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

December 9, 2020 updated by: Novartis Pharmaceuticals

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)

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 Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

465

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294-0006
        • Novartis Investigative Site
    • Arkansas
      • Little Rock, Arkansas, United States, 72202
        • Novartis Investigative Site
    • California
      • Beverly Hills, California, United States, 90211
        • Novartis Investigative Site
      • Huntington Beach, California, United States, 92648
        • Novartis Investigative Site
      • Newport Beach, California, United States, 92663
        • Novartis Investigative Site
      • Northridge, California, United States, 91325
        • Novartis Investigative Site
      • Santa Ana, California, United States, 92704
        • Novartis Investigative Site
      • Van Nuys, California, United States, 91405
        • Novartis Investigative Site
    • Connecticut
      • Greenwich, Connecticut, United States, 06830
        • Novartis Investigative Site
      • Norwalk, Connecticut, United States, 06851
        • Novartis Investigative Site
      • Stamford, Connecticut, United States, 06905
        • Novartis Investigative Site
      • Trumbull, Connecticut, United States, 06611
        • Novartis Investigative Site
    • Delaware
      • Newark, Delaware, United States, 19713
        • Novartis Investigative Site
    • Florida
      • Atlantis, Florida, United States, 33462
        • Novartis Investigative Site
      • Aventura, Florida, United States, 33180
        • Novartis Investigative Site
      • Bradenton, Florida, United States, 34209
        • Novartis Investigative Site
      • Coral Gables, Florida, United States, 33134
        • Novartis Investigative Site
      • Daytona Beach, Florida, United States, 32117
        • Novartis Investigative Site
      • Doral, Florida, United States, 33166
        • Novartis Investigative Site
      • Fort Lauderdale, Florida, United States, 33312
        • Novartis Investigative Site
      • Hialeah, Florida, United States, 33012
        • Novartis Investigative Site
      • Inverness, Florida, United States, 34452
        • Novartis Investigative Site
      • Jacksonville, Florida, United States, 32223
        • Novartis Investigative Site
      • Jupiter, Florida, United States, 33458
        • Novartis Investigative Site
      • Miami, Florida, United States, 33126
        • Novartis Investigative Site
      • Miami, Florida, United States, 33135
        • Novartis Investigative Site
      • Miami, Florida, United States, 33125
        • Novartis Investigative Site
      • Miami, Florida, United States, 33133
        • Novartis Investigative Site
      • Miami, Florida, United States, 33144
        • Novartis Investigative Site
      • Miami, Florida, United States, 33176
        • Novartis Investigative Site
      • Miami, Florida, United States, 33155
        • Novartis Investigative Site
      • Miami, Florida, United States, 33165
        • Novartis Investigative Site
      • Miami, Florida, United States, 33166
        • Novartis Investigative Site
      • Naples, Florida, United States, 34102
        • Novartis Investigative Site
      • Saint Augustine, Florida, United States, 32086
        • Novartis Investigative Site
    • Georgia
      • Athens, Georgia, United States, 30606
        • Novartis Investigative Site
      • Augusta, Georgia, United States, 30912
        • Novartis Investigative Site
      • Blue Ridge, Georgia, United States, 30513
        • Novartis Investigative Site
      • Eatonton, Georgia, United States, 31024
        • Novartis Investigative Site
      • Macon, Georgia, United States, 31201
        • Novartis Investigative Site
    • Idaho
      • Coeur d'Alene, Idaho, United States, 83814
        • Novartis Investigative Site
    • Illinois
      • Fairview Heights, Illinois, United States, 62208
        • Novartis Investigative Site
      • Gurnee, Illinois, United States, 60031
        • Novartis Investigative Site
    • Kansas
      • Overland Park, Kansas, United States, 66209
        • Novartis Investigative Site
    • Kentucky
      • Owensboro, Kentucky, United States, 42303
        • Novartis Investigative Site
    • Louisiana
      • Baton Rouge, Louisiana, United States, 70808
        • Novartis Investigative Site
      • Eunice, Louisiana, United States, 70535
        • Novartis Investigative Site
      • Minden, Louisiana, United States, 71055
        • Novartis Investigative Site
      • Monroe, Louisiana, United States, 71201
        • Novartis Investigative Site
      • Slidell, Louisiana, United States, 70458
        • Novartis Investigative Site
    • Maryland
      • Baltimore, Maryland, United States, 21237
        • Novartis Investigative Site
    • Michigan
      • Alpena, Michigan, United States, 49707
        • Novartis Investigative Site
      • Owosso, Michigan, United States, 48867
        • Novartis Investigative Site
      • Saginaw, Michigan, United States, 48604
        • Novartis Investigative Site
    • Nebraska
      • Lincoln, Nebraska, United States, 68506
        • Novartis Investigative Site
      • Omaha, Nebraska, United States, 68131
        • Novartis Investigative Site
    • Nevada
      • Las Vegas, Nevada, United States, 89128
        • Novartis Investigative Site
    • New Jersey
      • Hillsborough, New Jersey, United States, 08844
        • Novartis Investigative Site
      • Linden, New Jersey, United States, 07036
        • Novartis Investigative Site
      • Manalapan, New Jersey, United States, 07726
        • Novartis Investigative Site
      • Mountain Lakes, New Jersey, United States, 07046
        • Novartis Investigative Site
    • New York
      • Bronx, New York, United States, 10469
        • Novartis Investigative Site
      • Buffalo, New York, United States, 14215
        • Novartis Investigative Site
      • Lake Success, New York, United States, 11042
        • Novartis Investigative Site
      • Rosedale, New York, United States, 11422
        • Novartis Investigative Site
    • North Carolina
      • Charlotte, North Carolina, United States, 28227
        • Novartis Investigative Site
      • Greenville, North Carolina, United States, 27834
        • Novartis Investigative Site
      • Lenoir, North Carolina, United States, 28645
        • Novartis Investigative Site
    • Pennsylvania
      • Yardley, Pennsylvania, United States, 19067
        • Novartis Investigative Site
    • Tennessee
      • Jackson, Tennessee, United States, 38301
        • Novartis Investigative Site
    • Texas
      • Amarillo, Texas, United States, 79106-4165
        • Novartis Investigative Site
      • Houston, Texas, United States, 77094
        • Novartis Investigative Site
      • McKinney, Texas, United States, 75069
        • Novartis Investigative Site
      • McKinney, Texas, United States, 75071
        • Novartis Investigative Site
      • Sherman, Texas, United States, 75092
        • Novartis Investigative Site
      • Tomball, Texas, United States, 77375
        • Novartis Investigative Site
      • Webster, Texas, United States, 77598
        • Novartis Investigative Site
    • Virginia
      • Richmond, Virginia, United States, 23219
        • Novartis Investigative Site
    • Washington
      • Richland, Washington, United States, 99352
        • Novartis Investigative Site
      • Spokane, Washington, United States, 99204
        • Novartis Investigative Site
    • Wisconsin
      • Manitowoc, Wisconsin, United States, 54220
        • Novartis Investigative Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: 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.
Drug: LCZ696 (sacubitril/valsartan)
24/26mg, 49/51mg and 97/103mg oral, tablets.
Other Names:
  • LCZ696
Drug: Placebo of Enalapril
matching placebo (2.5mg, 5mg and 10mg) oral, tablets
ACTIVE_COMPARATOR: 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).
Drug: Enalapril
2.5mg, 5mg, and 10mg, oral, tablets
Drug: Placebo of LCZ696
matching placebo (24/26mg, 49/51mg and 97/103mg) oral, tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Baseline, Week 12

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Time Frame: 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
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
Time Frame: 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
pre-dose and 4 hours post dose at week 4
Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)
Time Frame: Baseline, Week 12
Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP)
Baseline, Week 12
Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain
Time Frame: Baseline, Week 12
Parameter measured by echocardiography.
Baseline, Week 12
Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi)
Time Frame: Baseline, Week 12
Parameter measured by echocardiography
Baseline, Week 12
Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging)
Time Frame: Baseline, Week 12
Parameter measured by echocardiography
Baseline, Week 12
Change From Basekine in Echocardiographic Measure: Mitral E/E'
Time Frame: Baseline, Week 12
Parameter measured by echocardiography
Baseline, Week 12
Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF)
Time Frame: Baseline, Week 12
Parameter measured by echocardiography
Baseline, Week 12
Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees)
Time Frame: Baseline, Week 12
Parameter measured by echocardiography
Baseline, Week 12
Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi)
Time Frame: Baseline, Week 12
Parameter measured by echocardiography
Baseline, Week 12
Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi)
Time Frame: Baseline, Week 12
Parameter measured by echocardiography
Baseline, Week 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Novartis Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

August 17, 2016

Primary Completion (ACTUAL)

December 13, 2018

Study Completion (ACTUAL)

January 26, 2019

Study Registration Dates

First Submitted

August 5, 2016

First Submitted That Met QC Criteria

August 17, 2016

First Posted (ESTIMATE)

August 22, 2016

Study Record Updates

Last Update Posted (ACTUAL)

January 5, 2021

Last Update Submitted That Met QC Criteria

December 9, 2020

Last Verified

March 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CLCZ696BUS08

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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