HFrEF Polypill in Sri Lanka RCT
Trial statusRecruiting
Trial phasePhase 3
Trial typeInterventional
Biological sexAll
Age18+
SponsorWashington University School of Medicine
About this trial
The aim of this study is to evaluate, in adults with HFrEF in Sri Lanka, the effects of an HFrEF polypill implementation strategy on the composite rate of cardiovascular disease mortality and recurrent heart failure hospitalizations, compared with usual care over a minimum of 12-months of follow-up.
Primary outcome of the study:
1\) Composite rate of cardiovascular disease mortality and recurrent heart failure hospitalizations over study duration
Secondary outcomes of the study:
1. Rate of cardiovascular disease mortality over study duration 2. Rate of recurrent heart failure hospitalizations over the study duration 3. Rate of all-cause mortality over the study duration 4. Change in left ventricular ejection fraction at 12-months and end of study assessed by transthoracic echocardiogram 5. Change in BNP levels at 12 months and end of study 6. Change in overall and domain specific health-related quality of life at 12-months and end of study assessed by a translated validated version of the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) 7. Change in physician-reported New York Heart Association class at 12-months and end of study 8. Adherence to guideline-directed medical therapy assessed by pill count and MARS-5 questionnaire at baseline, 1-, 6-, 12-months, and end of study. Persistence assessed as continuation of assigned therapy at each follow-up visit. Dose optimization assessed as proportion achieving target doses (Strength 3 of the polypill, or comparable individual GDMT doses in the comparator arm) at 6-, 12-months, and end of study.
Safety outcomes:
1. Proportion of participants with serious adverse events according to Good Clinical Practice guidelines over study duration 2. Proportion of participants with adverse events of special interest over study duration 3. Proportion of participants with adverse events leading to HF drug discontinuation over study duration 4. Mean change from baseline to 12-months and end of study in serum potassium (mEq/L) 5. Mean change from baseline to 12-months and end of study in serum creatinine (mg/dL)
Participants will be randomly assigned 1:1 stratified by sex and site to one of two groups, intervention (experimental arm) or usual care (control arm). 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. Both groups will be observed over a minimum of 12-months of follow-up to assess key outcomes.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Adults (≥18 years old)
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 left ventricular ejection fraction (EF ≤40%)
New York Heart Association Class II, III, or IV symptoms
Disqualifiers
Known contraindication to any of the HFrEF polypill components (e.g., advanced renal disease, bradycardia, allergy, amongst others).
Significant renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2).
Raised serum potassium >5 mEq/L.
Symptomatic hypotension or systolic BP <100 mmHg as per the average of last 2 of the 3 measurements at visit 1.
Trial design
Design model
Parallel
Treatments tested in this trial
Usual Care
Other interventionParticipants 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 will receive their HFrEF medications through the pharmacy at the sites, where guideline-directed medical therapy are dispensed without charge to participants when available on the public hospital formulary.
HFrEF Polypill
DrugThe study intervention is a HFrEF polypill consisting of bisoprolol (beta-blocker), losartan (ARB), eplerenone (MRA), and dapagliflozin (SGLT2i) manufactured using the over-encapsulation method. There will be 3 strengths of the HFrEF polypill available: Strength 1: bisoprolol 2.5 mg + losartan 25 mg + eplerenone 25 mg + dapagliflozin 10 mg Strength 2: bisoprolol 5 mg + losartan 50 mg + eplerenone 25 mg + dapagliflozin 10 mg Strength 3: bisoprolol 10 mg + losartan 100 mg + eplerenone 50 mg + dapagliflozin 10 mg.
Treatment groups
1,672 Participants
are divided into 2 treatment groupsGroup A: Usual CareActive comparator 1 intervention
Group B: HFrEF PolypillExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Composite rate of cardiovascular disease mortality and recurrent heart failure hospitalizations over study duration
Cardiovascular disease mortality is defined as death due to acute myocardial infarction, worsening heart failure, stroke, sudden cardiac death, arrhythmia, pulmonary embolism, cardiovascular procedures or their complications, other vascular causes, or any death of unknown cause unless a non-cardiovascular etiology is clearly established. HF hospitalization is defined as any unplanned hospitalization for at least 24 hours, for which the primary cause is 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.
Time frame
1 month, 3 month, 6 month, 9 month, 12 month study visits, and every 3 months thereafter through study completion, an average of 18 months.Secondary outcomes
1
Rate of cardiovascular disease mortality over study duration
Cardiovascular disease mortality is defined as death due to acute myocardial infarction, worsening heart failure, stroke, sudden cardiac death, arrhythmia, pulmonary embolism, cardiovascular procedures or their complications, other vascular causes, or any death of unknown cause unless a non-cardiovascular etiology is clearly established. Adjudicated by the blinded Outcome Adjudication Committee.
Time frame
1 month, 3 month, 6 month, 9 month, 12 month study visits, and every 3 months thereafter, through study completion, an average of 18 months.2
Rate of recurrent heart failure hospitalizations over the study duration
HF hospitalization is defined as any unplanned hospitalization for at least 24 hours, for which the primary cause is 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.
Time frame
1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.3
Rate of all-cause mortality over the study duration
All-cause mortality is defined as death due to any cause.
Time frame
1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.4
Change in left ventricular ejection fraction at 12-months and end of study assessed by transthoracic echocardiogram
Time frame
Baseline, 12 months, and at study completion, an average of 18 months.Other outcomes
1
Proportion of participants with serious adverse events according to Good Clinical Practice guidelines over study duration
Proportion of participants with serious adverse events according to Good Clinical Practice (GCP) guidelines (ICH E6 \[R3\]) over the study duration.
Time frame
1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.2
Proportion of participants with adverse events of special interest over study duration
Adverse events of special interest: 1. symptomatic hypotension 2. diabetic ketoacidosis 3. severe hypoglycemia 4. lower limb amputation 5. hyperkalemia 6. worsening renal function 7. falls
Time frame
1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.3
Proportion of participants with adverse events leading to HF drug discontinuation over study duration
Time frame
1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.4
Mean change from baseline to 12-months and end of study in serum potassium (mEq/L)
Time frame
Baseline, 1 month, 3 months, 6 months, 9 months, 12 months, and at study completion, an average of 18 months.Sponsors and contacts
Click on the lead sponsor to view all of their trials.
Washington University School of Medicine
Lead sponsor
Centre for Chronic Disease Control, India
Collaborator
National Heart, Lung, and Blood Institute (NHLBI)
Collaborator
RemediumOne
Collaborator
University of Kelaniya
Collaborator
The George Institute
Collaborator
Source ClinicalTrials.gov