An Open-Label, Pilot Study to Assess the Effects of Hepatic Ultrasound Insonification on Glucometabolic Parameters in Subjects With T2DM
Phase: NA
Conditions: Type 2 Diabetes
Sponsor: General Electric Research

GE Research 
Clinical Study Protocol 
Confidential 
Page 1 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Clinical Development Ultrasound Insonification 
Clinical Study Protocol GE-HUI-01 
An Open-Label, Pilot Study to Assess the Effects of Hepatic Ultrasound 
Insonification on Glucometabolic Parameters in Subjects with T2DM 
 
Sponsor: 
GE Research 
One Research Circle, 
Niskayuna, New York, 12309 
USA 
Sponsor Contact: 
Christopher Puleo, BS, PhD 
Senior Biomedical Engineer 
CRO: 
ProSciento, Inc. 
855 3rd Avenue, Suite 4400 
Chula Vista, CA, 91911 
USA 
Authors: 
Marcus Hompesch, MD (ProSciento, Inc), Christopher 
Puleo, BS, PhD (GE Research), Jeffrey M. Ashe, MS, BS 
(GE Research), Victoria Cotero, BS, PhD (GE Research), 
Kirk Wallace, BS, PhD (GE Research), John Graf, BS, 
PhD (GE Research) 
Document type: 
Clinical Study Protocol 
IDE number: 
TBD 
Version number: 
V 4.0 
Development phase: 
1 
Release date: 
 
24Sep2020 
Statement of Confidentiality 
This document contains ProSciento Inc. and GE Research privileged or confidential information and is 
provided to you as an investigator, potential investigator, sponsor, or consultant, solely for review by you, 
your staff, and applicable institutional review board(s). The information is not to be disclosed to others 
without written authorization from ProSciento Inc. and GE Research. 
NCT # 
04502212

GE Research 
Clinical Study Protocol 
Confidential 
Page 2 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
A separate contact information list will be provided. 
1.2 
Document History 
Version 
Revision 
Date 
Revision Description 
1.0 
13-Mar-2020 
Original Document 
2.0 
(Amendment 1) 
26-May-2020 
1. Revisions to the Protocol for Submitting an 
Investigational Device Exemption (IDE) 
Application 
Language in regard to nonsignificant risk 
assessment has been taken out. 
Section 1.3 Approval, section 4.4 Summary of 
Known and Potential Risks and Benefits, 
section 10.3.6 Summary of Pre-Clinical 
/Clinical Studies, section 14.0 Ethical Aspects 
of the Study, section 14.2 Regulatory 
Authorities 
2. Fitness Tracking has been canceled 
The recording of physical activity and sleep via 
fitness tracking device will not be performed in 
this study 
Section 2.0 Study Summary, section 6.2 Study 
Description, section 9.1.18 Physical Activity 
and Sleep Recording, section 16.0 SOE in the 
Appendix 
3. Clarification of Inconsistencies 
Adjustment of protocol language in order to 
clarify inconsistency between protocol language 
and procedures stated in the Schedule of Events 
(SOE) around assessments on Days 8 and 22.  
Section 2.0 Study Summary, section 6.2 Study 
Description 
4. Change to Inflammatory Biomarkers 
Blood samples for the assessment of 
inflammatory biomarkers may be stored for 
potential later analysis. Additionally, IL-1β will 

GE Research 
Clinical Study Protocol 
Confidential 
Page 3 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
not be analyzed. 
Section 2.0 Study Summary, section 5.3 
Exploratory/Other Objectives and Endpoints, 
section 9.1.8 Procedures for Clinical 
Laboratory Samples, section 9.1.24 
Assessments of Ultrasound Insonification 
Effects 
5. Clarification/Explanation of Terminology 
Additional language has been added to specify 
the term plasma glucose. 
Section 9.1.15 Self -Monitoring of Blood 
Glucose  
6. Specification of Monitoring process 
Additional language has been added to specify 
the monitoring procedures for the study. 
Section 13.1 Monitoring 
7. Correction of Typographical Errors and 
adjustment of wording for better clarity 
Correction throughout the entire document. 
3.0 
(Amendment 2) 
25-June-2020 Revisions to the protocol based on feedback 
from the US FDA 
1. Change to the Inclusion Criterion #3 
Only subjects on stable treatment with diet and 
exercise or stable treatment with metformin 
monotherapy are included, as judged by the 
qualified Principal Investigator. Subjects on 
other oral anti diabetic drugs (OADs) will not 
be included in the study. 
Section 2.0 Study Summary, section 7.1 
Inclusion Criteria, section 7.3 Prohibited 
Medication 
2. Adding of Exclusion Criteria #2: 
A subject who is already indicated for 
medication escalation of their current diabetic 
therapy, or, who based upon study entry 
criteria, would be indicated for medication 
escalation during the course of the study (as 
assessed by the Principal Investigator). 

GE Research 
Clinical Study Protocol 
Confidential 
Page 4 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Section 2.0 Study Summary, section 7.2 
Exclusion Criteria 
3. Removal of Wash-out Period 
As subjects taking OADs in addition to 
metformin will not be included, the wash-out 
period is not needed and has been removed. 
Section 2.0 Study Summary, section 6.1 Study 
Design, section 6.2 Study Description, section 
6.3 Rationale for Study Design and Endpoints, 
section 9.1.13 Wash-Out Period, section 9.1.14 
Self-monitoring of Blood Glucose (SMBG), 
section 16.0 Appendix 
4. Change of FPG Threshold 
FPG level for which subjects are instructed to 
contact study staff will be lowered from 270 
mg/dL to 220 mg/dL. 
Section 2.0 Study Summary, section 6.2 Study 
Description, section 9.1.14 Self-monitoring of 
blood glucose (SMBG) 
5. Shortening of Screening Period 
The screening period will be shortened to 28 
days, as the wash-out period is removed. 
Section 2.0 Study Summary, section 6.1 Study 
Design, section 6.2 Study Description, section 
16.0 Appendix 
6. Revision of Duration of Participation 
The overall duration of participation in this 
study will be shorter for each subject due to the 
withdrawal of the wash-out period and 
consecutive shortening of screening period. 
Section 2.0 Study Summary 
7. Revisions to reflect the abbreviated 
requirements per IDE Regulations 
Language in regard to nonsignificant risk 
assessment has been added. 
Section 1.3 Approval, section 4.4 Summary of 
Known and Potential Risks and Benefits, 
section 14.0 Ethical Aspects of the Study 

GE Research 
Clinical Study Protocol 
Confidential 
Page 5 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Other Revisions 
8. Adjustment of Language around Telephone 
Visits/Calls 
Wording added to check for subject’s BG in 
order to provide consistent language for visits 
throughout the protocol. 
Section 2.0 Study Summary, section 6.2 Study 
Description 
9. Adjustment of Language for Exclusion 
Criterion  
History or active hepatic disease added to the 
exclusion criterion #14 in the main protocol in 
order to have consistent language in synopsis 
and main protocol. 
Section 7.2 Exclusion Criteria 
10. Removal of Specific Laboratory Parameters 
to be collected for Exploratory/Other 
Endpoints 
For the inflammatory biomarkers, blood 
samples will not be analyzed for tumor necrosis 
factor alpha (TNF-α) and norepinephrine. For 
long-term glucose parameters, blood samples 
will not be analyzed for 1,5-Anhydroglucitol. 
Section 2.0 Study Summary, section 3.0 List of 
Abbreviations, section 4.3 Summary of Pre-
Clinical /Clinical Studies, section 5.3 
Exploratory/Other Objectives and Endpoints, 
section 9.1.8 Procedures for Clinical 
Laboratory Samples, section 9.1.23 
Assessments of Ultrasound Insonification 
Effects, section 16.0 Appendix 
4.0 
(Amendment 3) 
24-Sep-2020 
Revisions: 
1. Changes to the Inclusion Criterion # 5 and 
Inclusion Criterion #6 
Criterion for BMI will be widened to BMI ≤ 
40.0 kg/m2. Criterion for inclusion of waist 
circumference will be widened to ≤ 45 inches 
(≤ 114 cm) to account for sedentary lifestyle of 
subjects due to COVID-19. Subjects with a 

GE Research 
Clinical Study Protocol 
Confidential 
Page 6 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
BMI > 35.0 kg/m2 (old criterion) and ≤ 40.0 
kg/m2 (new criterion) and/or a waist 
circumference between > 40 inches (old 
criterion) and ≤ 45 inches (new criterion) will 
need to undergo an ultrasound examination for 
eligibility (including visibility of the porta 
hepatis and a measured distance from the skin 
surface to the porta hepatis target not to exceed 
10 cm), followed by a 30-day wait period 
starting after the ultrasound examination has 
been performed, in order to comply with 
exclusion criterion # 35. Eligibility criteria will 
be re-assessed after the wait period. Therefore, 
the screening period will be extended for these 
subjects. 
Section 2.0 Study Summary, section 6.1 Study 
Design, section 6.2 Study Description, section 
7.1 Inclusion Criteria, section 9.1.2 Screening, 
section 9.1.26 Hepatic Ultrasound at 
Screening, section 16.0 Appendix 
2. Change of Exclusion Criterion #3 
Subjects with moderate peripheral neuropathy 
will be excluded and only subjects with mild 
peripheral neuropathy may be included in the 
study. The Toronto Neuropathy Scoring System 
will be used for the assessment of the 
neuropathy and is referenced in the Appendix. 
Section 2.0 Study Summary, section 7.2 
Exclusion Criteria, section 9.1.4 Physical 
Examination, section 16.0 Appendix 
3. Clarification to Ultrasound Examinations 
Ultrasound examination during the first 
ultrasound insonification will be performed to 
ensure that the target area can be visualized or 
stimulated and a measured distance from the 
skin surface to the porta hepatis target does not 
exceed 10 cm. 
Section 6.2 Study Description, section 9.1.24 
Hepatic Ultrasound Insonification 
4. Incorporation of Protocol Clarification 
Letter # 1, dated 25 Aug 2020: 

GE Research 
Clinical Study Protocol 
Confidential 
Page 7 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
a) Insonification Approximate Start Time 
Insonification may start at approximately 07:00 
h, but may be staggered and performed between 
07:00h and 08:30 h to allow an extra 30 min to 
allow for COVID-19 testing procedures prior to 
insonification. 
Section 2.0 Study Summary, section 6.2 Study 
Description, section 8.4 Regimen of Hepatic 
Ultrasound Insonification, section 9.1.24 
Hepatic Ultrasound Insonification 
b) Exclusion Criteria #1 – History of Insulin 
Clarification of insulin use prior to the study: 
Subjects who have participated in studies with 
insulin or given insulin during hospitalization 
(e.g. to manage diabetes when oral therapy is 
not allowed) outside of a 3-month window 
should not be excluded from participation as 
this is not considered ongoing treatment.  
Section 2.0 Study Summary, section 7.3 
Prohibited Medication 
c) Rescheduling Visits – Insonification Visits 
(Day 15, 16, 17) 
Subjects will be given up to 5 days to 
reschedule check-in on Day 15, in case of a 
weekend/holiday or subject’s personal issue. 
However, once checked-in for Day 15, there 
would not be a window to reschedule remaining 
insonification procedures (Day 16 & 17). 
Section 9.1.12 Check-in Procedure 
 
 
1.3 
Approval 
Representatives of Sponsor and Principal Investigator will sign the agreement on the 
protocol.

GE Research 
Clinical Study Protocol 
Confidential 
Page 10 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION .......................................................... 2 
1.1 
Contacts ................................................................................................... 2 
1.2 
Document History .................................................................................... 2 
1.3 
Approval .................................................................................................. 7 
2.0 
STUDY SUMMARY ................................................................................... 14 
3.0 
LIST OF ABBREVIATIONS ...................................................................... 25 
4.0 
INTRODUCTION ....................................................................................... 28 
4.1 
Background ............................................................................................ 28 
4.2 
Rationale for the Proposed Study............................................................ 29 
4.3 
Summary of Pre-Clinical /Clinical Studies ............................................. 29 
4.4 
Summary of Known and Potential Risks and Benefits ............................ 29 
4.5 
Rationale for Treatment and Dose .......................................................... 30 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ................................................ 31 
5.1 
Primary Objectives and Endpoints .......................................................... 31 
5.2 
Secondary Objectives and Endpoints ...................................................... 31 
5.3 
Exploratory/Other Objectives and Endpoints .......................................... 32 
6.0 
STUDY DESIGN AND DESCRIPTION ..................................................... 34 
6.1 
Study Design .......................................................................................... 34 
6.2 
Study Description ................................................................................... 35 
6.3 
Rationale for Study Design and Endpoints.............................................. 38 
6.4 
Discontinuation and Stopping Criteria .................................................... 39 
6.4.1 
Criteria for Early Termination of the Study ................................ 39 
6.4.2 
Criteria for Early Termination of Individual Subjects................. 39 
7.0 
STUDY POPULATION .............................................................................. 41 
7.1 
Inclusion Criteria .................................................................................... 41 
7.2 
Exclusion Criteria................................................................................... 41 
7.3 
Prohibited Medications ........................................................................... 44 
8.0 
STUDY MATERIALS AND EQUIPMENT ................................................ 46 
8.1 
Investigational Device ............................................................................ 46 
8.2 
Storage of Investigational Device ........................................................... 46 
8.3 
Packaging, and Labeling of Investigational Products/Device .................. 46 
8.4 
Regimen of Hepatic Ultrasound Insonification ....................................... 46 
8.5 
Ultrasound Insonification Effect ............................................................. 47 
8.6 
Randomization and Blinding .................................................................. 47 
8.7 
Auxiliary Supply .................................................................................... 48 

GE Research 
Clinical Study Protocol 
Confidential 
Page 11 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
9.0 
STUDY PLAN............................................................................................. 49 
9.1 
Study Procedures .................................................................................... 49 
9.1.1 
Informed Consent and HIPAA Release ...................................... 49 
9.1.2 
Screening................................................................................... 49 
9.1.3 
Demographics and Medical History ........................................... 50 
9.1.4 
Physical Examination ................................................................ 50 
9.1.5 
Height, Weight, BMI, and Waist Circumference ........................ 50 
9.1.6 
Vital Signs ................................................................................. 51 
9.1.7 
Concomitant Illness and Therapy ............................................... 51 
9.1.8 
Procedures for Clinical Laboratory Samples .............................. 51 
9.1.9 
Contraception ............................................................................ 53 
9.1.10 
Pregnancy .................................................................................. 54 
9.1.11 
ECG Procedure .......................................................................... 54 
9.1.12 
Check-in Procedure ................................................................... 55 
9.1.13 
Fasting Plasma Glucose ............................................................. 55 
9.1.14 
Self-Monitoring of Blood Glucose (SMBG) .............................. 56 
9.1.15 
Standardized Meals ................................................................... 56 
9.1.16 
Dietary and Nutrition Counseling .............................................. 57 
9.1.17 
Physical Activity ....................................................................... 57 
9.1.18 
CGMS ....................................................................................... 57 
9.1.19 
Oral Glucose Tolerance Test (OGTT) ........................................ 57 
9.1.20 
Overnight IV Insulin Infusion .................................................... 58 
9.1.21 
Intravenous Infusion of Stable Isotope Labeled Glucose and 
Assessment of Endogenous Glucose Production ........................ 58 
9.1.22 
Two-step Hyperinsulinemic, Euglycemic Clamp ....................... 59 
9.1.23 
Assessments of Ultrasound Insonification Effects ...................... 63 
9.1.24 
Hepatic Ultrasound Insonification .............................................. 63 
9.1.25 
Blood Volume ........................................................................... 63 
9.1.26 
Hepatic Ultrasound at Screening ................................................ 63 
10.0 
ADVERSE DEVICE EFFECTS ................................................................... 65 
10.1 
Definitions ............................................................................................. 65 
10.1.1 
Adverse Device Effect (ADE) ................................................... 65 
10.1.2 
Clinical Laboratory Adverse Device Event ................................ 65 
10.1.3 
Unanticipated Adverse Device Effect (UADE) .......................... 65 
10.1.4 
Severity of ADEs ....................................................................... 65 
10.1.5 
Relationship to Study Treatment ................................................ 66 

GE Research 
Clinical Study Protocol 
Confidential 
Page 12 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
10.2 
Procedures.............................................................................................. 66 
10.2.1 
Collection and Recording of ADEs ............................................ 66 
10.2.2 
Collection and Reporting of UADEs .......................................... 67 
10.3 
Anticipated ADEs .................................................................................. 67 
10.3.1 
Hypoglycemia ........................................................................... 67 
10.3.2 
Procedure Related Adverse Events ............................................ 68 
10.3.3 
Risks Related to CGMS ............................................................. 68 
10.3.4 
Risks Related to OGTT.............................................................. 68 
10.3.5 
Risks Related to Repeated Blood Draws .................................... 69 
10.3.6 
Risk Related to Hepatic Insonification ....................................... 69 
10.4 
Follow-up of ADEs and UADEs ............................................................ 69 
10.4.1 
Safety Reporting to IRBs and Regulatory Authorities ................ 70 
11.0 
DATA HANDLING AND MANAGEMENT .............................................. 71 
11.1 
Data Management .................................................................................. 71 
11.2 
CRFs (Electronic)................................................................................... 71 
11.2.1 
Clinical Data Management Workflow ........................................ 71 
11.2.2 
Data Entry of eCRFs.................................................................. 72 
11.2.3 
Corrections to eCRFs ................................................................. 72 
11.2.4 
PI Approval of eCRF Data ......................................................... 72 
11.3 
Retention of Documents ......................................................................... 72 
12.0 
STATISTICAL METHODS ........................................................................ 73 
12.1 
Statistical and Analytical Plans ............................................................... 73 
12.1.1 
Analysis Sets ............................................................................. 73 
12.1.2 
Analysis of Demographics and Other Baseline Characteristics ... 73 
12.1.3 
Analysis of the Endpoints for Ultrasound Insonification ............ 73 
12.1.4 
Safety Analysis and Endpoints ................................................... 75 
12.2 
Interim Analysis ..................................................................................... 76 
12.3 
Determination of Sample Size ................................................................ 76 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE ............................. 77 
13.1 
Monitoring ............................................................................................. 77 
13.2 
Protocol Deviations ................................................................................ 77 
14.0 
ETHICAL ASPECTS OF THE STUDY ...................................................... 79 
14.1 
Institutional Review Board ..................................................................... 79 
14.2 
Responsibilities of the Principal Investigator .......................................... 79 
14.3 
Informed Consent ................................................................................... 80 
14.4 
Subject Confidentiality ........................................................................... 80 

GE Research 
Clinical Study Protocol 
Confidential 
Page 13 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
14.5 
Property Rights ...................................................................................... 81 
14.6 
Publication, Disclosure, and Clinical Study Registration Policy .............. 81 
15.0 
REFERENCES ............................................................................................ 83 
16.0 
APPENDIX ................................................................................................. 84 
 
LIST OF IN-TEXT TABLES 
Table 7-1 Prohibited Medications ............................................................................ 44 
Table 9-1 Clinical Laboratory Assessments ............................................................. 52 
Table 9-2 Sampling Schedule for OGTT .................................................................. 58 
Table 9-3 Schedule for Clamp and Tracer ................................................................ 62 
Table 16-1 Schedule of Events (SOE) ...................................................................... 84 
Table 16-2 Schedule of Events (SOE) for Subjects with BMI> 35.0 kg/m2 and ≤ 40.0 
kg/m2 and/or Waist Circumference > 40 and ≤ 45 inches .................. 86 
Table 16-3 Toronto Clinical Neuropathy Scoring System ........................................ 89 
 
LIST OF IN-TEXT FIGURES 
Figure 6-1 Study Design Schematic ......................................................................... 34 
Figure 9-2 Schematic of Clamp Procedure ............................................................... 61 
 

GE Research 
Clinical Study Protocol 
Confidential 
Page 14 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
2.0 
STUDY SUMMARY 
Name of 
Investigational 
Product 
Hepatic Ultrasound Insonification using General Electric LOGIQ E10 
with C1-6 Probe 
Protocol Number 
GE-HUI-01 
Protocol Title  
An Open-Label, Pilot Study to Assess the Effects of Hepatic Ultrasound 
Insonification on Glucometabolic Parameters in Subjects with T2DM  
Primary 
Objectives and 
Endpoints 
To evaluate the effect of hepatic ultrasound insonification on changes 
from baseline in whole-body insulin sensitivity during a two-step 
hyperinsulinemic, euglycemic clamp (H-E Clamp) with stable isotope 
labeled glucose tracer, assessed by: 
• 
Glucose disposal rate: insulin ratio during steady state (M/I) 
• 
Endogenous glucose production (EGP) 
• 
Rate of glucose disappearance (Rd) 
Secondary 
Objectives and 
Endpoints 
To evaluate safety and tolerability of hepatic ultrasound insonification in 
subjects with T2DM, assessed by: 
• 
Incidence and severity of adverse device effects (ADEs) 
[including liver injury] 
• 
Incidence and severity of clinically significant laboratory 
abnormalities 
• 
Change from baseline in vital signs (blood pressure, temperature, 
respiratory rate, and heart rate) 
• 
Incidence and severity of clinical findings on physical 
examination 
• 
Change from baseline in 12-lead electrocardiogram (ECG) 
parameters; the primary ECG endpoint will be QTcF 
To evaluate the effect of hepatic ultrasound insonification on changes 
from baseline in whole-body insulin sensitivity during a two-step 
hyperinsulinemic, euglycemic clamp (H-E Clamp), assessed by: 
• 
Insulin Sensitivity Index (SI) 
• 
Glucose disposal rate during steady state (M) 
• 
Glucose metabolic clearance rate during steady state (MCR) 
To evaluate the effect of hepatic ultrasound insonification on change from 
baseline in glucose tolerance and insulin secretion, assessed by an oral 
glucose tolerance test (OGTT)  
• 
Area under the curve (AUC), total and incremental time, e.g., 
AUC0-180min 
To evaluate the effect of hepatic ultrasound insonification on glucose 
metabolism parameters, assessed by: 
• 
Change from baseline in blood glucose (BG) profiles assessed 
with continuous glucose monitoring system (CGMS) 

GE Research 
Clinical Study Protocol 
Confidential 
Page 15 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
o Time spent in defined glucose ranges 
o Average daily glucose 
o BG variability parameters (e.g., coefficient of variation as 
percentage of mean level [% CV], etc.) 
o Low blood glucose index (LBGI) 
o High blood glucose index (HBGI) 
• 
Change from baseline in Homeostasis Model Assessment of 
Insulin Resistance (HOMA-IR) 
• 
Change from baseline in Homeostatic Model Assessment of 
Insulin Secretion (HOMA-B) 
• 
Change from baseline in fasting plasma glucose (FPG) 
Exploratory/ 
Other Objectives 
and Endpoints 
To evaluate the effect of hepatic ultrasound insonification on glucose 
metabolism parameters, assessed by: 
• 
Change from baseline in exploratory biomarkers (blood samples 
will be stored for potential later analysis), e.g., but not limited to: 
o Glucagon 
o Glucagon-like peptide 1 (GLP-1), total 
o Leptin 
o Ghrelin 
• 
Change from baseline in long-term glucose parameters 
o Hemoglobin A1c (HbA1c) 
o Fructosamine 
• 
Change from baseline in lipid metabolism parameters  
o Free fatty acids (FFAs) 
o Triglycerides (TG) 
o Total cholesterol 
o Low-density lipoprotein (LDL-C) 
o High-density lipoprotein (HDL-C) 
o Very low-density lipoprotein (VLDL-C) 
• 
Change from baseline in inflammatory biomarkers (blood samples 
will be stored for potential later analysis), e.g., but not limited to: 
o Cytokines (IL-6) 
o Adiponectin  
o C-reactive protein (CRP) 
Phase of 
Development 
1 
Number of Study 
Sites 
1 
Study Population 
 
Subjects with T2DM 

GE Research 
Clinical Study Protocol 
Confidential 
Page 16 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Number of 
Subjects 
Approximately 15 subjects will participate in this study. Drop-outs may be 
replaced in order to achieve 15 completed subjects. 
Summary of 
Study Design 
 
This is an open label, exploratory pilot study to assess the effects of 
hepatic ultrasound insonification on glucometabolic parameters in subjects 
with T2DM through selective hepatic ultrasound of the porta hepatis 
region of the liver utilizing pulsed ultrasound.  
Assessments will be performed via CGMs, OGTT, HE-clamp with stable 
isotope labeled glucose ([6,6-2H2] glucose), measurements of insulin 
secretion and resistance (e.g. HOMA-IR), change in glucose parameters, 
inflammatory biomarkers and potential analysis of exploratory 
biomarkers.  
The study will be conducted in 1 cohort, enrolling approximately 15 
subjects. 
Subjects will undergo a Screening Period of up to 28 days, an 
approximately two week (Days -1 to 14) Observational Period, follow by 
three consecutive days of ultrasound Insonification (Days 15, 16 and 17) 
and a second Observation Period of 11 additional days (Days 18 to 28). 
Screening: 
A Screening Visit will be performed up to 28 days prior to the first in-
house period to identify eligible subjects for the study. For eligible 
subjects with a BMI > 35.0 and ≤ 40.0 kg/m2 and/or a waist circumference 
> 40 and ≤ 45 inches, an ultrasound examination will be added to confirm 
eligibility, and the screening period will be extended for at least 30 days 
for these subjects. 
In-house Period 1: 
Day -1: Subjects will check in to the clinic in the morning on Day -1 for a 
3-day in-house period. A urine pregnancy test (if applicable), and urine 
drug screen and alcohol breath test will be collected. 
 Subjects get instructions on maintaining their regular diet and physical 
activity.  
Subjects will receive standardized meals throughout their in-house stay. 
Food intake will be recorded during the entire in-house period by study 
staff. 
Subjects will be connected to a CGM (e.g., Dexcom G6) for the entire 
study period. Subjects will be blinded to the CGMS data. Continuous 
glucose monitoring data from Day -1 to Day 14 will be used for the 
baseline assessment. Subjects will be provided with a glucometer. They 
will be instructed on how to use the glucometer and to monitor their 
fasting plasma glucose levels daily during the outpatient periods. They 
will be instructed to contact the study staff, if FPG > 220 mg/dL, they 
experience symptoms of hypoglycemia, or measures an FPG < 70 mg/dL. 
Subjects will be frequently contacted by qualified study site staff to review 
their fasting plasma glucose values. 
Blood samples will be taken for safety assessments. 
Subjects will be instructed to fast overnight. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 17 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Day 1: Following ≥ 10 hour overnight fast, in the morning on Day 1, 
fasting blood samples will be taken for the assessment of various 
metabolic parameters as well as for banking for future exploratory 
measurements. 
Thereafter, an OGTT will be performed over 180 min as a baseline 
assessment. Standardized meals will be provided following the OGTT and 
in preparation of the clamp, that will be performed on the next day. 
Approximately around/after 22:00 h, subjects will receive a low-dose 
overnight intravenous (IV) infusion of insulin to titrate the BG to a target 
level of 100 mg/dl (± 10%) in preparation for the H-E clamp. 
Approximately at midnight, a primed-continuous IV infusion of stable 
isotope labeled glucose ([6,6-2H2]glucose) will also be initiated for the 
measurement of EGP. 
Day 2: After completing the fasting EGP assessments, subjects will 
undergo a 6-hour H-E clamp with stable isotope labeled glucose. 
Following their glucose clamp, subjects will be monitored post clamp to 
ensure adequate glycemic stabilization. They will be provided with a 
standardized meal and may then be released home. 
Telephone Visits: Subjects will be contacted every other day until they 
come in for the next in-house period, to remind the subjects of their diet 
and exercise regimes and to check subjects BG.  
Outpatient Visit(s): 
Subjects will check-in on Day 8 for their outpatient visit. A sensor change 
of the CGMS device will be performed. Blood samples will be taken for 
safety assessments. A urine pregnancy test (if applicable), and urine drug 
screen and alcohol breath test will be collected. Subjects will be re-
instructed to maintain their usual diet and physical activity regimes.  
In-house Period 2: 
Day 15: Subjects will check in to the clinic in fasting conditions on Day 
15 for a 4-day in-house period. A urine pregnancy test (if applicable), and 
urine drug screen and alcohol breath test will be collected. Blood samples 
will be taken in the fasting state prior to any assessment for the analysis of 
FPG, safety parameters, various metabolic parameters, as well as for 
banking for future exploratory measurements. 
They will get re-instructed to maintain their regular diet and physical 
activity. Subjects will receive standardized meals throughout their in-
house stay. Food intake will be recorded during the entire in-house period 
by study staff. 
Subjects will undergo the first of three ultrasound insonifications 
(following ≥ 10 hour overnight fast). Insonifications will be performed on 
three consecutive days (Days 15, 16 and 17). Subjects will be insonified 
by the stimulus pulse for 15 minutes on each day for a total of 45 minutes 
per study. Breath holds and image targeting will extend the total duration 
that the probe is on the subject (without the stimulus). Insonification will 
be performed, starting at approximately between 07:00 h and 08:30 h. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 18 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Day 16: Following ≥ 10 hour overnight fast, in the morning of Day 16, 
subjects will undergo the second of three ultrasound insonifications. 
Thereafter, an OGTT will be performed over 180 min. Standardized meals 
will be provided following the OGTT and in preparation of the clamp, that 
will be performed on the next day. 
Approximately around/after 22:00 h, subjects will receive a low-dose IV 
infusion of insulin to titrate the BG to a target level of 100 mg/dl (± 10%) 
in preparation for the H-E clamp. Approximately at midnight, a primed-
continuous IV infusion of stable isotope labeled glucose will also be 
initiated for the measurement of EGP. 
Day 17: Following ≥ 10 hour overnight fast, in the morning of Day 17, 
subjects will undergo the last of three ultrasound insonifications. All 
insonifications will be performed around the same time on each day. 
Subjects will be monitored for any evidence of hypoglycemia, liver injury, 
or any other device related adverse effect. 
Thereafter, subjects will undergo fasting EGP measurements and a 6-hour 
H-E clamp. During the clamp procedure, IV infusion with stable isotope 
labeled glucose will be continued to assess EGP suppression at Step 1 and 
Step 2 of the clamp. 
Following the glucose clamp, subjects will be monitored post clamp to 
ensure adequate glycemic stabilization. Subjects will receive a 
standardized meal at the end of the procedure.  
Day 18: Blood samples will be taken in the fasting state for safety 
assessments, metabolic parameters as well as for banking for exploratory 
biomarkers. A sensor change of the CGMS device will be performed.  
Subjects may be released home or may be asked to stay in-house for an 
extended time, if deemed appropriate and needed by the Principal 
Investigator to monitor for the risk of hypoglycemic episodes. 
Telephone Visits: Subjects will be contacted every other day until the 
Follow-up Visit, to remind the subjects of their diet /exercise and to check 
subjects BG. 
Outpatient Visit(s): 
Subjects will check-in on Day 22 for their outpatient visit. A urine 
pregnancy test (if applicable), and urine drug screen and alcohol breath 
test will be collected. Blood samples will be taken for safety 
assessments. Subjects will be re-instructed on maintaining their regular 
diet and physical activity.  
Follow-up Visit: 
A Follow-up Visit will be performed on day 28 for final safety procedures, 
blood sampling in fasted state for safety, metabolic parameters as well as 
for banking for future exploratory biomarkers will be performed. A urine 
pregnancy test (if applicable), and urine drug screen and alcohol breath 
test will be collected. CGM data will be uploaded to site computer via 
USB transfer from CGM receiver.  

GE Research 
Clinical Study Protocol 
Confidential 
Page 19 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Subjects will be instructed to transition back to their regular diabetes 
medication regimen. 
 
Sampling and Assessment: 
Safety assessments will occur throughout the duration of the study, 
including monitoring of adverse device effects (ADEs), clinical laboratory 
tests (chemistry, hematology, and urinalysis), vital signs measurements 
(blood pressure, heart rate, respiration rate, and aural temperature), 12-
lead electrocardiograms (ECGs), and physical examinations. 
Unscheduled outpatient visits: 
Additional, unscheduled outpatient visits may occur, in the event the 
CGMS might get dislodged and the sensor would need to be re-inserted by 
clinic staff. 
Treatment/ 
Intervention 
Selective ultrasound stimulation of the porta hepatis region. 
Route of 
Administration 
Ultrasound probe will be placed against the abdomen in order to 
administer insonification. 
Duration of 
Participation 
The duration of participation in this study, including Screening, 
Treatment, Observation and Follow-up will approximately be up to 8 
weeks for each subject. 
For subjects with a BMI > 35.0 and ≤ 40.0 kg/m2 and/or a waist 
circumference > 40 and ≤ 45 inches, the duration of participation in this 
study will approximately be 12-13 weeks. 
Inclusion Criteria  Subjects who meet all the following criteria at Screening to be eligible to 
participate in the study:  
1. Male or female subjects with type 2 diabetes ≥ 12 months. 
2. Age ≥ 21 and ≤ 75 years. 
3. Stable treatment with diet and exercise or stable treatment with 
metformin monotherapy. Stable treatment is defined as no change 
in treatment during the last 3 months.  
4. HbA1c > 6.5% and< 10% by local laboratory analysis (one retest 
is permitted with the result of the last test being conclusive). 
5. Body Mass Index (BMI) ≥ 18 to ≤ 40.0 kg/m2. Subjects within the 
range of >35 to ≤ 40 kg/m2 need to undergo an ultrasound 
examination for eligibility. 
6. Waist circumference ≤ 45 inches (≤ 114 cm). Subjects within the 
range of >40 to ≤ 45 inches need to undergo an ultrasound 
examination for eligibility. 
7. Considered generally healthy upon completion of medical history, 
physical examination and biochemical investigations as judged by 
the Principal Investigator. 
8. Female subjects must be non-pregnant and non-lactating and have 
a negative serum pregnancy test at Screening. Females may be 

GE Research 
Clinical Study Protocol 
Confidential 
Page 20 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
surgically sterile, postmenopausal or of child-bearing potential. 
Females of childbearing potential must be using an acceptable 
method of birth control. For specific details please see section 
9.1.9 Contraception. 
9. Ability to provide written informed consent. 
Exclusion 
Criteria 
Subjects who meet any of the following criteria at screening will be 
excluded from participating in the study: 
1. History or current diagnosis with T1DM or T2DM subjects on 
insulin or other injectable therapies not allowed for this study (as 
listed in table of Prohibited Medication below). 
2. A subject who is already indicated for medication escalation of 
their current diabetic therapy, or, who based upon study entry 
criteria, would be indicated for medication escalation during the 
course of the study (as assessed by the qualified Principal 
Investigator). 
3. A subject who has diabetic complications, i.e., acute proliferative 
retinopathy or maculopathy, severe gastroparesis, and/or moderate 
or severe neuropathy, in particular autonomic neuropathy, as 
judged by the Principal Investigator.  
4. Recurrent severe hypoglycemia (more than 1 event ≤ 6 month) or 
hypoglycemic unawareness or recent severe ketoacidosis 
(hospitalization ≤ 6 month), as judged by the Principal 
Investigator. 
5. Persistent systolic blood pressure > 150 mm Hg and/or diastolic 
blood pressure > 95 mm Hg at screening. (Subjects may be re-
checked once on the same day). 
6. Treatment with antihypertensive medication is not allowed, unless 
antihypertensive medication is given on a stable dose for at least 2 
months prior to screening. 
7. Subjects with a clinically significant history or active disease of 
any of the following body systems:  pulmonary,  neurological 
(including dementia, neurodegenerative disease, movement 
disorder, spinal disorders), pancreatic (including pancreatitis), 
immunological or systemic inflammatory (including systemic 
lupus erythematosus [SLE], rheumatoid arthritis [RA]), 
dermatological, endocrine, genitourinary or hematological 
(including sickle cell anemia or other anemia syndromes, 
monocytosis, thrombocytopenia). 
8. Subjects with a history or clinically active malignancy (history of 
basal cell carcinoma [BCC] is allowed). 
9. History or current diagnosis of cardiac dysrhythmias or heart 
disease, defined as symptomatic heart failure (New York Heart 
Association class III or IV), myocardial infarction, unstable 
angina requiring medication.  

GE Research 
Clinical Study Protocol 
Confidential 
Page 21 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
10. Transient ischemic attack [TIA], cerebral infarct, or cerebral 
hemorrhage.  
11. Invasive cardiovascular procedure, such as coronary artery bypass 
graft surgery (CABG), or angioplasty/percutaneous coronary 
intervention (PCI) within 6 months of screening.  
12. Presence of clinically significant ECG findings (e.g., QTcF > 450 
msec for males, QTcF > 470 msec for females, LBBB) at 
Screening, or cardiac arrhythmia requiring medical or surgical 
treatment within 6 months prior to screening. 
13. History of renal disease or abnormal kidney function tests at 
Screening (glomerular filtration rate [GFR] < 60 mL/min/1.73m2 
as estimated using the MDRD equation).  
14. History or clinically significant active hepatic disease or clinically 
significant abnormal hepatic function tests at Screening suggestive 
of hepatic impairment (e.g., ALT and/or AST >2 x ULN), total 
bilirubin > 1 x ULN). 
15. Subjects with a history or presence of any psychiatric disorder 
that, in the opinion of the Principal Investigator, might confound 
the results of the trial or pose additional risk in administering the 
investigational product to the subject. 
16. Personal or family history of hypercoagulability or 
thromboembolic disease, including deep vein thrombosis and/or 
pulmonary embolism (PE) 
17. History of surgical treatment for obesity (bariatric surgery, gastric 
banding, etc.) or any other gastrointestinal surgery (including 
appendectomy, cholecystectomy), any malabsorption disorder, 
severe gastroparesis, any GI procedure for weight loss (including 
LAP-BAND®), as well as clinically significant gastrointestinal 
disorders (e.g. peptic ulcers, severe GERD) at Screening.  
18. History of any major surgery within 3 months prior to screening. 
19. Any nerve stimulation study or implanted stimulator, including 
previously or currently implanted vagus nerve stimulator, 
previously or currently implanted spinal cord stimulator, other 
implanted electronic medical device, such as implanted pacemaker 
or cardioverter/defibrillator (AICD) or history of seizures. 
20. Diagnosis of sleep apnea. 
21. Participation in an investigational study within 30 days of 
screening or 5 half-lives within the last dose of any investigational 
product given during the investigational study, whichever is 
longer. 
22. Current use of any drugs (other than current treatment for diabetes 
mellitus) that are known to interfere with glucose or insulin 
metabolism as stated below in table prohibited medication. 
23. Thyroid hormone use is not allowed unless medication is given on 
a stable dose for at least 3 months prior to screening. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 22 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
24. Chronic use of acetaminophen, and inability to wash-out and 
abstain from use during the study, as it would interfere with the 
CGMS assessment. 
25. Subject is unable to tolerate adhesive tape or has any unresolved 
adverse skin reaction in the area of the sensor placement. 
26. Implanted pacemaker or cardioverter/defibrillator (AICD). 
27. Daily use of more than 5 cigarettes/day or equivalent use of any 
tobacco- or nicotine-containing product (such as, but not limited 
to vaping, transdermal nicotine patch, nicotine gum use, etc.) 
within 4 weeks prior to screening. Subjects must be able to abstain 
from any tobacco or nicotine containing products during 
confinement period. 
28. Any use of marijuana within 4 weeks prior to screening and 
positive test at screening. 
29. History of any active infection, except mild viral disease, such as 
common cold, within 30 days prior to screening. 
30. History of any recent traumatic injury, including intracerebral 
hemorrhage and visceral injury.  
31. History of alcohol or illicit drug abuse as judged by the Principal 
Investigator within past 12 months or positive test at screening. 
Any use of alcohol within 4 days prior to baseline assessment. 
Subjects must be able to abstain from any alcohol during 
confinement period. 
32. Known history or positive test for hepatitis B surface antigen 
(HBsAg), hepatitis C antibody (HCV Ab), human 
immunodeficiency virus type 1 (HIV-1) or type 2 (HIV-2) 
33. Donation or loss of > 500 mL of blood or blood product within 56 
days prior to screening 
34. Mental incapacity, unwillingness or language barriers precluding 
adequate understanding and to follow verbal commands during the 
ultrasound session or cooperation.  
35. An abdominal ultrasound scan or exam within 1 month prior to 
screening and/or any pre-planned ultrasound examinations during 
the study, or the need to participate in any unplanned outside 
ultrasound procedures during study. 
Prohibited 
Medication 
Medication or Class 
Indication/Reason 
From time point 
specified until the end 
of the study 
Antihypertensive 
medication  
Hypertension 
Excluded unless on 
stable dose for at least 
2 months prior to 
screening 
Lipid lowering drugs 
that are known to 
Hyperlipidemia 
Must be on a stable 
dose within 3 months 
prior to screening 

GE Research 
Clinical Study Protocol 
Confidential 
Page 23 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
interfere with glucose 
or insulin metabolism 
Non-prescription 
drugs/over-the-counter 
or herbal that are 
known to interfere 
with glucose or insulin 
metabolism 
 
Within one week prior 
to check-in for first in-
house period 
Anti-coagulants 
(Coumadin, Xarelto) 
Thrombotic 
syndromes, 
arrhythmias 
Within one week of 
screening 
Analgesics 
(acetaminophen) 
Pain 
Within one day of 
CGMS treatment 
Oral or systemic long-
acting corticosteroids, 
immunosuppressive 
agents 
E.g., chronic or acute 
non-infectious 
inflammatory 
conditions, auto-
immune diseases 
Within 3 months prior 
to screening 
Topiramate, 
monoamine oxidase 
(MAO) inhibitors, 
growth hormone. 
Use of any drugs that 
are known to interfere 
with glucose or insulin 
metabolism 
Within 3 months prior 
to screening 
Anticholinergic drugs, 
antispasmodics (e.g., 
modafinil, 
phenytoin), 5HT3 
antagonists, dopamine 
antagonists, or opiates, 
antiemetics, antacids  
Reduction/modification 
of GI motility 
Within 2 weeks prior to 
screening 
Orlistat, lorcaserin, 
sibutramine, etc., 
including over-the-
counter and herbal 
supplements, or any 
medication with a 
labelled indication for 
weight loss or gain 
Weight control 
treatment 
Within 3 months prior 
to screening. 
Any anti-diabetic 
medication, including 
herbal medicines, 
OADs, insulin and 
incretins. 
 (only metformin 
allowed) 
Diabetes 
Any prior treatment of 
insulin within 3 months 
prior to screening and 
incretins.  
Selective serotonin 
reuptake inhibitors 
(SSRIs), serotonin 
norepinephrine 
Depression, anxiety, 
psychiatric disorders 
 
Within 3-month prior 
to screening. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 24 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
reuptake inhibitors 
(SNRIs), 
antipsychotics, 
lithium.  
Use of SSRIs and 
SNRIs (including 
7bupropion) 
For reasons other than 
active psychiatric 
indications (e.g., 
migraine, weight loss, 
smoking cessation) 
Within 3-month prior 
to screening. 
Sample Size 
The sample size of 15 subjects was empirically determined and consistent 
with typical sample sizes used for similar exploratory studies to assess 
robust data. 
Statistical 
Methods 
Data analyses will follow the statistical analysis plan (SAP). 
Safety Set: The Safety population will consist of all subjects who received 
at least 1 hepatic ultrasound insonification. This will be the primary 
analysis population for the evaluation of exposure and safety. 
Ultrasound Insonification Effect Set: The ultrasound insonification effect 
population will consist of all subjects who received at least 1 hepatic 
ultrasound insonification. It is the same as the safety set and will be the 
primary analysis population for the primary endpoint. 
The analysis of the endpoints for Ultrasound Insonification will be 
summarized descriptively. 
Safety and tolerability will be assessed based on adverse device effects, 
tolerability, laboratory parameters, physical examination, vital signs, and 
ECG parameters throughout the duration of the study. Safety analysis will 
involve examination of the descriptive statistics and individual subject 
listings for effects of study treatment on clinical tolerability and safety. 
Safety data will be summarized using the safety analysis set.  

GE Research 
Clinical Study Protocol 
Confidential 
Page 25 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
3.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADE 
Adverse device effect 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUCGIR 
Area under the glucose infusion rate-time curve 
BG 
Blood glucose 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
BW 
Body weight 
CDM 
Clinical data management 
C.I. 
Confidence interval 
CL/F 
Apparent clearance 
CGMS 
Continuous glucose monitoring system 
Cmax 
Maximum concentration  
CRF 
Case report form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CV 
Coefficient of variation 
DFT 
Deviation from target 
DMP 
Data management plan 
DNA 
Deoxyribonucleic acid 
ECG  
Electrocardiogram 
eCRF 
Electronic CRF 
EGP 
Endogenous glucose production 
FDA 
Food and Drug Administration 
FFA 
Free fatty acid 
FPG 
Fasting plasma glucose 
FSFV 
First subject first visit 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GIR 
Glucose infusion rate 
GLP-1 
Glucagon-like peptide 1 
HbA1C 
Glycosylated hemoglobin 
HBGI 
High blood glucose index 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
H-E Clamp 
Hyperinsulinemic euglycemic clamp 
HIV 
Human immunodeficiency virus 

GE Research 
Clinical Study Protocol 
Confidential 
Page 26 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
HOMA 
Homeostasis Model Assessment 
HSV 
Herpes simplex virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IL 
Interleukin 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
Kg 
Kilogram 
lb 
Pound 
LBGI 
Low blood glucose index 
LDL 
Low-density lipoprotein 
LS mean 
Least square mean 
M 
Glucose disposal rate during steady state 
Mcg 
Microgram 
MCR 
Glucose metabolic clearance rate during steady state 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
NCA 
Non-compartmental analysis 
NDA 
New Drug Application 
Nmol 
Nanomol 
NPH 
Neutral Protamine Hagedorn insulin 
NSAID 
Non-steroid anti-inflammatory drugs 
OAD 
Oral antidiabetic drug 
OGTT 
Oral glucose tolerance test 
OTC 
Over the counter 
PE 
Physical examination 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
Rd 
Rate of glucose disappearance 
rDNA 
Recombinant deoxyribonucleic acid 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SI 
Insulin Sensitivity Index 
SOE 
Schedule of events 
SUSAR 
Suspected unexpected serious adverse reaction 
T1DM 
Type 1 Diabetes Mellitus 
T2DM 
Type 2 Diabetes Mellitus 
t½ 
Terminal insulin half-life 

GE Research 
Clinical Study Protocol 
Confidential 
Page 27 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
TG 
Triglycerides 
tGIRmax 
Time to maximum glucose infusion rate 
Tmax 
Time to maximum serum insulin concentration (in 
concentration time curve) 
TSH 
Thyroid-stimulating hormone 
U 
Unit 
UADE 
Unanticipated adverse device effect 
ULN 
Upper limit of normal 
US 
United States  
USP 
Unites States Pharmacopeia 
VLDL 
Very low-density lipoprotein 
Vz/F 
Apparent volume of distribution at terminal phase 
WHO 
World Health Organization 
YSI 
YSI Stat 2300 glucose analyzer 
 

GE Research 
Clinical Study Protocol 
Confidential 
Page 28 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
4.0 
INTRODUCTION 
4.1 
Background 
Recently, preclinical and clinical studies have been performed on the stimulation of the 
vagus nerve. Most studies have utilized implanted vagus nerve stimulators (VNS; 
implanted at the cervical vagus position). Several studies have shown promise in using 
the stimulator to modulate signaling along neuro-immune pathways/reflexes. Preclinical 
studies have shown that one such reflex is dependent on a vagus nerve signal that reaches 
the spleen, alters concentration of norepinephrine and acetylcholine, and modulates the 
release and production of cytokines by resident macrophages.1,2 One of the main 
cytokines under regulation by this reflex is tumor necrosis factor (TNF). Interestingly, 
TNF is the target of biologic therapies that inhibit TNF signaling in rheumatoid arthritis 
([RA] and other chronic inflammatory disease) patients.3 In RA, symptomatic relief can 
be achieved in up to 50% of patients using anti-TNF biologics, and recently a first-of-its-
kind study has shown that VNS significantly inhibited TNF production for up to 84 days 
in a pilot study in RA patients (with a concomitant decrease in disease severity as 
measured by standardized clinical composite scores).3 
 
Based on the initial success of using VNS in a bioelectronic medicine (i.e., use of nerve 
stimulators to effect specific molecular and/or drug target); 2,4 several groups are 
targeting other (non-splenic) organs, disease applications, and drug targets. In prior 
literature, the brain-liver connection is well established and includes vagal sensory neural 
innervation.5 The central nervous system (CNS) is known to control glucoregulatory 
response to both hyper- and hypoglycemia.5-8 However, past VNS experiments measuring 
effects of metabolic processes have shown complex and contrary results.9-12 This is in 
part due to the complexity of the innervation of the liver (i.e., combined afferent and 
efferent innervation with different function depending on innervation site with the liver), 
and the inability of implants to stimulate specific neurons (having specific function) 
within nerves. 
 
Recently, GE has published results on the use of focused, pulsed ultrasound to stimulate 
small sub-sets of neurons within organs.13,14 This data includes stimulation of sub-organ 
sites within the liver (surrounding the porta hepatis and sensory vagal innervation points) 
and prevention or reversal in several models of hyperglycemia (including LPS-induced 
hyperglycemia and Fatty Zucker Diabetes/Obesity models). Unlike VNS studies, the 
precision stimulus has allowed for stimulation of a specific liver-hypothalamic pathway, 
mapping of the nerve modulation effect, and daily stimulation of the liver site for long 
term (weeks-month) prevention of diabetes symptoms in several diabetes and obesity 
models.  
 

GE Research 
Clinical Study Protocol 
Confidential 
Page 29 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
For this study, the commercially available ultrasound device, GE General Electric 
LOGIQ E10 and C16 Probe, will be used to perform hepatic ultrasound insonification in 
patients with T2DM on metformin monotherapy. This device and probe have previously 
received IRB approval to perform splenic insonification and measure inflammatory 
markers from blood samples in healthy human subjects. Additionally, IRB approval has 
previously been received to perform liver insonification in healthy subjects and subjects 
with pre-diabetes. In clinical feasibility studies, the system is set to an elastography 
imaging mode that is utilized within the commercial product for hepatic elastography 
testing. A pulsed ultrasound stimulus like those utilized in this standard imaging 
procedure will be applied to the liver (at the porta hepatis region) in this study. Please 
refer to the User’s Manuals for further information on the device and the customized 
instructions for the pulsed insonification in the elastography setting. 
4.2 
Rationale for the Proposed Study 
The primary outcome to determine whether diagnostic-level ultrasound to the liver has a 
biological effect, which is measured as a statistically significant change in the primary 
and secondary markers listed within this protocol (including measures of glucose 
utilization, glucose tolerance, insulin sensitivity, and glucoregulation). 
4.3 
Summary of Pre-Clinical /Clinical Studies 
A clinical feasibility study has recently been completed that observes the biological 
effects of ultrasound insonification of the spleen. It is performed in healthy subjects after 
insonification of the spleen with pulsed ultrasound using the elastography setting within 
the commercial LOGIQ E10 with C1-6 probe. This study is being conducted to determine 
if insonification has a biological effect on inflammation markers. This study is being 
performed based on past GE data showing that the cholinergic anti-inflammatory 
pathway can be activated by pulsed ultrasound in the spleen.13 
Additional, pre-clinical studies from GE have demonstrated that pulsed ultrasound 
focused on specific locations in the liver (i.e. porta hepatis) modifies glucose regulation 
and insulin sensing and may have beneficial effects in rodent models of diabetes and 
obesity.13,14 This feasibility study is designed to test whether insonification at the liver 
site has a biological effect on measures of glucose utilization, glucose tolerance, insulin 
sensitivity, and glucoregulation. 
4.4 
Summary of Known and Potential Risks and Benefits 
Although subjects participating in this study will not directly benefit, the knowledge 
gained may help other people in the future by leading to changes in clinical care. Given 
the study goal of determining whether insonification at the liver site has a biological 
effect on measures of glucose utilization, glucose tolerance, insulin sensitivity, and 
glucoregulation, this study may lead to better methods for treatment. 
The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1‐6‐D 
XDclear abdominal, curvilinear probe are FDA cleared (K173555) with the indication for 

GE Research 
Clinical Study Protocol 
Confidential 
Page 30 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
ultrasound evaluation of fetal, abdominal, pediatric, small organ (breast, testes, thyroid), 
neonatal cephalic, adult cephalic, cardiac (pediatric and adult), peripheral vascular, 
musculoskeletal conventional and superficial, urology (including prostate), transrectal, 
transvaginal, transesophageal, and intraoperative (abdominal, thoracic, and vascular). 
Since the ultrasound device will be used in this study to achieve organ‐specific biological 
effects, it is being used off‐label on this study, and therefore, is considered 
investigational. Although its use in this study is considered investigational, its use is 
considered to constitute minimal risk given that it will be operated within the confines of 
its FDA‐cleared equipment parameters and below the guidelines established by the FDA 
for ultrasound equipment. The FDA guidelines indicate that the derated global maximum 
acoustic output should not exceed preamendment acoustic output exposure levels. In the 
case of diagnostic ultrasound, the global maximum derated spatial‐peak temporal‐average 
intensity (ISPTA – the highest intensity measured at any point in the ultrasound beam 
averaged over the pulse repetition period) is ≤ 720 mW/cm2 with either the global 
maximum mechanical index being ≤ 1.9 or the global maximum derated spatial‐peak 
pulse‐average intensity (ISPPA – the highest intensity measured at any point in the 
ultrasound beam averaged over the temporal duration of the pulse) being ≤ 190 W/cm2 
(not including ophthalmic use). These FDA guideline values are significantly higher than 
the maximum spatial‐peak temporal‐average intensity to be delivered on this study. 
The Food and Drug Administration (FDA) has determined that this clinical study is a 
nonsignificant risk (NSR) device study, because it does not meet the definition of a 
significant risk (SR device under $812.3(m) of the Investigational Device Exemption 
(IDE) regulation (21 CFR 812). An NSR study is subject to the abbreviated requirements 
as described in § 812.2(b) of the IDE regulations. 
4.5 
Rationale for Treatment and Dose  
Insonifications will be performed on three consecutive days (Days 15, 16 and 17) for 15 
minutes of ultrasound push-pulse waveform exposure on each day for a total of 45 
minutes. Fifteen (15) minutes was chosen as a typical procedure time for imaging, 
specifically elastography imaging sessions in clinical practice. The 15-minute dose will 
be targeted to the porta hepatis by the ultrasonographer, and the ultrasonographer may 
choose to perform breath holds during the procedure in order to locate and target the 
ultrasound pushpulses on the porta hepatis. If breath holds are utilized during targeting, 
the subject will be allowed 2-3 minutes between breath holds (and this waiting period 
will not count toward the 15-minute dose or ultrasound duration). 

GE Research 
Clinical Study Protocol 
Confidential 
Page 31 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Primary Objectives and Endpoints 
To evaluate the effect of hepatic ultrasound insonification on changes from baseline in 
whole-body insulin sensitivity during a two-step hyperinsulinemic, euglycemic clamp (H-
E Clamp) with stable isotope labeled glucose tracer, assessed by: 
• Glucose disposal rate: insulin ratio during steady state (M/I) 
• Endogenous glucose production (EGP) 
• Rate of glucose disappearance (Rd) 
5.2 
Secondary Objectives and Endpoints 
To evaluate safety and tolerability of hepatic ultrasound insonification in subjects with 
T2DM, assessed by: 
• Incidence and severity of adverse device effects (ADEs) [including, liver injury] 
• Incidence and severity of clinically significant laboratory abnormalities 
• Change from baseline in vital signs (blood pressure, temperature, respiratory rate, 
and heart rate) 
• Incidence and severity of clinical findings on physical examination 
• Change from baseline in 12-lead electrocardiogram (ECG) parameters; the 
primary ECG endpoint will be QTcF 
To evaluate the effect of hepatic ultrasound insonification on changes from baseline in 
whole-body insulin sensitivity during a two-step hyperinsulinemic, euglycemic clamp (H-
E Clamp), assessed by: 
• Insulin Sensitivity Index (SI) 
• Glucose disposal rate during steady state (M) 
• Glucose metabolic clearance rate during steady state (MCR) 
To evaluate the effect of hepatic ultrasound insonification on change from baseline in 
glucose tolerance and insulin secretion, assessed by an oral glucose tolerance test 
(OGTT)  
• Area under the curve (AUC), total and incremental time, e.g., AUC0-180min 
To evaluate the effect of hepatic ultrasound insonification on glucose metabolism 
parameters, assessed by: 
• Change from baseline in blood glucose (BG) profiles assessed with continuous 
glucose monitoring system (CGMS) 
o Time spent in defined glucose ranges 

GE Research 
Clinical Study Protocol 
Confidential 
Page 32 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
o Average daily glucose 
o BG variability parameters (e.g., coefficient of variation as percentage of 
mean level [% CV], etc.) 
o Low blood glucose index (LBGI) 
o High blood glucose index (HBGI) 
• Change from baseline in Homeostasis Model Assessment of Insulin Resistance 
(HOMA-IR) 
• Change from baseline in Homeostatic Model Assessment of Insulin Secretion  
(HOMA-B) 
• Change from baseline in fasting plasma glucose (FPG) 
5.3 
Exploratory/Other Objectives and Endpoints 
To evaluate the effect of hepatic ultrasound insonification on glucose/metabolism 
parameters, assessed by: 
• Change from baseline in exploratory biomarkers (blood samples will be stored for 
potential later analysis), e.g., but not limited to: 
o Glucagon 
o Glucagon-like peptide 1 (GLP-1), total 
o Leptin 
o Ghrelin 
• Change from baseline in long-term glucose parameters 
o Hemoglobin A1c (HbA1c) 
o Fructosamine 
• Change from baseline in lipid metabolism parameters  
o Free fatty acids (FFAs) 
o Triglycerides (TG) 
o Total cholesterol 
o Low-density lipoprotein (LDL-C) 
o High-density lipoprotein (HDL-C) 
o Very low-density lipoprotein (VLDL-C) 
• Change from baseline in inflammatory biomarkers (blood samples will be stored 
for potential later analysis), e.g., but not limited to: 
o Cytokines (IL-6) 

GE Research 
Clinical Study Protocol 
Confidential 
Page 33 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
o Adiponectin  
o C-reactive protein (CRP) 

GE Research 
Clinical Study Protocol 
Confidential 
Page 34 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is an open label, exploratory pilot study to assess the effects of hepatic ultrasound 
insonification on glucometabolic parameters in subjects with T2DM through selective 
hepatic ultrasound of the porta hepatis region of the liver utilizing pulsed ultrasound.  
Assessments will be performed via CGMS, OGTT, H-E clamp with stable isotope labeled 
glucose ([6,6-2H2] glucose), measurements of insulin secretion and resistance (e.g. 
HOMA-IR), change in glucose parameters, inflammatory biomarkers and potential 
analysis of exploratory biomarkers.  
The study will be conducted in 1 cohort, enrolling approximately 15 subjects. Drop-outs 
may be replaced. 
Subjects will undergo a Screening Period of up to 28 days, an approximately two week 
(Days -1 to 14) Observational Period, followed by three consecutive days of hepatic 
ultrasound insonification (Days 15, 16 and 17) and a second Observation Period of 11 
additional days (Days 18 to 28).The Observational Period is divided in an In-house 
Period and an Outpatient Visit (OPV). For eligible subjects with a BMI > 35.0 and ≤ 40.0 
kg/m2 and/or a waist circumference > 40 and ≤ 45 inches, an ultrasound examination will 
be added to confirm eligibility, and the screening period will be extended for at least 30 
days for these subjects. 
 
Figure 6-1 Study Design Schematic 
 
*Screening Period will be extended for at least 30 days, for subjects with BMI> 35.0 and ≤ 40.0 kg/m2 
and/or waist circumference >40 and ≤ 45 inches. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 35 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
6.2 
Study Description 
Screening Visit: 
At Screening, potential subjects for the study will be provided with written and oral 
information about the study and the procedures involved. Subjects have to sign the 
institutional review board (IRB) informed consent form (ICF) prior to entering the study. 
The Screening Visit will be performed up to 28 days prior to the first in-house period, to 
identify eligible subjects for the study. For eligible subjects with a BMI > 35.0 and ≤ 40.0 
kg/m2 and/or waist circumference > 40 and ≤ 45 inches, an ultrasound examination will 
be added to the screening assessments to confirm eligibility. For these subjects, the 
screening period will be extended for at least 30 days, starting after the ultrasound 
examination has been performed. Eligibility per inclusion and exclusion criteria will be 
re-assessed in a second screening visit prior to the first In-house Period. 
All assessments performed at the Screening visit are stated in the Schedule of Events 
(SOE) and will be recorded in the electronic case report form (eCRF). See section 9.1.2 
and 11.2 for further details. 
In-house Period 1: 
Day -1: 
Subjects will check in to the clinic in the morning on Day -1 for a 3-day in-house period.  
Check-in assessments will be performed to ensure subjects meet the check-in 
requirements. A urine pregnancy test (if applicable), and urine drug screen and alcohol 
breath test will be collected. Blood samples will be taken for safety assessments. 
Subjects get instructions on maintaining their current diet and physical activity.  
Subjects will receive standardized meals throughout their in-house stay. Food intake will 
be recorded during the entire in-house period by study staff. 
Subjects will be connected to a CGMs (e.g., Dexcom G6) and will continue wearing this 
for the entire study period. Subjects will be blinded to the CGMS data. Monitoring data 
from Day -1 to Day 14 will be used for the baseline monitoring evaluation. Subjects will 
be provided with a glucometer. They will be instructed on how to use the glucometer and 
to monitor their fasting plasma glucose levels daily during the outpatient periods. They 
will be instructed to contact the study staff, if FPG > 220 mg/dL, they experience 
symptoms of hypoglycemia, or measures an FPG < 70 mg/dL. Subjects will be frequently 
contacted by qualified study site staff to review their fasting plasma glucose values. 
It will be ensured that subjects have an adequate fasting time prior to the assessments on 
Day 1.  
Day 1: 
Following ≥ 10 hour overnight fast, in the morning on Day 1, blood samples will be taken 
in the fasting state for the assessment of various metabolic parameters and biomarkers, as 
well as for banking for future exploratory measurements. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 36 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Thereafter, at approximately 08:00 h-09:00 h, an OGTT will be performed over 180 min 
as a baseline assessment. Standardized meals will be provided following the OGTT and 
in preparation of the clamp, that will be performed on the next day. 
At approximately 22:00 h, subjects will receive a low-dose intravenous (IV) infusion of 
insulin (e.g., NovoLog®) to titrate the BG to a target level of 100 mg/dl (± 10%) in 
preparation for the H-E clamp. Approximately at midnight, a primed-continuous IV 
infusion of stable isotope labeled glucose ([6,6-2H2]glucose) will also be initiated for the 
measurement of EGP. 
Day 2: 
After completing the fasting EGP assessments, subjects will undergo a 6-hour H-E clamp 
with stable isotope labeled glucose as baseline assessment. Blood sampling during the 
clamp will follow time points as indicated in the Clamp Sampling Schedule. Following 
their glucose clamp, subjects will be monitored post clamp to ensure adequate glycemic 
stabilization. They will be provided with a standardized meal and may then be released 
home. 
Telephone Visits: 
Subjects will be contacted every other day until they come in for the next in-house 
period, to remind the subjects of their diet /exercise and to check subjects BG. 
Outpatient Visit: 
Subjects will check-in on Day 8 for their outpatient visit. A sensor change of the CGMS 
device will be performed. Blood samples will be taken in the fasting state prior to any 
assessment for the analysis of FPG A urine pregnancy test (if applicable), and urine drug 
screen and alcohol breath test will be collected. Safety parameters (vital signs, 12-lead 
ECG, and recording of concomitant medications and adverse device events) and 
metabolic parameters (body weight/BMI) will be assessed. Subjects will be re-instructed 
on maintaining their regular diet and physical activity regimes. 
In-house Period 2: 
Day 15: 
Subjects will check in to the clinic in fasting conditions on Day 15 for a 4-day in-house 
period. Check-in assessments will be performed to ensure subjects meet the check-in 
requirements. A urine pregnancy test (if applicable), and urine drug screen and alcohol 
breath test will be collected. Fasting blood samples will be taken prior to any assessment 
for the analysis of safety parameters, various metabolic parameters, as well as for 
banking for future exploratory measurements. 
Subjects will undergo the first of three ultrasound insonifications (following ≥ 10 hour 
overnight fast). If sonographer is not able to visualize or stimulate target area during the 
first ultrasound insonification, or a measured distance from the skin surface to the porta 
hepatis target exceeds 10 cm, the subject will be excluded from the study. Excluded 
subjects may be replaced. Insonifications will be performed on three consecutive days 
(Days 15, 16 and 17). Subjects will be insonified by the stimulus pulse for 15 minutes on 
each day for a total of 45 minutes/study. Breath holds and image targeting will extend the 

GE Research 
Clinical Study Protocol 
Confidential 
Page 37 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
total duration that the probe is on the subject (without the stimulus). Insonifications will 
be performed between 07:00 h to 08:30 h. 
Subjects will receive standardized meals after the insonification and throughout their in-
house stay. Food intake and exercise will be recorded during the entire in-house period by 
study staff. 
Subjects will be re-instructed on maintaining their regular diet and physical activity 
regimens. 
Day 16: 
Following ≥ 10 hour overnight fast, in the morning of Day 16, subjects will undergo the 
second of three ultrasound insonifications. Insonification for each subject will take place 
at approximately the same time of day as on Day 15. 
Thereafter, at approximately 08:00 h-09:00 h, an OGTT will be performed over 180 min. 
OGTT should start at approximately the same as on Day 1 for the subject. Standardized meals 
will be provided following the OGTT and in preparation of the clamp, that will be 
performed on the next day.  
Approximately around/after 22:00 h, subjects will receive a low-dose IV infusion of 
insulin to titrate the BG to a target level of 100 mg/dl (± 10%) in preparation for the H-E 
clamp. Approximately at midnight, a primed-continuous IV infusion of stable isotope 
labeled glucose will also be initiated for the measurement of EGP. 
Day 17: 
Following ≥ 10 hour overnight fast, in the morning of Day 17, subjects will undergo last 
of three ultrasound insonifications. Insonification for each subject will take place at 
approximately the same time of day as on Day 15 and Day 16.  
Thereafter, fasting EGP assessments will be performed, and subjects will start the 6-hour 
H-E clamp with stable isotope labeled glucose.  
Following the glucose clamp, subjects will be monitored post clamp to ensure adequate 
glycemic stabilization. Subjects will receive a standardized meal at the end of the 
procedure.  
Day 18: 
Blood samples will be taken in the fasting state prior to any assessment for the analysis of 
FPG, for safety assessments, various metabolic parameters as well as for banking for 
future exploratory measurements A sensor change of the CGMS device will be 
performed.  
Subjects may be released home or may be asked to stay in-house for an extended time, if 
deemed appropriate and needed by the Principal Investigator. 
Telephone Visits: Subjects will be contacted every other day until the Follow-up Visit, to 
remind the subjects of their diet /exercise and to check subjects BG. 
Outpatient Visit: 
Subjects will check-in on Day 22 for their outpatient visit. Blood samples will be taken in 
the fasting state prior to any assessment for the analysis of FPG. A urine pregnancy test 
(if applicable), and urine drug screen and alcohol breath test will be collected. Safety 

GE Research 
Clinical Study Protocol 
Confidential 
Page 38 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
assessments (vital signs, 12-lead ECG, and recording of concomitant medications and 
adverse device events) and metabolic parameters (body weight/BMI) will be assessed. 
Subjects will be re-instructed on maintaining their regular diet and physical activity.  
Follow-up Visit: 
A Follow-up Visit will be performed on day 28 for final safety procedures, blood 
sampling will be taken in the fasting state prior to any assessment for the analysis of 
FPG, for safety, various metabolic parameters as well as for banking for future 
exploratory measurements. A urine pregnancy test (if applicable), and urine drug screen 
and alcohol breath test will be collected. 
CGM data will be uploaded to site computer via USB transfer from CGM receiver.  
Subjects will be instructed to transition back to their regular diabetes medication regimen. 
Sampling and Assessment: 
Safety assessments will occur throughout the duration of the study, including monitoring 
of adverse device effects (ADEs), clinical laboratory tests (chemistry, hematology, and 
urinalysis), vital signs measurements (blood pressure, heart rate, respiration rate, and 
aural temperature), 12-lead electrocardiograms (ECGs), and physical examinations. 
Unscheduled Outpatient Visits: 
Additional, unscheduled outpatient visits may occur, in case the CGMS might get 
dislodged and the sensor would need to be re-inserted by clinic staff.  
6.3 
Rationale for Study Design and Endpoints 
The aim of this exploratory, pilot study is to determine the effect of hepatic ultrasound 
insonification on insulin sensitivity, glycemic, metabolic and lipid parameters, as well as 
on various biomarkers in subjects with T2DM.  
Subjects with T2DM will participate in the study, as these subjects are an important 
target population. These subjects are characterized by relative rather than absolute insulin 
deficiency in association with variable degrees of insulin resistance.  
Subjects on metformin therapy will continue the stable drug dose throughout the entire 
study.  
Subjects will be supplied with a CGMS to ensure that blood glucose levels are monitored 
closely. CGM as assessment has been chosen to assess the ultrasound insonification 
effects with a standardized method for efficacy.  As assessment of insulin secretion and 
resistance, an OGTT and H-E clamp will be performed. 
Whole-body insulin sensitivity will be assessed with the 2-step H-E clamp procedure. 
The use of two-stepped IV insulin infusions is used in combination with IV stable isotope 
labeled glucose infusion to allow the differentiation between hepatic (EGP) and 
peripheral insulin sensitivity.  
Due to the variability in fasting blood glucose concentrations in subjects with diabetes 
mellitus, which might affect the metabolic response, an overnight baseline period will be 

GE Research 
Clinical Study Protocol 
Confidential 
Page 39 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
used to establish the target plasma glucose concentration of 100 mg/dL (± 10%) prior to 
fasting EGP measurements. 
Endogenous glucose production will be measured in the fasting state prior to the start of 
the clamp and suppression of EGP during step 1 of the 2-step H-E clamp. It will be 
assessed using a stable isotope labeled glucose ([6,6-2H2]glucose) tracer method. 
Insulin will be infused at a low dose, followed by a high dose. During the low-dose IV 
insulin infusion, EGP will be partially suppressed, while during the high dose IV insulin 
infusion, EGP will be near completely suppressed. 
Metabolic changes in response to glucose ingestion will be assessed via an OGTT. It will 
be performed to assess the postprandial carbohydrate metabolism to see changes in 
insulin and glucose response. 
The other glucometabolic endpoints of this study are chosen to investigate 
additionalultrasound insonification effects. 
6.4 
Discontinuation and Stopping Criteria 
6.4.1 Criteria for Early Termination of the Study 
The study will be completed as planned unless one or more of the following criteria are 
satisfied that require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of the study 
device that indicates a change in the known risk/benefit profile, such that the 
risk/benefit is no longer acceptable for subjects participating in the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises subject safety. 
• Failure to meet expected enrollment goals 
• Administrative Reasons 
In the event that the Sponsor, IRB), or regulatory authority elects to terminate or suspend 
the study or the participation of an investigational site, a study-specific procedure for 
early termination or suspension will be provided by the Sponsor or delegate; the 
procedure will be followed by the investigational site during the course of termination or 
study suspension. 
6.4.2 Criteria for Early Termination of Individual Subjects 
Subjects may discontinue from the study for any of the following reasons: 
• Voluntary withdrawal of consent (mandatory removal from study) 
Subjects may withdraw their consent to participate in the study at any time. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 40 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
If a subject withdraws consent, the date and reason for consent withdrawal should be 
documented. Subjects will be encouraged to remain in the clinic for safety assessments 
(in case they are currently in one of the in-house periods) until the Principal Investigator 
deems that it is safe for the subject to be discharged. Subject data will be included in the 
analysis up to the date of the consent withdrawal. 
• ADE or UADE that requires discontinuation at the discretion of the Principal 
Investigator 
• Protocol violation: If protocol violation or concurrent illness occurs, which, in the 
clinical judgment of the Principal Investigator or after discussion with the Sponsor, 
may invalidate the study by interfering with the investigation, the subject will be 
withdrawn by the Principal Investigator. 
• Lost to follow-up. The subject did not return to the clinic and attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented. 
• Discretion of Principal Investigator (document reason on CRF) 
• Subject becomes pregnant or begins breastfeeding (mandatory) 
• Study discontinuation by Sponsor 
Wherever possible, the tests and evaluations, including those listed for the Follow-up 
Visit should be performed for all subjects who discontinue prior to the completion of the 
study. 
In the event the Principal Investigator determines to terminate a subject participation in 
the Clinical Study, the Principal Investigator must notify the Sponsor of such decision 
and rationale immediately in writing. In all cases, the appropriate IRB and other 
applicable regulatory authorities shall be informed. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 41 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
Subjects who meet all the following criteria at Screening to be eligible to participate in 
the study:  
1. Male or female subjects with type 2 diabetes ≥ 12 months. 
2. Age ≥ 21 and ≤ 75 years. 
3. Stable treatment with diet and exercise or stable treatment with metformin 
monotherapy. Stable treatment is defined as no change in treatment during the last 
3 months.  
4. HbA1c > 6.5% and< 10% by local laboratory analysis (one retest is permitted 
with the result of the last test being conclusive). 
5. Body Mass Index (BMI) ≥ 18 to ≤ 40.0 kg/m2. Subjects within the range of >35 
to ≤ 40 kg/m2 need to undergo an ultrasound examination for eligibility. 
6. Waist circumference ≤ 45 inches (≤ 114 cm). Subjects within the range of >40 to 
≤ 45 inches need to undergo an ultrasound examination for eligibility. 
7. Considered generally healthy upon completion of medical history, physical 
examination and biochemical investigations as judged by the Principal 
Investigator. 
8. Female subjects must be non-pregnant and non-lactating and have a negative 
serum pregnancy test at Screening. Females may be surgically sterile, 
postmenopausal or of child-bearing potential. Females of childbearing potential 
must be using an acceptable method of birth control. For specific details please 
see section 9.1.9 Contraception. 
9. Ability to provide written informed consent. 
7.2 
Exclusion Criteria 
Subjects who meet any of the following criteria at screening will be excluded from 
participating in the study: 
1. History or current diagnosis with T1DM or T2DM subjects on insulin or other 
injectable therapies not allowed for this study (as listed in table of Prohibited 
Medication below). 
2. A subject who is already indicated for medication escalation of their current 
diabetic therapy, or, who based upon study entry criteria, would be indicated for 
medication escalation during the course of the study (as assessed by the qualified 
Principal Investigator). 

GE Research 
Clinical Study Protocol 
Confidential 
Page 42 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
3. A subject who has acute proliferative retinopathy or maculopathy, severe 
gastroparesis, and/or moderate or severe neuropathy, in particular autonomic 
neuropathy, as judged by the Principal Investigator.  
4. Recurrent severe hypoglycemia (more than 1 event ≤ 6 month) or hypoglycemic 
unawareness or recent severe ketoacidosis (hospitalization ≤ 6 month), as judged 
by the Principal Investigator. 
5. Persistent systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 
95 mm Hg at screening. (Subjects may be re-checked once on the same day). 
6. Treatment with antihypertensive medication is not allowed, unless 
antihypertensive medication is given on a stable dose for at least 2 months prior to 
screening. 
7. Subjects with a clinically significant history or active disease of any of the 
following body systems:  pulmonary, neurological (including dementia, 
neurodegenerative disease, movement disorder, spinal disorders), pancreatic 
(including pancreatitis), immunological or systemic inflammatory (including 
systemic lupus erythematosus [SLE], rheumatoid arthritis [RA]), dermatological, 
endocrine, genitourinary or hematological (including sickle cell anemia or other 
anemia syndromes, monocytosis, thrombocytopenia). 
8. Subjects with a history or clinically active malignancy (history of basal cell 
carcinoma [BCC] is allowed). 
9. History or current diagnosis of cardiac dysrhythmias or heart disease, defined as 
symptomatic heart failure (New York Heart Association class III or IV), 
myocardial infarction, unstable angina requiring medication. 
10. Transient ischemic attack [TIA], cerebral infarct, or cerebral hemorrhage. 
11. Invasive cardiovascular procedure, such as coronary artery bypass graft surgery 
(CABG), or angioplasty/percutaneous coronary intervention (PCI) within 6 
months of screening.  
12. Presence of clinically significant ECG findings (e.g., QTcF > 450 msec for males, 
QTcF > 470 msec for females, LBBB) at Screening, or cardiac arrhythmia 
requiring medical or surgical treatment within 6 months prior to screening. 
13. History of renal disease or abnormal kidney function tests at Screening 
(glomerular filtration rate [GFR] < 60 mL/min/1.73m2 as estimated using the 
MDRD equation).  
14. History or active hepatic disease or clinically significant abnormal hepatic 
function tests at Screening suggestive of hepatic impairment (e.g., ALT and/or 
AST >2 x ULN), total bilirubin > 1 x ULN). 
15. Subjects with a history or presence of any psychiatric disorder that, in the opinion 
of the Principal Investigator, might confound the results of the trial or pose 
additional risk in administering the investigational product to the subject. 
16. Personal or family history of hypercoagulability or thromboembolic disease, 
including deep vein thrombosis and/or pulmonary embolism (PE) 

GE Research 
Clinical Study Protocol 
Confidential 
Page 43 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
17. History of surgical treatment for obesity (bariatric surgery, gastric banding, etc.) 
or any other gastrointestinal surgery (including appendectomy, cholecystectomy), 
any malabsorption disorder, severe gastroparesis, any GI procedure for weight 
loss (including LAP-BAND®), as well as clinically significant gastrointestinal 
disorders (e.g. peptic ulcers, severe GERD) at Screening.  
18. History of any major surgery within 3 months prior to screening. 
19. Any nerve stimulation study or implanted stimulator, including previously or 
currently implanted vagus nerve stimulator, previously or currently implanted 
spinal cord stimulator, other implanted electronic medical device, such as 
implanted pacemaker or cardioverter/defibrillator (AICD) or history of seizures. 
20. Diagnosis of sleep apnea. 
21. Participation in an investigational study within 30 days prior to dosing or 5 half-
lives within the last dose of the investigational product given during the 
investigational study, whichever is longer. 
22. Current use of any drugs (other than current treatment for diabetes mellitus) that 
are known to interfere with glucose or insulin metabolism as stated below in table 
prohibited medication. 
23. Thyroid hormone use is not allowed unless medication is given on a stable dose 
for at least 3 months prior to screening. 
24. Chronic use of acetaminophen, and inability to wash-out and abstain from use 
during the study, as it would interfere with the CGMS assessment. 
25. Subject is unable to tolerate adhesive tape or has any unresolved adverse skin 
reaction in the area of the sensor placement. 
26. Implanted pacemaker or cardioverter/defibrillator (AICD). 
27. Daily use of more than 5 cigarettes/day or equivalent use of any tobacco- or 
nicotine-containing product (such as, but not limited to vaping, transdermal 
nicotine patch, nicotine gum use, etc.) within 4 weeks prior to screening. Subjects 
must be able to abstain from any tobacco or nicotine containing products during 
confinement period. 
28. Any use of marijuana within 4 weeks prior to screening and positive test at 
screening. 
29. History of any active infection, except mild viral disease, such as common cold, 
within 30 days prior to screening. 
30. History of any recent traumatic injury, including intracerebral hemorrhage and 
visceral injury.  
31. History of alcohol or illicit drug abuse as judged by the Principal Investigator 
within past 12 months or positive test at screening. Any use of alcohol within 4 
days prior to baseline assessment. Subjects must be able to abstain from any 
alcohol during confinement period. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 44 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
32. Known history or positive test for hepatitis B surface antigen (HBsAg), hepatitis 
C antibody (HCV Ab), human immunodeficiency virus type 1 (HIV-1) or type 2 
(HIV-2) 
33. Donation or loss of > 500 mL of blood or blood product within 56 days prior to 
screening. 
34. Mental incapacity, unwillingness or language barriers precluding adequate 
understanding and to follow verbal commands during the ultrasound session or 
cooperation. 
35. An abdominal ultrasound scan or exam within 1 month prior to screening and/or 
any pre-planned ultrasound examinations during the study, or the need to 
participate in any unplanned outside ultrasound procedures during study. 
7.3 
Prohibited Medications 
Use of the agents listed in Table 7-1 (prescription or nonprescription) is prohibited from 
the time points specified until completion of all study activities. 
Table 7-1 Prohibited Medications 
Medication or Class 
Indication/Reason 
From time point specified until 
the end of the study 
Antihypertensive medication  
Hypertension 
Excluded unless on stable dose 
for at least 2 months prior to 
screening 
Lipid lowering drugs that are 
known to interfere with glucose 
or insulin metabolism 
Hyperlipidemia 
Must be on a stable dose within 3 
months prior to screening 
Non-prescription drugs/over-
the-counter or herbal that are 
known to interfere with glucose 
or insulin metabolism 
 
Within one week prior to check-
in for first in-house period 
Anti-coagulants (Coumadin, 
Xarelto) 
Thrombotic syndromes, 
arrhythmias 
Within one week of screening 
Analgesics 
(acetaminophen) 
Pain 
Within one day of CGMS 
treatment 
Oral or systemic long-acting 
corticosteroids, 
immunosuppressive agents 
E.g., chronic or acute non-
infectious inflammatory 
conditions, auto-immune 
diseases 
Within 3 months prior to 
screening 
Topiramate, monoamine 
oxidase (MAO) inhibitors, 
growth hormone. 
Use of any drugs that are known 
to interfere with glucose or 
insulin metabolism 
Within 3 months prior to 
screening 
Anticholinergic drugs, 
antispasmodics (e.g., modafinil, 
Reduction/modification of GI 
motility 
Within 2 weeks prior to 
screening 

GE Research 
Clinical Study Protocol 
Confidential 
Page 45 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
phenytoin), 5HT3 antagonists, 
dopamine antagonists, or 
opiates, antiemetics, antacids  
Orlistat, lorcaserin, sibutramine, 
etc., including over-the-counter 
and herbal supplements, or any 
medication with a labelled 
indication for weight loss or 
gain 
Weight control treatment 
Within 3 months prior to 
screening. 
Any anti-diabetic medication, 
including herbal medicines, 
OADs, insulin and incretins. 
(only metformin allowed) 
Diabetes 
Any prior treatment of insulin 
within 3 months prior to 
screening and incretins.  
Selective serotonin reuptake 
inhibitors (SSRIs), serotonin 
norepinephrine reuptake 
inhibitors (SNRIs), 
antipsychotics, lithium.  
Depression, anxiety, psychiatric 
disorders 
 
Within 3-month prior to 
screening. 
Use of SSRIs and SNRIs 
(including bupropion) 
For reasons other than active 
psychiatric indications (e.g., 
migraine, weight loss, smoking 
cessation) 
Within 3-month prior to 
screening. 
 

GE Research 
Clinical Study Protocol 
Confidential 
Page 46 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
8.0 
STUDY MATERIALS AND EQUIPMENT 
8.1 
Investigational Device 
GE LOGIQ™ E10 Imaging Ultrasound System and the C1-6 probe will be used in this 
study. Device is commercially available. Product is manufactured by General Electric 
Company, USA. 
The equipment necessary for this study is being provided by General Electric to 
ProSciento as a loan in order to conduct this study. Upon completion of the study, the 
provided ultrasound equipment will be returned to General Electric. While in possession 
by ProSciento, the system will be used and maintained in accordance to the terms of the 
clinical trial agreement (CTA). This includes, but is not limited to, securely maintaining 
the equipment at ProSciento and only using it for this research study. 
For additional information please see the User Guide. 
8.2 
Storage of Investigational Device 
The investigational device must be kept in an appropriate, limited-access, secure location. 
The system components will be labeled with the statement "CAUTION ‐ Investigational 
Device. Limited by United States Law to Investigational Use." The components will also 
be labeled with the manufacturer name, manufacturer’s place of business, 
packer/distributer (in accordance with 801.1), and the quantity of contents, as 
appropriate. 
Information on each use of the device will be documented, and a device accountability 
log will be maintained. Information on each component of the system will be provided in 
the Operations Manual and as available will include labeling, booklet, user manuals, and 
FDA Letters. 
8.3 
Packaging, and Labeling of Investigational Products/Device 
The Sponsor will provide the Principal Investigator with the device/equipment needed for 
the insonification in accordance with specific country regulatory requirements. The 
devices/ equipment will be packaged and shipped to the investigational site after 
verification of device output pressure by 3rd party (Acertara). The device will be labelled 
for research use only (including at log-on screen). 
8.4 
Regimen of Hepatic Ultrasound Insonification 
The porta hepatis of the liver, is a deep, short, transverse fissure that is located across the 
left posterior region of the undersurface of the right lobe of the liver. The porta hepatis 
encompasses the portal triad (the main portal vein, common hepatic artery, and common 
bile ducts), lymphatics, nerves, and connective tissue. The portal vein, hepatic artery, and 
nerves derived from the left vagal trunk and sympathetic plexus ascend the porta hepatis, 
whereas the common bile duct and lymphatics descend the porta hepatis. The nerves that 

GE Research 
Clinical Study Protocol 
Confidential 
Page 47 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
run through the porta hepatis are branches of the left vagus nerve and sympathetic 
branches of the celiac plexus. 
Assessment of the porta hepatis region with ultrasound insonifications will be performed 
by a specialized health care professional, specialized in ultrasonic imaging, with 
appropriate training in the assessment of the liver and porta hepatis region, as well as in 
using the GE LOGIQ™ E10 Imaging Ultrasound System. Insonification will be 
performed on three consecutive days during the study (Days 15, 16 and 17). Subjects will 
be insonified by the stimulus pulse for 15 minutes on each day, for a total of 45 minutes. 
The sonographer will perform all ultrasound examinations in all subjects of this study. 
The sonographer will have the option of performing targeting and insonification during 
breath holds in order to aid in identification and ultrasound delivery to the target location. 
If breath holds are utilized, the subject will be allowed 1-2 minutes during each breath 
hold (during which ultrasound is not being applied), these rest periods will no count 
toward the 15-minute dose or ultrasound delivery time target.  
For the actual assessment, subjects need to be in fasting conditions for ≥10 h prior to 
assessment. Insonifications will start between approximately 07:00 h and 08:30 h on each 
insonification day. 
For details and images that represent the anatomical area, please see the customized 
instructions on the insonification and the Operations Manual. 
8.5 
Ultrasound Insonification Effect 
If a study procedure error occurs (including, but not limited to Principal Investigator 
errors, and/or study subject non-compliance), it should be documented as Protocol 
Deviation. A brief description should be provided in the deviation, including whether the 
subject was symptomatic (list symptoms) or asymptomatic, and the event accidental or 
intentional. 
Details should be captured on the Dosing Case Report Form. If the subject was exposed 
to the procedure for a time that exceeds protocol specifications and the subject is 
symptomatic, then the symptom(s) should be documented as an ADE and be reported.  
Should a study procedure error occur, the Principal Investigator or designee should 
contact the Sponsor or designee within 24 hours.  
8.6 
Randomization and Blinding 
As this is an exploratory, open-label study, no randomization or blinding will be 
performed and no-unblinding codes are required. 
If subjects drop out or are removed from the study, they may be replaced until the 
anticipated number of subjects have completed the study. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 48 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
8.7 
Auxiliary Supply 
ProSciento will supply laboratory material necessary for the safety hematology, 
biochemistry, and urinalyses (incl. pregnancy test) in collaboration with the laboratory. 
ProSciento will also provide all necessary material needed for the glucose clamp 
procedure. Glucose, sodium chloride solutions, insulin, heparin, syringes, and needles 
used in the clamp will be provided by ProSciento, as well as, standard accessories 
necessary for an ultrasound examination including ultrasound gel. 
 

GE Research 
Clinical Study Protocol 
Confidential 
Page 49 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
9.0 
STUDY PLAN 
9.1 
Study Procedures 
9.1.1 Informed Consent and HIPAA Release 
Written informed consent will be obtained from each subject prior to performing any 
study-specific evaluations. The HIPAA release is embedded in the informed consent 
document. The informed consent document is subject to review and approval by the 
Sponsor and will be approved by a qualified IRB. The IRB-approved document must 
contain, at minimum, the eight basic elements of informed consent set forth in applicable 
law. Only the most recently IRB-approved informed consent document must be used to 
consent prospective study subjects. The Principal Investigator (according to applicable 
regulatory requirements), or a person designated by the Principal Investigator and under 
the Principal Investigator’s responsibility, will fully inform the potential study subject of 
all pertinent aspects of the Clinical Study, including written information given 
approval/favorable opinion by the IRB.  
Prior to the potential subject’s participation in the Clinical Study, the written informed 
consent form must be signed, name filled in and personally dated by the subject and by 
the person who conducted the informed consent discussion, and by the Principal 
Investigator. One copy of the signed and dated informed consent document will be given 
to the subject and the original retained by the Principal Investigator/site. 
9.1.2 Screening 
Investigators must account for all subjects who sign informed consent forms. The 
Principal Investigator will keep a Subject Screening and Enrollment Log at the 
investigational site. Subjects who have screen failed may be allowed to re-screen once at 
the discretion of the Principal Investigator. A new screening number will be assigned. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for this study and will be invited for the in-house periods.  
Subjects will be instructed on factors influencing insulin sensitivity. They will be 
instructed on maintaining their usual diet and exercise programs for the duration of the 
study and refraining from strenuous exercise prior to the study assessments/check-in to 
the in-house periods, avoidance of alcohol and herbal products, smoking or medication 
and illness/infection. Specific factors will be assessed at check-in for the in-house 
periods. 
If subjects are fasting (only water for ≥ 10 hours), all screening assessments may be done 
on the same day. If subjects are not fasting, they will be invited to return for a second 
screening visit as available to complete any missing screening procedures (e.g. laboratory 
assessments) within the available screening window. 
For eligible subjects with a BMI> 35.0 and ≤ 40.0 kg/m2 and/or a waist circumference > 
40 and ≤ 45 inches, an ultrasound examination will be added to the screening assessments 

GE Research 
Clinical Study Protocol 
Confidential 
Page 50 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
to confirm eligibility. Aim is to confirm, that the porta hepatis/region of interest can be 
viewed, a measured distance from the skin surface to the porta hepatis target does not 
exceed 10 cm, and it is validated that the subject will be well suited for the insonification 
procedure during the study. Please see section 9.1.26 Hepatic Ultrasound at Screening for 
details. If subjects are fasting on the day of the screening visit (only water for ≥ 10 
hours), the ultrasound examination may be performed on the same day. If subjects are not 
fasting, they will be invited to return for a second screening visit as available to complete 
the missing ultrasound procedure. 
If subjects are not eligible per the above stated ultrasound examination, they will be 
recorded as screen failure. If subjects are eligible per the above stated ultrasound 
examination, they will continue with the 30-day wait period, starting after the ultrasound 
examination has been performed, in order to comply with exclusion criterion # 35. 
Eligibility will be re-assessed on Day -1 based on lab results and examinations that have 
been performed prior to Day -1, so that all eligibility criteria from screening can be re-
assessed on Day -1. Re-assessment can be performed after a 30-day wait period, starting 
after the ultrasound examination. For details please see the Schedule of Events (SOE). 
9.1.3 Demographics and Medical History 
Demographic information and medical history, including diabetes and smoking status, and 
medication history will be obtained at Screening. Subjects who are current regular smokers 
will not be eligible for inclusion into the study. 
9.1.4 Physical Examination 
The baseline physical examination will consist of the following body systems: (1) eyes; 
(2) ears, nose, throat, neck, thyroid; (3) cardiovascular system; (4) respiratory system; (5) 
gastrointestinal system, mouth; (6) dermatologic system; (7) extremities; (8) 
musculoskeletal system; (9) central and peripheral nervous system and (10) lymph nodes. 
The Toronto Clinical Neuropathy Score will be used to assess the severity of peripheral 
neuropathy. All aspects of the test, including questionnaire, sensory tests and reflex tests 
will be performed by a qualified and trained Investigator.  
Please see Table 16-3 for the Toronto Clinical Neuropathy Scoring System. The methods 
for the conduct of the sensory testing will be specified in the Operations Manual. 
An abbreviated physical exam (based on symptoms and including examination of 
cardiovascular, respiratory, gastrointestinal and nervous system) will be performed by the 
Principal Investigator (or a qualified physician at the investigational site) at time points 
indicated in the Schedule of Events (SOE). A complete physical examination may be 
performed in case the subjects have symptoms or at the discretion of the Principal 
Investigator. 
9.1.5 Height, Weight, BMI, and Waist Circumference 
Height (without shoes) in meters will be measured once, during the Screening visit. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 51 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Weight (without shoes) in kg will be measured fasting in the morning, with light clothing 
and post void at time points indicated in the Schedule of Events (SOE). 
BMI (kg/m2) will be calculated from height and weight. 
Waist circumference (cm) will be measured once, during the Screening, with a tape 
measure in standing position. 
9.1.6 Vital Signs 
Vital signs will include body temperature (aural), supine blood pressure (after 5 minutes 
resting), respiration rate and pulse rate (after 5 minutes resting). Vital signs will be 
measured daily during the in-house period.  
On clamp days, vital signs will be assessed pre-clamp and post-clamp procedures.  
Vital sign measurements will be performed at days indicated in the Schedule of Events 
(SOE). Additional measures will be performed as deemed necessary by the Principal 
Investigator. 
9.1.7 Concomitant Illness and Therapy 
Concomitant therapy is any medication given in addition to the investigational product 
(including over-the-counter medications, herbal medications, and vitamin supplements) 
administered between screening and follow-up.  
Concomitant illness is any significant medical condition or disease that is present at study 
start (signing of informed consent). This includes clinically significant laboratory, 
electrocardiogram (ECG), or physical examination abnormalities noted at screening 
examination. 
Details of all concomitant illnesses and therapies must be recorded at study entry and 
must be recorded on the subject’s CRF. Any changes in concomitant medication must be 
recorded at each visit. If the change influences the subject’s eligibility to continue in the 
study, the Sponsor must be informed. The information collected for each concomitant 
medication includes, at a minimum, start date, stop date or continuing, and indication.  
ADEs related to administration of these therapies or procedures must also be documented 
on the appropriate eCRF. 
9.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. Safety 
parameter should be taken in the morning after an overnight fast, prior to any pre-planned 
study procedures. 
Laboratory samples will be taken as described in the Schedule of Events (SOE). 

GE Research 
Clinical Study Protocol 
Confidential 
Page 52 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Table 9-1 Clinical Laboratory Assessments 
Hematology 
Serum Chemistry 
Urinalysis 
CBC with differential: 
Hematocrit 
Hemoglobin 
mean corpuscular volume 
(MCV) 
mean corpuscular hemoglobin 
(MCH) 
mean corpuscular hemoglobin 
concentration (MCHC) 
red cell distribution width 
(RDW) 
percentage and absolute 
differential counts 
platelet count  
red cell count (RBC) 
white blood cell count (WBC) 
 
Hepatic function panel: 
Alanine aminotransferase 
(ALT/SGPT) 
albumin, serum 
alkaline phosphatase, serum 
aspartate aminotransferase 
(AST/SGOT) 
bilirubin, direct (a) 
bilirubin, total 
protein, total, serum 
Renal function panel: 
Albumin, serum 
BUN 
BUN: creatinine ratio 
calcium, serum 
carbon dioxide, total 
chloride, serum 
creatinine, serum 
glucose, plasma 
phosphorus, serum 
potassium, serum 
sodium, serum 
Additional parameters: 
Gamma-Glutamyl Transferase 
Uric Acid 
Routine urinalysis with 
microscopic examination on 
positives (b): 
Color 
appearance, 
specific gravity 
pH 
protein 
glucose 
ketones 
occult blood 
leukocyte esterase 
nitrite 
bilirubin 
urobilinogen 
 
Diagnostic Screening 
Serum/Plasma/Whole Blood 
Urine 
Breath 
Viral serology: 
Hepatitis B surface antigen 
(HBsAg) 
Hep C antibody (anti-HCV) 
Anti-HIV-1 
Anti-HIV-2 
Thyroid-stimulating hormone 
(TSH) (c) 
Coagulation: 
Partial thromboplastin time  
(PTT) 
PT 
International normalized ratio 
(INR) 
Lipid profile: 
Cholesterol, total 
Drug Screen Profile 
Urine drug screen (12 panel) via 
commercial kit at the site. 
Urine drug screen at screening, 
at check-in for each day -1 via 
commercial kit at the 
investigational site. 
 
Female Subjects Only 
Human chorionic gonadotropin 
(hCG) performed at Screening. 
Follicle-stimulating hormone 
(FSH) test for postmenopausal 
women (defined as amenorrheic 
female subjects <60 years of age 
and not surgically sterile) at 
Screening. 
Alcohol breath test at timepoints 
stated in the SOE at the 
investigational site 

GE Research 
Clinical Study Protocol 
Confidential 
Page 53 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
HDL-C (Cholesterol) 
LDL-C 
VLDL-C 
Triglycerides 
FFA 
Glucose Metabolism 
Parameter: 
Fasting Plasma Glucose (FPG) 
HbA1c 
Fructosamine 
HOMA-IR 
HOMA-B 
Fasting Insulin 
Fasting C-Peptide 
Incretins/exploratory 
biomarkers: 
Total GLP-1 
Glucagon 
Leptin 
Ghrelin 
Inflammatory biomarker: 
Cytokines (IL-6) 
Adiponectin  
CRP 
 
Urine pregnancy testing via 
commercial kit at the site at 
timepoints stated in the 
Schedule of Events. 
(a) Assess only if total bilirubin ≥2.0 mg/dL. 
(b) Microscopic analysis should be performed only if urine evaluations are abnormal. 
(c) In the event of abnormal TSH, Free T3/T4 may be collected at Principal Investigator discretion. 
 
The responsible laboratories will perform all assigned laboratory tests, e.g., listed above. 
Specialty labs may be responsible for specific laboratory parameters. The results of 
laboratory tests will be sent to the Principal Investigator or designee, who is responsible 
for reviewing these results. All laboratory safety data will be faxed or transferred 
electronically. 
Laboratory reports must be signed and dated by the Principal Investigator or designee 
indicating that the report has been reviewed and any abnormalities have been assessed for 
clinical significance. 
All clinically significant laboratory abnormalities must be recorded as an ADE. A 
clinically significant laboratory abnormality may be verified by retesting and may be 
followed upon discretion of the Principal Investigator. 
9.1.9 Contraception 
Female subjects must be non-pregnant and non-lactating. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 54 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Females may be either surgically sterile (e.g., bilateral tubal occlusion, hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy) or post-menopausal for >12 months 
without alternative medical cause. The site will make an effort to retrieve medical records 
to document the sterility, however, the absence of records will not exclude the subject. In 
the event that medical records cannot be obtained, serum pregnancy testing will be 
conducted at Screening, and urine pregnancy testing will be conducted throughout the 
study. Postmenopausal status will be confirmed through testing of FSH levels outside the 
norm based on specific lab at screening for amenorrheic female subjects < 60 years of 
age. 
Only female subjects of childbearing potential must use highly effective contraceptive 
methods, that are considered those with failure rate less than 1% undesired pregnancies 
per year “with perfect use”, including hormonal intrauterine devices (coil), oral hormonal 
contraceptives, sexual abstinence, or a surgically sterilized partner. Subjects on hormonal 
contraception must be on stable hormonal contraception for >2 month prior to Screening 
and for the entire study.  
Male subjects are not required to use any methods of contraception.  
9.1.10 Pregnancy 
In the event a subject becomes pregnant during the study, she should be withdrawn. 
However, the subject will be encouraged to complete the post-treatment follow-up 
portion of the study to the extent that study procedures do not interfere with the 
pregnancy. 
If the pregnancy occurs at any time during the study, the pregnancy should be reported 
immediately to the Sponsor, using a pregnancy notification form. 
Study subjects will give consent on enrollment that the Principal Investigator will report 
any pregnancy during the study to the Sponsor and that they will be asked to provide 
information about her pregnancy, delivery, and the health of her infant until age one 
month. Payment for all aspects of obstetrical care, child, or related care will be the 
subject’s responsibility.  
All reported pregnancies will be followed up to final outcome, using the pregnancy and 
pregnancy follow-up forms. The outcome, including any premature termination, will be 
reported to the Sponsor. An evaluation after the birth of the child may also be conducted. 
Study-related pregnancy complications must be recorded as adverse event(s).  
9.1.11 ECG Procedure  
A standard 12-lead ECG will be recorded after 5 minutes in a supine position. 
The Principal Investigator (or designee) will interpret the ECG’s by use of an electronic 
measurement using the following categories: within normal limits, abnormal but not 
clinically significant, or abnormal with clinical significance. ECGs are performed 
according to the Schedule of Events (SOE). The following parameters will be recorded 

GE Research 
Clinical Study Protocol 
Confidential 
Page 55 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
from the subject’s ECG trace as calculated by the machine algorithm: heart rate, QT 
interval, PR interval, QRS interval, RR interval, and QTc (corrected) using the Fridericia 
correction (QTcF = QT ÷ cube root of the R-R interval [where R-R is the duration of the 
entire cardiac cycle]). 
When ECGs are to be collected at the same time point as a blood collection, ECGs should 
be collected first to avoid any artificially increased heart rates due to the blood collection. 
ECGs on clamp days will be performed before and after the clamp procedure.  
In some cases, it may be appropriate to repeat abnormal ECGs. If a machine-read QTc 
value is prolonged, repeat measurements may not be necessary if the Principal 
Investigator’s interpretation determines that the QTc value is in the acceptable range. 
9.1.12 Check-in Procedure 
All subjects will check in to the clinic in the morning to the In-house Periods. The 
following will be assessed: 
1. Alcohol breath test. 
2. Urine drug screen. 
3. Urine pregnancy test.  
4. Any use of prescription or non-prescription medicine/herbal medicine other than the 
allowed concomitant medications. 
5. Any medical condition that could interfere with glucose metabolism, as judged by the 
Principal Investigator. 
6. Any vigorous exercise 24 hours prior to check-in to the in-house periods (for example: 
heavy lifting, weight training, calisthenics, and aerobic activity). 
Subjects who fulfill one or more of the stated criteria at check-in, will not be able to 
continue onto the in-house period. The in-house period will be rescheduled. Each in-
house period may be rescheduled no more than once. Subjects will be given up to 5 days 
to reschedule check-in on Day 15, in case of a weekend/holiday or subject’s personal 
issue. However, once checked-in for Day 15, there will not be a window to reschedule 
remaining insonification procedures (Day 16 & 17). After that, the subject will be 
excluded from the study. Replacement of subjects is be permitted. 
9.1.13 Fasting Plasma Glucose 
Fasting plasma glucose will be measured during the in-clinic period with an YSI 2300 
STAT glucose analyzer (YSI) at time points stated in the Schedule of Events (SOE). On 
the days that subjects are treated for hypoglycemic events during the evening hours, the 
morning lab will not be in the fasting state. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 56 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
9.1.14 Self-Monitoring of Blood Glucose (SMBG) 
Subjects will also be provided with a SMBG device for glucose monitoring. They will be 
instructed on how to use the glucometer and to monitor their fasting plasma glucose 
levels. For further details on capturing data and documentation, please see the Operations 
Manual.  
In this study, a BG meter (e.g., Accu-Check® Aviva Plus) will be used, so that data can 
be downloaded by the site at the study visits. A confirmation measurement of the glucose 
values may be performed by a standard glucose analyzer.  
Although subjects apply whole blood to the test strip, the system has been calibrated to 
deliver plasma‑like values for easier comparison to laboratory results. The term plasma 
glucose will be used throughout the protocol in reference to the glucometer results, while 
the term blood glucose will be used in reference to the blood sample that is used for 
measurement. 
Subjects will be instructed to perform a SMBG check every morning in fasting condition 
(FPG) during the outpatient period. 
Additional blood glucose measurements can be performed by fingerstick at any time for 
safety reason, or when a CGMS measurement needs to be confirmed or validated.  
Subjects will be instructed to monitor their fasting plasma glucose levels daily during the 
outpatient period. Subjects will be frequently contacted by qualified study site staff via 
telephone calls to review their fasting plasma glucose values. These phone calls/phone 
visits will be documented in a Telephone Log. For further details please see the 
Operations Manual. 
Subjects are instructed to contact study staff if they measure an FPG (after 10 hours of 
fasting) > 220 mg/dL, experiences symptoms of hypoglycemia, or measures an FPG < 70 
mg/dL. A confirmation measurement of the glucose values may be performed by a 
laboratory method (YSI). In case FPG value have reached the stated limits, and values are 
confirmed by a standard glucose analyzer, subjects will be counseled on how to keep 
their FPG within these limits. The subject will then have a reassessment, per PI 
discretion, of their FPG, confirmed by the glucose analyzer. If the retested and verified 
FPG is still outside the stated thresholds they will be dropped from the study and may be 
replaced. At the end of the study, subjects may keep their glucometer to measure to 
control their blood glucose at home. 
9.1.15 Standardized Meals 
During in-house period(s), subjects will receive standardized meals. These meals will be 
provided up to 12 hours prior to OGTT and start of scheduled clamp procedures. Meals 
will be provided after the OGTT and or clamp procedure have been terminated.  
The standardized weight maintaining meals will be provided using estimated BMR × 
activity factor of 1.5 to determine daily caloric intake. Macronutrient composition will be 
standardized. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 57 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
9.1.16 Dietary and Nutrition Counseling 
Subjects will be counseled to maintain their normal diet and exercise regimen. They will 
be instructed not to start any new diets, supplements, or exercise programs during the 
study.  
9.1.17 Physical Activity 
Subjects will be instructed to maintain their usual exercise programs for the duration of 
the study. Subjects will be asked to refrain from vigorous exercise 24 hours prior to 
check-in to the in-house periods and during in-house stays (for example: heavy lifting, 
weight training, calisthenics, and aerobic activity). 
9.1.18 CGMS 
All subjects will be connected to a CGMS (e.g., Dexcom G6, San Diego, CA, USA) to 
register blood glucose concentrations during the study as described in the Operations 
Manual.  
Please refer to the User Guide for all detailed device instructions and the Operations 
Manual. 
In case the CGMS might get dislodged and the sensor would need to be re-inserted, 
subjects would be asked to come to the clinic. 
9.1.19 Oral Glucose Tolerance Test (OGTT) 
An oral glucose tolerance test (OGTT) will be administered at the time points specified in 
the Schedule of Events (SOE).  
Subjects will be fasted ≥ 10 hours prior to the OGTT. At approximately 08:00 h-09:00 h 
the OGTT will begin. Subjects will be asked to drink 75 g of glucose in a 10-fluid ounce 
beverage over 5 minutes. The glucose ingestion will be followed by approximately 100 
mL of water. The subject will rest for the duration of test and will abstain from eating. 
Only small amounts of water may be consumed for the duration of the test. Sampling for 
fasting glucose, C-peptide, insulin sampling will be performed before the OGTT and 15, 
30, 60, 90, 120, 150 and 180 min after the start of the glucose administration. 
The time of all blood draws and the time when the subjects start to drink the glucose 
solution will be recorded. 
OGTT sampling schedule: Time points are relative to start of OGTT procedure. All 
samples will be taken within a window of ± 3-minutes.  
All OGTT procedures during the in-house periods on Day 1 and Day 16 will follow the 
same schedule. 
The OGTT procedure for each subject (inter-individual) will start one hour (nominal 
time) after the start of their hepatic ultrasound insonification. A window of ± 15 minutes 
will be allowed. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 58 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Insonification and OGTT on Days 1 and 16 should start at the same time (actual time) for 
each subject (intra-individual).  
Table 9-2 Sampling Schedule for OGTT 
 
Nominal time (min) 
relative to Start of 
OGTT 
 
-15 
0 
15 
30 
60 
90 
120 
150 
180 
 
Standard Test 
Solution 
(75 g dextrose) 
 
 
X 
 
 
 
 
 
 
 
Plasma Glucose 
X 
 
X 
X 
X 
X 
X 
X 
X 
Insulin and C-peptide 
X 
 
X 
X 
X 
X 
X 
X 
X 
9.1.20 Overnight IV Insulin Infusion 
At approximately 22:00 pm on the evening prior to a clamping procedure, an overnight 
IV insulin infusion to achieve plasma glucose levels of approximately 100 ± 10 mg/dL 
during the last two hours of the overnight IV infusion prior to the fasting EGP assessment 
period. Glucose levels will be monitored frequently.   
On the evening prior to the clamp procedure, subjects will receive a standardized dinner, 
which will be followed by an approximately 10-hour overnight fast.  
The aim is to only use insulin to achieve the target glucose level and to avoid 
simultaneous infusion of glucose. In case blood glucose levels are lower than the target 
level, an IV glucose infusion may be used and recorded.  
The amount of insulin administered will be recorded and expressed in mU/m2/min for 
each individual subject considering his/her body surface area. GIR will be recorded 
during the entire clamp procedure. 
For details please see the Operations Manual. 
9.1.21 Intravenous Infusion of Stable Isotope Labeled Glucose and Assessment of 
Endogenous Glucose Production 
Endogenous glucose production or EGP will be measured in the fasting state prior to the 
start of the clamp and during the 2-step H-E clamp procedure to assess insulin-induced 
suppression of EGP using a stable isotope labeled glucose ([6,6-2H2]glucose) tracer 
method.  

GE Research 
Clinical Study Protocol 
Confidential 
Page 59 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
A primed-continuous IV infusion of [6,6-2H2]glucose will be initiated prior to the clamp 
and continued throughout the clamp at various rates. At approximately midnight, 5.5 mg 
[6,6-2H2]glucose/kg body weight will be injected (priming dose) over 10 minutes, 
followed by a constant infusion of 0.05 mg [6,6-2H2]glucose/kg body weight/min until 
the end of the fasting EGP assessment period, followed by a rate of 0.025 mg [6,6-2H2] 
glucose/kg body weight/min from beginning to end of the Step 1 insulin infusion. The 
[6,6-2H2]glucose infusion is discontinued at the end of the Step 1 of the clamp. Blood 
samples will be taken during the last 30 minutes of the fasting, step 1 and step 2 periods 
(see Table 9-3). The glucose enrichment in the plasma will be measured using gas 
chromatography-mass spectrometry (GC-MS). EGP will be calculated during the last 30 
minutes of each assessment period from the dilution of the infused stable isotope labeled 
glucose using the steady-state method of Steele. 
For details please see the Operations Manual and Pharmacy Manual. 
9.1.22 Two-step Hyperinsulinemic, Euglycemic Clamp 
On the evening prior to the clamp procedure, subjects will receive a standardized dinner, 
which will be followed by an approximately 10-hour overnight fast.  
Subjects will receive an overnight insulin IV infusion to achieve plasma glucose levels of 
approximately 100 ± 10 mg/dL during the last two hours of the overnight IV infusion 
prior to the fasting EGP assessment period. 
Subjects will be connected to the Biostator prior to the start of the clamp procedure. 
During step 1 and step 2 of the clamp procedure, insulin will be infused at two infusion 
rates each lasting approximately 180 minutes and D20W will be enriched with stable 
isotope labeled glucose to achieve a stable isotope glucose enrichment comparable to that 
of plasma in the fasting state (e.g., 2.5 to 3% for plasma [6,6-2H2]glucose). Insulin will be 
infused IV by means of a precision pump for 180 min at the following rate: 
Step 1: For the Step 1 insulin infusion of the clamp procedures at Day 2, an amount of 10 
mU/m2/min will be added to the average insulin infusion rate which was provided per 
algorithm over the last 2 hours of the overnight infusion. This will be calculated for each 
individual subject.  
For the Step 1 insulin infusion of the clamp procedures at Day 17, the insulin infusion rate 
should be identical to the rate used at Day 2. It is important that each subject receives the 
same insulin infusion rate on Day 17 that he/she received on Day 2. 
Step 2: After 180 minutes (end of Step 1), the insulin infusion will be increased to 120 
mU/m2/min for a further 180 minutes (Step 2) of the clamp for all subjects at Day 2 and 
Day 17. This will provide supraphysiological insulin concentrations that will near-
maximally stimulate glucose disposal. EGP is expected to be near maximally suppressed. 
The glucose infusion rate (GIR; 20% v/v) required to maintain arterialized venous blood 
glucose (glucose oxidase method) at the target level of 100 ± 10 mg/dL will be recorded 
throughout the clamp. The steady-state period for insulin sensitivity measurements is 

GE Research 
Clinical Study Protocol 
Confidential 
Page 60 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
defined as the time from 150 to 180 minutes following the initiation of the continuous 
insulin infusion during each step, and the GIR recorded during the last 30 minutes 
(steady-state) of each insulin infusion step is used for the determination of insulin 
sensitivity. Blood samples for the determination of plasma glucose will be drawn at 
scheduled time points before and during the clamp. 
 Insulin infusion rates may be adjusted per PI discretion and discussion. 
The clamp procedure will terminate approximately 6 hours after the initiation of Step 1. 
The insulin infusion will be discontinued after the last blood sample has been collected.  
As a background validation with a second methodology for safety, the standardized 
measurements of the Biostator will be verified on a regular basis using the YSI reference 
device at approximately every 30 minutes. 
All clamp procedures will follow the same schedule. 
For details please see the Operations Manual. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 61 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Figure 9-2 Schematic of Clamp Procedure 
 

GE Research 
Clinical Study Protocol 
Confidential 
Page 62 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Table 9-3 Schedule for Clamp and Tracer 
Parameter 
Time in Hours of Day (time is approximate) 
22:00 
24:00 8:30 
8:40 
8:50 
9:00 
11:30 
11:40 
11:50 
12:00 
14:30 
14:40 
14:50 
15:00 
Primed Continuous 
[6,6-2H2] 
Glucose Infusion 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
Overnight Insulin 
Infusion Glucose 
Control 
X 
X 
→ 
→ 
→ 
X 
Step 1 Insulin 
Infusion (low dose) 
X 
→ 
→ 
→ 
X 
Step 2 Insulin 
Infusion (high dose) 
X 
→ 
→ 
→ 
X 
Dextrose 20% 
Infusion Enriched 
With [6,6-2H2] 
Glucose 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
Plasma [6,6-2H2] 
Glucose Enrichment 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Glucose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Insulin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FFA/Triglycerides 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Sample may be taken within window of 22:00 h and 24:00 h. It is of importance, that the sample is taken prior to the start of the [6,6-
2H2]glucose infusion.

GE Research 
Clinical Study Protocol 
Confidential 
Page 63 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
9.1.23 Assessments of Ultrasound Insonification Effects 
Blood for analyses for the assessment of ultrasound insonification effects will be 
collected at the time points indicated in the Schedule of Events (SOE). Sampling for 
exploratory biomarkers such as incretins/ metabolic hormones (total GLP-1, Ghrelin, 
Glucagon, Leptin), glucose parameters (HbA1c, Fructosamine), lipid metabolism 
parameters (total cholesterol, LDL-C, HDL-C, VLDL-C, Triglycerides, Free Fatty 
Acids), as well as inflammatory biomarkers (Cytokines [IL-6], Adiponectin, CRP) will be 
collected, and analyzed or stored for future analysis. 
9.1.24 Hepatic Ultrasound Insonification 
Patients should report if they need/participate in any outside ultrasound procedures 
during study. 
All three insonifications will be performed after an overnight fast (no food or drinks 
except for water for at least 10 hours) at approximately the same time on each day. 
Insonification will start at approximately 07:00 h each day. If multiple subjects are 
scheduled for insonification on one day, insonification may be staggered and performed 
between 07:00 h and 08:30 h on that day. Clock time of insonification will be recorded 
and the same subjects (intra-individual) will undergo their insonification at approximately 
the same time (actual time) on each day. A window of ± 15 minutes will be allowed. 
Insonifications will be performed prior to any other assessment, such as OGTT or start of 
H-E clamp. 
Check of Imaging Criteria on Day 15: 
If sonographer is not able to visualize or stimulate target area on ultrasound, or a 
measured distance from the skin surface to the porta hepatis target exceeds 10 cm, 
subjects will be excluded from the study and may be replaced. 
For details on the hepatic ultrasound insonification, image saving, data recording and data 
transfer, please see the Operations Manual and the customized instructions on pulsed 
insonification in the elastography setting. 
9.1.25 Blood Volume 
Total blood sampling volume for subjects will be stated in the Laboratory Manual for this 
study. 
9.1.26 Hepatic Ultrasound at Screening 
Only eligible subjects with a BMI > 35.0 and ≤ 40.0 kg/m2 and/or waist circumference > 
40 and ≤ 45 inches will need to undergo this ultrasound examination at Screening.  
Aim is to confirm, that the porta hepatis/region of interest can be viewed, the measured 
distance from the skin surface to the porta hepatis target does not exceed 10 cm, and it is 

GE Research 
Clinical Study Protocol 
Confidential 
Page 64 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
validated that the subject will be well suited for the insonification procedure during the 
study.  
The ultrasound examination will be performed after an overnight fast (no food or drinks 
except for water for at least 10 hours). If sonographer is not able to visualize the target 
area on ultrasound, or the measured distance from the skin surface to the porta hepatis 
target exceeds 10 cm, subjects will be excluded from the study and may be replaced. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 65 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
10.0 
FOR DETAILS ON THE HEPATIC ULTRASOUND, IMAGE SAVING, 
DATA RECORDING AND DATA TRANSFER, PLEASE SEE THE 
OPERATIONS MANUAL. ADVERSE DEVICE EFFECTS 
10.1 
Definitions 
10.1.1 Adverse Device Effect (ADE) 
An ADE is any undesirable and unintended medical event occurring to a subject in a 
clinical study, whether or not related to the study procedures. This includes events from 
the first study related activity after the subject has signed the informed consent and until 
post treatment follow-up period as defined in the protocol. The following should not be 
recorded as ADEs, if recorded as medical history/concomitant illness on the CRF at 
screening: 
• 
Pre-planned procedure, unless the condition for which the procedure was planned 
has worsened from the first study related activity after the subject has signed the 
informed consent 
• 
Pre-existing conditions found as a result of screening procedures 
• 
Pre-existing events that has not worsened in intensity or frequency from baseline 
10.1.2 Clinical Laboratory Adverse Device Event 
A clinical laboratory ADE is any clinically significant laboratory abnormality that 
suggests a disease and/or organ toxicity and is of a severity, which requires active 
management, (i.e. more frequent follow-up or diagnostic investigation). 
A laboratory re-test and/or continued monitoring of an abnormal value is not considered 
an intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention. 
10.1.3 Unanticipated Adverse Device Effect (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application) or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
10.1.4 Severity of ADEs 
ADEs will be graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE v5.0). The different categories of intensity 
(severity) are characterized as follows: 

GE Research 
Clinical Study Protocol 
Confidential 
Page 66 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Grade 1 
Mild; asymptomatic, or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
Activities of Daily Living (ADL)  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden 
10.1.5 Relationship to Study Treatment 
The relationship of each ADE to the study procedure(s) will be assessed by the Principal 
Investigator or Sub-Investigator on the basis of his/her clinical judgment and the 
following definitions: 
1= Related: 
The ADE follows a reasonable temporal sequence from the exposure to the study 
procedures, and cannot be reasonably explained by the subject’s clinical state or other 
factors (e.g., disease under study, concurrent diseases, or concomitant medications). 
 
The ADE follows a reasonable temporal sequence from exposure to the study procedures, 
and represents a known reaction to the study treatments or procedures, or is predicted by 
the known pharmacological properties of the treatment. 
 
The ADE resolves with discontinuation of the investigational product and/or recurs with 
rechallenge, if applicable. 
 
2 = Not Related: 
The ADE does not follow a reasonable temporal sequence from exposure to the study 
procedures, or can be reasonably explained by the subject’s clinical state or other factors 
(e.g., disease under study, concurrent diseases and concomitant medications). 
10.2 
Procedures 
10.2.1 Collection and Recording of ADEs 
Collection of all ADEs (UADEs and ADEs) will commence from the time the subject 
signs the informed consent to participate in the study until the post-treatment follow-up 

GE Research 
Clinical Study Protocol 
Confidential 
Page 67 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
visit. At each study visit and throughout the in-house treatment period, the Principal 
Investigator will assess whether any subjective ADEs have occurred. In order to avoid 
bias in eliciting ADEs, a non-specific question, such as “How have you been feeling 
since your last visit?” may be asked. Subjects may report ADEs occurring at any other 
time during the study. 
All subjects experiencing ADEs must be monitored and given appropriate medical 
treatment at the discretion and judgement of the Principal Investigator until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to baseline 
or until there is a satisfactory explanation for the changes observed. All ADEs will be 
documented in the ADE page of the eCRF, whether or not the Principal Investigator 
concludes that the event is related to the treatment/procedure. The event term, start and 
stop dates, severity, action taken and outcome, will be documented. 
10.2.2 Collection and Reporting of UADEs 
When an UADE occurs, the Principal Investigator should report it according to the 
following procedure: 
An UADE form must be completed immediately or within 24 hours of first onset or 
notification of the event. The information should be completed as fully as possible but 
contain, at a minimum a short description of the event and the reason why the event is 
categorized as serious, subject identification number, Principal Investigator’s name, name 
of the study procedure and a causality assessment. 
In the interest of subject safety, and in order to fulfill regulatory requirements, all UADEs 
should be reported to the IRB and Sponsor or a designated qualified vendor within 24 
hours of the Study Center’s first knowledge of the event, but in no event later than 10 
working days.  
The collection of UADEs will begin after the subject signs the informed consent form 
and stop at the end of the subject’s follow-up period. An Initial UADE Form should be 
completed, and a copy should be securely faxed or e-mailed to the Sponsor or designated 
qualified vendor. 
10.3 
Anticipated ADEs 
Normal precautions taken for a human study, including the provision of emergency 
equipment, will be taken during this study. Qualified and well-trained physicians and 
medical staff will instruct the subjects.  
Possible anticipated, adverse effects or inconveniences for subjects participating in the 
study procedure are: 
10.3.1 Hypoglycemia 
There is a small risk of severe hypoglycemia (requiring assistance of the study staff) 
when an exogenous insulin analog is administered. The glucose clamp will be performed 

GE Research 
Clinical Study Protocol 
Confidential 
Page 68 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
under continuous surveillance and frequent monitoring of blood glucose levels as 
specified. Since there is simultaneous IV infusion of glucose, the occurrence of severe 
hypoglycemia is unlikely. If a blood glucose value < 70 mg/dL is recorded and confirmed 
by YSI, or the subject has neurogenic symptoms (palpitations, tremor, hunger, sweats) or 
symptoms of neuroglycopenia (confusion, lethargy, agitation, reduced level of 
consciousness), the subject must be treated at the discretion of the Principal Investigator 
to prevent or alleviate neuroglycopenic symptoms. Treatment may include ingestion of 
carbohydrates (e.g., apple juice), IV glucose bolus injections, IV glucose infusions or 
other methods as required per Principal Investigator. Subjects will be monitored closely, 
and it will be a clinical decision made by the Principal Investigator to move from oral to 
IV glucose bolus, to IV glucose infusion. Severe hypoglycemia (as defined by the ADA 
Workgroup) should be treated at the Principal Investigator’s discretion according to best 
available medical practice. As a safety precaution, a glucose solution will be available 
near the subject.  
Hypoglycemic events will be recorded as adverse events, if symptoms develop or if blood 
glucose measured is < 70 mg/dL, even if no symptoms are present. The subjects will only 
be discharged from the clinic, if deemed safe by the Principal Investigator. 
10.3.2 Procedure Related Adverse Events 
Study procedures involve the placement of an IV catheter which may lead to allergic 
reaction, redness, swelling, bruising, pain, bleeding or infection at catheter insertion site.  
The study procedures also involved the use of adhesive to secure the placement medical 
equipment. The adhesive may cause an allergic reaction, redness, swelling or itching 
when in contact with the skin. 
10.3.3 Risks Related to CGMS 
During the study, CGMS will be used. The CGM poses no major risks to the subjects. 
CGMS sensor placement may lead to mild skin irritation at the insertion site, such as 
erythema, edema, rash, bleeding, itching, bruising, scaling skin, and induration. Rarely 
sensors may fracture, and a small piece may remain under the skin which will need to be 
removed by a study clinician. This may cause mild discomfort, bruising, or temporary 
bleeding. In order to avoid risks, CGM catheter will be placed under sterile conditions by 
experienced staff members. In the case of signs of inflammation or bruising at the sensor 
insertion site, the sensor will be removed immediately, and standard of care will apply. 
The subjects will be given one of the study physician or nurse practitioner’s cell phone 
number to contact for any questions, concerns or problems. 
10.3.4 Risks Related to OGTT 
Subjects will participate in OGTTs during the study, which may lead to nausea or 
gastrointestinal discomfort following the drink. Subjects will be asked to lie flat and rest 
as typically these feelings pass very quickly. If the nausea does not pass, then the study 
will be terminated and they will be offered food to eat, which will mitigate the problem. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 69 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
10.3.5 Risks Related to Repeated Blood Draws 
Subjects will participate in several blood draws throughout the course of the study which 
have the potential to cause a venous line-vasovagal response, bruising, tenderness, and 
rarely infection. Treatment of any complications, if necessary, usually involves warm 
compresses to the area for one to several days. Although the study involves numerous 
blood draws, it is considered minimal risk since the study will only involve healthy adult 
individuals. In addition, the overall blood volume that will be collected, will be below the 
maximum blood collection volume deemed minimal risk (i.e., no more than 550 ml in an 
8‐week period). 
10.3.6 Risk Related to Hepatic Insonification 
The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1‐6‐D 
XDclear abdominal curvilinear probe are FDA cleared (K173555) with the indication for 
ultrasound evaluation of fetal, abdominal, pediatric, small organ (breast, testes, thyroid), 
neonatal cephalic, adult cephalic, cardiac (pediatric and adult), peripheral vascular, 
musculoskeletal conventional and superficial, urology (including prostate), transrectal, 
transvaginal, transesophageal, and intraoperative (abdominal, thoracic, and vascular). 
Since the ultrasound device will be used on this study to test for organ‐specific biological 
effects, it is being used off‐label on this study, and therefore, is considered 
investigational. Although its use in this study is considered investigational, its use is 
considered to constitute minimal risk given that it will be operated within the confines of 
its FDA‐cleared equipment parameters and below the guidelines established by the FDA 
for ultrasound equipment. The FDA guidelines indicate that the derated global maximum 
acoustic output should not exceed preamendment acoustic output exposure levels. In the 
case of diagnostic ultrasound, the global maximum derated spatial‐peak temporal‐average 
intensity (ISPTA – the highest intensity measured at any point in the ultrasound beam 
averaged over the pulse repetition period) is ≤ 720 mW/cm2 with either the global 
maximum mechanical index being ≤ 1.9 or the global maximum derated spatial‐peak 
pulse‐average intensity (ISPPA – the highest intensity measured at any point in the 
ultrasound beam averaged over the temporal duration of the pulse) being ≤ 190 W/cm2 
(not including ophthalmic use). 
10.4 
Follow-up of ADEs and UADEs 
All ADEs should be followed up and subjects will be rendered appropriate medical care 
and treatment at the discretion of the Principal Investigator until resolution or until the 
Principal Investigator and Sponsor concludes that “further follow-up is not necessary”. If 
the ADE has not resolved by the post-treatment follow-up visit, the stop date will be 
recorded as “ongoing.” 
All UADEs should be followed up until resolution or permanent outcome of the event or 
until the Principal Investigator and Sponsor judge that further follow-up is not necessary. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 70 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
If information is not available at the time of the first report and becomes available at a 
later date, the Principal Investigator should complete a follow-up UADE form at the 
earliest possible or provide other written documentation and send it electronically  within 
24 hours of receipt of information to the Sponsor or designee. Copies of any relevant data 
from the hospital notes (e.g., ECGs, laboratory tests, discharge summary, postmortem 
results) should be sent accordingly. 
All other non-serious ADEs must be followed until the outcome of the event is 
“recovering” (for chronic conditions), or “recovered”, or until the end of the post-
treatment follow-up stated in the protocol, whichever comes first, and until all queries 
related to these ADE’s have been resolved. 
10.4.1 Safety Reporting to IRBs and Regulatory Authorities 
The Sponsor or a Contract Research Organization (CRO) will be responsible for 
reporting all UADEs to FDA. Principal Investigator and IRBs, as applicable, in 
accordance with national regulations in the country where the study is conducted.  
Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, UADEs will be submitted to IRB and FDA within 10 days. 
Institution and/or Principal Investigator shall promptly, in accordance with applicable 
laws, rules and regulations and the procedures specified in the Protocol, advise Sponsor 
and the IRB, as applicable of any adverse events and adverse reactions occurring during 
the conduct of the Study that become known to it/him/her.  Without limiting the 
generality of the foregoing, Institution and/or Principal Investigator shall notify Sponsor 
or the medical monitor of any serious adverse events and serious adverse reactions 
encountered in the Study (including, without limitation, all serious and unexpected 
adverse reactions that the Principal Investigator suspects may be Study Device related) 
via email within 24 hours of making such discovery to enable Sponsor to timely report 
such events in accordance with applicable laws, rules and regulations as required to and 
any applicable regulatory authority including, as applicable the FDA. Additionally, 
Institution and/or Principal Investigator shall: (i) provide all communications with the 
IRB to Sponsor; and (ii) cooperate with Sponsor to investigate the Adverse Event and 
provide all documentation requested by Sponsor. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 71 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
11.0 
DATA HANDLING AND MANAGEMENT 
Clinical Data Management (CDM) is the responsibility of ProSciento, Chula Vista, USA. 
With permission of the Sponsor, Data Management may be delegated under an agreement 
of transfer of responsibilities to a qualified vendor of ProSciento. 
11.1 
Data Management 
The full details of procedures for data handling will be documented in the Data 
Management Plan (DMP). 
ADEs and medical history will be coded using the current version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medications will be coded 
using the World Health Organization (WHO) WHODrug Global dictionary. The 
MedDRA version used will be recorded in the Study Master File documentation. 
Unique numbers will identify the subject and the biological material obtained from the 
subject. Appropriate measures such as encryption or deletion will be enforced to protect 
the identity of human subjects in all presentations and publications as required by 
local/regional/national requirements, and data exchanges with sponsor. 
Data from screening failures will be entered into the database. The data for screen 
failures will be limited to ICF date, demographics, and eligibility assessment including 
reason(s) for screen fail.  
Laboratory data from the central laboratory will be electronically transferred to 
ProSciento for database reconciliation purposes and loading into EDC for data review 
purposes.  
The laboratory will provide one copy of the laboratory reports to the site staff. The site 
staff will receive all laboratory data electronically or based on FAX reports directly from 
the laboratory. The Principal Investigator must review, evaluate, sign and date the 
laboratory printouts upon receipt. The signed print-out of the laboratory reports are 
source data. 
All other results and laboratory tests will be transferred electronically to the responsible 
Data Management Unit.  
Clamp and CGMS data will be prepared for data transfer by ProSciento, and provided to 
the Sponsor (or through designated CROs). 
11.2 
CRFs (Electronic) 
11.2.1 Clinical Data Management Workflow 
Electronic CRFs will be developed by ProSciento’s Clinical Data Management (CDM) or 
an authorized CDM department, in collaboration with the clinical study team and 
statistician. CDM will document the process workflow in the DMP. After data entry, 
monitor(s) will source data verify (SDV) the eCRFs against the source documents. 
Queries may be issued to clarify the data entered. The PI will electronically sign the 

GE Research 
Clinical Study Protocol 
Confidential 
Page 72 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
eCRFs after all data have been entered and all queries have been resolved. If corrections 
and/or resolution of queries are required after PI approvals, those eCRFs affected by 
changes will be re-signed by the PI. The database may be locked after the PI approvals 
are completed. 
After database lock, CDM study design documentation and locked eCRFs (PDF) will be 
created and will be provided to the Sponsor. 
11.2.2 Data Entry of eCRFs 
Data required for analyses and subject safety assessments will be entered from source 
documentation into eCRFs. Instructions for data entry will be provided in the eCRF 
Completion Guidelines, developed by ProSciento’s CDM department. All site staff 
involved with entering data into the eCRFs will be trained prior to gaining access to the 
study database. 
11.2.3 Corrections to eCRFs 
Queries may be generated by the eCRF system during data entry, and queries may be 
generated by CDM staff, monitors, PIs, the Sponsor, and other data reviewers during the 
course of the study. Only specific site personnel will be authorized to make corrections to 
the eCRFs; CDM will train personnel prior to granting access in the eCRF system. 
Corrections will be made directly in the eCRF – by modifying existing data, adding new 
data, or deleting data, as appropriate. All data corrections will be logged in the electronic 
audit trail. 
11.2.4 PI Approval of eCRF Data 
The Principal Investigator or authorized staff must ensure that all information derived 
from source documentation is consistent with the source information and accurately 
reflected in the eCRFs. By electronically signing the eCRFs, the Principal Investigator 
confirms that the information is complete and correct. 
11.3 
Retention of Documents 
At the completion of the study, all records created by and under the supervision of the 
Principal Investigator should be maintained in accordance with the requirements of the 
regulatory authority guideline and the GCP Guideline. These will be available for 
inspection at any time by the Sponsor or the FDA. 
Clinical study documents are archived upon completion of the study and maintained for 
at least 15 years from the study closure or longer in accordance with local regulation and 
applicable regulatory authority guidelines, and the study sponsor will be notified prior to 
destruction of study records. 
 

GE Research 
Clinical Study Protocol 
Confidential 
Page 73 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
12.0 
STATISTICAL METHODS 
12.1 
Statistical and Analytical Plans 
ProSciento or qualified designee will be responsible for the statistical services, including 
statistical analysis, statistical reports and the statistical analysis plan (SAP). 
An SAP will be prepared prior to database lock, that will provide further details regarding 
the definition of analysis variables and analysis methodology to address all study 
objectives. It will also provide any changes or additions to the analyses that are not 
apparent in the protocol. 
12.1.1 Analysis Sets 
12.1.1.1 Safety Set 
The Safety population will consist of all subjects who received at least 1 hepatic 
ultrasound insonification. This will be the primary analysis population for the evaluation 
of exposure and safety. 
12.1.1.2 Ultrasound Insonification Effect Set 
The ultrasound insonification effect population will consist of all subjects who received 
at least 1 hepatic ultrasound insonification. It is the same as the safety set and will be the 
primary analysis population for the primary endpoint. 
12.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all subjects. Summary 
statistics (e.g., number of subjects, mean, median, standard deviation, and range) will be 
generated for continuous variables (e.g., age and weight) and the number and percentage 
of subjects within each category will be presented for categorical variables. 
12.1.3 Analysis of the Endpoints for Ultrasound Insonification 
12.1.3.1 Two-Step Hyperinsulinemic-Euglycemic Clamp Analysis 
The analysis of the two-step H-E Clamp will consist of summarizing whole-body insulin 
sensitivity and EGP results. Results will be summarized descriptively. 
Changes in insulin sensitivity will be assessed by the following calculations:  
• SIclamp:  
Insulin Sensitivity Index 
• M: 
 
Glucose disposal rate during steady state  
• MCR:  
Glucose metabolic clearance rate during steady state  
• M/I: 
 
Glucose metabolism: insulin ratio during steady state 
Insulin Sensitivity Index (SIclamp)  

GE Research 
Clinical Study Protocol 
Confidential 
Page 74 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
The insulin sensitivity index (SIclamp) will be calculated using the formula below, with 
Step 1 indicating the first phase of the clamp, or the period of administration of the first 
(lower) insulin infusion rate and Step 2 indicating the second phase of the clamp or the 
period of administration of the second (higher) insulin infusion rate. Mean glucose 
infusion rates and mean insulin concentrations will be calculated during steady state (the 
last 30 minutes of the clamp step) for the applicable step(s). 
SIclamp =
mean(GIR)Step2 −mean(GIR)Step1
ൣmean(I)Step2-mean(I)Step1൧×උmean(BG)Steps1&2ඏ 
Change from baseline (CFB) of SIclamp will then be computed for each subject as 
CFB൫SIclamp൯= SIclamp2 −SIclamp1, where clamp 2 is the second clamp and clamp 1 is 
the first clamp (completed on Day 2; prior to first insonification). Change from baseline 
of SIclamp, together with SIclamp for each clamp individually, will be included in the 
efficacy analysis dataset.  
Glucose disposal rate (M) during steady state  
Glucose disposal rate (M) is obtained as the glucose infusion rate per min corrected for 
body weight and/or fat free mass.  Glucose disposal rate will be calculated separately for 
Step 1 and Step 2 and for each clamp. 
Glucose metabolic clearance rate (MCR) during steady state  
Glucose metabolic clearance rate (MCR) is calculated using the formula below for each 
clamp. Rates will be compared. Glucose MCR will be calculated separately for Step 1 
and Step 2, with Step 1 indicating the first phase of the clamp, or the period of 
administration of the first (lower) insulin infusion rate and Step 2 indicating the second 
phase of the clamp or the period of administration of the second (higher) insulin infusion 
rate.  
MCR=100× mean(M)
mean(BG) 
Glucose metabolism: insulin ratio (M/I) during steady state  
Insulin ratio (M/I) will be calculated for each clamp and ratios will be compared. This is 
the preferred measure and primary endpoint. Glucose metabolism: insulin ratio (M/I) is 
calculated as the glucose disposal rate (M) divided by the insulin concentration (I).   
 
The planned analyses will be described in more detail in the statistical analysis plan 
(SAP). 
12.1.3.2 EGP 
Fasting EGP 
Prior to the two-step H-E Clamp, fasting EGP will be assessed utilizing a low 
primed-continuous infusion of a stable isotope-labeled glucose. At each blood collection 

GE Research 
Clinical Study Protocol 
Confidential 
Page 75 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
time point, plasma glucose enrichments will be measured to determine steady state and to 
determine fasting EGP using steady-state equations (Steele 1959). 
Insulin-mediated EGP Suppression 
For each clamp, the degree of EGP suppression from the fasting EGP value will be 
determined during the last 30 minutes point during each step of the two-step H-E Clamp 
using the following equation: 
% EGP suppression = 1 - (EGP clamp/EGP fasting) 
 
Partial suppression of EGP during Step 1 is assessed to determine hepatic insulin 
sensitivity and EGP suppression during Step 2 will be measured to confirm EGP was 
(near) fully suppressed to allow the determination of extrahepatic insulin sensitivity. 
 
Rate of Glucose Disappearance (Rd) 
Under steady state conditions, the Rate of Glucose Disappearance (Rd) is equal to the 
Rate of Glucose Appearance (Ra) and under these conditions Ra is calculated from the 
dilution of plasma [6,6-2H2]glucose during constant infusion of [6,6-2H2]glucose.  Rd will 
be calculated during steady state in the fasting period and during Step 1 and Step 2 of the 
clamp. 
12.1.4 Safety Analysis and Endpoints 
Safety of the procedure will be assessed by collection and review of adverse device 
effects, laboratory parameters, physical examination, vital signs, and ECG parameters 
throughout the duration of the study. Safety analysis will involve examination of the 
descriptive statistics and individual subject listings for effects of study treatment on 
clinical tolerability and safety. 
Safety data will be summarized using the safety analysis set.  
12.1.4.1 Adverse Device Effects 
All ADEs will be coded using MedDRA. Data will be summarized using preferred term 
and primary system organ class. 
ADE summaries will include the overall incidence (by system organ class and preferred 
term), events by maximum intensity, event by relationship to study procedure, events 
leading to discontinuation of study, and serious adverse events.  
ADE data and UADEs will be listed by subject. 
12.1.4.2 Vital Signs, ECGs and Physical Examinations 
Absolute values and changes from baseline will be assessed for vital sign and ECG 
parameters at specified timepoints. Abnormal findings will be listed. Graphical 
presentation of vital sign and ECG parameters at specified timepoints may be provided. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 76 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Changes in physical examination at each timepoint will be listed by subject. 
12.1.4.3 Clinical Laboratory Assessments 
Absolute values and changes from baseline will be assessed for hematology, serum 
chemistry and urinalysis parameters. Post-baseline shifts in parameter values will be 
presented for the worst on-study observed values. Clinically significant laboratory 
parameters will be listed. 
All laboratory data will be listed and will include a flag for abnormal high or low values 
and clinically significant results.  
12.2 
Interim Analysis 
There are no planned interim analyses. 
12.3 
Determination of Sample Size 
No formal sample size calculations were performed as this is an exploratory study. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 77 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Monitoring 
The study will be monitored by M Squared Associates Inc., 575 Eighth Avenue, Suite 
1212, New York, NY 10018. 
Monitoring visits to the study site will be made periodically during the study to ensure 
that all aspects of the protocol and GCP are followed, CRFs are completed correctly, and 
subjects’ safety is monitored. The Monitor will conduct a detailed training before First 
Subject First Visit (FSFV) (Initiation Visit), a monitoring visit at least once during the 
clinical part of the study, and a monitoring visit at least once after Last Subject Last Visit 
(LSLV). Furthermore, the Monitor will be available and maintain direct communication 
with the study site by telephone and e-mail throughout the trial.  
To ensure investigator compliance per 21 CFR 812.46, monitoring of the investigational 
sites will be conducted by the sponsor or the sponsor’s representative according to the 
monitoring plan developed specifically for this study. To ensure that the investigator and 
site staff understand and accept the defined responsibilities, the monitor will maintain 
regular correspondence with the site during the course of the study to verify the 
acceptability of the facilities, compliance with the investigational plan and relevant FDA 
regulations, and the maintenance of complete records. Monitoring will include review 
and resolution of missing or inconsistent results and source document checks (i.e., 
comparison of submitted study results to original reports) to assure the accuracy of the 
reported data.  
The investigators and institutions will permit the sponsor or sponsor’s representative to 
perform study-related monitoring, audits, IRB review, and regulatory inspections by 
providing direct access to source data/documentation. 
Clinical Research Associates (CRAs) of ProSciento, Inc., 855 3rd Avenue, Chula Vista, 
CA 91911, will monitor the clamp data of this study. 
The Monitor must be given direct access to source documents, such as original 
documents, data, and records. Direct access includes permission to examine, analyze, 
verify any record(s) and report(s) that are important to evaluation of the clinical study. 
The study will be monitored to verify integrity and validity of the data. Monitoring will 
follow a Monitoring Plan. 
Additional QC monitoring of the clinical study for protocol and GCP compliance will be 
conducted periodically by qualified staff of ProSciento, Inc. 
13.2 
Protocol Deviations 
The Principal Investigator should not deviate from the protocol, except where necessary 
to eliminate an immediate hazard to study subjects. Should other circumstances arise that 
will require deviation from protocol-specified procedures, unless there is an emergency 
or immediate need, the Principal Investigator should contact the medical monitor and 

GE Research 
Clinical Study Protocol 
Confidential 
Page 78 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Sponsor to review and discuss the implications of the deviation and determine the 
appropriate course of action. Any deviation must be documented, stating the reason and 
date, the action taken, and the impact for the subject and/or the study. The documentation 
must be kept in the Principal Investigator’s Study File and the Sponsor’s Study Master 
File.   

GE Research 
Clinical Study Protocol 
Confidential 
Page 79 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
14.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted in accordance with the Protocol, the International 
Conference on Harmonization (ICH), Guideline for Good Clinical Practice: Consolidated 
Guidance (E6 R2) and applicable regulatory requirements including clinical research 
guidelines established by the Basic Principles defined in the U.S. 21 CFR Parts 11, 50, 54 
and 56, and is subject to the abbreviated requirements of the investigational device 
exemptions (IDE) defined in the US 21 CFR 812.2(b), and the principles enunciated in 
the Declaration of Helsinki (revised version Fortaleza 2013). 
14.1 
Institutional Review Board 
Prior to commencement of the study, the protocol, any amendments, subject 
information/informed consent form, any other written information to be provided to the 
subject, subject recruitment procedures, information about payments and compensation 
available to subjects if not mentioned in the subject information, the Principal 
Investigator’s current CV and/or other documentation evidencing qualifications, and 
other documents as required by the local Institutional Review Board (IRB) should be 
submitted. Written approval/favorable opinion must be obtained from IRB prior to 
commencement of the clinical study start. 
The Principal Investigator shall provide to Sponsor or its designee a copy of the written 
and dated approval/favorable opinion by the applicable the IRB.  
During the study, the Principal Investigator must promptly report the following to the 
IRB: UADEs, substantial amendments to the protocol, non-substantial amendments, 
deviations to the protocol implemented to eliminate immediate hazards to the subjects, 
new information that may affect adversely the safety of the subjects or the conduct of the 
study (including new risk/benefit analysis in case it will have an impact on the planned 
follow-up of the subjects), annually written summaries of the study status and other 
documents as required by the local IRB. 
Substantial amendments must not be implemented before approval/favorable opinion, 
unless necessary to eliminate hazards to the subjects. 
The Principal Investigator must maintain an accurate and complete record of all 
submissions made to the IRB. The records should be filed in the Principal Investigator’s 
Study File and copies must be provided to the Sponsor.  
14.2 
Responsibilities of the Principal Investigator 
The Principal Investigator will conduct this clinical study in compliance with all 
applicable national, state, local or regional laws. The Principal Investigator will align his 
or her conduct in accordance with the “Responsibilities of the Principal Investigator”. 
The Principal Investigator may appoint other individuals as he/she may deem appropriate 
as Sub-Investigators to assist in the conduct of the Clinical Study in accordance with the 
Clinical Study Protocol. All Sub-Investigators shall be timely appointed and listed. The 

GE Research 
Clinical Study Protocol 
Confidential 
Page 80 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Sub-Investigators will be supervised by and under the responsibility of the Principal 
Investigator. The Principal Investigator will provide them with a Clinical Study Protocol 
and all necessary information and document training and adhere to all Investigator 
Requirements (e.g., providing financial disclosure, curriculum vitae [CV], signed 
investigator agreement, etc.). Each Sub-Investigator is responsible for fulfilling all of the 
obligations directed to them by the Principal Investigator.  
In compliance with the Clinical Study Protocol, Good Clinical Practice and applicable 
regulatory requirements, the Principal Investigator must permit auditing by or on the 
behalf of the Sponsor and inspection by applicable regulatory authorities. The Principal 
Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel are bound by professional 
secrecy and as such will not disclose any personal identity or personal medical 
information. The Principal Investigator will make every effort to help with the 
performance of the audits and inspections, giving access to all necessary facilities, data, 
and documents. As soon as the Principal Investigator is notified of a future inspection by 
the authorities, he or she will inform the Sponsor or its designee and authorize the 
Sponsor or its designee to participate in this inspection. Any results and information 
arising from the inspections by the regulatory authorities will be immediately 
communicated to the Sponsor. The Principal Investigator shall take appropriate measures 
required by the Sponsor to take corrective actions for all problems found during the audit 
or inspections. 
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the 
applicable local laws and regulations.  
14.3 
Informed Consent 
Once signed, the original informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) will be stored in the Principal 
Investigator’s site file. The Principal Investigator must document the date the subject 
signs the informed consent in the subject’s medical record. Copies of the signed informed 
consent form, the signed subject authorization form (if applicable), and subject 
information sheet (if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or 
the relevant subject’s legally acceptable representative in the same manner as the original 
informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised informed 
consent form. 
14.4 
Subject Confidentiality 
The Sponsor and designees affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Subject records will be kept private except when 
ordered by law. The following individuals will have access to study subject records: 

GE Research 
Clinical Study Protocol 
Confidential 
Page 81 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Principal Investigator and designees, study Sponsor, monitors and auditors, the FDA, 
other government offices and the IRB. 
Throughout this study, a subject’s source data will only be linked to the Sponsor’s 
clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, 
age, or date of birth, and subject initials may be used to verify the subject and accuracy of 
the subject’s unique identification number. 
The Principal Investigator must agree to permit the Sponsor’s monitor or designee’s 
monitor, representatives from any regulatory authority, the Sponsor’s designated auditors, 
and the appropriate IRB to review the subject’s source data or documents, including, but 
not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process. The confidentiality 
of the verified data and the protection of the subjects must be respected during these 
inspections. 
Copies of any subject source documents that are provided to the Sponsor must have 
certain personally identifiable information removed. 
14.5 
Property Rights 
All information disclosed or provided by the Sponsor (or any company/institution acting 
on their behalf), or produced during the Clinical Study, including but not limited to, the 
Clinical Study Protocol, the case report forms, the Principal Investigator’s Brochure and 
results obtained during the course of the Clinical Study, is confidential and the property 
of the Sponsor. No rights, title, or license to such data are granted to ProSciento by this 
protocol. The Principal Investigator and all persons under his/her authority agrees to 
undertake to keep confidential and not to disclose the information to any third party 
without the prior written approval of the Sponsor. 
All information, documents and study drug provided by Sponsor or its designee are and 
remain the sole property of the Sponsor. The Principal Investigator shall not mention any 
information or the study drug in any application for a patent or for any other intellectual 
property rights. 
All results, data, documents and inventions, which arise directly or indirectly from the 
Clinical Study in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all results at its own discretion, without limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to 
patent, develop, market or otherwise use the results of the Clinical Study. 
14.6 
Publication, Disclosure, and Clinical Study Registration Policy 
The Principal Investigator will provide the Sponsor with truthful, accurate and complete 
test results and all data derived from the study. During the study, only the Sponsor may 

GE Research 
Clinical Study Protocol 
Confidential 
Page 82 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
make study information available to other study investigators or to regulatory agencies, 
except as required by law or regulation. Except as otherwise allowable in the clinical 
study site agreement, any public disclosure (including publicly accessible websites) 
related to the protocol or study results, other than study recruitment materials and/or 
advertisements, is the sole responsibility and prerogative of the Sponsor. 
ProSciento or its designee and Sponsor will be responsible for preparing the Clinical 
Study Report. When all data has been fully analyzed, ProSciento or Sponsor will 
communicate the results of the Clinical Study to the Principal Investigator(s) at Sponsor’s 
sole option.  
The Principal Investigator or qualified designee agrees to use this information only and 
strictly in connection with this Clinical Study and not for other purposes without the prior 
written permission from the Sponsor. ProSciento and the Principal Investigator may 
publish or present the results of the Clinical Study or any data derived from the Study 
only in accordance with the requirement of Section 9.1 of the Clinical Study Agreement 
having an effective date of 19 December 2019. Prior to any publication, the Sponsor must 
be given the opportunity to review and comment upon any manuscript, poster, or paper 
that contains data derived or generated from this study in order to be aware of all written 
and oral presentations of the data.   
The study may be registered on publicly accessible websites (e.g., ClinicalTrials.gov) 
according to applicable law, regulation and guidance, after discussion with the Sponsor. 

GE Research 
Clinical Study Protocol 
Confidential 
Page 83 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
15.0 
REFERENCES 
1. Borovikova, L. V et al. Vagus nerve stimulation attenuates the systemic 
inflammatory response to endotoxin. Nature 405, 458–462 (2000). 
2. Tracey, K. J. Reflexes in Immunity. Cell 164, 343–344 (2016). 
3. Koopman, F. A. et al. Vagus nerve stimulation inhibits cytokine production and 
attenuates disease severity in rheumatoid arthritis. Proc. Natl. Acad. Sci. 113, 
8284–8289 (2016). 
4. Olofsson, P. S. & Tracey, K. J. Bioelectronic medicine: technology targeting 
molecular mechanisms for therapy. J. Intern. Med. 282, 3–4 (2017). 
5. Yi, C.-X., la Fleur, S. E., Fliers, E. & Kalsbeek, A. The role of the autonomic 
nervous liver innervation in the control of energy metabolism. Biochim. Biophys. 
Acta 1802, 416–431 (2010). 
6. Reyes, T. M., Walker, J. R., DeCino, C., Hogenesch, J. B. & Sawchenko, P. E. 
Categorically distinct acute stressors elicit dissimilar transcriptional profiles in the 
paraventricular nucleus of the hypothalamus. J. Neurosci. 23, 5607–5616 (2003). 
7. Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to 
insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006). 
8. Pavlov, V. A. & Tracey, K. J. The vagus nerve and the inflammatory reflex—
linking immunity and metabolism. Nat. Rev. Endocrinol. 8, 743–754 (2012). 
9. Stauss, H. et. al. Modulation of blood glucose concentration by vagal nerve 
stimulation. FASEB 828.6 (2015). 
10. Tanida, M. et al. Leptin receptor signaling in the hypothalamus regulates hepatic 
autonomic nerve activity via phosphatidylinositol 3-kinase and AMP-activated 
protein kinase. J. Neurosci. 35, 474–484 (2015). 
11. Meyers, E. E., Kronemberger, A., Lira, V., Rahmouni, K. & Stauss, H. M. 
Contrasting effects of afferent and efferent vagal nerve stimulation on insulin 
secretion and blood glucose regulation. Physiol. Rep. 4, e12718 (2016). 
12. Malbert, C.-H., Picq, C., Divoux, J.-L., Henry, C. & Horowitz, M. Obesity-
Associated Alterations in Glucose Metabolism Are Reversed by Chronic Bilateral 
Stimulation of the Abdominal Vagus Nerve. Diabetes 66, 848 LP-857 (2017). 
13. Cotero, V. et al. Noninvasive sub-organ ultrasound stimulation for targeted 
neuromodulation. Nat. Commun. 10, 952 (2019). 
14. Puleo, C. M. et al. Noninvasive neuromodulation of the peripheral nerve 
pathways using ultrasound and its current therapeutic implications. in CSH 
Perspectives: Bioelectronic Medicine (2019). 
 

GE Research 
Clinical Study Protocol 
Confidential 
Page 84 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
16.0 
APPENDIX 
Table 16-1 Schedule of Events (SOE) 
ASSESSMENTS 
SCREEN 
IN-HOUSE 
PERIOD 1 
OPV 
IN-HOUSE 
PERIOD 2 
OPV 
F/U 
Observational Period 1 
(Days -1 to Day 14) 
Insonification 
(Days 15-17) 
Observational Period 2 
(Days 18 to Day 28) 
Visit/ 
Timepoint (Day) 
Start 
Day 
-28 
-1 
1 
2 
8 
15 
16 
17 
18 
22 
28 
Study  
Intervention/ 
Insonification 
 
 
 
 
 
X 
X 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Assess eligibility 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
Sequestered in 
clinic/unit 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Physical 
examination (PE) 
X 
 
 
 
 
 
 
 
 
 
 
Abbreviated PE 
 
X 
 
 
 
X 
 
 
X 
 
X 
Hematology, 
serum chemistry 
& urinalysis  
X 
X 
 
 
 
X 
 
 
X 
 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Hep B, Hep C, 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(urine)  
 
X 
 
 
X 
X 
 
 
 
X 
X 
Pregnancy test 
(serum)  
X 
 
 
 
 
 
 
 
 
 
 
FSH if 
postmenopausal 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug 
screen & alcohol 
breath test 
X 
X 
 
 
X 
X 
 
 
 
X 
X 
Weight, BMI 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG   
X 
X 
 
X 
 
X 
 
X 
 
 
X 
Instructions on 
SMBG /glucose 
via fingerstick to 
measure during 
outpatient 
periods (Days 3-
14 and 19-27) 
 
X 
 
 
 
 
 
 
 
 
 

GE Research 
Clinical Study Protocol 
Confidential 
Page 85 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
ASSESSMENTS 
SCREEN 
IN-HOUSE 
PERIOD 1 
OPV 
IN-HOUSE 
PERIOD 2 
OPV 
F/U 
Observational Period 1 
(Days -1 to Day 14) 
Insonification 
(Days 15-17) 
Observational Period 2 
(Days 18 to Day 28) 
Visit/ 
Timepoint (Day) 
Start 
Day 
-28 
-1 
1 
2 
8 
15 
16 
17 
18 
22 
28 
Study  
Intervention/ 
Insonification 
 
 
 
 
 
X 
X 
X 
 
 
 
Record 
concomitant 
medications 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
Record ADEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Standardized 
meals 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
CGMS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGMS sensor 
insertion/ change 
 
X 
 
 
X 
 
 
 
X 
 
 
Overnight fast 
 ≥ 10 hours 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Check of imaging 
criteria 
 
 
 
 
 
X 
 
 
 
 
 
OGTT 
 
 
X 
 
 
 
X 
 
 
 
 
Insulin and 
glucose  tracer 
infusion overnight 
 
 
X 
X 
 
 
X 
X 
 
 
 
Blood sampling 
for EGP 
 
 
 
X 
 
 
 
X 
 
 
 
Initiation of 
Clamp procedure 
 
 
 
X 
 
 
 
X 
 
 
 
Fasting plasma 
glucose 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HOMA-IR 
 
 
X 
 
 
X 
 
 
X 
 
X 
Explorataory 
biomarkers for 
assessment and 
potential storage 
 
 
X 
 
 
X 
 
 
X 
 
X 
Glucose 
parameters (e.g., 
Fructosamine) 
 
 
X 
 
 
X 
 
 
X 
 
X 
Lipid 
meatabolism 
parameters (e.g. 
FFA, 
triglycerides) 
 
 
X 
 
 
X 
 
 
X 
 
X 
Inflammatory 
biomarkers (e.g., 
adipnectin, CRP) 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 

GE Research 
Clinical Study Protocol 
Confidential 
Page 86 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Table 16-2 Schedule of Events (SOE) for Subjects with BMI> 35.0 kg/m2 and ≤ 40.0 
kg/m2 and/or Waist Circumference > 40 and ≤ 45 inches 
ASSESSMENTS 
SCREENI 
PERIOD 
IN-HOUSE 
PERIOD 1 
OPV 
IN-HOUSE 
PERIOD 2 
OPV 
F/U 
 
Observational Period 1 
(Days -1 to Day 14) 
Insonification 
(Days 15-17) 
Observational Period 2 
(Days 18 to Day 28) 
Visit/ 
Timepoint (Day) 
Start 
Day—50  
-1 
1 
2 
8 
15 
16 
17 
18 
22 
28 
Study  
Intervention/ 
Insonification 
 
 
 
 
 
X 
X 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Assess eligibility 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
Re-assess 
eligibility criteria 
 
X** 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
Sequestered in 
clinic/unit 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Physical 
examination (PE) 
X 
 
 
 
 
 
 
 
 
 
 
Abbreviated PE 
 
X 
 
 
 
X 
 
 
X 
 
X 
Hematology, 
serum chemistry & 
urinalysis  
X 
X 
 
 
 
X 
 
 
X 
 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Hep B, Hep C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(urine)  
 
X 
 
 
X 
X 
 
 
 
X 
X 
Pregnancy test 
(serum)  
X 
 
 
 
 
 
 
 
 
 
 
FSH if 
postmenopausal 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
& alcohol breath 
test 
X 
X 
 
 
X 
X 
 
 
 
X 
X 
Weight, BMI 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Waist 
circumference 
X 
 
 
 
 
 
 
 
 
 
 
Hepatic 
ultrasound  
(Screening only) 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG   
X 
X 
 
X 
 
X 
 
X 
 
 
X 

GE Research 
Clinical Study Protocol 
Confidential 
Page 87 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
ASSESSMENTS 
SCREENI 
PERIOD 
IN-HOUSE 
PERIOD 1 
OPV 
IN-HOUSE 
PERIOD 2 
OPV 
F/U 
 
Observational Period 1 
(Days -1 to Day 14) 
Insonification 
(Days 15-17) 
Observational Period 2 
(Days 18 to Day 28) 
Visit/ 
Timepoint (Day) 
Start 
Day—50  
-1 
1 
2 
8 
15 
16 
17 
18 
22 
28 
Study  
Intervention/ 
Insonification 
 
 
 
 
 
X 
X 
X 
 
 
 
Instructions on 
SMBG /glucose via 
fingerstick to 
measure during 
outpatient periods 
(Days 3-14 and 19-
27) 
 
X 
 
 
 
 
 
 
 
 
 
Record 
concomitant 
medications 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
Record ADEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Standardized 
meals 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
CGMS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGMS sensor 
insertion/ change 
 
X 
 
 
X 
 
 
 
X 
 
 
Overnight fast 
 ≥ 10 hours 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Check of imaging 
criteria 
 
 
 
 
 
X 
 
 
 
 
 
OGTT 
 
 
X 
 
 
 
X 
 
 
 
 
Insulin and glucose  
tracer infusion 
overnight 
 
 
X 
X 
 
 
X 
X 
 
 
 
Blood sampling for 
EGP 
 
 
 
X 
 
 
 
X 
 
 
 
Initiation of Clamp 
procedure 
 
 
 
X 
 
 
 
X 
 
 
 
Fasting plasma 
glucose 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HOMA-IR 
 
 
X 
 
 
X 
 
 
X 
 
X 
Explorataory 
biomarkers for 
assessment and 
potential storage 
 
 
X 
 
 
X 
 
 
X 
 
X 
Glucose 
parameters (e.g., 
Fructosamine) 
 
 
X 
 
 
X 
 
 
X 
 
X 
Lipid meatabolism 
parameters (e.g. 
FFA, triglycerides) 
 
 
X 
 
 
X 
 
 
X 
 
X 
Inflammatory 
biomarkers (e.g., 
adipnectin, CRP) 
 
 
X 
 
 
X 
 
 
X 
 
X 

GE Research 
Clinical Study Protocol 
Confidential 
Page 88 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
*Study Visit to be performed ≥ 30 days after hepatic ultrasound screening examination. 
**Necessary laboratory analyses and examinations need to be performed prior to Day -1, so that all 
eligibility criteria from screening can be re-assessed on Day -1. Re-assessment can be performed after a 30-
day wait period, starting after the ultrasound examination.  

GE Research 
Clinical Study Protocol 
Confidential 
Page 89 of 89  
Protocol No. GE-HUI-01 
 
Version 4.0 24Sep2020 
-GE CONFIDENTIAL- 
Table 16-3 Toronto Clinical Neuropathy Scoring System