used. Images will be 
selected for use in accordance with the study protocol inclusion and exclusion criteria. 
9.5 
Interim Analyses 
An interim analysis of the data is planned to follow a completion of a minimum of 72 
completed Cohort 1 mass reads by each reader in Part 2 to assess intermediate 
performance results. 
9.6 
Protocol Deviations 
The study data will be evaluated for major and minor protocol deviations. This will be 
limited to missing and incomplete reads from the Feasibility Study.   
At study completion, the number and type of protocol deviations will be analyzed by the 
study biostatistician to review the events by reader to determine whether there are 
statistical concerns. The biostatistician will report findings to the study sponsor.  
The findings will be used to improve the pivotal study design in the event that the pivotal 
study is to proceed. 
9.7 
Outcomes  
Outcomes will be analyzed according to the PIONEER Truth Panel findings and the 
pathology diagnosis (if available) as truth; Truth Panel Benign (TPB) will be a benign 
diagnosis.  The final analyses will be performed following database lock.  
9.8 
Data Analyses 
All analyses will be performed in a GCP-controlled environment using SAS v9.3 or 
higher and StatXact v10 or later unless otherwise specified. 

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All significance testing will be two-sided; results will be presented using two-sided p-
values and two-sided 95% confidence intervals.  All p-values are considered to be 
descriptive. 
Methods of analysis for the MRMC design will be analyzed treating readers as random 
effects and treatment and masses as fixed effects and also by MRMC analysis methods 
by Obuchowski and Rockette where both reader and mass are random effects (see 
references). Two-sided 95% confidence intervals will be computed for the Imagio 
(IUS+OA) as well as Imagio (IUS+OA) - versus IUS differences in ROC AUC and the 
differences in downgrade and upgrade percentages separately for benign and malignant 
masses. The same analyses will be performed for the SenoGram versus IUS and versus 
Imagio (IUS+OA).  These outcomes will be used to guide decisions regarding pivotal 
study design.    
For each endpoint, Cohort 1 subgroup analyses will be performed in the same manner 
for those with a prior mammogram as well as for those without a prior mammogram. 
1. Sensitivity, Specificity, Partial ROC AUC, and Specificity for Fixed Sensitivity 
Individual reader specificity and sensitivity will be calculated from simple counts for 
POMs to construct the respective ROC curves for IUS, the Imagio (IUS+OA) and the 
SenoGram.  GEE and ANOVA will be used to describe overall specificity and sensitivity 
as well as to compute the two-sided 95% confidence intervals for the OA-IUS differences 
for sensitivity and for specificity. 
The specificity advantage for fixed sensitivity will be the primary endpoint.  It will be 
computed from the respective ROC curves which are generated according to the POMs 
corresponding to the 95-99% sensitivity range.  To compute the specificity advantage for 
fixed sensitivity, interpolation may be required; a fixed sensitivity will be targeted, e.g., 
98%.  To compute the specificity advantage and the partial area under the ROC, the 
specificities and sensitivities may need to be further computed from the ROC curves as 
needed.  The McClish method will be used to analyze and compare the partial ROC 
curves.  The variances will be computed to construct the two-sided 95% CIs for Imagio 
(IUS+OA), IUS, and for the Imagio (IUS+OA) -IUS difference.  The same analyses will 
be performed for the SenoGram versus IUS and versus Imagio (IUS+OA). 
In addition, the interpolation and the corresponding variance estimate will also permit the 
calculation of the specificity difference for fixed sensitivity (e.g. 98%) as well as the two-
sided 95% confidence interval for the difference.     
2. Upgrades and Downgrades 
Separately for benign + TPB masses and malignant masses, downgrades and upgrades 
will be jointly assessed for each diagnostic category using a McNemar paired 
comparison test for Imagio (IUS+OA) versus IUS.  In addition, two-sided 95% confidence 
intervals will be computed for the OA-IUS differences for both specificity and sensitivity; 
superiority will be sought for specificity while non-inferiority will be sought for sensitivity. 
Refer to Table 1 below. 
 
 

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Table 1: Upgrades and Downgrades 
 
Imagio (IUS+OA) Clinical 
Significance Criteria 
Imagio (IUS+OA) Statistical 
Significance Criteria 
Benign + TPB Downgrades 
BR4a→BR2-3; BR3→BR2 
Establish an advantage 
Benign + TPB Upgrades 
BR2-3→BR4-5; BR2→BR3-4-5 
Rule out a disadvantage 
Malignant Upgrades 
BR2→BR4-5; BR3→BR4-5 
Establish an advantage 
Malignant Downgrades 
BR4→BR2-3; BR5→BR2-3 
Rule out a disadvantage 
Supporting descriptive statistics will be computed as follows for the correct downgrades 
and incorrect upgrades for benign masses. Refer to Table 2 below. 
Table 2: Correct Downgrades and Incorrect Upgrades 
 Imagio (IUS+OA) Outcome  
(IUS→Imagio) 
Benign + TPB Masses 
BR4a→BR3 
% (IB3/IB4a) 
BR4a→BR2 
% (IB2/IB4a) 
BR3→BR2 
% (IB2/IB3) 
Correct Downgrade 
% (IBN/IBD) 
 Imagio (IUS+OA) Outcome 
(IUS→Imagio) 
Benign + TPB Masses 
BR2→BR3+ 
% (IB3-5/IB2) 
BR3→BR4a+ 
% (IB4-5/IB3) 
Incorrect Upgrade 
% (IBN/IBD) 
Supporting descriptive statistics will be computed as follows for the correct upgrades and 
incorrect downgrades for malignant masses.  Refer to Table 3 below. 
Table 3: Correct Upgrades and Incorrect Downgrades 
 Imagio (IUS+OA) Outcome 
(IUS→Imagio) 
Malignant Masses 
BR2→BR4-5 
% (IC4-5/IC2) 
BR3→BR4-5 
% (IC4-5/IC3) 
Correct Upgrades 
% (ICN/ICD) 
 Imagio (IUS+OA) Outcome 
(IUS→Imagio) 
Malignant Masses 
BR4->BR2-3 
% (IC2-3/IC4) 
BR5->BR2-3 
% (IC2-3/IC5) 
Incorrect Downgrades 
% (ICN/ICD) 

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To assess the cumulative effect of downgrades and upgrades for combined benign 
masses and malignant masses, a net gain will be computed for downgrades and 
upgrades. The net gain will be computed in SAS according to contrast statements for the 
ANOVA models to simultaneously analyze reader and mass.  The weight (W) of the 
malignant outcomes (TP and FN) will be computed to determine the value (A-B+W(C-D)) 
that achieves statistical significance.  The same analyses will be performed for the 
SenoGram versus IUS and versus Imagio. Refer to Table 4 below. 
Table 4: Net Gain 
 
 Imagio (IUS+OA) Relative to IUS 
Benign Masses Picked Up 
A 
Benign Masses Lost 
B 
Malignant Masses Picked Up 
C 
Malignant Masses Lost 
D 
Numeric Gain 
A-B+C-D 
3. Move Forward Criteria 
The move forward criteria will be dependent on data from the above endpoints.  As 
illustration, the following criteria would justify conducting the Pivotal Study: 
• 
An Imagio (IUS+OA) specificity advantage versus IUS for fixed sensitivity;   
• 
An Imagio (IUS+OA) specificity advantage with a minimal OA sensitivity 
disadvantage;  
• 
An Imagio (IUS+OA) advantage for benign mass downgrades with a minimal 
Imagio (IUS+OA) disadvantage for malignant mass upgrades.  
The same analyses will be performed for the SenoGram versus IUS and versus Imagio.  
Depending which criteria are selected for inclusion as pivotal study primary endpoints, 
the pivotal study will be designed to have 80% power with two-sided 5% Type I error; 
there are 1,757 masses available from the PIONEER Pivotal Study. 
4. NLR 
The NLR ((1-sensitivity)/specificity) will be computed using the standard formula with 
two-sided 95% CIs computed using exact 2x2 contingency table methods.  A two-sided 
95% CI for the NLR <1 and favoring OA will indicate improvement in NLR; the relative 
NLR will also be computed relative to IUS. The same analysis will be performed for 
SenoGram versus IUS and versus Imagio (IUS+OA). 
5. Graphical Displays 
The BI-RADS findings for Imagio and SenoGram will be displayed separately for benign 
masses using three separate scales (0-2%, 2-50%, 50-100%) to better represent reader 
opinions and Senogram outcomes.  The 0-2% scale will be on an expanded scale to 
allow the readers to more precisely identify the respective POM for Imagio and likelihood 
of malignancy for the SenoGram. 

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10.  
DATA COLLECTION AND QUALITY ASSURANCE 
10.1 
Data Management  
Independent read data for this study is populated in Medidata Rave EDC System via 
direct data entry during read sessions from readers and read monitor staff. Electronic 
data collection forms in Rave will be built during study start-up and designed to meet 
study aims and statistical analysis needs. Electronic case report forms are created 
based on the study protocol, ACR-CRI scope of work statement, contract, data flows, 
and data collection needs. The ACR-CRI Data Manager will ensure the eCRFs are 
tested appropriately, maintain proper version control and all internal and 
external/Sponsor stakeholders approve the content prior to finalization. 
10.2 
Quality Assurance  
10.2.1 Training 
Reader training will be provided as described in section 5.2 above. 
10.2.2 Quality Control  
Monitoring of the readers will be done by ACR in accordance with the procedures 
outlined under the Reader Study Process Work Flow Section of the protocol and the 
Independent Review Charter. 
10.3.4 Monitoring 
Monitoring methods for assuring data quality for each reader, accurate qualification of 
each reader and reader responsibilities during the read process will be documented in 
the Independent Review Charter. 
11.  
PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 
Informed Consent Forms 
Not applicable for this study.  
11.2 
Participant Confidentiality  
Reader sets will be de-identified to maintain PIONEER study participant’s confidentiality 
according to the Health Insurance Portability and Accountability Act (HIPAA), any special 
data security requirements as stipulated by participating readers, and record retention 
per the sponsor’s requirements. 
Any data, forms, reports, video recordings, and other records that the participating 
reader receives from the sponsor will be identified only by a participant identification 
number (Participant ID, PID) from the PIONEER study to maintain confidentiality. All 
records will be kept in a locked file cabinet. All computer entry and networking programs 
will be done using PIDs only. Information will not be released without written permission 
of the participant, except as necessary for monitoring by the FDA. 
11.3 
Study Discontinuation  
The study may be discontinued at any time by the sponsor for futility or by FDA, or other 
government agencies as part of their duties to ensure that research participants are 
protected. 

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12.  
PUBLICATION OF RESEARCH FINDINGS 
Any presentation, abstract, or manuscript will be made available for review by the 
sponsor prior to submission. 
Study results may be published in support of reimbursement.   
Seno will review and approve all manuscripts.   
13.  
REFERENCES  
1. Dorfman, D.D., Berbaum, K.S., & Metz, C.E. (1992). Receiver operating 
characteristic rating analysis: Generalization to the population of readers and 
patients with the jackknife method. Investigative Radiology, 27, 723-731. 
2. Obuchowski, N.A., & Rockette, H.E. (1995). Hypothesis testing of diagnostic 
accuracy for multiple readers and multiple tests: An ANOVA approach with 
dependent observations. Communications in Statistics-Simulation and Computation, 
24, 285-308. 
3. Hillis, S.L., Obuchowski, N.A., Schartz, K.M., & Berbaum, K.S. (2005). A comparison 
of the Dorfman-Berbaum-Metz and Obuchowski-Rockette methods for receiver 
operating characteristic (ROC) data. Statistics in Medicine, 24, 1579-1607 
DOI:10.1002/sim.2024. 
4. Hillis, S.L. (2007). A comparison of denominator degrees of freedom for multiple 
observer ROC analysis.  Statistics in Medicine, 26:596-619 DOI:10.1002/sim.2532.  
5. Hillis, S.L., Berbaum, K.S., & Metz, C.E. (2008). Recent developments in the 
Dorfman-Berbaum-Metz procedure for multi-reader ROC study analysis. Academic 
Radiology, 15, 647-661. DOI:10.1016/j.acra.2007.12.015.  
 
 

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14. 
VERSION HISTORY 
Version 
Date 
Description of Changes 
1 
27 June 
2018 
Original protocol 
2 
24 Sept 
2018 
Section 1.1 - Primary Objectives - revised to include  
1. To select the effectiveness endpoints and determine the 
corresponding sample size required for the Pivotal study. 
2. To evaluate the gain in Imagio (Imagio Internal Ultrasound 
[IUS] + Opto-acoustic [OA]) specificity versus IUS controlling 
for sensitivity 
CDU benchmark classification objectives were removed. 
Section 1.2 - Secondary Objectives- revised to include: 
• 
the Imagio (IUS+OA) partial Receiver Operator Characteristic 
(ROC) Area under the Curve (AUC) corresponding to the IUS 
sensitivity over 95-99% sensitivity 
• 
the sensitivity and specificity for Imagio (IUS+OA) versus IUS 
according to multiple models for readers and masses used for 
assessing sources of variation 
• 
 the Negative Likelihood Ratio (NLR) for IUS versus Imagio 
(IUS+OA). 
• 
Imagio (IUS+OA) downgrades and upgrades relative to IUS for 
benign and malignant masses 
• 
the net gain (new True Positives [TP] + new True Negatives 
[TN] – new False Positives [FP] – new False Negatives [FN]) 
estimate of Imagio (IUS+OA) versus IUS combining benign 
and malignant masses.   
• 
the usage and performance of the SenoGram model for the 
purposes of determining whether it will be adjusted prior to 
starting the pivotal study  
Section 1.3 - Other Objectives- revised to include: 
To evaluate the following overall and for individual readers for IUS 
versus Imagio (IUS+OA): 
• 
the differentiation between benign versus malignant masses 
with respect to  Imagio (IUS+OA) feature scores 
Section 1.3 - Other Objectives- revised to include: 

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Version 
Date 
Description of Changes 
2, cont. 
24 Sept 
2018 
To evaluate the following overall and for individual readers for IUS 
versus Imagio (IUS+OA): 
• 
the differentiation between benign versus malignant masses 
with respect to  Imagio (IUS+OA) feature scores 
Section 2.1 - Primary Endpoints - revised endpoints to correspond 
to objectives 
Section 2.2 - Secondary Endpoints - revised endpoints to 
correspond to objectives 
CDU benchmark classification endpoints were removed. 
Section 2.3 – Exploratory Endpoints – revised endpoints to 
correspond to objectives and added mammography endpoint 
Section 4 – Study Design- modified to sequential design.  5 -10 
readers to read both Part 1 and 2 of the study with a minimum 30-
day wash-out period in between 
SenoGram- language added:  “When all data has been entered, 
but prior to a final submission of the data, the user interface will 
graphically display the model’s predicted likelihood of malignancy 
[Not to be confused with POM].  The SenoGram figure will also 
display threshold lines that correspond to estimated sensitivities of 
98%, 98.5%, 99%, and 99.5%, in relationship to the boundaries 
between BI-RADS categories.  
“Critically, the SenoGram is trained on cases not selected for 
Cohort 1 of this study”. 
Section 5.1 Reader Qualification Criteria 
Removed criteria “ that is at least 70% breast imaging” 
Added criteria:  Ability to participate and read all masses in both 
IUS and OA/US reader sessions 
Section 5.2 – Reader Training – revised and re-ordered training 
sections adding Question and Answer sections 
Part 4 revised to: 
Readers reading Part 2 must pass a proficiency test before starting 
their Imagio (IUS+OA) reads.  If this is not achieved the first time 
the reader takes the test, the reader will be given targeted 
remediation training to their deviations and a second opportunity to 
take the test on a different set of test cases.  If the reader does not 
pass the second time, they will be dropped from the study 
participation and not continue with Part 2 reads. In the case of 
dropped readers that do not pass the proficiency test or 
discontinue the study for any other reason (e.g., illness, personal 
emergency), then the IUS data for those readers will be analyzed 
separately. 

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Version 
Date 
Description of Changes 
2, cont. 
24 Sept 
2018 
Section 6.2 Exclusion criteria 
Exclusion criteria modified to: 
• 
Critical missing views for mammogram cases, IUS or OA stills 
and video that would preclude case from being evaluated by 
readers 
Section 6.3 Reader Set Selection Criteria  
The following was added: 
• 
BBRF will prepare the mass read order for Part 2 of the study. 
Section 7.1 Reader Study Process Work Flow 
The following language was modified to read: 
“The images automatically undergo a de-identification process in 
TRIADTM, whereby all personal identifier DICOM tags in the image 
metadata are de-identified according to TRIADTM’s anonymization 
profile. If any personal identifiers are burned into exams received, 
ACR CRI staff will remove that by pixel cleaning. ACR-CRI 
imaging technologists will first perform quality control (QC-1) to 
document an inventory of all exams and their attributes.  ACR-CRI 
contracted multiple mass quality control reviewer will assess the 
image sets (QC-2) for inclusion by identifying and labeling Mass 1 
on all modalities submitted for a given subject case where multiple 
masses are present. The acceptable image sets from the ACR QC 
(QC-1 and QC-2) process will be approved by BBRF and 
considered ready for central read. 
BBRF will generate the study’s mass randomization scheme for 
Part 2 of the study.  Masses will be randomized separately for Part 
1 and Part 2 to keep readers blinded to the fact that they are 
reading repeat cases. The QC-1 and QC-2 checks will be 
documented in study specific procedure documents and outputs of 
such checks documented on study specific forms, all of which will 
be archived in an electronic Trial Master File (eTMF) and ACR CRI 
clinical databases.” 
“BBRF will generate the study’s mass randomization scheme for 
Part 2 of the study”. 
Section 7.2 Schedule of Reader Sessions 
Section 7.2 was modified to accommodate 2 parts to study: 
Part 1 will include standard reader training on an image viewing 
workstation, eCRF completion, etc. There will be a minimum 30-
day wash-out period in between the reader’s last part 1 read 
session and the reader’s start of part 2 read sessions. 

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Version 
Date 
Description of Changes 
2, cont. 
24 Sept 
2018 
Part 2 will include Imagio (IUS+OA) training and a proficiency test. 
The same 5-10 study readers from Part 1, will read Part 2   If a 
reader fails the proficiency test and re-test, they will be dropped 
from the study at that time. 
Section 7.3  Description of Reading Environment 
The first sentence was modified to: 
After completion of standard training and Imagio (IUS+OA) training 
(as applicable), each of the readers will use an image display and 
electronic data capture workstation to perform image analysis, 
working alongside an ACR Read Monitor, for all reading sessions. 
Section 7.4 Randomization 
The following sentence was modified to: 
BBRF will generate randomized mass list for Part 2 of the study.   
Section 7.5 Blinding 
• 
Mammograms (if available) was added 
Section 9 – Statistical Considerations was rewritten to 
accommodate revised study objectives and endpoints 
Section 9.1 General Design Issues 
Modified to accommodate revised objectives and endpoints 
Section 9.5 Interim Analyses 
The following sentence was modified to: 
An interim analysis of the data is planned to follow a completion of 
a minimum of 72 completed Cohort 1 mass reads by each reader 
to assess intermediate performance results. 
Section 9.6 Protocol Deviations 
The following sentence was modified to:  
The study data will be evaluated for major and minor protocol 
deviations. This will be limited to missing and incomplete reads 
from the Feasibility Study.   
Artifact reference was removed. 
Section 9.8 Data Analyses 
This section was modified to accommodate the revised study 
objectives and endpoints 
Multiple formatting and administrative changes were made 
throughout the document 

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Version 
Date 
Description of Changes 
3 
01Nov2018 
Protocol Cover Page - Indication for Use, modified to: 
The Imagio™ breast imaging system is indicated for use by a 
trained and qualified healthcare provider for evaluation of breasts 
in women who are referred for a diagnostic breast work-up 
(including both palpable and non-palpable masses), following 
clinical presentation, mammography, diagnostic, screening, or 
staging methodology.  In ultrasound mode, the device can be used 
to assess BI-RADS1-6.  For BI-RADS 3-5 lesions, the ultrasound 
mode should be initially used to assess the lesion before moving to 
OA. In Opto-Acoustic (OA) mode, the Imagio™ provides 
information about the central nidus, boundary and peripheral 
zones to assist in the assessment of BI-RADS category and 
diagnosis of the benign or malignant lesion(s) of interest. Using OA 
and the corresponding features of the lesion(s) allows for improved 
classification of the mass of interest as compared to ultrasound 
alone in BIRADS 3-5 masses. 
Section 1.2 Secondary Objectives, modified first bullet to: 
• 
the Imagio (IUS+OA) partial Receiver Operator Characteristic 
(ROC) Area under the Curve (AUC) for 95-99% vs IUS for 95-
99% sensitivity 
• 
Deleted last bullet: the graphical display of BI-RADS 2-3 
findings on expanded scales for the purposes of demonstrating 
Imagio and SenoGram benefit for downgrading benign masses 
Revised : 2. ENDPOINTS - endpoints to include a separate 
mammogram analysis 
Section 2.1 Primary Endpoint, modified to: To evaluate the 
following overall and for individual readers for IUS versus Imagio 
(IUS+OA) 
Section 2.2 Secondary Endpoints 
Item 2 modified to: the Cumulative effect of downgrades and 
upgrades for combined benign masses and malignant masses 
Item 3 – Senogram Usage: modified to Sensitivity and specificity 
discordance with Imagio (IUS+OA) 
Section 4 Study Design: this section was revised to reflect the 
changes to the study design. 
Section 5.1 Reader Qualification: this section was revised to reflect 
less stringent qualification criteria. 
Section 5.2 Reader Training:  
Item 1 – Didactic Training: deleted review of previous studies 
(PIONEER and MASETRO) 

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Version 
Date 
Description of Changes 
3, cont. 
01Nov2018 
Item 4 – Pass / Fail Criteria: this section was modified to reflect 
change in pass/fall criteria 
Section 7.1 Reader Study Process Work Flow, modified third 
paragraph to: BBRF will generate the study mass randomization 
scheme for the study. 
Section 7.2 Schedule of Reader Sessions: this section was revised 
to reflect the changes in the study design. 
Section 7.4 Graphical Interface for BI-RADS Category and POM 
Rating: this section was modified to clarify its usage in the study 
Section 7.5 Randomization, modified to BBRF will generate the 
randomized study read list. 
Section 9.8 Data Analyses, added: item 5 Graphical Displays 
Multiple formatting changes and typo corrections throughout the 
document