Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04633005 |
| Other study ID # |
UTexasSouthwestern |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Early Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
November 15, 2021 |
| Est. completion date |
December 1, 2025 |
Study information
| Verified date |
January 2024 |
| Source |
University of Texas Southwestern Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Heart failure with a reduced ejection fraction (HFrEF) represents a significant public health
burden in the United States, with a growing prevalence particularly among African Americans
and Hispanic Americans and individuals of low socioeconomic status (SES). Although effective
therapies exist, gaps in their uptake contribute substantially to the excess burden of heart
failure. The "polypill" is an inexpensive once daily pill containing three agents proven to
improve morbidity and mortality in heart failure and represents potential strategy for
increasing the utilization of proven HF therapies. The proposed study is a pragmatic,
single-center, randomized trial to test the feasibility and effectiveness of a polypill-based
strategy for the treatment of HFrEF in a low-income, racially diverse population.
Description:
Heart failure poses a major public health challenge in the United States. It affects more
than 6.2 million people and is the leading cause of hospitalization among older adults, with
a growing prevalence among Black, Hispanic, and low-income populations.
Despite advances in the treatment of heart failure, the associated morbidity and mortality
remain high. From the time of heart failure diagnosis, survival is approximately 50% at
5-years and 10% at 10-years.8 Improved mortality and hospitalization rates have been observed
due to the advent of mortality-reducing HFrEF therapies and earlier diagnosis. Nonetheless,
substantial gaps in the uptake of guideline-directed medical therapies (GDMT) exist. GDMT,
which include beta-blockers (BB), angiotensin converting enzyme inhibitors (ACEI),
angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA), have
been demonstrated to reduce all-cause mortality by > 50% when used in combination.
Nonetheless, fewer than 25% of eligible patients currently receive these medications at any
dose, with socially disadvantaged groups having the lowest rates of utilization.
The polypill is an alternative management strategy. The polypill combines multiple
evidence-based medications in a single pill, which reduces pill burden and improves
adherence. Therapy with multiple medications can be conveniently initiated at an early stage
of disease, increasing the overall therapeutic benefit accrued over time. This is
particularly relevant in settings where patients experience barriers to care due to high cost
burden with copays associated with medication initiation, frequent lab tests, and need for
multiple follow up visits.
Polypills have been shown to be feasible and effective in multiple settings, including in the
prevention and treatment of cardiovascular disease (CVD). They have been well tolerated and
additionally demonstrate significant improvements in adherence when compared to usual
therapies in randomized control trials. However, no randomized trial to date has evaluated a
polypill strategy for the treatment of heart failure, a condition in which pill burden and
adherence pose substantial challenges to management.
The proposed study is a single-center, randomized trial to test the feasibility and
effectiveness of a polypill-based strategy for the treatment of HFrEF (EF ≤40%) in a
low-income population. The setting for our proposed study is Parkland Hospital in Dallas,
Texas, a large county hospital that serves a racially diverse, uninsured population. We will
utilize 4 distinct polypill formulations to allow for up-titration of the beta-blocker
component of the polypill. The pill will contain spironolactone 12.5 mg, empagliflozin 10 mg,
and 25 mg, 50 mg, 100 mg, or 150 mg of metoprolol succinate. The once-daily polypill will be
added to baseline therapy with a renin-angiotensin system antagonist (ACEI, ARB, or ARNI).
We hypothesize that use of a polypill-based strategy in HFrEF will be feasible and lead to
improved left ventricular systolic function and lower circulating NT-pro BNP levels compared
with usual care. These hypotheses will be tested in the following aims:
Primary Aim: To determine whether the use of a polypill for HFrEF leads to higher left
ventricular ejection fraction (LVEF) compared with usual care in a low-income population. We
will randomize 175 HFrEF patients who are not on optimal guideline-directed medical therapy
to a polypill-based strategy versus usual care for 12 months. The primary endpoint will be
the change in LVEF, obtained by cardiac MRI (CMR). CMR provides the greatest accuracy and
reproducibility of the non-invasive cardiac imaging modalities.
Secondary Aim: To determine whether the use of a polypill for HFrEF leads to lower
circulating NT-proBNP levels compared with usual care in a low-income population. Changes in
circulating NT-proBNP concentrations from baseline to 12-months will be compared in
participants
The primary endpoint is the change in LVEF over 12 months, based on prior studies
demonstrating measurable changes in systolic function and cardiac biomarkers within 6 to 12
months of treatment with GDMT. LVEF will be assessed using cardiac MRI at baseline and the
end of the study period. We hypothesize that polypill use will be associated with greater
improvement in LVEF compared with usual care.Key secondary endpoints will include NT-proBNP,
a serum marker of neurohormonal stress, and a well-validated surrogate endpoint for HF
trials. NT-proBNP levels have been associated with short- and long-term clinical outcomes for
all stages of HFrEF and receive a class I, Level of Evidence A recommendation for diagnosis
and assessment of prognosis in clinical HF guidelines.Prior trials have demonstrated more
than a 2-fold increased risk of in-hospital mortality associated with NT-proBNP levels in the
highest vs. lowest quartile, and associations of NT-proBNP levels with 1-year mortality and
illness course when measured serially. NT-proBNP levels respond to GDMT, with significant
reductions in levels accompanying the use of beta-blockers, ACEI/ARB, MRA, and SGLT2i in 6 to
12 months post-initiation of therapy. Other secondary endpoints of interest include adherence
to GDMT, as assessed by MMAS-8 score and pill count, quality of life assessed using the
Kansas City Cardiomyopathy (KCCQ) Questionnaire, and 6-minute walk distance (6-MWD).
The trial will be led by study investigators from the University of Texas Southwestern with
joint appointments within the Parkland Health and Hospital System. The proposal builds on the
team's prior experience conducting clinical trials of cardiovascular therapies in low-income,
diverse populations. The trial can be performed efficiently and cost-effectively within the
Parkland Health and Hospital System.
After securing permission from the clinical director and providers within the Parkland Health
and Hospital System and Parkland Cardiology Clinic, the study team will begin active
screening for patients with new diagnosis of heart failure within the Parkland Cardiology
Clinic and inpatient Parkland Cardiology service. We will enroll adults age ≥18 years with de
novo or chronic HFrEF (LVEF ≤ 40%) with recent hospitalization or outpatient visit at
Parkland who are not on optimal GDMT. De novo HFrEF will be defined as new-onset HFrEF with
hospitalization for HF or outpatient diagnosis with 90 days of screening. Chronic HFrEF will
include patients with a known diagnosis of HFrEF for more than 3 months.
To achieve the target enrollment, the study team will enroll participants during inpatient
hospitalization and from outpatient clinics. Patients will be started on the polypill prior
to discharge or at the first outpatient visit after heart failure hospitalization. In both
settings, the polypill will be substituted for the individual component medications, with
other medications continued as prescribed. The team will include a study coordinator with
extensive experience performing clinical trials at Parkland Health & Hospital Systems. The
team will perform pre-screening using EHR data after obtaining permission from the Parkland
inpatient and clinic heart failure attendings. Patients deemed eligible for participation
will be contacted prior to discharge from their HF hospitalization or at the time of their
initial visit to cardiology clinic following discharge. Patients will be informed about the
study, its goals, and the risks and benefits of participating, and will be invited to
participate. Potential participants will be asked to fill out a questionnaire seeking
information on medication use, health status, and on the characteristics to assess potential
eligibility. Eligible participants may also be identified based on review of the EHR
post-discharge and will be contacted through an introductory letter and pre-screening
questionnaire. . Based on our initial experience, we estimate that we will need to contact
700 patients over the 4-year enrollment period to enroll 175 patients in the study. In our
prior polypill trial, conducted in an outpatient setting, we observed a 45% response rate to
the initial invitation, of which ~50% met eligibility criteria and consented to
randomization. We will record all contact attempts and responses to determine recruitment
rates and reasons for entry or non-entry into the trial. The study team has substantial
experience with recruitment of participants for clinical trials and observational studies at
Parkland Hospital.
Participants who meet eligibility criteria will be invited to enroll in the trial.
Participants will be randomly assigned in a 1:1 ratio using a computerized algorithm. Block
randomization will be performed according to baseline use of a polypill component and
race/ethnicity group. The randomization key will be maintained by a faculty member with no
involvement in the trial.
The study investigators will prescribe the polypill to those in the active arm. In response
to the initial polypill prescription, participants will receive an initial pill vial
containing a 30-day supply of medication via overnight shipping. Subsequent refills of 30-day
supply will be made available by overnight shipping. Patients will be contacted by the study
team every month, 1 week before the end of their 30-day supply, to follow up on their
clinical status and adherence to the therapy. Participants will be instructed to take one
pill per day for the duration of the study. All polypill medication, including unopened or
partially used containers, will be maintained at the study site for eventual return to the
vendor. As this is an open-label trial, there will be no placebo provided in the usual care
arm. Participants in the usual care arm will also receive their medications free of cost in
30-day supplies with overnight shipping and receive monthly follow up calls.
In accordance with local regulatory requirements, the investigator or designated research
staff will document the quantity of polypill dispensed and/or administered to study
participants, the amount returned by study participants, and the amount received from and
returned to the vendor when applicable. Product accountability records will be maintained
throughout the course of the study. Concomitant medications and non-drug therapies not
specifically prohibited by the study are allowed. All concomitant medications taken during
the study will be recorded by study staff. Prohibited medications include all medications
that interact with the components of the polypill or are contraindicated in patients with
HFrEF.
At the baseline visit informed consent will be obtained. Responses to the baseline
questionnaire will be reviewed by a study coordinator as a final check on inclusion and
exclusion criteria and current medication use. A medical and social history will be obtained.
Vital signs will be measured in seated participants, according to standardized protocols. A
15 mL blood sample will be obtained for eligibility laboratories. Pre-menopausal women will
undergo a rapid urine pregnancy test.
At 1, 3, 6, 9 and 12 months post-randomization, participants will be sent follow-up
questionnaires and scheduled for a follow-up visit at the outpatient clinic. At these
follow-up visits, the study coordinators will review questionnaires for completeness, assess
vital signs, collect a blood sample, assess medication adherence by pill count and the MMAS-8
questionnaire, assess for medication safety, tolerance, and side effects. The up-titration in
GDMT or polypill beta-blocker dose will be performed, as tolerated on each visit. A 6-minute
walk test and quality of life assessment using the KCCQ will be performed at baseline, 6
months, and 12 months as detailed below using protocols identical to those of the baseline
visit. A metabolic panel test will be performed at each follow-up to assess for hyperkalemia
or kidney dysfunction. Additional clinic visits will be allowed at the discretion of the
patients' physicians.
Subjects will receive $25 per study visit. In addition, subjects will also receive $25 for
their CMR visits at baseline and follow up. Participants will also receive travel vouchers
and/or transportation reimbursements for their follow-up visits.
