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

NCT02874794 | Completed Phase 4 Results

• 1 other identifier: CLCZ696BUS08
• Study Type: interventional
• Target: 465
• Locations: 1 country
• Sites: 81

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.

Conditions

Heart Failure and Reduced Ejection Fraction

Keywords

Heart Failure; Reduced Ejection Fraction; Central Aortic Stiffness; Vascular; Echocardiogram; Aortic Stiffness

Outcome Measures

Primary Outcomes (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.

  Baseline, Week 12

Secondary Outcomes (11)

• 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

Study Arms (2)

LCZ696 (sacubitril/valsartan)

EXPERIMENTAL

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); Drug: Placebo of Enalapril

Enalapril

ACTIVE COMPARATOR

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; Drug: Placebo of LCZ696

Interventions

LCZ696 (sacubitril/valsartan) DRUG

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

Also known as: LCZ696

LCZ696 (sacubitril/valsartan)

Enalapril DRUG

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

Enalapril

Placebo of Enalapril DRUG

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

LCZ696 (sacubitril/valsartan)

Placebo of LCZ696 DRUG

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

Enalapril

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (81)

Novartis Investigative Site

Birmingham, Alabama, 35294-0006, United States

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Novartis Investigative Site

Little Rock, Arkansas, 72202, United States

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Novartis Investigative Site

Beverly Hills, California, 90211, United States

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Novartis Investigative Site

Huntington Beach, California, 92648, United States

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Novartis Investigative Site

Newport Beach, California, 92663, United States

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Novartis Investigative Site

Northridge, California, 91325, United States

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Novartis Investigative Site

Santa Ana, California, 92704, United States

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Novartis Investigative Site

Van Nuys, California, 91405, United States

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Novartis Investigative Site

Greenwich, Connecticut, 06830, United States

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Novartis Investigative Site

Norwalk, Connecticut, 06851, United States

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Novartis Investigative Site

Stamford, Connecticut, 06905, United States

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Novartis Investigative Site

Trumbull, Connecticut, 06611, United States

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Novartis Investigative Site

Newark, Delaware, 19713, United States

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Novartis Investigative Site

Atlantis, Florida, 33462, United States

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Novartis Investigative Site

Aventura, Florida, 33180, United States

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Novartis Investigative Site

Bradenton, Florida, 34209, United States

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Novartis Investigative Site

Coral Gables, Florida, 33134, United States

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Novartis Investigative Site

Daytona Beach, Florida, 32117, United States

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Novartis Investigative Site

Doral, Florida, 33166, United States

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Novartis Investigative Site

Fort Lauderdale, Florida, 33312, United States

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Novartis Investigative Site

Hialeah, Florida, 33012, United States

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Novartis Investigative Site

Inverness, Florida, 34452, United States

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Novartis Investigative Site

Jacksonville, Florida, 32223, United States

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Novartis Investigative Site

Jupiter, Florida, 33458, United States

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Novartis Investigative Site

Miami, Florida, 33125, United States

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Novartis Investigative Site

Miami, Florida, 33126, United States

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Novartis Investigative Site

Miami, Florida, 33133, United States

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Novartis Investigative Site

Miami, Florida, 33135, United States

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Novartis Investigative Site

Miami, Florida, 33144, United States

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Novartis Investigative Site

Miami, Florida, 33155, United States

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Novartis Investigative Site

Miami, Florida, 33165, United States

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Novartis Investigative Site

Miami, Florida, 33166, United States

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Novartis Investigative Site

Miami, Florida, 33176, United States

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Novartis Investigative Site

Naples, Florida, 34102, United States

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Novartis Investigative Site

Saint Augustine, Florida, 32086, United States

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Novartis Investigative Site

Athens, Georgia, 30606, United States

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Novartis Investigative Site

Augusta, Georgia, 30912, United States

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Novartis Investigative Site

Blue Ridge, Georgia, 30513, United States

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Novartis Investigative Site

Eatonton, Georgia, 31024, United States

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Novartis Investigative Site

Macon, Georgia, 31201, United States

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Novartis Investigative Site

Coeur d'Alene, Idaho, 83814, United States

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Novartis Investigative Site

Fairview Heights, Illinois, 62208, United States

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Novartis Investigative Site

Gurnee, Illinois, 60031, United States

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Novartis Investigative Site

Overland Park, Kansas, 66209, United States

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Novartis Investigative Site

Owensboro, Kentucky, 42303, United States

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Novartis Investigative Site

Baton Rouge, Louisiana, 70808, United States

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Novartis Investigative Site

Eunice, Louisiana, 70535, United States

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Novartis Investigative Site

Minden, Louisiana, 71055, United States

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Novartis Investigative Site

Monroe, Louisiana, 71201, United States

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Novartis Investigative Site

Slidell, Louisiana, 70458, United States

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Novartis Investigative Site

Baltimore, Maryland, 21237, United States

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Novartis Investigative Site

Alpena, Michigan, 49707, United States

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Novartis Investigative Site

Owosso, Michigan, 48867, United States

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Novartis Investigative Site

Saginaw, Michigan, 48604, United States

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Novartis Investigative Site

Lincoln, Nebraska, 68506, United States

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Novartis Investigative Site

Omaha, Nebraska, 68131, United States

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Novartis Investigative Site

Las Vegas, Nevada, 89128, United States

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Novartis Investigative Site

Hillsborough, New Jersey, 08844, United States

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Novartis Investigative Site

Linden, New Jersey, 07036, United States

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Novartis Investigative Site

Manalapan, New Jersey, 07726, United States

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Novartis Investigative Site

Mountain Lakes, New Jersey, 07046, United States

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Novartis Investigative Site

Buffalo, New York, 14215, United States

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Novartis Investigative Site

Lake Success, New York, 11042, United States

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Novartis Investigative Site

Rosedale, New York, 11422, United States

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Novartis Investigative Site

The Bronx, New York, 10469, United States

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Novartis Investigative Site

Charlotte, North Carolina, 28227, United States

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Novartis Investigative Site

Greenville, North Carolina, 27834, United States

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Novartis Investigative Site

Lenoir, North Carolina, 28645, United States

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Novartis Investigative Site

Yardley, Pennsylvania, 19067, United States

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Novartis Investigative Site

Jackson, Tennessee, 38301, United States

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Novartis Investigative Site

Amarillo, Texas, 79106-4165, United States

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Novartis Investigative Site

Houston, Texas, 77094, United States

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Novartis Investigative Site

McKinney, Texas, 75069, United States

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Novartis Investigative Site

McKinney, Texas, 75071, United States

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Novartis Investigative Site

Sherman, Texas, 75092, United States

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Novartis Investigative Site

Tomball, Texas, 77375, United States

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Novartis Investigative Site

Webster, Texas, 77598, United States

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Novartis Investigative Site

Richmond, Virginia, 23219, United States

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Novartis Investigative Site

Richland, Washington, 99352, United States

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Novartis Investigative Site

Spokane, Washington, 99204, United States

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Novartis Investigative Site

Manitowoc, Wisconsin, 54220, United States

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Related Publications (5)

• 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.

  PMID: 40678912 DERIVED

• 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.

  PMID: 35560696 DERIVED

• 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.

  PMID: 35115085 DERIVED

• 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.

  PMID: 33663237 DERIVED

• 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.

  PMID: 31475296 DERIVED

Related Links

• A Plain Language Trial Summary is available on novartisclinicatrials.com

MeSH Terms

Conditions

Heart Failure, Systolic; Heart Failure

Interventions

sacubitril and valsartan sodium hydrate drug combination; sacubitril; Valsartan; Enalapril

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential; Dipeptides; Oligopeptides; Peptides

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 5, 2016
• First Posted: August 22, 2016
• Study Start: August 17, 2016
• Primary Completion: December 13, 2018
• Study Completion: January 26, 2019
• Last Updated: January 5, 2021
• Results First Posted: March 19, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share

Locations

US (81)