A Randomized Trial of Udenafil Therapy in Patients With Mild Pulmonary Hypertension [ULTIMATE-Mild PHT]

Sponsor

Seoul National University Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT01696240

Collaborator

Dong-A Pharmaceutical Co., Ltd. (Industry), Seoul National University Bundang Hospital (Other)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Mild Pulmonary Hypertension	Drug: Placebo Drug: Udenafil (Zydena)	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Udenafil Therapy to Improve Symptomatology, Exercise Tolerance and Hemodynamics in Patients With Mild Pulmonary Hypertension [ULTIMATE-Mild PHT]

Study Start Date :

Sep 1, 2012

Anticipated Primary Completion Date :

Dec 1, 2013

Anticipated Study Completion Date :

Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo 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 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. Other Names: The same placebo drug of NCT01553721.
Active Comparator: 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.	Drug: Udenafil (Zydena) 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. Other Names: DA-8159 (CAS No 268203-93-6)

Arm

Intervention/Treatment

Placebo Comparator: Placebo

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

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.

Other Names:

The same placebo drug of NCT01553721.

Active Comparator: 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.

Drug: Udenafil (Zydena)

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.

Other Names:

DA-8159 (CAS No 268203-93-6)

Outcome Measures

Primary Outcome Measures

Change of maximal VO2 in cardiopulmonary exercise test [Baseline and 12th weeks]
Comparison between groups and within groups.

Secondary Outcome Measures

Change of symptomatic status expressed as New York Heart Association (NYHA) functional class [Baseline, 4th week, and 12th week]
Comparison between groups and within groups.
Change of pulmonary artery systolic pressure (PASP) in echocardiography at rest and during exercise [Baseline and 12th week]
Comparison between groups and within groups.
Change of left ventricular systolic function expressed as ejection fraction (EF), fractional shortening (FS) in echocardiography [Baseline and 12th week]
Comparison between groups and within groups.
Change of ventilator efficiency (VE/VCO2 slope) in cardiopulmonary exercise test [Baseline and 12th week]
Comparison between groups and within groups.
Change of plasma concentration of BNP [Baseline, 4th week, and 12th week]
Comparison between groups and within groups.
All-cause death [12th week]
The occurrence of all-cause mortality during 12 week follow-up
Cardiac death [12th week]
The occurrence of cardiac death including sudden cardiac death during 12 week follow-up
Admission for heart failure [12th week]
Admission due to congestive heart failure during 12 week follow-up
Composite clinical endpoints [12th week]
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
Safety endpoint [12th week]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
2	Seoul National University Hospital	Seoul		Korea, Republic of	110-744

Sponsors and Collaborators

Seoul National University Hospital
Dong-A Pharmaceutical Co., Ltd.
Seoul National University Bundang Hospital

Investigators

Study Chair: Yong-Jin Kim, MD, PhD, Seoul National University Hospital
Principal Investigator: Goo-Yeong Cho, MD, PhD, Seoul National University Hospital
Study Director: Hyung-Kwan Kim, MD, PhD, Seoul National University Hospital
Study Director: Seung-Pyo Lee, MD, Seoul National University Hospital
Study Director: Yeonyee Yoon, MD, Seoul National University Hospital
Study Director: Kyung-Hee Kim, MD, Seoul National University Hospital
Study Director: In-Chang Hwang, MD, Seoul National University Hospital