HFrEF Polypill in Sri Lanka RCT

Heart Failure With Reduced Ejection Fraction Polypill in Sri Lanka: A Multi-Center Type I Hybrid Randomized Controlled Trial

Primary Outcome:

Composite of cardiovascular death or recurrent heart failure hospitalization over study duration

Secondary Outcomes:

Cardiovascular death over study duration Recurrent heart failure hospitalizations over study duration All-cause mortality over study duration Change in left ventricular ejection fraction from baseline to 12 months by echocardiogram.

Change in natriuretic peptide levels from baseline to 12 months. Change in health-related quality of life from baseline to 12 months using the Kansas City Cardiomyopathy Questionnaire.

Change in New York Heart Association functional class from baseline to 12 months.

Adherence to heart failure medications assessed by pill count and questionnaire, medication persistence assessed as continuation of assigned therapy after initiation, and dose optimization assessed as proportion achieving final/target doses over study duration

Safety Outcomes:

Proportion of participants with serious adverse events or sudden unexpected serious adverse reaction over study duration Proportion with adverse events of special interest (symptomatic hypotension, diabetic ketoacidosis, severe hypoglycemia, lower limb amputation, hyperkalemia, or worsening kidney function) over study duration Proportion of participants who stop study drug because of adverse events over study duration Change in serum potassium over study duration Change in serum creatinine over study duration

Participants will be randomly assigned to one of two groups, intervention or usual care. The intervention group will be given four guideline-recommended medications for heart failure with reduced ejection fraction, combined in one over-encapsulated pill, with three dose strength options (at the discretion of their treating physician). Both groups will be observed over a minimum of 12-months of follow-up to assess their medication adherence, clinical symptoms, laboratory measures, health related quality of life, and need for medication adjustment amongst other measures.

Study Overview

• Status: Not yet recruiting
• Conditions: Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Other: Comparator Arm; Drug: HFrEF Polypill

Detailed Description

The study intervention will be a heart failure with reduced ejection fraction (HFrEF) polypill consisting of bisoprolol (beta-blocker), losartan (ARB), eplerenone (MRA), and dapagliflozin (SGLT2i) manufactured using the over-encapsulation method and will undergo extensive stability testing to ensure quality. There will be 3 strengths of the HFrEF polypill available to facilitate initiation with low dose to prioritize clinical tolerability and laboratory safety and titration to higher doses of the HFrEF polypill. The dose of initiation and titration will be at the investigator's discretion. The HFrEF polypill will be delivered by licensed physicians responsible for managing heart failure at participating sites. Eligible providers must have formal medical qualifications in Sri Lanka and be actively involved in the care of patients with HFrEF. This includes cardiologists, internists, or general practitioners with experience in heart failure management. All participating physicians will receive standardized training on the study protocol including titration protocol, HFrEF polypill composition, and guidance for patient counseling prior to trial initiation to ensure consistent and accurate delivery of the intervention. Participants receiving the HFrEF polypill will also receive a "HFrEF polypill card" that delineates the drugs and doses included in the HFrEF polypill combination and contact information for the local study team in case of hospitalization at another facility.

HFrEF polypill combinations by strength:

HFrEF polypill strength 1: bisoprolol 2.5 mg + losartan 25 mg + eplerenone 25 mg + dapagliflozin 10 mg HFrEF polypill strength 2: bisoprolol 5 mg + losartan 50 mg + eplerenone 25 mg + dapagliflozin 10 mg HFrEF polypill strength 3: bisoprolol 10 mg + losartan 100 + eplerenone 50 mg + dapagliflozin 10 mg

Participants in the comparator control group will receive usual care from their healthcare providers. Providers will be encouraged to treat all participants according to international and local clinical practice guidelines. Participants in the intervention group will be provided with the HFrEF polypill by the study, and participants in the control group will be provided HFrEF medications through the pharmacy at the public hospital site(s) in Sri Lanka where they are generally free of cost.

• Study Type: Interventional
• Enrollment (Estimated): 1656
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anubha Agarwal, MD MSc; Phone Number: 314-362-1291; Email: anubha@wustl.edu
• Study Contact Backup: Name: Adam Hively, MPH; Email: adamh@wustl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults (≥18 years old)
2. Diagnosis of heart failure with reduced ejection fraction (HFrEF) including clinical symptoms or clinical signs or natriuretic peptide elevation AND echocardiographic or other evidence of reduced ejection fraction (EF≤40%)
3. New York Heart Association Class II, III, or IV symptoms

Exclusion Criteria:

1. Known contraindication to any of the HFrEF polypill components (e.g., advanced renal disease, bradycardia, allergy, amongst others).
2. Significant renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2)
3. Raised serum potassium >5 mEq/L.
4. Symptomatic hypotension or systolic BP <100 mmHg as per the average of last 2 of the 3 measurements at visit 1.
5. Symptomatic bradycardia or second or third-degree heart block without a pacemaker on ECG review at visit 1.
6. History of type 1 diabetes mellitus.
7. Women who are pregnant, breastfeeding or of childbearing potential and are not using and do not plan to continue using medically acceptable form of contraception throughout the study (pharmacological or barrier methods).
8. Concomitant illness, physical impairment or mental condition which in the opinion of the study team/ primary physician could interfere with the conduct of the study including outcome assessment.
9. Participation in a concurrent interventional medical investigation or pharmacologic clinical trial. Patients in observational, natural history or epidemiological studies not involving an intervention are eligible.
10. Participant's responsible physician believes it is not appropriate for participant to participate in the study.
11. Inability or unwillingness to provide written informed consent.
12. Involvement in the planning and/or conduct of the study.
13. Unable to complete study procedures and/or plan to move out of the study site area in the next 2 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study Intervention arm; Participants in the intervention group will be provided the HFrEF polypill by the study.	Drug: HFrEF Polypill; The heart failure with reduced ejection fraction (HFrEF) polypill will include 4 guideline recommended medications used to treat HFrEF patients. The dose of initiation and titration will be at the investigator's discretion. HFrEF polypill strength 1: bisoprolol 2.5 mg + losartan 25 mg + eplerenone 25 mg + dapagliflozin 10 mg; HFrEF polypill strength 2: bisoprolol 5 mg + losartan 50 mg + eplerenone 25 mg + dapagliflozin 10 mg; HFrEF polypill strength 3: bisoprolol 10 mg + losartan 100 + eplerenone 50 mg + dapagliflozin 10 mg
Active Comparator: Control arm; Participants in the comparator control arm will receive usual care, as per their physician's discretion.	Other: Comparator Arm; Participants in the comparator control group will receive usual care by their healthcare providers. Providers will be encouraged to treat all participants according to international and local clinical practice guidelines.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite rate of cardiovascular disease mortality and recurrent HF hospitalizations	Cardiovascular disease mortality is defined as death due to acute myocardial infarction, worsening heart failure, stroke, sudden cardiac death, arrhythmia, pulmonary embolism, cardiovascular procedures, vascular causes, or any death of unknown cause unless a non-cardiovascular etiology is clearly established. Recurrent HF hospitalizations is defined as any hospitalization in which the primary cause is worsening heart failure, accompanied by objective evidence of decompensation and requiring initiation or intensification of HF-specific therapy, occurring after a documented period of clinical stability of at least 12 hours since the prior HF event. Adjudicated by the blinded Outcome Adjudication Committee.	1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of cardiovascular disease mortality	Cardiovascular disease mortality is defined as death due to acute myocardial infarction, worsening heart failure, stroke, sudden cardiac death, arrhythmia, pulmonary embolism, cardiovascular procedures, vascular causes, or any death of unknown cause unless a non-cardiovascular etiology is clearly established. Adjudicated by the blinded Outcome Adjudication Committee.	1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
Rate of recurrent heart failure hospitalizations	Recurrent HF hospitalizations is defined as any hospitalization in which the primary cause is worsening heart failure, accompanied by objective evidence of decompensation and requiring initiation or intensification of HF-specific therapy, occurring after a documented period of clinical stability of at least 12 hours since the prior HF event. Adjudicated by the blinded Outcome Adjudication Committee.	1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
Rate of all-cause mortality	All-cause mortality is defined as death due to any cause.	1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
Change in left ventricular ejection fraction	How much the heart's pumping ability changes over one year, measured using a heart ultrasound test (echocardiogram).	Baseline, 12 months
Natriuretic peptide levels change	Change in a blood test that reflects heart stress using a validated commercially available immunoassay (i.e., BNP) from baseline to 12 months.	Baseline, 12 months
Change in overall and domain specific health-related quality of life	Health-related quality of life (HRQoL) will be assessed using a validated, translated Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23). The KCCQ-23 measures overall and domain-specific HRQoL, including physical limitation, symptom frequency and impact, quality of life, and social limitation. Scores are transformed to a 0-100 scale, with higher scores indicating better health status; change from baseline to 12 months will be analyzed for overall and domain-specific scores. Overall summary score will be used as a secondary outcome. Domain-specific scores will be considered exploratory.	Baseline, 12 months
Physician-reported New York Heart Association class change	Change in how severe heart failure symptoms are over 12 months, as rated by the doctor (New York Heart Association class).	Baseline, 12 months
Adherence to guideline-directed medical therapy	Medication adherence assessed by pill count.	Baseline, 1 month, 3 months, 6 months, 9 months, 12 months
Adherence to Guideline-Directed Medical Therapy	Medication adherence assessed by MARS-5 questionnaire	Baseline, 1 month, 3 month, 6 month, 9 month, 12 month
Persistence to Guideline-Directed Medical Therapy	Medication persistence assessed as continuation of assigned therapy after initiation	Baseline, 1 month, 3 month, 6 month, 9 month, 12 month
Optimization of Guideline-Directed Medical Therapy	Dose optimization assessed as proportion achieving final/target doses	6 and 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious adverse events or sudden unexpected serious adverse reaction	Proportion of participants with serious adverse events or sudden unexpected serious adverse reaction according to the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines (ICH E6 [R3]) over the study duration.	1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
Adverse Events of Special Interest	Adverse events of special interest defined as: a) symptomatic hypotension defined as systolic blood pressure < 90 mmHg and associated symptoms of light-headedness, dizziness, or pre-syncope, b) diabetic ketoacidosis, c) severe hypoglycemic event, d) lower limb amputation, e) hyperkalemia defined as serum potassium greater than or equal to 5.5 mEq/L, and f) worsening renal function defined as ≥50% increase in serum creatinine or at a lower threshold per physician judgement.	1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
Adverse events leading to study drug discontinuation	Number of participants who stop the study medication because of side effects during the study.	1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
Serum potassium (mEq/L) change	Mean (average) change in serum potassium levels over study duration	Baseline, 1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
Serum creatinine (mg/dL) change	Mean (average) change in a serum creatinine over study duration	Baseline, 1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Centre for Chronic Disease Control, India; The George Institute; RemediumOne

Publications and helpful links

Helpful Links

• Related Info
• Related Info
• Related Info
• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: February 11, 2026
• First Submitted That Met QC Criteria: May 1, 2026
• First Posted (Actual): May 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 14, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Heart Failure; Heart Failure with Reduced Ejection Fraction; HFrEF; Polypill; South Asia; Sri Lanka
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure
• Other Study ID Numbers: 202605087

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: When the study is over, research findings will be available at www.ClinicalTrials.gov and Sri Lanka Clinical Trials Registry. Laboratory results will be shared with participants and their health care providers. The research findings will also be published in the form of research articles or presented at scientific meetings.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No