Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction

Phase 4

Completed

Conditions: Heart Failure and Reduced Ejection Fraction

Interventions: Drug: LCZ696 (sacubitril/valsartan)
Drug: Enalapril
Drug: Placebo of Enalapril
Drug: Placebo of LCZ696

Registration Number: NCT02874794

Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 465

Inclusion Criteria

History of HTN and one of the following at BOTH screening and pre-randomization:
1. SBP >105 mm Hg on antihypertensive medication.
2. 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.
1. If the patient is currently taking an ACEi, a 36-hour washout is required prior to randomization (Visit 2).
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.

Key

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LCZ696 (sacubitril/valsartan)	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.
LCZ696 (sacubitril/valsartan)	Placebo of Enalapril	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.
Enalapril	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).
Enalapril	Placebo of LCZ696	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).

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Aortic Characteristic Impedance at Week 12	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 Outcome Measures

Name	Time	Method
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 coefficients between changes from baseline in aortic characteristic impedance (dyne x sec/cm5) and biomarker levels such as BNP (pg/ML) during both trough 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	Pearson correlation coefficient between changes from baseline in aortic characteristic impedance (dyne x sec/cm5) and biomarker levels such as U-cGMP/U-creatinine ratio (nmol/mmol) during both trough 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 N-terminal pro-brain natriuretic peptide (NT-proBNP)
Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain	Baseline, Week 12	Parameter measured by echocardiography.
Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi)	Baseline, Week 12	Parameter measured by echocardiography
Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging)	Baseline, Week 12	Parameter measured by echocardiography
Change From Basekine in Echocardiographic Measure: Mitral E/E'	Baseline, Week 12	Parameter measured by echocardiography
Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF)	Baseline, Week 12	Parameter measured by echocardiography
Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees)	Baseline, Week 12	Parameter measured by echocardiography
Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi)	Baseline, Week 12	Parameter measured by echocardiography
Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi)	Baseline, Week 12	Parameter measured by echocardiography