Heart Failure, Congestive
Conditions
Keywords
Systolic heart failure, Bisoprolol, Concor, Echocardiogram
Brief summary
This is a prospective, open-labeled, multi-centric trial to evaluate the effect of bisoprolol (between low dose and high dose) on surrogate markers of heart failure in Korea.
Detailed description
Subjects with systolic congestive heart failure (CHF) will be enrolled in this study after proper evaluation of NT-proBNP, global assessment of CHF, 6-minute walking test and improvement score of New York Heart Association (NYHA) and echocardiogram (left ventricular chamber size and ejection fraction \[LVEF\]). Each subject will be orally administered bisoprolol for 6 months starting at 1.25 mg at the Week 0 and titrated up to 10 mg during the 6 month period if the persistent standing systolic blood pressure (SBP) is greater than (\>) 90 millimeter of mercury (mm Hg) and there is no symptom of hypotension at the current dose medication (syncope, loss of consciousness, dizziness when standing up). OBJECTIVES Primary objective: • To evaluate the effect of bisoprolol (between low dose and high dose) on surrogate markers of heart failure in Korea Secondary objectives: * To evaluate bisoprolol for the effects on clinical improvement of heart failure in Korea: 1. New York Heart Association (NYHA), 2. 6-minutes walking test 3. Echocardiogram (left ventricular chamber size and LVEF) * Hospitalization due to heart failure * To evaluate the safety and tolerability of bisoprolol * Global assessment of CHF
Interventions
DRUGLow Dose Bisoprolol
Bisoprolol tablet (Concor) will be administered orally at a starting dose of 1.25 milligram (mg) once daily for 2 weeks. The dose will be further escalated from 1.25 mg to 2.5 mg once daily after 2 weeks and will be administered up to 26 weeks, only if the previous administered dose is well tolerated. If the subject could not tolerate the increased dose, then the last tolerated dose will be maintained up to 26 weeks.
DRUGHigh Dose Bisoprolol
Bisoprolol tablet (Concor) will be administered orally at a starting dose of 3.75 mg once daily for 2 weeks. The dose will be subsequently increased to 5 mg, 7.5 mg, or 10 mg once daily every two weeks and will be administered up to 26 weeks, only if the previous administered dose is well tolerated. If the subject could not tolerate the increased dose, then the last tolerated dose will be maintained up to 26 weeks.
Sponsors
Merck Ltd.
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with heart failure and at the age of 18 (inclusive) to 80 (exclusive) * Subjects with NYHA Class II-IV with dyspnea * Subjects with left ventricular ejection fraction (LVEF) of 40 percent or below on the echocardiogram * Eligible subjects who meet the criteria, are capable of participating in the study, and provide written informed consent to study participation after receiving a clear explanation about the study objective and nature
Exclusion criteria
* A subject who cannot understand or does not agree to the study contents * Subjects with conduction defect of 2nd degree or above atrioventricular block * Subjects with heart rate less than (\<) 60 beats at rest * Subjects with systolic blood pressure \< 100 mm Hg at rest * Subjects with renal failure (serum creatinine \> 2.0 milligram per deciliter \[mg/dL\]) * Subjects with unrecovered pulmonary edema * Subjects with history of myocardial infarction or stroke within 3 months * Subjects with history of coronary intervention or coronary bypass within 6 months * Subjects with heart failure due to mitral valve without valve replacement or aortic valvular disease (excluding moderate or less severe mitral insufficiency secondary to left ventricular expansion) * Subjects with history of valve replacement within the past 6 months * Subjects with history or scheduled heart transplantation * Subjects with reversible obstructive pulmonary disease * Subjects with other cases where beta blockers are contraindicated * Any surgical or internal disease that may put the subject at a higher risk due to study participation or may interfere with the subjects compliance to study requirements or completion of the study, based on the judgment of the Investigator * A subject with history of non-compliance to drug prescriptions or who is not willing to comply with the protocol * Subjects with a history of treated or untreated malignant tumor within the past 5 years * Pregnant or lactating women * Subjects with heart failure due to acute myocarditis * Subjects with continuous ventricular tachycardia with history of syncope within 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Week 26 | Baseline and Week 26 | B-type natriuretic peptide (BNP) is a substance secreted from the ventricles or lower chambers of the heart in response to changes in pressure that occur when heart failure develops and worsens. The level of BNP in the blood increases when heart failure symptoms worsen, and decreases when the heart failure condition is stable. The BNP level in a person with heart failure is higher than in a person with normal heart function. The percent change of NT-pro BNP was calculated according to the formula: N-terminal pro B-type natriuretic peptide (NT-proBNP) reduction ratio = 100\*(Baseline NT-proBNP - Week 26 NT-proBNP)/Baseline NT-proBNP. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 6-minute Walking Test (6-MWT) Distance at Week 26 | Baseline and Week 26 | 6-minute Walking Test (6-MWT) distance was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. |
| Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Week 26 | Baseline and Week 26 | LVEF was defined as the fraction of blood (in percent) pumped out of the heart's left ventricular chamber with each heart beat and it is used to measure the cardiac output for the heart. |
| Change From Baseline in Echocardiographic Left Ventricular Size at Week 26 | Baseline and Week 26 | Left ventricle size was measured as systolic and diastolic Left Ventricular Internal Dimension (LVID). Diastolic dimension was measured of the left ventricle at the level of the chordae tendineae. The systolic dimension was measured as the smallest dimension between the left septal endocardium and the posterior wall endocardium during systole, whether or not the two walls were exactly apposed. |
| Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Baseline and Week 26 | New York Heart Association (NYHA) classification of heart failure: Class I: No limitation: ordinary physical exercise does not cause undue fatigue, dyspnea, or palpitations. Class II: Slight limitation of physical activity: comfortable at rest but ordinary activity results in fatigue, palpitations, or dyspnea. Class III: Marked limitation of physical activity: comfortable at rest but less than ordinary activity results in symptoms. Class IV: Unable to carry out any physical activity without discomfort: symptoms of heart failure are present even at rest with increased discomfort with any physical activity. |
| Number of Participants With Adverse Events (AEs) | Baseline up to Week 26 | An adverse event (AE) is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. |
| Mean Change From Baseline in Global Assessment of Congestive Heart Failure (CHF) Score at Week 26 | Baseline and Week 26 | Global assessment of CHF: The Investigator defined, graded, and recorded the participant's symptoms and signs by using a 6-point CHF scale ranging from 0 (unassessable), 1 (worsened), 2 (no change), 3 (mildly improved), 4 (moderately improved) and 5 (markedly improved). |
| Number of Participants Who Were Re-hospitalized Due to Heart Failure and Who Died Due to Cardiovascular Disorder | Baseline up to Week 26 | — |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Bisoprolol Bisoprolol tablet (Concor) administered orally at a starting dose of 1.25 milligram (mg) once daily for 2 weeks. The dose was further escalated from 1.25 mg to 2.5 mg once daily after 2 weeks and was administered up to 26 weeks, only if the previous administered dose was well tolerated. If the participant didn't tolerate the increased dose, then the last tolerated dose was maintained up to 26 weeks. | 52 |
| High Dose Bisoprolol Bisoprolol tablet (Concor) administered orally at a starting dose of 3.75 mg once daily for 2 weeks. The dose was subsequently increased to 5 mg, 7.5 mg, or 10 mg once daily every two weeks and was administered up to 26 weeks, only if the previous administered dose was well tolerated. If the participant didn't tolerate the increased dose, then the last tolerated dose was maintained up to 26 weeks. | 107 |
| Total | 159 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Exclusion criterion | 0 | 1 |
| Overall Study | No primary endpoint evaluation | 14 | 6 |
| Overall Study | Protocol Violation | 8 | 5 |
Baseline characteristics
| Characteristic | Low Dose Bisoprolol | High Dose Bisoprolol | Total |
|---|---|---|---|
| Age, Continuous | 62.88 years STANDARD_DEVIATION 11.52 | 57.68 years STANDARD_DEVIATION 12.28 | 59.38 years STANDARD_DEVIATION 12.24 |
| Sex: Female, Male Female | 34 Participants | 83 Participants | 117 Participants |
| Sex: Female, Male Male | 18 Participants | 24 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 45 / 66 | 71 / 114 |
| serious Total, serious adverse events | 16 / 66 | 9 / 114 |
Outcome results
Primary
Percent Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Week 26
B-type natriuretic peptide (BNP) is a substance secreted from the ventricles or lower chambers of the heart in response to changes in pressure that occur when heart failure develops and worsens. The level of BNP in the blood increases when heart failure symptoms worsen, and decreases when the heart failure condition is stable. The BNP level in a person with heart failure is higher than in a person with normal heart function. The percent change of NT-pro BNP was calculated according to the formula: N-terminal pro B-type natriuretic peptide (NT-proBNP) reduction ratio = 100\*(Baseline NT-proBNP - Week 26 NT-proBNP)/Baseline NT-proBNP.
Time frame: Baseline and Week 26
Population: ITT population included all the randomized participants who had at least one dose of the investigational product. 'N' (number of participants analyzed) signifies participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Bisoprolol | Percent Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Week 26 | 8.02 Percent change | Standard Deviation 113.78 |
| High Dose Bisoprolol | Percent Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Week 26 | 9.50 Percent change | Standard Deviation 117.56 |
Secondary
Change From Baseline in 6-minute Walking Test (6-MWT) Distance at Week 26
6-minute Walking Test (6-MWT) distance was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.
Time frame: Baseline and Week 26
Population: ITT population included all the randomized participants who had at least one dose of the investigational product. 'N' (number of participants analyzed) signifies participants who were evaluable for this measure. 'n' signifies number of participants who were evaluable for specified categories at different time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Bisoprolol | Change From Baseline in 6-minute Walking Test (6-MWT) Distance at Week 26 | Baseline (n=52, 103) | 347.58 Meter | Standard Deviation 123.35 |
| Low Dose Bisoprolol | Change From Baseline in 6-minute Walking Test (6-MWT) Distance at Week 26 | Change at Week 26 (n=47, 102) | 41.59 Meter | Standard Deviation 103.45 |
| High Dose Bisoprolol | Change From Baseline in 6-minute Walking Test (6-MWT) Distance at Week 26 | Change at Week 26 (n=47, 102) | 28.45 Meter | Standard Deviation 161.66 |
| High Dose Bisoprolol | Change From Baseline in 6-minute Walking Test (6-MWT) Distance at Week 26 | Baseline (n=52, 103) | 368.11 Meter | Standard Deviation 169.04 |
Secondary
Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Week 26
LVEF was defined as the fraction of blood (in percent) pumped out of the heart's left ventricular chamber with each heart beat and it is used to measure the cardiac output for the heart.
Time frame: Baseline and Week 26
Population: ITT population included all the randomized participants who had at least one dose of the investigational product. 'N' (number of participants analyzed) signifies participants who were evaluable for this measure. 'n' signifies number of participants who were evaluable for specified categories at different time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Week 26 | Baseline (n=52, 106) | 28.68 Percent LVEF | Standard Deviation 7.47 |
| Low Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Week 26 | Change at Week 26 (n=50, 106) | 8.83 Percent LVEF | Standard Deviation 9.47 |
| High Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Week 26 | Baseline (n=52, 106) | 27.61 Percent LVEF | Standard Deviation 6.72 |
| High Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Week 26 | Change at Week 26 (n=50, 106) | 14.22 Percent LVEF | Standard Deviation 11.81 |
Secondary
Change From Baseline in Echocardiographic Left Ventricular Size at Week 26
Left ventricle size was measured as systolic and diastolic Left Ventricular Internal Dimension (LVID). Diastolic dimension was measured of the left ventricle at the level of the chordae tendineae. The systolic dimension was measured as the smallest dimension between the left septal endocardium and the posterior wall endocardium during systole, whether or not the two walls were exactly apposed.
Time frame: Baseline and Week 26
Population: ITT population included all the randomized participants who had at least one dose of the investigational product. 'N' (number of participants analyzed) signifies participants who were evaluable for this measure. 'n' signifies number of participants who were evaluable for specified categories at different time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Size at Week 26 | Baseline: Systolic LVID (n=51, 104) | 54.25 Milliliter LVID | Standard Deviation 8.8 |
| Low Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Size at Week 26 | Change at Week 26: Systolic LVID (n=47, 102) | 5.46 Milliliter LVID | Standard Deviation 7.25 |
| Low Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Size at Week 26 | Baseline: Diastolic LVID (n=52, 106) | 64.28 Milliliter LVID | Standard Deviation 7.99 |
| Low Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Size at Week 26 | Change at Week 26: Diastolic LVID (n=50, 106) | 3.12 Milliliter LVID | Standard Deviation 4.37 |
| High Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Size at Week 26 | Change at Week 26: Diastolic LVID (n=50, 106) | 5.49 Milliliter LVID | Standard Deviation 8.45 |
| High Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Size at Week 26 | Baseline: Systolic LVID (n=51, 104) | 54.69 Milliliter LVID | Standard Deviation 8.95 |
| High Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Size at Week 26 | Baseline: Diastolic LVID (n=52, 106) | 63.40 Milliliter LVID | Standard Deviation 7.87 |
| High Dose Bisoprolol | Change From Baseline in Echocardiographic Left Ventricular Size at Week 26 | Change at Week 26: Systolic LVID (n=47, 102) | 9.84 Milliliter LVID | Standard Deviation 9.32 |
Secondary
Mean Change From Baseline in Global Assessment of Congestive Heart Failure (CHF) Score at Week 26
Global assessment of CHF: The Investigator defined, graded, and recorded the participant's symptoms and signs by using a 6-point CHF scale ranging from 0 (unassessable), 1 (worsened), 2 (no change), 3 (mildly improved), 4 (moderately improved) and 5 (markedly improved).
Time frame: Baseline and Week 26
Population: ITT population included all the randomized participants who had at least one dose of the investigational product. 'N' (number of participants analyzed) signifies participants who were evaluable for this measure. 'n' signifies number of participants who were evaluable for specified categories at different time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Bisoprolol | Mean Change From Baseline in Global Assessment of Congestive Heart Failure (CHF) Score at Week 26 | Baseline (n=52, 106) | 2.52 Units on a scale | Standard Deviation 1.02 |
| Low Dose Bisoprolol | Mean Change From Baseline in Global Assessment of Congestive Heart Failure (CHF) Score at Week 26 | Change at Week 26 (n=51, 106) | 0.45 Units on a scale | Standard Deviation 1.27 |
| High Dose Bisoprolol | Mean Change From Baseline in Global Assessment of Congestive Heart Failure (CHF) Score at Week 26 | Change at Week 26 (n=51, 106) | 0.69 Units on a scale | Standard Deviation 1.41 |
| High Dose Bisoprolol | Mean Change From Baseline in Global Assessment of Congestive Heart Failure (CHF) Score at Week 26 | Baseline (n=52, 106) | 2.71 Units on a scale | Standard Deviation 0.92 |
Secondary
Number of Participants Who Were Re-hospitalized Due to Heart Failure and Who Died Due to Cardiovascular Disorder
Time frame: Baseline up to Week 26
Population: ITT population included all the randomized participants who had at least one dose of the investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low Dose Bisoprolol | Number of Participants Who Were Re-hospitalized Due to Heart Failure and Who Died Due to Cardiovascular Disorder | Death due to cardiovascular disorder | 0 Participants |
| Low Dose Bisoprolol | Number of Participants Who Were Re-hospitalized Due to Heart Failure and Who Died Due to Cardiovascular Disorder | Re-hospitalization due to heart failure | 3 Participants |
| High Dose Bisoprolol | Number of Participants Who Were Re-hospitalized Due to Heart Failure and Who Died Due to Cardiovascular Disorder | Re-hospitalization due to heart failure | 3 Participants |
| High Dose Bisoprolol | Number of Participants Who Were Re-hospitalized Due to Heart Failure and Who Died Due to Cardiovascular Disorder | Death due to cardiovascular disorder | 0 Participants |
Secondary
Number of Participants With Adverse Events (AEs)
An adverse event (AE) is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.
Time frame: Baseline up to Week 26
Population: Safety analysis population included all the randomized participants who had at least one dose of the investigational product had post-dose safety data confirmed at least once by the Investigator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Bisoprolol | Number of Participants With Adverse Events (AEs) | 45 Participants |
| High Dose Bisoprolol | Number of Participants With Adverse Events (AEs) | 73 Participants |
Secondary
Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA)
New York Heart Association (NYHA) classification of heart failure: Class I: No limitation: ordinary physical exercise does not cause undue fatigue, dyspnea, or palpitations. Class II: Slight limitation of physical activity: comfortable at rest but ordinary activity results in fatigue, palpitations, or dyspnea. Class III: Marked limitation of physical activity: comfortable at rest but less than ordinary activity results in symptoms. Class IV: Unable to carry out any physical activity without discomfort: symptoms of heart failure are present even at rest with increased discomfort with any physical activity.
Time frame: Baseline and Week 26
Population: ITT population included all the randomized participants who had at least one dose of the investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Baseline: Class III | 25.00 Percentage of participants |
| Low Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Week 26: Class I | 21.15 Percentage of participants |
| Low Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Baseline: Class II | 73.08 Percentage of participants |
| Low Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Week 26: Class II | 69.23 Percentage of participants |
| Low Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Baseline: Class IV | 1.92 Percentage of participants |
| Low Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Week 26: Class III | 9.62 Percentage of participants |
| High Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Week 26: Class III | 3.74 Percentage of participants |
| High Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Baseline: Class II | 74.77 Percentage of participants |
| High Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Baseline: Class III | 24.30 Percentage of participants |
| High Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Baseline: Class IV | 0.93 Percentage of participants |
| High Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Week 26: Class I | 42.06 Percentage of participants |
| High Dose Bisoprolol | Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) | Week 26: Class II | 54.21 Percentage of participants |