Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes.

NCT02887183 | Completed Phase 4 Results FDA Drug

• 1 other identifier: CLCZ696BUS13
• Study Type: interventional
• Target: 794
• Locations: 1 country
• Sites: 77

Brief Summary

This study was to determine early and more chronic changes in concentrations of biomarkers related to mechanisms of action (MOA) and effects of sacubitril/valsartan therapy over a period of 12 months, and correlated these biomarker changes with cardiac remodeling parameters, patient-reported outcomes and cardiovascular outcomes.

Conditions

Heart Failure

Keywords

Heart failure; Reduced left ventricular ejection fraction; HFrEF; NT-proBNP; Cardiac remodeling; sacubitril/valsartan; KCCQ; biomarkers

Outcome Measures

Primary Outcomes (4)

• Change in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to One Year

  Change in concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to one year

  Baseline, one year

• Change in Left Atrial Volume Index (LAVi), Left Ventricular End Diastolic Volume Index (LVEDVi), Left Ventricular End Systolic Volume Index (LVESVi), and From Baseline to One Year

  Change in left atrial volume index (LAVi), left ventricular end diastolic volume index (LVEDVi), left ventricular end systolic volume index (LVESVi), and from baseline to one year

  Baseline, one Year

• Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to One Year

  Change in Left ventricular ejection fraction (LVEF) from baseline to one year. LVEF is a measurement expressed as a percentage of how much blood the left ventricle pumps out with each contraction.

  Baseline, one year

• Change in Log-transformed NT-proBNP and Change in Structural Cardiac Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to One Year

  Pearson's correlation coefficient was calculated between change in log-transformed NT-proBNP and change in structural cardiac measurements LVESVi, LVEDVi, LAVi, and LVEF from baseline to one year.

  Baseline, one year

Secondary Outcomes (6)

• Change in Log-transformed NT-proBNP Concentration and Change in Echocardiographic Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to Month 6

  Baseline, Month 6

• Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Change in Left Atrial Volume Index (LAVi) by Selected Groups of Interest at Month 6

  Baseline, Month 6

• Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Systolic Volume Index (LVESVi) by Selected Groups of Interest at Month 6

  Baseline, Month 6

• Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Diastolic Volume Index (LVEDVi) by Selected Groups of Interest at Month 6

  Baseline, Month 6

• Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular Ejection Fraction (LVEF) by Selected Groups of Interest at Month 6

  Baseline, Month 6

Study Arms (1)

LCZ696(sacubitril/valsartan)

OTHER

Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.

Drug: LCZ696 (sacubitril/valsartan)

Interventions

LCZ696 (sacubitril/valsartan) DRUG

LCZ696 (sacubitril/valsartan) was supplied as unscored, ovaloid, film-coated oral tablets in the strengths of 24/26 mg, 49/51 mg, 97/103 mg to be taken twice daily (bid)

LCZ696(sacubitril/valsartan)

Eligibility Criteria

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

You may qualify if:

• Written informed consent must be obtained before any assessment is performed.
• Men and women ≥ 18 years of age.
• LVEF ≤ 40% subjects who are candidates for on-label sacubitril/valsartan treatment per standard of care.
• New York Heart Association (NYHA) Functional class II-IV.
• LVEF ≤40% via any local measurement within the past 6 months using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography provided no subsequent study documenting an EF of \>40%. If the EF measurement is expressed as a value range, the average of the range endpoint values should be used as the EF.
• If a subject is on a loop diuretic, they must be on a stable dose for 2 weeks prior to baseline.

You may not qualify if:

• pregnant or nursing women
• women of child bearing potential not using highly effective method of contraception during dosing and for 7 days after stopping study medication
• History of hypersensitivity to any of the study drugs, including history of hypersensitivity to drugs of similar chemical classes, or allergy to angiotensin converting enzyme inhibitor (ACEIs), Angiotensin II Receptor Blockers (ARBs), or Neutral endopeptidase (NEP) inhibitors as well as known or suspected contraindications to the study drugs.
• History of angioedema drug related or otherwise.
• Requirement of treatment with either ACE inhibitor and/or ARB.
• Subjects with a heart transplant or ventricular assistance device (VAD) or intent to transplant (on transplant list) or implant a VAD.
• Subjects with a cardio resynchronization therapy devices (CRT/CRT-D) implanted within 6 months of screening visit.
• Subjects who are currently taking inotropic agents.
• Current or prior treatment with sacubitril/valsartan.
• Subjects taking medications prohibited by the protocol.
• Subjects with diabetes mellitus who are taking aliskiren.
• Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days until the expected pharmacodynamic effect has returned to baseline, whichever is longer.
• Concomitant use of nesiritide.
• Bile acid sequestering agents such as cholestyramine or colestipol are prohibited to avoid interference with study drug absorption.
• Any hospital admission/discharge related to heart failure within 2 weeks prior to baseline.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (77)

Novartis Investigative Site

Birmingham, Alabama, 35243, United States

Location

Novartis Investigative Site

Fort Payne, Alabama, 35967, United States

Location

Novartis Investigative Site

Guntersville, Alabama, 35976, United States

Location

Novartis Investigative Site

Bakersfield, California, 93308, United States

Location

Novartis Investigative Site

Long Beach, California, 90806, United States

Location

Novartis Investigative Site

Los Alamitos, California, 90720, United States

Location

Novartis Investigative Site

Sylmar, California, 91342, United States

Location

Novartis Investigative Site

West Haven, Connecticut, 06516, United States

Location

Novartis Investigative Site

Belle Glade, Florida, 33430, United States

Location

Novartis Investigative Site

Bradenton, Florida, 34209, United States

Location

Novartis Investigative Site

Hollywood, Florida, 33312, United States

Location

Novartis Investigative Site

Homestead, Florida, 33030, United States

Location

Novartis Investigative Site

Jupiter, Florida, 33458, United States

Location

Novartis Investigative Site

Lake Worth, Florida, 334361, United States

Location

Novartis Investigative Site

Miami, Florida, 33126, United States

Location

Novartis Investigative Site

Miami, Florida, 33133, United States

Location

Novartis Investigative Site

Miami, Florida, 33155, United States

Location

Novartis Investigative Site

Miami, Florida, 33173, United States

Location

Novartis Investigative Site

Port Orange, Florida, 32127, United States

Location

Novartis Investigative Site

Wellington, Florida, 33449, United States

Location

Novartis Investigative Site

Arlington Heights, Illinois, 60005, United States

Location

Novartis Investigative Site

Aurora, Illinois, 60504, United States

Location

Novartis Investigative Site

Lombard, Illinois, 60148, United States

Location

Novartis Investigative Site

Oak Lawn, Illinois, 60453, United States

Location

Novartis Investigative Site

Louisville, Kentucky, 40207, United States

Location

Novartis Investigative Site

Owensboro, Kentucky, 42303, United States

Location

Novartis Investigative Site

Crowley, Louisiana, 70526, United States

Location

Novartis Investigative Site

Shreveport, Louisiana, 71101, United States

Location

Novartis Investigative Site

West Monroe, Louisiana, 71291, United States

Location

Novartis Investigative Site

Baltimore, Maryland, 21220, United States

Location

Novartis Investigative Site

Baltimore, Maryland, 21229, United States

Location

Novartis Investigative Site

Columbia, Maryland, 21044, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02114, United States

Location

Novartis Investigative Site

Haverhill, Massachusetts, 01830, United States

Location

Novartis Investigative Site

Springfield, Massachusetts, 01104, United States

Location

Novartis Investigative Site

Kalamazoo, Michigan, 49008, United States

Location

Novartis Investigative Site

Minneapolis, Minnesota, 55415, United States

Location

Novartis Investigative Site

Belzoni, Mississippi, 39038, United States

Location

Novartis Investigative Site

Jackson, Mississippi, 39209, United States

Location

Novartis Investigative Site

Southhaven, Mississippi, 38671, United States

Location

Novartis Investigative Site

Bozeman, Montana, 59715, United States

Location

Novartis Investigative Site

Lincoln, Nebraska, 68506, United States

Location

Novartis Investigative Site

Lincoln, Nebraska, 68526, United States

Location

Novartis Investigative Site

Omaha, Nebraska, 68114, United States

Location

Novartis Investigative Site

Nashua, New Hampshire, 03060, United States

Location

Novartis Investigative Site

Buffalo, New York, 14215, United States

Location

Novartis Investigative Site

Lake Success, New York, 11042, United States

Location

Novartis Investigative Site

Potsdam, New York, 13676, United States

Location

Novartis Investigative Site

The Bronx, New York, 10461, United States

Location

Novartis Investigative Site

Greensboro, North Carolina, 27410, United States

Location

Novartis Investigative Site

Hickory, North Carolina, 28601, United States

Location

Novartis Investigative Site

Winston-Salem, North Carolina, 27103, United States

Location

Novartis Investigative Site

Hillsboro, Oregon, 97123, United States

Location

Novartis Investigative Site

Oregon City, Oregon, 97045, United States

Location

Novartis Investigative Site

Portland, Oregon, 97225, United States

Location

Novartis Investigative Site

Camp Hill, Pennsylvania, 17011, United States

Location

Novartis Investigative Site

Wyomissing, Pennsylvania, 19610, United States

Location

Novartis Investigative Site

Yardley, Pennsylvania, 19067, United States

Location

Novartis Investigative Site

Simpsonville, South Carolina, 29681, United States

Location

Novartis Investigative Site

Germantown, Tennessee, 38138, United States

Location

Novartis Investigative Site

Austin, Texas, 78704, United States

Location

Novartis Investigative Site

Beaumont, Texas, 77701, United States

Location

Novartis Investigative Site

Bryan, Texas, 77802, United States

Location

Novartis Investigative Site

Dallas, Texas, 75231, United States

Location

Novartis Investigative Site

Houston, Texas, 77081, United States

Location

Novartis Investigative Site

Hunstville, Texas, 77340, United States

Location

Novartis Investigative Site

McKinney, Texas, 75013, United States

Location

Novartis Investigative Site

Sherman, Texas, 75092, United States

Location

Novartis Investigative Site

Tomball, Texas, 77375, United States

Location

Novartis Investigative Site

Tyler, Texas, 75701, United States

Location

Novartis Investigative Site

White River Junction, Vermont, 05009, United States

Location

Novartis Investigative Site

Midlothian, Virginia, 23114, United States

Location

Novartis Investigative Site

Richmond, Virginia, 23219, United States

Location

Novartis Investigative Site

Richmond, Virginia, 23226, United States

Location

Novartis Investigative Site

Richmond, Virginia, 23230, United States

Location

Novartis Investigative Site

Richmond, Virginia, 23249, United States

Location

Novartis Investigative Site

Tacoma, Washington, 98405, United States

Location

Related Publications (13)

• Myhre PL, Liu Y, Kulac IJ, Claggett BL, Prescott MF, Felker GM, Butler J, Pina IL, Rouleau JL, Zile MR, McMurray JJV, Ward JH, Solomon SD, Januzzi JL. Changes in mid-regional pro-adrenomedullin during treatment with sacubitril/valsartan. Eur J Heart Fail. 2023 Aug;25(8):1396-1405. doi: 10.1002/ejhf.2957. Epub 2023 Jul 11.

  PMID: 37401523 DERIVED

• Mohebi R, Liu Y, Felker GM, Prescott MF, Pina IL, Butler J, Ward JH, Solomon SD, Januzzi JL. Prediction of Left Ventricular Ejection Fraction Change Following Treatment With Sacubitril/Valsartan. JACC Heart Fail. 2023 Jan;11(1):44-54. doi: 10.1016/j.jchf.2022.09.009. Epub 2022 Nov 9.

  PMID: 36599549 DERIVED

• Murphy SP, Ward JH, Pina IL, Felker GM, Butler J, Maisel AS, Meng X, Prescott MF, Solomon SD, Januzzi JL. Age Differences in Effects of Sacubitril/Valsartan on Cardiac Remodeling, Biomarkers, and Health Status. JACC Heart Fail. 2022 Dec;10(12):976-988. doi: 10.1016/j.jchf.2022.07.001. Epub 2022 Sep 7.

  PMID: 36456072 DERIVED

• Mohebi R, Liu Y, Pina IL, Prescott MF, Butler J, Felker GM, Ward JH, Solomon SD, Januzzi JL Jr. Dose-Response to Sacubitril/Valsartan in Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol. 2022 Oct 18;80(16):1529-1541. doi: 10.1016/j.jacc.2022.08.737.

  PMID: 36229089 DERIVED

• Myhre PL, Prescott MF, Claggett B, Felker GM, Butler J, Pina IL, Maisel AS, Williamson KM, Ward JH, Solomon SD, Januzzi JL. Comparative Effect of Angiotensin Receptor Neprilysin Inhibition on B-type Natriuretic Peptide Levels Measured by Three Different Assays: The PROVE-HF Study. Clin Chem. 2022 Nov 3;68(11):1391-1398. doi: 10.1093/clinchem/hvac148.

  PMID: 36103292 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

• Murphy SP, Prescott MF, Maisel AS, Butler J, Pina IL, Felker GM, Ward JH, Williamson KM, Camacho A, Kandanelly RR, Solomon SD, Januzzi JL. Association Between Angiotensin Receptor-Neprilysin Inhibition, Cardiovascular Biomarkers, and Cardiac Remodeling in Heart Failure With Reduced Ejection Fraction. Circ Heart Fail. 2021 Jun;14(6):e008410. doi: 10.1161/CIRCHEARTFAILURE.120.008410. Epub 2021 May 15.

  PMID: 33998243 DERIVED

• Khan MS, Felker GM, Pina IL, Camacho A, Bapat D, Ibrahim NE, Maisel AS, Prescott MF, Ward JH, Solomon SD, Januzzi JL, Butler J. Reverse Cardiac Remodeling Following Initiation of Sacubitril/Valsartan in Patients With Heart Failure With and Without Diabetes. JACC Heart Fail. 2021 Feb;9(2):137-145. doi: 10.1016/j.jchf.2020.09.014. Epub 2020 Dec 9.

  PMID: 33309581 DERIVED

• Murphy SP, Prescott MF, Camacho A, Iyer SR, Maisel AS, Felker GM, Butler J, Pina IL, Ibrahim NE, Abbas C, Burnett JC Jr, Solomon SD, Januzzi JL. Atrial Natriuretic Peptide and Treatment With Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction. JACC Heart Fail. 2021 Feb;9(2):127-136. doi: 10.1016/j.jchf.2020.09.013. Epub 2020 Nov 11.

  PMID: 33189632 DERIVED

• Pina IL, Camacho A, Ibrahim NE, Felker GM, Butler J, Maisel AS, Prescott MF, Williamson KM, Claggett BL, Desai AS, Solomon SD, Januzzi JL; PROVE-HF Investigators. Improvement of Health Status Following Initiation of Sacubitril/Valsartan in Heart Failure and Reduced Ejection Fraction. JACC Heart Fail. 2021 Jan;9(1):42-51. doi: 10.1016/j.jchf.2020.09.012. Epub 2020 Nov 11.

  PMID: 33189630 DERIVED

• Ibrahim NE, Pina IL, Camacho A, Bapat D, Felker GM, Maisel AS, Butler J, Prescott MF, Abbas CA, Solomon SD, Januzzi JL Jr; Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure (PROVE-HF) Study Investigators. Racial and Ethnic Differences in Biomarkers, Health Status, and Cardiac Remodeling in Patients With Heart Failure With Reduced Ejection Fraction Treated With Sacubitril/Valsartan. Circ Heart Fail. 2020 Nov;13(11):e007829. doi: 10.1161/CIRCHEARTFAILURE.120.007829. Epub 2020 Oct 3.

  PMID: 33016100 DERIVED

• Januzzi JL Jr, Prescott MF, Butler J, Felker GM, Maisel AS, McCague K, Camacho A, Pina IL, Rocha RA, Shah AM, Williamson KM, Solomon SD; PROVE-HF Investigators. Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction. JAMA. 2019 Sep 17;322(11):1085-1095. doi: 10.1001/jama.2019.12821.

  PMID: 31475295 DERIVED

• Januzzi JL, Butler J, Fombu E, Maisel A, McCague K, Pina IL, Prescott MF, Riebman JB, Solomon S. Rationale and methods of the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF). Am Heart J. 2018 May;199:130-136. doi: 10.1016/j.ahj.2017.12.021. Epub 2018 Feb 13.

  PMID: 29754651 DERIVED

Related Links

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

MeSH Terms

Conditions

Heart Failure

Interventions

sacubitril and valsartan sodium hydrate drug combination; sacubitril; Valsartan

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

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 29, 2016
• First Posted: September 2, 2016
• Study Start: October 25, 2016
• Primary Completion: October 22, 2018
• Study Completion: October 22, 2018
• Last Updated: October 7, 2021
• Results First Posted: December 5, 2019

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share

Locations

US (77)