RAZE: The Effects of Ranolazine on Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction

• Sponsor: University of California, San Diego (Other)
• Overall Status: Completed
• CT.gov ID: NCT01505179
• Collaborator: Gilead Sciences (Industry)
• Enrollment: 10
• Location: 1
• Arms: 2
• Duration (Months): 47
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure With Preserved Ejection Fraction	Drug: Ranolazine; Drug: Placebo	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effects of Ranolazine on Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ranolazine Patients with be given 500 mg by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)	Drug: Ranolazine; Patients with be given 500 mg by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period); Other Names: Ranexa
Placebo Comparator: Placebo Patients will be given 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)	Drug: Placebo; Patients will be given 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)

Outcome Measures

Primary Outcome Measures

1. Change in Exercise Capacity at 6 Weeks [6 weeks]

   Exercise capacity in terms of exercise duration (time in seconds) as described for the baseline value, is repeated at 6 weeks.

2. Change in Oxygen Consumption (VO2) at 6 Weeks [6 weeks]

   Oxygen consumption (VO2) as described at baseline is remeasured after 6 weeks of drug vs placebo.

Secondary Outcome Measures

1. Change in Quality of Life (QOL) Score [6 weeks]

   The Minnesota Living with Heart Failure (HF) Questionnaire was re-administered at the 6 week time point. The total quality of life (QOL) scores were compared to the baseline score. The well-validated Minnesota Living with Heart Failure questionnaire is self-administered, has 21 questions and takes 5-10 minutes to complete. The test measures perceived health-related QOL. Each question is scored from 0 to 5 on the Likert scale, where 0 is 'none', and 5 is 'very much'. QOL scores range from 0 to 105; a lower score represents a better quality of life. After an intervention, a decrease in score reflects an improvement in QOL. A minimally important difference in the total score is 5 points.

2. Change in Doppler Echocardiographic Parameters, Septal E/e' Ratio (E/e') [6 weeks]

   Doppler echo allows non-invasive evaluation of diastolic cardiac function. The mitral inflow velocity (E) correlates with LV filling pressure, but is influenced by myocardial relaxation time (RT) and filling pressure. The early diastolic septal mitral annular tissue velocity (e') varies with RT alone. The unitless ratio of the E to e' velocities (E/e') is considered a reliable surrogate of LV filling pressure. Prediction of normal diastolic filling pressure is most reliable when E/e' is < 8; and of abnormal filling pressure when E/e' is > 15. The percent change is reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

1. 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

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	San Diego	California	United States	92037

Sponsors and Collaborators

• University of California, San Diego
• Gilead Sciences

Investigators

• Principal Investigator: Denise D Barnard, MD, University of California, San Diego

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Denise Barnard, Clinical Professor of Medicine, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT01505179
• Other Study ID Numbers: IN-US-259-0109; 110344
• First Posted: Jan 6, 2012
• Last Update Posted: Jan 18, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Denise Barnard, Clinical Professor of Medicine, University of California, San Diego: HFPEF; Heart Failure; HF w/ preserved EF; Preserved EF; Preserved Ejection Fraction; Diastolic Dysfunction
• Additional relevant MeSH terms: Heart Failure; Ranolazine

Study Results

Participant Flow

Recruitment Details	Between 12/2011 and 3/2013, the UCSD Echo database of >4500 patients (pts) and their electronic medical records were screened. Of the 1200 pts with left ventricular (LV) ejection fraction (EF) >45%, only 60 pts met all inclusion criteria. Informed consent was obtained from 10 pts who were subsequently randomized and completed study protocols.
Pre-assignment Detail	Pts meeting all inclusion criteria were most often excluded due to the presence of atrial fibrillation, being unable to perform the minimum exercise effort required, or walked > 550 meters on the 6MW test. The remaining pts were excluded for acute heart failure (HF) decompensation, baseline QTc > 500 ms or participation in another clinical trial .

Arm/Group Title	Ranolazine Group	Placebo Group
Arm/Group Description	Patients with be given 500 mg Ranolazine by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)	Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)
Period Title: Overall Study
STARTED	6	4
COMPLETED	6	4
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ranolazine Group	Placebo Group	Total
Arm/Group Description	Patients with be given 500 mg Ranolazine by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)	Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)	Total of all reporting groups
Overall Participants	6	4	10
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	79.5	75.5	77.9
Sex: Female, Male (Count of Participants)
Female	3 50%	4 100%	7 70%
Male	3 50%	0 0%	3 30%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Exercise Duration (seconds) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [seconds]	608.6 (253.1)	328.8 (128.8)	496.7 (206.5)
Peak Oxygen Uptake (VO2) (mL O2/kg/min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL O2/kg/min]	15.9 (2.3)	15.7 (2.1)	15.8 (2.3)
6MW test distance (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	382.5 (88.2)	298.2 (76.3)	348.8 (83.4)
BNP (pg/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/mL]	111.7 (86.4)	184.8 (87.1)	140.9 (86.6)
Quality of Life (QOL) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	36.7 (20.3)	48.8 (36.3)	41.5 (26.7)
Septal E/e' Doppler velocity ratio (unitless) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [unitless]	16.2 (3.2)	17.0 (5.8)	16.5 (4.2)

Outcome Measures

1. Primary Outcome

Title	Change in Exercise Capacity at 6 Weeks
Description	Exercise capacity in terms of exercise duration (time in seconds) as described for the baseline value, is repeated at 6 weeks.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Entire study population

Arm/Group Title	Ranolazine Group	Placebo Group
Arm/Group Description	Patients with be given 500 mg Ranolazine by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)	Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)
Measure Participants	6	4
Mean (Standard Deviation) [seconds]	659.9 (284.5)	300.5 (92.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.47
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Change in Oxygen Consumption (VO2) at 6 Weeks
Description	Oxygen consumption (VO2) as described at baseline is remeasured after 6 weeks of drug vs placebo.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Entire study population

Arm/Group Title	Ranolazine Group	Placebo Group
Arm/Group Description	Patients with be given 500 mg Ranolazine by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)	Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)
Measure Participants	6	4
Mean (Standard Deviation) [ml/kg/min]	17.8 (3.4)	13.5 (4.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Change in Quality of Life (QOL) Score
Description	The Minnesota Living with Heart Failure (HF) Questionnaire was re-administered at the 6 week time point. The total quality of life (QOL) scores were compared to the baseline score. The well-validated Minnesota Living with Heart Failure questionnaire is self-administered, has 21 questions and takes 5-10 minutes to complete. The test measures perceived health-related QOL. Each question is scored from 0 to 5 on the Likert scale, where 0 is 'none', and 5 is 'very much'. QOL scores range from 0 to 105; a lower score represents a better quality of life. After an intervention, a decrease in score reflects an improvement in QOL. A minimally important difference in the total score is 5 points.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

The analysis population is comprised of the 10 patients who were eligible and consented for participation in the trial. Six patients were assigned to the Ranolazine group and four to the placebo group, randomization was by chance.

Arm/Group Title	Ranolazine Group	Placebo Group
Arm/Group Description	Patients with be given 500 mg Ranolazine by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)	Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)
Measure Participants	6	4
Mean (Standard Deviation) [units on a scale]	38.2 (24.7)	50.9 (65.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Change in Doppler Echocardiographic Parameters, Septal E/e' Ratio (E/e')
Description	Doppler echo allows non-invasive evaluation of diastolic cardiac function. The mitral inflow velocity (E) correlates with LV filling pressure, but is influenced by myocardial relaxation time (RT) and filling pressure. The early diastolic septal mitral annular tissue velocity (e') varies with RT alone. The unitless ratio of the E to e' velocities (E/e') is considered a reliable surrogate of LV filling pressure. Prediction of normal diastolic filling pressure is most reliable when E/e' is < 8; and of abnormal filling pressure when E/e' is > 15. The percent change is reported.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Entire Study Population

Arm/Group Title	Ranolazine Group	Placebo Group
Arm/Group Description	Patients with be given 500 mg Ranolazine by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)	Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)
Measure Participants	6	4
Mean (Standard Deviation) [percent change]	-15 (35)	-1 (9.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Duration of trial, 6 weeks.
Adverse Event Reporting Description	The definition of adverse events and serious adverse events are not different from those found in clinicaltrials.gov definitions. The study sponsor was provided with quarterly reports regarding any/all defined AE's and SAE's for patients in our study. The sponsor provided us with safety letters and reports of AE/SAE's regarding ranolazine in all active clinical trials (globally).
Arm/Group Title	Ranolazine Group		Placebo Group
Arm/Group Description	Patients with be given 500 mg Ranolazine by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)		Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)
All Cause Mortality
	Ranolazine Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/4 (0%)
Serious Adverse Events
	Ranolazine Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Ranolazine Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		1/4 (25%)
General disorders
Minor adverse event	1/6 (16.7%)	1	1/4 (25%)	1

Limitations/Caveats

Due to slower than anticipated enrollment, only 10 subjects out of an intended 40 completed the study in the time allowed by the sponsor. The statistical analyses and inferences are restricted by low sample size and population baseline differences.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.