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

Heart Failure Clinical Trial

— PROVE-HF  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02887183
• Other study ID #: CLCZ696BUS13
• Status: Completed
• Phase: Phase 4
• Start date: October 25, 2016
• Est. completion date: October 22, 2018

Study information

• Verified date: October 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 794
• Est. completion date: October 22, 2018
• Est. primary completion date: October 22, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• LCZ696 (sacubitril/valsartan)
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)

Locations

Country	Name	City	State
United States	Novartis Investigative Site	Arlington Heights	Illinois
United States	Novartis Investigative Site	Aurora	Illinois
United States	Novartis Investigative Site	Austin	Texas
United States	Novartis Investigative Site	Bakersfield	California
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Beaumont	Texas
United States	Novartis Investigative Site	Belle Glade	Florida
United States	Novartis Investigative Site	Belzoni	Mississippi
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Bozeman	Montana
United States	Novartis Investigative Site	Bradenton	Florida
United States	Novartis Investigative Site	Bronx	New York
United States	Novartis Investigative Site	Bryan	Texas
United States	Novartis Investigative Site	Buffalo	New York
United States	Novartis Investigative Site	Camp Hill	Pennsylvania
United States	Novartis Investigative Site	Columbia	Maryland
United States	Novartis Investigative Site	Crowley	Louisiana
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Fort Payne	Alabama
United States	Novartis Investigative Site	Germantown	Tennessee
United States	Novartis Investigative Site	Greensboro	North Carolina
United States	Novartis Investigative Site	Guntersville	Alabama
United States	Novartis Investigative Site	Haverhill	Massachusetts
United States	Novartis Investigative Site	Hickory	North Carolina
United States	Novartis Investigative Site	Hillsboro	Oregon
United States	Novartis Investigative Site	Hollywood	Florida
United States	Novartis Investigative Site	Homestead	Florida
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Hunstville	Texas
United States	Novartis Investigative Site	Jackson	Mississippi
United States	Novartis Investigative Site	Jupiter	Florida
United States	Novartis Investigative Site	Kalamazoo	Michigan
United States	Novartis Investigative Site	Lake Success	New York
United States	Novartis Investigative Site	Lake Worth	Florida
United States	Novartis Investigative Site	Lincoln	Nebraska
United States	Novartis Investigative Site	Lincoln	Nebraska
United States	Novartis Investigative Site	Lombard	Illinois
United States	Novartis Investigative Site	Long Beach	California
United States	Novartis Investigative Site	Los Alamitos	California
United States	Novartis Investigative Site	Louisville	Kentucky
United States	Novartis Investigative Site	McKinney	Texas
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Midlothian	Virginia
United States	Novartis Investigative Site	Minneapolis	Minnesota
United States	Novartis Investigative Site	Nashua	New Hampshire
United States	Novartis Investigative Site	Oak Lawn	Illinois
United States	Novartis Investigative Site	Omaha	Nebraska
United States	Novartis Investigative Site	Oregon City	Oregon
United States	Novartis Investigative Site	Owensboro	Kentucky
United States	Novartis Investigative Site	Port Orange	Florida
United States	Novartis Investigative Site	Portland	Oregon
United States	Novartis Investigative Site	Potsdam	New York
United States	Novartis Investigative Site	Richmond	Virginia
United States	Novartis Investigative Site	Richmond	Virginia
United States	Novartis Investigative Site	Richmond	Virginia
United States	Novartis Investigative Site	Richmond	Virginia
United States	Novartis Investigative Site	Sherman	Texas
United States	Novartis Investigative Site	Shreveport	Louisiana
United States	Novartis Investigative Site	Simpsonville	South Carolina
United States	Novartis Investigative Site	South Haven	Mississippi
United States	Novartis Investigative Site	Springfield	Massachusetts
United States	Novartis Investigative Site	Sylmar	California
United States	Novartis Investigative Site	Tacoma	Washington
United States	Novartis Investigative Site	Tomball	Texas
United States	Novartis Investigative Site	Tyler	Texas
United States	Novartis Investigative Site	Wellington	Florida
United States	Novartis Investigative Site	West Haven	Connecticut
United States	Novartis Investigative Site	West Monroe	Louisiana
United States	Novartis Investigative Site	White River Junction	Vermont
United States	Novartis Investigative Site	Winston-Salem	North Carolina
United States	Novartis Investigative Site	Wyomissing	Pennsylvania
United States	Novartis Investigative Site	Yardley	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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	Change in Log-transformed NT-proBNP Concentration and Change in Echocardiographic Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to Month 6	Pearson's correlation coefficient was calculated between change in log-transformed NT-proBNP and change in echocardiographic measurements LVESVi, LVEDVi, LAVi, and LVEF from baseline to Month 6	Baseline, Month 6
Secondary	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	Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LAVi from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline.; Subjects with new onset HF and/or RAAS naïve.; Subjects who are not receiving the target sacubitril/valsartan dose.	Baseline, Month 6
Secondary	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	Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVESVi from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline.; Subjects with new onset HF and/or RAAS naïve.; Subjects who are not receiving the target sacubitril/valsartan dose.	Baseline, Month 6
Secondary	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	Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVEDVi from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline.; Subjects with new onset HF and/or RAAS naïve.; Subjects who are not receiving the target sacubitril/valsartan dose.	Baseline, Month 6
Secondary	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	Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVEF from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline.; Subjects with new onset HF and/or RAAS naïve.; Subjects who are not receiving the target sacubitril/valsartan dose.	Baseline, Month 6
Secondary	Mean Change in the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score From Baseline to Month 12	The KCCQ-23 is a self-administered questionnaire and requires, on average, 4-6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). A change of 5 points on the scale scores, either as a group mean difference or an intra-individual change appears to be clinically significant, based on comparisons of changes in the scale scores to clinical indicators and subject global reports of change. The analysis will be done for groups of subjects with N-terminal pro-brain natriuretic peptide<1000 pg/mL and N-Terminal pro-brain natriuretic peptide>=1000 pg/mL at Month 12.	Baseline, month 12

External Links

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