Heart Failure
Conditions
Keywords
Chronic Heart Failure, Bisoprolol, Heart rate control
Brief summary
This is a single-arm, open label, interventional, multi-center, phase 4 pilot study.
Interventions
DRUGBisoprolol
Participants received Bisoprolol orally, once daily at a dose of 1.25 milligram (mg) up to Weeks 3, and then it was up-titrated to 2.5 mg up to Week 6, 3.75 mg up to Week 10, 5 mg up to Week 14, 7.5 mg up to Week 18 and 10 mg up to Week 26.
Sponsors
Merck Serono Co., Ltd., China
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* 18-80 year, male or female. * Chronic Heart failure subjects with medical history of cardiac disease or other related cardiovascular disease. * Left ventricular ejection fraction (LVEF) less than or equal to (=\<) 40 percent (%). * New York Heart Association (NYHA) class of II - IV * NYHA II ： Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue or palpitation. * NYHA III：Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes undue breathlessness, fatigue or palpitation. * NYHA IV：Unable to carry on any physical activity without discomfort. Symptoms at rest can be present. If any physical activity is undertaken, discomfort increased. * Signed Informed Consent Form (ICF).
Exclusion criteria
* Acute coronary syndrome (ACS) within 3 months. * Under beta-blocker treatment for the last 2 weeks. * Under other medicine treatment which may affect heart rate, like Non-dihydropyridine calcium channel blockers (NDHP-CCBs) or ivabradine for the last 2 weeks; Under Digoxin treatment \[more than (\>) 0.125 milligram (mg)\]. * Uncontrolled Diabetes \[hemoglobin A1c, (HbA1c) \>7.5%\]. * Severe or uncontrolled hypertension \[resting Systolic Blood Pressure (SBP) \>180 millimeters of mercury (mmHg), or resting Diastolic Blood Pressure (DBP) \>110mmHg at screening period\]. * Severe hypotension \[resting SBP less than (\<) 90mmHg, or resting DBP\<50mmHg\]. * Resting heart rate \<60 beat per minute (bpm). * Any contradiction to Bisoprolol according to label, including: * Acute heart failure or during episodes of heart failure decompensation requiring intravenous inotropic therapy. * Cardiogenic shock. * Atrioventricular block of second or third degree (without a pacemaker). * Sick sinus syndrome. * Sinoatrial block. * Slowed heart rate, causing symptoms (symptomatic bradycardia), * Decreased blood pressure, causing symptoms (symptomatic hypotension), * Severe bronchial asthma or severe chronic obstructive pulmonary disease. * Sever forms of peripheral arterial occlusive disease and Raynaud's syndrome. * Untreated phaeochromocytoma. * Metabolic acidosis. * Hypersensitivity to bisoprolol or to any of the excipients. * Severe Arrhythmia including atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter or ventricular tachycardia. * Significant valvular heart disease, congenital heart disease, pulmonary heart disease or perinatal heart disease. * Acute pulmonary edema. * Severe hepatic dysfunction, defined as: * Serum Alanine Aminotransferase (ALT) \> triple the upper limit of the normal range; and/or * Serum Aspartate Aminotransferase (AST) \> triple the upper limit of the normal value range and/or * Severe renal dysfunction, defined as: * Serum creatinine \> twice the upper limit of the normal range * Chronic Kidney Disease (glomerular filtration rate \<45 Milliliter per minute). * Hyperthyroidism or hypothyroidism. * Severe infectious disease, example (eg) Human Immunodeficiency Virus positive or active tuberculosis. * Severe autoimmune disease, e.g. lupus erythematosus, multiple sclerosis. * Severe respiratory, digestive, hematological disease (including Anemia of Hb \< 100 gram per litre) or tumor. * Known to be hypersensitivity to Bisoprolol, or any of the excipient. * Substance or alcohol abuse. * Received heart transplantation or pacemaker implantation; revascularization treatment within 3 months; or plan to receive above treatment in 6 months. * Currently undertaking other treatment that may affect the safety and/or efficacy evaluation, e.g. beta receptors agonists, et cetera. * No legal ability or legal ability is limited. * Subjects unlikely to cooperate in the study or with inability or unwillingness to give informed consent. * Child-bearing period women without effective contraceptive measures, pregnancy and lactation. * Participation in another clinical trial within the past 90 days. * Other significant condition that in the Investigator's opinion would exclude the subject from the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Resting Heart Rate at Week 6 | Baseline, Week 6 | Heartbeats in each minute were calculated and averaged to obtain the resting heart rate. |
| Change From Baseline in Resting Heart Rate at Week 14 | Baseline, Week 14 | Heartbeats in each minute were calculated and averaged to obtain the resting heart rate. |
| Change From Baseline in Resting Heart Rate at Week 26 | Baseline, Week 26 | Heartbeats in each minute were calculated and averaged to obtain the resting heart rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Left Ventricular End-diastolic Dimension (LVEDD) at Baseline, Week 14 and 26 | Baseline, Week 14 and 26 | Left Ventricular End-diastolic Dimension was measured by Ultrasound cardiogram. |
| Interventricular Septal Thickness (IVST) at Baseline, Week 14 and 26 | Baseline, Week 14 and 26 | Interventricular septal thickness was measured by Ultrasound cardiogram. |
| Ratio of Early (E) to Late (A) Ventricular Filling Velocities (E/A Ratio) at Baseline, Week 14 and Week 26 | Baseline, Week 14 and Week 26 | Early to late ratio was measured by ultrasound cardiogram. |
| Number of Participants With Clinically Relevant Systolic and Diastolic Blood Pressure | Screening (Week -2) up to Week 26 | Blood pressure (systolic and diastolic) measurement was taken at sitting position, with the elbow at the same level with the heart. Number of participants with clinically relevant systolic and diastolic blood pressure reported based on the assessment of the investigator. |
| Number of Participants With New York Heart Association (NYHA) Class | Baseline, Week 26 | The NYHA classification assesses the severity of symptoms of heart failure. Here NYHA class of II - IV was assessed. NYHA II: Slight limitation of physical activity, comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue or palpitation. NYHA III: Marked limitation of physical activity, comfortable at rest, but less than ordinary activity causes undue breathlessness, fatigue or palpitation. NYHA IV: Unable to carry on any physical activity without discomfort, symptoms at rest can be present. If any physical activity is undertaken, discomfort increased. |
| Percentage of Participants With Resting Heart Rate Less Than 70 Beats Per Minute (Bpm) and More Than 55 Bpm | Baseline up to Week 26 | Resting heart rate measurement was taken at sitting position for a continuous record of 3 minutes. Heartbeats in each minute was calculated and averaged to obtain the resting heart rate. |
| Quality of Life Based on Minnesota Living With Heart Failure (MLHF) at Baseline and End of Treatment | Baseline, end of treatment (Week 26) | MLHF questionnaire has 21 items. Questions assess the impact of frequent physical symptoms of heart failure and the effects of heart failure on physical and social functions. Each question had a possible score of 0 (best) to 5 (worst), for a total of 0 to 105. The higher the summed score, the worse is the impact of heart failure on a participant's quality of life. |
| Change From Baseline in Resting Heart Rate at Week 3, 10 and 18 | Baseline, Week 3, 10 and 18 | Heartbeats in each minute were calculated and averaged to obtain the resting heart rate. |
| 6-Minute Walk Test | Baseline and End of treatment (Week 26) | 6-min walk test was a practical simple test that requires a 100-feet hallway but no exercise equipment or advanced training for technicians. Walking is an activity performed daily by all but the most severely impaired participants. This test measures the distance that a participant can quickly walk on a flat, hard surface in a period of 6 minutes. |
| Number of Participants With Abnormal Value of N-terminal Pro-B-type Natriuretic Peptide (NT Pro-BNP) | Baseline up to End of treatment (Week 26) | Routine blood tests was performed to measure NT Pro-BNP. The normal range for NT Pro-BNP varies from 0 picograms/milliliter (pg/mL) (lower limit of normal value) -125 pg/mL (upper limit of normal value). |
| Mean 24 Hour, Day Time and Night Time Heart Rate | Baseline, week 6, 14 and end of treatment (Week 26) | Holter monitor was used to measure heart rate (24 hour, day time, night time). |
| Number of Participants With Arrhythmia | Baseline up to end of treatment (Week 26) | Holter monitor was used to diagnose arrhythmia. |
| Number of Participants With 24 Hour Heart Rate With More Than 70 Beats Per Minute (Bpm) and Less Than 55 Bpm | Baseline, week 6, 14 and end of treatment (Week 26) | Holter monitor was used to measure heart rate. |
| Number of Participants With Medicine Compliance Assessed by Medication Procession Ratio (MPR) | Up to Week 26 | MPR is used to assess the medicine compliance. MPR is defined as the actual drug number taken by the participants divided by the drug number should be taken by the participants according to the protocol. MPR between 80%-100% is defined as good compliance. Medication rate of less than (\<) 80% or greater than (\>)100% is defined as insufficient compliance. |
| Number of Participants With All Cause Mortality, Cardiac Death, or Re-admission Due to Heart Failure | Up to Week 26 | Number of participants with all-cause mortality, cardiac death, or re-admission due to heart failure was reported. |
| Quality of Life Based on the Medical Outcomes Study Item Short From Health Survey (SF-36) at Baseline and End of Treatment | Baseline, end of treatment (Week 26) | Short Form Health Survey (SF-36), an instrument composed by 8 subscales: Physical Functioning, Physical Role Function, Bodily Pain, General Health, Vitality, Social Functioning, Emotional Role Function and Mental Health. The individual question items (Likert scale 0-4) are first summed for each item under the various sections. Then, those summary scores are then standardized on a scale between 0 and 1 using the mean and standard deviation of the actual scores and finally, weighted to a scale between 0 and 100. The items contributing to a scale are scored so that a higher score represents better health, and they are averaged together to create the scale score. Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. |
| Left Ventricular Ejection Fraction (LVEF) at Baseline, Week 14 and 26 | Baseline, Week 14 and 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. Ultrasound cardiogram performed to measure LVEF. |
| Left Ventricular End-Systolic Dimension (LVESD) at Baseline, Week 14 and 26 | Baseline, Week 14 and 26 | Left Ventricular End-Systolic Dimension was measured by Ultrasound cardiogram. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bisoprolol Participants received Bisoprolol orally, once daily at a dose of 1.25 milligram (mg) up to Weeks 3, and then it was up-titrated to 2.5 mg up to Week 6, 3.75 mg up to Week 10, 5 mg up to Week 14, 7.5 mg up to Week 18 and 10 mg up to Week 26. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Study termination | 20 |
Baseline characteristics
| Characteristic | Bisoprolol |
|---|---|
| Age, Continuous | 48.37 Years STANDARD_DEVIATION 13.931 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 20 |
| other Total, other adverse events | 10 / 20 |
| serious Total, serious adverse events | 4 / 20 |
Outcome results
Primary
Change From Baseline in Resting Heart Rate at Week 14
Heartbeats in each minute were calculated and averaged to obtain the resting heart rate.
Time frame: Baseline, Week 14
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Primary
Change From Baseline in Resting Heart Rate at Week 26
Heartbeats in each minute were calculated and averaged to obtain the resting heart rate.
Time frame: Baseline, Week 26
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Primary
Change From Baseline in Resting Heart Rate at Week 6
Heartbeats in each minute were calculated and averaged to obtain the resting heart rate.
Time frame: Baseline, Week 6
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Secondary
6-Minute Walk Test
6-min walk test was a practical simple test that requires a 100-feet hallway but no exercise equipment or advanced training for technicians. Walking is an activity performed daily by all but the most severely impaired participants. This test measures the distance that a participant can quickly walk on a flat, hard surface in a period of 6 minutes.
Time frame: Baseline and End of treatment (Week 26)
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Secondary
Change From Baseline in Resting Heart Rate at Week 3, 10 and 18
Heartbeats in each minute were calculated and averaged to obtain the resting heart rate.
Time frame: Baseline, Week 3, 10 and 18
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Secondary
Interventricular Septal Thickness (IVST) at Baseline, Week 14 and 26
Interventricular septal thickness was measured by Ultrasound cardiogram.
Time frame: Baseline, Week 14 and 26
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Secondary
Left Ventricular Ejection Fraction (LVEF) at Baseline, Week 14 and 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. Ultrasound cardiogram performed to measure LVEF.
Time frame: Baseline, Week 14 and 26
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Secondary
Left Ventricular End-diastolic Dimension (LVEDD) at Baseline, Week 14 and 26
Left Ventricular End-diastolic Dimension was measured by Ultrasound cardiogram.
Time frame: Baseline, Week 14 and 26
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Secondary
Left Ventricular End-Systolic Dimension (LVESD) at Baseline, Week 14 and 26
Left Ventricular End-Systolic Dimension was measured by Ultrasound cardiogram.
Time frame: Baseline, Week 14 and 26
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Secondary
Mean 24 Hour, Day Time and Night Time Heart Rate
Holter monitor was used to measure heart rate (24 hour, day time, night time).
Time frame: Baseline, week 6, 14 and end of treatment (Week 26)
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Secondary
Number of Participants With 24 Hour Heart Rate With More Than 70 Beats Per Minute (Bpm) and Less Than 55 Bpm
Holter monitor was used to measure heart rate.
Time frame: Baseline, week 6, 14 and end of treatment (Week 26)
Population: The safety population included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bisoprolol | Number of Participants With 24 Hour Heart Rate With More Than 70 Beats Per Minute (Bpm) and Less Than 55 Bpm | 0 Participants |
Secondary
Number of Participants With Abnormal Value of N-terminal Pro-B-type Natriuretic Peptide (NT Pro-BNP)
Routine blood tests was performed to measure NT Pro-BNP. The normal range for NT Pro-BNP varies from 0 picograms/milliliter (pg/mL) (lower limit of normal value) -125 pg/mL (upper limit of normal value).
Time frame: Baseline up to End of treatment (Week 26)
Population: The safety population included all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bisoprolol | Number of Participants With Abnormal Value of N-terminal Pro-B-type Natriuretic Peptide (NT Pro-BNP) | 19 Participants |
Secondary
Number of Participants With All Cause Mortality, Cardiac Death, or Re-admission Due to Heart Failure
Number of participants with all-cause mortality, cardiac death, or re-admission due to heart failure was reported.
Time frame: Up to Week 26
Population: The safety population included all participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bisoprolol | Number of Participants With All Cause Mortality, Cardiac Death, or Re-admission Due to Heart Failure | All-cause mortality | 1 Participants |
| Bisoprolol | Number of Participants With All Cause Mortality, Cardiac Death, or Re-admission Due to Heart Failure | Cardiac death | 0 Participants |
| Bisoprolol | Number of Participants With All Cause Mortality, Cardiac Death, or Re-admission Due to Heart Failure | Re-admission due to heart failure | 0 Participants |
Secondary
Number of Participants With Arrhythmia
Holter monitor was used to diagnose arrhythmia.
Time frame: Baseline up to end of treatment (Week 26)
Population: The safety population included all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bisoprolol | Number of Participants With Arrhythmia | 0 Participants |
Secondary
Number of Participants With Clinically Relevant Systolic and Diastolic Blood Pressure
Blood pressure (systolic and diastolic) measurement was taken at sitting position, with the elbow at the same level with the heart. Number of participants with clinically relevant systolic and diastolic blood pressure reported based on the assessment of the investigator.
Time frame: Screening (Week -2) up to Week 26
Population: The safety population included all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bisoprolol | Number of Participants With Clinically Relevant Systolic and Diastolic Blood Pressure | 0 Participants |
Secondary
Number of Participants With Medicine Compliance Assessed by Medication Procession Ratio (MPR)
MPR is used to assess the medicine compliance. MPR is defined as the actual drug number taken by the participants divided by the drug number should be taken by the participants according to the protocol. MPR between 80%-100% is defined as good compliance. Medication rate of less than (\<) 80% or greater than (\>)100% is defined as insufficient compliance.
Time frame: Up to Week 26
Population: The safety population included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bisoprolol | Number of Participants With Medicine Compliance Assessed by Medication Procession Ratio (MPR) | MPR: Good Compliance | 18 Participants |
| Bisoprolol | Number of Participants With Medicine Compliance Assessed by Medication Procession Ratio (MPR) | MPR: Insufficient compliance | 0 Participants |
| Bisoprolol | Number of Participants With Medicine Compliance Assessed by Medication Procession Ratio (MPR) | Not evaluated | 2 Participants |
Secondary
Number of Participants With New York Heart Association (NYHA) Class
The NYHA classification assesses the severity of symptoms of heart failure. Here NYHA class of II - IV was assessed. NYHA II: Slight limitation of physical activity, comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue or palpitation. NYHA III: Marked limitation of physical activity, comfortable at rest, but less than ordinary activity causes undue breathlessness, fatigue or palpitation. NYHA IV: Unable to carry on any physical activity without discomfort, symptoms at rest can be present. If any physical activity is undertaken, discomfort increased.
Time frame: Baseline, Week 26
Population: The safety population included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bisoprolol | Number of Participants With New York Heart Association (NYHA) Class | Baseline: NYHA class II | 10 Participants |
| Bisoprolol | Number of Participants With New York Heart Association (NYHA) Class | Baseline: NYHA class III | 10 Participants |
| Bisoprolol | Number of Participants With New York Heart Association (NYHA) Class | Baseline: NYHA class IV | 0 Participants |
| Bisoprolol | Number of Participants With New York Heart Association (NYHA) Class | Week 26: NYHA class II | 2 Participants |
| Bisoprolol | Number of Participants With New York Heart Association (NYHA) Class | Week 26: NYHA class III | 1 Participants |
| Bisoprolol | Number of Participants With New York Heart Association (NYHA) Class | Week 26: NYHA class IV | 0 Participants |
| Bisoprolol | Number of Participants With New York Heart Association (NYHA) Class | Week 26: Not evaluated | 17 Participants |
Secondary
Percentage of Participants With Resting Heart Rate Less Than 70 Beats Per Minute (Bpm) and More Than 55 Bpm
Resting heart rate measurement was taken at sitting position for a continuous record of 3 minutes. Heartbeats in each minute was calculated and averaged to obtain the resting heart rate.
Time frame: Baseline up to Week 26
Population: The safety population included all subjects who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisoprolol | Percentage of Participants With Resting Heart Rate Less Than 70 Beats Per Minute (Bpm) and More Than 55 Bpm | 0 percentage of participants |
Secondary
Quality of Life Based on Minnesota Living With Heart Failure (MLHF) at Baseline and End of Treatment
MLHF questionnaire has 21 items. Questions assess the impact of frequent physical symptoms of heart failure and the effects of heart failure on physical and social functions. Each question had a possible score of 0 (best) to 5 (worst), for a total of 0 to 105. The higher the summed score, the worse is the impact of heart failure on a participant's quality of life.
Time frame: Baseline, end of treatment (Week 26)
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Secondary
Quality of Life Based on the Medical Outcomes Study Item Short From Health Survey (SF-36) at Baseline and End of Treatment
Short Form Health Survey (SF-36), an instrument composed by 8 subscales: Physical Functioning, Physical Role Function, Bodily Pain, General Health, Vitality, Social Functioning, Emotional Role Function and Mental Health. The individual question items (Likert scale 0-4) are first summed for each item under the various sections. Then, those summary scores are then standardized on a scale between 0 and 1 using the mean and standard deviation of the actual scores and finally, weighted to a scale between 0 and 100. The items contributing to a scale are scored so that a higher score represents better health, and they are averaged together to create the scale score. Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively.
Time frame: Baseline, end of treatment (Week 26)
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.
Secondary
Ratio of Early (E) to Late (A) Ventricular Filling Velocities (E/A Ratio) at Baseline, Week 14 and Week 26
Early to late ratio was measured by ultrasound cardiogram.
Time frame: Baseline, Week 14 and Week 26
Population: Data was not collected since the study was terminated early due to limited beta-blocker naive participants among newly diagnosed heart failure participants which led barrier to the recruitment.