Heart Failure
Conditions
Brief summary
This study intends to measure the effects of valsartan/sacubitril compared to baseline standard medical heart failure therapy on reverse remodeling using echocardiographic endocardial surface analysis techniques to assess changes in ventricular volume, function, and shape.
Detailed description
This study intends to measure the effects of valsartan/sacubitril compared to baseline standard medical heart failure therapy on reverse remodeling using echocardiographic endocardial surface analysis techniques to assess changes in ventricular volume, function, and shape. Furthermore, Metaiodobenzylguanidine (MIBG) scintigraphy and the heart to mediastinum ratio will be used to assess Left Ventricle (LV) volume regression and risk reduction. The investigators also intend to measure the effects of valsartan/sacubitril on exercise capacity as assessed by the 6 minute walk test and peak Volume of Oxygen (V02) on cardiopulmonary exercise testing. Additionally, the investigators will examine the impact of valsartan/sacubitril on functional status and quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Qualia Health (a novel iPhone application that incorporates Fitbit technology to provide a real time daily 6 minute step count and assesses quality of life using a series of short targeted questions. The investigators will also measure Brain Natriuretic Peptide (BNP), N-terminal of the Prohormone Brain Natriuretic Peptide (NT-proBNP), and Rho-kinase (a biomarker associated with heart failure) levels at multiple time-points throughout the study period.
Interventions
DRUGEntresto
Sponsors
University of Chicago
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females aged ≥18 years 2. Congestive Heart Failure (CHF) New York Heart Association (NYHA) class II-IV with 25%≤ Left Ventricular Ejection Fraction (LVEF) ≤40% (ECHO within last 6 months) * NT-proBNP ≥ 600 pg/mL OR * NT-proBNP ≥ 400 pg/mL and a hospitalization for heart failure within the last 12 months 3. Stable and optimized on an angiotensin-converting-enzyme inhibitor (ACEI) equivalent to enalapril ≥ 10 twice a day (BID) for at least 4 weeks 4. Stable and optimized on a beta-blocker for at least 4 weeks 5. Optimized dosing of aldosterone antagonist at stable dose for at least 4 weeks
Exclusion criteria
1. History of angioedema 2. estimated glomerular filtration rate (eGFR) \< 30 ml/min/1.73 m2 at screening 3. Serum potassium \> 5.2 mmol/L at screening 4. Symptomatic hypotension as defined by Investigator, systolic blood pressure (SBP) \< 100 mmHg at screening 5. Current acute decompensated heart failure 6. History of severe pulmonary disease 7. Active malignancy 8. Requirement for treatment with both angiotensin-converting-enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARB)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in LV Remodeling 2D End-Diastolic Diameter (cm) | Baseline,1 year | LV Remodeling 2D End-Diastolic Diameter (cm) |
| Change From Baseline in LV Remodeling 2D End-Systolic Diameter (cm) | Baseline,1 year | LV Remodeling 2D End-Systolic Diameter (cm) |
| Change From Baseline in LV Remodeling Global Longitudinal Strain (%) | Baseline,1 year | LV Remodeling Global Longitudinal Strain (%) |
| Change From Baseline in LV Remodeling Left Atrial Volume (mL) | Baseline,1 year | LV Remodeling Left Atrial Volume (mL) |
| Change From Baseline in LV Remodeling 3D End-Diastolic Volume (mL) | Baseline,1 year | LV Remodeling 3D End-Diastolic Volume (mL) |
| Change From Baseline in LV Remodeling 3D End-Systolic Volume (mL) | Baseline,1 year | LV Remodeling 3D End-Systolic Volume (mL) |
| Change From Baseline in LV Remodeling LV Ejection Fraction (%) | Baseline,1 year | LV Remodeling LV Ejection Fraction (%) |
| Change From Baseline in RV Remodeling End Systolic Volume (mL) | Baseline,1 year | RV Remodeling End Systolic Volume (mL) |
| Change From Baseline in LV Remodeling Conicity (%) | Baseline,1 year | LV Remodeling Conicity (%) |
| Change From Baseline in LV Remodeling Sphericity (%) | Baseline,1 year | LV Remodeling Sphericity (%) |
| Change From Baseline in RV Remodeling End-Diastolic Volume (mL) | Baseline,1 year | RV Remodeling End-Diastolic Volume (mL) |
| Change From Baseline in RV Remodeling Ejection Fraction (%) | Baseline,1 year | RV Remodeling Ejection Fraction (%) |
| Change From Baseline in RV Remodeling Septal Curvature (%) | Baseline,1 year | RV Remodeling Septal Curvature (%) |
| Change From Baseline in RV Remodeling Free-Wall Curvature (%) | Baseline,1 year | RV Remodeling Free-Wall Curvature (%) |
| Change From Baseline in RV Remodeling Tricuspid Regurgitation | Baseline,1 year | RV Remodeling Tricuspid Regurgitation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Blood Pressure - Systolic (mmHg) | Baseline,1 year | Blood Pressure - Systolic (mmHg) |
| Change From Baseline in Blood Pressure - Diastolic (mmHg) | Baseline,1 year | Blood Pressure - Diastolic (mmHg) |
| Change From Baseline in Exercise Performance - CPX - Peak RER | Baseline,1 year | Exercise Performance - CPX - Peak RER (Respiratory Exchange Ratio) |
| Change From Baseline in Rho-associated Protein Kinase (ROCK) | Baseline,1 year | Rho-associated protein kinase (ROCK) |
| Change From Baseline in (MIBG) Early hm Ratio | Baseline,1 year | Cardiac 123Iodine-metaiodobenzylguanidine (MIBG) Early heart/mediastinum ratio (hm) ratio |
| Change From Baseline in (MIBG) Late hm Ratio | Baseline,1 year | Cardiac 123Iodine-metaiodobenzylguanidine (MIBG) Late heart/mediastinum ratio (hm) ratio |
| Change From Baseline in Exercise Performance - CPX - VE/VC02 | Baseline,1 year | Exercise Performance - CPX - VE/VC02 |
| Change From Baseline in NT-proBNP Levels | Baseline,1 year | NT-proBNP levels (pg/ml) |
| Change From Baseline in Exercise Performance - 6 Minute Walk | Baseline,1 year | Exercise Performance - 6 Minute Walk |
| Change From Baseline in Exercise Performance - CPX - Peak VO2 (mL/kg/Min) | Baseline,1 year | Exercise Performance - CPX - Peak VO2 (mL/kg/min) |
| Change From Baseline in KCCQ - Physical Limitation | Baseline,1 year | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. |
| Change From Baseline in KCCQ - Symptom Stability | Baseline,1 year | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. |
| Change From Baseline in KCCQ - Symptom Frequency | Baseline,1 year | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. |
| Change From Baseline in KCCQ - Symptom Burden | Baseline,1 year | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. |
| Change From Baseline in KCCQ - Total Symptom | Baseline,1 year | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. |
| Change From Baseline in KCCQ - Self Efficacy | Baseline,1 year | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. |
| Change From Baseline in KCCQ - Quality of Life Score | Baseline,1 year | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. |
| Change From Baseline in KCCQ - Social Limitation | Baseline,1 year | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. |
| Change From Baseline in KCCQ - Overall Summary | Baseline,1 year | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. |
| Change From Baseline in KCCQ - Clinical Summary | Baseline,1 year | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. |
Countries
United States
Participant flow
Recruitment details
This is a prospective, single-arm longitudinal study, 40 patients were initiated on valsartan/sacubitril after a two week run in period of ACE or ARB alone.
Participants by arm
| Arm | Count |
|---|---|
| Open Label Entresto All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure. In this study subjects will take this drug as they normally would for their standard of care.
Entresto | 40 |
| Total | 40 |
Baseline characteristics
| Characteristic | Open Label Entresto |
|---|---|
| Age, Continuous | 55 Years STANDARD_DEVIATION 12.4 |
| Blood Pressure Diastolic | 76 mmHg STANDARD_DEVIATION 14.6 |
| Blood Pressure Systolic | 127 mmHg STANDARD_DEVIATION 22.6 |
| Exercise Performance- 6 Minute Walk | 425 Meter STANDARD_DEVIATION 102 |
| Exercise Performance - CPX -Peak RER | 1.14 meters STANDARD_DEVIATION 0.1 |
| Exercise Performance - CPX - Peak VO2 | 17.5 mL/kg/min |
| Exercise Performance - CPX - VE/VC02 | 33 ratio |
| Heart Failure Etiology Ischemic (ICM) | 10 Participants |
| Heart Failure Etiology Nonischemic (NICM) | 24 Participants |
| Heart Failure Etiology Unknown | 6 Participants |
| hm ratio (MIBG) Early hm ratio | 1.54 ratio |
| hm ratio (MIBG) Late hm ratio | 1.43 ratio |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary | 91 scores on a scale |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary | 82 scores on a scale |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical limitation | 90 scores on a scale |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Quality of Life Score | 67 scores on a scale |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Self Efficacy | 88 scores on a scale |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Social Limitation | 81 scores on a scale |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Symptom Burden | 92 scores on a scale |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Symptom Frequency | 89 scores on a scale |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Symptom Stability | 50 scores on a scale |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom | 89 scores on a scale |
| LV Remodeling 2D End-Diastolic Diameter | 6.0 cm STANDARD_DEVIATION 0.8 |
| LV Remodeling 2D End-Systolic Diameter | 5.3 cm STANDARD_DEVIATION 0.9 |
| LV Remodeling 3D End-Diastolic Volume | 243.5 mL |
| LV Remodeling 3D End-Systolic Volume | 159.7 mL |
| LV Remodeling Conicity | 0.75 percent STANDARD_DEVIATION 0.03 |
| LV Remodeling Left Atrial Volume | 90.9 mL |
| LV Remodeling LV Ejection Fraction | 32 percent STANDARD_DEVIATION 7 |
| LV Remodeling Sphericity | 0.73 percent STANDARD_DEVIATION 0.05 |
| LV Remodeling-Global Longitudinal Strain (%) | -12.9 percent STANDARD_DEVIATION 2.8 |
| New York Heart Association (NYHA) Class Class II | 26 Participants |
| New York Heart Association (NYHA) Class Class III | 13 Participants |
| New York Heart Association (NYHA) Class Unknown | 1 Participants |
| NT-proBNP levels | 333 pg/mL |
| Race (NIH/OMB) Ethnicity American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Ethnicity Asian | 2 Participants |
| Race (NIH/OMB) Ethnicity Black or African American | 23 Participants |
| Race (NIH/OMB) Ethnicity More than one race | 0 Participants |
| Race (NIH/OMB) Ethnicity Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Ethnicity Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Ethnicity White | 15 Participants |
| Region of Enrollment United States | 40 Participants |
| Rho-kinase (Rock) | 1 ng/mL |
| RV Remodeling Ejection Fraction | 50 percent STANDARD_DEVIATION 10 |
| RV Remodeling End-Diastolic Volume | 143 cm |
| RV Remodeling End Systolic Volume | 73 cm |
| RV Remodeling Septal Curvature | 0.86 percent STANDARD_DEVIATION 0.15 |
| RV Remodeling - Free-Wall Curvature | 1.17 percent |
| RV Remodeling - Tricuspid Regurgitation Mild | 4 Participants |
| RV Remodeling - Tricuspid Regurgitation Mild-Moderate | 2 Participants |
| RV Remodeling - Tricuspid Regurgitation Moderate | 0 Participants |
| RV Remodeling - Tricuspid Regurgitation Moderate-Severe | 1 Participants |
| RV Remodeling - Tricuspid Regurgitation No | 3 Participants |
| RV Remodeling - Tricuspid Regurgitation Severe | 0 Participants |
| RV Remodeling - Tricuspid Regurgitation Trace | 30 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 40 |
| other Total, other adverse events | 4 / 40 |
| serious Total, serious adverse events | 4 / 40 |
Outcome results
Primary
Change From Baseline in LV Remodeling 2D End-Diastolic Diameter (cm)
LV Remodeling 2D End-Diastolic Diameter (cm)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Entresto | Change From Baseline in LV Remodeling 2D End-Diastolic Diameter (cm) | Baseline | 6 cm | Standard Deviation 0.8 |
| Open Label Entresto | Change From Baseline in LV Remodeling 2D End-Diastolic Diameter (cm) | 1 year | 6 cm | Standard Deviation 0.7 |
Comparison: Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.p-value: <0.001t-test, 2 sided
Primary
Change From Baseline in LV Remodeling 2D End-Systolic Diameter (cm)
LV Remodeling 2D End-Systolic Diameter (cm)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Entresto | Change From Baseline in LV Remodeling 2D End-Systolic Diameter (cm) | Baseline | 5.3 cm | Standard Deviation 0.9 |
| Open Label Entresto | Change From Baseline in LV Remodeling 2D End-Systolic Diameter (cm) | 1 year | 4.5 cm | Standard Deviation 0.9 |
Comparison: Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.p-value: <0.001t-test, 2 sided
Primary
Change From Baseline in LV Remodeling 3D End-Diastolic Volume (mL)
LV Remodeling 3D End-Diastolic Volume (mL)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in LV Remodeling 3D End-Diastolic Volume (mL) | Baseline | 243.5 mL |
| Open Label Entresto | Change From Baseline in LV Remodeling 3D End-Diastolic Volume (mL) | 1 year | 160.2 mL |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: <0.001Sign test
Primary
Change From Baseline in LV Remodeling 3D End-Systolic Volume (mL)
LV Remodeling 3D End-Systolic Volume (mL)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in LV Remodeling 3D End-Systolic Volume (mL) | Baseline | 159.7 mL |
| Open Label Entresto | Change From Baseline in LV Remodeling 3D End-Systolic Volume (mL) | 1 year | 90.7 mL |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: <0.001Sign test
Primary
Change From Baseline in LV Remodeling Conicity (%)
LV Remodeling Conicity (%)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Entresto | Change From Baseline in LV Remodeling Conicity (%) | Baseline | 0.75 percentage of conicity | Standard Deviation 0.03 |
| Open Label Entresto | Change From Baseline in LV Remodeling Conicity (%) | 1 year | 0.77 percentage of conicity | Standard Deviation 0.02 |
Comparison: Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.p-value: 0.13t-test, 2 sided
Primary
Change From Baseline in LV Remodeling Global Longitudinal Strain (%)
LV Remodeling Global Longitudinal Strain (%)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Entresto | Change From Baseline in LV Remodeling Global Longitudinal Strain (%) | Baseline | -12.9 percentage of global longitudinal strain | Standard Deviation 2.8 |
| Open Label Entresto | Change From Baseline in LV Remodeling Global Longitudinal Strain (%) | 1 year | -15.3 percentage of global longitudinal strain | Standard Deviation 3.5 |
Comparison: Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.p-value: <0.001t-test, 2 sided
Primary
Change From Baseline in LV Remodeling Left Atrial Volume (mL)
LV Remodeling Left Atrial Volume (mL)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in LV Remodeling Left Atrial Volume (mL) | Baseline | 90.9 mL |
| Open Label Entresto | Change From Baseline in LV Remodeling Left Atrial Volume (mL) | 1 year | 65.6 mL |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: <0.001Sign test
Primary
Change From Baseline in LV Remodeling LV Ejection Fraction (%)
LV Remodeling LV Ejection Fraction (%)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Entresto | Change From Baseline in LV Remodeling LV Ejection Fraction (%) | Baseline | 32 percentage of ejection fraction | Standard Deviation 7 |
| Open Label Entresto | Change From Baseline in LV Remodeling LV Ejection Fraction (%) | 1 year | 43 percentage of ejection fraction | Standard Deviation 9 |
Comparison: Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.p-value: <0.001t-test, 2 sided
Primary
Change From Baseline in LV Remodeling Sphericity (%)
LV Remodeling Sphericity (%)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Entresto | Change From Baseline in LV Remodeling Sphericity (%) | Baseline | 0.73 percentage of sphericity | Standard Deviation 0.05 |
| Open Label Entresto | Change From Baseline in LV Remodeling Sphericity (%) | 1 year | 0.71 percentage of sphericity | Standard Deviation 0.03 |
Comparison: Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.p-value: 0.95t-test, 2 sided
Primary
Change From Baseline in RV Remodeling Ejection Fraction (%)
RV Remodeling Ejection Fraction (%)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Entresto | Change From Baseline in RV Remodeling Ejection Fraction (%) | Baseline | 50 percentage of ejection fraction | Standard Deviation 10 |
| Open Label Entresto | Change From Baseline in RV Remodeling Ejection Fraction (%) | 1 year | 50 percentage of ejection fraction | Standard Deviation 8 |
Comparison: Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.p-value: 0.65t-test, 2 sided
Primary
Change From Baseline in RV Remodeling End-Diastolic Volume (mL)
RV Remodeling End-Diastolic Volume (mL)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in RV Remodeling End-Diastolic Volume (mL) | Baseline | 143 mL |
| Open Label Entresto | Change From Baseline in RV Remodeling End-Diastolic Volume (mL) | 1 year | 104 mL |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: <0.001Sign test
Primary
Change From Baseline in RV Remodeling End Systolic Volume (mL)
RV Remodeling End Systolic Volume (mL)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in RV Remodeling End Systolic Volume (mL) | Baseline | 73 mL |
| Open Label Entresto | Change From Baseline in RV Remodeling End Systolic Volume (mL) | 1 year | 47 mL |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: <0.001Sign test
Primary
Change From Baseline in RV Remodeling Free-Wall Curvature (%)
RV Remodeling Free-Wall Curvature (%)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in RV Remodeling Free-Wall Curvature (%) | Baseline | 1.17 percentage of free-wall curvature |
| Open Label Entresto | Change From Baseline in RV Remodeling Free-Wall Curvature (%) | 1 year | 1.14 percentage of free-wall curvature |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.76Sign test
Primary
Change From Baseline in RV Remodeling Septal Curvature (%)
RV Remodeling Septal Curvature (%)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Entresto | Change From Baseline in RV Remodeling Septal Curvature (%) | Baseline | 0.86 percentage of septal curvature | Standard Deviation 0.15 |
| Open Label Entresto | Change From Baseline in RV Remodeling Septal Curvature (%) | 1 year | 0.77 percentage of septal curvature | Standard Deviation 0.8 |
Comparison: Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.p-value: 0.06Sign test
Primary
Change From Baseline in RV Remodeling Tricuspid Regurgitation
RV Remodeling Tricuspid Regurgitation
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | 1 year | Moderate | 0 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | Baseline | No | 3 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | Baseline | Trace | 30 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | Baseline | Mild | 4 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | Baseline | Mild-Moderate | 2 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | Baseline | Moderate | 0 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | Baseline | Moderate-Severe | 1 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | Baseline | Severe | 0 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | 1 year | No | 8 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | 1 year | Trace | 16 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | 1 year | Mild | 9 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | 1 year | Mild-Moderate | 0 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | 1 year | Moderate-Severe | 0 Participants |
| Open Label Entresto | Change From Baseline in RV Remodeling Tricuspid Regurgitation | 1 year | Severe | 0 Participants |
Comparison: Primary outcome was presented at baseline and 1-year as frequency and percentages based upon the Shapiro-Wilks test of normality, and then analyzed with the Fisher exact test.p-value: 0.07Fisher Exact
Secondary
Change From Baseline in Blood Pressure - Diastolic (mmHg)
Blood Pressure - Diastolic (mmHg)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in Blood Pressure - Diastolic (mmHg) | Baseline | 82 mmHg |
| Open Label Entresto | Change From Baseline in Blood Pressure - Diastolic (mmHg) | 1 year | 76 mmHg |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.01Sign test
Secondary
Change From Baseline in Blood Pressure - Systolic (mmHg)
Blood Pressure - Systolic (mmHg)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in Blood Pressure - Systolic (mmHg) | Baseline | 131 mmHg |
| Open Label Entresto | Change From Baseline in Blood Pressure - Systolic (mmHg) | 1 year | 114 mmHg |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: <0.001Sign test
Secondary
Change From Baseline in Exercise Performance - 6 Minute Walk
Exercise Performance - 6 Minute Walk
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Entresto | Change From Baseline in Exercise Performance - 6 Minute Walk | Baseline | 425 meters | Standard Deviation 102 |
| Open Label Entresto | Change From Baseline in Exercise Performance - 6 Minute Walk | 1 year | 486 meters | Standard Deviation 124 |
Comparison: Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.p-value: <0.001t-test, 2 sided
Secondary
Change From Baseline in Exercise Performance - CPX - Peak RER
Exercise Performance - CPX - Peak RER (Respiratory Exchange Ratio)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Entresto | Change From Baseline in Exercise Performance - CPX - Peak RER | Baseline | 1.14 ratio | Standard Deviation 0.1 |
| Open Label Entresto | Change From Baseline in Exercise Performance - CPX - Peak RER | 1 year | 1.06 ratio | Standard Deviation 0.1 |
Comparison: Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.p-value: <0.001t-test, 2 sided
Secondary
Change From Baseline in Exercise Performance - CPX - Peak VO2 (mL/kg/Min)
Exercise Performance - CPX - Peak VO2 (mL/kg/min)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in Exercise Performance - CPX - Peak VO2 (mL/kg/Min) | Baseline | 17.5 mL/kg/min |
| Open Label Entresto | Change From Baseline in Exercise Performance - CPX - Peak VO2 (mL/kg/Min) | 1 year | 19.5 mL/kg/min |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.02Sign test
Secondary
Change From Baseline in Exercise Performance - CPX - VE/VC02
Exercise Performance - CPX - VE/VC02
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in Exercise Performance - CPX - VE/VC02 | Baseline | 33 ratio |
| Open Label Entresto | Change From Baseline in Exercise Performance - CPX - VE/VC02 | 1 year | 33 ratio |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.82Sign test
Secondary
Change From Baseline in KCCQ - Clinical Summary
KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in KCCQ - Clinical Summary | Baseline | 91 score on a scale |
| Open Label Entresto | Change From Baseline in KCCQ - Clinical Summary | 1 year | 94.5 score on a scale |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.056Sign test
Secondary
Change From Baseline in KCCQ - Overall Summary
KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in KCCQ - Overall Summary | Baseline | 82 score on a scale |
| Open Label Entresto | Change From Baseline in KCCQ - Overall Summary | 1 year | 90 score on a scale |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.005Sign test
Secondary
Change From Baseline in KCCQ - Physical Limitation
KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in KCCQ - Physical Limitation | Baseline | 90 score on a scale |
| Open Label Entresto | Change From Baseline in KCCQ - Physical Limitation | 1 year | 96 score on a scale |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.11Sign test
Secondary
Change From Baseline in KCCQ - Quality of Life Score
KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in KCCQ - Quality of Life Score | 1 year | 83 score on a scale |
| Open Label Entresto | Change From Baseline in KCCQ - Quality of Life Score | Baseline | 67 score on a scale |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.002Sign test
Secondary
Change From Baseline in KCCQ - Self Efficacy
KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in KCCQ - Self Efficacy | Baseline | 88 score on a scale |
| Open Label Entresto | Change From Baseline in KCCQ - Self Efficacy | 1 year | 100 score on a scale |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.28Sign test
Secondary
Change From Baseline in KCCQ - Social Limitation
KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in KCCQ - Social Limitation | Baseline | 81 score on a scale |
| Open Label Entresto | Change From Baseline in KCCQ - Social Limitation | 1 year | 94 score on a scale |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.008Sign test
Secondary
Change From Baseline in KCCQ - Symptom Burden
KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in KCCQ - Symptom Burden | Baseline | 92 score on a scale |
| Open Label Entresto | Change From Baseline in KCCQ - Symptom Burden | 1 year | 92 score on a scale |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.059Sign test
Secondary
Change From Baseline in KCCQ - Symptom Frequency
KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in KCCQ - Symptom Frequency | Baseline | 89 score on a scale |
| Open Label Entresto | Change From Baseline in KCCQ - Symptom Frequency | 1 year | 92 score on a scale |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.035Sign test
Secondary
Change From Baseline in KCCQ - Symptom Stability
KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in KCCQ - Symptom Stability | Baseline | 50 score on a scale |
| Open Label Entresto | Change From Baseline in KCCQ - Symptom Stability | 1 year | 50 score on a scale |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.17Sign test
Secondary
Change From Baseline in KCCQ - Total Symptom
KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in KCCQ - Total Symptom | Baseline | 89 score on a scale |
| Open Label Entresto | Change From Baseline in KCCQ - Total Symptom | 1 year | 92 score on a scale |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.054Sign test
Secondary
Change From Baseline in (MIBG) Early hm Ratio
Cardiac 123Iodine-metaiodobenzylguanidine (MIBG) Early heart/mediastinum ratio (hm) ratio
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.~0 participants analyzed at 1 year as data were not collected.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in (MIBG) Early hm Ratio | Baseline | 1.54 ratio |
Secondary
Change From Baseline in (MIBG) Late hm Ratio
Cardiac 123Iodine-metaiodobenzylguanidine (MIBG) Late heart/mediastinum ratio (hm) ratio
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.~0 participants analyzed at 1 year as data were not collected
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in (MIBG) Late hm Ratio | Baseline | 1.43 ratio |
Secondary
Change From Baseline in NT-proBNP Levels
NT-proBNP levels (pg/ml)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in NT-proBNP Levels | Baseline | 333 pg/ml |
| Open Label Entresto | Change From Baseline in NT-proBNP Levels | 1 year | 290 pg/ml |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.03Sign test
Secondary
Change From Baseline in Rho-associated Protein Kinase (ROCK)
Rho-associated protein kinase (ROCK)
Time frame: Baseline,1 year
Population: All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label Entresto | Change From Baseline in Rho-associated Protein Kinase (ROCK) | Baseline | 1.1 ng/mL |
| Open Label Entresto | Change From Baseline in Rho-associated Protein Kinase (ROCK) | 1 year | 0.7 ng/mL |
Comparison: Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.p-value: 0.001Sign test