Pilot Study of On-Cart Liver Fat Quantification (LFQ) Feature to Assess Correlation With Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) Results in a Pediatric Population
Phase: NA
Conditions: Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Steatohepatitis
Sponsor: Philips Clinical & Medical Affairs Global

 
 
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Pilot Study of On-Cart Liver Fat Quantification (LFQ) Feature to Assess Correlation 
with Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) Results 
in a Pediatric Population 
 
Short Title: Pediatric LFQ Phase 2 Pilot Study 
CTMS Protocol ID: US-GIS-Pediatric Liver Fat Quantification Phase 2-2020-10983 
 
Clinical Study Protocol Version 1.0 
Date: July 6, 2020 
 
 
Document Revision History 
Version 
Amendment 
Version Date 
Summary of Changes  
1.0 
N/A 
July 6, 2020 
Initial release 
 
 
 
Clinical Study Sponsor  
Philips Ultrasound 
22100 Bothell Everett Highway 
Bothell, WA 98021 
(888) 744-5477 
Sponsor Business Lead  
 
Gary Ng, Principal Scientist, Philips Ultrasound (GI) 
22100 Bothell Everett Highway 
Bothell, WA 98021 
Sponsor Research Lead 
 
Hua Xie, Principal Scientist, Philips Research North America 
2 Canal Park 
Cambridge, MA 02141 
Clinical Development Lead  
Jessica Parsons, Senior Clinical Development Scientist 
22100 Bothell Everett Highway 
Bothell, WA 98021 
Clinical Operations Lead 
Jeddah Wegerhoff, Senior Clinical Operations Manager 
22100 Bothell Everett Highway 
Bothell, WA 98021 
Biostatistics Lead 
Kevin Najarian, Global Director of Biostatistics and Data Management 
3000 Minuteman Rd 
Andover, MA 01810 
 
 
 

 
 
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Investigators, Clinical Study Sites, and Reviewing IRB Information 
 
Principal Investigators 
This information is maintained separately in the Trial Master File (TMF) for  
US-GIS-Pediatric Liver Fat Quantification Phase 2-2020-10983 
Co/Sub-Investigators 
Clinical Study Sites 
Reviewing IRBs 
 
Note: Signed Investigator Agreements are maintained separately from the Sponsor Approvals provided 
above.  The blank Investigator Agreement is provided in Section 22 of this Clinical Study Protocol. 
 
 

 
 
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Sponsor Approvals 
 
 
Pilot Study of On-Cart Liver Fat Quantification (LFQ) Feature to Assess Correlation with Magnetic 
Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) Results in a Pediatric Population 
 
Short Title: Pediatric LFQ Phase 2 Pilot Study 
CTMS Protocol ID: US-GIS-Pediatric Liver Fat Quantification Phase 2-2020-10983 
 
 
 
________________________________________________________ 
 
____________ 
Jessica Parsons (Author) 
 
 
 
 
 
 
 
Date 
Sr. Clinical Development Scientist, Clinical and Medical Affairs 
 
 
 
 
 
 
 
________________________________________________________ 
 
____________ 
Gary Ng 
 
 
 
 
 
 
 
 
 
Date 
Principal Scientist, Philips Ultrasound (GI) 
 
 
 
 
 
 
 
 
 
 
________________________________________________________ 
 
____________ 
Hua Xie  
 
 
 
 
 
 
 
 
 
Date 
Principal Scientist, Philips Research North America 
 
 
 
 
 
 
 
 
 
________________________________________________________ 
 
____________ 
Jeddah Wegerhoff 
 
 
 
 
 
 
 
 
Date 
Sr. Clinical Operations Manager, Clinical and Medical Affairs  
 
 
 
 
 
 
________________________________________________________ 
 
____________ 
Kevin Najarian  
 
 
 
 
 
 
 
 
Date 
Global Director of Biostatistics and Data Management, Clinical and Medical Affairs 
 
 

 
 
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Clinical Study Synopsis – Pediatric LFQ Phase 2 Pilot Study 
Study Title 
Pilot Study of On-Cart Liver Fat Quantification (LFQ) Feature to Assess Correlation with 
Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) Results in a 
Pediatric Population 
Short Title 
Pediatric LFQ Phase 2 Pilot Study 
Protocol ID 
US-GIS-Pediatric Liver Fat Quantification Phase 2-2020-10983 (short ID: 10983) 
Country/Region 
All clinical sites in the USA 
Regulatory Path 
Non-significant risk device and study per 21 CFR 812.3(m) 
Investigational Device  
Philips EPIQ Ultrasound System with imaging transducers (C5-1 and/or mC7-2) and 
investigational LFQ software (on-cart) 
Study Design  
Multicenter single-arm pilot study 
Enrollment 
Up to 150 subjects across all investigational sites 
Primary Objective 
To assess the correlation between each of several quantitative ultrasound biomarkers 
derived from the investigational LFQ feature and the known liver fat percentage obtained 
from MRI-PDFF, in order to identify which ultrasound biomarkers can best estimate the 
liver fat content. 
Secondary Objectives 
To evaluate the robustness of the investigational LFQ feature in the clinical environment 
by determining inter-operator variability in quantitative ultrasound biomarker 
measurements made on the same set of LFQ ultrasound images and the overall data 
acquisition failure rate (i.e., percentage of subjects who have unacceptable image quality 
due to technical limitations). 
Study-Related 
 Procedures 
Study-related procedures will consist of a single ultrasound imaging examination 
conducted with the Philips EPIQ Ultrasound System with investigational LFQ software.   
In addition, a standard MRI-PDFF examination is also required, unless MRI-PDFF is 
performed prior to enrollment as part of standard of care at the clinical site.  No other 
procedures are required.  All imaging procedures (investigational LFQ ultrasound exam 
and MRI-PDFF exam) must be completed within an 8-week window (+ 5 days). 
Study Duration 
Approximately 1 year from first subject enrollment to last subject visit 
Subject’s Participation 
Up to 8 weeks from enrollment to completion of all study-related procedures 
Primary  
Performance  
Endpoints 
The primary performance endpoints are measurements of the quantitative ultrasound 
biomarkers that are believed to be correlated with liver fat content and/or liver stiffness.  
The following specific biomarkers may be measured, though not all are required to be 
reported for every subject:  
• 
Hepatorenal Index (HRI) (unitless) 
• 
Acoustic attenuation (dB/cm/MHz) 
• 
Nakagami parameter (unitless) 
• 
Tissue viscosity (Pa∙s) (or viscosity-related metric) 
• 
Speed of sound (m/s) 
• 
Tissue stiffness (kPa) 
Performance of these endpoints will be evaluated by assessing their correlation with 
known liver fat percentages reported from MRI-PDFF. 

 
 
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Secondary 
Performance  
Endpoints 
• 
Inter-operator variability as measured by the difference in quantitative ultrasound 
biomarker measurements acquired from the same set of LFQ ultrasound images by 
two different operators who have undergone standardized training  
• 
Data acquisition failure rate as measured by percentage of subjects who have 
unacceptable image quality due to inadequate acoustic scanning windows, motion 
artifacts, or other technical limitations 
Primary Safety 
Endpoints 
Number and seriousness of any Adverse Device Effects reported  
Subject Population 
Subjects will be identified from a pediatric population suspected of having or diagnosed 
with NAFLD/NASH and who are eligible to undergo standard abdominal ultrasound 
imaging and MRI-PDFF. 
Inclusion Criteria 
• 
Subjects at least 5 years old up through and including 21 years old who are able to 
provide informed consent to participate or have a legal representative/parent/legal 
guardian who is able to provide informed consent for the subject to participate. 
• 
Subjects must be eligible for a standard abdominal ultrasound examination and 
standard non-contrast MRI examination. 
In addition, at least one of the following criteria must also be met: 
• 
Overweight or obese (BMI-for-age ≥ 85th percentile). 
• 
Diagnosed with Type 2 diabetes per standard clinical guidelines. 
• 
Diagnosed with hypercholesterolemia per standard clinical guidelines. 
• 
Diagnosed with or clinically suspected of having NAFLD/NASH based on previous 
medical record, medical imaging, liver biopsy, and/or laboratory testing. 
Exclusion Criteria 
• 
History of moderate/heavy/binge alcohol consumption exceeding NIAAA guidelines.1 
• 
Evidence of hepatotoxicity or cirrhosis in the clinical judgment of the investigator. 
• 
History of chronic liver disease other than NAFLD (e.g., viral, cholestatic, or 
autoimmune). 
• 
Use of drugs associated with hepatic steatosis:2 
o 
Amiodarone  
o 
Methotrexate 
o 
Nucleoside reverse transcriptase inhibitors (didanosine, stavudine) 
o 
Valproic acid 
o 
Dexamethasone 
o 
Tamoxifen 
o 
5-FU-based adjuvant chemotherapy 
o 
Apo-B inhibitors (mipomersen, lomitapide) 
o 
Tetracycline exceeding 2 g/day 
o 
Acetylsalicylic acid exceeding 150 mg/kg 
 
1 National Institute on Alcohol Abuse and Alcoholism. URL: https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-
consumption/moderate-binge-drinking 
2 List adapted from Amacher DE and Chalasani N. Drug-Induced Hepatic Steatosis. Semin Liver Dis 34: 205-214 (2014). 
 

 
 
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• 
Subjects with hepatic lesions that cannot be excluded from the imaging field during 
ultrasound LFQ data acquisition. 
• 
Subjects anticipated or planned to undergo any therapeutic intervention during 
enrollment period that, at discretion of the Investigator, may affect liver fat content 
(e.g., chemotherapy). 
• 
History of previous liver surgery or hepatic implants that, at the discretion of the 
Investigator, may adversely impact ultrasound or MRI image quality or the subject’s 
eligibility to undergo ultrasound or MRI. 
Follow-up  
Assessments 
None – subject participation ends at time of imaging procedure completion 
Data Shared  
with Sponsor 
De-identified ultrasound imaging data (biomarker measurements, DICOM files of static 
images and cineloops, raw radiofrequency data), de-identified MRI-PDFF imaging data 
(DICOM files), radiology reports of MRI-PDFF studies including fat percentage results, 
and pertinent health records including laboratory test results related to liver function (if 
available) and liver biopsy reports (if available) may be shared with Philips as part of the 
study, following appropriate privacy protections.  All Protected Heath Information (PHI) 
will be removed before sharing. 
 
 
 
 
 

 
 
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Table of Contents 
 
1. List of Abbreviations .............................................................................................................. 11 
2. Introduction ............................................................................................................................. 12 
2.4.1 
Philips EPIQ Ultrasound System and Imaging Transducers (C5-1 and mC7-2) ...... 13 
2.4.2 
Philips Investigational LFQ Feature: Ultrasound Biomarkers for NAFLD/NASH ...... 14 
2.4.3 
Physiological Basis for Correlation of Ultrasound Biomarkers with Disease State .. 15 
3. Rationale for Conducting Clinical Study ............................................................................... 17 
3.1.1 
Statement of Risk Level ......................................................................................... 17 
3.1.2 
Anticipated Clinical Benefits ................................................................................... 17 
3.1.3 
Anticipated Adverse Device Effects ........................................................................ 17 
3.1.4 
Clinical Study Participation Risks ........................................................................... 17 
3.1.5 
Interactions from Concomitant Medications or Treatments ..................................... 18 
3.1.6 
Risk Mitigations ...................................................................................................... 18 
3.1.7 
Risk to Benefit Ratio ............................................................................................... 18 
4. Clinical Study Design: Objectives and Endpoints ................................................................ 21 
4.2.1 
Overall Aim ............................................................................................................ 21 
4.2.2 
Primary Objective ................................................................................................... 21 
4.2.3 
Secondary Objective .............................................................................................. 21 
4.3.1 
Primary Safety Endpoints ....................................................................................... 22 
4.3.2 
Primary Performance Endpoints ............................................................................. 22 
4.3.3 
Secondary Performance Endpoints ........................................................................ 22 

 
 
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5. Study Subjects ........................................................................................................................ 24 
5.6.1 
Study Duration - Global .......................................................................................... 26 
5.6.2 
Study Duration – Individual Subject ........................................................................ 26 
6. Study Procedures ................................................................................................................... 27 
6.4.1 
Visit 1: Screening, Enrollment, Investigational LFQ Ultrasound Exam, and MRI-
PDFF Exam ........................................................................................................................... 27 
6.4.2 
Visit 2 (Optional): Investigational LFQ Ultrasound Exam (if not already performed) 29 
6.4.3 
Visit 3 (Optional): Study-Related MRI-PDFF Exam (if not already performed) ........ 30 
6.4.4 
Study Exit ............................................................................................................... 30 
6.5.1 
Cases where MRI-PDFF is Performed Prior to Enrollment ..................................... 31 
6.5.2 
Cases where MRI-PDFF is Performed as a Study-Related Procedure after 
Enrollment ............................................................................................................................. 32 
7. Data Analysis and Statistical Considerations ....................................................................... 34 
7.2.1 
Intention-to-Treat Group ......................................................................................... 34 
7.2.2 
Per-Protocol Group ................................................................................................ 34 

 
 
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7.2.3 
Per-Protocol with Optimal Data Acquisition Group ................................................. 34 
8. Monitoring Plan ....................................................................................................................... 36 
9. Data Management, Quality Assurance, and Confidentiality Standards .............................. 37 
10. 
Amendments to the Clinical Study Protocol .................................................................. 38 
11. 
Deviations from the Clinical Study Protocol .................................................................. 39 
12. 
Investigator and Site Qualifications ............................................................................... 40 
13. 
Product Labelling and Accountability ............................................................................ 41 
13.1.1 
Product Labeling .................................................................................................... 41 
13.1.2 
Accountability Documentation ................................................................................ 41 
13.1.3 
Monitoring .............................................................................................................. 41 
13.2.1 
Accountability Documentation ................................................................................ 41 
13.2.2 
Accountability Reporting ......................................................................................... 42 
13.2.3 
Study Product Return ............................................................................................. 42 
14. 
Informed Consent (including Assent for Minors) .......................................................... 42 

 
 
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15. 
Safety Events: Definitions, Reporting, and Follow-up .................................................. 43 
16. 
Vulnerable Populations ................................................................................................... 47 
17. 
Suspension or Premature Termination of the Clinical Study ....................................... 47 
18. 
Publication Policy ............................................................................................................ 47 
19. 
Registration on Publically-Accessible Clinical Study Registry .................................... 48 
20. 
Statements of Compliance .............................................................................................. 48 
21. 
Referenced Documents ................................................................................................... 48 
22. 
Investigator Agreement ................................................................................................... 49 
23. 
Selected Bibliography ..................................................................................................... 50 
 
 
 

 
 
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1. 
List of Abbreviations 
 
 
Abbreviation 
Definition 
AE 
Adverse Event 
AUROC 
Area Under Receiver Operating Characteristic 
CAP 
Controlled Attenuation Parameter (EchoSens Fibroscan) 
CFR 
United States Code of Federal Regulation 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTMS 
Clinical Trial Management System 
DDE 
Direct Data Entry 
DICOM 
Digital Imaging and Communications in Medicine (format standard) 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption (FDA) 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ITT 
Intention-to-Treat subject population 
LFQ 
Liver Fat Quantification 
MRI-PDFF 
Magnetic Resonance Imaging - Proton Density Fat Fraction 
NAFLD 
Non-alcoholic fatty liver disease 
NASH 
Non-alcoholic steatohepatitis 
NPO 
Nil per os (nothing by mouth) 
PHI 
Protected Health Information 
PP 
Per-Protocol subject population 
PP-ODA 
Per-Protocol with Optimal Data Acquisition subject population 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis Software 
SoS 
Speed of sound 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
VCTE 
Vibration-Controlled Transient Elastography (EchoSens Fibroscan) 
 
 
 

 
 
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2. 
Introduction 
 
 
Overview and Purpose of Clinical Study 
 
Philips Ultrasound is developing an investigational ultrasound-based Liver Fat Quantification (LFQ) 
software feature intended to provide a noninvasive imaging solution for detection, staging, and 
longitudinal monitoring of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis 
(NASH) in the at-risk pediatric and adult populations.  This investigational LFQ feature is designed to 
integrate with the Philips EPIQ Ultrasound System and specific imaging transducers (C5-1 and mC7-2), 
all of which are already commercially available, in order to expand the range of clinical imaging-based 
biomarkers for detecting, staging, and monitoring NAFLD.   
 
The current benchmark for noninvasive imaging-based LFQ is Magnetic Resonance Imaging Proton 
Density Fat Fraction (MRI-PDFF), which can provide sensitive quantitative assessments of steatosis for 
diagnosis and disease staging; however, MRI-PDFF is cost-prohibitive when repeated measurements 
are necessary for monitoring therapeutic response or disease progression.  The goal of the Philips 
investigational LFQ feature is to enable rapid noninvasive ultrasound-based measurements of steatosis 
with reduced cost and capital equipment complexity compared to MRI-PDFF.  The investigational LFQ 
feature is intended to complement Philips’ currently available ElastQTM shear wave imaging solution to 
provide a comprehensive set of ultrasound-based liver assessment tools to evaluate both steatosis and 
fibrosis.  This approach will give the health care provider a complete suite of noninvasive tools to assess 
disease severity and monitor the effectiveness of any prescribed interventions (e.g., pharmaceutical 
therapy, diet restrictions, and/or other lifestyle modifications).   
 
This clinical study will involve performing a series of medical imaging procedures of the abdomen using 
both ultrasound and MRI modalities in pediatric subjects at risk for or already diagnosed with NAFLD.  
The primary objective of this clinical study is to assess the correlation between each of several 
quantitative ultrasound biomarkers derived from the investigational LFQ feature and the known liver fat 
percentage obtained from MRI-PDFF, in order to identify which ultrasound biomarkers can best estimate 
liver fat content in the pediatric population.  This correlation assessment will enable final product 
development of the Philips ultrasound-based LFQ feature.   
 
 
Context of Study in Clinical Development Plan   
 
The clinical study described in this protocol represents the first pilot study in which the investigational 
LFQ feature will be installed on the Philips EPIQ Ultrasound System (‘on-cart’) and deployed in real-time 
during abdominal ultrasound examinations.  Earlier studies of the investigational LFQ feature were ‘off-
cart’ and were limited to off-line processing of ultrasound data.  Transitioning to this on-cart pilot study is 
an important step that will enable the LFQ algorithm to be evaluated under real-world clinical conditions.  
The evidence obtained from this pilot study will be used to complete development of the investigational 
LFQ algorithm and inform future product claims, which will then be validated in the setting of a 
subsequent confirmatory study. 
 
 
Intended Population and Indications   
 
Participants in this clinical study will be drawn from the male and female pediatric population in the 
United States suspected of having or diagnosed with liver disease on the NAFLD spectrum, including 
non-alcoholic steatohepatitis (NASH).  Complete inclusion/exclusion criteria are specified in Section 5.   
 
 
 

 
 
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Description of Investigational Device 
 
As described in Table 1, the investigational device that is the subject of this clinical study is 
manufactured by Philips Ultrasound and consists of three main components: (1) the FDA-cleared Philips 
EPIQ Ultrasound System with ElastQTM shear wave imaging, (2) FDA-cleared ultrasound imaging 
transducers (C5-1 and mC7-2), and (3) the investigational LFQ software package, which is currently 
under development by Philips and does not yet have regulatory clearance.  The investigational LFQ 
software will be installed on the EPIQ Ultrasound System when this study is performed.  These 
components are summarized in Table 1. 
 
Table 1.  Identification of Manufacturer and Investigational Device Components 
Device Manufacturer 
Philips Ultrasound 
22100 Bothell Everett Highway 
Bothell, WA 98021 
(888) 744-5477 
Device Component 
Investigational Status 
Regulatory Clearance 
Philips EPIQ Ultrasound System 
with ElastQTM 
FDA cleared, marketed in US 
510(k): K182857 
Philips C5-1 imaging transducer 
FDA cleared, marketed in US 
510(k): K182857 
Philips mC7-2 imaging transducer 
FDA cleared, marketed in US 
510(k): K182857 
Philips LFQ software package 
Investigational: not cleared for 
commercial use in USA 
n/a 
 
2.4.1 Philips EPIQ Ultrasound System and Imaging Transducers (C5-1 and mC7-2) 
 
The intended use of the Philips EPIQ Ultrasound System is for diagnostic ultrasound imaging and fluid 
flow analysis of the human body.  When coupled with the C5-1 imaging transducer, the cleared 
indications for use per 510(k) K182857 are abdominal, fetal/obstetrical, fetal echo, gynecological, 
urological, pediatric, and peripheral vessel imaging applications.  When coupled with the mC7-2 imaging 
transducer, the cleared indications for use per 510(k) K182857 are abdominal and pediatric imaging 
applications.  The only portion of the device that comes in contact with the subject under normal use is 
the surface of the imaging transducer (C5-1 or mC7-2), which has been tested for compliance with 
applicable biological safety standards (see Table 3).  The EPIQ Ultrasound System and imaging 
transducers (C5-1 and mC7-2) are shown in Figure 1 below. 

 
 
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Figure 1.  Philips EPIQ Ultrasound System. ① Monitor ② On/Off Switch ③ Control Module ④ 
Transducer receptacle locks ⑤ Transducer receptacles ⑥ side panel ⑦ brake/steering lock pedal ⑧ 
touch screen ⑨ peripheral bays ⑩ Philips C5-1 Imaging Transducer (curvilinear, 5 – 1 MHz frequency) 
⑪ Philips mC7-2 Imaging Transducer (curvilinear, 7 – 2 MHz frequency). 
 
2.4.2 Philips Investigational LFQ Feature: Ultrasound Biomarkers for NAFLD/NASH 
 
The investigational LFQ feature is a software package under development intended for use with certain 
Philips ultrasound imaging systems including the EPIQ Ultrasound System.  The LFQ feature works in 
conjunction with standard Philips ultrasound system hardware and transducers to collect acoustic 
signals from the liver for analysis during abdominal ultrasound examinations.  These acoustic signals are 
processed via a series of specialized algorithms to measure several quantitative ultrasound biomarkers 
that are believed to correlate with liver fat content and may therefore provide relevant information for 
NAFLD/NASH diagnosis and staging.   
 
There are multiple candidate quantitative ultrasound biomarkers derived from these acoustic signals that 
are currently being evaluated in the Philips investigational LFQ feature, though additional biomarkers 
may be identified during ongoing development.  Some of these biomarkers may be measured in real-
time during the investigational LFQ exam, while others will be calculated from offline processing.  In 
addition, an established biomarker measured using the Philips ElastQTM shear wave imaging feature, 
tissue stiffness, may be used to assess the degree of tissue fibrosis to determine whether a patient’s 
NAFLD may have progressed to NASH.  These various quantitative ultrasound biomarkers are 
described in Table 2.   
 
 
 
10 
11 

 
 
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Table 2.  Candidate Quantitative Ultrasound Biomarkers for Assessing NAFLD/NASH 
Biomarker 
Units 
Qualitative Correlation with NAFLD/NASH 
Hepatorenal Index (HRI) 
(echogenicity) 
(source: investigational LFQ) 
unitless 
Increased steatosis is associated with increased liver 
echogenicity, manifested as an increased HRI value (ratio of 
the echogenicity (‘brightness’) of the liver parenchyma 
relative to that of the adjacent renal cortex).   
Acoustic attenuation 
(source: investigational LFQ) 
dB/cm/MHz 
Increased steatosis is associated with an increased acoustic 
attenuation value in the liver. 
Nakagami parameter 
(backscatter statistics) 
(source: investigational LFQ) 
unitless 
Increased steatosis is associated with an increased 
Nakagami parameter, which represents a shift in the 
ultrasound backscatter distribution. 
Tissue Viscosity 
(source: investigational LFQ) 
Pa∙s 
Increased steatosis and/or liver inflammation may be 
associated with increased tissue viscosity in the liver. 
Speed of sound 
(source: investigational LFQ) 
m/s 
Increased steatosis may be associated with a decreased 
speed of sound (SoS) in the liver. 
Tissue stiffness 
(source: cleared ElastQTM 
shear wave imaging) 
kPa 
Increased fibrosis is associated with increased tissue 
stiffness and increased shear wave velocity in the liver. 
 
These represent the known candidate quantitative ultrasound biomarkers under consideration presently, 
and this list may evolve over time.  As a result, not all of these biomarkers are required to be measured 
in every subject, and it is possible that additional candidates may be added.   
 
2.4.3 Physiological Basis for Correlation of Ultrasound Biomarkers with Disease State 
 
These ultrasound biomarkers are leveraged in the investigational LFQ feature and the ElastQTM shear 
wave imaging feature because each is directly influenced by the physiology of the NAFLD disease 
process.  Brief overviews of the physiological basis of these biomarkers are described below: 
 
a. Hepatorenal Index (HRI) / Liver Echogenicity: As a biological tissue, fatty tissue characteristically 
has a lower acoustic impedance than other soft tissue types.  As a result, as lipid content increases 
in the liver, the difference between the acoustic impedance of the liver and that of the surrounding 
abdominal tissues will increase accordingly.  This increased impedance mismatch causes larger 
acoustic reflections to occur during standard B-mode ultrasound imaging, resulting in an increased 
liver echogenicity (‘brightness’) compared to that of surrounding tissues.  When the echogenicity of 
the liver is referenced against that of the adjacent renal cortex, fatty liver will therefore result in an 
increased HRI that can be readily detected.  For example, HRI cutoff values of 1.49, 1.86 and 2.23 
have be reported to predict 5%, 25% and 60% steatosis, respectively (Webb et al. 2009). 
 
b. Acoustic Attenuation: The presence of fatty tissue will increase the attenuation of the ultrasound 
beam as it propagates through the tissue, due in part to acoustic absorption being higher for fatty 
tissues than in other soft tissue types.  For example, Yasutomo et al. (2002) reported that 
attenuation coefficient values were 0.59 ± 0.10 dB/cm/MHz in normal livers vs. 0.80 ± 0.12 

 
 
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dB/cm/MHz in fatty livers (P<.0001).  Regions of high fat content in the liver may therefore have 
elevated acoustic attenuation coefficients. 
 
c. Nakagami Parameter (Backscatter Statistics): The large vacuoles of triglycerides that accumulate in 
hepatocytes when steatosis is present alter the arrangement of scatterers within the tissue, thereby 
affecting the underlying statistics of the backscattered ultrasound signals.  The Nakagami parameter 
considers the envelope of the backscattered signal to detect shifts in the distribution of scatterers.  
For example, Wan et al. (2015) reported an increase in Nakagami parameter from 0.62 ± 0.11 to 
1.02 ± 0.07 in two groups of patients with normal and severe steatosis, respectively.  Regions of high 
fat content in the liver may therefore demonstrate an increased Nakagami parameter. 
 
d. Tissue Viscosity (or viscosity-related metric): The change in liver tissue composition that occurs 
during NAFLD due to excessive deposition of viscous triglycerides and associated inflammatory 
responses in hepatocytes may result in an increase in tissue viscosity.  For example, Sugimoto et al. 
(2018) explored the possibility that viscosity may be increased in steatotic patients with liver 
necroinflammation and found a correlation, whereby higher viscosity was indicative of greater 
inflammation.  Other alternative metrics related to tissue viscosity may also be explored as part of 
the investigational LFQ feature. 
 
e. Speed of Sound: Fatty tissue has a decreased speed of sound (acoustic velocity) compared to most 
other biological tissue types, due to its reduced density relative to predominantly water-bearing 
tissues.  In a preliminary clinical trial (Imbault et al. 2017), speed of sound results were found to be 
highly correlated with MRI-PDFF (R2  =  0.69) and biopsy (AUROC  =  0.952) results.  Regions of high 
fat content in the liver may therefore demonstrate lower speed of sound measurements. 
 
f. 
Tissue Stiffness and Shear Wave Velocity: As NAFLD progresses into NASH and/or cirrhosis, the 
ensuing chronic inflammation results in widespread parenchymal fibrosis and scarring within the 
liver.  This global fibrotic process increases the elasticity of the liver and causes it to lose 
compliance, resulting in increased tissue stiffness that can be detected using ultrasound 
elastography techniques.  The Philips LFQ feature will complement the commercially available 
ElastQTM shear wave imaging feature, which remotely induces shear waves and monitors the 
velocity of their propagation through the liver to obtain measurements of tissue stiffness.  The liver 
stiffness and shear wave velocity measurements can then be used as a surrogate marker for fibrosis 
to monitor the progression of NAFLD to NASH. 
 
 
 

 
 
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3. 
Rationale for Conducting Clinical Study 
 
Justification for conducting this clinical study in human subjects is based on the low risk profile of the 
investigational device and the study design, the clear evidence of a clinical unmet need that the Philips 
investigational LFQ feature intends to address, and the comprehensive preclinical product testing that 
has been performed to demonstrate subject and user safety.  These aspects are discussed individually 
in the following sections.   
 
 
Risks and Benefits of the Investigational Device and Clinical Study 
 
3.1.1 Statement of Risk Level 
 
This clinical study is expected to be an IDE-exempt Non-Significant Risk Study, as defined in 21 CFR 
812.3(m), because the only study-related procedures required are an abdominal ultrasound examination 
using the investigational LFQ software and a commercially available MRI-PDFF examination, if not 
performed prior to enrollment.  No additional risk to subjects is expected beyond that associated with 
any standard diagnostic abdominal ultrasound imaging or MRI procedure.  Due to the overall low risk 
profile of this study, it is expected that only IRB/EC approval will be needed.   
 
3.1.2 Anticipated Clinical Benefits 
 
There are no direct health benefits to the subject for participating in this study because no treatment or 
diagnosis is being provided by study-related procedures.  The ultrasound examination performed using 
the investigational LFQ software will not provide any diagnostic or health-related information to the 
subject or the clinician.  However, for those subjects who will undergo MRI-PDFF as a study-related 
procedure, this examination may provide additional information regarding their health that they would not 
otherwise receive.   
 
3.1.3 Anticipated Adverse Device Effects 
 
There are no significant Anticipated Adverse Events and Anticipated Adverse Device Effects associated 
with this clinical study because the investigational procedure is limited to noninvasive diagnostic 
ultrasound imaging of the abdomen using the investigational LFQ software.  The Philips EPIQ 
Ultrasound System with investigational LFQ software and the imaging transducers (C5-1 and mC7-2) 
have been verified to comply with harmonized safety standards governing all diagnostic ultrasound 
imaging devices (e.g., IEC 60601-1-2 and IEC 60601-2-37, see Table 3) and therefore pose no 
additional risk to subjects beyond that associated with any other diagnostic ultrasound imaging 
procedure of the abdomen.  Only nonserious ADEs, if any, are therefore anticipated; these may include: 
 
• 
potential discomfort during the ultrasound examination due to body positioning  
• 
potential discomfort during the ultrasound examination due to pressure exerted by the ultrasound 
transducer when it is pressed against the abdominal skin 
 
3.1.4 Clinical Study Participation Risks 
 
Beyond the risks associated with the Anticipated Adverse Device Effects listed above, participation in 
this clinical study includes other types of risks.  These include standard risks associated with the MRI-
PDFF examination, if that procedure is conducted as a study-related procedure.  MRI-PDFF-associated 
risks include anxiety due to claustrophobic feeling while in the MRI machine and the potential for injury if 

 
 
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the subject has undisclosed contraindications to MRI (e.g., implantable devices including pacemakers, 
certain types of artificial joints, etc.).  These contraindications will be fully discussed during the subject’s 
informed consent discussion for the MRI-PDFF procedure. Moreover, the MRI equipment makes loud 
banging noises as it takes images which might be uncomfortable for the patient, for which earphones 
may be used. The MRI equipment also has the potential to cause localized warming of the skin and the 
underlying tissues. The patient may also experience dizziness or rarely nausea, which in most cases 
only lasts a short time. No case of permanent problems is known. 
 
3.1.5 Interactions from Concomitant Medications or Treatments 
 
There are no safety risks expected due to interactions with any concomitant medications or treatments, 
since this clinical study involves medical imaging procedures only. 
 
3.1.6 Risk Mitigations 
 
Risks will be mitigated by using standard clinical sonography techniques during all LFQ ultrasound 
examinations to minimize subject discomfort.  Furthermore, Philips’ risk management activities are 
compliant with EN-ISO 14971:2012 (Medical devices: Application of risk management to medical 
devices), which ensures that all risks are identified, assessed, and mitigated to acceptable levels. 
 
Risks of MRI-PDFF will be mitigated through standard-of-care informed consent procedures that will 
disclose all contraindications and known risks of MRI to the subject before the procedure is performed.   
 
3.1.7 Risk to Benefit Ratio 
 
Based on consideration of the above information, this clinical study generally has a low risk profile but 
may provide valuable information to enable product development of a noninvasive NAFLD screening 
and staging tool.  While there is no immediate or direct benefit to subjects for participating in this study, 
the general body of medical knowledge related to metabolic liver disease will be advanced by providing 
new information regarding noninvasive ultrasound biomarkers for NAFLD and NASH. 
 
 
Disease State and Clinical Unmet Need 
 
Hepatic steatosis is the abnormal and excessive intracellular accumulation of triglycerides within 
hepatocytes, which causes oxidative stress and inflammation over time (Idilman et al. 2013).  
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders that range from simple steatosis to 
more severe manifestations including nonalcoholic steatohepatitis (NASH) and cirrhosis.  A hallmark of 
NAFLD is that it is not precipitated by alcohol consumption but is instead a hepatic manifestation of 
metabolic syndrome, which is associated with obesity, insulin resistance, Type 2 diabetes mellitus, 
hypertension, hyperlipidemia, and cardiovascular disease. NAFLD is currently estimated to affect 30-
40% of all US adults, including 70% of Type 2 diabetics and obese adults.3  In the pediatric population, 
the prevalence of NAFLD has been estimated to be between 3–12%, but may possibly be as high as 
70–80% among those children who are considered obese (Alisi et al. 2012).  Approximately 20% of 
patients with NAFLD will progress to develop NASH and the attendant risks of cirrhosis, hepatocellular 
carcinoma, and liver-related morbidity and mortality. Moreover, NAFLD is often asymptomatic until its 
later stages, so there is a pressing clinical need for cost-effective screening and diagnostic techniques. 
 
 
3 National Institute of Diabetes and Digestive and Kidney Diseases. URL: https://www.niddk.nih.gov 
 

 
 
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For comprehensive liver assessment, clinicians need information about fibrosis, steatosis, and 
inflammatory processes occurring within the liver.  Currently, liver biopsy and MRI-PDFF are the 
generally accepted techniques available for definitive liver fat quantification and serve as reference 
methods to accurately diagnose and stage hepatic steatosis.  However, liver biopsies are invasive 
procedures that carry risk of bleeding and perforation, and they are limited by spatial sampling bias.  
While MRI-PDFF provides accurate measurements of steatosis, it is cost-prohibitive for longitudinal 
monitoring and cannot be deployed in real-time.  A third option known as CAP (Controlled Attenuation 
Parameter) is available using the Fibroscan product (EchoSens, Paris, France).  When used together, 
Fibroscan’s CAP and Vibration-Controlled Transient Elastography (VCTE™) can provide simultaneous 
liver steatosis and fibrosis assessment.  However, the Fibroscan product has been associated with rates 
of unreliable results on the order of 15% (Myers et al. 2011) due to frequent invalid measurements in 
patients with high body mass index (BMI) or central obesity, which are comorbidities often encountered 
in NAFLD patients.  The Fibroscan product also fails on patients with liver ascites and liver masses.  
Additionally, because the Fibroscan product lacks a fully integrated conventional ultrasound imaging 
capability, clinicians have no visual guidance to ensure that the VCTETM measurement is performed in a 
uniform region of the liver.  
 
The investigational LFQ feature under development for the Philips EPIQ Ultrasound System is intended 
to overcome some of these practical limitations associated with other clinically available methods for 
NAFLD/NASH diagnosis and staging.  By integrating a LFQ capability into the Philips EPIQ Ultrasound 
System to provide complementary information to Philips’ existing Shear Wave Elastography (SWE) 
imaging capabilities, 2D imaging, and flow assessment, a state-of-the-art imaging-based solution is 
envisioned to noninvasively detect and monitor both liver steatosis and fibrosis in real-time. 
 
 
Compliance with Medical Device Safety Standards and Good Clinical Practice 
Standards 
 
The Philips EPIQ Ultrasound System used with on-cart investigational LFQ software and the 
commercially-available C5-1 and mC7-2 ultrasound imaging transducers are considered safe for use in 
human subjects in this clinical study because extensive safety testing has been conducted to confirm the 
safety profile and all hardware is FDA-cleared via 510(k) as per Table 1.  Furthermore, the only portion 
of the device that contacts the subject’s body is the commercially available imaging transducer (C5-1 or 
mC7-2).   
 
The Philips EPIQ Ultrasound System with investigational LFQ software and the imaging transducers 
(C5-1 and mC7-2) comply with the following medical device safety standards listed in Table 3.  In 
addition, this clinical study is designed to comply with the Good Clinical Practice standard listed in Table 
3.  Compliance with these standards confirms that adequate evidence of safety and human subject 
protection has been established to justify use of the investigational device on human subjects. 
 
 
 

 
 
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Table 3: Compliance with Medical Device Safety and Good Clinical Practice Standards 
 
Standard Name and Description 
Electrical Safety 
EN/IEC 60601-1 – Medical electrical equipment – Part 1: General requirements for basic 
safety and essential performance.  The Philips EPIQ System with investigational LFQ 
software and the imaging transducers (C5-1 and mC7-2) have been designed and verified to 
comply with the electrical safety requirements of this standard, including requirements for 
electrical ground bond, leakage current, and dielectric withstand.  
Electromagnetic 
Compatibility 
EN/IEC 60601-1-2 – Medical electrical equipment – Part 1-2: General requirements for basic 
safety and essential performance – Collateral standard: Electromagnetic compatibility – 
Requirements and tests.  The Philips EPIQ System with investigational LFQ software and the 
imaging transducers (C5-1 and mC7-2) have been designed and verified to comply with the 
radiated and conducted emission requirements of this standard. 
Usability 
EN/IEC 60601-1-6 – Medical electrical equipment – Part 1-6: General requirements for basic 
safety and essential performance – Collateral standard: Usability.  The Philips EPIQ System 
with investigational LFQ software and the imaging transducers (C5-1 and mC7-2) have been 
designed and verified to comply with the usability requirements of this standard. 
Diagnostic 
Ultrasound 
Imaging 
EN/IEC 60601-2-37 – Medical electrical equipment – Part 2-37: Particular requirements for 
basic safety and essential performance of ultrasonic medical diagnostic and monitoring 
equipment.  The Philips EPIQ System with investigational LFQ software and the imaging 
transducers (C5-1 and mC7-2) have been designed and verified to comply with the diagnostic 
ultrasound imaging requirements of this standard.  
Biological Safety 
EN/ISO 10993-1 – Biological evaluation of medical devices – Part 1: Evaluation and testing 
within a risk management process.  The patient contact surface of the imaging transducers 
(C5-1 and mC7-2) has been designed and verified to comply with the biological safety 
requirements of this standard and FDA Memorandum G95-1:1995.  The evaluations included 
cytotoxicity, sensitization, and intracutaneous reactivity testing for surface devices with 
limited-duration skin contact. 
Risk Management 
EN/ISO 14971 – Medical devices: Application of risk management to medical devices.  The 
risk assessment and mitigation procedures for the Philips EPIQ System with investigational 
LFQ software and the imaging transducers (C5-1 and mC7-2)  have been conducted in 
compliance with the requirements of this standard. 
Clinical 
Investigation 
EN/ISO 14155 – Clinical investigation of medical devices for human subjects: Good clinical 
practice.  This clinical study of the Philips EPIQ System with investigational LFQ software and 
the imaging transducers (C5-1 and mC7-2)  is designed and conducted to comply with the 
content and human protections requirements of this standard.  This compliance ensures that 
clinical investigations adhere to current Good Clinical Practice (GCP) guidelines. 
Device Labeling 
EN/ISO 15223-1 – Symbols to be used with medical device labels, labeling, and information 
to be supplied – Part 1: General requirements.  The labelling associated with the Philips EPIQ 
System with investigational LFQ software and the imaging transducers (C5-1 and mC7-2) has 
been designed and verified to comply with the requirements of this standard. 
 
 
 

 
 
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4. 
Clinical Study Design: Objectives and Endpoints 
 
 
Overview of Study Design Attributes 
 
This clinical study will be conducted in the United States under the approval of one or more recognized 
IRBs and in compliance with GCP guidelines defined in ISO 14155:2011, the Declaration of Helsinki, and 
all applicable federal and local laws and regulations.  This study is a prospective single-arm pilot study 
intended to gather data to support final product development of the investigational LFQ feature.  No 
specific a priori performance claims are being validated during this study, though data from this study 
are intended to inform future claims regarding the performance of the LFQ feature.   
 
Subject data from all clinical sites are intended to be pooled for analysis.  Separate analysis tiers are 
planned as described in Section 7 (Data Analysis and Statistical Considerations) for the Intention-to-
Treat (ITT), Per Protocol (PP), and Per-Protocol with Optimal Data Acquisition (PP-ODA) groups.  
Though all data are intended to be pooled, it is possible that sub-analyses may be conducted in which 
subjects from each clinical site are evaluated as a cohort due to variations in the standard MRI-PDFF 
imaging protocol that may exist among the clinical sites.  Also, it is possible that sub-analyses may be 
conducted depending on subjects’ medical histories (e.g., presence of concomitant disease(s)). 
 
 
Study Aims and Objectives 
 
4.2.1 Overall Aim 
 
The overall aim of this clinical study is to demonstrate that the investigational LFQ feature on the Philips 
EPIQ Ultrasound System is a viable solution to the clinical unmet need for a noninvasive and cost-
effective liver fat quantification tool that clinicians can deploy in real-time.  In order to be considered a 
viable solution, the quantitative ultrasound biomarkers measured by the investigational LFQ feature 
need to demonstrate correlation with the liver fat percentage provided by the current noninvasive 
imaging-based benchmark, MRI-PDFF.  In addition, the investigational LFQ feature needs to 
demonstrate robustness in the clinical environment. These aims are addressed in the primary and 
secondary objectives below.  
 
4.2.2 Primary Objective 
 
The primary objective of this clinical study is to assess the correlation between each of several 
quantitative ultrasound biomarkers derived from the investigational LFQ feature and the known liver fat 
percentage obtained from MRI-PDFF, in order to identify which ultrasound biomarkers can best estimate 
liver fat content.  Quantitative liver fat percentages will be obtained from each subject’s MRI-PDFF 
examination to serve as the baseline reference (‘ground truth’) for a given subject.  The correlation 
between ultrasound biomarkers and MRI-PDFF liver fat percentage will be measured per the 
considerations included in Section 7 (Data Analysis and Statistical Considerations).   
 
4.2.3 Secondary Objective 
 
The secondary objective of this study is to evaluate the robustness of the investigational LFQ feature in 
the clinical environment.  Robustness will be assessed by determining inter-operator variability in 
quantitative ultrasound biomarker measurements made on the same set of LFQ ultrasound images and 
the overall data acquisition failure rate (i.e., percentage of subjects who have unacceptable image 
quality due to technical limitations). 
 

 
 
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Study Endpoints 
 
4.3.1 Primary Safety Endpoints 
 
The primary safety endpoints assessed in this study will be the number and seriousness of any Adverse 
Device Effects reported during the study, which will be recorded for each subject.  As described in 
Section 15.2 below, due to the nature of this clinical study in which only routine medical imaging 
procedures are performed, there are no significant Adverse Device Effects anticipated. 
 
4.3.2 Primary Performance Endpoints 
 
The primary performance endpoints are measurements of the quantitative ultrasound biomarkers that 
are believed to be correlated with liver fat content and/or liver stiffness.  As described in Section 2.4.2 
above, the following specific biomarkers may be measured either in real-time during the investigational 
LFQ ultrasound exam or during offline processing after the ultrasound exam is complete: 
• 
Hepatorenal Index (HRI) (unitless) 
• 
Acoustic attenuation (dB/cm/MHz) 
• 
Nakagami parameter (unitless) 
• 
Tissue viscosity (Pa∙s) (or viscosity-related metric) 
• 
Speed of sound (m/s) 
• 
Tissue stiffness (kPa) 
 
These candidate quantitative ultrasound biomarkers may evolve over time and, consequently, not all of 
these endpoints are required to be measured in every subject.  Performance of these endpoints will be 
evaluated by assessing their correlation with known liver fat percentages reported from MRI-PDFF per 
the considerations included in Section 7 (Data Analysis and Statistical Considerations).   
 
4.3.3 Secondary Performance Endpoints 
 
Secondary performance endpoints will include the following: 
• 
Inter-operator variability: difference in quantitative ultrasound biomarker measurements acquired 
from the same set of LFQ ultrasound images by two different operators who have undergone 
standardized training.  These operators will be unaware of each other’s impressions/findings 
during the investigational LFQ ultrasound exam (see Section 4.4). 
• 
Data acquisition failure rate: percentage of subjects who have unacceptable image quality due to 
inadequate acoustic scanning windows, motion artifacts, or other technical limitations.  Whether 
or not image quality is acceptable in each case will be determined by Philips personnel in 
consultation with investigators. 
 
 
 
 
 
 
 
 

 
 
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Measures to Minimize Bias 
 
The following measures will be taken to minimize and/or avoid bias in this clinical study:  
 
• 
Standardized product training materials will be developed and distributed to all clinical sites to 
ensure that the investigational LFQ feature is deployed by all operators in a consistent manner in 
all subjects.  This will help to ensure that data of uniform quality are obtained from all subjects.  
• 
A process will be instituted at each clinical site to ensure that the two operators who conduct 
separate LFQ biomarker measurements on the same set of LFQ ultrasound images do not 
discuss each other’s impressions/findings in order to avoid influencing each other. 
• 
Standardized clinical instructions will be communicated to each subject to ensure uniformity in 
their preparation for their study-related ultrasound examination (for example, all subjects will be 
asked to abstain from eating or drinking for at least 3 hours before their ultrasound examinations, 
as described in Section 6.4 below). 
• 
The Philips EPIQ Ultrasound System and the imaging transducers (C5-1 and mC7-2) are highly 
regulated medical devices that have been calibrated to provide known and reproducible acoustic 
output.  Therefore, the ultrasound data obtained from each subject will be elicited in a controlled 
manner using standardized equipment. 
 
 
 

 
 
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5. 
Study Subjects 
 
In general, subjects for this study will be drawn from the pediatric population at risk for, or already 
diagnosed with, disease on the NAFLD spectrum, up to and including NASH.  Subjects must meet all of 
the following specific inclusion and exclusion criteria to qualify for enrollment. 
 
 
Inclusion Criteria 
 
All of the following inclusion criteria must be met at the time of screening before the subject can be 
enrolled into the study: 
 
• 
Subjects at least 5 years old up through and including 21 years old who are able to provide informed 
consent to participate or have a legal representative/parent/legal guardian who is able to provide 
informed consent for the subject to participate. 
• 
Subject must be eligible for a standard abdominal ultrasound examination and standard non-contrast 
MRI examination. 
In addition, at least one of the following criteria must also be met: 
• 
Overweight or obese (BMI-for-age ≥ 85th percentile). 
• 
Diagnosed with Type 2 diabetes per standard clinical guidelines. 
• 
Diagnosed with hypercholesterolemia per standard clinical guidelines. 
• 
Diagnosed with or clinically suspected of having NAFLD/NASH based on previous medical record, 
medical imaging, liver biopsy, and/or laboratory testing. 
 
 
Exclusion Criteria 
 
Subjects are not eligible for enrollment if any of the following criteria are met: 
 
• 
History of moderate/heavy/binge alcohol consumption exceeding NIAAA guidelines4. 
• 
Evidence of hepatotoxicity or cirrhosis in the clinical judgment of the investigator. 
• 
History of chronic liver disease other than NAFLD (e.g., viral, cholestatic, or autoimmune). 
• 
Use of drugs associated with hepatic steatosis:5 
o 
Amiodarone  
o 
Methotrexate 
o 
Nucleoside reverse transcriptase inhibitors (didanosine, stavudine) 
o 
Valproic acid 
o 
Dexamethasone 
 
4 National Institute on Alcohol Abuse and Alcoholism. URL: https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-
consumption/moderate-binge-drinking 
5 List adapted from Amacher DE and Chalasani N. Drug-Induced Hepatic Steatosis. Semin Liver Dis 34: 205-214 (2014). 
 

 
 
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o 
Tamoxifen 
o 
5-FU-based adjuvant chemotherapy 
o 
Apo-B inhibitors (mipomersen, lomitapide) 
o 
Tetracycline exceeding 2 g/day 
o 
Acetylsalicylic acid exceeding 150 mg/kg 
• 
Subjects with hepatic lesions that cannot be excluded from the imaging field during ultrasound LFQ 
data acquisition. 
• 
Subjects anticipated or planned to undergo any therapeutic intervention during enrollment period 
that, at discretion of the Investigator, may affect liver fat content (e.g., chemotherapy). 
• 
History of previous liver surgery or hepatic implants that, at the discretion of the Investigator, may 
adversely impact ultrasound or MRI image quality or the subject’s eligibility to undergo ultrasound or 
MRI. 
 
 
Point of Enrollment 
 
Subjects who sign the Informed Consent Form are screened for eligibility at Visit 1. Subjects meeting all 
inclusion/exclusion criteria will then be enrolled into the study. 
 
 
Withdrawal or Discontinuation Criteria 
 
Study participation is voluntary. Subjects or their legal representative/parent/legal guardian may refuse 
to consent or may withdraw from the study at any time without penalty or loss of benefits to which the 
subject is otherwise entitled.  Subjects or their legal representative/parent/legal guardian may withdraw 
from the study in person, in writing (including via email), or via telephone communication with any study 
personnel.  The Investigator may discontinue a subject’s participation in this study without his/her 
consent if significant non-compliance is noted or if, in the opinion of the Investigator, the health or safety 
of a subject is affected adversely by participation in the study. 
 
Because this study does not involve long-term longitudinal follow-up, new subjects can be enrolled to 
replace any subjects who withdraw their consent or are removed by the Investigator, up to the point at 
which the maximum enrollment limit is reached.  There is no required follow-up for withdrawn subjects 
due to the non-therapeutic nature of this study, in which only medical imaging data are being collected 
and no treatment intervention is involved. 
 
 
Number of Subjects 
 
This study will enroll up to a maximum of 150 subjects across all clinical sites combined.  Each site is 
expected to enroll at least 20 subjects, though additional subjects may be enrolled at a given site within 
the overall limit of this investigational protocol.   
 
The number of subjects enrolled will affect the statistical confidence in the correlation level observed 
between each quantitative ultrasound biomarker and the liver fat percentage measured by MRI-PDFF.  
This sample size effect is discussed in Section 7 below (Data Analysis and Statistical Considerations).  
 

 
 
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Study Duration 
 
5.6.1 Study Duration - Global 
 
This clinical study is expected to last for up to 1 year, from the first subject’s enrollment to completion of 
the last subject’s involvement.  After all subjects have exited the study, post-enrollment activities will be 
undertaken for a period of approximately 6 months (monitoring, data analysis, data review/querying, 
database lock, final report generation, publication generation if appropriate, etc.) 
 
5.6.2 Study Duration – Individual Subject 
 
The duration of each subject’s participation in this study is expected to be no more than approximately 8 
weeks, from the time of initial enrollment to completion of all visits for imaging procedures (ultrasound 
and MRI).  There is no follow-up period for this study, except for any continued follow-up in the event of 
an unresolved Adverse Device Effect as specified in Section 15. 
 
 
Enrollment Period 
 
The study’s entire enrollment period is expected to last for up to 1 year, consistent with the global study 
duration listed above. 
 
 
Subject Reimbursement and Compensation 
 
Subjects enrolled in this study or their legal representative/parent/legal guardian will be reimbursed for 
any parking fees incurred at the clinical site and may receive additional compensation within clinical site 
guidelines in acknowledgment of their time needed to complete all study-related procedures during one 
or more study visits.  If more than one visit is required to complete study-related procedures, subjects 
may receive reimbursement for parking fees and additional compensation on a per-visit basis or a lump 
sum basis, according to the clinical site’s standard procedure. 
 
 

 
 
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6. 
Study Procedures 
 
 
Investigational LFQ Ultrasound Exam 
 
All subjects enrolled in this study will undergo a single abdominal ultrasound examination using the 
investigational LFQ feature on the Philips EPIQ Ultrasound System with the C5-1 and/or mC7-2 imaging 
transducers.  See Section 6.4 for details.   
 
 
MRI-PDFF Exams 
 
Additionally, all subjects enrolled in this study will also undergo a standard MRI-PDFF examination, 
unless this procedure has been performed as part of the subject’s clinical standard of care prior to study 
enrollment within an acceptable time window defined in Section 6.3.  Therefore, because the MRI-PDFF 
examination may or may not be performed as a study-related procedure, the number and nature of 
required study visits is expected to vary among the clinical sites (see Section 6.4 for details). 
 
 
Time Interval for All Imaging Procedures 
 
The investigational LFQ ultrasound exam and MRI-PDFF imaging procedure (clinically-scheduled or 
study-related) must be completed within a 8-week interval (+ 5 days).  Therefore, in order for a clinically-
scheduled MRI-PDFF examination performed prior to enrollment to be considered valid for the purposes 
of this study, it must have been completed no more than 8 weeks (+ 5 days) prior to completion of the 
subject’s investigational LFQ ultrasound examination.  This restriction is intended to ensure that the 
subject’s liver fat status does not change significantly during the time between the MRI-PDFF and 
investigational LFQ ultrasound examination. 
 
 
Schedule and Description of Study Procedures  
 
As a result of the above considerations, subjects enrolled in this study will have at least one study visit 
and may have up to three study visits, depending on the scheduling of their ultrasound and MRI-PDFF 
examinations at each clinical site.  Individual study visits and their specific procedures will consist of the 
events described below. 
 
6.4.1 Visit 1: Screening, Enrollment, Investigational LFQ Ultrasound Exam, and MRI-PDFF Exam 
 
Visit 1 consists of screening and enrollment activities and may also include the investigational LFQ 
ultrasound examination and/or the MRI-PDFF exam, if being performed as a study-related procedure.  
However, the LFQ ultrasound exam and/or MRI-PDFF exam may be performed during one or more 
subsequent visits, depending on Investigator preference or scheduling constraints.  If subjects are to 
undergo the investigational LFQ ultrasound exam during Visit 1, they will be asked to fast (NPO) for at 
least 3 hours prior to arrival. 
 
Visit 1 will consist of the following procedures: 
 
 
 
 
 

 
 
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Table 4: Study Procedures during Visit 1 (Screening, Enrollment, LFQ Ultrasound, and/or MRI-PDFF) 
Procedure 
Description 
Informed 
Consent 
(including 
Assent for 
Minors)  
The potential subject, or their legal representative/parent/legal guardian will be given the 
most current IRB/EC-approved Informed Consent Form (ICF) to read.  He/she will be 
provided ample time for review and an opportunity to ask questions about the study.  If 
the subject agrees to participate, they will sign the ICF and be given a copy of the 
signed document for their records.  All components of the consent process will be 
documented.  Only after informed consent has been obtained may the remaining study 
procedures begin.  If the potential subject is a minor, age-appropriate assent will be 
included in the Informed Consent Form.  A detailed description of the consent process is 
provided in Section 14.    
Assessment of 
Eligibility 
The Investigator will assess the subject’s eligibility for this study per the inclusion and 
exclusion criteria listed in Section 5.1 – 5.2 and will document the outcome of the 
eligibility assessment.  If the subject qualifies, he or she will then undergo the study-
related LFQ ultrasound examination described below if time permits. 
Study-Related   
LFQ Ultrasound 
Examination 
 
(Note: may be 
conducted in a 
subsequent visit) 
Adherence to the 3-hour NPO minimum will be verified; any deviations will be noted in 
the subject’s records.  The subject will be placed in the supine or lateral decubitus 
position, depending on which provides the optimal scanning window.  The subject’s shirt 
or gown will be lifted or removed and standard ultrasound imaging gel will be applied to 
the skin in the appropriate region.  The EPIQ ultrasound system with ElastQTM, the 
investigational LFQ software, and the C5-1 and/or mC7-2 imaging transducers will be 
used to conduct the abdominal ultrasound exam using standard sonographic 
techniques.  The entire ultrasound exam is expected to last approximately 15 minutes.  
The subject may be placed in multiple positions during this time to assess various 
imaging angles.  Study staff will monitor for any Adverse Events (AEs) during or after the 
ultrasound exam and will document any AEs appropriately (see Section 15). 
Study-Related  
MRI-PDFF Exam 
 
(Note: may be 
conducted in a 
subsequent visit) 
If the subject does not already have MRI-PDFF data available from a clinical standard of 
care exam within the prior 8 weeks (+ 5 days), the subject will undergo a non-contrast 
abdominal MRI examination using the clinical site’s standard PDFF acquisition protocol 
and procedure.  Study staff will monitor for any Adverse Events (AEs) during or after the 
MRI-PDFF exam and will document any AEs appropriately (see Section 15). 
Data Collection  
and Transmittal  
During the study-related ultrasound exam, real-time biomarker measurements will be 
collected.  In addition, DICOM images, cineloops, and raw ultrasound radiofrequency 
(RF) data may also be collected for offline post-processing by Sponsor personnel.  
These datasets will be captured and transmitted to the Sponsor using appropriate de-
identification procedures and privacy protections via the methods listed in Section 9.3. 
Data from the MRI-PDFF exam, including DICOM images and radiology reports 
including fat percentage results, will be transmitted to the Sponsor using appropriate de-
identification procedures and privacy protections via the methods listed in Section 9.3. 
 
 
 

 
 
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6.4.2 Visit 2 (Optional): Investigational LFQ Ultrasound Exam (if not already performed) 
 
If the investigational LFQ ultrasound examination is not performed during the screening and enrollment 
visit due to Investigator preference or scheduling constraints, it may be conducted during a subsequent 
visit.  This visit must occur within the 8-week window (+ 5 days) specified for all imaging procedures in 
Section 6.3 above.  If subjects are to undergo the LFQ ultrasound exam during Visit 2, they will be asked 
to fast (NPO) for at least 3 hours prior to arrival. 
 
If conducted, Visit 2 will consist of the following events: 
 
Table 5: Study Procedures during Optional Visit 2 (LFQ Ultrasound Exam if not already performed) 
Procedure 
Description 
Concomitant 
Medications 
/Procedures 
A concomitant medications/procedures assessment will be performed to ensure than 
the subject has not begun taking any prohibited medications (Section 5.2) or 
undergone any prohibited procedures during the interval between the most recent 
study visit and the current visit. 
Study-Related 
LFQ Ultrasound 
Examination 
 
(if not performed 
during Visit 1) 
Adherence to the 3-hour NPO minimum will be verified; any deviations will be noted in 
the subject’s records.  The subject will be placed in the supine or lateral decubitus 
position, depending on which provides the optimal scanning window.  The subject’s 
shirt or gown will be lifted or removed and standard ultrasound imaging gel will be 
applied to the skin in the appropriate region.  The EPIQ ultrasound system with 
ElastQTM, the investigational LFQ software, and the C5-1 and/or mC7-2 imaging 
transducers will be used to conduct the abdominal ultrasound exam using standard 
sonographic techniques.  The entire ultrasound exam is expected to last approximately 
15 minutes.  The subject may be placed in multiple positions during this time to assess 
various imaging angles. Study staff will monitor for any Adverse Events (AEs) during or 
after the ultrasound exam and will document any AEs appropriately (see Section 15). 
Data Collection 
and Transmittal  
During the study-related ultrasound exam, real-time biomarker measurements will be 
collected.  In addition, DICOM images, cineloops, and raw ultrasound radiofrequency 
(RF) data may also be collected for offline post-processing by Sponsor personnel.  
These datasets will be captured and transmitted to the Sponsor using appropriate de-
identification procedures and privacy protections via the methods listed in Section 9.3. 
 
 
 

 
 
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6.4.3 Visit 3 (Optional): Study-Related MRI-PDFF Exam (if not already performed) 
 
Some subjects may have had a MRI-PDFF examination performed as part of their clinical standard of 
care prior to enrollment; in that case, no additional MRI-PDFF examination is required unless the prior 
examination was conducted more than 8 weeks (+ 5 days) prior to the investigational LFQ ultrasound 
examination as specified in Section 6.3 above. 
 
For subjects undergoing MRI-PDFF as a study-related procedure, the MRI-PDFF examination may be 
combined with any of the other visits as scheduling permits, and therefore there may not be a separate 
visit required for this procedure.  There is no required sequence for the MRI-PDFF examination with 
respect to the investigational LFQ ultrasound examination, and it can occur either prior to or after the 
ultrasound examination.  However, the MRI-PDFF examination must be completed within the 8-week 
window (+ 5 days) specified for all imaging procedures in Section 6.3. 
 
If a separate visit is conducted for the MRI-PDFF exam, Visit 3 will consist of the following events: 
 
Table 6: Study Procedures during Optional Visit 3 (MRI-PDFF Exam if not already performed) 
Procedure 
Description 
Concomitant 
Medications 
/Procedures 
A concomitant medications/procedures assessment will be performed to ensure 
than the subject has not begun taking any prohibited medications (Section 5.2) or 
undergone any prohibited procedures during the interval between the most recent 
study visit and the current visit. 
Study-Related  
MRI-PDFF Exam 
 
(if not performed 
during Visit 1 or 2) 
The subject will undergo a non-contrast abdominal MRI examination using the 
clinical site’s standard PDFF acquisition protocol and procedure.  Study staff will 
monitor for any Adverse Events (AEs) during or after the MRI-PDFF exam and will 
document any AEs appropriately (see Section 15). 
Data Collection  
and Transmittal  
Data from the MRI-PDFF exam, including DICOM images and radiology reports 
including fat percentage results, will be transmitted to the Sponsor using 
appropriate de-identification procedures and privacy protections via the methods 
listed in Section 9.3. 
 
6.4.4 Study Exit 
 
Once the subject has completed the last scheduled imaging procedure (LFQ ultrasound exam or MRI-
PDFF exam), he/she will exit from the study.  There is no follow-up period for this study, except for any 
continued follow-up necessary in the event of an unresolved Adverse Device Effect as specified in 
Section 15. 
 
 
 
 

 
 
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Diagrams of Study Procedures 
 
6.5.1 Cases where MRI-PDFF is Performed Prior to Enrollment 
 
Figure 2 provides an overview of study procedures per visit for subjects undergoing clinically-scheduled 
MRI-PDFF prior to enrollment.  Subjects in this group will have up to 2 study visits. 
 
 
 
 
Figure 2.  Study diagram for subjects undergoing clinically-scheduled MRI-PDFF prior to study 
enrollment.  Up to two study visits are required, and the LFQ ultrasound and MRI procedures must be 
completed within an 8-week window (+ 5 days).   
 
 

 
 
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6.5.2 Cases where MRI-PDFF is Performed as a Study-Related Procedure after Enrollment 
 
Figure 3 provides an overview of study procedures per visit for subjects undergoing MRI-PDFF as a 
study-related procedure after enrollment.  Subjects in this group will have up to 3 study visits. 
 
 
 
Figure 3.  Study diagram for subjects undergoing MRI-PDFF as a study-related procedure after 
enrollment.  Up to three study visits are required, and the LFQ ultrasound and MRI procedures must be 
completed within an 8-week window (+ 5 days).  The MRI-PDFF exam can be performed during the 
same visit as the LFQ ultrasound exam, or can be scheduled for a different visit. 
 
 
 
 
 
 
 

 
 
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Unscheduled Visits 
 
All unscheduled visits or procedures occurring during the subject’s participation in this study will be 
recorded in the subject’s study record with the following elements noted:  
 
• 
Date 
• 
Reason for visit/procedure  
• 
Follow-up 
• 
Signature or initials of study staff and date(s)  
 
Any reportable Adverse Events, concomitant medication changes, and/or Clinical Study Protocol 
deviations will be reported in the subject’s study record.  Any significant Adverse Events and/or 
deviations must be reported to the Sponsor upon discovery (see Sections 11.1 and 15.3 for details).   
 
 
Procedures Performed by Sponsor Representatives 
 
None of the study procedures described above that involve direct interaction with the subject will be 
completed by Philips personnel; however, offline processing of investigational LFQ ultrasound data may 
be completed by Philips representatives on an ongoing basis. 
 
 
Types of Data Collected and Shared with Sponsor 
 
The following types of data may be collected and shared with Philips during the course of this study.  All 
data, regardless of type, will be de-identified before being shared with Philips and will comply with 
Philips privacy protection policies and HIPAA Privacy Rule requirements as described in Section 9.  All 
records will be codified with a unique study subject identification number and will not contain any 
Protected Health Information (PHI).   
 
• 
Ultrasound biomarker measurements for those biomarkers that are measured in real-time during 
the investigational LFQ ultrasound exam 
• 
Ultrasound biomarker measurements for those biomarkers that are calculated offline after the 
investigational LFQ ultrasound exam 
• 
Raw ultrasound data (e.g., radiofrequency (RF) data) from investigational LFQ ultrasound exam 
• 
DICOM images and cineloops from the investigational LFQ ultrasound exam and the MRI-PDFF 
exam 
• 
Subject health record information directly related to liver status, including laboratory reports for 
bloodwork relevant to liver function, radiology reports from the MRI-PDFF exam including liver fat 
percentage results, and pathology reports from prior liver biopsy (if available).   
 
 
 
 

 
 
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7. 
Data Analysis and Statistical Considerations 
 
 
Plan for Interim Analyses 
 
Because this is a pilot study, ad hoc interim analyses are expected to be conducted as data become 
available in order to enable prioritization of quantitative ultrasound biomarker development during the 
course of the study.  Interim analyses will be conducted by Philips personnel on an as-needed basis to 
evaluate ongoing biomarker performance. 
 
 
Analysis Groups 
 
Separate analysis tiers are planned for the Intention-to-Treat (ITT), Per Protocol (PP), and Per-Protocol 
with Optimal Data Acquisition (PP-ODA) groups.  The term ‘ITT’ is used herein due to convention, even 
though no treatment of any sort is being administered during this study.  Correlation levels will be 
assessed between quantitative ultrasound biomarkers and MRI-PDFF fat percentages for the following 
sub-groups. 
 
7.2.1 Intention-to-Treat Group 
 
This is the full population of ‘all-comers’ consisting of all enrolled subjects who have any amount of 
investigational LFQ ultrasound data and MRI-PDFF data available, regardless of the quality of the 
imaging data received, whether any protocol deviations occurred, or the presence of other confounding 
effects that may result in outliers.  The correlation level between the ultrasound biomarkers and MRI-
PDFF fat percentage is expected to be lowest among the full ITT group. 
 
7.2.2 Per-Protocol Group 
 
This is the subset of the full ITT group who underwent the investigational ultrasound exam in compliance 
with this protocol, including those who adhered to the NPO restrictions, had no evidence of eligibility 
deviations at the time of imaging, etc.  The PP group may have variations in ultrasound image quality 
due to different data acquisition conditions that may be present at the time of scanning, including 
suboptimal scanning windows due to rib impingement, artifacts from subject motion, etc.  The correlation 
level between the ultrasound biomarkers and MRI-PDFF fat percentage is expected to be higher in the 
PP group than the ITT group. 
 
7.2.3 Per-Protocol with Optimal Data Acquisition Group 
 
This is the subset of the PP group who underwent the investigational ultrasound exam under optimal 
data acquisition conditions, including those who had optimal scanning windows due to minimal or absent 
rib shadowing, who had no motion artifacts from breathing, etc.  Subjects in this PP-ODA group will be 
identified by Philips personnel in collaboration with the PIs at each site, upon review of the data.  The 
correlation level between the ultrasound biomarkers and MRI-PDFF fat percentage is expected to be 
highest in this PP-ODA group.   
 
 

 
 
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Data Poolability 
 
Subject data from all clinical sites are intended to be pooled for analysis to broaden demographic 
representation; however, it is possible that sub-analyses may be conducted in which subjects from each 
clinical site are evaluated as a cohort if clinically significant variations in standard MRI-PDFF imaging 
protocols exist among the investigational sites.  Also, it is possible that sub-analyses may be conducted 
depending on subjects’ medical histories (e.g., presence of one or more concomitant diseases). 
 
 
Sample Size Considerations 
 
The primary performance endpoints listed in Section 4.3 (quantitative ultrasound biomarkers) will be 
evaluated by assessing their correlation with known liver fat percentages reported from MRI-PDFF.  The 
following biomarkers may be assessed for correlation: 
 
• 
Hepatorenal Index (HRI) (unitless) 
• 
Acoustic attenuation (dB/cm/MHz) 
• 
Nakagami parameter (unitless) 
• 
Tissue viscosity (Pa∙s) (or viscosity-related metric) 
• 
Speed of sound (m/s) 
• 
Tissue stiffness (kPa) 
 
Each biomarker’s correlation with the fat percentage reported from MRI-PDFF is considered to be an 
independent variable and will be analyzed independently. 
 
The sample size achieved during this study will affect statistical confidence in the correlation level 
observed between a given quantitative ultrasound biomarker and the MRI-PDFF-derived fat percentage.  
For illustrative purposes, Table 7 below shows the effect of various sample sizes on the lower bound of 
the 95% confidence interval (CI) around two example targeted correlation levels consistent with those 
observed in preliminary data.  In the case of a targeted Pearson’s product-moment correlation of 0.75, a 
sample size of 90 subjects provides a two-sided 95% CI around this targeted correlation with a lower 
bound of approximately 0.64.  If the targeted Pearson’s correlation increases to 0.80, this same sample 
size would result in a two-sided 95% CI with a lower bound of 0.71.  Correspondingly, these lower 
bounds increase with increasing sample size, up to the maximum enrollment of 150 subjects.   
 
Table 7: Lower Bound of 95% Confidence Interval for Targeted Pearson’s Correlations 
 
Targeted Correlation = 0.75 Targeted Correlation = 0.80 
Sample Size 
Lower Bound of 95% CI 
Lower Bound of 95% CI 
150 
0.670 
0.734 
140 
0.667 
0.731 
130 
0.663 
0.728 
120 
0.659 
0.725 
110 
0.655 
0.721 
100 
0.649 
0.716 
90 
0.643 
0.711 
 
If a Pearson’s correlation of 0.80 is observed for a given quantitative ultrasound biomarker and MRI-
PDFF ground truth in at least 90 subjects, there is >95% confidence that the true correlation exceeds 
0.7, which is taken to indicate a technically meaningful association between the two variables. 

 
 
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Additional Statistical Analysis Plan 
 
Additional statistical analysis considerations may be described in a separate Statistical Analysis Plan 
(SAP) for this study, consistent with ISO 14155:2011 guidance and Philips Ultrasound’s internal study 
management procedures (9060-0623, Clinical Study Statistical Analysis and Data Management).  This 
separate SAP may include provisions for sensitivity/specificity analyses to evaluate the investigational 
LFQ feature’s ability to discriminate among various steatosis stages or groupings of stages. 
 
8. 
Monitoring Plan 
 
 
Overview 
 
This study will be monitored using a risk-based monitoring approach, consistent with the FDA guidance 
Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring (2013) and Philips 
Ultrasound’s clinical study monitoring procedures (9060-0588 and 9060-0589).  Monitoring will ensure 
that documents used to originally record subject data (source documents) are maintained, and to verify 
that transcribed data are accurately reflected on the study electronic Case Report Forms (eCRFs).  See 
the associated Monitoring Plan for the nature, timing and intensity of planned monitoring, based on risks 
and critical data.  It will detail any planned remote monitoring, source data verification, Site Regulatory 
File review, and Informed Consent Form review, distinguishing between remote and on-site monitoring.  
It will also specify the monitoring team and required training.  The Monitoring Plan will be maintained in 
the Trial Master File.  
 
 
Source Documentation Access, Subject Privacy, and Subject Confidentiality 
 
A unique source record will be available for each study subject including completed Informed Consent 
Forms, other documentation of the consent process, medical history, concomitant medication review, 
and all records related to use of the investigational device on the subject.  See Section 9.1 for a detailed 
description of source documentation.   
 
Subject study information will remain confidential.  Subjects enrolled on study will be assigned a study ID 
code.  All data will then be reported per the unique Subject ID, ensuring all subject identifiers have been 
redacted before transmission to Sponsor, thus providing the Sponsor a ‘coded’ data set.  Only 
authorized personnel associated with the conduct and/or review of the study and the resultant data will 
have access to information that links subject identifiers to the corresponding assigned study code.  
Documentation of privacy and confidentiality training (e.g., data privacy, data protection laws, HIPAA, 
etc.), to site study team members will be maintained in the Site Regulatory File (SRF) or a centralized 
site record, accessible to sponsor and external monitors and/or auditors.   
  
The subject source record as well as other source documentation (e.g., completion of protocol study 
procedures, procedure findings, essential documents in the Site Regulatory File, copies of completed 
case report forms, etc.) must be made available for review by Philips or its designees, auditors, IRB/EC, 
and regulatory authorities.  All efforts must be made by all parties involved to ensure protection of 
subject confidentiality at all times throughout the clinical study.  Because of the need for study site(s) to 
release information to these parties, absolute confidentiality cannot be guaranteed.  Disclosure of 
subject information to personnel other than those permitted by Philips, its designees or representatives, 
or appropriate regulatory agencies is prohibited. 
 

 
 
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Study records will be kept in a secure area, protecting subject and overall study confidentiality.  The 
results of this research project may be presented at meetings or in publications; however, subject 
identity will not be disclosed in such publications.   
 
9. 
Data Management, Quality Assurance, and Confidentiality Standards 
 
 
Source Documentation, Reporting, and Maintenance 
 
Source Documentation is the original (first) collection of subject/study data.  If source data are captured 
more than once at different time points, the later collection serves as corroborating source 
documentation.  Source documents must have adequate study and subject identifiers and must be 
legible.   
 
For this study, source data may be captured manually in hard copy (on paper) as well as directly 
recorded into electronic case report forms (eCRFs), as described in the Electronic Data Capture System 
section below, at the time of procedure completion.  If source data are entered manually in hard copy 
form, a blue or black pen should be used.  Any eligibility metrics that will be directly recorded in eCRFs 
will be identified and reported to the Sponsor prior to study start.   
 
Source documentation must be maintained in a secure area.  Study-specific source documentation will 
have limited access to Investigator-delegated study staff.   
 
 
Electronic Data Capture System 
 
The DATATRAK electronic data capture (EDC) system is a secure, validated, US CFR Part 11 compliant 
EDC program provided by the Sponsor to facilitate data entry and storage for this study (DATATRAK, 
Mayfield Heights, OH).  It is an internet-based EDC system for reporting clinical data to the Sponsor via 
electronic Case Report Forms (eCRFs).  All subjects who consent to participate will be registered in the 
EDC system.   
 
Access to the EDC system will be protected by login identification and password.  The Sponsor will train 
delegated Site personnel on procedures for data entry into the web-based system. Following training, 
delegated staff will be provided ID codes and passwords unique to each team member’s delegated 
study role.  They will be trained on Philips guidelines for maintenance of electronic ID codes and 
passwords.  A staff member’s ID code/password will never be shared or used by another staff member, 
in any circumstance.  If prior training has already been delivered for other Philips-sponsored studies of 
similar design, this training may be reinforced via teleconference prior to study commencement as 
appropriate.  
 
 
Data Reporting to Sponsor 
 
Subject data will be reported to Philips via electronic Case Report Forms (eCRFs) using the DATATRAK  
electronic data capture (EDC) system described in Section 9.2.  Only staff that have been delegated by 
the Principal Investigator(s) will be able to enter or make changes to data in the case report forms.  
Additional anonymized data (DICOM images, cineloops, and raw ultrasound radiofrequency (RF) data) 
may be captured and transmitted via a qualified third-party image transfer service (e.g., AG Mednet, 
Boston, MA) with which Philips has contracted for this purpose or may be transmitted via the 
DATATRAK EDC system.  No central laboratories or radiology services are planned to be used during 
this study. 
 

 
 
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Data Review, Cleaning, and Query Resolution 
 
After study data are recorded and submitted to the EDC system, automated edit checks, programmed to 
ensure the collection of consistent and complete data, may be raised.  In addition, after data submission, 
Philips (or contracted) Clinical Monitors, Statisticians, and/or the Philips Clinical Data Management 
group may remotely review data listings generated at different time points during the study.  Data 
queries will be generated to resolve any discrepancies or concerns.   
 
Any data transcribed to eCRFs will be verified against source documents by the Sponsor or its 
designee(s) on a percentage of the subject population, per a risk-based monitoring approach as 
described in the Monitoring Plan associated with this study and maintained in the Trial Master File.  Data 
queries will be generated to resolve any discrepancies or concerns. 
 
Designees will be trained on the query issue and resolution process.  It is the responsibility of the 
designated personnel at each clinical site to respond to all edits checks and queries generated.  
Submitted data as well as all modifications to submitted data will be documented by the EDC system 
and available in audit trails. 
 
 
Data Retention and Duration 
 
Upon conclusion of the study, after all eCRFs are marked as complete and all discrepancies are 
resolved, the Principal Investigator will be notified to review and provide electronic signatures.  
Subsequently, a member of the Philips Clinical Data Management team will lock the database and 
deactivate the system. The final data set will be transferred to SAS for analysis at Philips.   
 
All study documentation (e.g., source documentation, completed Informed Consent Forms, Site 
Regulatory File documents, copies of completed eCRFs, etc.) will be securely retained until receipt of 
written authorization from Philips is given to destroy records.  At a minimum, the retention period will be 
two years after study completion, consistent with 21 CFR 812.140(d).  Philips may require that records 
are maintained for longer than this two year period; if so, the site will be notified accordingly. 
 
 
 Study Confidentiality Standards 
 
This Clinical Study Protocol, its associated methodologies, study devices, study-generated data, and the 
data management system contain confidential and proprietary information.  Release of such information 
outside the scope of planned study operation is prohibited.  All federal and local laws regarding 
protection of patient confidentiality will be followed, as well as any additional site-specific requirements 
that may be required. 
 
10. 
Amendments to the Clinical Study Protocol 
 
Any changes necessary to the Clinical Study Protocol after full execution are documented as protocol 
amendments.  Prior to execution at investigational sites, each protocol amendment must be: 
• 
submitted and approved by the applicable IRB/EC(s) 
• 
agreed to and signed by the Investigator(s) 
If the protocol amendment introduces any new information that affects Informed Consent, the Informed 
Consent Form will also be amended and submitted to the applicable IRB/EC for approval.  All records 
related to protocol amendments will be added to the Site Regulatory File and Trial Master File. 
 

 
 
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11. 
Deviations from the Clinical Study Protocol 
 
The Investigator(s) are not allowed to deviate from the Clinical Study Protocol, except for emergency 
circumstances (see ISO 14155 4.5.4b)).   
 
 
Deviation Recording, Reporting, and Analysis 
 
Completion of study-related procedures will be source documented.  A copy of eCRFs will be provided 
to study staff to serve as source document templates for documenting procedure completion and 
findings.  Sites may use their own templates for source documentation as well.  
 
Compliance and potential deviations will be assessed by study site designees.  At the beginning of each 
study visit, clinical site personnel will interview subjects for compliance to pre-study visit instructions (if 
any) and to assess whether any relevant concomitant medications have been taken by subjects that 
would affect their eligibility (see Section 5.2). 
 
Any deviations from this Study Protocol will be documented upon discovery and reported in the subject’s 
eCRFs.  Significant deviations (marked below with an asterisk) need to be reported immediately to the 
Sponsor (see Section 15.5).  Examples of non-compliance, including significant deviations, include but 
are not limited to:  
 
• 
failure to obtain informed consent prior to performing any study-related procedures* 
• 
enrollment of ineligible subject* 
• 
failure to complete any study-related procedure* 
• 
usage of prohibited medication or performance of any prohibited procedure during enrollment 
period (see Section 5.2) 
• 
failure to conduct any study-related procedure within specified time window (see Section 6.3) 
• 
failure to maintain specified fasting time prior to ultrasound examination (see Section 6.4) 
* = significant deviation that needs to be reported immediately to the Sponsor per Section 15.5 
 
 
Deviation Escalation and Notifications 
 
Site personnel associated with the conduct of this study must report any significant deviations from 
Good Clinical Practice or significant deviations from this Clinical Study Protocol to the Philips Clinical 
Study Manager.  Any deviations that affect subject’s rights, safety and well-being, or the scientific 
integrity of the clinical study must be reported to the approving IRB/EC and the Sponsor within 3 days.    
 
 
Interventions and Medications Prohibited during Study 
 
During each subject’s enrollment period (the time between when he or she is first enrolled and when all 
required imaging procedures are completed), usage of any of the medications listed in Section 5.2 is 
prohibited due to their association with drug-induced hepatic steatosis.  Performance of any therapeutic 
intervention that may affect the liver fat content during the enrollment period is also prohibited as listed in 
Section 5.2. 
 
While the potential for these confounding events is low due to the short enrollment period of each 
subject, it is nevertheless critical that the subject does not begin taking any of the prohibited medications 
or undergo a prohibited procedure until his or her participation has completed.  If any such events occur 
during the subject’s enrollment, the subject will need to be withdrawn from the study and a Study 
Protocol Deviation will need to be reported accordingly. 

 
 
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All other interventions, treatments, and medications that do not affect the subject’s ongoing eligibility are 
allowed during study participation. 
 
 
Corrective and Preventive Actions 
 
Prior to study initiation at each clinical site, delegated site staff will be trained to the Clinical Study 
Protocol at a Site Initiation Visit to ensure comprehensive understanding of study procedures and to 
optimize compliance to the protocol and Good Clinical Practice.  
 
Compliance and proper deviation reporting will be monitored periodically during remote and/or on-site 
monitoring visits for any required corrective actions, escalations (e.g., significant deviations), and/or 
notifications.  If non-compliance events are observed, corrective actions may include supplemental 
protocol training and discussions with the Investigator(s) and study staff to implement activities to 
prevent future recurrence.  Ongoing significant non-compliance may result in study discontinuation at the 
clinical site involved.    
 
12. 
Investigator and Site Qualifications 
 
Philips must ensure that Investigators selected to conduct this clinical study are appropriately 
credentialed and experienced in the medical field associated with this study.  Toward that end, each 
Investigator will provide a signed, accurate, non-misleading, and current copy of his or her curriculum 
vitae to Philips that demonstrates his or her qualifications to conduct this study and, if requested, will 
provide a list of sub-Investigators or health professionals who are assisting in the conduct of this study 
and similar documentation of their qualifications. 
 
Persons debarred from conducting or working in clinical studies by any court or regulatory agency will 
not be allowed to conduct or work on this study.  The Investigator will immediately disclose to Philips in 
writing if any person who is involved in conducting the study is debarred, or to the best of the 
Investigator’s knowledge, if any proceeding for debarment is pending or threatened.  The Investigator 
attests that he or she has not been personally debarred and will not use as an assistant any person who 
is debarred from participation in clinical studies under any provision of federal law (e.g., 21 CFR § 
312.70).  If such a debarment proceeding should occur, involving the Investigator or any assistant 
involved in the study, the Investigator will promptly inform Philips. Further, the Investigator attests that 
he/she, as well as any other person or entity affiliated with the Investigator or under the Investigator’s 
supervision as part of this study, is not excluded from participation in a Federal Health Care Program as 
defined in 42 U.S.C. § 1320a.   
 
The Investigator attests that the facilities where he/she will conduct this study have the necessary patient 
population and resources to properly conduct the study. 
 
 
 

 
 
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13. 
Product Labelling and Accountability 
 
Access to the study device will be controlled to prevent unauthorized use.  Further, the study device will 
be used only in this clinical study according to the procedures specified in this protocol.   
 
 
Sponsor Responsibilities 
 
13.1.1 Product Labeling 
 
The Philips EPIQ Ultrasound System with the on-cart LFQ feature is an investigational device.  The 
system will be labeled with an easily seen, clearly marked warning label stating ‘CAUTION – 
Investigational device.  Limited by Federal (or United States) laws to investigational use.’  
 
13.1.2 Accountability Documentation 
 
Philips will keep records documenting accountability for the investigational device from shipment to the 
clinical sites until return or disposal.  Records will be maintained in the Trial Master File (TMF).  
Required information regarding shipping will be documented as specified in the Master Device 
Accountability Log at each Clinical Site. 
 
13.1.3 Monitoring 
 
Accountability will be monitored by Philips personnel on an ongoing basis via on-site and/or remote 
monitoring, as designated in the Monitoring Plan for this clinical study.  Monitoring will ensure: 
 
• 
adequate supply of study devices 
• 
proper security of subject records and study devices 
• 
compliance to storage requirements  
• 
usage compliance  
• 
reconciliation 
 
Any discrepancies will be raised with study personnel upon discovery.  Discrepancy management and 
resolution will be documented and filed with the Accountability Log in the Site Regulatory File and Trial 
Master File. 
 
 
Site Responsibilities 
 
Upon receipt, product shipments will be inventoried and accountability documented in the provided 
Product Accountability Log.  Once subjects are enrolled, product usage tracking will be documented at 
the subject level.  At the conclusion of the study, all investigational products will be reconciled and 
accounted for prior to return to the Sponsor.  
 
13.2.1 Accountability Documentation 
 
Study Investigator(s) or authorized designee(s) will keep records documenting study product 
accountability from receipt until return to the Sponsor.  Records will be maintained in the Site Regulatory 
File (SRF).  The following will be documented on the provided Product Accountability Log: 
 
 
 

 
 
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Product Receipt by Clinical Site 
 
• 
Study product names 
• 
Quantities received 
• 
Receipt dates 
• 
Product IDs (e.g., lot or batch numbers, serial numbers and/or unique codes, as applicable) 
• 
Name of person who processed product receipt 
 
Product Usage at Clinical Site 
 
• 
Device usage dates (by subject IDs) 
 
Product Return to Sponsor 
 
• 
Study product names 
• 
Quantities returned 
• 
Return dates  
• 
Product IDs (e.g., lot or batch numbers, serial numbers and/or unique codes, as applicable) 
• 
Name of person(s) who reconciled study product 
 
13.2.2 Accountability Reporting 
 
Once received product has been inventoried, a copy of the completed Accountability Log will be 
provided to the Sponsor for confirmation purposes.  Subject-specific product accountability will be 
reported in the subject’s (e)CRFs.   
 
13.2.3 Study Product Return 
 
The Philips EPIQ Ultrasound System, C5-1 and/or mC7- 2 imaging transducer(s), and all accessories 
will be returned at the end of this study.  Once all returnable products are reconciled and accounted for 
on the Accountability Log, they will be returned to Philips using a Philips-specified shipping service per 
instructions that will be provided at the time of device return. 
 
14. 
Informed Consent (including Assent for Minors) 
 
 
Process for Obtaining Informed Consent (including Assent for Minors) 
 
Study participation is voluntary.  In order for potential subjects to decide whether they would like to 
participate, an informed consent discussion will be conducted according to the process described in ISO 
14155: 2011.  Potential subjects, and/or their legal representatives, will be given the most current 
IRB/EC-approved Informed Consent Form to read.  They will be provided ample time for review and an 
opportunity to ask questions about the study.  If they agree to participate, they will sign the Informed 
Consent Form and be given a copy of the signed document for their records.  Each of these 
actions/steps will be documented.  Only after informed consent has been obtained may study-related 
procedures begin. 
 
If the subject is a minor, an age-appropriate assent will be included in the Informed Consent Form to be 
completed by the subject or his/her parent/legal guardian, as appropriate.  
 

 
 
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Availability of New Information 
 
Any new information about the study that may affect a enrolled subject’s decision to be in the study, or 
their legal representative/parent/legal guardian’s decision for the subject to be in the study (e.g., 
changed procedures, safety, etc.), will be communicated in a timely manner.  Depending on the nature 
of the new information, subjects who have completed the study may or may not be informed, 
documenting the decision and justification as well as any activities for informing completed subjects.  
Additionally, the approving IRB/EC and/or regulatory authority will also be informed.  The currently 
approved Informed Consent Form will be updated and submitted to the approving IRB/EC and/or 
regulatory authority for review and approval.  Active subjects will be re-consented, following the above 
process, with the newly-approved consent form. 
 
 
Inability to Provide Consent 
 
For this study, eligible subjects or their legal representative/parent/legal guardian must be willing and 
physically/mentally able to give their informed consent for the subject to participate. If potential subjects 
or their legal representative/parent/legal guardian are unable to provide consent, they may not 
participate.  Minors must assent to their study participation where applicable. 
 
15. 
Safety Events: Definitions, Reporting, and Follow-up   
 
Subject safety will be monitored to detect any product deficiencies or risks from the time of consent until 
conclusion of the study or, if applicable, resolution of a safety event.  This will include monitoring for 
Adverse Events and Adverse Device Effects, as defined in ISO 14155:2011. 
 
 
Safety Event Definitions 
 
The following definitions are adopted from ISO 14155:2011: 
 
Adverse Event (AE):  Any untoward medial 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/product. 
 
Serious Adverse Event (SAE): Any Adverse Event that leads to any of the following: 
• 
Death 
• 
Serious deterioration in the health of the subject that results in any of the following: 
o 
a life-threatening illness or injury, or 
o 
a permanent impairment of a body structure or a body function, or 
o 
in-patient or prolonged hospitalization, or 
o 
medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function 
• 
Fetal distress, fetal death or a congenital abnormality or birth defect 
 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the study protocol, 
without serious deterioration in health is not considered a Serious Adverse Event.   
 

 
 
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Adverse Device Effect (ADE): An Adverse Event related to the use of an investigational medical 
device.  This definition includes AEs resulting from insufficient or inadequate instructions for use, 
deployment, installation, or operation, or from any malfunction of the investigational medical device.  
This definition also includes any event resulting from use error or from intentional misuse of the 
investigational medical device. 
 
Serious Adverse Device Effect (SADE):  An Adverse Device Effect that has resulted in any of the 
consequences characteristic of a Serious Adverse Event.  
 
Unanticipated Adverse Device Effect (UADE): An Adverse Device Effect that does not meet the 
definition of SADE but which by its nature, incidence, severity, or outcome has not been identified in this 
Clinical Study Protocol or the current version of the device’s Risk Analysis Report. 
 
Unanticipated Serious Adverse Device Effect (USADE): A Serious Adverse Device Effect which by 
its nature, incidence, severity, or outcome has not been identified in this Clinical Study Protocol or the 
current version of the device’s Risk Analysis Report. 
 
Device Deficiency: Any inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety, or performance.  Device Deficiencies include malfunctions, use errors, and inadequate 
labeling (including instructions for use).   
 
 
Foreseeable Safety Events 
 
There are no significant foreseeable safety events associated with this study.  As discussed in Section 
3.1 above, no significant ADEs are anticipated during this study because the investigational procedure is 
limited to noninvasive diagnostic ultrasound imaging of the abdomen using the investigational LFQ 
software.  The Philips EPIQ Ultrasound System with investigational LFQ software and the imaging 
transducers (C5-1 and mC7-2) have been verified to comply with harmonized safety standards 
governing all diagnostic ultrasound imaging devices (e.g., IEC 60601-1-2 and IEC 60601-2-37, see 
Table 3) and therefore pose no additional risk to subjects beyond that associated with any other 
abdominal ultrasound imaging procedure.  Only the following nonserious ADEs are therefore anticipated 
to occur: 
 
• 
potential discomfort during the ultrasound examination due to body positioning  
• 
potential discomfort during the ultrasound examination due to pressure exerted by the ultrasound 
transducer when it is pressed against the abdominal skin. 
 
 
Safety Event Reporting 
 
All Adverse Events, Adverse Device Effects, and Device Deficiencies will be collected at the time of 
reporting by the subject or detection by the Investigator.  They will be source documented and 
maintained as part of the study record and reported in the (e)CRFs.   
 
An assessment of the following metrics will be made by the Investigator for each Adverse Event:   
 
• 
severity,  
• 
seriousness, 
• 
anticipated or unanticipated, 
• 
relation to study participation or investigational device, 

 
 
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• 
action taken, 
• 
outcome (resolution, sequelae, etc.) 
 
The following will be reported in the eCRFs for each Device Deficiency that occurs: 
 
• 
device ID, 
• 
device event description, 
• 
date of deficiency, 
• 
whether the deficiency caused or could have caused an Adverse Device Effect to occur. 
 
The disposition of all safety events, assignment of relatedness, and determination of seriousness is the 
responsibility of the Investigator.   
 
The following adverse changes from baseline require reporting to Philips: 
 
• 
any Unanticipated Adverse Device Effect (UADE) that is either possibly related or related to the 
investigational device and which is not specified in Section 15.2 above.   
• 
any Serious Adverse Device Effect 
• 
any Serious Adverse Event, whether or not it is related to the investigational device 
The following Device Deficiencies require reporting to Philips:  
 
• 
All Device Deficiencies related to the quality, durability, reliability, safety, or performance of the 
investigational medical device, including user or use errors and equipment failures. 
• 
Any Device Deficiency that could have potentially led to a SADE if: 
o 
suitable action had not been taken, 
o 
timely intervention had not been made, or  
o 
circumstances had been less fortunate. 
 
Any other Adverse Event or Device Deficiency that does not meet any of the above criteria does not 
require reporting to the Sponsor, unless the approving IRB/EC requires reporting.  An Investigator may 
always opt to report any safety event even if it does not meet any of the above criteria.  Examples of 
Adverse Events that do not need to be reported to Philips include instances such as:  
 
• 
Broken bone from a car accident 
• 
A seasonal head cold 
• 
Headache, if it isn’t at least possibly related to the investigational device or study procedure 
• 
Infection, if it isn’t at least possibly related to the investigational device or study procedure 
 
All Adverse Events will be reported in the final Clinical Study Report for this study. 
 
 
Concomitant Medications 
 
At Visit 1, baseline concomitant medications will be source documented and reviewed by the 
Investigator or clinical staff against the eligibility criteria.  Only changes to baseline medications (i.e., 

 
 
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changes to amount, frequency, etc.) or the addition of new medications require reporting in the eCRFs.  
Changes in baseline medications will be reviewed with the Investigator to determine whether they may 
constitute Adverse Events or safety concerns. 
 
 
Expedited Reporting Requirements 
 
Any SAE, SADE, or Device Deficiency that could have led to a SADE must be immediately reported to 
the Philips Clinical Study Manager within 24 hours of the Investigator learning of the event. 
 
Promptly following such a report, the Investigator will provide a detailed written report of the event. 
Additionally, upon Philips’ request, the Investigator will provide any additional information related to the 
safety reporting of a particular event.  The Investigator is responsible for reporting the event to the 
approving IRB/EC as dictated by the guidelines defined by the IRB/EC and, if applicable, regulatory 
authorities.  Additionally, the Investigator will report to regulatory authorities as required by national 
regulations.   
 
 
Safety Monitoring Time Period 
 
Subject safety will be monitored to detect any changes in health status present at enrollment.  Subject 
safety will be monitored from the time each subject signs the Informed Consent Form until conclusion of 
study participation.  An Adverse Event that is present at the time of study completion is to be designated 
as ongoing on the eCRF (e.g., ‘Recovering/Resolving’ or ‘Not Recovered/Not Resolved’).  However, all 
ongoing events that require expedited reporting, as described in Section 15.5, or other important medical 
findings in the opinion of the Investigator, are to be followed until resolution.   
 
 
Data Monitoring Committee 
 
There is no Data Monitoring Committee planned for this pilot study.  
 
 
Sponsor Monitoring and Reporting of Safety Events 
 
Philips will monitor the Investigator’s documentation, assessment, and reporting of all safety events 
occurring during this clinical study.  The timing and frequency of safety monitoring will be outlined in the 
associated Monitoring Plan.  Subsequent to monitoring of site records and reports, Philips will review 
and classify Adverse Events and ensure ongoing safety evaluation of the clinical study as described in 
ISO 14155:2011.  In cases of disagreements with Investigator assessments, Philips will communicate 
both opinions to concerned parties (IRB/EC and regulatory authorities as applicable).   
 
Philips will inform all Investigators in writing of all SADEs at all clinical sites that have been reported to 
Philips and ensure reporting to their IRBs/ECs, if required by national regulations or the IRB/EC, 
whichever is more stringent.  Philips will ensure that all IRBs/ECs and the applicable regulatory 
authorities are informed of significant new information about the clinical study.   
 
Lastly, in case of SADEs and Device Deficiencies that could have led to SADEs, Philips will determine 
whether the device’s Risk Management File needs to updated and will assess whether corrective or 
preventive action is required.   
 
 
Methods for Assessing Safety Events 
 
Adverse Events and Adverse Device Effects may be identified through direct observation of the subject 
by the Investigator or other clinical staff during health assessments or physical examinations, in 

 
 
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response to open-ended questioning by the Investigator or other clinical staff during study visits, or by 
unsolicited reports from subjects themselves. 
 
16. 
Vulnerable Populations 
 
According to ISO 14155:2011, a vulnerable subject is an individual whose willingness to volunteer in a 
clinical study could be unduly influenced by the expectation, whether justified or not, of benefits 
associated with participation or of retaliatory response from senior members of a hierarchy in case of 
refusal to participate.  This study involves vulnerable subjects because it intends to enroll 
children/minors.  The specific informed consent process (including, where applicable, informed assent 
from minors) is described in Section 14.  Each reviewing IRB will ensure that the informed 
consent/assent language is appropriate based on the clinical guidelines at each site.  After the subject 
exits from the study, no medical care will be provided except for any continued follow-up necessary in 
the event of an unresolved Adverse Device Effect as specified in Section 15. 
 
17. 
Suspension or Premature Termination of the Clinical Study 
 
This clinical study may be terminated by Philips immediately upon notice to the Investigator if any of the 
following conditions occur: 
 
• 
Authorization and approval to conduct the study is withdrawn by any authorized regulatory agency 
or IRB or the study is placed on clinical hold. 
• 
New preclinical or clinical data from this or other studies emerge which supports early termination. 
• 
Any Adverse Device Effect emerges in this or other studies that is of such magnitude or incidence, 
in the opinion of Philips or one or more Investigators, to support termination. 
• 
Philips may also terminate the study for any internal business reasons at any time, at its sole 
discretion. 
 
In addition, participation at an individual clinical site may be terminated in cases of repeated or ongoing 
non-compliance with this clinical study protocol or ethical standards specified by Good Clinical Practice 
(e.g., ISO 14155:2011). 
 
In the event of suspension or premature termination of this clinical study for any of the reasons specified 
above, no follow-up of study subjects is required unless there is an ongoing Adverse Device Effect that 
has not resolved at the time of study suspension or termination.  In that case, the affected subject will be 
followed until Adverse Device Effect resolution is documented. 
 
18. 
Publication Policy 
 
The results of this clinical study may be submitted for publication to clinical or medical journals or to 
congresses or conferences for podium presentations.  The rights for publication of results from this study 
remain with Philips.  The Investigator must request permission from Philips prior to initiating any 
publication.  Permission must be requested and received in writing.  Review and approval by Philips of 
any data, abstract, or manuscript is required.  Philips reserves the right to delay publication to review the 
presentation of study methodology, data collection, data analysis, interpretation of data, proprietary 
information or patented technology.  A request for delay and the reason(s) will be communicated by 
Philips to the Investigator in writing.  Philips ultimately reserves the right to deny any request to publish.   
 

 
 
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19. 
Registration on Publically-Accessible Clinical Study Registry 
 
This clinical study does not meet the criteria to be considered an “Applicable Clinical Trial” (ACT) under 
42 CFR 11.22(b); therefore, there is no mandatory requirement to register this study on the publically-
accessible federal clinical trial registry maintained by the National Institutes of Health, ClinicalTrials.gov.   
 
However, the International Committee of Medical Journal Editors (ICMJE), which represents many 
academic and clinical journals that may be considered for publication of results generated during this 
study, typically requires prospective clinical study registration as a condition of publication.  Because 
Philips or the Investigator(s) may pursue publication of results from this study, Philips intends to register 
this study on ClinicalTrials.gov and submit results to the registry upon study completion.  Philips 
Ultrasound’s study registration procedure (9020-0543, Registration and Disclosure of Clinical Studies) 
will be followed to document justification for this registration decision.  Per federal regulations, study 
registration will be completed within 21 days of first subject enrollment in this study. 
 
20. 
Statements of Compliance 
 
The ethical principles for the treatment of human subjects in this clinical study have their origin in the 
Declaration of Helsinki.  This study will be conducted according to the IRB/EC-approved Clinical Study 
Protocol, any other additional stipulations imposed by the IRB/EC as a condition of approval, and all 
national regulatory requirements in the United States.  This study will also be conducted in compliance 
with Good Clinical Practice as described in ISO 14155:2011 – Clinical Investigation of Medical Devices 
for Human Subjects – Good Clinical Practice.  This Clinical Study Protocol complies with the content 
requirements of ISO 14155:2011. 
 
21. 
Referenced Documents  
 
The following Philips Ultrasound Clinical Affairs procedures are referenced in this protocol. 
 
Document ID 
Document Title 
9060-0617 
Clinical Study Protocol Development and Approval Procedure 
9060-0623  
Clinical Study Statistical Analysis and Data Management 
9020-0543 
Registration and Disclosure of Clinical Studies 
9060-0588 
Clinical Study Monitoring Global Procedure 
9060-0589 
Clinical Study Monitoring Plan Procedure 
 
  
 
 

 
 
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22. 
Investigator Agreement 
 
I agree to conduct this study as specified in this Clinical Study Protocol in accordance with the Sponsor’s 
guidelines, other applicable FDA regulations, Good Clinical Practice, and any conditions of approval imposed 
by the reviewing IRB/EC.  The Sponsor’s guidelines include, but are not limited to, the Investigator performing 
the following duties: 
 
• 
Submit this Clinical Study Protocol and the Informed Consent Form to an IRB/EC and ensure approval 
from the IRB/EC is secured prior to initiating the study. 
• 
Ensure that properly executed written informed consent is obtained from each subject prior to the use of 
any study device or performance of any study-related procedures. 
• 
Provide Philips with a current curriculum vitae and documentation of current medical licensure. 
• 
Provide comprehensive financial disclosure information to allow Philips to make an accurate disclosure 
statement as required under 21 CFR Part 54 for the course of the investigation and for up to one year 
after its completion. 
• 
Provide supervision of and restricted access to all investigational study devices used with human 
subjects.   
• 
Permit Philips and/or regulatory agencies to inspect study facilities and pertinent records at reasonable 
times and in a reasonable manner that ensures subject confidentiality.  If this study is to be inspected by 
a regulatory agency, Philips is to be notified as soon as possible. 
• 
Submit any proposed change in or significant deviation from this Clinical Study Protocol to the IRB/EC 
using a signed formal amendment document prepared by the Sponsor.  Any proposed changes or 
deviations from this Clinical Study Protocol require that the Informed Consent Form also reflects such 
changes or deviations and that the revised Informed Consent Form be approved by an IRB/EC. 
• 
Document and report any individual Clinical Study Protocol deviations and violations and provide full 
explanations of such deviations and/or violations. 
• 
Submit reports of Adverse Events and other safety-related information to the Sponsor and IRB/EC as 
outlined in this Clinical Study Protocol. 
• 
If applicable, submit timely progress reports to the IRB/EC and Sponsor at appropriate intervals on a 
schedule determined by the IRB/EC or Sponsor. 
• 
Record keeping: Maintain adequate and accurate records for each subject enrolled to document 
completion of all study procedures, related observations, and other key data (such as safety, compliance, 
and product accountability) pertinent to the study.  The investigator must maintain these records for a 
period as specified by Philips following completion of the study. 
I agree that all information provided to me by the Sponsor including pre-clinical data, study protocols, 
electronic databases, CRFs, and verbal and written information will be kept strictly confidential and confined 
to the clinical personnel involved in conduct of the study.  It is recognized that this information may be related 
in confidence to the IRB/EC.  I also understand that reports or information about the study or its progress will 
not be provided to anyone not involved in the trial other than the Sponsor or other legally constituted authority. 
 
______________________________________  
_____________________________________  
Investigator’s Signature 
 
 
 
Date 
 
 
 
 
______________________________________  
_____________________________________ 
Investigator’s Printed Name 
 
 
 
Investigator’s Institution 

 
 
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23. 
Selected Bibliography 
 
Alisi A, Feldstein AE, Villani A, Raponi M, and Nobili V. Pediatric nonalcoholic fatty liver disease: 
A multidisciplinary approach. Nat Rev Gastroenterol Hepatol 9: 152-161 (2012). 
Amacher DE and Chalasani N.  Drug-Induced Hepatic Steatosis.  Semin Liver Dis 34: 205-214 (2014). 
Berzigotti A, et al.  Novel ultrasound-based methods to assess liver disease: The game has just begun.  Digest 
Liver Disease 50: 107–112 (2018).   
Bruno C, et al.  ARFI: from basic principles to clinical applications in diffuse chronic disease — a review.  Insights 
Imaging 7:735–746 (2016). 
Fujii Y, et al.  A New Method for Attenuation Coefficient Measurement in the Liver: Comparison With the Spectral 
Shift Central Frequency Method.  J Ultrasound Med 21:783–788 (2002). 
Imbault M, et al. Robust sound speed estimation for ultrasound-based hepatic steatosis assessment. Phys 
Med Biol. 62(9): 3582-3598-775 (2017).  
Idilman IS, et al.  Hepatic Steatosis: Quantification by Proton Density Fat Fraction with MR Imaging versus 
Liver Biopsy. Radiology 267(3): 767-775 (2013). 
Karanijia RN, et al.  Hepatic steatosis and fibrosis: Non-invasive assessment.  World J Gastroenterol 22(45): 
9880-9897 (2016). 
Kramer H, et al.  Accuracy of Liver Fat Quantification with Advanced CT, MRI, and Ultrasound Techniques: 
Prospective Comparison With MR Spectroscopy.  Am J Roentgenol 208(1): 92–100 (2017). 
Marshall RH, et al.  Hepatorenal index as an accurate, simple, and effective tool in screening for steatosis.  Am 
J Roentgenol 199(5): 997-1002 (2012). 
Mikolasevic I, et al. Transient elastography (FibroScan®) with controlled attenuation parameter in the 
assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease — Where do we stand?  
World J Gastroenterol 22(32): 7236-7251 (2016). 
Myers RP, et al.  Feasibility and Diagnostic Performance of the FibroScan XL Probe for Liver Stiffness 
Measurement in Overweight and Obese Patients.  Hepatology 55(1): 199-208 (2011). 
Stal, P.  Liver fibrosis in non-alcoholic fatty liver disease – diagnostic challenge with prognostic significance.  
World J Gastroenterol 21(39): 11077-11087 (2015). 
Sugimoto K, et al. Value of Viscosity and Viscoelasticity Measurement in Patients with NAFLD Using Shear 
Wave Ultrasound Elastography. Kanzo 59(7): 370-373 (2018). 
Wan YL, et al.  Effects of fatty infiltration in human livers on the backscattered statistics of ultrasound imaging.  
Proc Inst Mech Eng H. 229(6): 419-428 (2015).  
Webb M, et al.  Diagnostic value of a computerized hepatorenal index for sonographic quantification of liver 
steatosis.  Am J Roentgenol 192(4): 909-914 (2009).  
Yasutomo F, et al.  A New Method for Attenuation Coefficient Measurement in the Liver: Comparison With the 
Spectral Shift Central Frequency Method.  J Ultrasound Med 21:783–788 (2002).