Clinical trial NCT01505179: The Effects of Ranolazine on Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction
Official title: The Effects of Ranolazine on Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Heart Failure With Preserved Ejection Fraction
Keywords: HFPEF
Heart Failure
HF w/ preserved EF
Preserved EF
Preserved Ejection Fraction
Diastolic Dysfunction
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: Gilead Sciences
First posted: 2012-01-06
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether treatment with Ranolazine will improve exercise capacity in patients with Heart Failure with preserved left ventricular ejection fraction, or HFPEF.

Detailed description: Denise Barnard, M.D., and her associates, are conducting a research study to find out more about ways to improve symptoms in patients with Heart Failure with Preserved Ejection Fraction (HFPEF). Heart failure with preserved ejection fraction is a condition where the heart squeezes well but is stiff. This stiffness in the heart muscle makes the heart unable to fill, leading to shortness of breath and decreased exercise tolerance. Subjects with HFPEF are asked to participate in this study. There will be approximately 40 participants enrolled in this study. The purpose of this study is to investigate the effects of Ranolazine (Ranexa) in patients with HFPEF. The study is sponsored by the manufacturers of the drug, Gilead Pharmaceuticals.

Ranolazine is a drug that affects the ion channels in the heart. In patients with heart failure, these ion channels do not work properly, and contribute to make the heart stiff. A stiff heart leads to the symptoms of shortness of breath which patients with HFPEF experience. Due to its properties, Ranolazine may improve this stiffness. Ranolazine could improve subject's shortness of breath and ability to exercise.

Currently, ranolazine carries FDA approval for the treatment of chronic angina only. We intend to study ranolazine in patients with HFPEF, in the absence of documented ischemia, to determine whether the drug's lusitropic properties can improve exercise capacity in HFPEF patients.

Previous trials of ranolazine in patients with chronic angina found that there was a dose-dependent relationship between improvements in exercise capacity and ranolazine. However, there did appear to be a plateau in which 1500 mg of ranolazine twice daily improved exercise capacity only slightly more than 1000 mg of ranolazine given twice daily. Additionally, there was a substantially higher rate of adverse events (mainly nausea, dizziness, and asthenia) with the higher dose. Given the desire to maximize benefit and minimize the risk of adverse events, ranolazine 1000 mg by mouth twice daily was chosen as the target dose.

To properly evaluate the effects of Ranolazine, this research study is set up as a double blind, placebo controlled study. Subjects will be randomly assigned (like rolling a dice) to either Ranolazine or placebo (inactive substance). Subjects will have a 50% chance of getting the study drug and 50% chance of getting placebo.

Eligibility criteria: I. Inclusion Criteria

* Age \> 18 years old
* Diagnosis of Heart Failure (HF) with Preserved Ejection Fraction (PEF)

  * Signs or symptoms of heart failure (breathlessness, pulmonary congestion, edema, fatigue), NYHA (New York Heart Association) Class II-III HF AND
  * LVEF (Left Ventricular Ejection Fraction) \> 45% AND
  * Evidence of elevated LV filling pressures

    1. E/e-prime (E/e') mitral ratio \> 8. Mitral E/e' ratio has been proposed as a noninvasive measure of left ventricular filling pressure.
    2. Brain natiuretic peptide (BNP) \> 80 pg/mL. BNP is biomarker of ventricular wall stress.
* Pulmonary Artery systolic pressure estimated at \> 35 mm Hg on echocardiography
* Stable medical management for at least 1 month

II. Exclusion Criteria

* Inability to perform 6 minute walk (6MW) test or 6 minute walk distance \> 550 meters at baseline
* Inability to perform the Naughton protocol exercise test, or an absolute contraindication to exercise testing
* Decompensated heart failure
* Clinically significant valvular disease or congenital cardiac defects
* Clinical diagnosis of Chronic obstructive pulmonary disease (COPD) or significant lung pathology
* Prior treatment with ranolazine
* Percutaneous coronary intervention within the past 6 months or planned intervention during the study period
* Acute coronary syndrome within the prior 2 months
* Presence of uncorrected perfusion defects on stress testing
* Presence of angina
* Any rhythm other than sinus
* Electrocardiogram measured QTc interval \> 500 msec
* Clinically significant hepatic impairment (ALT/AST \> 3x upper limit of normal)
* Participation in another investigational drug or device study within 1 month prior to screening
* Females of childbearing potential
* Current treatment with potent inhibitors of hepatic cytochrome P450 (CYP) enzyme complex pathways affecting drug metabolism (e.g. ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir)
* Current treatment with CYP3A and/or P-Glycoprotein (Pgp) inducers (e.g. rifampin, rifampicin, carbamazepine, St. John's wort)
* Any other conditions that in the opinion of the investigators are likely to prevent compliance with the study protocol or pose a safety concern if the subject participates in the study.

Primary outcomes:
measure: Change in Exercise Capacity at 6 Weeks
timeFrame: 6 weeks
measure: Change in Oxygen Consumption (VO2) at 6 Weeks
timeFrame: 6 weeks
Secondary outcomes:
measure: Change in Quality of Life (QOL) Score
timeFrame: 6 weeks
measure: Change in Doppler Echocardiographic Parameters, Septal E/e' Ratio (E/e')
timeFrame: 6 weeks
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
Study officials:
affiliation: University of California, San Diego
name: Denise D Barnard, MD
role: PRINCIPAL_INVESTIGATOR
References: