Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event (HFpEF Decompensation) Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation (PARAGLIDE-HF)

Overview

The effect of sacubitril/valsartan vs. valsartan on changes in NT-proBNP, safety, and tolerability in HFpEF patients with a WHF event (HFpEF decompensation) who have been stabilized and initiated at the time of or within 30 days post-decompensation.

Full Title of Study: “A Multicenter, Randomized, Double-blind, Double-dummy, Parallel Group, Active Controlled Study to Evaluate the Effect of Sacubitril/Valsartan (LCZ696) Versus Valsartan on Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event (HFpEF Decompensation) Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation (PARAGLIDE-HF)”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Treatment
  • Masking: Double (Participant, Investigator)
• Study Primary Completion Date: December 14, 2022

Detailed Description

The purpose of this study is to assess the effect of sacubitril/valsartan vs. valsartan on changes in NT-proBNP, safety, and tolerability in HFpEF patients with a WHF event (HFpEF decompensation) who have been stabilized and initiated at the time of or within 30 days post-decompensation

Interventions

• Drug: sacubitril/valsartan
  • Sacubitril/valsartan (LCZ696) is available as 24/26 mg, 49/51 mg, and 97/103 mg in tablet form to be taken orally, twice daily, for the double-blind period. Valsartan matching placebo is available as 40 mg, 80 mg, and 160 mg in tablet form to be taken orally, twice daily, for the double-blind period.
• Drug: valsartan
  • Valsartan is available as 40 mg, 80 mg, and 160 mg in tablet form to be taken orally, twice daily, for the double-blind period. Sacubitril/valsartan (LCZ696) matching placebo is available as 24/26 mg, 49/51 mg, and 97/103 mg in tablet form to be taken orally, twice daily, for the double-blind period.

Arms, Groups and Cohorts

• Experimental: sacubitril/valsartan
  • randomized in a 1:1 ratio: sacubitril/valsartan to valsartan for up to approximately 20 months of double-blind treatment. Initial dose at randomization will be determined based on the patient’s previous dose of or lack of ACEi/ARB immediately prior to current WHF event (HFpEF decompensation), or at the time of post-decompensation randomization. Study treatment will be titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg twice daily (Dose Level 3). Patients will be required to take a total of two tablets twice daily (one tablet of active sacubitril/valsartan and one tablet of valsartan matching placebo pack).
• Active Comparator: valsartan
  • randomized in a 1:1 ratio: sacubitril/valsartan to valsartan for up to approximately 20 months of double-blind treatment. Initial dose at randomization will be determined based on the patient’s previous dose of or lack of ACEi/ARB immediately prior to current WHF event (HFpEF decompensation), or at the time of post-decompensation randomization. Study treatment will be titrated to the target dose of valsartan 160 mg twice daily (Dose Level 3). Patients will be required to take a total of two tablets twice daily (one tablet of active valsartan and one tablet of sacubitril/valsartan (LCZ696) matching placebo pack).

Clinical Trial Outcome Measures

Primary Measures

• Proportional change in NT-proBNP from baseline to the average of weeks 4 and 8
  • Time Frame: Baseline to weeks 4 and 8
  • To demonstrate the effect of sacubitril/valsartan vs. valsartan on time-averaged proportional change in NT-proBNP from baseline to Weeks 4 and 8 in HFpEF patients with a WHF event (HFpEF decompensation) who have been stabilized for and initiated at the time of or within 30 days post-decompensation

Secondary Measures

• Composite hierarchical outcome
  • Time Frame: Baseline, Weeks 4, Weeks 8, and Overtime Up to 84 Weeks
  • The effect of sacubitril/valsartan vs. valsartan on 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 (from baseline to Weeks 4 and 8) using win ratio methodology
• Cumulative number of recurrent composite events overtime
  • Time Frame: Overtime up to Week 84
  • To assess the effect of sacubitril/valsartan vs. valsartan on total composite events based on CV death, HF hospitalizations, and urgent HF visits
• Incidences of a composite endpoint of worsening renal function
  • Time Frame: Overtime up to Week 84
  • To assess the effect of sacubitril/valsartan vs. valsartan on the incidences of a composite endpoint of worsening renal function (renal death, reaching ESRD, or decline in eGFR >/= 50%)
• Proportional change in NT-proBNP from baseline to Week 8
  • Time Frame: Baseline to week 8
  • To assess the effect of sacubitril/valsartan vs. valsartan on change in NT-proBNP from baseline to Week 8
• Proportional change from baseline in hs-Troponin (high sensitivity) at Weeks 4 and 8
  • Time Frame: Baseline, Week 4 and Week 8
  • To assess the effect of sacubitril/valsartan vs. valsartan on change from baseline in hs-Troponin (high sensitivity) at Weeks 4 and 8

Participating in This Clinical Trial

Inclusion Criteria

1. Signed informed consent must be obtained prior to participation in the study 2. Patients >=18 years of age, male or female 3. Current hospitalization for Worsening Heart Failure (WHF) (HFpEF decompensation), or within 30 days of discharge following a WHF event (defined as hospitalization, emergency department (ED) visit or out-of-hospital urgent HF visit, all requiring IV diuretics). 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 after IV diuresis for HFpEF is given (and no earlier than 36 hours from their last ACEi dose if applicable) and within 30 days post-decompensation after presentation with acute HFpEF decompensation and meeting the following definitions of hemodynamic stability: Randomized patients will have been hemodynamically stable defined in this study as: 1. SBP >=100mmHg for the preceding 6 hours prior to randomization; no symptomatic hypotension 2. No increase (intensification) in IV diuretic dose within last 6 hours prior to randomization 3. No IV inotropic drugs for 24 hours prior to randomization 4. No IV vasodilators including nitrates within last 6 hours prior to randomization 4. HFpEF with most recent LVEF > 40% (within past 3 months) 5. Elevated NT-proBNP or BNP at the time of acute HFpEF decompensation or post-decompensation screening (and within 72 hours for out-of-hospital randomization, if applicable): a. Patients not in Atrial Fibrillation(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/mL b. Patients recruited in-hospital will be randomized based on the qualifying local lab value in-hospital NT-proBNP or BNP value. c. Patients enrolled post-decompensation can be randomized based on their NT-proBNP or BNP value in the following way: i. if enrolling in post-decompensation 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 ii. would require (re)drawing NT-proBNP or BNP labs in post-decompensation setting if the lab value is not already available within the last 72 hours). 6) Has not taken an ACEi for 36 hours prior to randomization EXCLUSION CRITERIA:

1. Any clinical event within the 90 days prior to randomization that could have reduced the LVEF (i.e., myocardial infarction (MI), coronary artery bypass graft (CABG), unless an echo measurement was performed after the event confirming the LVEF to be > 40% 2. Entresto™ (sacubitril/valsartan) usage within the past 60 days 3. 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 inpatient randomization or 72 hours prior to outpatient randomization 4. Serum potassium > 5.2 mEq/L at most recent assessment prior to randomization and within 24 hours prior to inpatient randomization or 72 hours prior to outpatient randomization 5. 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 6. 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. 7. Isolated right HF in the absence of left-sided structural heart disease 8. 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 9. Patients with a known history of angioedema due to any etiology 10. 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 11. A cardiac or non-cardiac medical condition other than HF with an estimated life expectancy of < 6 months 12. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy including suspected or confirmed amyloid heart disease (amyloidosis) 13. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate > 110 bpm 14. Clinically significant congenital heart disease felt to be the cause of the patient's symptoms and signs of HF 15. Coronary or carotid artery disease or valvular heart disease likely to require surgical or percutaneous intervention within the duration of the trial 16. 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 17. 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 18. Participation in any other clinical trial involving investigational agents or devices within the past 30 days 19. Current confirmed COVID19 infection 20. Past COVID19 infection with persistent symptom burden suspected due to COVID19 (further defined in Section 5.2). 21. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. 22. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug and for 7 days off of study drug. Highly effective contraception methods are defined in protocol.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 99 Years

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • Novartis Pharmaceuticals
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • Novartis Pharmaceuticals, Study Director, Novartis Pharmaceuticals