A Multicenter, Randomized, Double-blind, Double-dummy, Parallel Group, Active-controlled, Forced-titration, 12-week Comparison of Combined Angiotensin-neprilysin Inhibition With Sacubitril and Valsartan Versus Enalapril on Changes in Central Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction (HFrEF)
Trial Snapshot
- Phase
- Phase 4
- Status
- Completed
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 465
- Locations
- 1
- Primary Endpoint
- Change From Baseline in Aortic Characteristic Impedance at Week 12
Study Overview
Brief Summary
To determine whether treatment with sacubitril/valsartan provides a superior effect on aortic characteristic impedance compared to enalapril in patients with heart failure and reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%) after 12 weeks of treatment. The primary endpoint is the change in aortic characteristic impedance (Zc = dP/dQ in early systole) between baseline and Week 12.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Care Provider, Investigator)
Eligibility Criteria
- Ages
- 50 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •History of HTN and one of the following at BOTH screening and pre-randomization:
- •SBP >105 mm Hg on antihypertensive medication.
- •SBP >/= 140 mm Hg and NOT on antihypertensive medication.
- •NYHA class I-III heart failure and with reduced ejection fraction </= 40%, as determined by any local measurement made within the past 12 months using echocardiography, MUGA, CT scanning, MRI, ventricular angiography or single-photon emission computed tomography (SPECT), provided no subsequent measurement above 40%. Patients who have had an intervening medical event (e.g. myocardial infarction) or procedure (e.g. revascularization, cardiac resynchronization), must have a reassessment of EF ≥ 3 months following the event to ensure that eligibility criteria are still met.
- •On stable doses of treatment with guideline-directed therapy, other than ACEis and ARBs prior to randomization.
- •If the patient is currently taking an ACEi, a 36-hour washout is required prior to randomization (Visit 2).
- •If the patient is currently taking an ARB, they must discontinue the ARB before initiation of study treatment however washout is not required.
- •On an optimal medical regiment of diuretics and background medications to effectively treat co-morbidities such as HTN, DM, and coronary artery disease.
Exclusion Criteria
- •History of hypersensitivity to any of the study drigs, including history of hypersensitivity to drugs of similar chemical classes, or allergy to ACEis, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs.
- •Previous history of intolerance to sacubitril and valsartan, ACEi or ARB standard of care doses despite appropriate and gradual up-titration.
- •History of angioedema, drug-related or otherwise.
- •Requirement of treatment with both ACE inhibitor and ARB.
- •Current or prior treatment with sacubitril and valsartan.
Arms & Interventions
LCZ696 (sacubitril/valsartan)
minimum dose: 24/26mg, BID, oral, tablet maximum dose: 97/103mg, BID, oral, tablet All patients will begin on Dose Level 1 (24/26mg) and will be titrated every two weeks to target Dose level 3 (97/103mg). LCZ696 tablets will be provided for the 12-week open label extension.
Intervention: LCZ696 (sacubitril/valsartan) (Drug)
LCZ696 (sacubitril/valsartan)
minimum dose: 24/26mg, BID, oral, tablet maximum dose: 97/103mg, BID, oral, tablet All patients will begin on Dose Level 1 (24/26mg) and will be titrated every two weeks to target Dose level 3 (97/103mg). LCZ696 tablets will be provided for the 12-week open label extension.
Intervention: Placebo of Enalapril (Drug)
Enalapril
minimum dose: 2.5mg, BID, oral, tablet maximum dose: 10 mg, BID, oral tablet All patients will begin on Dose Level 1 (2.5mg) and will be titrated every two weeks to target Dose level 3 (10mg).
Intervention: Enalapril (Drug)
Enalapril
minimum dose: 2.5mg, BID, oral, tablet maximum dose: 10 mg, BID, oral tablet All patients will begin on Dose Level 1 (2.5mg) and will be titrated every two weeks to target Dose level 3 (10mg).
Intervention: Placebo of LCZ696 (Drug)
Outcomes
Primary Outcomes
Change From Baseline in Aortic Characteristic Impedance at Week 12
Time Frame: Baseline, Week 12
Aortic characteristic impedance, Zc, is the ratio of the change in pressure (dP)produced by a given change in flow (dQ) in early systole, i.e., Zc = dP/dQ. Zc is related directly to aortic wall stiffness and inversely to lumen area.
Secondary Outcomes
- Change From Basekine in Echocardiographic Measure: Mitral E/E'(Baseline, Week 12)
- Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: B-type Natriuretic Peptide (BNP) During Both Trough and 4 Hours Post-dose at Week 4(Pre-dose and 4 hours post dose at week 4)
- Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: cGMP/U-creatinine During Both Trough and 4 Hours Post-dose at Week 4(pre-dose and 4 hours post dose at week 4)
- Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)(Baseline, Week 12)
- Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain(Baseline, Week 12)
- Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi)(Baseline, Week 12)
- Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging)(Baseline, Week 12)
- Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF)(Baseline, Week 12)
- Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees)(Baseline, Week 12)
- Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi)(Baseline, Week 12)
- Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi)(Baseline, Week 12)