Enhancing the Natriuretic Peptide System in HFpEF: A Randomized Double-Blind Placebo-Controlled Triple Crossover Study

21-008978

The purpose of this study is to look at the differences in how individuals with heart failure with preserved ejection fraction in the presence of chronic kidney disease (HFpEF-CKD) and exercise induced dyspnea without objective findings of fluid retention (HFpEF-EI) bodies function using drugs Sacubatril/Valsartan (Entresto) and MANP.

2022-11-04

2027-04-01

2027-04-01

Early phase I

60

Inclusion Criteria: Group 1: HFpEF-CKD-will consist of 30 subjects with: * Ejection fraction of equal or greater than 55%; and * Evidence of increased LV filling pressures, including at least 2 of the following: average septal-lateral E/e' ratio ≥ 15; tricuspid regurgitation (TR) peak velocity \> 2:8 m/s; * Left atrial volume index \>34mL/m\^2 assessed by echocardiography; and * Previous diagnosis of HF with New York Heart Association (NYHA) functional class II-III symptoms on chronic diuretic therapy; and * CKD defined as glomerular filtration rate (eGFR) of 15-80 mL/min/1.73 m\^2 as estimated by the Modification of Diet in Renal Disease equation. Subject needs to be on stable dose of chronic diuretic for at least 4 weeks prior to study and maintained on the same dose for the duration of the study. In addition to the exclusion criteria listed below, to ensure a more homogenous group of subjects, we will exclude subjects with Diabetes or BMI \> 35 (because endogenous natriuretic peptide levels are low in obese subjects). Group 2: HFpEF-EI-will consist of 30 subjects with: * Ejection fraction of equal or greater than 55%; and * Previous invasive determination of normal pulmonary capillary wedge pressure (\< 15 mmHg) at rest and ≥ 25 mmHg during exercise; and * New York Heart Association (NYHA) functional class II-III symptoms; and * Glomerular filtration rate (eGFR) of \> 50 mL/min/1.73 m\^2 as estimated by the Modification of Diet in Renal Disease equation. In addition to the exclusion criteria listed below, to ensure a more homogenous group of subjects, we will exclude subjects with Diabetes or BMI\>35 (because endogenous natriuretic peptide levels are low in obese subjects). Exclusion Criteria: * Body mass index \> 35. * Blood pressure \< 100/60 or \> 180/100 mmHg. * Diabetes. * Myocardial infarction within 6 months of screening. * Unstable angina within 6 months of screening, or any evidence of myocardial ischemia. * Significant valvular heart diseases. * Hypertrophic, restrictive or obstructive cardiomyopathy. * Constrictive pericarditis. * Primary pulmonary hypertension. * Biopsy proven active myocarditis. * Severe congenital heart diseases. * Cardiac amyloidosis. * Fabry disease. * Sarcoidosis. * Sustained ventricular tachycardia or ventricular fibrillation within 14 days of screening. * Second or third degree heart block without a permanent cardiac pacemaker. * Stroke within 3 months of screening, or other evidence of significantly compromised CNS perfusion. * Hemoglobin \< 9 g/dl * ALT \> 2 times the upper limit of normal; * serum sodium of \< 135 mEq/dL or \> 160 mEq/dL. * Serum potassium of \< 3.5 mEq/dL or \> 5.7 mEq/dL. * Other acute or chronic medical conditions or laboratory abnormality which may increase the risks associated with study participation or may interfere with interpretation of the data. * Received an investigational drug within 1 month prior to dosing. * Patients with an allergy to iodine; * female subject who is pregnant or breastfeeding. * In the opinion of the investigator, is unlikely to comply with the study protocol or is unsuitable for any reasons.

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE1', 'PHASE2'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'CROSSOVER', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'DOUBLE', 'whoMasked': ['PARTICIPANT', 'INVESTIGATOR']}}, 'enrollmentInfo': {'count': 60, 'type': 'ESTIMATED'}}

2024-04-09