HFrEF Polypill in Sri Lanka RCT

Official title

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

Overview

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.

Interventions

• Other Usual Care
  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 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.
• Drug HFrEF Polypill
  The 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 + dapa

Primary outcome measures

• Composite rate of cardiovascular disease mortality and recurrent heart failure hospitalizations over study duration [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 outcome measures (8)

• Rate of cardiovascular disease mortality over study duration [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.]
• Rate of recurrent heart failure hospitalizations 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.]
• Rate of all-cause mortality 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.]
• 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.]
• Change in BNP levels at 12 months and end of study [Time frame: Baseline, 12 months, and at study completion, an average of 18 months.]
• Change in overall and domain specific health-related quality of life at 12-months and end of study [Time frame: Baseline, 12 months, and at study completion, an average of 18 months.]
• Change in physician-reported New York Heart Association class at 12-months and end of study [Time frame: Baseline, 12 months, and at study completion, an average of 18 months.]
• Adherence to guideline-directed medical therapy, persistence and dose optimization [Time frame: Baseline, 1, 6, 12 months, and at study completion, an average of 18 months]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• 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.
• Symptomatic bradycardia or second or third-degree heart block without a pacemaker on ECG review at visit 1.
• History of type 1 diabetes mellitus.
• Women who are pregnant, breastfeeding or of childbearing potential and are not using and do not plan to continue using a highly acceptable form of contraception throughout the study (pharmacological or barrier methods).
• 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.
• 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.
• Participant's responsible physician believes it is not appropriate for participant to participate in the study.
• Inability or unwillingness to provide written informed consent.
• Involvement in the planning and/or conduct of the study.
• Unable to complete study procedures and/or plan to move out of the study site area in the next 12 months.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Sri Lanka · 10 centers

• National Hospital Kandy — Kandy
• Teaching Hospital Kurunegala — Kurunegala
• Teaching Hospital Jaffna — Jaffna
• National Hospital Galle — Galle
• National Hospital of Sri Lanka — Colombo
• University Hospital - General Sir John Kotelawala Defence University — Colombo
• Colombo South Teaching Hospital — Dehiwala
• Gampaha District General Hospital — Gampaha
• … and 2 more centers

Identifiers

NCT: NCT07569640 · 202605087

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗