NCT04128891.

Study name	Study of sacubitril/valsartan on myocardIal oxygenation and fibrosis in heart failure with preserved ejection fraction (PRISTINE‐HF)
Methods	Study design: parallel RCT Anticipated completion date: 1 February 2024
Participants	Estimated enrolment: 60 Inclusion criteria: "Written informed consent will be obtained before any assessment is performed ≥ 40 years of age, male or female LVEF ≥45% by echocardiography during the screening period Symptom(s) of heart failure requiring treatment with diuretic(s) for at least 30 days prior to screening visit Current symptom(s) of heart failure (NYHA functional class II to IV) Structural heart disease evidenced by at least 1 of the following echocardiography findings:Left atrial (LA) enlargement defined by at least 1 of the following: LA width (diameter) ≥3.8 cm or LA length ≥5.0 cm or LA area ≥20 cm2 or LA volume ≥55 ml or LA volume index ≥29 ml/m2Left ventricular hypertrophy defined by septal thickness or posterior wall thickness ≥1.2 cm Elevated NT‐proBNP (atleast 1 of the following)NT‐proBNP >300 pg/ml for patients not in atrial fibrillation or >900 pg/ml for patients in atrial fibrillation during initial screeningHeart failure hospitalization (defined as heart failure listed as the major reason for hospitalization) within 9 months prior to screening visit and NT‐proBNP >200 pg/ml for patients not in atrial fibrillation or >600 pg/ml for patients in atrial fibrillation during initial screening" Exclusion criteria: "Any prior echocardiographic measurement of LVEF <45% Acute coronary syndrome (including myocardial infarction), cardiac surgery, other major cardiovascular surgery, or percutaneous coronary intervention within 3 months Known unrevascularized epicardial coronary artery disease (> 50% stenosis in any major epicardial coronary artery) Current acute decompensated heart failure requiring augmented therapy with intravenous diuretic agents, vasodilator agents, and/or inotropic drugs Patients who require treatment with 2 or more of the following: an angiotensin converting enzyme inhibitor, an angiotensin receptor blocker, or a renin inhibitor History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes Patients with a known history of angioedema Probable alternative diagnoses that in the opinion of the investigator could account for the patient's heart failure symptoms such as significant pulmonary disease (including primary pulmonary hypertension), anaemia, or obesity. Specifically, patients with the following are excluded:Severe pulmonary disease including chronic obstructive pulmonary disease (i.e., requiring home oxygen therapy, chronic oral steroid therapy or hospitalized for pulmonary decompensation within 12 months) orHaemoglobin <10 g/dl, orBody mass index >40 kg/m2 Patients with any of the following:Systolic blood pressure (SBP) ≥180 mm Hg at entry, orSBP >150 mm Hg and <180 mm Hg at entry unless the patient is receiving 3 or more antihypertensive drugs.SBP <110 mm Hg at entry Current participation in another investigational drug or device. Patients with history of any dilated cardiomyopathy, including peripartum cardiomyopathy, chemotherapy‐induced cardiomyopathy, or viral myocarditis Evidence of right‐sided heart failure in the absence of left‐sided structural heart disease Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy Clinically significant congenital heart disease that could be the cause of the patient's symptoms and signs of heart failure Presence of hemodynamically significant valvular heart disease in the opinion of the investigator Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within the 3 months Carotid artery disease or valvular heart disease likely to require surgical or percutaneous intervention during the trial Life‐threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or atrial flutter with a resting ventricular rate >110 beats per minute Patients with a cardiac resynchronization therapy device Patients with prior major organ transplant or intent to transplant (i.e., on transplant list) Any surgical or medical condition that 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 Any surgical or medical condition that might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including but not limited to any of the following: any history of pancreatic injury, pancreatitis, or evidence of impaired pancreatic function/injury within the past 5 years Evidence of hepatic disease as determined by any 1 of the following: SGOT (AST) or SGPT (ALT) values exceeding 3× the upper limit of normal, bilirubin >1.5 mg/dl at entry Patients with severe renal impairment of the following: eGFR <30 ml/min/1.73 m2 as calculated by the Modification in Diet in Renal Disease (MDRD) formula at entry Presence of known functionally significant bilateral renal artery stenosis Patients with serum potassium >5.2 mmol/l (mEq/l) at entry History or presence of any other disease with a life expectancy of <3 years History of noncompliance to medical regimens and patients who are considered potentially unreliable History or evidence of drug or alcohol abuse within the past 12 months Persons directly involved in the execution of this protocol History of malignancy of any organ system (other than localized basal or squamous cell carcinoma of the skin or localized prostate cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases Pregnant or nursing (lactating) women Women of child‐bearing potential Contraindications to CMR (claustrophobia, implanted medical devices like pacemakers / defibrillators, cochlear implants, intracranial clips, iron fragments in eyes, inability to lie flat for the scanning period) Contraindications to Gadolinium (eGFR <30 ml/min/1.73 m2 as calculated by the MDRD formula at entry or previous know serious allergy) Contraindications to Adenosine (second or third‐degree atrioventricular block, asthma, concurrent dipyridamole use)"
Interventions	Sacubitril/valsartan versus valsartan Two years
Outcomes	improvement in microvascular function and ischaemia, as assessed by OS‐CMR at rest and stress; microvascular dysfunction; myocardial fibrosis; left ventricular diastolic function; NYHA class; 6‐minute walk test; heart failure related hospitalisations; cardiac mortality; all‐cause mortality
Starting date	1 February 2020
Contact information	Professor Selvanayagam: joseph.selva@sa.gov.au
Notes