Heart FailurePhase 4PROVE-HFNCT02887183
Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes.
A Phase 4 study testing LCZ696 (sacubitril/valsartan) in people with Heart Failure, run by Novartis Pharmaceuticals at 77 sites in United States.
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure
- What is being tested?
- LCZ696 (sacubitril/valsartan)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 794 participants
- Where
- 77 sitesUnited States
- Study dates
- 25 Oct 2016to 22 Oct 2018
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
- 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.
Who cannot join
- 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.
- 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.
Show all 20Show fewer
- 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.
- The use of outpatient or inpatient i.v. diuretic therapy within 2 weeks prior to baseline.
- Enrollment in another clinical trial within 30 days of screening.
- Potassium > 5.2 mEq/L at screening.
- History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within one year.
Trial locations and contacts
77 sites in 1 country.
77 sites in 1 country
United States77 sites
Novartis Investigative Site
Arlington Heights, Illinois, 60005
Novartis Investigative Site
Aurora, Illinois, 60504
Novartis Investigative Site
Austin, Texas, 78704
Novartis Investigative Site
Bakersfield, California, 93308
Novartis Investigative Site
Baltimore, Maryland, 21220
Novartis Investigative Site
Baltimore, Maryland, 21229
Novartis Investigative Site
Beaumont, Texas, 77701
Novartis Investigative Site
Belle Glade, Florida, 33430
Novartis Investigative Site
Belzoni, Mississippi, 39038
Novartis Investigative Site
Birmingham, Alabama, 35243
Novartis Investigative Site
Boston, Massachusetts, 02114
Novartis Investigative Site
Bozeman, Montana, 59715
Novartis Investigative Site
Bradenton, Florida, 34209
Novartis Investigative Site
Bryan, Texas, 77802
Novartis Investigative Site
Buffalo, New York, 14215
Novartis Investigative Site
Camp Hill, Pennsylvania, 17011
Novartis Investigative Site
Columbia, Maryland, 21044
Novartis Investigative Site
Crowley, Louisiana, 70526
Novartis Investigative Site
Dallas, Texas, 75231
Novartis Investigative Site
Fort Payne, Alabama, 35967
Novartis Investigative Site
Germantown, Tennessee, 38138
Novartis Investigative Site
Greensboro, North Carolina, 27410
Novartis Investigative Site
Guntersville, Alabama, 35976
Novartis Investigative Site
Haverhill, Massachusetts, 01830
Novartis Investigative Site
Hickory, North Carolina, 28601
Novartis Investigative Site
Hillsboro, Oregon, 97123
Novartis Investigative Site
Hollywood, Florida, 33312
Novartis Investigative Site
Homestead, Florida, 33030
Novartis Investigative Site
Houston, Texas, 77081
Novartis Investigative Site
Hunstville, Texas, 77340
Novartis Investigative Site
Jackson, Mississippi, 39209
Novartis Investigative Site
Jupiter, Florida, 33458
Novartis Investigative Site
Kalamazoo, Michigan, 49008
Novartis Investigative Site
Lake Success, New York, 11042
Novartis Investigative Site
Lake Worth, Florida, 334361
Novartis Investigative Site
Lincoln, Nebraska, 68506
Novartis Investigative Site
Lincoln, Nebraska, 68526
Novartis Investigative Site
Lombard, Illinois, 60148
Novartis Investigative Site
Long Beach, California, 90806
Novartis Investigative Site
Los Alamitos, California, 90720
Novartis Investigative Site
Louisville, Kentucky, 40207
Novartis Investigative Site
McKinney, Texas, 75013
Novartis Investigative Site
Miami, Florida, 33126
Novartis Investigative Site
Miami, Florida, 33133
Novartis Investigative Site
Miami, Florida, 33155
Novartis Investigative Site
Miami, Florida, 33173
Novartis Investigative Site
Midlothian, Virginia, 23114
Novartis Investigative Site
Minneapolis, Minnesota, 55415
Novartis Investigative Site
Nashua, New Hampshire, 03060
Novartis Investigative Site
Oak Lawn, Illinois, 60453
Novartis Investigative Site
Omaha, Nebraska, 68114
Novartis Investigative Site
Oregon City, Oregon, 97045
Novartis Investigative Site
Owensboro, Kentucky, 42303
Novartis Investigative Site
Port Orange, Florida, 32127
Novartis Investigative Site
Portland, Oregon, 97225
Novartis Investigative Site
Potsdam, New York, 13676
Novartis Investigative Site
Richmond, Virginia, 23219
Novartis Investigative Site
Richmond, Virginia, 23226
Novartis Investigative Site
Richmond, Virginia, 23230
Novartis Investigative Site
Richmond, Virginia, 23249
Novartis Investigative Site
Sherman, Texas, 75092
Novartis Investigative Site
Shreveport, Louisiana, 71101
Novartis Investigative Site
Simpsonville, South Carolina, 29681
Novartis Investigative Site
Southhaven, Mississippi, 38671
Novartis Investigative Site
Springfield, Massachusetts, 01104
Novartis Investigative Site
Sylmar, California, 91342
Novartis Investigative Site
Tacoma, Washington, 98405
Novartis Investigative Site
The Bronx, New York, 10461
Novartis Investigative Site
Tomball, Texas, 77375
Novartis Investigative Site
Tyler, Texas, 75701
Novartis Investigative Site
Wellington, Florida, 33449
Novartis Investigative Site
West Haven, Connecticut, 06516
Novartis Investigative Site
West Monroe, Louisiana, 71291
Novartis Investigative Site
White River Junction, Vermont, 05009
Novartis Investigative Site
Winston-Salem, North Carolina, 27103
Novartis Investigative Site
Wyomissing, Pennsylvania, 19610
Novartis Investigative Site
Yardley, Pennsylvania, 19067
About this study
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.
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
- Being tested
- LCZ696 (sacubitril/valsartan)
- Keywords
- Heart failure, Reduced left ventricular ejection fraction, HFrEF, NT-proBNP, Cardiac remodeling, sacubitril/valsartan, KCCQ, biomarkers
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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)
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: LCZ696 (sacubitril/valsartan) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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
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
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: Baseline, Month 6
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.
Measured: Baseline, month 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Sep 2016 (estimated)
- Study start25 Oct 2016
- Primary completion22 Oct 2018
- Study completion22 Oct 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 794 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02887183
- Sponsor's protocol ID
- CLCZ696BUS13
- Acronym
- PROVE-HF
- Status last verified
- Oct 2021
- First submitted
- 29 Aug 2016
- Last updated
- 7 Oct 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- Individual data sharing
- Yes: 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
Publications
Omar AMS, Murphy S, Felker GM, Pina I, Butler J, Liu Y, Mohebi R, Bhatia K, Ward JH, Williamson KM, Solomon SD, Januzzi JL, Contreras J. Isovolumic Contraction Velocity in Heart Failure With Reduced Ejection Fraction and Effect of Sacubitril/Valsartan: the PROVE-HF Study. J Card Fail. 2024 May;30(5):653-665. doi: 10.1016/j.cardfail.2023.10.001. Epub 2023 Oct 8.
PubMed 37816446Myhre 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.
PubMed 37401523Mohebi 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.
PubMed 36599549Murphy 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.
PubMed 36456072Mohebi 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.
PubMed 36229089Myhre 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.
PubMed 36103292Myhre 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.
PubMed 35115085Murphy 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.
PubMed 33998243Khan 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.
PubMed 33309581Murphy 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.
PubMed 33189632Pina 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.
PubMed 33189630Ibrahim 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.
PubMed 33016100Januzzi 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.
PubMed 31475295Januzzi 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.
PubMed 29754651
Study at a glance
From the registry record, last updated by the sponsor on 7 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT02887183
- Acronym / sponsor ID
- PROVE-HF / CLCZ696BUS13
- Conditions
- Heart Failure
- Keywords
- Heart failure, Reduced left ventricular ejection fraction, HFrEF, NT-proBNP, Cardiac remodeling, sacubitril/valsartan, KCCQ, biomarkers
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 794 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 25 Oct 2016 (actual)
- Primary completion
- 22 Oct 2018 (actual)
- Study completion
- 22 Oct 2018 (actual)
- First posted
- 2 Sep 2016 (estimated)
- Results
- Posted 5 Dec 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| LCZ696(sacubitril/valsartan) | Other | Drug: 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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:
- 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.
Key exclusion criteria (20 listed)
- 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.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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) | Drug | LCZ696(sacubitril/valsartan) |
Primary outcome
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
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
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.
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.
6 secondary outcomes
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
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
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
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
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
Mean Change in the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score From Baseline to Month 12
Time frame: Baseline, month 12
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Oct 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37816446Omar AMS, Murphy S, Felker GM, Pina I, Butler J, Liu Y, Mohebi R, Bhatia K, Ward JH, Williamson KM, Solomon SD, Januzzi JL, Contreras J. Isovolumic Contraction Velocity in Heart Failure With Reduced Ejection Fraction and Effect of Sacubitril/Valsartan: the PROVE-HF Study. J Card Fail. 2024 May;30(5):653-665. doi: 10.1016/j.cardfail.2023.10.001. Epub 2023 Oct 8.
- Derived from this study: PubMed 37401523Myhre 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.
- Derived from this study: PubMed 36599549Mohebi 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.
- Derived from this study: PubMed 36456072Murphy 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.
- Derived from this study: PubMed 36229089Mohebi 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.
- Derived from this study: PubMed 36103292Myhre 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.
- Derived from this study: PubMed 35115085Myhre 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.
- Derived from this study: PubMed 33998243Murphy 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.
- Derived from this study: PubMed 33309581Khan 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.
- Derived from this study: PubMed 33189632Murphy 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.
- Derived from this study: PubMed 33189630Pina 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.
- Derived from this study: PubMed 33016100Ibrahim 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.
- A Plain Language Trial Summary is available on novartisclinicaltrials.comLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
77 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing LCZ696 (sacubitril/valsartan) in people with Heart Failure, run by Novartis Pharmaceuticals at 77 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 77 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Dec 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to One Year (time frame: Baseline, one year). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02887183, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Oct 2021.