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)

• 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: Merck KGaA, Darmstadt, Germany
• Collaborator: Merck Ltd.
• Information provided by (Responsible Party): Merck KGaA, Darmstadt, Germany

Tracking Information

• First Submitted Date: February 22, 2010
• First Posted Date: February 24, 2010
• Results First Submitted Date: July 30, 2013
• Results First Posted Date: February 14, 2014
• Last Update Posted Date: February 14, 2014
• Study Start Date: October 2009
• Actual Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 13, 2014)

Percent Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Week 26 [ Time Frame: Baseline and Week 26 ]

B-type natriuretic peptide (BNP) is a substance secreted from the ventricles or lower chambers of the heart in response to changes in pressure that occur when heart failure develops and worsens. The level of BNP in the blood increases when heart failure symptoms worsen, and decreases when the heart failure condition is stable. The BNP level in a person with heart failure is higher than in a person with normal heart function. The percent change of NT-pro BNP was calculated according to the formula: N-terminal pro B-type natriuretic peptide (NT-proBNP) reduction ratio = 100*(Baseline NT-proBNP - Week 26 NT-proBNP)/Baseline NT-proBNP.

Original Primary Outcome Measures (submitted: February 22, 2010)

Change of surrogate markers of heart failure (NT-proBNP reduction ratio) [ Time Frame: Baseline to Final visit after 6 months ]

NT-proBNP reduction ratio = [100*(baseline NT-proBNP - follow-up NT-proBNP)/baseline NT-proBNP]

Current Secondary Outcome Measures (submitted: January 13, 2014)

• Percentage of Participants Classified as Class I to IV According to New York Heart Association (NYHA) [ Time Frame: Baseline and Week 26 ]
  New York Heart Association (NYHA) classification of heart failure: Class I: No limitation: ordinary physical exercise does not cause undue fatigue, dyspnea, or palpitations. Class II: Slight limitation of physical activity: comfortable at rest but ordinary activity results in fatigue, palpitations, or dyspnea. Class III: Marked limitation of physical activity: comfortable at rest but less than ordinary activity results in symptoms. Class IV: Unable to carry out any physical activity without discomfort: symptoms of heart failure are present even at rest with increased discomfort with any physical activity.
• Change From Baseline in 6-minute Walking Test (6-MWT) Distance at Week 26 [ Time Frame: Baseline and Week 26 ]
  6-minute Walking Test (6-MWT) distance was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.
• Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Week 26 [ Time Frame: Baseline and Week 26 ]
  LVEF was defined as the fraction of blood (in percent) pumped out of the heart's left ventricular chamber with each heart beat and it is used to measure the cardiac output for the heart.
• Change From Baseline in Echocardiographic Left Ventricular Size at Week 26 [ Time Frame: 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.
• Number of Participants Who Were Re-hospitalized Due to Heart Failure and Who Died Due to Cardiovascular Disorder [ Time Frame: Baseline up to Week 26 ]
• Number of Participants With Adverse Events (AEs) [ Time Frame: Baseline up to Week 26 ]
  An adverse event (AE) is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.
• Mean Change From Baseline in Global Assessment of Congestive Heart Failure (CHF) Score at Week 26 [ Time Frame: 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).

Original Secondary Outcome Measures (submitted: February 22, 2010)

• Changes of improvement score [ Time Frame: Baseline to Final visit after 6 months ]
  NYHA, physician assessment, 6-minutes walking test and echocardiogram
• Readmission due to aggravation of heart failure, death. [ Time Frame: During the treatment period from Baseline to Final visit after 6 months ]
• Safety and tolerability of bisoprolol [ Time Frame: During the treatment period from Baseline to the Final visit after 6 months ]
  Safety and tolerability comprises of observing and recording of adverse events.
• Occurrence of major clinical event of heart failure [ Time Frame: During the treatment period from Baseline to Final visit ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: Prospective, Open-labeled Trial in Patients With Systolic Heart Failure to Evaluate Bisoprolol Treatment for the Effects on Surrogate Markers of Heart Failure in Korea (PRISM)
• Brief Summary: This is a prospective, open-labeled, multi-centric trial to evaluate the effect of bisoprolol (between low dose and high dose) on surrogate markers of heart failure in Korea.

Detailed Description

Subjects with systolic congestive heart failure (CHF) will be enrolled in this study after proper evaluation of NT-proBNP, global assessment of CHF, 6-minute walking test and improvement score of New York Heart Association (NYHA) and echocardiogram (left ventricular chamber size and ejection fraction [LVEF]). Each subject will be orally administered bisoprolol for 6 months starting at 1.25 mg at the Week 0 and titrated up to 10 mg during the 6 month period if the persistent standing systolic blood pressure (SBP) is greater than (>) 90 millimeter of mercury (mm Hg) and there is no symptom of hypotension at the current dose medication (syncope, loss of consciousness, dizziness when standing up).

OBJECTIVES

Primary objective:

• To evaluate the effect of bisoprolol (between low dose and high dose) on surrogate markers of heart failure in Korea

Secondary objectives:

• To evaluate bisoprolol for the effects on clinical improvement of heart failure in Korea:

  1. New York Heart Association (NYHA),
  2. 6-minutes walking test
  3. Echocardiogram (left ventricular chamber size and LVEF)
• Hospitalization due to heart failure
• To evaluate the safety and tolerability of bisoprolol
• Global assessment of CHF

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Heart Failure, Congestive

Intervention

• Drug: Low Dose Bisoprolol
  Bisoprolol tablet (Concor) will be administered orally at a starting dose of 1.25 milligram (mg) once daily for 2 weeks. The dose will be further escalated from 1.25 mg to 2.5 mg once daily after 2 weeks and will be administered up to 26 weeks, only if the previous administered dose is well tolerated. If the subject could not tolerate the increased dose, then the last tolerated dose will be maintained up to 26 weeks.
  Other Name: Concor
• Drug: High Dose Bisoprolol
  Bisoprolol tablet (Concor) will be administered orally at a starting dose of 3.75 mg once daily for 2 weeks. The dose will be subsequently increased to 5 mg, 7.5 mg, or 10 mg once daily every two weeks and will be administered up to 26 weeks, only if the previous administered dose is well tolerated. If the subject could not tolerate the increased dose, then the last tolerated dose will be maintained up to 26 weeks.
  Other Name: Concor

Study Arms

• Experimental: Low Dose Bisoprolol
  Intervention: Drug: Low Dose Bisoprolol
• Experimental: High Dose Bisoprolol
  Intervention: Drug: High Dose Bisoprolol

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 22, 2010): 180
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 2012
• Actual Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subjects with heart failure and at the age of 18 (inclusive) to 80 (exclusive)
• Subjects with NYHA Class II-IV with dyspnea
• Subjects with left ventricular ejection fraction (LVEF) of 40 percent or below on the echocardiogram
• Eligible subjects who meet the criteria, are capable of participating in the study, and provide written informed consent to study participation after receiving a clear explanation about the study objective and nature

Exclusion Criteria:

• A subject who cannot understand or does not agree to the study contents
• Subjects with conduction defect of 2nd degree or above atrioventricular block
• Subjects with heart rate less than (<) 60 beats at rest
• Subjects with systolic blood pressure < 100 mm Hg at rest
• Subjects with renal failure (serum creatinine > 2.0 milligram per deciliter [mg/dL])
• Subjects with unrecovered pulmonary edema
• Subjects with history of myocardial infarction or stroke within 3 months
• Subjects with history of coronary intervention or coronary bypass within 6 months
• Subjects with heart failure due to mitral valve without valve replacement or aortic valvular disease (excluding moderate or less severe mitral insufficiency secondary to left ventricular expansion)
• Subjects with history of valve replacement within the past 6 months
• Subjects with history or scheduled heart transplantation
• Subjects with reversible obstructive pulmonary disease
• Subjects with other cases where beta blockers are contraindicated
• Any surgical or internal disease that may put the subject at a higher risk due to study participation or may interfere with the subjects compliance to study requirements or completion of the study, based on the judgment of the Investigator
• A subject with history of non-compliance to drug prescriptions or who is not willing to comply with the protocol
• Subjects with a history of treated or untreated malignant tumor within the past 5 years
• Pregnant or lactating women
• Subjects with heart failure due to acute myocarditis
• Subjects with continuous ventricular tachycardia with history of syncope within 3 months

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Korea, Republic of

Administrative Information

• NCT Number: NCT01074307
• Other Study ID Numbers: EMD 084000-608
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Merck KGaA, Darmstadt, Germany
• Study Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborators: Merck Ltd.

Investigators

• Study Director: Medical Responsible; Merck Ltd.

• PRS Account: Merck KGaA, Darmstadt, Germany
• Verification Date: January 2014