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.
Descripción general del estudio
Estado
Intervención / Tratamiento
Descripción detallada
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.
Tipo de estudio
Inscripción (Estimado)
Fase
- Fase 3
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Anubha Agarwal, MD MSc
- Número de teléfono: 314-362-1291
- Correo electrónico: anubha@wustl.edu
Copia de seguridad de contactos de estudio
- Nombre: Adam Hively, MPH
- Correo electrónico: adamh@wustl.edu
Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
- Adulto
- Adulto Mayor
Acepta Voluntarios Saludables
Descripción
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 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 medically 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 2 months.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Único
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
|---|---|
|
Experimental: Estudiar el brazo de intervención
El estudio proporcionará a los participantes en el grupo de intervención el Polypill HFREF.
|
La insuficiencia cardíaca con la fracción de eyección reducida (HFREF) Polypill incluirá 4 medicamentos recomendados por la guía utilizados para tratar pacientes con HFREF. La dosis de iniciación y titulación será a discreción del investigador. Hfref Polypill Strength 1: Bisoprolol 2.5 mg + losartán 25 mg + eplerenona 25 mg + dapagliflozin 10 mg; Hfref Polypill Strength 2: bisoprolol 5 mg + losartan 50 mg + eplerenona 25 mg + dapagliflozin 10 mg; HFREF POLYPILL Strength 3: Bisoprolol 10 mg + losartan 100 + eplerenona 50 mg + dapagliflozin 10 mg |
|
Comparador activo: Control arm
Participants in the comparator control arm will receive usual care, as per their physician's discretion.
|
Los participantes en el grupo de control de comparación recibirán atención habitual por parte de sus proveedores de atención médica.
Se alentará a los proveedores a tratar a todos los participantes de acuerdo con las pautas de práctica clínica internacional y local.
|
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Composite rate of cardiovascular disease mortality and recurrent HF hospitalizations
Periodo de tiempo: 1 month, 3 months, 6 months, 9 months, 12 months, 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, 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.
|
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Rate of cardiovascular disease mortality
Periodo de tiempo: 1 month, 3 months, 6 months, 9 months, 12 months, 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, 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
Periodo de tiempo: 1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
|
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
Periodo de tiempo: 1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
|
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
Periodo de tiempo: Baseline, 12 months
|
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
Periodo de tiempo: Baseline, 12 months
|
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
Periodo de tiempo: Baseline, 12 months
|
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
Periodo de tiempo: Baseline, 12 months
|
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
Periodo de tiempo: Baseline, 1 month, 3 months, 6 months, 9 months, 12 months
|
Medication adherence assessed by pill count.
|
Baseline, 1 month, 3 months, 6 months, 9 months, 12 months
|
|
Adherence to Guideline-Directed Medical Therapy
Periodo de tiempo: Baseline, 1 month, 3 month, 6 month, 9 month, 12 month
|
Medication adherence assessed by MARS-5 questionnaire
|
Baseline, 1 month, 3 month, 6 month, 9 month, 12 month
|
|
Persistence to Guideline-Directed Medical Therapy
Periodo de tiempo: Baseline, 1 month, 3 month, 6 month, 9 month, 12 month
|
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
Periodo de tiempo: 6 and 12 months
|
Dose optimization assessed as proportion achieving final/target doses
|
6 and 12 months
|
Otras medidas de resultado
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Serious adverse events or sudden unexpected serious adverse reaction
Periodo de tiempo: 1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
|
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
Periodo de tiempo: 1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
|
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
Periodo de tiempo: 1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
|
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
Periodo de tiempo: Baseline, 1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
|
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
Periodo de tiempo: Baseline, 1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
|
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.
|
Colaboradores e Investigadores
Publicaciones y enlaces útiles
Enlaces Útiles
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Estimado)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
- 202605087
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Descripción del plan IPD
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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