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

NCT ID: NCT02874794

Last Updated: 2021-01-05

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

465 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-08-17

Study Completion Date

2019-01-26

Brief Summary

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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.

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Detailed Description

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Conditions

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Heart Failure and Reduced Ejection Fraction

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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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.

Group Type EXPERIMENTAL

LCZ696 (sacubitril/valsartan)

Intervention Type DRUG

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

Placebo of Enalapril

Intervention Type DRUG

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

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).

Group Type ACTIVE_COMPARATOR

Enalapril

Intervention Type DRUG

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

Placebo of LCZ696

Intervention Type DRUG

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

Interventions

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LCZ696 (sacubitril/valsartan)

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

Intervention Type DRUG

Enalapril

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

Intervention Type DRUG

Placebo of Enalapril

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

Intervention Type DRUG

Placebo of LCZ696

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

Intervention Type DRUG

Other Intervention Names

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LCZ696

Eligibility Criteria

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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.

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.
Minimum Eligible Age

50 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Novartis Pharmaceuticals

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

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Novartis Investigative Site

Birmingham, Alabama, United States

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Novartis Investigative Site

Little Rock, Arkansas, United States

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Beverly Hills, California, United States

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Huntington Beach, California, United States

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Newport Beach, California, United States

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Northridge, California, United States

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Santa Ana, California, United States

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Van Nuys, California, United States

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Greenwich, Connecticut, United States

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Norwalk, Connecticut, United States

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Stamford, Connecticut, United States

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Trumbull, Connecticut, United States

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Newark, Delaware, United States

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Atlantis, Florida, United States

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Aventura, Florida, United States

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Bradenton, Florida, United States

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Coral Gables, Florida, United States

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Daytona Beach, Florida, United States

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Doral, Florida, United States

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Fort Lauderdale, Florida, United States

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Hialeah, Florida, United States

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Inverness, Florida, United States

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Jacksonville, Florida, United States

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Jupiter, Florida, United States

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Miami, Florida, United States

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Miami, Florida, United States

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Miami, Florida, United States

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Miami, Florida, United States

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Miami, Florida, United States

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Miami, Florida, United States

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Miami, Florida, United States

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Naples, Florida, United States

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Saint Augustine, Florida, United States

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Athens, Georgia, United States

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Augusta, Georgia, United States

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Blue Ridge, Georgia, United States

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Eatonton, Georgia, United States

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Macon, Georgia, United States

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Coeur d'Alene, Idaho, United States

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Fairview Heights, Illinois, United States

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Gurnee, Illinois, United States

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Overland Park, Kansas, United States

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Owensboro, Kentucky, United States

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Baton Rouge, Louisiana, United States

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Eunice, Louisiana, United States

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Minden, Louisiana, United States

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Monroe, Louisiana, United States

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Slidell, Louisiana, United States

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Baltimore, Maryland, United States

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Alpena, Michigan, United States

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Owosso, Michigan, United States

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Saginaw, Michigan, United States

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Lincoln, Nebraska, United States

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Omaha, Nebraska, United States

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Las Vegas, Nevada, United States

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Hillsborough, New Jersey, United States

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Linden, New Jersey, United States

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Manalapan, New Jersey, United States

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Mountain Lakes, New Jersey, United States

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Buffalo, New York, United States

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Lake Success, New York, United States

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Rosedale, New York, United States

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The Bronx, New York, United States

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Charlotte, North Carolina, United States

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Greenville, North Carolina, United States

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Lenoir, North Carolina, United States

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Yardley, Pennsylvania, United States

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Jackson, Tennessee, United States

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Amarillo, Texas, United States

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Houston, Texas, United States

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McKinney, Texas, United States

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McKinney, Texas, United States

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Sherman, Texas, United States

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Tomball, Texas, United States

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Webster, Texas, United States

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Richmond, Virginia, United States

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Richland, Washington, United States

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Spokane, Washington, United States

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Manitowoc, Wisconsin, United States

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Countries

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United States

References

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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 Jul 18. doi: 10.1002/ejhf.3760. Online ahead of print.

Reference Type DERIVED
PMID: 40678912 (View on PubMed)

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.

Reference Type DERIVED
PMID: 35560696 (View on PubMed)

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.

Reference Type DERIVED
PMID: 35115085 (View on PubMed)

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.

Reference Type DERIVED
PMID: 33663237 (View on PubMed)

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.

Reference Type DERIVED
PMID: 31475296 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

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https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=514

A Plain Language Trial Summary is available on novartisclinicatrials.com

Other Identifiers

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CLCZ696BUS08

Identifier Type: -

Identifier Source: org_study_id

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