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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 (PRISM)

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ClinicalTrials.gov Identifier: NCT01074307
Recruitment Status : Completed
First Posted : February 24, 2010
Results First Posted : February 14, 2014
Last Update Posted : February 14, 2014
Sponsor:
Collaborator:
Merck Ltd.
Information provided by (Responsible Party):
Merck KGaA, Darmstadt, Germany

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Heart Failure, Congestive
Interventions Drug: Low Dose Bisoprolol
Drug: High Dose Bisoprolol
Enrollment 180
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Low Dose Bisoprolol High Dose Bisoprolol
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 66 114
Completed 44 102
Not Completed 22 12
Reason Not Completed
No primary endpoint evaluation             14             6
Exclusion criterion             0             1
Protocol Violation             8             5
Arm/Group Title Low Dose Bisoprolol High Dose Bisoprolol Total
Hide Arm/Group Description 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. 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 of all reporting groups
Overall Number of Baseline Participants 52 107 159
Hide Baseline Analysis Population Description
Intention-to-treat (ITT) population included all the randomized participants who had at least one dose of the investigational product. Baseline data has been provided for 159 participants (ITT population).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 52 participants 107 participants 159 participants
62.88  (11.52) 57.68  (12.28) 59.38  (12.24)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 52 participants 107 participants 159 participants
Female
34
  65.4%
83
  77.6%
117
  73.6%
Male
18
  34.6%
24
  22.4%
42
  26.4%
1.Primary Outcome
Title Percent Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Week 26
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Low Dose Bisoprolol High Dose Bisoprolol
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 51 107
Mean (Standard Deviation)
Unit of Measure: Percent change
8.02  (113.78) 9.50  (117.56)
2.Secondary Outcome
Title Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA)
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all the randomized participants who had at least one dose of the investigational product.
Arm/Group Title Low Dose Bisoprolol High Dose Bisoprolol
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 52 107
Measure Type: Number
Unit of Measure: Percentage of participants
Baseline: Class II 73.08 74.77
Baseline: Class III 25.00 24.30
Baseline: Class IV 1.92 0.93
Week 26: Class I 21.15 42.06
Week 26: Class II 69.23 54.21
Week 26: Class III 9.62 3.74
3.Secondary Outcome
Title Change From Baseline in 6-minute Walking Test (6-MWT) Distance at Week 26
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Low Dose Bisoprolol High Dose Bisoprolol
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 52 103
Mean (Standard Deviation)
Unit of Measure: Meter
Baseline (n=52, 103) 347.58  (123.35) 368.11  (169.04)
Change at Week 26 (n=47, 102) 41.59  (103.45) 28.45  (161.66)
4.Secondary Outcome
Title Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Week 26
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Low Dose Bisoprolol High Dose Bisoprolol
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 52 106
Mean (Standard Deviation)
Unit of Measure: Percent LVEF
Baseline (n=52, 106) 28.68  (7.47) 27.61  (6.72)
Change at Week 26 (n=50, 106) 8.83  (9.47) 14.22  (11.81)
5.Secondary Outcome
Title Change From Baseline in Echocardiographic Left Ventricular Size at Week 26
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Low Dose Bisoprolol High Dose Bisoprolol
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 52 106
Mean (Standard Deviation)
Unit of Measure: Milliliter LVID
Baseline: Systolic LVID (n=51, 104) 54.25  (8.80) 54.69  (8.95)
Change at Week 26: Systolic LVID (n=47, 102) 5.46  (7.25) 9.84  (9.32)
Baseline: Diastolic LVID (n=52, 106) 64.28  (7.99) 63.40  (7.87)
Change at Week 26: Diastolic LVID (n=50, 106) 3.12  (4.37) 5.49  (8.45)
6.Secondary Outcome
Title Number of Participants Who Were Re-hospitalized Due to Heart Failure and Who Died Due to Cardiovascular Disorder
Hide Description [Not Specified]
Time Frame Baseline up to Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all the randomized participants who had at least one dose of the investigational product.
Arm/Group Title Low Dose Bisoprolol High Dose Bisoprolol
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 52 107
Measure Type: Number
Unit of Measure: Participants
Re-hospitalization due to heart failure 3 3
Death due to cardiovascular disorder 0 0
7.Secondary Outcome
Title Number of Participants With Adverse Events (AEs)
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Low Dose Bisoprolol High Dose Bisoprolol
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 66 114
Measure Type: Number
Unit of Measure: Participants
45 73
8.Secondary Outcome
Title Mean Change From Baseline in Global Assessment of Congestive Heart Failure (CHF) Score at Week 26
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Low Dose Bisoprolol High Dose Bisoprolol
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 52 106
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Baseline (n=52, 106) 2.52  (1.02) 2.71  (0.92)
Change at Week 26 (n=51, 106) 0.45  (1.27) 0.69  (1.41)
Time Frame Baseline up to Week 26
Adverse Event Reporting Description 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.
 
Arm/Group Title Low Dose Bisoprolol High Dose Bisoprolol
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Low Dose Bisoprolol High Dose Bisoprolol
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Low Dose Bisoprolol High Dose Bisoprolol
Affected / at Risk (%) Affected / at Risk (%)
Total   16/66 (24.24%)   9/114 (7.89%) 
Cardiac disorders     
Cardiac failure * 1  1/66 (1.52%)  2/114 (1.75%) 
Cardiac failure congestive * 1  1/66 (1.52%)  0/114 (0.00%) 
Myocardial infarction * 1  1/66 (1.52%)  0/114 (0.00%) 
Pericardial effusion * 1  0/66 (0.00%)  1/114 (0.88%) 
Gastrointestinal disorders     
Abdominal discomfort * 1  1/66 (1.52%)  1/114 (0.88%) 
General disorders     
Asthenia * 1  1/66 (1.52%)  2/114 (1.75%) 
Chest discomfort * 1  1/66 (1.52%)  0/114 (0.00%) 
Chest Pain * 1  1/66 (1.52%)  0/114 (0.00%) 
Oedema peripheral * 1  1/66 (1.52%)  0/114 (0.00%) 
Sudden cardiac death * 1  2/66 (3.03%)  1/114 (0.88%) 
Metabolism and nutrition disorders     
Diabetic foot * 1  1/66 (1.52%)  0/114 (0.00%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal pain * 1  1/66 (1.52%)  0/114 (0.00%) 
Intervertebral disc protrusion * 1  0/66 (0.00%)  1/114 (0.88%) 
Nervous system disorders     
Cerebral infarction * 1  1/66 (1.52%)  1/114 (0.88%) 
Dizziness * 1  1/66 (1.52%)  0/114 (0.00%) 
Insomnia * 1  1/66 (1.52%)  0/114 (0.00%) 
Renal and urinary disorders     
Flank pain * 1  1/66 (1.52%)  0/114 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnoea * 1  5/66 (7.58%)  3/114 (2.63%) 
Upper respiratory tract infection * 1  1/66 (1.52%)  0/114 (0.00%) 
Haemoptysis * 1  0/66 (0.00%)  1/114 (0.88%) 
Vascular disorders     
Hypotension * 1  1/66 (1.52%)  0/114 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (15.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Low Dose Bisoprolol High Dose Bisoprolol
Affected / at Risk (%) Affected / at Risk (%)
Total   45/66 (68.18%)   71/114 (62.28%) 
Cardiac disorders     
Cardiac failure * 1  1/66 (1.52%)  4/114 (3.51%) 
Gastrointestinal disorders     
Diarrhoea * 1  0/66 (0.00%)  4/114 (3.51%) 
General disorders     
Asthenia * 1  2/66 (3.03%)  6/114 (5.26%) 
Chest discomfort * 1  6/66 (9.09%)  3/114 (2.63%) 
Oedema * 1  0/66 (0.00%)  9/114 (7.89%) 
Oedema peripheral * 1  3/66 (4.55%)  1/114 (0.88%) 
Nervous system disorders     
Dizziness * 1  10/66 (15.15%)  15/114 (13.16%) 
Psychiatric disorders     
Insomnia * 1  3/66 (4.55%)  1/114 (0.88%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnoea * 1  8/66 (12.12%)  11/114 (9.65%) 
Dyspnoea exertional * 1  3/66 (4.55%)  3/114 (2.63%) 
Nasopharyngitis * 1  2/66 (3.03%)  6/114 (5.26%) 
Upper respiratory tract infection * 1  4/66 (6.06%)  4/114 (3.51%) 
Vascular disorders     
Hypotension * 1  3/66 (4.55%)  4/114 (3.51%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (15.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Merck KGaA Communication Center
Organization: Merck Serono, a division of Merck KGaA
Phone: +49-6151-72-5200
EMail: service@merckgroup.com
Layout table for additonal information
Responsible Party: Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier: NCT01074307    
Other Study ID Numbers: EMD 084000-608
First Submitted: February 22, 2010
First Posted: February 24, 2010
Results First Submitted: July 30, 2013
Results First Posted: February 14, 2014
Last Update Posted: February 14, 2014