Carvedilol SR Study for Biomarkers From Blood and Urine and Safety of in Patients With Heart Failure With Preserved Ejection Fraction

Study Overview
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Brief Summary
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Beta blockers have been used to reduce the mortality and heart failure rehospitalization in heart failure with reduced ejection fraction (HFrEF) patients in addition to ACEI/ARB, MRA, ivabradine and ARNI. However, the effective and safe medical therapy is not well established in heart failure with preserved ejection fraction (HFpEF) yet. Recent meta-analysis showed that beta blockers may also be beneficial for reducing the mortality and heart failure rehospitalization in HFpEF like HFrEF. However, the clinical effect and safety of carvedilol have been largely unknown in HFpEF. Therefore, CAYMUS HFpEF is the exploratory study to assess the change of surrogate markers (NTproBNP, hsTn) when treated with carvedilol SR vs. placebo in HFpEF patients

Official Title
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Carvedilol SR Study for Biomarkers From Blood and Urine and Safety of in Patients With Heart Failure With Preserved Ejection Fraction : a Prospective, Randomized, Double Blind, Placebo-controlled, Multicenter, Pilot Trial (CAYMUS-HFpEF)

Conditions
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Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: Carvedilol SR
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedure Male or female, aged ≥ 19 years Patients with chronic HF (Chronic Heart Failure) NYHA (New York Heart Association classification) class II-IV and preserved EF (Ejection Fraction)(LVEF (Left Ventricular Ejection Fraction) > 40 %) and elevated NT-proBNP (N-terminal of the prohormone brain natriuretic peptide) > 200 pg/ml for patients without AF, OR > 600 pg/ml for patients with AF, analysed at the Central laboratory at Visit 1 Structural heart disease within 6 months prior to Visit 1 using echocardiagraphy Exclusion Criteria: Myocardial infarction, coronary artery bypass graft surgery or other major cardiovascular surgery, stroke or TIA (Transient Ischaemic Attack) in past 90 days prior to Visit 1 Contraindication to beta blocker Heart transplant recipient or listed for heart transplant Hospitalization plan for PCI, coronary artery bypass graft surgery, other cardiac invasive interventions (e.g. catheter ablation, pacemaker, CRT, ICD implantation) Acute decompensated HF (Heart Failure) Symptomatic hypotension or systolic blood pressure < 100 mmHg) Patients with CrCl < 30 ml/min using creatinine-based CKD-EPI equations Elevated liver enzymes (3 times over upper reference limit) or liver cirrhosis Symptomatic bradycardia or heart rate < 60/min Allergy, adverse drug reaction, hypersensitivity to carvedilol Life expectancy < 6 months (e.g. metastatic malignancy) Pregnancy, or women of childbearing age

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Carvedilol SR vs. Placebo
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carvedilol SR<br>Carvedilol SR 8mg, 16mg, 32mg | Drug: Carvedilol SR<br>* blood pressure, heart rate based titrated carvedilol SR for 24 weeks<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum NT-proBNP value change after Drug(Carvedilol SR or Placebo) administration. | The maximum NT-proBNP value change at baseline. | Baseline | 
| The Maximum NT-proBNP value change after Drug(Carvedilol SR or Placebo) administration. | The maximum NT-proBNP value change from baseline to 8 weeks. | 8 weeks | 
| The Maximum NT-proBNP value change after Drug(Carvedilol SR or Placebo) administration. | The maximum NT-proBNP value change from baseline to End of trial(24weeks). | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The changes of maximum surrogate markers values(hsTn, hsCRP, sST2, Galectine-3, IGFBP7, Neprilysin, D-dimer, MMP-2, Cystatin C, NAG, NGAL, KIM-1, BUN, Creatinine, Chloride, Na, K, PICP and spondin-1) after Drug(Carvedilol SR or Placebo) administration. | the change of surrogate markers(hsTn, hsCRP etc) at baseline. | Baseline | 
| The changes of maximum surrogate markers values(hsTn, hsCRP, sST2, Galectine-3, IGFBP7, Neprilysin, D-dimer, MMP-2, Cystatin C, NAG, NGAL, KIM-1, BUN, Creatinine, Chloride, Na, K, PICP and spondin-1) after Drug(Carvedilol SR or Placebo) administration. | the change of surrogate markers(hsTn, hsCRP etc) after 8 weeks. | 8 weeks | 
| The changes of maximum surrogate markers values(hsTn, hsCRP, sST2, Galectine-3, IGFBP7, Neprilysin, D-dimer, MMP-2, Cystatin C, NAG, NGAL, KIM-1, BUN, Creatinine, Chloride, Na, K, PICP and spondin-1) after Drug(Carvedilol SR or Placebo) administration. | the change of surrogate markers(hsTn, hsCRP etc) after 16 weeks. | 16 weeks | 
| The changes of maximum surrogate markers values(hsTn, hsCRP, sST2, Galectine-3, IGFBP7, Neprilysin, D-dimer, MMP-2, Cystatin C, NAG, NGAL, KIM-1, BUN, Creatinine, Chloride, Na, K, PICP and spondin-1) after Drug(Carvedilol SR or Placebo) administration. | the change of surrogate markers(hsTn, hsCRP etc) from baseline to end of trial(24 weeks) | 24 weeks | 
| The change in degree of dyspnea using VAS questionnaire | the change of dyspnea at baseline. | Baseline | 
| The change in degree of dyspnea using VAS questionnaire | the change of dyspnea after 8 weeks. | 8 weeks | 
| The change in degree of dyspnea using VAS questionnaire | the change of dyspnea after 16 weeks. | 16 weeks | 
| The change in degree of dyspnea using VAS questionnaire | the change of dyspnea from baseline to end of trial(24 weeks) | 24 weeks | 
| the change of body weight | the change of body weight at baseline. | Baseline | 
| the change of body weight | the change of body weight after 8 weeks. | 8 weeks | 
| the change of body weight | the change of body weight after 16 weeks. | 16 weeks | 
| the change of body weight | the change of body weight from baseline to end of trial(24 weeks) | 24 weeks | 
| the frequency of symptomatic hypotension, symptomatic bradycardia and AV block above 2nd degree | the frequency of symptomatic hypotension, symptomatic bradycardia and AV block above 2nd degree during the tiral | Baseline | 
| the frequency of symptomatic hypotension, symptomatic bradycardia and AV block above 2nd degree | the frequency of symptomatic hypotension, symptomatic bradycardia and AV block above 2nd degree during the tiral | 8 weeks | 
| the frequency of symptomatic hypotension, symptomatic bradycardia and AV block above 2nd degree | the frequency of symptomatic hypotension, symptomatic bradycardia and AV block above 2nd degree during the tiral | 16 weeks | 
| the frequency of symptomatic hypotension, symptomatic bradycardia and AV block above 2nd degree | the frequency of symptomatic hypotension, symptomatic bradycardia and AV block above 2nd degree during the tiral | 24 weeks | 
| the frequency of hypo/hyperkalemia and worsening kidney function | the frequency of hypo/hyperkalemia and worsening kidney function during the trial | Baseline | 
| the frequency of hypo/hyperkalemia and worsening kidney function | the frequency of hypo/hyperkalemia and worsening kidney function during the trial | 8 weeks | 
| the frequency of hypo/hyperkalemia and worsening kidney function | the frequency of hypo/hyperkalemia and worsening kidney function during the trial | 16 weeks | 
| the frequency of hypo/hyperkalemia and worsening kidney function | the frequency of hypo/hyperkalemia and worsening kidney function during the trial | 24 weeks | 
| all-cause hospitalization & mortality | all-cause hospitalization & mortality during the trial | Baseline | 
| all-cause hospitalization & mortality | all-cause hospitalization & mortality during the trial | 8 weeks | 
| all-cause hospitalization & mortality | all-cause hospitalization & mortality during the trial | 16 weeks | 
| all-cause hospitalization & mortality | all-cause hospitalization & mortality during the trial | 24 weeks |