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HFrEF Polypill in Sri Lanka RCT

25 août 2026 mis à jour par: Anubha Agarwal, Washington University School of Medicine

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

Aperçu de l'étude

Statut

Recrutement

Les conditions

Intervention / Traitement

Description détaillée

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.

Type d'étude

Interventionnel

Inscription (Estimé)

1672

Phase

  • Phase 3

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Coordonnées de l'étude

  • Nom: Anubha Agarwal, MD MSc
  • Numéro de téléphone: +1 314-362-1291
  • E-mail: anubha@wustl.edu

Sauvegarde des contacts de l'étude

  • Nom: Asita de Silva, MBBS DPhil FRCP
  • Numéro de téléphone: +94 11 2961241
  • E-mail: asita@kln.ac.lk

Lieux d'étude

  • Sri Lanka
    • Central Province
      • Kandy, Central Province, Sri Lanka, 20000
        • Recrutement
        • National Hospital Kandy
        • Contact:
        • Sous-enquêteur:
          • Zanoona Siddeek
    • North Western Province
      • Kurunegala, North Western Province, Sri Lanka, 60000
        • Pas encore de recrutement
        • Teaching Hospital Kurunegala
        • Contact:
        • Sous-enquêteur:
          • Aruna Jayawarna
    • Northern Province
      • Jaffna, Northern Province, Sri Lanka, 40000
        • Recrutement
        • Teaching Hospital Jaffna
        • Contact:
          • Poopalan Lakshman
          • Numéro de téléphone: +94 212 223 348
          • E-mail: drplcc7@gmail.com
        • Sous-enquêteur:
          • Thepana Sasiharan
        • Sous-enquêteur:
          • Sebastian Heavenly
    • Ratnapura
      • Colombo, Ratnapura, Sri Lanka, 70000
        • Pas encore de recrutement
        • Rathnapura Teaching Hospital
        • Contact:
    • Southern Province
      • Galle, Southern Province, Sri Lanka, 80000
        • Recrutement
        • National Hospital Galle
        • Contact:
        • Sous-enquêteur:
          • Piumi Rajawardhana
        • Sous-enquêteur:
          • T.G Sandamali
    • Western Province
      • Colombo, Western Province, Sri Lanka, 00100
        • Pas encore de recrutement
        • National Hospital of Sri Lanka
        • Contact:
        • Sous-enquêteur:
          • Chandrike Ponnamperuma
        • Sous-enquêteur:
          • Thisal Semina
        • Sous-enquêteur:
          • Tanya Pereira
        • Sous-enquêteur:
          • Neranja Weerakoon
        • Sous-enquêteur:
          • Chandana Wijesingha
        • Sous-enquêteur:
          • Bhathiya Ranasinghe
      • Colombo, Western Province, Sri Lanka, 10290
        • Pas encore de recrutement
        • University Hospital - General Sir John Kotelawala Defence University
        • Contact:
          • Namal Wijesinghe
          • Numéro de téléphone: +94 112044555
          • E-mail: namalw@gmail.com
        • Sous-enquêteur:
          • Subash Karunarathna
        • Sous-enquêteur:
          • Sandali Wijewardena
        • Sous-enquêteur:
          • Gishara Hemachandra
        • Sous-enquêteur:
          • Sashini Amarasinghe
      • Dehiwala, Western Province, Sri Lanka, 10350
        • Recrutement
        • Colombo South Teaching Hospital
        • Contact:
        • Sous-enquêteur:
          • Geethani Gunasekara
      • Gampaha, Western Province, Sri Lanka, 11000
        • Pas encore de recrutement
        • Gampaha District General Hospital
        • Contact:
      • Negombo, Western Province, Sri Lanka, 11500
        • Pas encore de recrutement
        • District General Hospital Negombo
        • Contact:
        • Sous-enquêteur:
          • Anusha de Silva
      • Ragama, Western Province, Sri Lanka, 11010
        • Recrutement
        • Colombo North Teaching Hospital
        • Contact:
        • Sous-enquêteur:
          • Thushari Gunawardana
        • Sous-enquêteur:
          • Sinthi Sivarajah
        • Sous-enquêteur:
          • Anjalee Weerasuriya

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

  • Adulte
  • Adulte plus âgé

Accepte les volontaires sains

Non

La 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 left ventricular 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 a highly 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 12 months.

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: Randomisé
  • Modèle interventionnel: Affectation parallèle
  • Masquage: Seul

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Comparateur actif: 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.
Autre: 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.
Expérimental: 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 + dapagliflozin 10 mg

Every intervention participant will be established on the highest tolerated strength of the HFrEF polypill, with Strength 3 as the target dose. Following initiation at the strength matched to the participant's background guideline-directed medical therapy, the polypill strength will be advanced by one level at each scheduled study visit aligned with the initiation and titration protocol.
Médicament: 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 + dapagliflozin 10 mg.

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
Composite rate of cardiovascular disease mortality and recurrent heart failure hospitalizations over study duration
Délai: 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.

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.
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.

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Rate of cardiovascular disease mortality over study duration
Délai: 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.

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.
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
Délai: 1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.

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.
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
Délai: 1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.
All-cause mortality is defined as death due to any cause.
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
Délai: Baseline, 12 months, and at study completion, an average of 18 months.
Baseline, 12 months, and at study completion, an average of 18 months.
Change in BNP levels at 12 months and end of study
Délai: Baseline, 12 months, and at study completion, an average of 18 months.
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
Délai: Baseline, 12 months, and at study completion, an average of 18 months.
Health-related quality of life (HRQoL) will be assessed by a translated validated Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23)
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
Délai: Baseline, 12 months, and at study completion, an average of 18 months.
Baseline, 12 months, and at study completion, an average of 18 months.
Adherence to guideline-directed medical therapy, persistence and dose optimization
Délai: Baseline, 1, 6, 12 months, and at study completion, an average of 18 months

Adherence to guideline-directed medical therapy assessed by pill count and MARS-5 questionnaire.

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.
Baseline, 1, 6, 12 months, and at study completion, an average of 18 months

Autres mesures de résultats

Mesure des résultats
Description de la mesure
Délai
Proportion of participants with serious adverse events according to Good Clinical Practice guidelines over study duration
Délai: 1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.
Proportion of participants with serious adverse events according to Good Clinical Practice (GCP) guidelines (ICH E6 [R3]) over the study duration.
1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.
Proportion of participants with adverse events of special interest over study duration
Délai: 1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.

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
1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.
Proportion of participants with adverse events leading to HF drug discontinuation over study duration
Délai: 1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.
1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.
Mean change from baseline to 12-months and end of study in serum potassium (mEq/L)
Délai: Baseline, 1 month, 3 months, 6 months, 9 months, 12 months, and at study completion, an average of 18 months.
Baseline, 1 month, 3 months, 6 months, 9 months, 12 months, and at study completion, an average of 18 months.
Mean change from baseline to 12-months and end of study in serum creatinine (mg/dL)
Délai: Baseline, 1 month, 3 months, 6 months, 9 months, 12 months, and at study completion, an average of 18 months.
Baseline, 1 month, 3 months, 6 months, 9 months, 12 months, and at study completion, an average of 18 months.

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

Washington University School of Medicine

Collaborateurs

National Heart, Lung, and Blood Institute (NHLBI)
Centre for Chronic Disease Control, India
University of Kelaniya
The George Institute
RemediumOne

Publications et liens utiles

La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.

Liens utiles

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude (Réel)

17 août 2026

Achèvement primaire (Estimé)

1 avril 2029

Achèvement de l'étude (Estimé)

1 avril 2029

Dates d'inscription aux études

Première soumission

11 février 2026

Première soumission répondant aux critères de contrôle qualité

1 mai 2026

Première publication (Réel)

6 mai 2026

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Réel)

28 août 2026

Dernière mise à jour soumise répondant aux critères de contrôle qualité

25 août 2026

Dernière vérification

1 août 2026

Plus d'information

Termes liés à cette étude

Mots clés

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

  • 202605087

Plan pour les données individuelles des participants (IPD)

Prévoyez-vous de partager les données individuelles des participants (DPI) ?

OUI

Description du régime IPD

De-identified participant-level data and accompanying data dictionaries will be made available to qualified investigators upon reasonable request and following approval by the Steering Committee, consistent with NIH data-sharing policies. Requests must include a methodologically sound proposal and a data use agreement ensuring participant confidentiality.

Délai de partage IPD

De-identified individual participant data will become available after publication of the primary results manuscript and remain available thereafter, subject to Steering Committee approval of each request.

Critères d'accès au partage IPD

Qualified investigators may request access by submitting a methodologically sound proposal to the study Steering Committee. Approved requests require a signed data use agreement ensuring participant confidentiality, consistent with NIH data-sharing policies.

Type d'informations de prise en charge du partage d'IPD

  • PROTOCOLE D'ÉTUDE
  • SÈVE

Informations sur les médicaments et les dispositifs, documents d'étude

Étudie un produit pharmaceutique réglementé par la FDA américaine

Non

Étudie un produit d'appareil réglementé par la FDA américaine

Non

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