Investigator Studies Program (MISP)

Clinical Protocol Template

Requirements for Submitting a Full Clinical Protocol

Section #1 - MISP Protocol Identification

Assessment of Guideline Directed Medical Therapy Adherence in Heart Failure Patients
Study Title: with Reduced Ejection Fraction (HFrEF) and Residual Risk to Worsening Heart Failure: A
retrospective review of EHR at two large US academic health systems

Request Date:
April 12, 2023

Institution Name Duke University Health System

Investigator Contact
Information:
- Full ad- Marat Fudim
dress 40 Duke Medicine Cir Clinic 2F/2G, Durham, NC 27710
- Phone Tel: 917-544-4377
No. Fax: 919-681-7177
- Fax No. email: Marat.fudim@dm.duke.edu
- E-mail

MISP Template: Clinical Protocol 1 Version: JAN2023

 Section #2- Core Protocol

2.1 List the objectives.

The primary objective of this study is to determine the adherence of

HFrEF patients to GDMT over a two year period following their initial di-
agnosis. Since adherence to GDMT is a critical component to reducing
morbidity and mortality and improving quality of life for patients with
HF, it is essential for clinicians to better understand the realities of ad-
herence for patients in a real-world clinical setting.

The secondary objective of this study is to identify patients who have

residual risk for worsening HF (WHF) despite GDMT and to character-
ize any findings in this subset of patients that might be the target of ad-
ditional research and medications. In particular, we wish to identify pa-
tients who are being treated with GDMT and an sGC medication, such
as vericiguat, to determine if the addition of this medication has a sig-
2.1 Objectives & Hy- nificant impact on improving residual risk to WHF over a two year pe-
potheses riod following initiation of therapy.
2.1.1 List the clinical hypotheses.

We hypothesize that overall adherence to GDMT will be much lower

than anticipated, with certain subsets of patients at greater risk for be-
ing denied or delayed access to GDMT, and others who may be unable
to continue GDMT despite early initiation of treatment. When we com-
pare clinical outcomes between these patients, we expect to see signif-
icant differences between patients with continued adherence to GDMT
and those without with regard to WHF and mortality. Ultimately, this
study will characterize GDMT adherence in HFrEF patients over a two
year period, and its subsequent impact on clinical outcomes, including
hospitalizations, complications, and mortality. We additionally hypothe-
size that patients who are treated with GDMT and the addition of an
sGC will have overall lower rates of WHF and improved outcomes in
mortality. The findings from this study have the potential to inform in-
terventions aimed at patients with residual risk for WHF despite
GDMT.

MISP Template: Clinical Protocol 2 Version: JAN2023

 Heart failure (HF) remains a significant burden on healthcare systems and pa-
tients worldwide, with an estimated prevalence of 26 million globally. In the
United States, HF affects approximately 6.2 million individuals. With an aging
population and an increase in prevalence of co-morbidities and risk factors, it
is projected that number will be 8 million by the year 2030 [1]. HF is a associ-
ated with a high risk of morbidity and mortality, and as a result is a leading
cause of hospitalizations in the US, with an estimated annual cost of over $30
billion [2].

HF with a reduced ejection fraction (HFrEF) constitutes roughly half of all

cases of HF, and guideline-directed medical therapy (GDMT) has been shown
to significantly improve outcomes in this subset of patients [3]. GDMT in-
cludes the use of four classes of medications: renin-angiotensin-aldosterone
2.2 Background & system inhibitors (RAAS-I), β-blockers, mineralocorticoid-receptor-antago-
Rationale, Signifi- nists (MRA), and recently, the addition of SGLT2 inhibitors.
cance of Selected
Topic & Preliminary GDMT has been shown to extend the lifespan of patients with HF by six years
Data
[4] in addition to improving their overall quality of life. However, there re-
mains a subset of patients who continue to have worsening heart failure
(WFH) despite treatment with GDMT. Recently, a class of drugs known as
soluble guanylate cyclase (sGC) stimulators has shown promise in the treat-
ment of heart failure. In particular, the sGC stimulator vericiguat has shown to
reduce the risk of cardiovascular death in patients with HFrEF [5].

There remains a critical need to better understand the prevalence of GDMT

adherence amongst HFrEF patients in the US outside of randomized con-
trolled trials (RCT). Furthermore, assessing the real-world adherence to
GDMT and its impact on clinical outcomes is crucial since evidence outside of
randomized controlled trials is limited. Finally, by identifying patients with
residual risk to WHF, despite treatment with GDMT, it provides opportunities
for further research and exploration of new medications, such as sGC stimula-
tors, that can improve outcomes in these patients.

MISP Template: Clinical Protocol 3 Version: JAN2023

 This retrospective observational study will evaluate the adherence of
HFrEF patients to GDMT over a two-year period following their initial
diagnosis, and its subsequent impact on clinical outcomes, including
hospitalizations, complications, and mortality.

The study will be conducted using Electronic Health Record (EHR)

data from patients at the Duke University Health System and two other
academic health systems over a four-year period from 2020 to 2024
and will be governed by an IRB approved protocol.

Using EHR data, this study will identify a cohort of patients newly diag-
nosed with HFrEF, meeting criteria for Stage C HF with a left ventricu-
lar ejection fraction (LVEF) of <40% who present at one of our study
sites between January 1, 2019 and December 31, 2020.

2.3 Study Design Data from the EHR will be collected over the following two years and
analyzed for medication (including dates when GDMT was initiated),
subsequent hospitalization, and clinical outcomes. For the purpose of
this study, we will define worsening heart failure (WHF) as any patient
on GDMT for three months who has an admission for a HF-related hos-
pitalization or admission for IV-diuretic therapy at any point in the dura-
tion of the study.

Additional patient data, including patient demographics, medications,

other diagnoses, hospitalization due to heart failure, changes in LVEF,
all-cause mortality, and cardiovascular mortality, will also be collected
and analyzed to determine patient outcomes, and to fulfill our sec-
ondary objectives.

Clientic software will be used to access, curate, and analyze data for
this study.

MISP Template: Clinical Protocol 4 Version: JAN2023

 To address the question of diversity in access and inclusion, this study
will collect data from two large academic health systems in the United
States, which will ensure representation of patients from diverse racial,
ethnic, and gender backgrounds, as well as different age groups. By in-
cluding all patients who meet the inclusion criteria regardless of race,
gender, ethnicity, or age, this study will provide real-world data that re-
flects the diversity of the patient population affected by heart failure.
This study will help address the issue of disparities in access to guide-
line-directed medical therapy (GDMT) in heart failure patients with re-
duced ejection fraction (HFrEF) by identifying patient subgroups that
may be under-treated or at risk of not receiving guideline-directed med-
2.4 Diversity & Inclu- ical therapy due to demographic and socio-economic factors. Under-
sion standing GDMT adherence in real-world settings, including how it may
vary by age, race, ethnicity, and gender, will help identify potential bar-
riers to adherence and inform targeted interventions to improve adher-
ence among diverse patient populations.
Overall, this study has the potential to improve the care of heart failure
patients by providing real-world data on GDMT adherence and its im-
pact on clinical outcomes, including the potential to extend lifespan and
improve quality of life. By including patients from diverse backgrounds,
this study will provide a more representative understanding of GDMT
adherence in the US and may help address disparities in access to
care.

This is a retrospective analysis of electronic health records, so while

we will not directly involve patients or patient advocates, our study de-
sign will take into consideration Patient Centered Outcomes Research
2.5 Patient Engage-
(PCOR) methods to guide the analysis and interpretation of our results.
ment We are committed to a research approach that values the perspectives
and needs of patients in the research process, and above all prioritizes
patient privacy and confidentiality at every stage of the research
process.

MISP Template: Clinical Protocol 5 Version: JAN2023

2.6 Study Flowchart

MISP Template: Clinical Protocol 6 Version: JAN2023

 After developing an IRB protocol, Clinetic will perform a feasibility anal-
ysis with Merck and Dr. Fudim (PI) from Duke University and together a
second site will be selected.

Once the site has been selected, Clinetic will work with Dr. Fudim and
Merck to design the Clinetic dashboard used to collect the data and es-
tablish the EHR data feeds.

Clinetic is a health technology company harnessing the potential of

Electronic Health Record (EHR) data to accelerate clinical research
and evidence generation. Clinetic has developed a software platform
to help sites and sponsors streamline clinical research. Our technology
connects to data from the EHR, curates these data inside health sys-
tems, and provides tools to assist with study planning and execution.
Clinetic has specialized expertise in accessing and surfacing deep clin-
ical insights from EHR data. Our platform enables investigators to bet-
ter characterize patient populations and monitor clinical trends ulti-
mately helping generate a growing number of real-world data publica-
tions.

Clinetic has established a growing network of 10 academic health sys-

2.7 Study Proce- tems representing more than 65 hospitals and 2,300 care locations
dures across 12 states. Clinetic collaborates with clinical experts at these in-
stitutions who understand the context of clinical data elements and how
to apply them to address specific research questions. We pair this clin-
ical understanding with technology and data science experts who read-
ily tackle the challenges associated with complex, messy data.
Clinetic was built with data security and patient privacy top of mind.
Our software is designed to keep all identified and protected health in-
formation behind the health system firewall. We are SOC2 Type 2 cer-
tified which means we have standard operating procedures for organi-
zational oversight, vendor management, risk management, and regula-
tory oversight. We are HIPAA compliant, support single sign on, and
enable identity provider service (IdP) integrations to help ensure that
only authorized personnel within the health system are accessing rele-
vant data.

Clinetic has master research agreements in place with academic health

systems including Duke and can efficiently contract across institutions
for multi-site observational real-world data studies. Additionally, the
Clinetic software platform is already installed behind the firewall at
Duke and several other academic health systems and there is a clear
pathway to connect to the structured and unstructured EHR data re-
quired for this study.

2.8 Study Duration 18 months

MISP Template: Clinical Protocol 7 Version: JAN2023

 The sample size for this study will be largely determined by the number of pa-
tients who present to one of our three health systems with an incident HF di-
agnosis with a LVEF<40%. Statistical power calculations will be performed by
a statistician at Duke University and will be based on the number of patients
identified in the incident HFrEF database. Multivariable analysis will be used
to compare outcome measurements with adherence, and to identify subsets
of patients (based on demographics, medications, co-morbidities) who are at
residual risk for worsening heart failure and adverse outcomes.

We will use statistical methods such as propensity score matching and re-
gression analysis to compare outcomes of patients who received vericiguat
with those who did not.

Duke University Health System is one of the largest health systems in the
southern United States and has over 4.7 million patient encounters each year
between their Emergency Department, inpatient, and outpatient clinics. The
other site has not been selected, but the aim will be to choose one other large
academic health center such as Jefferson Health who serve between1-2 mil-
lion patients each year.

The sample size for this study will be heavily determined based on our pri-
mary endpoint, which is to determine the adherence of HFrEF patients to
GDMT over two years. Past studies have shown that adherence to all medi-
2.9 Statistical Analy-
sis and Sample Size
cations in GDMT at suggested efficacy dosages has ranged anywhere from
Justification 1% in some studies to as high as 23%, with some medications (like beta-
blockers) having adherence rates of close to 70%.

In order to keep a confidence interval of 95%, even if our proportion of adher-

ent patients was 70% (which is well-beyond what we expect), our needed
sample size would be 384 patients.

For our secondary objectives, including whether addition of verciguat to

GDMT has an impact on improving outcomes, including residual risk for WHF
such as all-cause mortality, we will use power analysis of all-cause mortality
as reported in the VICTORIA trial. The effect size of vericiguat on mortality
was reported to be a hazard ratio of 0.90 (95% CI 0.82-0.98) in the VICTO-
RIA trial.

Assuming a 2-sided alpha of 0.05, a power of 80%, and a 10% loss, we will
need a total sample size of 416 patients to detect a hazard ratio of 0.90 with a
statistical significance.

By collecting data at two large US academic institutions over two years, we

hope to include at least 416 patients in our study. We anticipate that the sam-
ple size will be sufficient to detect differences in both primary and secondary
endpoints.

2.10 Specific Drug

This is a retrospective analysis of electronic health records, and will not
Supply Require-
ments require a drug supply.

MISP Template: Clinical Protocol 8 Version: JAN2023

 This is a retrospective analysis of EHR, no specific safety data will be
collected. However, we will ensure that all data is collected in line with
2.11 Adverse Experi-
ence Reporting
IRB guidelines for maximum patient safety of all protected health infor-
mation. Any breach in patient safety will be reported directly to the PI
who will confer with the IRB per all recommendations.
IRB costs for two sites - $11,000.00
Other startup costs- $5,000.00
PI Salary- $21,500.00
Sub-PI Salary- $21,500.00
2.12 Itemized Study Statistician Salary- $40,000.00
Budget Project Manager - $30,000.00
IT Data Specialist (2)- 36,000.00
Data Engineer- $60,000.00
Overhead 33%- $74,250.00
TOTAL: $299,250.00

1.Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of
heart failure in the United States: a policy statement from the American
Heart Association. Circ Heart Fail. 2013;6:606–619.

2. Benjamin EJ, Blaha MJ, Chiuve SE et al. Heart Disease and Stroke
Statistics-2017 Update: A Report From the American Heart Associa-
tion. Circulation 2017;135:e146-e603.

3. Heidenreich PA et al. 2022 AHA/ACC/HFSA Guideline for the Man-

agement of Heart Failure: A Report of the American College of Cardiol-
ogy/American Heart Association Joint Committee on Clinical Practice
2.13 References Guidelines. Circulation. 2022 May 3;145(18):e895-e1032.

4. Vaduganathan M, Claggett BL, Jhund PS, et al. Estimating lifetime

benefits of comprehensive disease-modifying pharmacological thera-
pies in patients with heart failure with reduced ejection fraction: a com-
parative analysis of three randomised controlled trials. Lancet
2020;396:121–8.

5. Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in Patients

with Heart Failure and Reduced Ejection Fraction. N Engl J Med.
2020;382(20):1883-1893.

We plan to submit a manuscript within six (6) months of the study to

2.14 Publication Plan the Journal of the American College of Cardiology, JAMA- Internal
Medicine, and Circulation.
2.15 Curriculum Vi-
tae
CV submitted for Marat Fudim, MD, MHS, FACC, FAHF

2.16 Protocol Sub-

mission for Investi-
Protocol submitted online

MISP Template: Clinical Protocol 9 Version: JAN2023

gator-Initiated Stud-
ies

MISP Template: Clinical Protocol 10 Version: JAN2023