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

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ClinicalTrials.gov Identifier: NCT02887183
Recruitment Status : Completed
First Posted : September 2, 2016
Last Update Posted : May 29, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This study is to determine early and more chronic changes in concentrations of biomarkers related to mechanisms of action (MOA) and effects of sacubitril/valsartan therapyover a period of 12 months, and correlate 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 : 797 participants
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
Drug Information available for: Valsartan

Arm Intervention/treatment
LCZ696(sacubitril/valsartan)
Subjects will receive sacubitril/valsartan (LCZ696) on Day 1. The initial dose will be determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available are: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3).
Drug: LCZ696 (sacubitril/valsartan)
LCZ696 (sacubitril/valsartan) is supplied as unscored, ovaloid, film-coated oral tablets in the strengths of 24/26 mg, 49/51 mg, 97/103 mg twice daily (bid)




Primary Outcome Measures :
  1. Pearson's Correlation coefficient between change from baseline in concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) and change in Left ventricular end systolic volume index (LVESVi) at one year [ Time Frame: Baseline, one year ]
    Pearson's correlation coefficient will be calculated between change in in log-transformed of NT-proBNP and change in structural cardiac measurement such as LVESVi from baseline to one year.

  2. Pearson's coefficient between change from baseline in concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) and change in Left ventricular end diastolic volume index (LVEDVi) at one year [ Time Frame: Baseline, one Year ]
    Pearson's correlation coefficient will be calculated between change in log-transformed NT-proBNP and change in structural cardiac measurement such as LVEDVi from baseline to one year.

  3. Pearson's Correlation coefficient between change from baseline in concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) and change in Left ventricular ejection fraction (LVEF) at one year [ Time Frame: Baseline, one year ]
    Pearson's correlation coefficient will be calculated between change in log-transformed NT-proBNP and change in structural cardiac measurement such as LVEF from baseline to one year.

  4. Pearson's Correlation coefficient between change from baseline in correlation of N-terminal pro-brain natriuretic peptide (NT-proBNP) and change in Left atrial volume index (LAVi) at one year [ Time Frame: Baseline, one year ]
    Pearson's correlation coefficient will be calculated between change in log-transformed NT-proBNP and change in structural cardiac measurement such as LAVi from baseline to one year.


Secondary Outcome Measures :
  1. Pearson's correlation coefficient between change from baseline in concentration of NT-proBNP and change in LVESVi 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 Heart failure with reduced ejection fraction (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 Renin angiotensin aldosterone system (RAAS) naïve.
    3. Subjects who are not receiving the target sacubitril/valsartan dose.

  2. Mean change in the 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.

  3. Pearson's correlation coefficient between change from baseline in NT-proBNP and change in LVEDVi 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.

  4. Pearson's correlation coefficient between change from baseline in NT-proBNP and change in LVEF 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.

  5. Pearson's correlation coefficient between change from baseline in NT-proBNP and change in LAVi 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.



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. 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.
  2. History of angioedema drug related or otherwise.
  3. Requirement of treatment with either ACE inhibitor and/or ARB.
  4. Subjects with a heart transplant or ventricular assistance device (VAD) or intent to transplant (on transplant list) or implant a VAD.
  5. Subjects with a cardio resynchronization therapy devices (CRT/CRT-D) implanted within 6 months of screening visit.
  6. Subjects who are currently taking inotropic agents.
  7. Current or prior treatment with sacubitril/valsartan.
  8. Subjects taking medications prohibited by the protocol.
  9. Subjects with diabetes mellitus who are taking aliskiren.
  10. 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.
  11. Concomitant use of nesiritide.
  12. Bile acid sequestering agents such as cholestyramine or colestipol are prohibited to avoid interference with study drug absorption.
  13. Any hospital admission/discharge related to heart failure within 2 weeks prior to baseline.
  14. The use of outpatient or inpatient i.v. diuretic therapy within 2 weeks prior to baseline.
  15. Enrollment in another clinical trial within 30 days of screening.
  16. . Potassium > 5.2 mEq/L at screening.
  17. 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


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Sponsors and Collaborators
Novartis Pharmaceuticals

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02887183     History of Changes
Other Study ID Numbers: CLCZ696BUS13
First Posted: September 2, 2016    Key Record Dates
Last Update Posted: May 29, 2019
Last Verified: May 2019
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Heart failure
Reduced left ventricular ejection fraction
HFrEF
NT-proBNP
Cardiac remodeling
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