Efficacy of Oral Bisoprolol on Heart Rate Reduction in Chinese Chronic Heart Failure Participants (Biso-CHF)

A Single-arm, Interventional, Multi-center, Pilot Study to Evaluate the Efficacy of Oral Bisoprolol on Heart Rate Reduction in Chinese Chronic Heart Failure Patients With NYHA Class II - IV (Biso-CHF Study)

This is a single-arm, open label, interventional, multi-center, phase 4 pilot study.

Study Overview

• Status: Terminated
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Bisoprolol

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100037
    • Fuwai Hospital Chinese Academy of Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bisoprolol	Drug: 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.; Other Names: Brand name: Concor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Resting Heart Rate at Week 6	Heartbeats in each minute were calculated and averaged to obtain the resting heart rate.	Baseline, Week 6
Change From Baseline in Resting Heart Rate at Week 14	Heartbeats in each minute were calculated and averaged to obtain the resting heart rate.	Baseline, Week 14
Change From Baseline in Resting Heart Rate at Week 26	Heartbeats in each minute were calculated and averaged to obtain the resting heart rate.	Baseline, Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Week 3, 10 and 18
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.	Baseline, Week 14 and 26
Left Ventricular End-Systolic Dimension (LVESD) at Baseline, Week 14 and 26	Left Ventricular End-Systolic Dimension was measured by Ultrasound cardiogram.	Baseline, Week 14 and 26
Left Ventricular End-diastolic Dimension (LVEDD) at Baseline, Week 14 and 26	Left Ventricular End-diastolic Dimension was measured by Ultrasound cardiogram.	Baseline, Week 14 and 26
Interventricular Septal Thickness (IVST) at Baseline, Week 14 and 26	Interventricular septal thickness was measured by Ultrasound cardiogram.	Baseline, Week 14 and 26
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.	Baseline, Week 14 and Week 26
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.	Screening (Week -2) up to Week 26
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.	Baseline, Week 26
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.	Baseline up to Week 26
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.	Baseline, end of treatment (Week 26)
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.	Baseline, end of treatment (Week 26)
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.	Baseline and End of treatment (Week 26)
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).	Baseline up to End of treatment (Week 26)
Mean 24 Hour, Day Time and Night Time Heart Rate	Holter monitor was used to measure heart rate (24 hour, day time, night time).	Baseline, week 6, 14 and end of treatment (Week 26)
Number of Participants With Arrhythmia	Holter monitor was used to diagnose arrhythmia.	Baseline up to end of treatment (Week 26)
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.	Baseline, week 6, 14 and end of treatment (Week 26)
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.	Up to Week 26
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.	Up to Week 26

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborators: Merck Serono Co., Ltd., China

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2017
• Primary Completion (Actual): December 26, 2018
• Study Completion (Actual): December 26, 2018

Study Registration Dates

• First Submitted: January 12, 2017
• First Submitted That Met QC Criteria: January 17, 2017
• First Posted (Estimate): January 20, 2017

Study Record Updates

• Last Update Posted (Actual): January 29, 2020
• Last Update Submitted That Met QC Criteria: January 20, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Chronic Heart Failure; Bisoprolol; Heart rate control
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Bisoprolol
• Other Study ID Numbers: MS200006-0039

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No