A Randomized Trial of Udenafil Therapy in Patients With Heart Failure With Preserved Ejection Fraction [ULTIMATE-HFpEF]

Study Overview
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Brief Summary
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The investigators hypothesized that udenafil, a newly developed phosphodiesterase type 5 inhibitor, would improve symptom, exercise capacity and hemodynamic status in patients with heart failure with preserved ejection fraction (HFpEF).

Detailed Description
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Heart failure with preserved ejection fraction (HFpEF) had been considered as a milder form of heart failure until 1990's. However, the prevalence and the prognosis of HFpEF were found to be similar to that of heart failure with reduced ejection fraction (HFrEF) and it is widely accepted that HFpEF is a separate entity of heart failure, substantially different from HFrEF. The pathophysiology of HFpEF can be contracted to the increased stiffness and impaired relaxation of left ventricle (LV), causing increased LV end-diastolic pressure and pulmonary venous pressure. These may lead to dyspnea, limited exercise capacity, and pulmonary congestion in patients. Current guidelines on treatment of HFpEF include appropriate blood pressure control, rate control in those with atrial fibrillation, and use of diuretics for pulmonary or peripheral edema. But there has been no evidence-based effective treatment strategy for HFpEF. Recently, phosphodiesterase type 5 (PDE-5) inhibitors (eg. sildenafil, vardenafil, tadalafil) have shown promising effects on heart failure, reducing pulmonary vascular resistance, improving LV systolic and diastolic function, exercise capacity and quality of life. These results infer that PDE-5 inhibitors might be beneficial in patients with HFpEF. Udenafil (Zydena), a newly developed PDE-5 inhibitor, has been proved to have similar efficacy and safety profile, compared with other PDE-5 inhibitors. Also, laboratory data showed that udenafil inhibits ventricular hypertrophy and fibrosis in rat heart failure model. Based on these results, we hypothesized that udenafil would improve symptom, exercise capacity and hemodynamic status in patients with HFpEF. In this 12-week, randomized, double-blind, placebo-controlled trial, patients with HFpEF will be enrolled according to the eligibility criteria. After randomization, study participants will be assigned to receive either 50mg of udenafil or placebo two times a day for 4 weeks, and then the dosage will be doubled to 100mg two times a day for next 8 weeks. Participants will attend study visits at baseline and weeks 4 and 12. Physical examination, medical history review, blood sample collection and electrocardiogram will be conducted on each study visits. At baseline and week 12, participants will undergo cardiopulmonary exercise test and exercise echocardiography. At every study visits, researchers will collect health information.

Official Title
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Udenafil Therapy to Improve Symptomatology, Exercise Tolerance and Hemodynamics in Patients With Heart Failure With Preserved Ejection Fraction: Phase III, Randomized, Double-blind, Placebo-controlled Trial [ULTIMATE-HFpEF Trial]

Conditions
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Diastolic Heart Failure

Intervention / Treatment
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* Drug: Placebo
* Drug: Udenafil (Zydena)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previous clinical diagnosis of heart failure with preserved ejection fraction (or diastolic heart failure) with current New York Heart association (NYHA) class II-IV symptoms Left ventricular ejection fraction (LVEF) greater than or equal to 50%, as determined by echocardiography in the 12 months before study entry Has experienced at least one of the following in the 12 months before study entry Hospitalization for decompensated heart failure Acute treatment with intravenous loop diuretics or hemofiltration E/E' ratio greater than or equal to 15 measured by echocardiography E/E' ratio greater than or equal to 8, and left atrial volume index (LAVI) greater than or equal to 40 ml/m2 measured by echocardiography E/E' ratio greater than or equal to 8 measured by echocardiography, and plasma BNP concentration greater or equal to 200 pg/ml Exclusion Criteria: History of reduced LVEF (less than 50%) Valve disease (greater than mild stenosis or regurgitation) Hypertrophic cardiomyopathy Infiltrative or inflammatory myocardial disease Pericardial disease Obstructive or restrictive lung disease Primary pulmonary arteriopathy Has neuromuscular, orthopedic, or other non-cardiac condition that prevents individual from exercise testing Has experienced myocardial infarction or unstable angina, or has undergone percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within 60 days before study entry Non-cardiac illness with estimated life expectancy less than 1 year at the time of study entry, based on the judgment of the physician Current use of nitrate therapy Current use of other phosphodiesterase 5 inhibitors (ie. sildenafil, vardenafil, tadalafil) for treatment of impotence or pulmonary artery hypertension Current use of cytochrome P450 3A4 inhibitors (ie. ketoconazole, itraconazole, erythromycin, saquinavir, cimetidine, protease inhibitors for HIV) Severe hypotension (systolic blood pressure [SBP] less than 90mmHg or diastolic blood pressure [DBP] less than 50mmHg) or uncontrolled hypertension (SBP greater than 180mmHg or DBP greater than 100mmHg) Resting heart rate (HR) greater than 100bpm Known severe renal dysfunction (estimated glomerular filtration rate [GFR] less than 30ml/min/1.73m2 by modified modification of diet in renal disease [MDRD] equation) Known severe liver disease (alanine transaminase [ALT] or aspartate aminotransferase [AST] level greater than three times the upper normal limit, alkaline phosphatase [ALP] or total bilirubin greater than two times the upper normal limit) History of leukemia, multiple myeloma or penile deformities that increase the risk for priapism (eg. Peyronie's disease) History of proliferative diabetic retinopathy, retinitis pigmentosa, nonischemic optic neuropathy, or unexplained visual disturbance Female patients currently pregnant or women of childbearing age who were not using contraception Listed for heart transplantation

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo arm<br>Capsule that is identically appearing with udenafil will be administered to patients in placebo group. For the first 4 weeks, patients will receive 50 mg of placebo drug two times a day, and then the dosage will be doubled to 100 mg two times a day for next 8 weeks. | Drug: Placebo<br>* Capsule, appears identical with udenafil, will be provided by Dong-A pharmaceutical company. Patients will receive 50 mg of placebo drug two times a day for 4 weeks, and then the dosage will be escalated to 100 mg two times a day for next 8 weeks.<br>* Other names: The same placebo drug of NCT01553721.;|
| Active Comparator: Udenafil<br>Patients will receive 50 mg of udenafil two times a day, and then the dosage will be doubled to 100 mg two times a day for next 8 weeks. | Drug: Udenafil (Zydena)<br>* Udenafil (Zydena), a newly developed PDE-5 inhibitor by Dong-A pharmaceutical company, will be administered to patients in this group, 50 mg two times a day for 4 weeks, and then the dosage will be escalated to 100 mg two times a day for next 8 weeks.<br>* Other names: DA-8159 (CAS No 268203-93-6);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of maximal VO2 in cardiopulmonary exercise test | Comparison between groups and within groups. | Baseline and 12th weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of ventilator efficiency (VE/VCO2 slope) in cardiopulmonary exercise test | Comparison between groups and within groups. | Baseline and 12th week | 
| Change of symptomatic status expressed as New York Heart Association (NYHA) functional class | Comparison between groups and within groups. | Baseline, 4th week, and 12th week | 
| Change of symptomatic status expressed as Borg dyspnea index | Comparison between groups and within groups. | Baseline, 4th week, and 12th week | 
| Change of pulmonary artery systolic pressure (PASP) in echocardiography at rest and during exercise | Comparison between groups and within groups. | Baseline and 12th week | 
| Change of left ventricular systolic function expressed as ejection fraction (EF), fractional shortening (FS) in echocardiography | Comparison between groups and within groups. | Baseline and 12th week | 
| Change of left ventricular diastolic function expressed as E velocity, E' velocity, E/E' ratio, E/A ratio | Comparison between groups and within groups. | Baseline and 12th week | 
| Change of left atrial volume | Comparison between groups and within groups. | Baseline and 12th week | 
| Change of plasma concentration of BNP | Comparison between groups and within groups. | Baseline, 4th week, and 12th week | 
| All-cause death | The occurrence of all-cause mortality during 12 week follow-up | 12th week | 
| Cardiac death | The occurrence of cardiac death including sudden cardiac death during 12 week follow-up | 12th week | 
| Admission for heart failure | Admission due to congestive heart failure during 12 week follow-up | 12th week | 
| Composite clinical endpoints | Composite clinical endpoints during 12 week follow-up, are defined as follows: Composite of all-cause death and admission for heart failure Composite of cardiac death and admission for heart failure | 12th week | 
| Safety endpoint | Safety endpoint during 12 week follow-up, is defined as follows: Development of facial flushing, febrile sensation, eyeball pain, visual disturbance, headache, penile erection. Intolerance or development of other adverse drug reactions related with study drug. | 12th week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure with Preserved Ejection Fraction, Diastolic Heart Failure, Exercise Capacity, Cardiopulmonary Exercise Test, Udenafil (Zydena), Phosphodiesterase Type 5 Inhibitors