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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 (EVALUATE-HF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02874794
Recruitment Status : Completed
First Posted : August 22, 2016
Results First Posted : March 19, 2020
Last Update Posted : January 5, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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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.

Condition or disease Intervention/treatment Phase
Heart Failure and Reduced Ejection Fraction Drug: LCZ696 (sacubitril/valsartan) Drug: Enalapril Drug: Placebo of Enalapril Drug: Placebo of LCZ696 Phase 4

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 465 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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)
Actual Study Start Date : August 17, 2016
Actual Primary Completion Date : December 13, 2018
Actual Study Completion Date : January 26, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arms and Interventions
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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 Name: 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


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  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 [ 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

  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 [ 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

  3. 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)

  4. Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain [ Time Frame: Baseline, Week 12 ]
    Parameter measured by echocardiography.

  5. Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi) [ Time Frame: Baseline, Week 12 ]
    Parameter measured by echocardiography

  6. Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging) [ Time Frame: Baseline, Week 12 ]
    Parameter measured by echocardiography

  7. Change From Basekine in Echocardiographic Measure: Mitral E/E' [ Time Frame: Baseline, Week 12 ]
    Parameter measured by echocardiography

  8. Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF) [ Time Frame: Baseline, Week 12 ]
    Parameter measured by echocardiography

  9. Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees) [ Time Frame: Baseline, Week 12 ]
    Parameter measured by echocardiography

  10. Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi) [ Time Frame: Baseline, Week 12 ]
    Parameter measured by echocardiography

  11. Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi) [ Time Frame: Baseline, Week 12 ]
    Parameter measured by echocardiography


Eligibility Criteria
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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02874794


Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] March 15, 2019
Statistical Analysis Plan  [PDF] March 26, 2019

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02874794    
Other Study ID Numbers: CLCZ696BUS08
First Posted: August 22, 2016    Key Record Dates
Results First Posted: March 19, 2020
Last Update Posted: January 5, 2021
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Heart Failure
Reduced Ejection Fraction
Central Aortic Stiffness
 Vascular
Echocardiogram
Aortic Stiffness
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Valsartan
Enalapril
Enalaprilat
Sacubitril and valsartan sodium hydrate drug combination
 Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors