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

January 30, 2013 updated by: Yong-Jin Kim, Seoul National University Hospital

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]

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).

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

52

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Korea, Republic of
      • Seoul, Korea, Republic of, 110-744
        • Recruiting
        • Seoul National University Hospital
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Hyung-Kwan Kim, MD, PhD
        • Sub-Investigator:
          • Kyung-Hee Kim, MD
        • Sub-Investigator:
          • Yeonyee E Yoon, MD
        • Sub-Investigator:
          • In-Chang Hwang, MD
    • Gyeonggi-do
      • Seongnam-si, Gyeonggi-do, Korea, Republic of, 463-707
        • Recruiting
        • Seoul National University Bundang Hospital
        • Contact:
        • Principal Investigator:
          • Goo-Yeong Cho, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: 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.
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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of maximal VO2 in cardiopulmonary exercise test
Time Frame: Baseline and 12th weeks
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
Time Frame: Baseline and 12th week
Comparison between groups and within groups.
Baseline and 12th week
Change of symptomatic status expressed as New York Heart Association (NYHA) functional class
Time Frame: Baseline, 4th week, and 12th week
Comparison between groups and within groups.
Baseline, 4th week, and 12th week
Change of symptomatic status expressed as Borg dyspnea index
Time Frame: Baseline, 4th week, and 12th week
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
Time Frame: Baseline and 12th week
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
Time Frame: Baseline and 12th week
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
Time Frame: Baseline and 12th week
Comparison between groups and within groups.
Baseline and 12th week
Change of left atrial volume
Time Frame: Baseline and 12th week
Comparison between groups and within groups.
Baseline and 12th week
Change of plasma concentration of BNP
Time Frame: Baseline, 4th week, and 12th week
Comparison between groups and within groups.
Baseline, 4th week, and 12th week
All-cause death
Time Frame: 12th week
The occurrence of all-cause mortality during 12 week follow-up
12th week
Cardiac death
Time Frame: 12th week
The occurrence of cardiac death including sudden cardiac death during 12 week follow-up
12th week
Admission for heart failure
Time Frame: 12th week
Admission due to congestive heart failure during 12 week follow-up
12th week
Composite clinical endpoints
Time Frame: 12th week

Composite clinical endpoints during 12 week follow-up, are defined as follows:

  1. Composite of all-cause death and admission for heart failure
  2. Composite of cardiac death and admission for heart failure
12th week
Safety endpoint
Time Frame: 12th week

Safety endpoint during 12 week follow-up, is defined as follows:

  1. Development of facial flushing, febrile sensation, eyeball pain, visual disturbance, headache, penile erection.
  2. Intolerance or development of other adverse drug reactions related with study drug.
12th week

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Seoul National University Hospital

Collaborators

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

Investigators

  • Study Chair: Yong-Jin Kim, MD, PhD, Seoul National University Hospital
  • Study Director: In-Chang Hwang, MD, Seoul National University Hospital
  • Principal Investigator: Goo-Yeong Cho, MD, PhD, Seoul National University Bundang Hospital
  • Study Director: Kyung-Hee Kim, MD, Seoul National University Hospital
  • Study Director: Yeonyee E Yoon, MD, Seoul National University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2012

Primary Completion (Anticipated)

April 1, 2013

Study Completion (Anticipated)

May 1, 2013

Study Registration Dates

First Submitted

May 13, 2012

First Submitted That Met QC Criteria

May 14, 2012

First Posted (Estimate)

May 15, 2012

Study Record Updates

Last Update Posted (Estimate)

January 31, 2013

Last Update Submitted That Met QC Criteria

January 30, 2013

Last Verified

January 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H-1202-006-396

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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