"Early R&D Clinical Evaluation of Opto-Acoustic Tomography for Detection and Diagnostic Differentiation of Thyroid Nodules"
Phase: NA
Conditions: Feasibility Study for Thyroid Indication
Sponsor: Seno Medical Instruments Inc.

 
 
 
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Thyroid Protocol:  
 
 
 
 
 
Title: 
“Clinical Evaluation of Opto-Acoustic Tomography for  
Detection and Diagnostic Differentiation of Thyroid Nodules” 
 
Protocol Number: 
Thyroid-01 
 
 
Device: 
Imagio™ Imaging System  
 
 
 
Sponsor: 
Seno Medical Instruments, Inc. 
 
 
 
Sponsor Contact: 
Shaan Schaeffer 
Vice President of Clinical Operations 
Seno Medical Instruments, Inc. 
5253 Prue Road, Suite 315 
San Antonio, TX  78240 
210-615-6501 
 
 
 
 
 
 
Date:  2/6/2018 
 
Thyroid Protocol Version 10.0 
 
 
 
 
 
 
Confidentiality Statement 
 
This document contains information that is the property of Seno Medical Instruments Inc. 
and therefore is provided to you in confidence for review by you, your staff, an applicable 
Institutional Review Board and regulatory authorities. It is understood that this information 
will not be disclosed to others without written approval from Seno Medical Instruments Inc., 
except to the extent necessary to obtain informed consent from those persons to whom 
Imagio may be administered. 
 

 
 
 
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REVISION HISTORY 
Version:   2.0   Date:  12/7/2016 
 K. Imler changed to P. Taige as sign off for 
Regulatory 
Section 6.2  corrected “breast” to thyroid 
Removed section 6.3 as it applies to breast 
 
Version:  3.0   Date:  1/12/2017 
T. Umbel added   to replace P. Taige as sign off  
Section 3.2 – Study Duration – study duration 
changed from 12-24 months 
 
Version: 4.0     Date: 1/30/2017 
Page 42/42- Updated Appendix D Thyroid 
Scanning Protocol from Rev 01 to Rev 02 
Version: 5.0     Date: 4/25/2017 
Replaced all ® with ™ when followed after 
Imagio throughout protocol 
 
Replaced CEO Tom Umbel as signatory with 
Ann Waterhouse VP of Regulatory and Quality 
Assurance;  Added signature of Steve Miller, 
VP of R&D 
 
Updated /corrected List of abbreviations for 
ADE, CRO, IUS, and OA/US 
 
Updated all instances of OA acronym to 
OA/US throughout the protocol and general 
formatting 
 
Section 1.2-Updated Photo of Imagio with 
OA/US probe only 
 
Section 1.3- Removed last sentence: 
This device is not intended to be used as a 
screening device or for definitive pathologic 
diagnosis. 
 
Section 1.4 removed statement: The majority 
of the population was white (n – 1,558; 79.0%).  
 
Section 3.2-Removed paragraphs describing 
image annotation requirements; removed 

 
 
 
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paragraph describing scanning protocol; 
added the collection of initials, DOB and 
subject number requirement to study images.  
All will be included in Core Lab Manual. 
 
Section 4.2-Clarified Exclusion Criteria 4 to 
include multiple lesion presence requirement 
of minimum separation of 1 cm between study 
lesion(s) from any other lesion(s) 
 
Section 5.1-Study Device description updated 
to appropriately describe Imagio as an 
investigational device in the US 
 
Section 6.2-Removed-Contamination due to 
insufficient cleaning materials due to it being 
listed in User Manual  
 
Section 6.3 moved heading and first following 
statement. 
 
Section 7.5-Updated Enrollment Failure 
definition to include Imaging Core Lab review 
and removing “subjects who have incomplete 
or unusable study device scans” 
 
Section 14.1-Removal of –“IRB committee and 
will provide appropriate therapy and follow-up 
of treated subjects” from last sentence. 
 
Page 42/42- Updated Appendix D Thyroid Scanning 
Protocol from Rev 02 to Rev 03. 
 
Version: 6.0     Date: 7/18/2017 
Section 4.2: 
Updated Inclusion Criteria #2 and extended 
window for standard of care imaging from 45 days 
to 90 days.  
 
Updated Exclusion Criteria # 10 to exclude 
previous FNA of target nodule of interest only if 
FNA was performed within 6 months of baseline 
IMAGIO scan. 
 
Section 7.1 - Table 1 Schedule of Events  footnote 
#2 was updated from 45 days to 90 days to match 
inclusion criteria #2 update. 
 

 
 
 
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Version: 7.0     Date: 9/8/2017 
Section 4.2: 
Updated Inclusion Criteria #2 and extended 
window for standard of care imaging from 90 days 
to 365 days.  
 
Section 7.1 - Table 1 Schedule of Events foot note 
#2 was updated from 90 days to 365 days to match 
inclusion criteria #2 update. 
 
Version: 8.0     Date: 11/01/2017 
Section 3.2  
Removed exclusion language limiting “up to two 
suspicious nodules” to be biopsied from the 
thyroid with “a maximum of 1from each lobe”. 
 
Added lesion numbering format to include thyroid 
and lymph node designation. 
 
Section 4.2: 
Modified Inclusion #5 and removed limitation of 
“no more than 2 (one in each lobe) thyroid 
nodules”. 
 
Removed Exclusion #4: Have greater than 2 
nodules (1 in each lobe) recommended for 
biopsy at baseline, study nodules cannot be 
touching any other nodules with a minimum 
separation of 1 cm;  
 
Modified Exclusion #9 (Previously #10) to 
reduce previous biopsy of target nodule of 
interest occurring prior to baseline Imagio scan 
from 6 months to 3 months. 
 
Section 5.1 
Modified Imagio “Instructions for Use” to “User 
Manual” to reflect correct document name 
 
Section 7.2.1 
Updated CDU imaging window from 45 days to 
365 days to stay consistent with version 7.0 
changes 
 
Updated Appendix D Thyroid Scanning Protocol 
from Rev 03 to Rev 05. 
Version: 9.0     Date: 11/30/2017 
Updated Appendix C: ACR TIRADs to reflect latest 
released ACR TIRADs Chart. 
Version: 10.0     Date: 2/6/2018 
Updated  Section 4.2 
 
Inclusion Criteria 2 Modified to: 

 
 
 
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Have an undiagnosed suspicious solid or mostly 
solid thyroid nodule. 
 
Exclusion Criteria 9 modified to shorten window to 
45 days 
 
Section 9- Eliminated language that is included in 
Imaging Core Lab Documents. 
 
Updated Scan Procedure to v06 
 

 
 
 
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Table of Contents 
PROTOCOL SIGNATURE PAGE ................................................................................................................. 2 
REVISION HISTORY .................................................................................................................................. 3 
TABLE OF CONTENTS ............................................................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................................................ 10 
1. 
INTRODUCTION ............................................................................................................................ 12 
1.1. 
Background of Thyroid Cancer .......................................................................................... 12 
1.2. 
Imagio – Device Description .............................................................................................. 12 
1.3. 
Intended Use ..................................................................................................................... 14 
1.4. 
Imagio Previous Studies .................................................................................................... 14 
2. 
STUDY OBJECTIVES ....................................................................................................................... 16 
2.1. 
Primary Objective .............................................................................................................. 16 
2.2. 
Secondary Objectives ........................................................................................................ 16 
3. 
STUDY PLAN.................................................................................................................................. 17 
3.1. 
Study Design ...................................................................................................................... 17 
3.2. 
Overall Study Design and Plan: Description ...................................................................... 17 
4. 
STUDY POPULATION ..................................................................................................................... 19 
4.1. 
Number of Subjects ........................................................................................................... 19 
4.2. 
Inclusion/Exclusion Criteria ............................................................................................... 20 
5. 
DESCRIPTION OF EXPERIMENTAL DESIGN AND METHODS .......................................................... 20 
5.1. 
Study Device ...................................................................................................................... 20 
5.2. 
Operator Credentials and Training .................................................................................... 20 
5.3. 
Cytopathology and/or Histopathology Review ................................................................. 21 
5.4. 
Comparators and Gold Standard ....................................................................................... 21 
5.5. 
Blinding .............................................................................................................................. 21 
5.6. 
Treatment Compliance ...................................................................................................... 21 
5.7. 
Packaging, Labeling, and Instructions for Use ................................................................... 21 
5.8. 
Storage and Accountability ............................................................................................... 21 
6. 
RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL INVESTIGATION ........... 22 
6.1. 
Anticipated Clinical Benefits .............................................................................................. 22 
6.2. 
Anticipated Adverse Device Effects ................................................................................... 22 
6.3. 
Risk/Benefit Rationale ....................................................................................................... 22 
7. 
STUDY PROCEDURES .................................................................................................................... 23 
7.1. 
Study Procedure Overview ................................................................................................ 23 
7.2. 
Study Visits and Procedures .............................................................................................. 25 
7.2.1. SCREENING/ENROLLMENT/IMAGING VISIT- DAY 1 .................................................................... 25 
7.2.2. BIOPSY PROCEDURE .................................................................................................................... 25 
7.3. 
Effectiveness Assessments ................................................................................................ 25 
7.4. 
Subject Withdrawal Criteria .............................................................................................. 26 
7.5. 
Enrollment Failures ........................................................................................................... 26 
8. 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS, UNANTICIPATED ADVERSE DEVICE EFFECTS AND DEVICE 
DEFICIENCIES ................................................................................................................................ 26 

 
 
 
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8.1. 
Definitions ......................................................................................................................... 26 
8.1.1. ADVERSE EVENT AND ADVERSE DEVICE EFFECTS ....................................................................... 26 
8.1.2. DEVICE DEFICIENCY ..................................................................................................................... 27 
8.1.3. SERIOUS ADVERSE EVENT AND SERIOUS ADVERSE DEVICE EFFECTS ......................................... 27 
8.1.4. UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (U(S)ADE) ............................................... 27 
8.2. 
Device relatedness ............................................................................................................ 28 
8.3. 
Severity .............................................................................................................................. 28 
8.4. 
Reporting ........................................................................................................................... 28 
8.4.1. REPORTING REQUIREMENTS ....................................................................................................... 28 
8.4.2. REPORTING TO SPONSOR ............................................................................................................ 28 
8.4.3. REPORTING TO REGULATORY AUTHORITIES ............................................................................... 28 
8.5. 
Emergency Contact Details................................................................................................ 28 
9. 
IMAGING CORE LAB ...................................................................................................................... 29 
10. MONITORING ............................................................................................................................... 29 
11. AUDITS AND INSPECTIONS ........................................................................................................... 29 
12. STATISTICAL METHODS ................................................................................................................ 29 
12.1. 
Study Hypotheses .............................................................................................................. 29 
12.2. 
Analysis Populations .......................................................................................................... 30 
12.3. 
Demographics and Baseline Characteristics ...................................................................... 30 
12.4. 
Sample Size Discussion ...................................................................................................... 30 
12.5. 
Analyses ............................................................................................................................. 30 
DEVELOPMENT OF GUIDELINES, INTERPRETATION RULES AND ESTIMATORS ........................... 30 
12.5.1. 
ACCEPTABILITY METRICS ................................................................................................... 31 
13. ADMINISTRATIVE CONSIDERATIONS ............................................................................................ 31 
13.1. 
Investigators and Study Administrative Structure ............................................................ 31 
13.2. 
IRB Committee................................................................................................................... 31 
13.3. 
Ethical Conduct of the Study ............................................................................................. 32 
13.4. 
Informed Consent .............................................................................................................. 32 
13.5. 
Subject Confidentiality ...................................................................................................... 32 
13.6. 
Case Report Forms and Study Records ............................................................................. 32 
13.7. 
Clinical Quality Assurance ................................................................................................. 33 
13.8. 
Protocol Amendments....................................................................................................... 33 
13.9. 
Protocol Deviations ........................................................................................................... 33 
13.9.1. 
CORRECTIVE AND PREVENTIVE ACTIONS .......................................................................... 34 
13.9.2. 
INVESTIGATOR DISQUALIFICATION CRITERIA ................................................................... 34 
13.10. Retention of Data .............................................................................................................. 34 
13.11. Statement of Compliance .................................................................................................. 34 
13.12. Financial Disclosure ........................................................................................................... 35 
13.13. Publication and Disclosure Policy ...................................................................................... 35 
14. SUSPENSION OR PREMATURE TERMINATION ............................................................................. 35 
14.1. 
Criteria for Premature Termination .................................................................................. 35 
APPENDIX A: ACR GUIDELINES REVISED 2013 (RESOLUTION 16) * ...................................................... 38 
APPENDIX B:  INVESTIGATOR’S AGREEMENT ....................................................................................... 39 

 
 
 
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APPENDIX C ACR TI-RADS: ..................................................................................................................... 40 
APPENDIX D- THYROID SCANNING PROTOCOL REV. 05 (SID-0000002854) ......................................... 41 
 
Table of Figures 
 
Figure 1: Imagio breast imaging system ......................................................................................... 13 
Figure 2 Key Switch ......................................................................................................................... 14 
Figure 3  Emergency stop ............................................................................................................... 14 
 
 
Table of Tables 
Table 1: SCHEDULE OF EVENTS ...................................................................................................... 23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACR 
American College of Radiology 
ADE 
Anticipated Adverse Device Event 
CDU 
Conventional Diagnostic Ultrasound 
CDI 
Color Doppler Imaging 
CI 
Confidence Interval 
CNB 
Core Needle Biopsy 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
DVAB 
Directional Vacuum – Assisted Biopsy 
eCRF 
Electronic CRF 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
EOS 
End of Study 
FDA 
Food and Drug Administration 
fMRI 
Functional Magnetic Resonance Imaging 
FN 
False Negative 
FNA 
Fine Needle Aspiration  
FNAB 
Fine Needle Aspiration Biopsy 
FP 
False Positive 
FPR 
False Positive Rate 
GCP 
Good Clinical Practice 
ICL 
Imaging Core Lab 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
ISO 
International Organization for Standardization 
ITD 
Intention to Diagnose 
IUS 
Imagio Ultrasound/Internal Ultrasound 
LOM 
Laser Optical Movie 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MRMC 
Multi-reader, Multi-case 
NDU 
Negative Diagnostic Ultrasound 
OA/US 
Opto-Acoustic 
NLR 
Negative Likelihood Ratio 
NPV 
Negative Predictive Value 
OR 
Odds Ratio 

 
 
 
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PDI 
Power Doppler Imaging 
PI 
Principal Investigator 
POM 
Probability of Malignancy 
PLR 
Positive Likelihood Ratio 
PPV 
Positive Predictive Value 
QAR 
Quality Assurance Reviewer 
SADE 
Serious Adverse Device Effect 
SAP 
Statistical Analysis Plan 
Se 
Sensitivity 
Sp 
Specificity  
SE  
Strain Elastography  
SWE 
Shearwave Elastography 
TI-RADS 
Thyroid Imaging Reporting and Data System 
TN 
True Negative 
TP 
True Positive 
TPR 
True Positive Rate 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
WHO 
World Health Organization 

 
 
 
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INTRODUCTION 
1.1. 
Background of Thyroid Cancer 
The incidence of thyroid nodules has increased tremendously in recent years [1]. The reasons for this increase 
are likely multifactorial but are largely attributed to widespread application of high-resolution ultrasound to the 
thyroid and the frequent incidental detection of nodules on other imaging modalities. In distinction to palpation, 
which demonstrates nodules in only 5% to 10% of the population, autopsy and sonography detect them in at 
least 60% [2-4].  Although common, malignancy in nodules remains relatively low ranging from 1.6% to 12%.  
Ultrasound is superior to other modalities in categorizing thyroid nodules however a definitive diagnosis is 
arrived at through the use of fine-needle aspiration (FNA), core biopsy or surgery.   This places a burden on the 
health care system and anxiety may occur in many patients. In addition, long-term studies by Ito et al [5] showed 
no difference in outcomes between patients with biopsy-proven differentiated papillary thyroid carcinomas <1 
cm undergoing thyroidectomy and those followed with no surgical intervention. 
The structure of the thyroid and the nature of thyroid cancer present a great challenge for imaging technologies 
to detect malignant nodules reliably and to differentiate them from benign nodules. Seno’s imaging technology 
addresses this challenge by utilizing 2 very different real time temporally fused modalities, opto-acoustic 
(OA/US) and diagnostic ultrasound(US), thus providing co-registered and temporally interleaved real time 
functional and anatomical information. This combination has the potential to add diagnostic information to help 
the radiologist better evaluate suspicious thyroid nodules in an efficient manner.   
 
1.2. 
Imagio – Device Description 
The Imagio provides the clinician with the display of 2-dimensional real-time images of the structures of the 
breast containing OA absorption and a co-registered B-mode ultrasound image. The Imagio hand-held OA 
transducer transmits predefined laser wavelengths (757nm and 1064nm) to illuminate the breast tissue.  
Internal light absorption, which occurs in the tissue, results in acoustic signals that can be detected by the 
multi-element wideband ultrasound transducer, a sub-assembly in the OA transducer.  The Imagio software 
acquires and processes the return OA and B-mode ultrasound signals to form and log images containing the 
structural and functional information associated with breast abnormalities. This information is presented to 
the clinician as a co-registered and temporally interleaved display of OA and B-mode ultrasound images and 
can be compared to conventional ultrasound image displayed alongside OA/US images.  
Separate from the OA imaging modality, the user can select conventional ultrasound modalities, i.e., B-mode 
ultrasound, Pulsed-Wave Doppler, Color/Power Doppler, and combined ultrasound modes, and thereby 
operate the Imagio in the same manner as a conventional ultrasound system. It is important to note that 
Doppler modes cannot be activated while in OA imaging mode.  The B-mode ultrasound includes image 
enhancing features, and the ability to measure and annotate images. The system is DICOM compliant and 
includes PACS connectivity.  
The Imagio is comprised of a system cart, which encloses the following sub-systems: 
• Ultrasound 
• Laser 
• Data Acquisition and Processing (DAP) module 
• Power Supplies 
• Power Control  
External to the cart, the user has access to the following elements: 

 
 
 
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• High Resolution Display Monitor with laser emission LED 
• Console with Touch Screen with soft keyboard 
• Optional QWERTY keyboard 
• Master Power key switch On/Off Control (attached to Console) 
• Emergency Power Off Control (attached to Console) 
• Remote Interlock 
• Foot switch 
• Laser coolant port and filling system 
• Calibration box 
• OA Probe 
• Ultrasound ports  
• System wheel lock 
• Protective eyewear 
 
 
 
Figure 1: Imagio breast imaging system 

 
 
 
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The laser energy emitted by the Imagio is Class 3b. To protect users and subjects, several safety features 
are included in the Imagio.  In order to turn on the device, a physical key is required to be inserted into the 
locked on/off switch and turned to the ON position (Figure 2). In order to enable the laser for possible 
emission, the user must enter a password.  After 15 minutes of inactivity, the user must enter the password 
again. Protective eyewear is provided for the user(s) and the patient/subject. Prior to the start of key tasks 
(i.e., calibration and laser authorization), the user must actively click “ok” to confirm that protective eyewear 
is applied to all persons in the room. Emission is activated by the footswitch and is indicated by an icon on 
the Display Monitor, the LED at the top of the Display Monitor, and an audible tone.  During clinical use, 
the laser will not emit if the OA Probe is not connected. An emergency stop is also provided (Figure 3). 
 
 
Figure 2 Key Switch 
 
Figure 3  Emergency stop 
 
1.3. 
Intended Use 
The Imagio system is a diagnostic functional and morphologic imaging system intended for the opto-acoustic 
(OA/US) evaluation of thyroid in men and/or women who have findings of thyroid nodules. The Imagio thyroid 
imaging system is intended to be used in the evaluation of thyroid nodules, regardless of the method or 
mechanism of initial detection, including both palpable and non-palpable nodules. Thyroid nodules may present 
as palpable nodules or may be detected incidentally on CT or MR scans of the neck or chest. They may also be 
detected as incidental findings on carotid doppler examinations. Occasionally they are detected as areas of 
increased activity on PET/CT scans. 
 
The Imagio multi-modality system utilizes opto-acoustic and ultrasound technologies to acquire, process, 
display, and log co-registered structural and functional information about thyroid abnormalities. This 
information is presented to the user as fused and temporally interleaved opto-acoustic and ultrasonic images.   
 
The Imagio system also includes real-time diagnostic ultrasound with color and pulsed Doppler. The grayscale 
ultrasound component may be used alone and includes image enhancing features, and the ability to measure 
and annotate images. The system is DICOM compliant and has PACS connectivity. Imagio is intended to be used 
by qualified healthcare professionals in the differentiation of benign from malignant thyroid lesions and to 
support them in their decisions.  
1.4. 
Imagio Previous Studies 
Early breast proof-of-concept studies provided the company with supporting data to modify and enhance 
diagnostic performance of the Imagio real time opto-acoustic functional imaging characteristics performed at 
the wavelengths of Nd:YAG and Alexandrite lasers. Imagio was also tested on gelatin phantoms simulating dense 

 
 
 
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breast with blood vessels having blood with various degrees of oxygen saturation. In-vitro experiments with 
various phantoms demonstrated that OA/US imaging is capable of not only visualizing shape and dimensions of 
blood vessels, but also differentiating deoxygenated blood from oxygenated blood. 
 
PREVIOUSLY PERFORMED IN VIVO SENO BREAST STUDIES WITH IMAGIO  
 
FEASIBILITY STUDY 
A Feasibility Study was conducted using a total of 155 subjects to determine the ability of Imagio to help identify 
and define benign and malignant OA features.  This study was conducted at CTRC and at South Texas Radiology 
Imaging Centers (STRIC).  The Feasibility Study provided data to further develop the algorithm and to identify 
separate sets of features that characterize benign and malignant disease. The Feasibility Study included subjects 
with masses classified as either negative diagnostic ultrasound (NDU) results or positive diagnostic ultrasound 
(PDU) results. The masses had varying histopathologic diagnoses, sizes, locations, and depths. The Feasibility 
Study subjects also had varying ages, ethnicities, and races. These subject-specific characteristics are intended 
to identify any unusual subpopulations. To date, there are no such known exclusions other than subjects with 
obscured views and subjects on medications with the potential to activate photosensitive dermatologic 
conditions.   
 
The Feasibility Study demonstrated 3 internal and 3 external OA features that correlate with benign vs. 
malignant mass histopathology [17-20]. The POM was significantly higher for malignant masses than for benign 
masses [21]. The specificity was 8% higher for Imagio than for CDU (24% for OA vs 16% for CDU) among those 
with benign disease, there was >40% relative reduction in the numbers with POM >2% in support of biopsy 
sparing [22]. There were no reported device related adverse events.  
 
SYSTEM VERIFICATON STUDY 
A subsequent System Verification Study was performed, enrolling a total of 44 subjects. The study was 
conducted at STRIC to evaluate the dual-wavelength performance of the Imagio breast imaging system in 
detecting suspicious lesions and for final tuning of the algorithm prior to embarking upon the pilot phase of the 
PIONEER study. The objectives of the System Verification Study were met and further conclusions could be 
drawn.  There were no reported adverse events. 
 
 
PIONEER STUDY 
The Pioneer Study was a prospective multi-center trial with 2105 subjects enrolled across 16 US clinical sites 
including CTRC. Subjects were prospectively enrolled upon confirmation of being BI-RADS 3, BI-RADS 4, or BI-
RADS 5, as confirmed by CDU evaluation of the suspicious mass(es). Images were collected at the clinical sites 
and sent to an Independent Imaging Core Lab who processed and checked image quality prior to images being 
processed and read by 7 independent readers.  
Of the 1,972 subjects in the Safety Population, the overall mean age 49.4 years; 44.7 years for benign subjects 
and 58.4 years for malignant (cancer) subjects, consistent with the age distribution at cancer diagnosis. Seventy-
two subjects (<4%) were noted to have more than one Study mass. 
The study had 1 primary effectiveness endpoint and 5 secondary effectiveness endpoints, all of which were 
achieved with statistical significance after accounting for multiplicity testing.  
There were no serious adverse device effects (SADEs), UADEs or deaths reported during the Study. Ten subjects 
(0.5%) reported 11 AEs that were considered related to the OA procedure. None were serious, all were mild in 
severity.    
 
MAESTRO STUDY 

 
 
 
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Five centers in the Netherlands participated in this prospective, controlled, multi-center, observational and post 
market surveillance study. Between March 2015 and February 2016, 217 patients with 223 mass lesions were 
included in this study.  Three patients were excluded due to technical failure (not exposed to OA) and 5 were 
excluded due to the absence of a biopsy (patients’ choice not to undergo further investigation). Therefore, 209 
patients with 215 lesions were included in the intent-to-diagnose population. The mean age of these patients 
was 47.8 years (range 19 to 84). Sensitivity was 95.5% versus 100% for CDU.  53.3% of CDU BI-RADS 4b masses 
were upgraded.   
 
The primary objective of this study was to downgrade benign CDU BR 4a, 4b masses to OA BR 2-3 and to Not 
downgrade malignant CDU BR 4a, 4b masses to OA BR 2-3.  Of the 146 benign lesions, 12.3% (18/146) were 
upgraded from BI-RADS 4a to 4b, 6.1% (9/146) were upgraded from BI-RADS 4b to 4c and 0.6% (1/146) was 
upgraded from 4b to 5. Among the 67 malignant lesions, 1.4% (1/67) was upgraded from BI-RADS 4a to 4b, 
44.7% (30/67) were upgraded from BI-RADS 4b to 4c and 2.8% (2/67) were upgraded from 4b to 5. From the 
215 lesions, 68.5% (146/215) were histologically as benign, 31.4% (67/215) were histologically malignant and 
0.1% (2/215) were considered high-risk lesions histologically. Among the 146 histologically benign masses, 
81.5% (119/146) were classified as BI-RADS 4a and 18.5% (27/146) were classified as BI-RADS 4b by CDU. Sixty 
benign lesions were correctly downgraded from BI-RADS 4a or 4b to 3 or 2 (p < 0.0001). From the benign lesions 
classified as BI-RADS 4a, 57 (48%) were downgraded to BI-RADS 3 or 2 according to OA (p < 0.0001), and from 
the 27 benign lesions classified as 4b, 6 (22%) were downgraded to BI-RADS 4a, 3 or 2 by OA (p = 0.0471).  One 
adverse event was noted not related to OA which was a hematoma post biopsy.  
 
PREVIOUSLY PERFORMED STUDIES WITH IMAGIO ON OTHER BODY STRUCTURES INCLUDING THE THYROID 
 
PLATFORM STUDY 
The Platform Study is an on-going early feasibility study designed to determine the ability of the Imagio OA 
device to image various body structures, thyroid being one of them.  A total of 15 subjects have been enrolled 
in the study, 13 of which have undergone thyroid OA scans.  The 13 subjects were comprised of 3 males and 10 
females.  The races of the enrolled subjects included 4 African American subjects and 9 Caucasian subjects.  The 
study population included subjects ranging in ages of 22-60.  There were 3 mild thyroid scan AEs reported 
consisting of tingling, pulsing, slight shock sensation.   
The purpose of this project is to evaluate the performance of the Imagio device in distinguishing malignant from 
benign thyroid nodules using the Imagio ultrasound (IUS) and opto-acoustic (OA) component of the device and 
to refine the device algorithm specific to thyroid nodule diagnosis and to develop guidelines for interpretation 
of thyroid OA studies.  The results will be used to further develop the pivotal study objectives and endpoints.  
 
 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective of this feasibility study is to provide an initial assessment of Imagio OA/US’s ability to 
distinguish between benign and malignant thyroid nodules, and when appropriate, between benign and 
metastatic cervical lymph nodes in subjects.  
2.2. 
Secondary Objectives 
There are two secondary objectives.  
• Complete tasks related to the development of the thyroid device algorithm, interpretation rules and 
estimators that will be used to determine clinical predictions.   

 
 
 
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• Obtain initial estimates of predictive value based on optimized clinical prediction rules including 
incremental improvement in specificity, percentage with correct downgrade in Thyroid Imaging and 
Reporting System (TI-RADS) Scores, percentage with correct upgrade in TI-RADS category, and negative 
likelihood ratio (NLR). 
 
 
STUDY PLAN 
3.1. 
Study Design 
This is a prospective feasibility study 
3.2. 
Overall Study Design and Plan: Description 
This is a feasibility study to assess Imagio OA/US’s ability to optimize the device algorithm specific to thyroid in 
order to detect the difference between benign and malignant thyroid nodules, and when appropriate, 
suspicious associated cervical lymph nodes.  Imagio evaluation will be performed according to the system’s 
instructions for use. The study will initially consent subjects with at least one nodule classified as suspicious 
enough to warrant recommendation for biopsy according to CDU.  In subjects with nodules very suspicious for 
malignancy in which there is a suspicion for metastatic lymph node disease that have also been recommended 
for biopsy, OA/US imaging will also be performed on the suspicious lymph node. 
All selected subjects will undergo an Imagio evaluation following consent and before any immediate fine needles 
aspiration biopsy (FNAB), core biopsy, or surgical excision.  The decision whether to recommend and perform 
ultrasound guided FNAB or core needle biopsy will be based upon standard of care conventional diagnostic 
thyroid ultrasound findings. Imagio IUS or OA findings will not be used as the reason to perform or to defer a 
biopsy or surgery.   
 
A total of approximately 110 nodules classified as TI-RADS 1-5 scheduled for biopsy will prospectively screened 
(subject signed inform consent) to get 100 evaluable nodules (acceptable OA images (via Seno Medical Director 
and/or Independent Core Lab (ICL) quality assurance process) collected with acceptable cytology/histology final 
diagnosis data.  It is expected that 10% of nodules will be enrollment failure leading to target evaluable analysis 
set of 100 nodules.  
Enrollment failures in the study would consist of subjects who did not have acceptable OA images collected 
and/or valid cytopathology cell counts or histopathology considered adequate for diagnosis. (Cytopathology 
insufficiency rates vary from about 1.5% - 20%). Thyroid nodules that have undergone FNAB, but have 
insufficient cellularity for cytopathologic assessment, cannot be used unless repeat FNAB is performed and 
shows adequate cellularity for diagnosis). 
 
The study will include a minimum number of thyroid nodules (TI-RADS 1-5) with adequate cytopathology or 
histopathology for diagnosis that include at least:  10 papillary thyroid carcinomas minimum, 10 Follicular 
neoplasms, and 30 benign nodules that include at least 5 Hashimoto (chronic lymphocytic thyroiditis) nodules. 
 
A significant percentage of FNABs result in insufficient cellularity for diagnosis. If the initial FNAB is deemed 
insufficient, either repeat FNAB or core biopsy that is sufficient for diagnosis will be required for the subject and 
thyroid nodule to be included in the study. An initial FNAB that is insufficient and is not repeated cannot be 
included in the study and will need to be replaced, unless the patient undergoes surgical removal of the nodule 
from which adequate histopathology is obtained. If both initial FNAB and repeat FNAB or core biopsy are 
insufficient, the subject and the thyroid nodule cannot be included in the study and the subject and nodule will 

 
 
 
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need to be replaced unless the patient undergoes surgical removal of the nodule that results in adequate 
histopathology for diagnosis. 
 
 
 
 
 
 
 
 
The study will be explained to the subject after the biopsy decision has been made based upon conventional 
diagnostic ultrasound (CDU) and then will be prospectively evaluated with Imagio OA/US.  The PI or Sub-PI from 
each site will evaluate all cases in an unblinded “real world” manner.   The OA study will be performed after 
CDU with full knowledge of other imaging findings as available (CT, MRI, PET, CT/PET, carotid ultrasound), clinical 
history, and personal risk history. All Imagio studies will be recorded during prescribed probe sweeps through 
the nodule and surrounding tissues. 
 
Additionally, the estimator generated in a previous study will be potentially developed to assist with scoring 
various features associated with the thyroid mass. Pathology data will be collected to assess histologic features 
of the nodule. The ultimate diagnosis depends on the cytopathologic examination of the FNAB thyroid nodule 
specimen by a cytopathologist or from a histopathologist in the case of a core needle or surgical excisional 
biopsy.  
  
When available, genetic biomarkers that may help distinguish more aggressive thyroid malignancies that require 
more aggressive treatment from less aggressive malignant nodules that might warrant less aggressive treatment 
or even merely observation on long term follow-up should be made available. These will usually come from 
surgical procedures such as lobectomy or complete thyroidectomy with or without central lymph node 
dissection. Such biomarkers might include: presence or absence of BRAF and/or RET mutations in papillary 
carcinoma, RAS and/or PPARG mutations in medullary carcinoma, and TP53 and/or P13K/AKT1 mutations in 
anaplastic carcinoma. These biomarkers may be critical, because the diagnosis of malignant versus benign might 
not be as important as the distinction between aggressive or undifferentiated thyroid malignant nodules that 
require aggressive treatment and less aggressive differentiated malignant nodules that require less aggressive 
treatment or merely observation on long term follow-up. Studies have shown that up to 60% of papillary thyroid 
carcinomas do not change over 6 years on imaging follow-up and might merely warrant watchful waiting on 
ultrasound rather than surgery (23).  
 
Study Duration 
 
In order for a subject to be enrolled in the study, he/she must have the following:  
 
• A Screening/Enrollment/Imaging Visit (Day 1) 
• Biopsy Visit (up to 45 days from Screening/Enrollment/Imaging Visit) 
• Second Biopsy Visit/ surgery visit (up to 45 days from First Biopsy Visit), if needed 
• Final Surgery (up to 45 days from Second Biopsy)  as applicable  
 
The minimum duration of study participation for a patient is 48 hours: if the Screening Visit, Enrollment Visit, 
Imaging Visit, Biopsy Visit all occur in sequential order within 48 hours.  In this scenario no further biopsy of 
thyroid or surgery is required. 
 
The maximum duration of study participation for a patient is 135 days 
 
The enrollment period will extend approximately 12-24 months.  
 
Imaging Data Collected-  

 
 
 
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The Imagio field of view (both OA/US and IUS) will include at least longitudinal and transverse views of the 
nodule at a minimum. Views will be obtained with and without measurement calipers, as the presence of 
calipers may interfere with surface characteristics evaluation from standard diagnostic and Imagio gray scale 
images. The views obtained during the OA/US scan and the labeling of the OA views must precisely replicate the 
views and annotation used for IUS, for comparative purposes. In some cases, additional views may be necessary. 
The scan protocols will be those recommended in ACR or AIUM Accreditation Committees for thyroid 
ultrasound. The CDU classification system will be based upon the new ACR TI-RADS committee 
recommendations (26). 
 
 
When more than one nodule is scanned and recommended for FNAB, the investigator should annotate the 
images to indicate which nodule is being designated nodule 1 and nodule 2. This will facilitate 
Histopathologist/Pathologist and potential Independent Readers interpreting the correct nodule. When a 
thyroid and lymph node (s) are both imaged with OA, the lymph node(s) should be assigned a number preceded 
by the letter T or L, respectively, (Ex. L-001).  
 
For both the IUS and OA/US scans video sweeps will be obtained in addition to still images. Scan protocols are 
located in Appendix D.  
 
SCANNING LYMPH NODES:  Data from Imagio evaluation of lymph nodes will also be collected for research 
purposes. When the investigator deems it necessary to scan the lymph nodes, he/she will perform Imagio 
imaging of any suspicious lymph node for which FNAB or surgical excision is recommended. Scan protocols are 
located in Appendix D.  
  
 
Additional data obtained that is required, if performed and available, includes: 
 
• CDU in all cases; 
• Images of ultrasound-guided FNAB or core biopsy in all cases;  
• Carotid Doppler examination if this is how the nodule was first detected 
• CT, MRI, or PET/CT, PET if this is how the nodule was first detected 
 
All images used for this study will be anonymized and deemed compliant. Subjects in this study will be assigned 
identifying subject numbers and their names and medical facility record numbers will be redacted from all 
accumulated images. The images will identify the subject only by subject initials, DOB and subject numbers. The 
subject number will be in the format of ###-###-###, with the first 3 digits being the country code, the second 
3 digits representing the site code, and the third three digits representing the subject code. The database that 
links the subject number with the subject names, medical facility record numbers, and birth dates will be 
maintained by the PI and sub-investigator and access to this database will be limited to the investigators and 
Seno Medical Instruments, Inc. and designees.  
 
 
STUDY POPULATION 
4.1. 
Number of Subjects 
A total of approximately 110 subjects with 110 nodules classified as TI-RADS 1-5 scheduled for biopsy will 
prospectively screened (subject signed inform consent) to get 100 evaluable nodules (acceptable OA images (via 

 
 
 
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ICL QA process) collected with acceptable cytology/histology final diagnosis data).  It is expected that 10% of 
nodules will be enrollment failure leading to target evaluable analysis set of 100 nodules.  
 
Enrollment failures in the study would consist of subjects who did not have acceptable OA images collected 
and/or valid cytopathology cell counts or histopathology considered adequate for diagnosis. (Cytopathology 
insufficiency rates vary from about 1.5% - 20%. Thyroid nodules that have undergone FNA, but have insufficient 
cellularity for cytopathologic assessment, cannot be used unless repeat FNA is performed and shows adequate 
cellularity for diagnosis). 
4.2. 
Inclusion/Exclusion Criteria  
Inclusion Criteria:  Subjects must meet all of the following criteria to be included in the study: 
1. Have been informed of the nature of the study and provided written informed consent, prior to initiation 
of any study activities;  
2. Have an undiagnosed suspicious solid or mostly solid thyroid nodule.;  
3. 18 years of age or older at the time of consent; 
4. Are willing and able to complete all procedures and assessments in accordance with the clinical protocol; 
and, 
5. Have received recommendation for and are scheduled for an ultrasound guided FNAB, ultrasound guided 
core biopsy, excisional biopsy, lobectomy or complete thyroidectomy of at least one thyroid nodule. 
 
Exclusion Criteria:   Subjects who meet any of the following criteria will be excluded from the study: 
 
1. Are prisoners; 
2. Have a condition or impediment (i.e., insect bites, poison ivy, open sores, chafing of the skin, scar, 
tattoos, moles, etc.); that could interfere with the intended field of view (within one probe length or 4 
cm of the nodule),  
3. Previous or on-going radioactive iodine treatment. 
 
4. Nodule to be biopsied is greater than 3.0 cm in maximum diameter; 
5. Is pregnant;  
6. Have an acute or a chronic hematoma and/or acute ecchymosis of the thyroid; 
7. Is experiencing photo-toxicity or photo-sensitivity or is undergoing treatment for a photo-sensitive 
condition such as porphyria or lupus erythematosus; 
8. Patient has received chemotherapy for any type of cancer within 90 days from date of screening CDU; 
9. Have had previous image guided FNAB or surgical biopsy of the target nodule of interest within the 45 
days of baseline Imagio Scan; 
10. Patient has participated in a clinical study of an investigational drug or device within 3 months prior to 
screening CDU that may have an impact on clinical outcomes; and, 
11. Patient has previously participated in this study. 
 
 
DESCRIPTION OF EXPERIMENTAL DESIGN AND METHODS 
5.1. 
Study Device 
The study will use Imagio to generate OA/US images.  Imagio is an investigational device in the US.  
 
Operator Credentials and Training  

 
 
 
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Experienced clinicians (or registered sonographers) will conduct all exams. Only radiologists or registered 
sonographers who have received approved training from Seno Medical Instruments, Inc. may perform the 
examinations. Clinician experience guidelines are included in the Imagio User Manual. The sponsor or a 
sponsor’s representative may be present during the procedure to provide technical assistance, if required. 
5.2. 
Cytopathology and/or Histopathology Review  
All biopsied nodules will be analyzed by a designated Cytopathologist and/or Histopathologist.  This may include 
the initial biopsy and/or any second core/surgical biopsy.     
5.3. 
Comparators and Gold Standard  
Imagio OA/US will be assessed as a diagnostic test in the classification of thyroid nodules. 
 
The CDU will serve as the “control” for comparative purposes. The ACR-TI-RADS committee classification system 
will be used to assess the thyroid nodule and the decision to biopsy with no single diagnostic methodology used 
to make this decision. CDU represents the subject-specific diagnostic tests used to make the thyroid nodule 
classification and the decision to biopsy. Imagio OA may not be used to determine final thyroid nodule 
classification or the decision to biopsy. If available, any data for and/or carotid duplex sonography, CT, MRI, or 
PET/CT, PET will also be used for comparative purposes. 
 
The histology obtained from FNAB, core biopsy, or surgical biopsy (at the nodule level) will serve as the gold 
standard.  
5.4. 
Blinding  
Subjects will not be blinded to best practice study procedures but will not have access to the Imagio OA 
evaluation result. 
 
The site investigators will have access to all subject data including the Imagio images and videos, and will assess 
and document the results of the OA study by completing the electronic data entry form (eCRF).   
 
The site investigators will have access to the background clinical information and to the subsequent 
histopathology report.     
5.5. 
Treatment Compliance 
The Imagio unit will be operated only by study personnel trained by Seno personnel or their representatives. 
5.6. 
Packaging, Labeling, and Instructions for Use 
Seno will ship Imagio devices to the participating site. Seno personnel will unpack and install the study device 
as well as conduct and document operator training for study personnel. 
 
5.7. 
Storage and Accountability  
Investigators will be responsible for ensuring that only authorized study personnel have access to the study 
device for study purposes in accordance with FDA guidelines.   

 
 
 
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RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL INVESTIGATION 
6.1. 
Anticipated Clinical Benefits 
The Imagio thyroid imaging system was designed to provide quick and precise evaluation of suspicious nodules 
(including both palpable and non-palpable nodules) or imaging findings when the thyroid nodule and when 
appropriate, suspicious cervical lymph node was first detected as an incidental finding on CDU, CT or MRI of the 
chest or neck, carotid duplex sonography, or on PET/CT. 
 
If proven valuable, the Imagio may contribute to a reduction in the number of biopsy procedures to be 
performed. Consequently, fewer patients will suffer from physical and emotional stress around the biopsy 
procedure and waiting period to get the result from the pathologist. 
 
In this study, the results of the Imagio scans do not determine whether or not biopsies need to be performed. 
The study participants will therefore not experience direct benefit. We hope that this study will contribute in 
the future to a more accurate diagnosis of thyroid nodules.  
6.2. 
Anticipated Adverse Device Effects 
List of potential risks and discomforts: 
 
• Tingling or warmth of the skin during the Imagio scan (0.4% or a 1 in 269 chance) that resolve at 
completion of the scan  
• Exposure to the laser of the Imagio (to both skin and eyes) 
• Exposure to the acoustic output 
• Phototoxicity when applying fragrance or lotion to the skin prior to scanning 
 
. 
6.3. 
Risk/Benefit Rationale 
Seno Medical Instruments, Inc. believes that any potential risk presented by this investigation has been 
minimized and that adequate testing, safeguards, and safety monitoring have been incorporated into the 
investigation to further minimize and mitigate the risks.  
 
 
The laser energy will be set to a level that is known as being below known harmful levels, which is unlikely to 
harm the thyroid or give any discomfort.  
 
Also, everyone in the examination room will be wearing protective eyewear in order to minimize risk of damage 
by laser light to the eyes 
 
Seno Medical Instruments, Inc. firmly believes that the value of the knowledge to be gained by conducting this 
clinical investigation to demonstrate the clinical value of the Imagio™ Thyroid Imaging System outweighs the 
potential risks posed to participating subjects.   
 
 

 
 
 
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STUDY PROCEDURES 
7.1. 
Study Procedure Overview 
The study procedures and the sequence in which they will occur are defined below in Table 1 below and 
described in greater detail in Section 7.2: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1: SCHEDULE OF EVENTS 

 
 
 
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Screening/ 
Enrollment/Imaging  
Visit1 
1st Biopsy 
Visit (≤45 
days after 
Imaging 
Visit) 
 
Additional 
surgical 
procedure  (≤45 
days after 2nd 
biopsy  as 
applicable) 
Evaluation 
2nd Biopsy 
Visit (≤45 
days after 
1st Biopsy 
Visit; as 
applicable) 
Informed Consent 
X 
 
 
 
Medical History 
X 
 
 
 
I/E Criteria 
X 
 
 
 
TI-RADS  Score  
X 
 
 
 
CDU thyroid  images 
(Doppler as applicable)  2 
X 
 
 
 
Other images/studies 
PET, CT, MRI, PET/CT, and 
Carotid Doppler2. 
X 
 
 
 
Biopsy Decision 
X 
 
 
 
Directed Thyroid History 
X 
 
 
 
Imagio OA Evaluation of 
thyroid and  lymph nodes 
(as applicable) 
X 
 
 
 
Ultrasound Guided FNA 
and/or core biopsy images 
of thyroid and lymph 
nodes (as applicable)  
 
X 
 
X 
 
 
 
Images uploaded to 
Imaging Core Lab  
X 
 
 
 
Adverse Event Evaluation 
X 
 
 
 
FNA or Core Biopsy 
Procedure (s) 
 
X 
X 
 
Surgical Biopsy/Treatment 
(as applicable) 
 
X 
X 
X 
Histopathology/Cytology  
Samples Collected 
including biomarkers (as 
applicable)  
 
X 
X 
X 
End of Study 
 
X3 
X3 
X4,5 
 
1The Screening/Enrollment/ Imaging, and Biopsy Visits may take place on the same date as the discretion of the investigator.  
2 CDU with or without Doppler (as available - CT, MRI, PET/CT, and carotid ultrasound, strain elastography and shear-wave elastography) within 365 
days of baseline Imagio Scan  
3For benign thyroid nodules, where cytopathology or histopathology is concordant with imaging findings, FNAB or core needle biopsy is the final 
procedure and End of Study.  
4If biopsy reveals malignant cytology or histology, further surgical treatment will likely be the final procedure and End of Study. Data associated with 
additional surgical procedures will only be collected up until the time that the confirmatory biopsy/surgical procedure takes place. 
5If a central lymph node dissection and/or lateral cervical lymph node dissection was performed during or after the thyroid procedure, surgical and 
histology data associated with those lymph node procedures will be collected.  
 
 
 
 
 
 
 
 
 
 

 
 
 
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7.2. 
Study Visits and Procedures 
7.2.1. 
 Screening/Enrollment/Imaging Visit- Day 1 
The following procedures will be conducted at the Screening/Enrollment Visit: 
• Perform informed consent; 
• Review inclusion /exclusion criteria; 
• verify from images and/or reports that a suspicious nodule was seen; 
• Confirm that CDU has been performed, for which the site radiologist has recommended either 
ultrasound-guided FNA and/or US-guided core needle biopsy, and will fall within 365 days of Imagio OA 
procedure.  
• Record demographics and directed thyroid history; and, 
• TI-RADS CDU-based classification  
• Imagio Imaging  
 
Upon enrollment, subjects receive a subject number that will be used on all documentation for the subject 
throughout the study. Subject numbers should be assigned in ascending order, and numbers should not be 
omitted or reused. The subject number is coupled with the site identification number for unique identification 
of each subject.  
 
Subjects will undergo the Imagio OA procedure. Subjects may be asked to return to the clinic to repeat the 
Imagio scan if (a) the image quality is not acceptable for review by A. Thomas Stavros, M.D. Seno’s Medical 
Director and/or the ICLs quality assurance reviewers (QARs) and (b) they have not yet undergone a biopsy 
procedure. Any adverse device effects or unanticipated adverse device effects that occur during this visit will be 
reported to appropriate authorities such as the IRB and FDA. In order to provide technical support, 
representatives from Seno Medical Instruments, Inc. or their designees may be present during the procedure.  
 
7.2.2. 
 Biopsy Procedure 
Patients will be scheduled for initial biopsy within 45 days of the Imagio OA/US procedure. Images of FNAB or 
Core Biopsy needle within the lesion are collected. If an FNAB is performed and results in insufficient cellularity 
for cytologic diagnosis and a repeat FNAB or core biopsy is required, this should be scheduled within 45 days 
after the first biopsy. The investigator is to ensure that the applicable site histopathology/cytology report is 
obtained.  If a surgical procedure is applicable, it would be scheduled within 45 days after the second biopsy. 
Surgical and histology data will be collected. 
7.3. 
Effectiveness Assessments 
Primary Effectiveness Endpoint:  
The primary metric for demonstration of feasibility is the incremental improvement in specificity.  An 
improvement of approximately 5% would be indicative of a successful feasibility study.   
 
Secondary Effectiveness Endpoints:  
The percentage of correct downgrades is the next most important metric.  Other metrics including sensitivity 
and negative likelihood ratios will be considered as supporting evidence.  
 

 
 
 
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7.4. 
Subject Withdrawal Criteria 
Subjects may be discontinued from the study for the following reasons if deemed appropriate by the Sponsor 
and /or Investigator: 
• Subject enters the study in violation of the protocol; 
• Subject deviates from the protocol during the study; 
• Pregnancy; 
• Withdrawal of consent; 
• If in the opinion of the investigator it is not in the subject’s best interest to continue (reason for 
withdrawal must be specified); and, 
• Termination of the study by the sponsor. 
 
Protocol Deviations will be reviewed by the Sponsor on a routine basis and any deviation that results in the 
exclusion of the subject from the statistical analyses will be documented in the final clinical study report. 
7.5. 
Enrollment Failures 
Subjects deemed enrollment failures according to the quality assurance review or failure to complete the biopsy 
evaluations) will be replaced during the active enrollment period of the study.  The following subjects will be 
considered enrollment failures and will be followed until all AEs are resolved: 
 
• Subjects found to be ineligible after the scan is conducted; 
• Subjects for whom the study device scans do not pass review (Seno Medical Director and/or Imaging 
Core Lab QAR review); and, 
• Subjects who have incomplete or unusable biopsy results. 
 
 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS, UNANTICIPATED ADVERSE DEVICE EFFECTS AND DEVICE 
DEFICIENCIES  
For the purposes of this study, only Imagio device-related adverse events (AE), unanticipated adverse device 
effects, procedure-related AEs and device deficiencies will be collected. AE and device deficiency collection will 
commence once the subject has provided written informed consent and the patient has entered OA Imagio 
scanning room.  
8.1. 
Definitions 
8.1.1. 
Adverse Event and Adverse Device Effects 
Adverse Event: any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the 
investigational medical device. 
 
NOTE 1:  This definition includes events related to the investigational medical device.  
NOTE 2:  This definition includes events related to the procedures involved.  
NOTE 3:  For users or other persons, this definition is restricted to events related to investigational medical 
devices. 

 
 
 
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Adverse Device Effect: adverse event related to the use of an investigational medical device. 
 
NOTE 1:  This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device.  
NOTE 2:  This definition includes any event resulting from use error or from intentional misuse of the 
investigational medical device. 
 
Unanticipated Adverse Device Effect: adverse event related to the use of an investigational medical device.   
 
NOTE 1:  This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device.  
NOTE 2:  This definition may include any event resulting from use error or from intentional misuse of the 
investigational medical device. 
 
8.1.2. 
 Device Deficiency 
Device Deficiency: inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
safety or performance. 
 
NOTE:  Device deficiencies include malfunctions, use errors, and inadequate labelling. 
 
8.1.3. 
 Serious Adverse Event and Serious Adverse Device Effects 
Serious adverse event (SAE): an adverse event that 
1. Led to death, 
2. Led to serious deterioration in the health of the subject, that either resulted in 
a. a life-threatening illness or injury, or 
b. a permanent impairment of a body structure or a body function, or 
c. in-patient or prolonged hospitalization (>24 hours), or 
d. medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
3. Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
Note: Preplanned events of hospitalization or surgical interventions will not be recorded as an SAE. 
 
Serious adverse device effect (SADE): adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
8.1.4. 
 Unanticipated (Serious) Adverse Device Effect (U(S)ADE) 
Anticipated serious adverse device effect (ASADE): is an effect which by its nature, incidence, severity or 
outcome has been identified in the risk analysis report.  
 
Unanticipated serious adverse device effect (USADE): serious adverse device effect which by its nature, 
incidence, severity or outcome has not been identified in the current version of the risk analysis report and 
section 6.2.  
 

 
 
 
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8.2. 
Device relatedness 
The potential relationship of the event to the investigational device or procedure will be judged by the 
investigator. The relation will be based on the following definitions: 
 
• Related - Definite causal relationship 
• Probable - Good reasons and sufficient documentation to assume a causal relationship 
• Possible - A causal relationship is conceivable and cannot be dismissed 
• Unlikely - The event is most likely related to an etiology other than the investigational product 
administration 
• Unrelated - Definitely no causal relationship 
 
Events classified as related, probable and possible are considered related and need to be reported. Events 
classified as unlikely and unrelated are not considered related and do not need to be reported. See section 8.4 
for more details. 
8.3. 
Severity 
The assessment of severity is a clinical determination of the intensity of an adverse event. The severity 
assessment for a clinical adverse event should be completed using the following definitions as guidelines: 
 
• Mild – Transient symptoms, no interference with the patient’s daily activities 
• Moderate – Marked symptoms, moderate interference with the patient’s daily activities 
• Severe- Considerable interference with the patient’s daily activities, which is unacceptable 
8.4. 
Reporting  
8.4.1. 
 Reporting Requirements 
For the purposes of study, only device-related events ((S)(U)ADEs), procedure-related events and device 
deficiencies will be reported. (S)ADE, procedure-related events and device deficiency collection will commence 
once the subject has provided written informed consent and the patient has entered OA Imagio scanning room.  
 
8.4.2. 
 Reporting to Sponsor 
All adverse events classified as serious adverse device effects or (SADEs) as well as serious unanticipated adverse 
device effects (SUADE) and possibly-, probably- or definitely-related to the device need to be reported to Seno 
within 24 hours of learning of the event, using the EDC system.  
 
8.4.3. 
 Reporting to Regulatory Authorities 
Events will be notified to the IRB per IRB guidelines and to FDA in accordance with FDA Guidelines.   
8.5. 
Emergency Contact Details 

 
 
 
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In the event discussion is necessary regarding the safety or treatment of a subject, investigators can call A. 
Thomas Stavros, MD at (office) 210-615-6501, ext. 142 or (mobile) 707-849-6548. 
 
 
IMAGING CORE LAB  
To ensure consistency, the assessment of all imaging studies including Imagio will be managed by an 
independent Imaging Core Lab (ICL) to perform quality assurance review of collected images.  
The Imaging Core Lab participating in this study will be: 
 
Medical Metrics 
2121 Sage Rd.  Suite 300 
Houston, TX  77056 
Phone 713-850-7500 
 
 
  MONITORING 
Monitoring of the study will be performed in accordance with FDA guidelines. Monitoring including source data 
verification should be routinely performed prior to the transfer of the data to Data Management. 
 
Site monitoring visits will be performed by the Seno or Seno’s representatives on a regular basis in accordance 
with the Monitoring Plan. During monitoring visits, data entered in the eCRF will be source verified for accuracy 
and completeness. In addition, protocol compliance and compliance with FDA regulations will be verified. The 
monitor should have direct access to source data for verification purposes. The eCRF data will be compared with 
data in the subjects’ medical records.  Such verification is essential to quality control.   
 
The Sponsor expects that, during monitoring visits, the study coordinator and Principal Investigator will be 
available, the source documentation will be available and that a suitable environment will be provided for 
review of study documents.  
 
 
  AUDITS AND INSPECTIONS 
Independent auditors from the Seno or Seno’s representative may request access to all study records, including 
source documents for inspection, audit and/or copying in keeping with applicable regulations.  The Principal 
Investigator should immediately notify the sponsor of an upcoming regulatory authority inspection.  
 
 
 STATISTICAL METHODS 
12.1. Study Hypotheses 
The overall hypothesis motivating this pilot feasibility study is that Imagio OA can provide incremental 
improvements in the clinical classification of thyroid nodules into benign and not benign and into finder 
subclasses.  To evaluate this hypothesis, a heterogeneous sample of at least 50 patients will evaluated and steps 
will be taken to optimize software parameter and clinical guidelines. Initial evaluation of reliability and validity 
will be obtained by having three independent readers make predictions first with conventional gold standard 
methods and then augmented with Imagio OA. These results will be summarized using conventional measures 
of diagnostic utility, with emphasis on incremental improvement in specificity, the percentage of correct down 
grades, the percentage of correct upgrades, and the negative likelihood ratio.  When appropriate, statistical 
estimates will be reported along with 95% confidence intervals. 

 
 
 
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12.2. Analysis Populations  
All analyses will be performed with the intention to diagnose (ITD) study population which consists of all subjects 
coming in for their scheduled Imaging Visit, having Imagio OA data declared evaluable, and having a biopsy of 
at least one nodule with evaluable cytology/histology results. 
12.3. Demographics and Baseline Characteristics 
The age, race, ethnicity, will be presented using descriptive statistics for the overall ITD population, by sites 
diagnostic status (benign, malignant).  
12.4. Sample Size Discussion 
Based on experience with feasibility studies performed for evaluation of breast nodules, the sample size for this 
feasibility study is driven by software and clinical rule development needs.  From this perspective, it was 
concluded that the reference set should include a minimum of 50 thyroid nodules with adequate cytopathology 
or histopathology for diagnosis that include: 10 papillary thyroid carcinomas minimum, 10 Follicular neoplasms, 
and 30 benign nodules that include at least 5 Hashimoto nodules.  Therefore, a total of 50 thyroid nodules will 
form the initial software development reference set.  Based on the rate of non-benign nodules, it is expected 
that about twice the number of patients needed will have to be evaluated to obtain the minimum sample sizes 
noted above.  Therefore, the target evaluable sample size is N=100.  The ‘extra’ benign nodules enrolled are 
important because they will increase the statistical precision of key measures of predictive value including the 
increment improvement in specificity.  It is estimated that roughly 10% of enrolled patients may have thyroid 
nodules for which FNAB cytopathology is inadequate (after initial and potential subsequent FNA) and in whom 
surgical excision is not performed cannot be included in the study and will be replaced.  To account for this 
N=110 nodules will be enrolled. As discussed below, this study will rely on the TI-RAD risk categorization 
(categories 1-5).  After 50 nodules are identified as evaluable, the clinical status will be summarized, and if it is 
projected that there will be too few non-benign nodules, subsequent enrollment will be restricted to TI-RAD 
categories 3, 4, and 5.  
12.5. Analyses 
The following outlines the steps to be taken to develop and tune the image creation and colorization algorithm 
and to develop the guidelines and interpretations rules that will be subsequently applied by three independent 
readers.  The steps will be performed collaboratively by the software engineer and Medical Director, with 
potential input at earlier stages from the site radiologists.  
DEVELOPMENT OF GUIDELINES, INTERPRETATION RULES AND ESTIMATORS 
1. Images and data will provide a basis for algorithm finalization, potential instrument improvements, the 
development of guidelines for interpretation of OA studies of thyroid nodules.  Permit Imagio OA 
optimizations with respect to specific parameters (e.g. illumination and detection conditions, laser 
pulse repetition rate, sound propagation characteristics, etc.). Optimizations may be different for 
thyroid nodules and for suspicious cervical lymph nodes. 
2. Compare in vivo opto-acoustic images with those obtained from standard diagnostic thyroid 
ultrasound, color Doppler imaging (CDI), power Doppler imaging (PDI), strain elastography (SE), or 
shear wave elastography (SWE). 

 
 
 
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3. Compare the in vivo opto-acoustic features with those obtained from standard diagnostic thyroid 
ultrasound color Doppler imaging (CDI), power Doppler imaging (PDI), strain elastography (SE), or shear 
wave elastography (SWE). 
4. Compare findings of conventional imaging modalities and those of opto-acoustic imaging with biopsy 
results for nodule size, location, type, and stage. 
5. Develop Imagio-based estimators for thyroid use.  
Once the above steps are completed, quantitative analyses will be performed similar those performed during 
previous pilot studies of the Imagio OA in breast imaging.  The predictive and clinical classification results based 
on the optimal results determined from the process above will be summarized, as will the results based on 
application of the preliminary guidelines by three independent raters. The primary summary of results will 
include five by five cross-tabulation of initial TI-RAD category by TI-RAD category based Imagio OA stratified by 
clinical status (e.g., benign vs not benign and papillary thyroid carcinomas vs Follicular neoplasms, and benign 
nodules.  These tables will be used to determine the percentages of correct downgrades (among benign 
nodules) and correct upgrades (among non-benign nodules).   Specificity will be determined as the percentage 
of benign nodules with a final TI-RAD score of 1 or 2 since these risk categories generally would not result in 
further invasive evaluation unless patient requested.   The improvement in specificity comparing initial TI-RAD 
to TI-RAD after Imagio OA is considered a primary endpoint in this study.  Sensitivity will be similarly evaluated.  
Where appropriate, 95% confidence intervals will be determined to evaluate statistical precision of the 
estimates.  The results will also be expressed in terms of negative likelihood ratios (NLR) at specific TI-RAD 
categories. The NLR is the false-negative fraction divided by the true negative fraction at each level of TI-RAD.   
For dichotomous tests, this is (1-sensitivity) divided by specificity.  NLRs as well as positive likelihood ratios 
represent an effective way to summarize the predictive capacity of diagnostic tests.  Pre-test probabilities are 
converted to pre-test odds (Pre-test Odds = Probability/1-Probability).  Post-test Odds for a negative test = Pre-
test Odds times NLR.  Post-test probability = Post-test Odds / (1 + Post-test Odds).   Analyses will be performed 
for each independent rater and for a consensus rule based on pooling predictions across raters.  Weighted Kappa 
statistics and measures of overall agreement will be used to summarize prediction reliability across rates.  
 
12.5.1. Acceptability Metrics 
The primary metric for demonstration of feasibility is the incremental improvement in specificity.  An 
improvement of approximately 5% would be indicative of a successful feasibility study.  The percentage of 
correct downgrades is the next most important metric.  Other metrics including sensitivity and NLR will be 
considered supported evidence. 
 
 
 ADMINISTRATIVE CONSIDERATIONS 
13.1. Investigators and Study Administrative Structure 
Each site will have a designated investigator and one or more study coordinators collectively responsible for the 
conduct of the study inclusive of referral, screening, enrollment, evaluation, documentation, and subsequent 
biopsy in accordance with FDA guidelines.  
13.2. IRB Committee  
The protocol and the informed consent form, and any other institution-specific documents, must have the 
approval of a properly constituted IRB Committee responsible for approving clinical studies. The signed IRB 

 
 
 
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Committee approval letter must specify the date of protocol and informed consent form approval and identify 
the documents approved including the investigator's name, the protocol version, date and title. Any subject 
materials or advertisements used to recruit subjects should also be reviewed and approved by the IRB 
Committee.   
13.3. Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles outlined within FDA and GCP regulations 
as well as local IRB requirements.   
13.4. Informed Consent 
A signed Informed Consent Form (ICF) must be obtained from the subject prior to performing any study-related 
procedures. The investigator or investigator’s designee will provide background information on the study, 
including the benefits and risks of all study-related procedures to the subject. The investigator or investigator’s 
designee will also encourage the prospective subject to ask questions about the study and will provide the 
subject with sufficient opportunity to consider whether or not to participate. After written consent has been 
documented, previously obtained clinical radiographic data can be used for the study. 
 
Original signed informed consent forms must be filed in the subject records at the site. A copy of the signed 
consent/assent form should also be provided to the subject.  
 
The ICF for this study will be prepared by the study investigator for conformance with the government and 
institution’s requirements for this class of diagnostic imaging. However, all changes requested by an investigator 
or an Ethics Committee, even those that may not be considered substantial and/or do not affect the rights, 
safety or welfare of a subject, must be approved by Seno.  If Seno determines that the revisions are substantial 
and/or affect the rights, safety or welfare of a subject, the ICF must be reviewed and approved by both Seno 
and the Institutional Review Board before the ICF can be utilized.  
13.5. Subject Confidentiality 
Confidentiality will be maintained in accordance with FDA and IRB regulations. Subject names must not be 
revealed to the sponsor or sponsor’s representatives. Only the subject identifier (number) will be recorded in 
the eCRF and if the subject’s name appears on any other document, it must be redacted and replaced with the 
subject identifier before a copy of the document is supplied to the sponsor or sponsor’s representatives. Study 
findings stored on a computer will be stored in accordance with local data protection laws. In the event of 
inadvertent communication of such information, immediate steps to redact the information from all study files 
will be implemented, with appropriate documentation in the subject study file.  
13.6. Case Report Forms and Study Records 
Data will be recorded using an electronic data capture (EDC) system, according to FDA regulations. The database 
is considered validated when the expected results are the same as the actual results, and the end users verify 
that the database performs according to the requirements. 
 
The data will include collecting images and videos plus the Laser Optical Movie (LOM) to be sent to the Seno 
and/or the Central Imaging Core Lab as applicable.   
 

 
 
 
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The validation report, design procedures, testing results, source code, and test eCRF cases are filed in the central 
files. Database maintenance will be provided throughout the study, as well as user support and administration 
(access and site user rights set-up, removal, etc.) 
 
The MedDRA dictionary will be used to code adverse device effects.  
 
The investigator is responsible for maintaining adequate and accurate medical records from which information 
will be transferred into the study database.  
13.7. Clinical Quality Assurance 
The sponsor, or the sponsor’s representative, may conduct audits at the investigational sites. Audits may 
include, but are not limited to, device supply, presence of required documents, the informed consent process, 
and comparison of eCRFs with source documents (original medical records, images). The investigator agrees to 
participate with audits conducted at a reasonable time, in a reasonable manner. 
13.8. Protocol Amendments  
Any amendment to the study protocol must be approved by the sponsor. A protocol amendment may not be 
implemented until after it has been approved by the IRB, unless immediate implementation of the change is 
necessary for subject safety. In this case, the protocol change must be documented in an amendment.  
 
Once a protocol amendment has received approval from the sponsor, it will be submitted to the IRB Committee 
for written approval.  
13.9. Protocol Deviations 
Protocol deviations may occur in two ways. 
1. Deviations from the protocol, contrary to protocol specifications (i.e., deviations from the protocol 
procedures, eligibility, instructions for use, visit windows, etc.).  
2. Deviations affecting the endpoint outcome not previously specified in the protocol (i.e., deviation that 
had not been previously considered in the protocol or eligibility criteria, but having a clear impact on the 
primary outcome measure) 
 
The investigator is not allowed to deviate from this protocol except as specified in FDA regulations. The 
Investigator should not implement any deviation from or changes to the protocol without approval by Seno and 
prior review and documented approval/favorable opinion from the IRB of a protocol amendment, except where 
necessary to eliminate immediate hazards to study subjects, or when the changes involve only logistical or 
administrative aspects of the study (e.g., change in monitors, change of telephone numbers). While every effort 
should be made to avoid protocol deviations, should a deviation be discovered, Seno must be informed 
immediately. Any protocol deviation impacting subject safety must be reported to A. Thomas Stavros, M.D. 
Seno’s Medical Director immediately.  
 
Deviations will be documented in the eCRF. Investigators will also adhere to procedures for reporting 
investigation deviations to their ethics committee in accordance with their specific reporting policies and 
procedures.  
 
Prior to final database lock, all protocol deviations will be reviewed and categorized as major (i.e., those that 
affect measurement or interpretation of the primary endpoint or related to safety) or minor (those not affecting 

 
 
 
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the primary endpoint). The presence of a major deviation will exclude subjects from the Intention to Diagnose 
(ITD) analysis population. 
 
13.9.1. Corrective and Preventive Actions 
Seno Medical and her representatives will evaluate protocol deviations during monitoring visits. Individual event 
corrective and preventive actions may be recommended at that time. In addition, deviations occurring across 
investigational sites will be reviewed by Seno Medical on a periodic basis to determine if more global preventive 
actions may be required.   
 
13.9.2. Investigator Disqualification Criteria 
Seno Medical reserves the right to terminate an investigator/investigational site for any of the following 
reasons: 
• Failure to secure subject informed consent including protection of personal data prior to enrollment. 
• Failure to report unanticipated adverse device effects within 24 hours of discovery (to Seno Medical) 
and to the ethics committee within its required reporting time after learning of the event. 
• Failure to report serious adverse device effects within 24 hours of discovery. 
• Repeated investigational plan deviations. 
• Repeated failure to appropriately complete case report forms. 
• Failure to enroll an adequate number of subjects. 
• Loss of or unaccounted for investigational product inventory. 
13.10. Retention of Data 
All records, including compact disks of images, must be retained at each clinical site and by Seno or Seno’s 
representatives for a period of two years after the latter of the following two dates: the date the study is closed 
or terminated or the date of the last approval of a marketing application and records are no longer needed to 
support a regulatory submission. All study records may be relevant to regulatory inspection.  
 
In the event that the Principal Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept the 
responsibility and the sponsor must be notified. 
 
Seno or Seno’s representatives should be contacted in advance if there is a desire to discard or relocate any 
records or if there are any questions regarding record retention. 
 
Seno or Seno’s representatives will maintain all records related to this study, according to FDA and IRB 
regulations.  
 
Required regulatory reports will be submitted per FDA guidelines. 
13.11. Statement of Compliance 
This clinical investigation will be conducted in compliance with the principles that have their origin in the 
Declaration of Helsinki, this clinical investigation plan, requirements of the approving ethics committee, FDA 
and GCP Regulations and other applicable regulatory requirements.  
 

 
 
 
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This clinical investigation will not be initiated until approval has been obtained from the IRB committee. Any 
additional requirements imposed by the IRB committee will be followed. No deviation from the protocol will be 
implemented without the prior review and approval of the IRB committee except where it may be necessary to 
eliminate an immediate hazard to a subject. In such case, the deviation will be reported to the IRB committee 
as soon as possible.  
13.12. Financial Disclosure 
Investigators will be asked to provide financial disclosure prior to authorization to begin the study as well as 
after the study is completed. Investigators will also be expected to share any situations which could introduce 
site-specific bias. 
13.13. Publication and Disclosure Policy 
The results of the study are the property of Seno Medical Instruments, Inc. All publications (manuscripts, 
abstracts or other modes of presentation) must be submitted at a time determined by Seno Medical 
Instruments, Inc. and must be reviewed and approved in writing by Seno Medical Instruments, Inc., in advance 
of submission. Co-authorship with any Seno Medical Instruments, Inc. personnel will be discussed and mutually 
agreed upon before submission of a manuscript to a publisher.  
 
 
 SUSPENSION OR PREMATURE TERMINATION 
14.1. Criteria for Premature Termination 
Seno Medical reserves the right to terminate an investigator/investigational site for any of the reasons provided 
in Section 13.9.2 of this study protocol: Investigator Disqualification Criteria. In addition, Seno Medical may 
choose to suspend or prematurely terminate the investigation for the following reasons: 
• Device deficiency or malfunction  
• Administrative decision  
 
 
Seno Medical will promptly notify the investigators.

 
 
 
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L, Hamper U, Langer J, Scoutt L, Stavros T, Teffey S, ACR Thyroid Imaging, Reporting and Data System (TI-
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APPENDIX A ACR GUIDELINES 
Revised 2013 (Resolution 16) * 
The American College of Radiology, with more than 30,000 members, is the principal organization of 
radiologists, radiation oncologists, and clinical medical physicists in the United States. The College is a 
nonprofit professional society whose primary purposes are to advance the science of radiology, improve 
radiologic services to the patient, study the socioeconomic aspects of the practice of radiology, and encourage 
continuing education for radiologists, radiation oncologists, medical physicists, and persons practicing in allied 
professional fields.  
The American College of Radiology will periodically define new practice parameters and technical standards 
for radiologic practice to help advance the science of radiology and to improve the quality of service to 
patients throughout the United States. Existing practice parameters and technical standards will be reviewed 
for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated.  
Each practice parameter and technical standard, representing a policy statement by the College, has 
undergone a thorough consensus process in which it has been subjected to extensive review and approval. 
The practice parameters and technical standards recognize that the safe and effective use of diagnostic and 
therapeutic radiology requires specific training, skills, and techniques, as described in each document. 
Reproduction or modification of the published practice parameter and technical standard by those entities not 
providing these services is not authorized.  

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APPENDIX B:  PROTOCOL SIGNATURE PAGE 
I have read the protocol and agree that it along with the Clinical Trial Agreement contain all of the details 
necessary to carry out the study. I will conduct this study according to the protocol and required FDA and GCP 
regulatory requirements and will complete the study in the time agreed. Potential additions or modifications to 
the study will be by mutual written agreement between the Sponsor and me and will be documented and filed, 
if required, with the Institutional Review Board and the Food and Drug Administration. 
I will provide copies of the protocol and other pertinent information to all individuals responsible to me who 
will assist in the study. 
The Sponsor and applicable regulatory authorities will have direct access to source documentation from which 
case reports have been generated to conduct monitoring and audit checks as needed. 
_______________________________________________ 
Printed Name of Investigator 
_______________________________________________ 
Signature of Investigator 
_________________________ 
Date  

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APPENDIX C ACR TI-RADS: 

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APPENDIX D- THYROID SCANNING PROTOCOL REV. 06 (SID-0000002854)