Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure (The RELAX Study)

This study has been completed.
Sponsor:
Collaborators:
Pfizer
Information provided by (Responsible Party):
Duke University
ClinicalTrials.gov Identifier:
NCT00763867
First received: September 30, 2008
Last updated: July 14, 2014
Last verified: July 2013
  Purpose

Diastolic heart failure (DHF), which affects older individuals and women at a disproportionate rate, is a condition that can lead to shortness of breath and fluid build-up in the lungs. This study will evaluate the effectiveness of the medication sildenafil at improving exercise ability and health outcomes in people with DHF.


Condition Intervention Phase
Heart Failure
Drug: Placebo
Drug: Sildenafil
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX)

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Exercise Capacity, as Determined by Peak Oxygen Uptake [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Exercise Capacity, as Determined by Peak Oxygen Uptake [ Time Frame: Change from Baseline to Week 12 ] [ Designated as safety issue: No ]
  • Exercise Capacity as Determined by Walk Distance [ Time Frame: Change from Baseline to Week 12 ] [ Designated as safety issue: No ]
    6 Minute Walk Distance

  • Composite Score Reflective of Clinical Status [ Time Frame: Measured at Week 24 ] [ Designated as safety issue: No ]

    Participants ranked sequentially with ranking stratified in one of three tiers based on:

    1. Death (lowest tier) The person with the shortest time from randomization to death is given the lowest rank within the tier.
    2. Hospitalizations due to cardiovascular or renal causes (middle tier) For patients alive, the ranking within this tier is based on time to hospitalization from randomization date. The person with the first cardiovascular or renal cause hospitalization will be given the lowest rank within the tier.
    3. Change in Minnesota Living with Heart Failure Questionnaire (MLWHFQ) from baseline (highest tier)

    The use of three tiers within the ranking reflects the greater adverse impact of death or cardiovascular hospitalization on clinical status without an arbitrary assignment as to the relative value of these events in relation to changes in quality of life. Rank order: 1-189 (higher values are better)


  • Exercise Capacity as Determined by Walk Distance [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    6 minute walk distance

  • Cardiopulmonary Exercise Test (CPET) Duration [ Time Frame: Change from Baseline to Week 12 ] [ Designated as safety issue: No ]
    To interpret the CPET Exercise Duration change endpoints, an increase in exercise duration between Baseline and Week 12/Week 24 is considered to be an improvement

  • Cardiopulmonary Exercise Test (CPET) Duration [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    To interpret the CPET Exercise Duration change endpoints, an increase in exercise duration between Baseline and Week 12/Week 24 is considered to be an improvement

  • Ventilatory Anaerobic Threshold [ Time Frame: Change from Baseline to Week 12 ] [ Designated as safety issue: No ]
    To interpret the Ventilatory Anaerobic Threshold (VAT) change endpoints, an increase in VAT between Baseline and Week 12/Week 24 is considered to be an improvement

  • Ventilatory Anaerobic Threshold [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    To interpret the Ventilatory Anaerobic Threshold (VAT) change endpoints, an increase in VAT between Baseline and Week 12/Week 24 is considered to be an improvement

  • Minnesota Living With Heart Failure Questionnaire (MLWHFQ) [ Time Frame: Change from Baseline to Week 12 ] [ Designated as safety issue: No ]

    The MLWHFQ is a self-administered, disease-specific measure of health related quality of life (QOL) that assesses patients perceptions of the influence of heart failure on physical, socioeconomic and psychological aspects of life. Patients respond to 21 items using a six-point response scale (0-5). The total summary score can range from 0-105 with a lower score reflecting better heart failure related QOL. Two sub-scale scores reflect physical (8 items) and emotional (5 items) impairment.

    Total score: 0 - 105 Physical subscore: 0 - 40 Emotional subscore: 0 - 25


  • Minnesota Living With Heart Failure Questionnaire [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    The MLWHFQ is a self-administered, disease-specific measure of health related quality of life (QOL) that assesses patients perceptions of the influence of heart failure on physical, socioeconomic and psychological aspects of life. Patients respond to 21 items using a six-point response scale (0-5). The total summary score can range from 0-105 with a lower score reflecting better heart failure related QOL. Two sub-scale scores reflect physical (8 items) and emotional (5 items) impairment.


Other Outcome Measures:
  • MRI Left Ventricular Mass [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in LV Mass is considered an improvement

  • MRI Left Ventricular Mass Index [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in Left Ventricular Mass Index is considered an improvement

  • MRI Left Ventricular End Diastolic Volume [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    An increase in Left Ventricular End Diastolic Volume is considered an improvement

  • MRI Left Ventricular End Diastolic Volume Index [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    An increase in Left Ventricular End Diastolic Volume Index is considered an improvement

  • MRI Left Ventricular End Systolic Volume Index [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    An increase in Left Ventricular End Systolic Volume Index is considered an improvement

  • MRI Left Ventricular Ejection Fraction (LVEF) [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    An increase in LVEF is considered an improvement

  • Echocardiogram Left Ventricular Mass [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in Left Ventricular Mass is considered an improvement

  • Medial Diastolic Elastance [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in Medial Diastolic Elastance is considered an improvement

  • Lateral Diastolic Elastance [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in Lateral Diastolic Elastance is considered an improvement

  • Medial Left Ventricular Relaxation [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    An increase in Left Ventricular relaxation is considered to be an improvement

  • Lateral Left Ventricular Relaxation [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    An increase in Left Ventricular relaxation is considered to be an improvement

  • Medial Filling Pressure [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in medial filling pressure is considered an improvement

  • Lateral Filling Pressure [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in lateral filling pressure is considered an improvement

  • ECHO Effective Arterial Elastance [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in Effective Arterial Elastance is considered an improvement

  • ECHO Systemic Vascular Resistance [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in Systemic Vascular Resistance is considered an improvement

  • MRI Effective Arterial Elastance [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in Effective Arterial Elastance is considered an improvement

  • MRI Systemic Vascular Resistance [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in Systemic Vascular Resistance is considered an improvement

  • MRI Aortic Thickness [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in Aortic Thickness is considered an improvement

  • MRI Aortic Distensibility [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    An increase in Aortic Distensibility is considered to be an improvement

  • ECHO Pulmonary Artery Systolic Pressure [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    A decrease in Pulmonary Artery Systolic Pressure is considered to be an improvement

  • Best Available Creatinine [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    Best available=local lab results only when core lab results not available

  • Best Available Glomerular Filtration Rate (GFR) [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
    Best available=local lab results when core lab results not available

  • Cystatin C [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
  • Uric Acid [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
  • N-terminal Pro B-type Natriuretic Peptide (NT Pro-BNP) [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
  • Aldosterone [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
  • High Sensitivity Troponin I [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
  • Procollagen III N-terminal Peptide [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
  • Endothelin-1 [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
  • High Sensitivity C-Reactive Protein [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
  • Collagen Type I (CITP) [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
  • Cyclic Guanosine Monophosphate (cGMP) [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
  • Galectin 3 [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]
  • Furosemide-Equivalent Dose [ Time Frame: Change from Baseline to Week 24 ] [ Designated as safety issue: No ]

Enrollment: 216
Study Start Date: September 2008
Study Completion Date: September 2012
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Placebo 20 mg three tid for 12 weeks followed by 60 mg tid for 12 weeks
Drug: Placebo
Other Name: Sugar pill to mimic Sildenafil
Experimental: Sildenafil
Sildenafil 20 mg three tid for 12 weeks followed by 60 mg tid for 12 weeks
Drug: Sildenafil
Other Name: Active Sildenafil

Detailed Description:

DHF is a condition in which one of the chambers of the heart, the left ventricle, loses its ability to relax completely because the muscle has become too stiff. When this occurs, the heart is unable to properly fill with blood, which can lead to decreased blood circulation. People with DHF may experience shortness of breath and pulmonary congestion, which is an abnormal build-up of fluid in the lungs. Current treatment for DHF includes guidelines/recommendations to lower blood pressure, stop smoking, and lose weight, but there are no medications available to specifically treat DHF. Sildenafil, commonly known as Revatio or Viagra, is a medication that increases the supply of blood to the lungs and reduces the workload of the heart. Preliminary studies have shown that sildenafil may be beneficial at improving heart and lung function in people with DHF, but more research is needed to confirm these findings. The purpose of this study is to determine if sildenafil can improve exercise ability and health outcomes in people with DHF.

This 24-week study will enroll people with DHF. Participants will be randomly assigned to receive either sildenafil or placebo three times a day for 24 weeks. Participants will attend study visits at baseline and Weeks 1, 4, 12, 13, and 24. At most study visits, the following procedures will occur: physical exam, medical history review, questionnaires, blood collection, 6-minute walk test to measure endurance, and an exercise test. At baseline and Week 24, participants will also undergo an electrocardiogram, which will measure the electrical activity of the heart, and a cardiac magnetic resonance imaging (MRI) procedure and an echocardiogram, which will both obtain pictures of the heart. At Weeks 3, 8, 16, and 20, study researchers will call participants to collect health information.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Previous clinical diagnosis of heart failure with current New York Heart Association (NYHA) Class II-IV symptoms
  • 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 diuretic or hemofiltration
    • Mean pulmonary capillary wedge pressure greater than 15 mm Hg or left ventricular end diastolic pressure (LVEDP) greater than 18 mm Hg at catheterization for dyspnea
    • Long term treatment with a loop diuretic and chronic diastolic dysfunction on echocardiography, as determined by left atrial enlargement
  • Left ventricular ejection fraction greater than or equal to 50%, as determined by a clinical echocardiogram or ventriculogram in the 12 months before study entry
  • Receiving stable medical therapy in the 30 days before study entry, as determined by no addition or removal of angiotensin converting enzyme inhibitor (ACE), angiotensin receptor blocker (ARB), beta-blockers, or calcium channel blockers (CCB) and no change in dosage of ACE, ARBs, beta-blockers, or CCBs of more than 100%

Exclusion Criteria:

  • Has a neuromuscular, orthopedic, or other non-cardiac condition that prevents individual from exercise testing on a bicycle ergometer or from walking in a hallway
  • Non-cardiac condition that limits life expectancy to less than 1 year at the time of study entry, based on the judgment of the physician
  • Current or anticipated future need for nitrate therapy
  • Valve disease (i.e., greater than mild aortic or mitral stenosis; greater than moderate aortic or mitral regurgitation)
  • Hypertrophic cardiomyopathy
  • Infiltrative or inflammatory myocardial disease (e.g., amyloid, sarcoid)
  • Pericardial disease
  • Primary pulmonary arteriopathy
  • Has experienced a heart attack or unstable angina, or has undergone percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) in the 60 days before study entry, or requires either PTCA or CABG at the time of study entry
  • Other clinically important causes of dyspnea, such as morbid obesity or significant lung disease, as defined by clinical judgment or use of steroids or oxygen for lung disease
  • Systolic blood pressure less than 110 mm Hg or greater than 180 mm Hg
  • Diastolic blood pressure less than 40 mm Hg or greater than 100 mm Hg
  • Resting heart rate (HR) greater than 100 bpm
  • History of reduced ejection fraction (less than 50%)
  • Implanted metallic device that will interfere with MRI examination (in people without atrial fibrillation)
  • Severe kidney dysfunction (estimated glomerular filtration rate [GFR] less than 20 ml/min/1.73m2 by modified modification of diet in renal disease [MDRD] equation)
  • Pregnant or not using an effective form of contraception
  • Hemoglobin level of less than 10 g/dL
  • Taking alpha antagonists or cytochrome P450 3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, saquinavir, cimetidine, or serum protease inhibitors for HIV)
  • Retinitis pigmentosa, previous diagnosis of nonischemic optic neuropathy, untreated proliferative retinopathy, or unexplained visual disturbance
  • Sickle cell anemia, multiple myeloma, leukemia, or penile deformities that increase the risk for priapism (e.g., angulation, cavernosal fibrosis, Peyronie's disease)
  • Severe liver disease (aspartate aminotransferase [AST] level greater than three times the normal limit, alkaline phosphatase or bilirubin greater than two times the normal limit)
  • In being consistent with American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, people with dyspnea and risk factors for coronary artery disease should have had a stress test and those people with a clinically indicated stress test demonstrating significant ischemia in the 1 year before study entry will be excluded.
  • Listed for heart transplantation
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00763867

Locations
United States, Arizona
Mayo Clinic Arizona
Phoenix, Arizona, United States, 85054
United States, Georgia
Morehouse School of Medicine
Atlanta, Georgia, United States, 30310
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
United States, Minnesota
Minnesota Heart Failure Network
Minneapolis, Minnesota, United States, 55415
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27705
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Utah
University of Utah Health Sciences Center
Murray, Utah, United States, 84107
United States, Vermont
University of Vermont - Fletcher Allen Health Care
Burlington, Vermont, United States, 05401
Canada, Quebec
Montreal Heart Institute
Montreal, Quebec, Canada, H1T - 1C8
Sponsors and Collaborators
Duke University
Pfizer
Investigators
Principal Investigator: Kerry L. Lee, PhD Duke Clinical Research Institute
Study Chair: Eugene Braunwald, MD Harvard University
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00763867     History of Changes
Other Study ID Numbers: Pro00018007, U01HL084904, U01 HL084904-01, 521
Study First Received: September 30, 2008
Results First Received: April 4, 2013
Last Updated: July 14, 2014
Health Authority: United States: Federal Government

Keywords provided by Duke University:
Heart Failure, Diastolic
Decompensated Heart Failure
Sildenafil
Exercise Capacity

Additional relevant MeSH terms:
Heart Failure
Heart Failure, Diastolic
Heart Diseases
Cardiovascular Diseases
Sildenafil
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents

ClinicalTrials.gov processed this record on October 01, 2014