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

Primary Purpose

Diastolic Heart Failure

Status
Unknown status
Phase
Phase 3
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Placebo
Udenafil (Zydena)
Sponsored by
Seoul National University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diastolic Heart Failure focused on measuring Heart Failure with Preserved Ejection Fraction, Diastolic Heart Failure, Exercise Capacity, Cardiopulmonary Exercise Test, Udenafil (Zydena), Phosphodiesterase Type 5 Inhibitors

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Seoul National University Bundang HospitalRecruiting
  • Seoul National University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo arm

Udenafil

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Change of maximal VO2 in cardiopulmonary exercise test
Comparison between groups and within groups.

Secondary Outcome Measures

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

Full Information

First Posted
May 13, 2012
Last Updated
January 30, 2013
Sponsor
Seoul National University Hospital
Collaborators
Dong-A Pharmaceutical Co., Ltd., Seoul National University Bundang Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01599117
Brief Title
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

2. Study Status

Record Verification Date
January 2013
Overall Recruitment Status
Unknown status
Study Start Date
October 2012 (undefined)
Primary Completion Date
April 2013 (Anticipated)
Study Completion Date
May 2013 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Seoul National University Hospital
Collaborators
Dong-A Pharmaceutical Co., Ltd., Seoul National University Bundang Hospital

4. Oversight

Data Monitoring Committee
Yes

5. 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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diastolic Heart Failure
Keywords
Heart Failure with Preserved Ejection Fraction, Diastolic Heart Failure, Exercise Capacity, Cardiopulmonary Exercise Test, Udenafil (Zydena), Phosphodiesterase Type 5 Inhibitors

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
52 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Placebo arm
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Udenafil
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
The same placebo drug of NCT01553721.
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Udenafil (Zydena)
Other Intervention Name(s)
DA-8159 (CAS No 268203-93-6)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change of maximal VO2 in cardiopulmonary exercise test
Description
Comparison between groups and within groups.
Time Frame
Baseline and 12th weeks
Secondary Outcome Measure Information:
Title
Change of ventilator efficiency (VE/VCO2 slope) in cardiopulmonary exercise test
Description
Comparison between groups and within groups.
Time Frame
Baseline and 12th week
Title
Change of symptomatic status expressed as New York Heart Association (NYHA) functional class
Description
Comparison between groups and within groups.
Time Frame
Baseline, 4th week, and 12th week
Title
Change of symptomatic status expressed as Borg dyspnea index
Description
Comparison between groups and within groups.
Time Frame
Baseline, 4th week, and 12th week
Title
Change of pulmonary artery systolic pressure (PASP) in echocardiography at rest and during exercise
Description
Comparison between groups and within groups.
Time Frame
Baseline and 12th week
Title
Change of left ventricular systolic function expressed as ejection fraction (EF), fractional shortening (FS) in echocardiography
Description
Comparison between groups and within groups.
Time Frame
Baseline and 12th week
Title
Change of left ventricular diastolic function expressed as E velocity, E' velocity, E/E' ratio, E/A ratio
Description
Comparison between groups and within groups.
Time Frame
Baseline and 12th week
Title
Change of left atrial volume
Description
Comparison between groups and within groups.
Time Frame
Baseline and 12th week
Title
Change of plasma concentration of BNP
Description
Comparison between groups and within groups.
Time Frame
Baseline, 4th week, and 12th week
Title
All-cause death
Description
The occurrence of all-cause mortality during 12 week follow-up
Time Frame
12th week
Title
Cardiac death
Description
The occurrence of cardiac death including sudden cardiac death during 12 week follow-up
Time Frame
12th week
Title
Admission for heart failure
Description
Admission due to congestive heart failure during 12 week follow-up
Time Frame
12th week
Title
Composite clinical endpoints
Description
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
Time Frame
12th week
Title
Safety endpoint
Description
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.
Time Frame
12th week

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 Hospitalization for decompensated heart failure Acute treatment with intravenous loop diuretics or hemofiltration 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 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Yong-Jin Kim, MD, PhD
Phone
82-10-3782-9382
Email
kimdamas@snu.ac.kr
First Name & Middle Initial & Last Name or Official Title & Degree
In-Chang Hwang, MD
Phone
82-10-5113-2395
Email
inchang.hwang@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yong-Jin Kim, MD, PhD
Organizational Affiliation
Seoul National University Hospital
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
In-Chang Hwang, MD
Organizational Affiliation
Seoul National University Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Goo-Yeong Cho, MD, PhD
Organizational Affiliation
Seoul National University Bundang Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hyung-Kwan Kim, MD, PhD
Organizational Affiliation
Seoul National University Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Seung-Pyo Lee, MD
Organizational Affiliation
Seoul National University Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Kyung-Hee Kim, MD
Organizational Affiliation
Seoul National University Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Yeonyee E Yoon, MD
Organizational Affiliation
Seoul National University Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Seoul National University Bundang Hospital
City
Seongnam-si
State/Province
Gyeonggi-do
ZIP/Postal Code
463-707
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Goo-Yeong Cho, MD, PhD
Phone
82-10-9870-9753
Email
cardioch@snu.ac.kr
First Name & Middle Initial & Last Name & Degree
Goo-Yeong Cho, MD, PhD
Facility Name
Seoul National University Hospital
City
Seoul
ZIP/Postal Code
110-744
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yong-Jin Kim, MD, PhD
Phone
82-10-3782-9382
Email
kimdamas@snu.ac.kr
First Name & Middle Initial & Last Name & Degree
In-Chang Hwang, MD
Phone
82-10-5113-2395
Email
inchang.hwang@gmail.com
First Name & Middle Initial & Last Name & Degree
Yong-Jin Kim, MD, PhD
First Name & Middle Initial & Last Name & Degree
Hyung-Kwan Kim, MD, PhD
First Name & Middle Initial & Last Name & Degree
Seung-Pyo Lee, MD
First Name & Middle Initial & Last Name & Degree
Kyung-Hee Kim, MD
First Name & Middle Initial & Last Name & Degree
Yeonyee E Yoon, MD
First Name & Middle Initial & Last Name & Degree
In-Chang Hwang, MD

12. IPD Sharing Statement

Citations:
PubMed Identifier
16855266
Citation
Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006 Jul 20;355(3):260-9. doi: 10.1056/NEJMoa051530.
Results Reference
background
PubMed Identifier
17428822
Citation
Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbely A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007 Oct;28(20):2539-50. doi: 10.1093/eurheartj/ehm037. Epub 2007 Apr 11.
Results Reference
background
PubMed Identifier
15665834
Citation
Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005 Feb;11(2):214-22. doi: 10.1038/nm1175. Epub 2005 Jan 23.
Results Reference
background
PubMed Identifier
17785618
Citation
Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007 Oct 2;116(14):1555-62. doi: 10.1161/CIRCULATIONAHA.107.716373. Epub 2007 Sep 4.
Results Reference
background
PubMed Identifier
21036891
Citation
Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study. Circ Heart Fail. 2011 Jan;4(1):8-17. doi: 10.1161/CIRCHEARTFAILURE.110.944694. Epub 2010 Oct 29.
Results Reference
background
PubMed Identifier
18318773
Citation
Kim BH, Lim HS, Chung JY, Kim JR, Lim KS, Sohn DR, Cho JY, Yu KS, Shin SG, Paick JS, Jang IJ. Safety, tolerability and pharmacokinetics of udenafil, a novel PDE-5 inhibitor, in healthy young Korean subjects. Br J Clin Pharmacol. 2008 Jun;65(6):848-54. doi: 10.1111/j.1365-2125.2008.03107.x. Epub 2008 Mar 3.
Results Reference
background
PubMed Identifier
14708417
Citation
Kang KK, Ahn GJ, Sohn YS, Ahn BO, Kim WB. DA-8159, a new PDE5 inhibitor, attenuates the development of compensatory right ventricular hypertrophy in a rat model of pulmonary hypertension. J Int Med Res. 2003 Nov-Dec;31(6):517-28. doi: 10.1177/147323000303100608.
Results Reference
background

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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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