- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01354613
Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction(HFpEF)
April 9, 2019 updated by: University of Wisconsin, Madison
Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction
Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of heart failure cases in the United States, affecting a primarily elderly population.
No treatment has been shown to affect mortality in HFpEF, which is more than 50% at five years a hospitalization.
This project explores the underlying cardiovascular physiology of patients with HFpEF with the goal of identifying new therapeutic targets that would allow improved treatment of this devastating disease.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
Heart failure with preserved ejection fraction (HFpEF) is a difficult disease to diagnose due to nonspecific symptoms and clinical findings.
The disease occurs in the elderly, who often have other illnesses and signs of aging that make diagnosis of heart failure more difficult.
Recently, it has been suggested that HFpEF, which has primarily been thought to be a diastolic disease, is in fact multifactorial, with elements of abnormal systolic function and increased vascular stiffness playing a role in disease pathology.
No treatment has been shown to reduce the high mortality of the disease.
However, few studies have evaluated this population of patients during periods of increased physiologic stress, despite the consistent clinical presentation of impaired exercise tolerance with few symptoms at rest.
This study explores the multifactorial physiology of HFpEF, with a detailed investigation of the specificity of abnormalities in contractile reserve and vascular stiffness for this disease, and exploration of the modifiability of these abnormalities.
The techniques used are non-invasive, involving echocardiographic evaluation of cardiac function, and measurement of arterial stiffness using tonometry.
The first aim of the study is to explore the specificity of a potential diagnostic test for HFpEF by investigating the change in ejection fraction before and after β-adrenergic stimulation with low-dose dobutamine in HFpEF compared to other groups important to distinguish clinically, specifically patients with shortness of breath due to pulmonary disease, and those with hypertension and left ventricular hypertrophy without clinical heart failure.
In the second aim, the study will investigate the ability of the calcium channel blocker, amlodipine, to restore normal contractile responses of the myocardium.
In the third aim, the role of arterial stiffness in drug responses in HFpEF will be explored.
It is anticipated that improved understanding of the complex physiology of this multifactorial disease gained through this study will lead to more rational design of large clinical trials studying promising agents for HFpEF that impact not only diastolic function, but contractile reserve and arterial properties as well.
Study Type
Interventional
Enrollment (Actual)
14
Phase
- Not Applicable
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
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Wisconsin
-
Madison, Wisconsin, United States, 53705
- UW - Madison
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-
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
16 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Male or female; Age 18 or older.
- Left ventricular ejection fraction ≥ 50%.
- Symptomatic heart failure or appropriate comparator group criteria
- Informed consent signed by the subject
Exclusion Criteria:
- Symptoms of active ischemia.
- Moderate or severe mitral or aortic stenosis, or severe aortic insufficiency.
- Serum creatinine > 3.0 or chronic hemodialysis.
- Known chronic hepatic disease; defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels > 3.0 times the upper limit of normal as read at the local lab.
- Severe renal dysfunction, i.e. glomerular filtration rate (GFR) <30 ml/min.
- Atrial fibrillation
- Myocardial infarction within the last year
- Coronary bypass surgery within the last 6 months
- Stroke within the last 6 months
- Known aortic aneurysm
- Contra-indication to withdrawal of beta blocker or antihypertensive medications
- Resting or orthostatic hypotension (SBP < 90 mmHg)
- Any gastrointestinal disorder which would interfere with drug absorption
- Any significant valvular heart disease, including prior multiple valve replacement.
- Pericardial Disease
- Infiltrative or hypertrophic cardiomyopathy
- Cor pulmonale
- Unstable coronary disease
- Pregnancy
- Any condition which may prevent the subject from adhering to the study protocol, as determined by the investigator
Heart Failure with Preserved Ejection Fraction
- Clinical evidence of heart failure with preserved ejection fraction, as manifest by at least 2 symptoms or signs, including dyspnea on exertion or at rest, orthopnea, jugular venous distention or hepatojugular reflux, rales or edema.
- Controlled systolic BP (< 150 mmHg on the day of study)
Pulmonary Disease Group
- Known obstructive airways disease with objective documentation of an isolated obstructive defect by pulmonary function testing.
- No history of heart failure.
- No history of cardiovascular disease, with the exception of hypertension or hyperlipidemia
- History and physical examination free of signs and symptoms of heart failure, including elevated jugular venous pressure, hepatojugular reflux, rales or edema.
- Baseline echocardiographic examination without evidence of heart failure, including systolic dysfunction of the LV or RV, or evidence of more than mild diastolic dysfunction on non-invasive assessment.
HTN/LVH Group
- Known history of hypertension.
- Echocardiographic evidence of left ventricular hypertrophy and diastolic dysfunction.
- No history or physical examination evidence of heart failure, including excessive dyspnea on exertion, dyspnea at rest, orthopnea, PND, jugular venous distention, hepatojugular reflux, rales or edema.
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: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: HFpEF
25 patients with clinically diagnosed heart failure with preserved ejection fraction, confirmed by Framingham criteria, with EF > 50% and without evidence of active ischemia or known severe CAD, valvular or pericardial disease, infiltrative or hypertrophic cardiomyopathy, cor pulmonale, severe pulmonary disease, or primary renal disease.
Subjects will receive amlodipine, oral administration for a period of 12 weeks.
|
IV administration at the initial study visit (all groups) and at the final study visit for the drug intervention arm (HFpEF group only).
Administration of low-dose dobutamine at 5mcg/kg/min and 10mcg/kg/min for periods of approximately 30minutes/dose for purposes of performing a low-dose stress exam on the heart.
Participants will be randomized to treatment with either amlodipine 5 mg daily or placebo, in double-blind fashion, 25 patients in each group.
12 week oral administration of 5mg/day, uptitrated to 10mg/day, determined by PI.
|
Experimental: Pulmonary Disease
20 patients with pulmonary disease and no clinical evidence of cardiovascular disease
|
IV administration at the initial study visit (all groups) and at the final study visit for the drug intervention arm (HFpEF group only).
Administration of low-dose dobutamine at 5mcg/kg/min and 10mcg/kg/min for periods of approximately 30minutes/dose for purposes of performing a low-dose stress exam on the heart.
|
Experimental: LVH/HTN
20 subjects with known left ventricular hypertrophy and clinically diagnosed hypertension without the diagnosis of heart failure.
|
IV administration at the initial study visit (all groups) and at the final study visit for the drug intervention arm (HFpEF group only).
Administration of low-dose dobutamine at 5mcg/kg/min and 10mcg/kg/min for periods of approximately 30minutes/dose for purposes of performing a low-dose stress exam on the heart.
|
Placebo Comparator: HFpEF placebo
25 patients with clinically diagnosed heart failure with preserved ejection fraction, confirmed by Framingham criteria, with EF > 50% and without evidence of active ischemia or known severe CAD, valvular or pericardial disease, infiltrative or hypertrophic cardiomyopathy, cor pulmonale, severe pulmonary disease, or primary renal disease.
Subjects will be administered a placebo for a period of 12 weeks.
|
IV administration at the initial study visit (all groups) and at the final study visit for the drug intervention arm (HFpEF group only).
Administration of low-dose dobutamine at 5mcg/kg/min and 10mcg/kg/min for periods of approximately 30minutes/dose for purposes of performing a low-dose stress exam on the heart.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in ejection fraction with 5mcg/kg/min dobutamine
Time Frame: day 0 and 12 week study visit
|
The primary outcome variable in this analysis will be change in ejection fraction from baseline at the 5 mcg dobutamine dose.
|
day 0 and 12 week study visit
|
Change in pulse wave velocity
Time Frame: 12 week study visit
|
Change in carotid-femoral pulse wave velocity (PWV) with 12 weeks of therapy with amlodipine or placebo will be the primary outcome variable.
|
12 week study visit
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Nancy K Sweitzer, MD, PhD, UW-Madison
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
April 1, 2011
Primary Completion (Actual)
December 1, 2013
Study Completion (Actual)
December 1, 2013
Study Registration Dates
First Submitted
May 5, 2011
First Submitted That Met QC Criteria
May 16, 2011
First Posted (Estimate)
May 17, 2011
Study Record Updates
Last Update Posted (Actual)
April 11, 2019
Last Update Submitted That Met QC Criteria
April 9, 2019
Last Verified
April 1, 2019
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Heart Diseases
- Cardiovascular Diseases
- Pathological Conditions, Anatomical
- Cardiomegaly
- Heart Failure
- Hypertrophy
- Hypertrophy, Left Ventricular
- Physiological Effects of Drugs
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Vasodilator Agents
- Autonomic Agents
- Peripheral Nervous System Agents
- Protective Agents
- Adrenergic Agonists
- Cardiotonic Agents
- Membrane Transport Modulators
- Calcium-Regulating Hormones and Agents
- Calcium Channel Blockers
- Adrenergic beta-Agonists
- Sympathomimetics
- Adrenergic beta-1 Receptor Agonists
- Amlodipine
- Dobutamine
Other Study ID Numbers
- H-2010-0061
- R21HL106103-01 (U.S. NIH Grant/Contract)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
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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