Evaluating the Impact of SomaSignal Tests on Medical Management and Change in Risk in Patients With Type 2 Diabetes at Higher Risk of Cardiovascular Disease
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Sponsor: Emory University

 
 
 
 
 
 
 
 
SomaSignal Tests on Medical Management and Change in Risk in 
Patients With Diabetes 
NCT05256706 
 
 
Date: November 14, 2022 
STUDY00003362 

Protocol Title: Precision SomaSignal DM: Evaluating the Impact of SomaSignal Tests on Medical 
Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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PROTOCOL TITLE:   Precision SomaSignal DM: Evaluating the Impact of SomaSignal 
Tests on Medical Management and Change in Risk in Patients with Type 2 Diabetes at 
Higher Risk of Cardiovascular Disease
PRINCIPAL INVESTIGATOR:
, MD, FRCP
Department of Medicine, Division of Cardiology
CO-INVESTIGATORS: 
, MD
Department of Medicine, Division of Cardiology
 MD, MSc, MBA
Department of Family and Preventive Medicine
VERSION: 5 – 14 November 2022
FUNDING SOURCE: Soma Logic, Inc

Protocol Title: Precision SomaSignal DM: Evaluating the Impact of SomaSignal Tests on Medical 
Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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REVISION HISTORY
Revision #
Version 
Date
Summary of Changes
1
12 Jan 2022
Changes for clarification.
2
12 May 2022
Updated transportation reimbursement and recruitment 
language
3
6 Sep 2022
Removing Kidney Function Test from Metabolic Factors 
Panel platform 
4
29 Sep 2022
Addition of Vital Signs collection at 6 month time point
5
14 Nov 2022
Clarifying language regarding re-consenting participants

Protocol Title: Precision SomaSignal DM: Evaluating the Impact of SomaSignal Tests on Medical 
Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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Table of Contents
1.
Study Summary .......................................................................................................................4
2.
Objectives................................................................................................................................5
3.
Background .............................................................................................................................6
4.
Study Endpoints ......................................................................................................................9
5.
Study Intervention.................................................................................................................10
6.
Procedures Involved..............................................................................................................11
7.
Data Specimen Banking.........................................................................................................13
8.
Sharing of Results with Participants......................................................................................14
9.
Study Timelines .....................................................................................................................14
10.
Inclusion and Exclusion Criteria.........................................................................................14
11.
Vulnerable Populations .....................................................................................................15
12.
Local Number of Participants ............................................................................................15
13.
Recruitment Methods........................................................................................................15
14.
Withdrawal of Participants................................................................................................16
15.
Risk to Participants ............................................................................................................16
16.
Potential Benefits to Participants......................................................................................17
17.
Compensation to Participants ...........................................................................................18
18.
Data Management and Confidentiality .............................................................................18
19.
Provisions to Protect the Privacy Interest of Participants .................................................19
20.
Economic Burden to Participants ......................................................................................19
21.
Informed Consent..............................................................................................................19
22.
Setting................................................................................................................................20
23.
Resources Available...........................................................................................................20
24.
References.........................................................................................................................21

Protocol Title: Precision SomaSignal DM: Evaluating the Impact of SomaSignal Tests on Medical 
Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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1. Study Summary
Project Title
Precision SomaSignal DM: Evaluating the Impact of SomaSignal Tests 
on Medical Management and Change in Risk in Patients with Type 2 
Diabetes at Higher Risk of Cardiovascular Disease
Project Design
Single-center, 2 parallel-group study, with an open-label extension to 
evaluate SomaSignal test Informed Medical Management (Informed) 
versus Standard of Care (Uninformed).
Primary Objective
Primary Aim: 
To determine whether informing clinicians of the SomaSignal 
Cardiovascular Disease in Type 2 Diabetes Test (SSCVD) leads to 
changes in prescriptions and/or medical management of participants 
with T2D in concordance with SSCVD results over a 6-month 
period (Informed arm) when compared to participants whose physicians 
are not informed of the test results (Uninformed arm). 
Secondary Objective(s)
Secondary Aims:  

To evaluate longitudinal changes in the (i) SSCVD test 
results and (ii) conventional risk factors over 6 months in 
participants whose clinicians were informed vs. those 
whose clinicians were uninformed of the SSCVD results.  

To determine whether changes in the SSCVD results and 
conventional risk factors over 6 months relate to (i) 
baseline SSCVD risk category group and (ii) changes in 
treatment.  

To evaluate the health economic impact of precision risk-stratified 
treatment. 

To determine if the additional information provided by 
the SomaSignal Metabolic Factor tests to the Uninformed group 
at the end of 6 months provides useful information to the patient 
and the clinician.  
Research Intervention
SomaSignal Testing
Study Population
Individuals with T2D with or without cardiovascular disease.
Sample Size
450 participants
Study Duration for 
individual participants
6 months
Study Specific 
Abbreviations/ 
Definitions 
Cardiovascular (CV), Cardiovascular Disease (CVD), Type 2 Diabetes 
(T2D), SomaSignal Cardiovascular Disease in Type 2 Diabetes 
(SSCVD), Complete Blood Count (CBC), Comprehensive Metabolic 
Panel (CMP), Hemoglobin A1C (HBa1C), Cardioprotective (CP), 

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Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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Laboratory developed test (LDT), College of American Pathologists 
(CAP), Clinical Laboratory Improvement Amendments (CLIA)
Funding Source (if any)
SomaLogic, Inc
2. Objectives
Primary Aim: 
1. To determine whether informing clinicians of the SSCVD test results leads to 
changes in prescriptions and/or medical management of participants with 
T2D in concordance with SSCVD results over a 6-month period (Informed 
arm) when compared to participants whose treatment is not informed by SSCVD 
test results (Uninformed arm). 
Secondary Aims:  
2. To evaluate longitudinal changes in the (i) SSCVD results and (ii) 
conventional risk factors over 6 months in participants whose clinicians were 
informed vs. those whose clinicians were uninformed of the SSCVD test results 
(Uninformed arm).  
3. To determine whether changes in the SSCVD score and conventional risk factors 
over 6 months relate to (i) baseline SSCVD risk category group and (ii) changes 
in treatment.  
4. To evaluate the health economic impact of precision risk-stratified treatment. 
5. To determine if the additional information provided by the SomaSignal Metabolic 
Factor tests provide useful information to the patient and the clinician.  
Open Label Extension  
Aims: The open label extension phase will be conducted in participants randomized to 
Arm 2 only (Uninformed arm with participants and clinicians not receiving SomaSignal 
tests results until the end of the study). This phase is designed to gather additional 
information about the clinical utility of the SSCVD test along with the SomaLogic 
Metabolic Factors panel with 9 test results that reflect changes in: Liver Fat, Glucose 
Tolerance, Alcohol Impact, Cardiorespiratory Fitness/VO2 max, Resting Energy Rate, 
Body Fat Percentage, Visceral Fat, Lean Body Mass. After the 6-month trial period is 
completed, the clinicians will discuss results of the SomaSignal Tests with the 
participant and make any adjustments to the care plan as needed.  Medical treatment 
decisions and recommendations will be documented in a case report form.
3. Background
Despite the development of novel lipid lowering (1,2,3), anti-inflammatory (4,5), 
antithrombotic (6), dual antiplatelet (7) and anti-diabetic (8,9) treatments, cardiovascular 
disease (CVD) remains the leading cause of death and disability worldwide (10).  
In clinical practice, it has also been observed that the use of novel glycemia-
lowering therapies with cardioprotective features remains profoundly low (less than 10% 
of eligible patients) despite proven efficacy, professional society guideline endorsement, 
and regulatory labels for CV benefit (11). It has been proposed that such low uptake is 
more related to insurance type and coverage than to risk assessment (12). The overall 

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Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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prescribing deficiency seems particularly acute in individuals with T2D, where it has 
been described in 2021 as a “Call for action to the cardiology community” (11). 
While it can be easy to blame prescribing deficiencies on complacent physicians and/or 
over-frugal payors, SomaLogic believes there is more likely to be a fundamental 
problem with the cost and risk-effective allocation of such therapies, which are neither 
low in cost nor free of adverse events. As current clinical trials and guidelines tend to 
“bundle” patients together, there is an absence of individualized assessment of residual 
cardiovascular risk.  This leads to physicians, patients, and payors being relatively 
uninformed as to the need for and/or likely benefits of such therapies in an individual. 
Simply giving every eligible patient a drug regardless of residual risk would be 
unaffordable and would create adverse effects and costs for people at low residual risk 
who might not actually benefit from the drugs. 
This problem arises because traditional cardiovascular risk factors assess unresolved 
risk inadequately in vulnerable patients with high observed event rates (13-15) and 
benefits occur independently of traditional risk factors (4, 5, 16, 8, 16, 17) as do adverse 
drug effects (18). Additionally, physicians’ traditional empirical use of some therapies, 
which are effective for lipids, blood pressure and glycemic control is undermined by the 
insensitivity to improvements of many traditional cardiovascular risk factors (age, sex, 
race, T2D status and hypertension history) and imaging measures (calcium 
score, carotid, and coronary imaging). This is important because novel agents, such as 
sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor 
agonists (GLP-1 RA) or anti-inflammatory drugs like canakinumab, reduce 
cardiovascular risk independently of changes in these factors.  
To resolve this lack of precision in risk assessment, SomaLogic has performed the 
largest ever proteomic program to date with over 36,000 samples from 26,000 
participants in eleven clinical studies, for a total of over 180,000,000 protein 
measurements, to develop and validate a surrogate proteomic endpoint 
for cardiovascular outcomes. The SomaSignal Cardiovascular Risk (SSCVD) test, a 27-
protein model encompassing ten biologic systems. The SSCVD has been found to be 
robust for consistency over time, insensitive to interfering substances and to differences 
in sample quality. It is currently commercially available as a laboratory developed test 
(LDT) under CAP accreditation /CLIA certification from SomaLogic’s central laboratory 
in Boulder, CO. It is also in-use by several pharmaceutical companies in their clinical 
trials programs. 
The SSCVD test was validated in patients with T2D to predict the four-year likelihood of 
a composite endpoint of myocardial infarction, stroke, hospitalization for heart failure or 
death. Outcome prediction was consistent across morbidities, demographics, and 
geographic regions and superior to a clinical model using typical risk-factors and 
laboratory measurements in six validation datasets; the Net Reclassification Index (NRI) 
was +0.43, AUCs were 0.73 vs. 0.63 and c-statistic 0.71 vs. 0.62. Event rates in four 
defined risk categories, based on the SSCVD were 5.6%, 11.2%, 20.0% and 

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Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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43.4%. There are no risk calculators currently available specifically for a higher risk 
population, so SomaLogic developed a clinical model derived from the ASCVD risk 
score (Pooled cohort equation or PCE), scaled to a 4-year prediction, and calibrated to 
the higher event prevalence in a higher risk population (Manuscript submitted). 
The validation datasets were divided into quintiles based on event rates and compared 
the ratio of event rates from the highest risk quintile to the lowest risk quintile. The ratio 
of observed event rates from quintile 5 to quintile 1 was 7.8 for the 27-protein model and 
2.9 for the derived clinical model.  Table 1 shows the key results and comparisons 
with the PCE- derived clinical model using demographic, medical and laboratory 
measures, and how the SSCVD responds more consistently to changes in risk than any 
one of the common biomarkers of risk: 
Table 1: Prediction of major adverse events using the SSCVD test compared to conventional 
clinical assessment  
 
In summary, compared to the PCE-derived clinical risk factor model, the SSCVD has a 
superior dynamic range of stratification, a greater ability to find patients whose risks are 
under assessed by traditional risk factors, and an improved discrimination between 
patients with different risks. Compared to typical biomarkers that might be used to 
capture some of the benefits of these novel mechanistic drugs, it is more sensitive and 
more consistently responsive to changes in risk. Elevated cardiovascular risk was also 
correctly detected in non-cardiovascular conditions with known higher cardiovascular 
event rates including T2D, cancer, rheumatoid arthritis, and smoking. (Manuscript 
submitted)
Additionally, an in-silico assessment of protein-based risk stratification as a tool to 
identify patients who would most benefit from enhanced cardio-protection was 
performed in the archived samples and data from the EXSCEL study (19) of 
approximately 5000 participants with T2D. During the study, the random “drop-in” rate of 
additional novel cardioprotective-antidiabetic drugs (SGLT2i) was approximately 15%. 

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Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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When stratifying this population with the SSCVD test, the rate of predicted vs. observed 
events were found to be accurate (Table 2) (Manuscript in preparation).
Equally important, SGLT2i utilization reduced the cardiovascular event rates in the sub-
group at “high” risk defined by protein-based risk stratification when compared with 
those “high” risk sub-group who did not receive additional cardioprotective medications. 
Of note, the allocation of additional medications during the study showed no relation to 
protein risk prediction (i.e., physicians making these therapeutic decisions were 
unaware of actual residual risks).  
  
Table 2. 
 
Risk Bin 
Drop in CP 
Medication 
(%)* 
Observed 
Event Rate 
Hazard Ratio 
Log-estimated 
Hazard Ratio 
(HR)  
p-value 
(logHR) 
Yes = 17 
(14.8%) 
0% 
(N = 0) 
Bin 1 – Low 
Risk
(N = 115) 
No = 98 
(85.2%) 
7.14% 
(N = 7) 
0.000  
-18.274 
0.998 
Yes = 222 
(12.6%) 
9.01% 
(N = 20) 
Bin 2 – Medium 
Low Risk
(N = 1,759) 
No = 1,537 
(87.4%) 
9.63% 
(N = 148) 
0.940  
 
-0.062 
0.782 
Yes = 238 
(12.2%) 
14.7% 
(N = 35) 
Bin 3 –  
Medium High 
Risk
(N = 1,944) 
No = 1,706 
(87.8%) 
15.0% 
(N = 256) 
0.957  
-0.044 
 
0.790 
Yes = 162 
(11.7%) 
25.9% 
(N = 42) 
Bin 4 –
High Risk
(N = 1,387) 
No = 1,225 
(88.3%) 
32.8% 
(N = 402) 
0.712  
-0.340 
0.030* 
Table 2: SSCVD stratification and 4-year observed event rate in the presence/absence of drop- 
in medications in the EXSCEL trial.  
Note that the participants in the EXSCEL trial match the intended population to be recruited for this 
study. 
*The highest risk bin (Bin 4) had a statistically significant impact of therapy.
Median Follow-Up for the EXSCEL trial was 3.5 years, which is less time than the 4-year event prediction 
time horizon, so observed event rates are lower than predicted event rates.
Our overarching hypothesis is that the provision of precise, individualized protein-based 
cardiovascular risk assessment to the clinician and the patient results in risk-concordant 
prescription of guideline-based cardioprotective therapies in individuals with T2D, such 
that the patients with the highest residual risk are more likely to receive additional 
therapy than the patients at low risk. 
4. Study Endpoints

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Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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PRIMARY ENDPOINTS
1.
To determine whether informing clinicians of the SSCVD test results leads to 
changes in prescriptions and/or medical management of participants with T2D 
in concordance with SSCVD results over a 6-month period (Informed 
arm) when compared to participants whose physicians are not informed of 
the test results (Uninformed arm). 
SECONDARY ENDPOINTS
1. To evaluate longitudinal changes in the (i) SSCVD results and (ii) conventional 
risk factors over 6 months in participants whose clinicians were informed vs. 
those whose clinicians were uninformed of the SSCVD results.
2. To determine whether changes in the SSCVD score and conventional risk factors 
over 6 months relate to (i) baseline SSCVD risk category group and (ii) changes 
in treatment. 
3. To enable future health economic analyses of the impact of precision risk-
stratified treatment. 
4. To determine whether provision of the SSCVD test along with the SomaLogic 
Metabolic Factors panel with  8 test results that reflect changes in: Liver Fat, 
Glucose Tolerance, Alcohol Impact, Cardiorespiratory Fitness/VO2 max, Resting 
Energy Rate, Body Fat Percentage, Visceral Fat, Lean Body Mass to physicians 
whose participants are randomized to the Uninformed group after 6 months 
results in changes in participant management.   
Outcome Measurements:  
The following measurements will be made at baseline and after 6 (+/-1 months).  
Primary Aim 
Changes in prescription medications and lifestyle interventions 
Secondary Aims: 
(i) SSCVD test results at baseline and 6 months; 
(ii) change in CVD risk factors measured using laboratory assessments 
(Complete Blood Count (CBC), Basic Metabolic Panel (BMP), Hemoglobin A1C, 
Lipid panel), anthropometric measurements (height, weight and BMI), 
lifestyle/behavioral changes (smoking, diet and exercise) measured using 
questionnaires.  
(iii) Physician experience questionnaire 
(iv) Participant adherence: to their medications will be quantified using the 
medication possession ratio (# of scripts filled/# of months participants are script 
eligible).  
Blood will be frozen at -80 degrees C for future evaluation of biomarkers including 
metabolites and micro RNAs.
5. Study Intervention

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Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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Figure 1: 
All participating providers will be provided education and training on SomaSignal testing 
including how to interpret and educate participants on the results.  The documents used 
in this training are included in Appendix A.
Enrolment and Randomization: 
Eligible participants based on the inclusion/exclusion criteria will provide written 
informed consent. 
All participants in the Informed arm will be provided SSCVD test information. The 
Uninformed arm will receive both the SSCVD and SomaSignal Metabolic Factor test 
information at the end of 6 months.
Participants will be randomized to one of 2 arms of the study. Randomization will be 
stratified based upon the presence on CVD. 
Treatment Arm
Intervention
Arm 1: (SSCVD 
Informed)
SomaSignal 
Informed Medical 
Management 
SSCVD
Blood draw for SSCVD test at baseline and 6 months (±50 days).
SSCVD results will be sent to the providers and participants 
approximately 2-4 weeks after testing. 
Participants visit or are contacted by their physician up to 50 days 
after baseline testing to discuss treatment strategy (no changes, 
add/remove medications, lifestyle intervention, etc.) 

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Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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Medical records will be reviewed by the study team to evaluate 
changes in treatment strategy.
Participants will be called 2 weeks, 2 months, and 4 months (+/- 7 
days) after the baseline visit to ask if they are following the 
treatment strategy. 
Arm 2: (SSCVD 
Uninformed) 
Standard of Care 
where the provider is 
not informed of the 
SSCVD test results 
Blood draw for SSCVD test at baseline and 6 months (±50 days).
SSCVD results will not be provided to the provider or participant 
until the 6-month visit. 
Participants visit or are contacted by their physician up to 50 days 
after baseline testing to discuss treatment strategy (no changes, 
add/remove medications, lifestyle intervention, etc.) 
Medical records will be reviewed by the study team to evaluate 
changes in treatment strategy.
Participants will be called 2 weeks, 2 months, and 4 months (+/- 7 
days) after the baseline visit to ask if they are following the 
treatment strategy.
After the 6-month period is completed, the providers will discuss 
results of the SSCVD and SomaSignal Metabolic Factor tests 
(obtained during the Baseline and 6-month blood draws) with the 
participant and make any adjustments to the care plan as 
needed.  
Medical records will be reviewed by the study team to evaluate 
changes in treatment strategy.
6. Procedures Involved
Blood Draws: Blood samples (45 ml) will be collected either at an Emory or Grady site 
from participants in both arms of the study at Baseline and after 6 months (+/- 50 days) 
for the SSCVD test and CVD risk factors measured using laboratory assessments 
(Complete Blood Count (CBC), Basic Metabolic Panel (BMP), Hemoglobin A1C, Lipid 
panel). 
Blood samples for the SomaSignal tests will be shipped to SomaLogic for analysis and 
the results will be delivered to Emory using secure electronic means. Remaining blood 
will be frozen at -80 degrees C and stored at Emory for future evaluation of biomarkers 
including metabolites and micro RNAs.

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Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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Vital Signs
Participants in both arms of the study will have their vital signs taken and recorded at 
their Baseline and 6 month visits.
Questionnaires
Participants will be asked about their medications, family and medical history, and 
lifestyle.  These questionnaires may be administered in person or online via REDCap.
Medical Record Review 
Clinical Data Abstraction will occur from the baseline visit to the 6-month (+/- 50 days) 
study visit. 
Phone Visit
Participants will be called 2 weeks, 2 months, and 4 months (+/- 7 days) after the 
baseline visit to ask if they are following the treatment strategy. 
Clinician Intervention/s: 
All participating clinicians will be educated through materials and webinars provided by 
SomaLogic.

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Management and Change in Risk of Diabetic Patients at Higher Risk of Cardiovascular Disease
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Informed Arm: 
For participants randomized to the Informed arm, the SSCVD test results will be 
provided to the participant’s clinicians approximately 2-4 weeks after the baseline blood 
draw.  
Clinicians will discuss results with the participant and make adjustments to the care plan 
as needed based on the SSCVD test results within 50 days of receiving 
results. Clinicians may advise participants to (i) either change the doses of existing 
medications within existing guidelines, (ii) prescribe additional guideline-based 
medications, (iii) advise additional lifestyle interventions, or (iv) advise no change.  This 
information will be documented in the case report forms. 
This test is neither intended to diagnose cardiovascular disease (CVD) nor replace 
standard of care protocols for this disease.  The physician should not rely solely on this 
information to make a decision on the best course of action for this patient.
Uninformed Arm: 
Clinicians will provide standard of care based on routine test results and without 
the SSCVD results. 
SSCVD and SomaSignal Metabolic Factor Panel results from participants from both the 
baseline and 6-month period will be provided to the study team at the 6-month study 
visit. 
The SomaSignal Metabolic Factor tests include evaluation of Liver Fat, Glucose 
Tolerance, Alcohol Impact, Cardiorespiratory Fitness/VO2 max, Resting Energy Rate, 
Body Fat Percentage, Visceral Fat, and Lean Body Mass. 
Any recommendations made to the participant by the physicians, based on obtaining 
the aforementioned test results will be collected.  
7. Data Specimen Banking
Data obtained from this study will be shared with SomaLogic, Inc. as per the clinical 
research data sharing agreement that will be developed as a separate document, prior 
to the start of this study. If applicable, all shared data and/or biological samples will be 
de-identified as per the Privacy Rule of the NIH (National Institutes of Health, 2007) and 
in accordance with Emory policies.
In the event that SomaLogic, Inc. performs similar studies with other institutions, the 
data obtained during this study may be combined for internal future studies or a meta-
analysis as appropriate. Data generated as part of this study will not be shared outside 
Emory and SomaLogic, Inc., unless expressly agreed to in writing and with the proper 
regulatory and contractual approvals.

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Blood will be frozen at -80 degrees C and stored at in secure freezers in the Woodruff 
Memorial Research Building for future evaluation by Emory investigators of biomarkers 
including metabolites and micro RNAs.
All specimens and data will be identified with a study ID number.  Direct identifiers will 
not be attached to any records or samples.  Study data will be kept in a secure storage 
area or password-protected database.  Access to this database will be restricted by a 
database manager.  Only those members of the study staff listed on the delegation of 
authority log will have access to identifiers. 
De-identified study data and specimens may be shared with Emory and non-Emory 
investigators to help them study cardiovascular diseases.  Any future use of data and 
specimens for research must be authorized by the Principal Investigator and approved 
by an Institutional Review Board.  The research investigators involved in this study and 
in future studies and any other individual who may have access to the blood sample and 
its derivatives are not authorized to and are forever prohibited from using this material 
for any attempt at cloning a human being. 
Information that may be released to researchers may include, but is not 
limited to: medical information, age, gender, ethnic background, family history, imaging 
data, blood samples and blood sample products.  Identifiers, like names, addresses, 
and social security numbers, will not be released, except if patients need to be 
contacted again for specific purposes in new studies.  All efforts will be made to keep 
identifying information confidential.  
8. Sharing of Results with Participants
Clinicians in both arms of the study will receive results of participants’ routine lab tests 
and will share them with participants.  
 
 

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9. Study Timelines
Event
Screening and 
Blood Draw 1 
(Baseline -
1month)
Baseline Visit
Phone Visit 
2 weeks, 
2 months, 
4 months
Blood Draw 2
+ 6 months 
after Baseline 
Visit
Final Study 
Visit
Informed Consent
X
Inclusion/Exclusion 
Criteria
X
Medical History
X
Standard of Care Visit
X
X
Vital signs/exam
X
Review of Medical 
Record/Concomitant 
Medications*
X
X
X
X
Questionnaires
X
X
X
Laboratory Tests-CBC, 
BMP, Hb A1C, Lipid panel
X
X
SomaSignal Test (blood 
draw)
X
X
Treatment changes and 
reasons
X
X
Open Label Extension
X1
1only for the Uninformed group
*Review of Medical Record including concomitant medications will occur during the 
course of the study
10.Inclusion and Exclusion Criteria
Patient Inclusion Criteria 

Male and female participants 40 years and older 

Diagnosis of T2D (according to ADA guidelines)

Able to provide consent 
Eligible for (per drug label/guidelines) at least one of the following drug classes: 
SGLT2i, PCSK9i, GLP-1 RA and not currently prescribed any of these classes of drugs, 
or only prescribed PCSK9i.
Patient Exclusion Criteria 

Systemic Lupus Erythematous (SLE) 

Pregnancy (as determined by self-report) 

Intolerance or contraindication for use of GLP1RA, SGLT2i, and PCSK9i

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
History of, an active, or untreated malignancy, in remission from a clinically 
significant malignancy (other than basal or squamous cell skin cancer, in situ 
carcinomas of the cervix, or in situ prostate cancer) for less than 5 years prior to, 
or are receiving or planning to receive therapy for cancer, at screening 

Inability to understand English (Currently, SomaSignal testing information, 
guides, educational materials, and reports are only available in English.) 
11.Vulnerable Populations
Vulnerable populations will not be enrolled in this study.
12.Local Number of Participants
Screening up to 600 participants with a goal of enrolling 450 participants.
13.Recruitment Methods
Participants will be recruited from Emory and Grady clinic providers treating individuals 
with T2D. Participants will be contacted via email (if available) and telephone calls to 
inquire about their interest in study participation. For prospective participants that are 
unable to be contacted by email or telephone, an IRB approved opt-out letter will be 
sent to the participants address that is on file by the coordinating staff through the 
United States Postal Service.
Eligible participants will sign an informed consent form prior to any research activities. 
Participants’ eligibility will be determined by the Principal Investigator and/or authorized 
study team member.
Participants who have a treatment relationship with the participating providers and 
deemed to meet the eligibility criteria, will be screened for this study. The Principal 
Investigator and/or authorized study team member will review the participant's history 
and medical records. Data gathered will be used to evaluate the participant’s eligibility 
according to the inclusion and exclusion criteria. 
A participant-screening log will be maintained throughout the study. The log will record 
all participants considered for enrollment in the trial and indicate whether they were 
enrolled or not enrolled. In the case of non-enrollment, an explanation will be provided 
on the log as to the reason for their exclusion.
14.Withdrawal of Participants
Participants shall have the ability to withdraw consent for study participation, and/or 
withdraw the use of their clinical information and/or biological samples at any time, 
without penalty or loss of benefit to which the participant is otherwise entitled, by 
contacting the Principal Investigator or a designated member of his research team. This 

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must be done in writing and addressed to the Principal Investigator at the address 
indicated on the cover page of the Informed consent form.
If a participant enrolled in this study decides to withdraw from the research, or an 
Investigator decides to terminate his/her participation, study investigators must follow 
accepted standard practices regarding the management of collected data about these 
participants, as follows:
•
Investigators must document in the research record each instance of a participant’s 
withdrawal, including the reasons for the withdrawal, if known.
 •
Previously collected blood samples, information that has been gathered, and all 
material from the participant's identifiable blood samples that they have at the time of 
the participant's withdrawal from the study will remain in the study to maintain the 
integrity of the research, in accordance with current FDA regulations.
•
The investigator(s) may ask the participant whether he/she will agree to continued 
follow-up and further collection of clinical information following his/her withdrawal.
•
If the participant withdraws and does not agree to the continued follow-up and 
collection of clinical information, the investigator(s) will discontinue access to the 
participant’s medical record or other confidential records, for purposes related to the 
study.
•
Following the participant’s withdrawal from the study, the study team will no longer 
contact the participant nor have access to his/her medical records for research 
purposes (unless specific informed consent has been obtained as described above).
15.Risk to Participants

Blood draw- risks associated with phlebotomy include pain as the needle enters 
the participant’s vein and the risk of bruising at the site of blood draw have been 
minimized by using existing trained staff.  If a participant has a reaction to the blood 
draw, staff will follow standard clinical procedures.   

SomaSignal test: All participants are to receive at least standard of care regardless 
of their SomaSignal insights. 
o
A false positive risk prediction would lead to potential prescription of a drug 
that the participant might not need; given that participants across the risk 
spectrum were included in the pivotal clinical trials for registration of the 
drugs, this is unlikely to lead to novel consequences not already observed 
in those studies – the most likely outcome is that the increment of benefit is 
small and not cost effective
o
A false negative risk prediction would lead to the avoidance of a prescription 
of a drug that the participant actually does need. Given that the participants 
are already eligible for these drugs but not taking them, this is at least no 
worse than the current standard of care. 

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
Breach in confidentiality- risk of inadvertent disclosure of PHI. Study Information 
sent from Emory to SomaLogic will be sent using a unique study ID such that the 
participant cannot be identified: site, age, and gender are not enough to identify 
these individuals.  SomaLogic will not have access to the study ID and participant 
name as that will be maintained within Emory. In the event of a breach, HIPAA 
reporting requirements will be followed.
16.Potential Benefits to Participants

Likely benefits to the participant:
o
Improved health outcomes in the subset of participants who have residual 
risk based on the SSCVD test that they were previously unaware of, and 
who may receive treatment with a drug or additional lifestyle intervention 
they were previously eligible for but were not undertaking at the start of 
the study

While this is likely to be manifest earlier in the informed group than 
in the uninformed group, the latter will ultimately be informed at the 
end of the 6-month study period

Participants in the low-risk group, based on the SSCVD test who do 
not receive any change in management will receive knowledge of 
their low-risk status 

Potential benefits:
o
Increased participant engagement and satisfaction from increased 
personalized medical knowledge 
o
Potential for increased participant recruitment and retention from offering 
cutting-edge innovation and technology
o
More efficient resource allocation and improved cost-effectiveness of 
pharmaceutical interventions through enhanced participant risk 
stratification 
o
Improved patient outcomes through personalized risk stratification, more 
precise clinical care, and improvements in triage of medical interventions 
and education 

Expanded research opportunities through providing participant proteomic 
measurements to Emory researchers
17.Compensation to Participants
Participants will receive $50 for each blood draw visit to compensate them for travel and 
parking. If participants complete both blood draws they will receive $100 total.
For participants that meet inclusion criteria into the study and require travel 
accommodations to and from Emory University, Grady Memorial Hospital and 
participating sites, contracts with Uber and Lyft have been negotiated to help 

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participants get to and from their appointments.  A study team member will help the 
participant set up and execute this task. 
18.Data Management and Confidentiality
A duly assigned study team member will perform primary data collection, drawn from 
review of source- documents (hospital charts) and from on-going study procedures. 
Some specific data for this study will be collected on a simplified Case Report Form 
either hardcopy or electronic.
Participants will receive a unique study identification (ID) number such that the 
participants’ identifiable information will be held separate from the main study database, 
using standard practices to protect participant confidentiality. This study ID number, with 
the participant gender and date of birth, will be included on the blood tube for the 
SomaSignal assay, as well as SomaSignal report.
Data will be stored in a secure, HIPAA-compliant electronic study database. Only 
SomaLogic, Inc. and study team from Emory will have access to this secure database. If 
data is shared with any other external collaborators, as described in the consent form, it 
will be de-identified and study ID numbers will not be included.
Data will be archived by SomaLogic, Inc. for 15 years and will be destroyed at the end 
of that time, in accordance with company policies. Destruction will include any paper 
documents as well as the electronic database.
Every precaution will be taken to protect the privacy of research participants and the 
confidentiality of their personal information. The Principal Investigator and his/her study 
team will maintain all participants’ information in accordance with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA) and Emory’s guidelines for 
compliance and privacy.
19.Provisions to Protect the Privacy Interest of Participants
 The study team will only collect participants’ personal information as described in the 
protocol. Study data will be kept in a secure storage area or password-protected 
database.  Access to this database will be restricted by a database manager.  Only 
those members of the study staff listed on the delegation of authority log will have 
access to identifiers.
To ensure privacy, participants’ data and samples will be identified with a study ID 
number.  The code linking participant identifiers to the study ID number will be kept in a 
separate password-protected file with access limited to the PI and a few members of the 
study staff.

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Participants will be informed that their participation in the study is voluntary and they are 
free to withdraw from the study at any time. Participants can refuse to answer any 
questions or have any procedures that make them uncomfortable. 
The study team will request a partial HIPAA waiver for identifying potential participants 
and determining eligibility.
20.Economic Burden to Participants
Participants will not have to pay for any of the research procedures in this study.
21.Informed Consent 
The study team will obtain written informed consent from participants prior to performing 
any study procedures.

Consent will be obtained in a private office, clinic or hospital room or via Zoom 
video conference or phone call using Docusign.

Prior to the first study visit, a member of the study staff will fully explain the study 
to participants either in-person or via an Zoom video conference or phone call.  
Participants will be given a copy of the consent form or it may be mailed or 
emailed via encrypted email to the participant prior to the consent discussion.  
Participants will be given time to read the approved informed consent form (ICF) 
and ask questions about the study prior to signing the consent form.

If there has been a substantial change to the research since the time of the 
original consent, such that research participation may no longer be consistent 
with the participant’s preferences and interests and the participant may need to 
reconsider the decision. If this occurs the tchanges to the study will be explained 
to the participant prior to their next scheduled study visit and they will be asked to 
sign a new consent form.

Members of the study team who may be involved in the consent process include 
the principal investigator, research coordinators, co-investigators, and research 
fellows.

Before enrollment, each prospective patient will be given a full explanation of the 
study.  The participant will be allowed to read the approved ICF and have any 
questions answered. Once the investigator is assured that the patient 
understands the implications of participating in the study, the participant will be 
asked to give consent to participate in the study by signing the ICF.

To minimize the possibility of coercion or undue influence, the person conducting 
the informed consent discussion will not be the participant’s usual healthcare 
provider.  Participants will be given the opportunity to read the consent form and 
discuss the research with family and friends before signing.

To determine capacity to consent, the participant will be asked a series of 
questions about the research to assess his/her understanding or the study 
procedures and potential risks.

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22.Setting
Potential participants will be recruited from outpatient cardiology, diabetes, and primary 
care clinics at Emory University Hospital (EUH), Emory University Hospital Midtown 
(EUHM), Emory Saint Joseph’s Hospital (ESJH), and Grady Memorial (GMH) hospitals 
and at Emory Clinic (EC) locations
Research procedures will be performed in private research/clinic rooms at EUH, EUHM, 
ESJH, GMH, EC and the Woodruff Memorial Research Building (WMB).
23.Resources Available
A Clinical Research Coordinator will be allocated to recruit participants and conduct 
study procedures. He/she will be assisted by Cardiology Research Fellows.  Other 
study staff will assist with the identification of potential participants, chart review and 
data entry. The study team has approximately 800 square feet of dedicated research 
space in 5 rooms in the Woodruff Memorial Research Building (WMB) with 3 beds and 2 
recliners available.  In Emory University Hospital (EUH), there are 2 research exam 
rooms and 3 offices available to conduct study visits.
It is not anticipated that additional medical services will be needed as a result of the 
research. If necessary EUH is a state-of-the-art, acute-care hospital that includes 
cardiac care, surgery, and 24/7 emergency services. The WMB is directly adjacent to 
EUH and is equipped with defibrillators.  Additionally, study staff are trained in Basic Life 
Support. 
All study staff will be trained on the protocol prior to study initiation.  Documentation of 
training and qualifications will be maintained in the study regulatory binders. The 
Research Manager will oversee the day-to-day activities of the coordinators/study 
nurses and other members of the study staff. The PI meets meet regularly with all 
personnel to review the progress of the study and communicate with them as needed to 
monitor adverse events and provide timely updates on changes to the protocol or 
procedures.
24.References
1. D. L. Bhatt et al., Cardiovascular Risk Reduction with Icosapent Ethyl for 
Hypertriglyceridemia. The New England journal of medicine 380, 11-22 (2019).
2. M. S. Sabatine et al., Evolocumab and Clinical Outcomes in Patients with 
Cardiovascular Disease. The New England journal of medicine 376, 1713-1722 (2017)

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3. R. S. Rosenson et al., Evinacumab in Patients with Refractory Hypercholesterolemia. 
The New England journal of medicine,  (2020).
4. P. M. Ridker et al., Antiinflammatory Therapy with Canakinumab for Atherosclerotic 
Disease. The New England journal of medicine 377, 1119-1131 (2017)
5. J. C. Tardif et al., Efficacy and Safety of Low-Dose Colchicine after Myocardial 
Infarction. The New England journal of medicine 381, 2497-2505 (2019)
6. J. W. Eikelboom et al., Rivaroxaban with or without Aspirin in Stable Cardiovascular 
Disease. The New England journal of medicine 377, 1319-1330 (2017).
7. M. P. Bonaca et al., Long-term use of ticagrelor in patients with prior myocardial 
infarction. The New England journal of medicine,  (2015)
8. S. L. Zheng et al., Association Between Use of Sodium-Glucose Cotransporter 2 
Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With 
All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-
analysis. JAMA 319, 1580-1591 (2018).
9. K. H. Sheahan, E. A. Wahlberg, M. P. Gilbert, An overview of GLP-1 agonists and 
recent cardiovascular outcomes trials. Postgrad Med J 96, 156-161 (2020).
10. D. S. Dhindsa, P. B. Sandesara, M. D. Shapiro, N. D. Wong, The Evolving 
Understanding and Approach to Residual Cardiovascular Risk Management. Front 
Cardiovasc Med 7, 88 (2020)
11. A. J. Nelson et al. Incorporating SGLT2i and GLP-1RA for Cardiovascular and 
Kidney Disease Risk Reduction; Call for Action to the Cardiology Community. 
Circulation 144;74-84 (2021). 
12. G. P. Hess, P. Natarajan, K. F. Faridi, A. Fievitz, L. Valsodottir, R. W. Yeh. 
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Therapy; Payer approvals and 
rejections and patient characteristics for successful prescribing.  Circulation 136; 00-00; 
2017
13. R. L. Coleman, R. J. Stevens, R. Retnakaran, R. R. Holman, Framingham, SCORE, 
and DECODE risk equations do not provide reliable cardiovascular risk estimates in 
type 2 diabetes. Diabetes Care 30, 1292-1293 (2007)
14. J. E. Dalton et al., Failure of Traditional Risk Factors to Adequately Predict 
Cardiovascular Events in Older Populations. J Am Geriatr Soc 68, 754-761 (2020)
15. I. J. Dahabreh, D. M. Kent, Index event bias as an explanation for the paradoxes of 
recurrence risk research. JAMA 305, 822-823 (2011)

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16. D. Fitchett et al., Empagliflozin Reduced Mortality and Hospitalization for Heart 
Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME 
Trial. Circulation 139, 1384-1395 (2019)
17. P. Ganz, R. Deo, R. F. Dubin, Proteomics for personalized cardiovascular risk 
assessment: in pursuit of the Holy Grail. European heart journal,  (2020).
18. S. A. Williams et al., Improving Assessment of Drug Safety Through Proteomics: 
Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of 
Torcetrapib. Circulation 137, 999-1010 (2018)
19. Holman RR et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in 
Type 2 Diabetes. NEJM 377:1228-1239 (2017).
20. Cardiovascular Disease and Risk Management: Standards of Medical Care in 
Diabetes – 2021. Diabetes Care 2021:44 (suppl 1):5125-5150.

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Appendix A
Provider Education and Training Materials are attached as a separate file.  See Emory 
University Provider Education Deck_15Sep2021.