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

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ClinicalTrials.gov Identifier: NCT01599117
Recruitment Status : Unknown
Verified January 2013 by Yong-Jin Kim, Seoul National University Hospital.
Recruitment status was:  Recruiting
First Posted : May 15, 2012
Last Update Posted : January 31, 2013
Sponsor:
Collaborators:
Dong-A Pharmaceutical Co., Ltd.
Seoul National University Bundang Hospital
Information provided by (Responsible Party):
Yong-Jin Kim, Seoul National University Hospital

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).

Condition or disease Intervention/treatment Phase
Diastolic Heart Failure Drug: Placebo Drug: Udenafil (Zydena) Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 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 Heart Failure With Preserved Ejection Fraction: Phase III, Randomized, Double-blind, Placebo-controlled Trial [ULTIMATE-HFpEF Trial]
Study Start Date : October 2012
Estimated Primary Completion Date : April 2013
Estimated Study Completion Date : May 2013

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Change of maximal VO2 in cardiopulmonary exercise test [ Time Frame: Baseline and 12th weeks ]
    Comparison between groups and within groups.


Secondary Outcome Measures :
  1. Change of ventilator efficiency (VE/VCO2 slope) in cardiopulmonary exercise test [ Time Frame: Baseline and 12th week ]
    Comparison between groups and within groups.

  2. 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.

  3. Change of symptomatic status expressed as Borg dyspnea index [ Time Frame: Baseline, 4th week, and 12th week ]
    Comparison between groups and within groups.

  4. 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.

  5. 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.

  6. 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.

  7. Change of left atrial volume [ Time Frame: Baseline and 12th week ]
    Comparison between groups and within groups.

  8. Change of plasma concentration of BNP [ Time Frame: Baseline, 4th week, and 12th week ]
    Comparison between groups and within groups.

  9. All-cause death [ Time Frame: 12th week ]
    The occurrence of all-cause mortality during 12 week follow-up

  10. Cardiac death [ Time Frame: 12th week ]
    The occurrence of cardiac death including sudden cardiac death during 12 week follow-up

  11. Admission for heart failure [ Time Frame: 12th week ]
    Admission due to congestive heart failure during 12 week follow-up

  12. 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

  13. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01599117


Contacts
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Contact: Yong-Jin Kim, MD, PhD 82-10-3782-9382 kimdamas@snu.ac.kr
Contact: In-Chang Hwang, MD 82-10-5113-2395 inchang.hwang@gmail.com

Locations
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Korea, Republic of
Seoul National University Bundang Hospital Recruiting
Seongnam-si, Gyeonggi-do, Korea, Republic of, 463-707
Contact: Goo-Yeong Cho, MD, PhD    82-10-9870-9753    cardioch@snu.ac.kr   
Principal Investigator: Goo-Yeong Cho, MD, PhD         
Seoul National University Hospital Recruiting
Seoul, Korea, Republic of, 110-744
Contact: Yong-Jin Kim, MD, PhD    82-10-3782-9382    kimdamas@snu.ac.kr   
Contact: In-Chang Hwang, MD    82-10-5113-2395    inchang.hwang@gmail.com   
Principal Investigator: Yong-Jin Kim, MD, PhD         
Sub-Investigator: Hyung-Kwan Kim, MD, PhD         
Sub-Investigator: Seung-Pyo Lee, MD         
Sub-Investigator: Kyung-Hee Kim, MD         
Sub-Investigator: Yeonyee E Yoon, MD         
Sub-Investigator: In-Chang Hwang, MD         
Sponsors and Collaborators
Seoul National University Hospital
Dong-A Pharmaceutical Co., Ltd.
Seoul National University Bundang Hospital
Investigators
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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: Hyung-Kwan Kim, MD, PhD Seoul National University Hospital
Study Director: Seung-Pyo Lee, MD Seoul National University Hospital
Study Director: Kyung-Hee Kim, MD Seoul National University Hospital
Study Director: Yeonyee E Yoon, MD Seoul National University Hospital
Publications:

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Responsible Party: Yong-Jin Kim, Associate Professor, Seoul National University Hospital
ClinicalTrials.gov Identifier: NCT01599117    
Other Study ID Numbers: H-1202-006-396
First Posted: May 15, 2012    Key Record Dates
Last Update Posted: January 31, 2013
Last Verified: January 2013
Keywords provided by Yong-Jin Kim, Seoul National University Hospital:
Heart Failure with Preserved Ejection Fraction
Diastolic Heart Failure
Exercise Capacity
Cardiopulmonary Exercise Test
Udenafil (Zydena)
Phosphodiesterase Type 5 Inhibitors
Additional relevant MeSH terms:
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Heart Failure
Heart Failure, Diastolic
Heart Diseases
Cardiovascular Diseases
Udenafil
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action