NCT03988634.

Study name	Changes in NT‐proBNP and outcomes, safety, and tolerability in HFpEF patients with acute decompensated heart failure (ADHF) who have been stabilized during hospitalization and initiated in‐hospital or within 30 days post‐discharge (PARAGLIDE‐HF)
Methods	Study design: parallel RCT Anticipated completion date: September 2021
Participants	Estimated enrolment: 800 Inclusion criteria: "Signed informed consent must be obtained prior to participation in the study Patients ≥40 years of age, male or female Currently hospitalized for or within 30 days following discharge of an acute decompensated HFpEF admission. Patients with a diagnosis of acute heart failure had to have symptoms and signs of fluid overload (i.e. jugular venous distention, edema or rales on auscultation or pulmonary congestion on chest x‐ray). Eligible patients will be randomized no earlier than 36 hours and within 30 days post‐discharge after presentation with acute HFpEF decompensation and meeting the following definitions of hemodynamic stability:In‐hospital randomized patients will have been hemodynamically stable defined in this study as:SBP≥100mmHg for the preceding 6 hours prior to randomization; no symptomatic hypotensionNo increase (intensification) in i.v. diuretic dose within last 6 hours prior to randomizationNo i.v. inotropic drugs for 24 hours prior to randomizationNo i.v. vasodilators including nitrates within last 6 hours prior to randomizationOut‐of‐hospital randomization patients will have been hemodynamically stabilized defined in this study as:SBP ≥100mmHg; no symptomatic hypotensionNo increase (intensification and/or change to IV) in diuretic dose within last 24 hours prior to randomizationNo i.v. inotropic drugs for 24 hours prior to randomization HFpEF with most recent LVEF >40% (within past 3 months) Elevated NT‐proBNP or BNP at the time of screening (and within 72 hours from inhospital screening to out‐of‐hospital randomization, if applicable)Patients not in AF at the time of biomarker assessment: NT‐proBNP ≥ 500pg/mL or BNP ≥ 150 pg/mL; patients in AF at the time of biomarker assessment: NT‐proBNP ≥ 1000pg/mL or BNP ≥ 300 pg/mLPatients recruited in‐hospital will be randomized based on the qualifying local lab value in‐hospital NT‐proBNP or BNP value. In‐hospital is the preferred method of enrollment.Patients enrolled out‐of‐hospital can be randomized based on their NT‐proBNP or BNP value in the following way:if enrolling in out‐of‐hospital setting then need eligible screening/local NTproBNP/BNP within 72 hours of randomization. The test value could be from recent hospitalization if within 72 hours or would require (re)drawing NT‐proBNP or BNP labs in out‐of‐hospital setting if the lab value is not already available within the last 72 hours Has not taken an ACEi for 36 hours prior to randomization" Exclusion criteria: "Any clinical event within the 90 days prior to randomization that could have reduced the LVEF (i.e., MI, CABG), unless an echo measurement was performed after the event confirming the LVEF to be >40% Currently taking Entresto™ (sacubitril/valsartan) or any prior use eGFR < 20ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at most recent assessment prior to randomization and within 24 hours prior to randomization Serum potassium > 5.2 mEq/L at most recent assessment prior to randomization and within 24 hours prior to randomization Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within 30 days prior to randomization Probable alternative diagnoses that in the opinion of the investigator could account for the patient's HF symptoms (i.e. dyspnea, fatigue) such as significant pulmonary disease (including primary pulmonary HTN), anemia or obesity. Specifically, patients with the following are excluded:Severe pulmonary disease including chronic obstructive pulmonary disease (COPD) (i.e. requiring home oxygen, oral steroid therapy) orHemoglobin (Hgb) < 9.5 g/dL males and < 9 g/dL females orBody mass index (BMI) > 50 kg/m2 at randomization Isolated right HF in the absence of left‐sided structural heart disease History of hypersensitivity (i.e. including angioedema), known or suspected contraindications, or intolerance to any of the study drugs including ARNIs (i.e.sacubitril/valsartan), and/or ARBs Patients with a known history of angioedema due to any etiology Patients with a history of heart transplant or LVAD, currently on the transplant list, or with planned intent to implant LVAD or CRT device within the initial three months of enrollment during the trial A cardiac or non‐cardiac medical condition other than HF with an estimated life expectancy of < 12 months Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy including amyloid heart disease (amyloidosis) Life‐threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate >110 bpm Clinically significant congenital heart disease felt to be the cause of the patient's symptoms and signs of HF Coronary or carotid artery disease or valvular heart disease likely to require surgical or percutaneous intervention within the duration of the trial Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study Known hepatic impairment (as evidenced by total bilirubin > 3 mg/dL, or increased ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension such as varices Participation in any other clinical trial involving investigational agents or devices within the past 30 days Pregnant or nursing women; women of childbearing potential that are not using a highly effective method of contraception until 1 week following last dose Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of study treatment"
Interventions	Sacubitril/valsartan versus valsartan 8 weeks
Outcomes	NT‐proBNP; composite hierarchical outcome consisting of: a) time to CV death, b) total HF hospitalizations, c) total urgent HF visits, and d) time‐averaged proportional change in NT‐proBNP; total composite events based on CV death, HF hospitalizations, and urgent HF visits; composite endpoint of worsening renal function (renal death, reaching ESRD, or decline in eGFR >/= 50%); hs‐Troponin (high sensitivity)
Starting date	27 June 2019
Contact information	Novartis Pharmaceuticals: novartis.email@novartis.com
Notes