Clinical trial NCT01696240: A Randomized Trial of Udenafil Therapy in Patients With Mild Pulmonary Hypertension [ULTIMATE-Mild PHT]
Official title: Udenafil Therapy to Improve Symptomatology, Exercise Tolerance and Hemodynamics in Patients With Mild Pulmonary Hypertension [ULTIMATE-Mild PHT]
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Mild Pulmonary Hypertension
Keywords: Pulmonary Hypertension
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: 2012-09-28
Enrollment: 40
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 mild pulmonary hypertension.

Detailed description: Pulmonary arterial hypertension is a devastating progressive disease increasingly debilitating symptoms. In the past few years, treatment of pulmonary hypertension has undergone an extraordinary evolution. A selective PDE-5 inhibitor, Sildenafil, has been shown to be as an effective pulmonary vasodilator as inhaled NO in patients with primary pulmonary hypertension and has recently been shown to improve exercise capacity, resting hemodynamics, and WHO functional class in patients with pulmonary hypertension. However, to date, the effect of Sildenafil have been mainly studied in patients with advanced disease.

Udenafil (Zydena), a newly developed PDE-5 inhibitor, has been proved to have similar efficacy and safety profile, compared with other PDE-5 inhibitors. However, to date, the effect of Udenafil in mild pulmonary HT has never been evaluated. Therefore, we hypothesized that Udenafil, a newly developed phosphodiesterase type 5 inhibitor, would improve symptom, exercise capacity and hemodynamic status in patients with mild pulmonary hypertension.

In this 12-week, randomized, double-blind, placebo-controlled trial, patients with mild pulmonary hypertension 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:

- Mild pulmonary hypertension defined as estimated pulmonary arterial systolic pressure of 30-50 mmHg (TR jet velocity of 2.5-3.4 m/sec) with current New York Heart association (NYHA) class II-IV symptoms, left ventricular ejection fraction (LVEF) greater than or equal to 50% at the time of study entry

Exclusion Criteria:

* Hospitalization for decompensated heart failure or acute treatment with intravenous loop diuretics or hemofiltration in the 12 months before study entry
* 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
* Significant obstructive or restrictive lung disease
* Valve disease (greater than mild stenosis or regurgitation)
* Hypertrophic cardiomyopathy
* Infiltrative or inflammatory myocardial disease
* Pericardial 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)
* 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

Primary outcomes:
measure: Change of maximal VO2 in cardiopulmonary exercise test
timeFrame: Baseline and 12th weeks
Secondary outcomes:
measure: Change of symptomatic status expressed as New York Heart Association (NYHA) functional class
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 ventilator efficiency (VE/VCO2 slope) in cardiopulmonary exercise test
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: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
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: 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: Yeonyee Yoon, MD
role: STUDY_DIRECTOR
affiliation: Seoul National University Hospital
name: Kyung-Hee Kim, MD
role: STUDY_DIRECTOR
affiliation: Seoul National University Hospital
name: In-Chang Hwang, MD
role: STUDY_DIRECTOR
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