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]
试验速览
- 阶段
- 3 期
- 入组人数
- 52
- 试验地点
- 2
- 主要终点
- Change of maximal VO2 in cardiopulmonary exercise test
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Placebo arm
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.
干预措施: Placebo (Drug)
Udenafil
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.
干预措施: Udenafil (Zydena) (Drug)
结局指标
主要结局
Change of maximal VO2 in cardiopulmonary exercise test
时间窗: Baseline and 12th weeks
Comparison between groups and within groups.
次要结局
- Change of ventilator efficiency (VE/VCO2 slope) in cardiopulmonary exercise test(Baseline and 12th week)
- Change of symptomatic status expressed as New York Heart Association (NYHA) functional class(Baseline, 4th week, and 12th week)
- Change of symptomatic status expressed as Borg dyspnea index(Baseline, 4th week, and 12th week)
- Change of pulmonary artery systolic pressure (PASP) in echocardiography at rest and during exercise(Baseline and 12th week)
- Change of left ventricular systolic function expressed as ejection fraction (EF), fractional shortening (FS) in echocardiography(Baseline and 12th week)
- Change of left ventricular diastolic function expressed as E velocity, E' velocity, E/E' ratio, E/A ratio(Baseline and 12th week)
- Change of left atrial volume(Baseline and 12th week)
- Change of plasma concentration of BNP(Baseline, 4th week, and 12th week)
- All-cause death(12th week)
- Cardiac death(12th week)
- Admission for heart failure(12th week)
- Composite clinical endpoints(12th week)
- Safety endpoint(12th week)
研究者
Yong-Jin Kim
Associate Professor
Seoul National University Hospital