Clinical trial NCT02887183: Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes.
Official title: A 52 Week, Open Label Evaluation of the Effects of Sacubitril/Valsartan (LCZ696) Therapy on Biomarkers, Myocardial Remodeling and Patient-reported Outcomes in Heart Failure With Reduced Left Ventricular Ejection Fraction.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Heart Failure
Keywords: Heart failure
Reduced left ventricular ejection fraction
HFrEF
NT-proBNP
Cardiac remodeling
sacubitril/valsartan
KCCQ
biomarkers
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-09-02
Enrollment: 794
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.


Eligibility criteria: Inclusion Criteria:

Based on the USPI for sacubitril/valsartan, subjects eligible for inclusion in this study must fulfill all of the following criteria at screening and baseline:

1. Written informed consent must be obtained before any assessment is performed.
2. Men and women ≥ 18 years of age.
3. LVEF ≤ 40% subjects who are candidates for on-label sacubitril/valsartan treatment per standard of care.
4. New York Heart Association (NYHA) Functional class II-IV.
5. 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.
6. If a subject is on a loop diuretic, they must be on a stable dose for 2 weeks prior to baseline.

Key Exclusion Criteria:

Subjects fulfilling any of the following criteria, at screening and prior to dispensing of study drug, are not eligible for inclusion in this study. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible subjects/subjects.

1. pregnant or nursing women
2. women of child bearing potential not using highly effective method of contraception during dosing and for 7 days after stopping study medication
3. 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.
4. History of angioedema drug related or otherwise.
5. Requirement of treatment with either ACE inhibitor and/or ARB.
6. Subjects with a heart transplant or ventricular assistance device (VAD) or intent to transplant (on transplant list) or implant a VAD.
7. Subjects with a cardio resynchronization therapy devices (CRT/CRT-D) implanted within 6 months of screening visit.
8. Subjects who are currently taking inotropic agents.
9. Current or prior treatment with sacubitril/valsartan.
10. Subjects taking medications prohibited by the protocol.
11. Subjects with diabetes mellitus who are taking aliskiren.
12. 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.
13. Concomitant use of nesiritide.
14. Bile acid sequestering agents such as cholestyramine or colestipol are prohibited to avoid interference with study drug absorption.
15. Any hospital admission/discharge related to heart failure within 2 weeks prior to baseline.
16. The use of outpatient or inpatient i.v. diuretic therapy within 2 weeks prior to baseline.
17. Enrollment in another clinical trial within 30 days of screening.
18. Potassium \> 5.2 mEq/L at screening.
19. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within one year.

Primary outcomes:
measure: Change in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to One Year
timeFrame: Baseline, one year
measure: 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
timeFrame: Baseline, one Year
measure: Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to One Year
timeFrame: Baseline, one year
measure: Change in Log-transformed NT-proBNP and Change in Structural Cardiac Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to One Year
timeFrame: Baseline, one year
Secondary outcomes:
measure: Change in Log-transformed NT-proBNP Concentration and Change in Echocardiographic Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to Month 6
timeFrame: Baseline, Month 6
measure: 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
timeFrame: Baseline, Month 6
measure: 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
timeFrame: Baseline, Month 6
measure: 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
timeFrame: Baseline, Month 6
measure: 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
timeFrame: Baseline, Month 6
measure: Mean Change in the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score From Baseline to Month 12
timeFrame: Baseline, month 12
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Fort Payne
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Guntersville
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Bakersfield
country: United States
facility: Novartis Investigative Site
state: California
city: Long Beach
country: United States
facility: Novartis Investigative Site
state: California
city: Los Alamitos
country: United States
facility: Novartis Investigative Site
state: California
city: Sylmar
country: United States
facility: Novartis Investigative Site
state: California
city: West Haven
country: United States
facility: Novartis Investigative Site
state: Connecticut
city: Belle Glade
country: United States
facility: Novartis Investigative Site
state: Florida
city: Bradenton
country: United States
facility: Novartis Investigative Site
state: Florida
city: Hollywood
country: United States
facility: Novartis Investigative Site
state: Florida
city: Homestead
country: United States
facility: Novartis Investigative Site
state: Florida
city: Jupiter
country: United States
facility: Novartis Investigative Site
state: Florida
city: Lake Worth
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Port Orange
country: United States
facility: Novartis Investigative Site
state: Florida
city: Wellington
country: United States
facility: Novartis Investigative Site
state: Florida
city: Arlington Heights
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Aurora
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Lombard
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Oak Lawn
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Louisville
country: United States
facility: Novartis Investigative Site
state: Kentucky
city: Owensboro
country: United States
facility: Novartis Investigative Site
state: Kentucky
city: Crowley
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Shreveport
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: West Monroe
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Baltimore
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Baltimore
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Columbia
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Haverhill
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Springfield
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Kalamazoo
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Minneapolis
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Belzoni
country: United States
facility: Novartis Investigative Site
state: Mississippi
city: Jackson
country: United States
facility: Novartis Investigative Site
state: Mississippi
city: South Haven
country: United States
facility: Novartis Investigative Site
state: Mississippi
city: Bozeman
country: United States
facility: Novartis Investigative Site
state: Montana
city: Lincoln
country: United States
facility: Novartis Investigative Site
state: Nebraska
city: Lincoln
country: United States
facility: Novartis Investigative Site
state: Nebraska
city: Omaha
country: United States
facility: Novartis Investigative Site
state: Nebraska
city: Nashua
country: United States
facility: Novartis Investigative Site
state: New Hampshire
city: Bronx
country: United States
facility: Novartis Investigative Site
state: New York
city: Buffalo
country: United States
facility: Novartis Investigative Site
state: New York
city: Lake Success
country: United States
facility: Novartis Investigative Site
state: New York
city: Potsdam
country: United States
facility: Novartis Investigative Site
state: New York
city: Greensboro
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Hickory
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Hillsboro
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Oregon City
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Portland
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Camp Hill
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Wyomissing
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Yardley
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Simpsonville
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Germantown
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Austin
country: United States
facility: Novartis Investigative Site
state: Texas
city: Beaumont
country: United States
facility: Novartis Investigative Site
state: Texas
city: Bryan
country: United States
facility: Novartis Investigative Site
state: Texas
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Hunstville
country: United States
facility: Novartis Investigative Site
state: Texas
city: McKinney
country: United States
facility: Novartis Investigative Site
state: Texas
city: Sherman
country: United States
facility: Novartis Investigative Site
state: Texas
city: Tomball
country: United States
facility: Novartis Investigative Site
state: Texas
city: Tyler
country: United States
facility: Novartis Investigative Site
state: Texas
city: White River Junction
country: United States
facility: Novartis Investigative Site
state: Vermont
city: Midlothian
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Richmond
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Richmond
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Richmond
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Richmond
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Tacoma
country: United States
facility: Novartis Investigative Site
state: Washington
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.