Trial Outcomes & Findings for A Prospective, Open-labeled, Multi-centric Trial in Subjects With Systolic Heart Failure to Evaluate Bisoprolol Treatment for the Effects on Surrogate Markers of Heart Failure in Korea (NCT NCT01074307)

Last Updated: 2014-02-14

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

180 participants

Primary outcome timeframe

Baseline and Week 26

Results posted on

2014-02-14

Participant Flow

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	66	114
Overall Study COMPLETED	44	102
Overall Study NOT COMPLETED	22	12

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study No primary endpoint evaluation	14	6
Overall Study Exclusion criterion	0	1
Overall Study Protocol Violation	8	5

Baseline Characteristics

A Prospective, Open-labeled, Multi-centric Trial in Subjects With Systolic Heart Failure to Evaluate Bisoprolol Treatment for the Effects on Surrogate Markers of Heart Failure in Korea

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Low Dose Bisoprolol n=52 Participants 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.	High Dose Bisoprolol n=107 Participants 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.	Total n=159 Participants Total of all reporting groups
Age, Continuous	62.88 years STANDARD_DEVIATION 11.52 • n=39 Participants	57.68 years STANDARD_DEVIATION 12.28 • n=41 Participants	59.38 years STANDARD_DEVIATION 12.24 • n=35 Participants
Sex: Female, Male Female	34 Participants n=39 Participants	83 Participants n=41 Participants	117 Participants n=35 Participants
Sex: Female, Male Male	18 Participants n=39 Participants	24 Participants n=41 Participants	42 Participants n=35 Participants

PRIMARY outcome

Timeframe: Baseline and Week 26

Outcome measures

Outcome measures
Measure	Low Dose Bisoprolol n=51 Participants 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.	High Dose Bisoprolol n=107 Participants 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.
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	9.50 Percent change Standard Deviation 117.56

SECONDARY outcome

Timeframe: Baseline and Week 26

Population: ITT population included all the randomized participants who had at least one dose of the investigational product.

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.

Outcome measures

Outcome measures
Measure	Low Dose Bisoprolol n=52 Participants 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.	High Dose Bisoprolol n=107 Participants 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.
Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) Baseline: Class II	73.08 Percentage of participants	74.77 Percentage of participants
Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) Baseline: Class III	25.00 Percentage of participants	24.30 Percentage of participants
Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) Baseline: Class IV	1.92 Percentage of participants	0.93 Percentage of participants
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	42.06 Percentage of participants
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	54.21 Percentage of participants
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	3.74 Percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Low Dose Bisoprolol n=52 Participants 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.	High Dose Bisoprolol n=103 Participants 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.
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	368.11 Meter Standard Deviation 169.04
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	28.45 Meter Standard Deviation 161.66

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Low Dose Bisoprolol n=52 Participants 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.	High Dose Bisoprolol n=106 Participants 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.
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	27.61 Percent LVEF Standard Deviation 6.72
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	14.22 Percent LVEF Standard Deviation 11.81

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Low Dose Bisoprolol n=52 Participants 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.	High Dose Bisoprolol n=106 Participants 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.
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	63.40 Milliliter LVID Standard Deviation 7.87
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	5.49 Milliliter LVID Standard Deviation 8.45
Change From Baseline in Echocardiographic Left Ventricular Size at Week 26 Baseline: Systolic LVID (n=51, 104)	54.25 Milliliter LVID Standard Deviation 8.80	54.69 Milliliter LVID Standard Deviation 8.95
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	9.84 Milliliter LVID Standard Deviation 9.32

SECONDARY outcome

Timeframe: Baseline up to Week 26

Population: ITT population included all the randomized participants who had at least one dose of the investigational product.

Outcome measures

Outcome measures
Measure	Low Dose Bisoprolol n=52 Participants 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.	High Dose Bisoprolol n=107 Participants 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.
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	3 Participants
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	0 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Low Dose Bisoprolol n=66 Participants 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.	High Dose Bisoprolol n=114 Participants 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.
Number of Participants With Adverse Events (AEs)	45 Participants	73 Participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Low Dose Bisoprolol n=52 Participants 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.	High Dose Bisoprolol n=106 Participants 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.
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	2.71 Units on a scale Standard Deviation 0.92
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	0.69 Units on a scale Standard Deviation 1.41

Adverse Events

Low Dose Bisoprolol

Serious events: 16 serious events

Other events: 45 other events

Deaths: 0 deaths

High Dose Bisoprolol

Serious events: 9 serious events

Other events: 71 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Low Dose Bisoprolol n=66 participants at risk 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.	High Dose Bisoprolol n=114 participants at risk 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.1% 8/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	9.6% 11/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	4.5% 3/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	2.6% 3/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Cardiac disorders Cardiac failure	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	3.5% 4/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Vascular disorders Hypotension	4.5% 3/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	3.5% 4/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Gastrointestinal disorders Diarrhoea	0.00% 0/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	3.5% 4/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Respiratory, thoracic and mediastinal disorders Nasopharyngitis	3.0% 2/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	5.3% 6/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Respiratory, thoracic and mediastinal disorders Upper respiratory tract infection	6.1% 4/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	3.5% 4/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Nervous system disorders Dizziness	15.2% 10/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	13.2% 15/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Psychiatric disorders Insomnia	4.5% 3/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.88% 1/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
General disorders Asthenia	3.0% 2/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	5.3% 6/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
General disorders Chest discomfort	9.1% 6/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	2.6% 3/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
General disorders Oedema	0.00% 0/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	7.9% 9/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
General disorders Oedema peripheral	4.5% 3/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.88% 1/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.

Additional Information

Merck KGaA Communication Center

Merck Serono, a division of Merck KGaA

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The investigator commits him/her to forward to sponsor all papers, manuscripts or conference abstracts intended for publication or presentation that contain data or results generated in connection with the study. Papers and abstracts must be available at sponsor's site in time before the planned submission date to allow for review and comments. Submission for publication need expressed written permission from the sponsor. Any publication should follow publication policy as described in protocol.
Publication restrictions are in place

Restriction type: OTHER

Measure	Low Dose Bisoprolol n=66 participants at risk 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.	High Dose Bisoprolol n=114 participants at risk 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.
Cardiac disorders Cardiac failure	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	1.8% 2/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Cardiac disorders Cardiac failure congestive	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Cardiac disorders Myocardial infarction	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Cardiac disorders Pericardial effusion	0.00% 0/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.88% 1/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Gastrointestinal disorders Abdominal discomfort	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.88% 1/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
General disorders Asthenia	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	1.8% 2/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
General disorders Chest discomfort	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
General disorders Chest Pain	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
General disorders Oedema peripheral	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
General disorders Sudden cardiac death	3.0% 2/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.88% 1/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Metabolism and nutrition disorders Diabetic foot	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.88% 1/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Nervous system disorders Cerebral infarction	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.88% 1/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Nervous system disorders Dizziness	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Nervous system disorders Insomnia	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Renal and urinary disorders Flank pain	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.6% 5/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	2.6% 3/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Respiratory, thoracic and mediastinal disorders Upper respiratory tract infection	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.88% 1/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.
Vascular disorders Hypotension	1.5% 1/66 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.	0.00% 0/114 • Baseline up to Week 26 An 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 IMP, regardless of causal relationship and even if no IMP has been administered.