Clinical trial NCT01599117: A Randomized Trial of Udenafil Therapy in Patients With Heart Failure With Preserved Ejection Fraction [ULTIMATE-HFpEF]
Official title: 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]
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Diastolic Heart Failure
Keywords: Heart Failure with Preserved Ejection Fraction
Diastolic Heart Failure
Exercise Capacity
Cardiopulmonary Exercise Test
Udenafil (Zydena)
Phosphodiesterase Type 5 Inhibitors
Lead sponsor: Seoul National University Hospital
Sponsor class: OTHER
Collaborators: name: Dong-A Pharmaceutical Co., Ltd.
name: Seoul National University Bundang Hospital
First posted: 2012-05-15
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

  1. Hospitalization for decompensated heart failure
  2. Acute treatment with intravenous loop diuretics or hemofiltration
  3. E/E' ratio greater than or equal to 15 measured by echocardiography
  4. 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
  5. 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

Primary outcomes:
measure: Change of maximal VO2 in cardiopulmonary exercise test
timeFrame: Baseline and 12th weeks
Secondary outcomes:
measure: Change of ventilator efficiency (VE/VCO2 slope) in cardiopulmonary exercise test
timeFrame: Baseline and 12th week
measure: Change of symptomatic status expressed as New York Heart Association (NYHA) functional class
timeFrame: Baseline, 4th week, and 12th week
measure: Change of symptomatic status expressed as Borg dyspnea index
timeFrame: Baseline, 4th week, and 12th week
measure: Change of pulmonary artery systolic pressure (PASP) in echocardiography at rest and during exercise
timeFrame: Baseline and 12th week
measure: Change of left ventricular systolic function expressed as ejection fraction (EF), fractional shortening (FS) in echocardiography
timeFrame: Baseline and 12th week
measure: Change of left ventricular diastolic function expressed as E velocity, E' velocity, E/E' ratio, E/A ratio
timeFrame: Baseline and 12th week
measure: Change of left atrial volume
timeFrame: Baseline and 12th week
measure: Change of plasma concentration of BNP
timeFrame: Baseline, 4th week, and 12th week
measure: All-cause death
timeFrame: 12th week
measure: Cardiac death
timeFrame: 12th week
measure: Admission for heart failure
timeFrame: 12th week
measure: Composite clinical endpoints
timeFrame: 12th week
measure: Safety endpoint
timeFrame: 12th week
Other outcomes:
Locations:
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
Study officials:
affiliation: Seoul National University Hospital
name: Yong-Jin Kim, MD, PhD
role: STUDY_CHAIR
affiliation: Seoul National University Hospital
name: In-Chang Hwang, MD
role: STUDY_DIRECTOR
affiliation: Seoul National University Bundang Hospital
name: Goo-Yeong Cho, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Seoul National University Hospital
name: Hyung-Kwan Kim, MD, PhD
role: STUDY_DIRECTOR
affiliation: Seoul National University Hospital
name: Seung-Pyo Lee, MD
role: STUDY_DIRECTOR
affiliation: Seoul National University Hospital
name: Kyung-Hee Kim, MD
role: STUDY_DIRECTOR
affiliation: Seoul National University Hospital
name: Yeonyee E Yoon, MD
role: STUDY_DIRECTOR
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