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Trial record 1 of 1 for:    NCT02887183
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Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes. (PROVE-HF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02887183
Recruitment Status : Completed
First Posted : September 2, 2016
Results First Posted : December 5, 2019
Last Update Posted : December 5, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Heart Failure Drug: LCZ696 (sacubitril/valsartan) Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 794 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
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.
Actual Study Start Date : October 25, 2016
Actual Primary Completion Date : October 22, 2018
Actual Study Completion Date : October 22, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
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)




Primary Outcome Measures :
  1. 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

  2. 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

  3. 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.

  4. 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.


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02887183


Locations
Show Show 77 study locations
Sponsors and Collaborators
Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] February 27, 2018
Statistical Analysis Plan  [PDF] February 22, 2019

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02887183    
Other Study ID Numbers: CLCZ696BUS13
First Posted: September 2, 2016    Key Record Dates
Results First Posted: December 5, 2019
Last Update Posted: December 5, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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


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Studies a U.S. FDA-regulated Drug Product: Yes
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Heart failure
Reduced left ventricular ejection fraction
HFrEF
NT-proBNP
Cardiac remodeling
sacubitril/valsartan
KCCQ
biomarkers
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Valsartan
LCZ 696
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action