Clinical trial NCT05164653: Program of Angiotensin-Neprilysin Inhibition in Admitted Patients With Worsening Heart Failure (PREMIER)
Official title: An Investigator-initiated, Multicenter, Prospective, Randomized, Open-label, Blinded-endpoint Study to Assess the Effect of In-hospital Initiation of Sacubitril Valsartan on the NT-proBNP Concentrations in Patients Admitted Due to Acute Exacerbation of Heart Failure (PREMIER)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Heart Failure
Keywords: Acute decompensated heart failure
Heart failure hospitalization
Sacubitril valsartan
NT-proBNP
Lead sponsor: Saga University
Sponsor class: OTHER
First posted: 2021-12-21
Enrollment: 400
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of this study is to assess the treatment effect of sacubitril valsartan versus conventional therapy for heart failure (HF) in admitted patients due to exacerbation of HF on the N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) concentrations.

Detailed description: The high rate of rehospitalization and mortality of patients hospitalized for acute exacerbation of HF, especially at the early phase after discharge, has long been a serious clinical concern. However, few trials evaluating drug therapies on the post-acute phase of HF showed positive and/or satisfying results. Therefore, it is urgently required to establish an efficient treatment strategy at that phase. Sacubitril valsartan is an angiotensin receptor-neprilysin inhibitor that was approved in Japan in 2020 for patients who are taking standard care of HF.

In this investigator-initiated, multicenter, 8-week, randomized controlled study (PREMIER), the investigators try to assess the effect of in-hospital initiation of sacubitril valsartan, compared to standard HF treatment, in patients who were admitted due to worsening heart failure, on the NT-proBNP concentrations.

Eligibility criteria: Inclusion Criteria:

1. Patients must provide written informed consent themselves to participate in this study
2. Aged 20 or older at consent (male or female)
3. Hospitalized due to worsening heart failure with both signs of congestion (such as edema, moist rales, and congestion on chest X-ray) and symptoms of heart failure (such as dyspnea on mild exertion or at rest) (any level of left ventricular ejection fraction)
4. NYHA class II-IV
5. Taking an ACE inhibitor or an ARB
6. Can undergo randomization within 7 days of current hospitalization
7. Patients who meet the following criteria of hemodynamic stability I. Systolic blood pressure ≥100 mm Hg II. No dose increase of intravenous diuretic within 6 hours before randomization III. No intravenous administration of vasodilator (such as carperitide or nitrates) or positive inotropic agent
8. Patients who meet the following reference range for natriuretic peptide level from 48 hours before current hospitalization to the time of eligibility determination

NT-proBNP ≥1200 pg/mL or BNP ≥300 pg/mL

Exclusion Criteria:

1. Currently taking oral sacubitril valsartan or have taken it within 30 days prior to randomization
2. History of hypersensitivity to ingredients in ARB, ACE inhibitor, or sacubitril valsartan; or expected to be contraindicated for or intolerant to any of these drugs
3. History of angioedema
4. Severe renal dysfunction (\<eGFR 30 mL/min/1.73 m\^2), on maintenance dialysis, or known bilateral renal artery stenosis (in patients with solitary kidney, known renal artery stenosis in the residual kidney)
5. Severe liver dysfunction (Child-Pugh class C)
6. Diabetic patients who are currently taking aliskiren fumarate
7. Serum potassium ≥5.3 mEq/L or more
8. Cardiogenic shock
9. On cardiopulmonary support, with a left ventricular assist device, or on a ventilator
10. Onset of stroke or acute coronary syndrome within 30 days prior to randomization
11. History of surgical or percutaneous treatment of cardiovascular disease within 30 days prior to randomization
12. Patients with an advanced plan for surgical or percutaneous treatment of cardiovascular disease or for coronary artery revascularization during an observation period
13. Patients with an advanced plan for pacemaker implantation, cardiac resynchronization therapy, or electrical cardioversion during an observation period
14. History or comorbidity of hypertrophic obstructive cardiomyopathy or infiltrative cardiomyopathy such as amyloidosis or sarcoidosis
15. Active pericardial disease
16. History of or awaiting heart transplant
17. Severe chronic respiratory disease or active infectious disease
18. Patients who are or might become pregnant or who are breastfeeding
19. Patients whom a study investigator determined to be unsuitable for the study (such as patients with comorbid active malignancy)

Primary outcomes:
measure: Proportional change in NT-proBNP concentrations from baseline to 8 weeks
timeFrame: 8 weeks
Secondary outcomes:
measure: Proportional change in NT-proBNP concentrations from baseline to 4 weeks
timeFrame: 4 weeks
measure: Reduction in NT-proBNP levels at 8 weeks
timeFrame: 8 weeks
measure: Reduction in NT-proBNP levels at 4 weeks
timeFrame: 4 weeks
measure: Mean reduction in NT-proBNP at 4 and 8 weeks
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in biomarkers (cardiac troponin T)
timeFrame: 8 weeks
measure: Percent change in biomarkers (cardiac troponin T)
timeFrame: 8 weeks
measure: Amount of change in biomarkers (C-reactive protein)
timeFrame: 8 weeks
measure: Percent change in biomarkers (C-reactive protein)
timeFrame: 8 weeks
measure: Amount of change in biomarkers (growth differentiation factor 15)
timeFrame: 8 weeks
measure: Percent change in biomarkers (growth differentiation factor 15)
timeFrame: 8 weeks
measure: Amount of change in biomarkers (soluble suppression of tumorigenesis-2)
timeFrame: 8 weeks
measure: Percent change in biomarkers (soluble suppression of tumorigenesis-2)
timeFrame: 8 weeks
measure: Amount of change in biomarkers (glycoalbumin)
timeFrame: 8 weeks
measure: Percent change in biomarkers (glycoalbumin)
timeFrame: 8 weeks
measure: Amount of change in biomarkers (1.5-anhydro-D-glucitol)
timeFrame: 8 weeks
measure: Percent change in biomarkers (1.5-anhydro-D-glucitol)
timeFrame: 8 weeks
measure: Amount of change in clinical parameters (weight)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (weight)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (body mass index)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (body mass index)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (blood pressure)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (blood pressure)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (heart rate)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (heart rate)
timeFrame: 4 weeks, 8 weeks
measure: Amount of changs in clinical parameters (red blood cell)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (red blood cell)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (hemoglobin)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (hemoglobin)
timeFrame: 4 weeks, 8 weeks
measure: Amount of chang in clinical parameters (hematocrit)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (hematocrit)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (platelet)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (platelet)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (hemoglobin A1c)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (hemoglobin A1c)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (fasting glucose)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (fasting glucose)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (total cholesterol)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (total cholesterol)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (high-density lipoprotein cholesterol)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (high-density lipoprotein cholesterol)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (non-high-density lipoprotein cholesterol)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (non-high-density lipoprotein cholesterol)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (triglyceride)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (triglyceride)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (aspartate aminotransferase)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (aspartate aminotransferase)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (alanine aminotransferase)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (alanine aminotransferase)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (γ-glutamyl transpeptidase)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (γ-glutamyl transpeptidase)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (uric acid)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (uric acid)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (creatinine)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (creatinine)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (estimated glomerular filtration rate)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (estimated glomerular filtration rate)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (sodium)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (sodium)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (potassium)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (potassium)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (Fibrosis-4)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (Fibrosis-4)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (estimated plasma volume)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (estimated plasma volume)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in clinical parameters (New York Heart Association class)
timeFrame: 4 weeks, 8 weeks
measure: Percent change in clinical parameters (New York Heart Association class)
timeFrame: 4 weeks, 8 weeks
measure: Amount of change in echocardiographic parameters (left ventricular end-diastolic volume)
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (left ventricular end-diastolic volume)
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (left ventricular end-systolic volume)
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (left ventricular end-systolic volume)
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (left ventricular ejection fraction)
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (left ventricular ejection fraction)
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (septal e')
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (septal e')
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (lateral e')
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (lateral e')
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (flow velocity pattern through the mitral orifice (E))
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (flow velocity pattern through the mitral orifice (E))
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (early mitral inflow velocity E and mitral annular early diastolic velocity e')
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (early mitral inflow velocity E and mitral annular early diastolic velocity e')
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (left ventricular mass index)
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (left ventricular mass index)
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (left atrial volume index)
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (left atrial volume index)
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (left ventricular outflow tract)
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (left ventricular outflow tract)
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (left ventricular outflow tract velocity time integral)
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (left ventricular outflow tract velocity time integral)
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (tricuspid regurgitation velocity)
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (tricuspid regurgitation velocity)
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters(inferior vena cava diameter)
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters(inferior vena cava diameter)
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (global longitudinal strain)
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (global longitudinal strain)
timeFrame: 8 weeks
measure: Amount of change in echocardiographic parameters (left atrial strain (2-chamber view and 4-chamber view))
timeFrame: 8 weeks
measure: Percent change in echocardiographic parameters (left atrial strain (2-chamber view and 4-chamber view))
timeFrame: 8 weeks
measure: Change in echocardiographic parameters (inferior vena cava diameter)
timeFrame: 8 weeks
measure: Amount of change in Kansas City Cardiomyopathy Questionnaire-12 score
timeFrame: 8 weeks
measure: Percentage of patients in Kansas City Cardiomyopathy Questionnaire-12 score
timeFrame: 8 weeks
measure: Time to first occurrences of the composite event of all-cause death or worsening heart failure event
timeFrame: 8 weeks
measure: Occurrences of the composite event of all-cause death or worsening heart failure events (total number of occurrences)
timeFrame: 8 weeks
measure: Occurrences of the composite event of all-cause death or worsening heart failure events (incidence of occurrences)
timeFrame: 8 weeks
measure: Occurrences of the individual components of composite events and cardiovascular death (total number of occurrences)
timeFrame: 8 weeks
measure: Occurrences of the individual components of composite events and cardiovascular death (incidence of occurrences)
timeFrame: 8 weeks
measure: Occurrences of the individual components of composite events and cardiovascular death (time until occurrence)
timeFrame: 8 weeks
measure: Occurrences of adverse events of interest (total number of occurrences)
timeFrame: 8 weeks
measure: Occurrences of adverse events of interest (time until occurrence)
timeFrame: 8 weeks
measure: Occurrences of other serious adverse events
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Saga
country: Japan
facility: Saga University Hospital
Study officials:
affiliation: Saga University Hospital
name: Koichi Node, Pr.,Dr.
role: PRINCIPAL_INVESTIGATOR
References: