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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: LCZ696 (sacubitril/valsartan)


Participation Criteria
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Eligibility Criteria
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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: 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. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: LCZ696(sacubitril/valsartan)<br>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)<br>* 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)<br>|

What is the study measuring?
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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 | 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 | 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 | 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 | 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 | 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 | 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HFrEF, Heart failure, Reduced left ventricular ejection fraction, NT-proBNP, Cardiac remodeling, sacubitril/valsartan, KCCQ, biomarkers