Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes. (PROVE-HF)

October 6, 2021 updated by: Novartis Pharmaceuticals

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.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

794

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35243
        • Novartis Investigative Site
      • Fort Payne, Alabama, United States, 35967
        • Novartis Investigative Site
      • Guntersville, Alabama, United States, 35976
        • Novartis Investigative Site
    • California
      • Bakersfield, California, United States, 93308
        • Novartis Investigative Site
      • Long Beach, California, United States, 90806
        • Novartis Investigative Site
      • Los Alamitos, California, United States, 90720
        • Novartis Investigative Site
      • Sylmar, California, United States, 91342
        • Novartis Investigative Site
    • Connecticut
      • West Haven, Connecticut, United States, 06516
        • Novartis Investigative Site
    • Florida
      • Belle Glade, Florida, United States, 33430
        • Novartis Investigative Site
      • Bradenton, Florida, United States, 34209
        • Novartis Investigative Site
      • Hollywood, Florida, United States, 33312
        • Novartis Investigative Site
      • Homestead, Florida, United States, 33030
        • Novartis Investigative Site
      • Jupiter, Florida, United States, 33458
        • Novartis Investigative Site
      • Lake Worth, Florida, United States, 334361
        • Novartis Investigative Site
      • Miami, Florida, United States, 33126
        • Novartis Investigative Site
      • Miami, Florida, United States, 33133
        • Novartis Investigative Site
      • Miami, Florida, United States, 33155
        • Novartis Investigative Site
      • Miami, Florida, United States, 33173
        • Novartis Investigative Site
      • Port Orange, Florida, United States, 32127
        • Novartis Investigative Site
      • Wellington, Florida, United States, 33449
        • Novartis Investigative Site
    • Illinois
      • Arlington Heights, Illinois, United States, 60005
        • Novartis Investigative Site
      • Aurora, Illinois, United States, 60504
        • Novartis Investigative Site
      • Lombard, Illinois, United States, 60148
        • Novartis Investigative Site
      • Oak Lawn, Illinois, United States, 60453
        • Novartis Investigative Site
    • Kentucky
      • Louisville, Kentucky, United States, 40207
        • Novartis Investigative Site
      • Owensboro, Kentucky, United States, 42303
        • Novartis Investigative Site
    • Louisiana
      • Crowley, Louisiana, United States, 70526
        • Novartis Investigative Site
      • Shreveport, Louisiana, United States, 71101
        • Novartis Investigative Site
      • West Monroe, Louisiana, United States, 71291
        • Novartis Investigative Site
    • Maryland
      • Baltimore, Maryland, United States, 21229
        • Novartis Investigative Site
      • Baltimore, Maryland, United States, 21220
        • Novartis Investigative Site
      • Columbia, Maryland, United States, 21044
        • Novartis Investigative Site
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Novartis Investigative Site
      • Haverhill, Massachusetts, United States, 01830
        • Novartis Investigative Site
      • Springfield, Massachusetts, United States, 01104
        • Novartis Investigative Site
    • Michigan
      • Kalamazoo, Michigan, United States, 49008
        • Novartis Investigative Site
    • Minnesota
      • Minneapolis, Minnesota, United States, 55415
        • Novartis Investigative Site
    • Mississippi
      • Belzoni, Mississippi, United States, 39038
        • Novartis Investigative Site
      • Jackson, Mississippi, United States, 39209
        • Novartis Investigative Site
      • South Haven, Mississippi, United States, 38671
        • Novartis Investigative Site
    • Montana
      • Bozeman, Montana, United States, 59715
        • Novartis Investigative Site
    • Nebraska
      • Lincoln, Nebraska, United States, 68506
        • Novartis Investigative Site
      • Lincoln, Nebraska, United States, 68526
        • Novartis Investigative Site
      • Omaha, Nebraska, United States, 68114
        • Novartis Investigative Site
    • New Hampshire
      • Nashua, New Hampshire, United States, 03060
        • Novartis Investigative Site
    • New York
      • Bronx, New York, United States, 10461
        • Novartis Investigative Site
      • Buffalo, New York, United States, 14215
        • Novartis Investigative Site
      • Lake Success, New York, United States, 11042
        • Novartis Investigative Site
      • Potsdam, New York, United States, 13676
        • Novartis Investigative Site
    • North Carolina
      • Greensboro, North Carolina, United States, 27410
        • Novartis Investigative Site
      • Hickory, North Carolina, United States, 28601
        • Novartis Investigative Site
      • Winston-Salem, North Carolina, United States, 27103
        • Novartis Investigative Site
    • Oregon
      • Hillsboro, Oregon, United States, 97123
        • Novartis Investigative Site
      • Oregon City, Oregon, United States, 97045
        • Novartis Investigative Site
      • Portland, Oregon, United States, 97225
        • Novartis Investigative Site
    • Pennsylvania
      • Camp Hill, Pennsylvania, United States, 17011
        • Novartis Investigative Site
      • Wyomissing, Pennsylvania, United States, 19610
        • Novartis Investigative Site
      • Yardley, Pennsylvania, United States, 19067
        • Novartis Investigative Site
    • South Carolina
      • Simpsonville, South Carolina, United States, 29681
        • Novartis Investigative Site
    • Tennessee
      • Germantown, Tennessee, United States, 38138
        • Novartis Investigative Site
    • Texas
      • Austin, Texas, United States, 78704
        • Novartis Investigative Site
      • Beaumont, Texas, United States, 77701
        • Novartis Investigative Site
      • Bryan, Texas, United States, 77802
        • Novartis Investigative Site
      • Dallas, Texas, United States, 75231
        • Novartis Investigative Site
      • Houston, Texas, United States, 77081
        • Novartis Investigative Site
      • Hunstville, Texas, United States, 77340
        • Novartis Investigative Site
      • McKinney, Texas, United States, 75013
        • Novartis Investigative Site
      • Sherman, Texas, United States, 75092
        • Novartis Investigative Site
      • Tomball, Texas, United States, 77375
        • Novartis Investigative Site
      • Tyler, Texas, United States, 75701
        • Novartis Investigative Site
    • Vermont
      • White River Junction, Vermont, United States, 05009
        • Novartis Investigative Site
    • Virginia
      • Midlothian, Virginia, United States, 23114
        • Novartis Investigative Site
      • Richmond, Virginia, United States, 23226
        • Novartis Investigative Site
      • Richmond, Virginia, United States, 23219
        • Novartis Investigative Site
      • Richmond, Virginia, United States, 23230
        • Novartis Investigative Site
      • Richmond, Virginia, United States, 23249
        • Novartis Investigative Site
    • Washington
      • Tacoma, Washington, United States, 98405
        • Novartis Investigative Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: LCZ696(sacubitril/valsartan)

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)
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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to One Year
Time Frame: Baseline, 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
Time Frame: 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
Baseline, one Year
Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to One Year
Time Frame: Baseline, 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
Time Frame: Baseline, 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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Log-transformed NT-proBNP Concentration and Change in Echocardiographic Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to Month 6
Time Frame: Baseline, 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
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
Time Frame: Baseline, 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:

  1. 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.
  2. Subjects with new onset HF and/or RAAS naïve.
  3. Subjects who are not receiving the target sacubitril/valsartan dose.
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
Time Frame: Baseline, 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:

  1. 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.
  2. Subjects with new onset HF and/or RAAS naïve.
  3. Subjects who are not receiving the target sacubitril/valsartan dose.
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
Time Frame: Baseline, 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:

  1. 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.
  2. Subjects with new onset HF and/or RAAS naïve.
  3. Subjects who are not receiving the target sacubitril/valsartan dose.
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
Time Frame: Baseline, 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:

  1. 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.
  2. Subjects with new onset HF and/or RAAS naïve.
  3. Subjects who are not receiving the target sacubitril/valsartan dose.
Baseline, Month 6
Mean Change in the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score From Baseline to Month 12
Time Frame: Baseline, 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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Novartis Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 25, 2016

Primary Completion (Actual)

October 22, 2018

Study Completion (Actual)

October 22, 2018

Study Registration Dates

First Submitted

August 29, 2016

First Submitted That Met QC Criteria

August 29, 2016

First Posted (Estimate)

September 2, 2016

Study Record Updates

Last Update Posted (Actual)

October 7, 2021

Last Update Submitted That Met QC Criteria

October 6, 2021

Last Verified

October 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CLCZ696BUS13

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD 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

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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