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Heart Failure and Reduced Ejection FractionPhase 4EVALUATE-HFNCT02874794

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

A Phase 4 study testing LCZ696 (sacubitril/valsartan) and Enalapril in people with Heart Failure and Reduced Ejection Fraction, run by Novartis Pharmaceuticals at 81 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 50 years and older
What is being tested?
LCZ696 (sacubitril/valsartan) and Enalapril
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
465 participants
Where
81 sitesUnited States
Study dates
17 Aug 2016to 26 Jan 2019
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 50 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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 locations and contacts

81 sites in 1 country.

81 sites in 1 country

United States81 sites

  • Novartis Investigative Site

    Alpena, Michigan, 49707

  • Novartis Investigative Site

    Amarillo, Texas, 79106-4165

  • Novartis Investigative Site

    Athens, Georgia, 30606

  • Novartis Investigative Site

    Atlantis, Florida, 33462

  • Novartis Investigative Site

    Augusta, Georgia, 30912

  • Novartis Investigative Site

    Aventura, Florida, 33180

  • Novartis Investigative Site

    Baltimore, Maryland, 21237

  • Novartis Investigative Site

    Baton Rouge, Louisiana, 70808

  • Novartis Investigative Site

    Beverly Hills, California, 90211

  • Novartis Investigative Site

    Birmingham, Alabama, 35294-0006

  • Novartis Investigative Site

    Blue Ridge, Georgia, 30513

  • Novartis Investigative Site

    Bradenton, Florida, 34209

  • Novartis Investigative Site

    Buffalo, New York, 14215

  • Novartis Investigative Site

    Charlotte, North Carolina, 28227

  • Novartis Investigative Site

    Coeur d'Alene, Idaho, 83814

  • Novartis Investigative Site

    Coral Gables, Florida, 33134

  • Novartis Investigative Site

    Daytona Beach, Florida, 32117

  • Novartis Investigative Site

    Doral, Florida, 33166

  • Novartis Investigative Site

    Eatonton, Georgia, 31024

  • Novartis Investigative Site

    Eunice, Louisiana, 70535

  • Novartis Investigative Site

    Fairview Heights, Illinois, 62208

  • Novartis Investigative Site

    Fort Lauderdale, Florida, 33312

  • Novartis Investigative Site

    Greenville, North Carolina, 27834

  • Novartis Investigative Site

    Greenwich, Connecticut, 06830

  • Novartis Investigative Site

    Gurnee, Illinois, 60031

  • Novartis Investigative Site

    Hialeah, Florida, 33012

  • Novartis Investigative Site

    Hillsborough, New Jersey, 08844

  • Novartis Investigative Site

    Houston, Texas, 77094

  • Novartis Investigative Site

    Huntington Beach, California, 92648

  • Novartis Investigative Site

    Inverness, Florida, 34452

  • Novartis Investigative Site

    Jackson, Tennessee, 38301

  • Novartis Investigative Site

    Jacksonville, Florida, 32223

  • Novartis Investigative Site

    Jupiter, Florida, 33458

  • Novartis Investigative Site

    Lake Success, New York, 11042

  • Novartis Investigative Site

    Las Vegas, Nevada, 89128

  • Novartis Investigative Site

    Lenoir, North Carolina, 28645

  • Novartis Investigative Site

    Lincoln, Nebraska, 68506

  • Novartis Investigative Site

    Linden, New Jersey, 07036

  • Novartis Investigative Site

    Little Rock, Arkansas, 72202

  • Novartis Investigative Site

    Macon, Georgia, 31201

  • Novartis Investigative Site

    Manalapan, New Jersey, 07726

  • Novartis Investigative Site

    Manitowoc, Wisconsin, 54220

  • Novartis Investigative Site

    McKinney, Texas, 75069

  • Novartis Investigative Site

    McKinney, Texas, 75071

  • Novartis Investigative Site

    Miami, Florida, 33125

  • Novartis Investigative Site

    Miami, Florida, 33126

  • Novartis Investigative Site

    Miami, Florida, 33133

  • Novartis Investigative Site

    Miami, Florida, 33135

  • Novartis Investigative Site

    Miami, Florida, 33144

  • Novartis Investigative Site

    Miami, Florida, 33155

  • Novartis Investigative Site

    Miami, Florida, 33165

  • Novartis Investigative Site

    Miami, Florida, 33166

  • Novartis Investigative Site

    Miami, Florida, 33176

  • Novartis Investigative Site

    Minden, Louisiana, 71055

  • Novartis Investigative Site

    Monroe, Louisiana, 71201

  • Novartis Investigative Site

    Mountain Lakes, New Jersey, 07046

  • Novartis Investigative Site

    Naples, Florida, 34102

  • Novartis Investigative Site

    Newark, Delaware, 19713

  • Novartis Investigative Site

    Newport Beach, California, 92663

  • Novartis Investigative Site

    Northridge, California, 91325

  • Novartis Investigative Site

    Norwalk, Connecticut, 06851

  • Novartis Investigative Site

    Omaha, Nebraska, 68131

  • Novartis Investigative Site

    Overland Park, Kansas, 66209

  • Novartis Investigative Site

    Owensboro, Kentucky, 42303

  • Novartis Investigative Site

    Owosso, Michigan, 48867

  • Novartis Investigative Site

    Richland, Washington, 99352

  • Novartis Investigative Site

    Richmond, Virginia, 23219

  • Novartis Investigative Site

    Rosedale, New York, 11422

  • Novartis Investigative Site

    Saginaw, Michigan, 48604

  • Novartis Investigative Site

    Saint Augustine, Florida, 32086

  • Novartis Investigative Site

    Santa Ana, California, 92704

  • Novartis Investigative Site

    Sherman, Texas, 75092

  • Novartis Investigative Site

    Slidell, Louisiana, 70458

  • Novartis Investigative Site

    Spokane, Washington, 99204

  • Novartis Investigative Site

    Stamford, Connecticut, 06905

  • Novartis Investigative Site

    The Bronx, New York, 10469

  • Novartis Investigative Site

    Tomball, Texas, 77375

  • Novartis Investigative Site

    Trumbull, Connecticut, 06611

  • Novartis Investigative Site

    Van Nuys, California, 91405

  • Novartis Investigative Site

    Webster, Texas, 77598

  • Novartis Investigative Site

    Yardley, Pennsylvania, 19067

Other trials in United States

About this study

Official title: 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.

Being tested
LCZ696 (sacubitril/valsartan), Enalapril, Placebo of Enalapril, Placebo of LCZ696
Keywords
Heart Failure, Reduced Ejection Fraction, Central Aortic Stiffness, Vascular, Echocardiogram, Aortic Stiffness
Medical subject headings
Heart Failure, Systolic, Heart Failure

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LCZ696 (sacubitril/valsartan)Drug

    Also called LCZ696

    24/26mg, 49/51mg and 97/103mg oral, tablets.

  • EnalaprilDrug

    2.5mg, 5mg, and 10mg, oral, tablets

  • Placebo of EnalaprilDrug

    matching placebo (2.5mg, 5mg and 10mg) oral, tablets

  • Placebo of LCZ696Drug

    matching placebo (24/26mg, 49/51mg and 97/103mg) oral, tablets

Study groups in NCT02874794
Study groupRoleWhat they receive
LCZ696 (sacubitril/valsartan)Experimentalminimum 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.
Receives: Drug: LCZ696 (sacubitril/valsartan); Drug: Placebo of Enalapril
EnalaprilActive comparatorminimum 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).
Receives: Drug: Enalapril; Drug: Placebo of LCZ696

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change From Baseline in Aortic Characteristic Impedance at 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.

    Measured: Baseline, Week 12

Secondary outcomes (11)

  1. 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

    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

    Measured: Pre-dose and 4 hours post dose at week 4

  2. 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

    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

    Measured: pre-dose and 4 hours post dose at week 4

  3. Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)

    Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP)

    Measured: Baseline, Week 12

  4. Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain

    Parameter measured by echocardiography.

    Measured: Baseline, Week 12

  5. Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi)

    Parameter measured by echocardiography

    Measured: Baseline, Week 12

  6. Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging)

    Parameter measured by echocardiography

    Measured: Baseline, Week 12

  7. Change From Basekine in Echocardiographic Measure: Mitral E/E'

    Parameter measured by echocardiography

    Measured: Baseline, Week 12

  8. Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF)

    Parameter measured by echocardiography

    Measured: Baseline, Week 12

  9. Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees)

    Parameter measured by echocardiography

    Measured: Baseline, Week 12

  10. Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi)

    Parameter measured by echocardiography

    Measured: Baseline, Week 12

  11. Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi)

    Parameter measured by echocardiography

    Measured: Baseline, Week 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Aug 2016 (estimated)
  2. Study start17 Aug 2016
  3. Primary completion13 Dec 2018
  4. Study completion26 Jan 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
465 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02874794
Sponsor's protocol ID
CLCZ696BUS08
Acronym
EVALUATE-HF
Status last verified
Mar 2020
First submitted
5 Aug 2016
Last updated
5 Jan 2021
Data monitoring committee
No
Individual data sharing
Yes: 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

Publications

  • Lee S, Claggett BL, Fang JC, Mitchell GF, Ward JH, Solomon SD, Skali H, Desai AS, Hegde SM. Changes in cardiac structure and function are associated with health-related quality of life in heart failure patients with reduced ejection fraction: Results from the EVALUATE-HF trial. Eur J Heart Fail. 2025 Nov;27(11):2582-2593. doi: 10.1002/ejhf.3760. Epub 2025 Jul 18.

    PubMed 40678912

  • Myhre PL, Claggett BL, Shah AM, Prescott MF, Ward JH, Fang JC, Mitchell GF, Solomon SD, Desai AS. Changes in cardiac biomarkers in association with alterations in cardiac structure and function, and health status in heart failure with reduced ejection fraction: the EVALUATE-HF trial. Eur J Heart Fail. 2022 Jul;24(7):1200-1208. doi: 10.1002/ejhf.2541. Epub 2022 May 30.

    PubMed 35560696

  • Myhre PL, Prescott MF, Murphy SP, Fang JC, Mitchell GF, Ward JH, Claggett B, Desai AS, Solomon SD, Januzzi JL. Early B-Type Natriuretic Peptide Change in HFrEF Patients Treated With Sacubitril/Valsartan: A Pooled Analysis of EVALUATE-HF and PROVE-HF. JACC Heart Fail. 2022 Feb;10(2):119-128. doi: 10.1016/j.jchf.2021.09.007. Epub 2022 Jan 12.

    PubMed 35115085

  • Mitchell GF, Solomon SD, Shah AM, Claggett BL, Fang JC, Izzo J, Abbas CA, Desai AS; EVALUATE-HF Investigators*. Hemodynamic Effects of Sacubitril-Valsartan Versus Enalapril in Patients With Heart Failure in the EVALUATE-HF Study: Effect Modification by Left Ventricular Ejection Fraction and Sex. Circ Heart Fail. 2021 Mar;14(3):e007891. doi: 10.1161/CIRCHEARTFAILURE.120.007891. Epub 2021 Mar 5.

    PubMed 33663237

  • Desai AS, Solomon SD, Shah AM, Claggett BL, Fang JC, Izzo J, McCague K, Abbas CA, Rocha R, Mitchell GF; EVALUATE-HF Investigators. Effect of Sacubitril-Valsartan vs Enalapril on Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2019 Sep 17;322(11):1077-1084. doi: 10.1001/jama.2019.12843.

    PubMed 31475296

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing LCZ696 (sacubitril/valsartan) and Enalapril in people with Heart Failure and Reduced Ejection Fraction, run by Novartis Pharmaceuticals at 81 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 81 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Mar 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change From Baseline in Aortic Characteristic Impedance at Week 12 (time frame: Baseline, Week 12). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02874794, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jan 2021.

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