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

Novartis

Status and phase: Completed; Phase 4

Conditions: Heart Failure and Reduced Ejection Fraction

Treatments: Drug: Placebo of LCZ696; Drug: Placebo of Enalapril; Drug: LCZ696 (sacubitril/valsartan); Drug: Enalapril

Study type: Interventional

Funder types: Industry

Identifiers

NCT02874794

CLCZ696BUS08

Details and patient eligibility

About

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.

Enrollment: 465 patients

Sex: All

Ages: 50+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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465 participants in 2 patient groups

LCZ696 (sacubitril/valsartan)

Experimental group

Description:

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.

Treatment:

Drug: LCZ696 (sacubitril/valsartan)

Drug: Placebo of Enalapril

Enalapril

Active Comparator group

Description:

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).

Treatment:

Drug: Placebo of LCZ696

Drug: Enalapril