The Effects of Ranolazine on CPET Parameters in Ischemic Cardiomyopathy Patients (ERIC)

• Sponsor: Cardiovascular Institute of the South Clinical Research Corporation (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01705509
• Collaborator: Gilead Sciences (Industry)
• Enrollment: 14
• Location: 1
• Arm: 1
• Actual Duration (Months): 54.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a proof of concept trial using ranolazine, a medication, in patients with known Coronary Artery Disease and reduced left ventricular function, EF < 40%. We propose that ranolazine therapy will result in demonstrative improvements in cardiac function that can be objectively assessed using the parameters measured with CPET. We propose that demonstrative improvement in CPET parameters on ranolazine will translate into improved patient outcomes for this patient population.

Condition or Disease	Intervention/Treatment	Phase
Cardiomyopathy	Drug: Ranolazine	N/A

Detailed Description

Selected patients will undergo a CPET evaluation. The initial CPET will identify patients with underlying ischemia and serve as a baseline study. Ischemia will be assessed using: 1) peak VO2: measures the peak transport of O2 to the tissues when O2 extraction from the blood is maximal; 2) the anaerobic threshold (AT): measures the sustainable work capacity in units of VO2; 3) the O2-pulse measurements at the AT peak VO2: estimate stroke volume at those levels of exercise; and 4) the relationship of O2 uptake to work rate (ΔVO2/ΔWR): provides information on the ability of the cardiac output to increase. Patients whoseCPET results meet the criteria for ischemia will be started on Ranexa 500mg BID and advanced within one week +/-4 days to 1000mg BID. A second CPET will be performed after 4 weeks +/- 4 days of maximum therapy. CPET results before and after therapy will undergo a statistical comparison. The initial off treatment CPET measurement will serve as the control to assess changes found during therapy. No medication changes or revascularization procedures will occur during the study. If patients require and undergo a medication change or a revascularization procedure, they will be excluded from the study.

Patients will be contacted at the completion of week one prior to up titration, then at the end of week two to ensure tolerance and compliance with the 1000mg BID dose. Patients will perform the second CPET study at week four +/- 1 week. The trial medication will be assessed and counted to ensure that patients have taken there allotted pill count for the duration of the study. Patients who are found to be noncompliant of less than 80% will be excluded from the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: The Effects of Ranolazine on CPET Parameters in Ischemic Cardiomyopathy Patients (ERIC)
• Actual Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Mar 31, 2017
• Actual Study Completion Date: Mar 31, 2017

Arms and Interventions

Arm

Intervention/Treatment

Other: Ranolazine Treatment Arm All patients who meet the criteria of ischemia will receive ranolazine after enrollment. The initial CPET will serve as the control. The second CPET after 30-days of therapy will serve as the therapy arm. CPET parameters will be assessed and compared both on and off therapy.

Drug: Ranolazine; The intervention will be ranolazine therapy after the initial CPET. The initial CPET will identify patients with underlying ischemia and serve as a baseline study. Patients whose CPET results meet the criteria for ischemia will be started on Ranexa 500mg BID and advanced within one week +/-4 days to 1000mg BID. A second CPET will be performed after 4 weeks +/- 4 days of maximum therapy. CPET results before and after therapy will undergo a statistical comparison. The initial off treatment CPET measurement will serve as the control to assess changes found during therapy.; Other Names: Ranexa

Outcome Measures

Primary Outcome Measures

1. Cardiopulmonary Exercise Test Parameters (CPET). [30 days]

   CPET parameters assessed will include the peak VO2: measures the peak transport of O2 to the tissues when O2 extraction from the blood is maximal; 2) the anaerobic threshold (AT): measures the sustainable work capacity in units of VO2; 3) the O2-pulse measurements at the AT and peak VO2: estimate stroke volume at those levels of exercise; and 4) the relationship of O2 uptake to work rate (ΔVO2/ΔWR): provides information on the ability of the cardiac output to increase.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients > 18 years of age will be enrolled in the trial.

• Stable patients without hospitalizations, medication changes or cardiac intervention within one month of the study will be enrolled.

• Patients must be able to complete the CPET protocol and must have demonstrable ischemia on the initial CPET evaluation.

• Patients must have a documented ejection fraction < 40%

1. LV function can be assessed via: i. Echocardiogram ii. MUGA or Nuclear Perfusion Scan iii. Left ventriculogram

• Patients must be Ranexa naive and without contraindication for Ranexa therapy.

Exclusion Criteria:

• QTc>500 msec on resting EKG

• Hepatic Impairment (Child-Pugh class A, B or C)

• Have received prior treatment with ranolazine

• Treatment with QT prolonging drugs as class 1A (e.g., quinidine), class III (e.g., sotalol, dofetilide) anti-arrhythmics, amiodarone and anti-psychotics (e.g., thioridazine, ziprasidone)

• Treatment with potent or moderately potent CYP3A inhibitors including ketoconazole and other azole antifungals, diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors or consumption of grapefruit juice or grapefruit juice containing products

• Have participated in another trial of an investigational device or drug within 30 days of screening

• Have end stage renal disease requiring dialysis

• Have any chronic illness likely to effect compliance with the protocol

• Have second or third degree atrioventricular block in the absence of a functioning ventricular pacemaker

• Have uncontrolled clinically significant cardiac arrhythmias, or a history of ventricular fibrillation, torsade de pointes, or other life-threatening ventricular arrhythmias

• Uncontrolled HTN defined as BP > /= 160/100 mm Hg

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cardiovascular Institute of the South	Lafayette	Louisiana	United States	70506

Sponsors and Collaborators

• Cardiovascular Institute of the South Clinical Research Corporation
• Gilead Sciences

Investigators

• Principal Investigator: Agostino G Ingraldi, M.D., Cardiovascular Institute of the South

Study Documents (Full-Text)

• Informed Consent Form - Sep 10, 2012
• Study Protocol - Feb 24, 2013

More Information

Publications

• Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart. 2006 Jul;92 Suppl 4:iv6-iv14.
• Belardinelli R, Lacalaprice F, Carle F, Minnucci A, Cianci G, Perna G, D'Eusanio G. Exercise-induced myocardial ischaemia detected by cardiopulmonary exercise testing. Eur Heart J. 2003 Jul;24(14):1304-13.
• Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation. 2006 May 23;113(20):2462-72. Review.
• Contini M, Andreini D, Agostoni P. Cardiopulmonary exercise test evidence of isolated right coronary artery disease. Int J Cardiol. 2006 Nov 10;113(2):281-2. Epub 2005 Nov 28.
• Itoh, H et al. Oxygen uptake abnormalities during exercise in coronary artery disease. In Cardiopulmonary Exercise Testing and Cardiovascular Health. Edited by K. Wasserman, Published by Futura Publishing Company, Armonk NY, 2002.
• Klainman E, Fink G, Lebzelter J, Zafrir N. Assessment of functional results after percutaneous transluminal coronary angioplasty by cardiopulmonary exercise test. Cardiology. 1998 May;89(4):257-62.
• Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Stafford R, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation. 2010 Feb 23;121(7):948-54. doi: 10.1161/CIRCULATIONAHA.109.192666. Erratum in: Circulation. 2010 Mar 30;121(12):e259.
• McMurray JJ, Petrie MC, Murdoch DR, Davie AP. Clinical epidemiology of heart failure: public and private health burden. Eur Heart J. 1998 Dec;19 Suppl P:P9-16. Review.
• Wenger NK, Chaitman B, Vetrovec GW. Gender comparison of efficacy and safety of ranolazine for chronic angina pectoris in four randomized clinical trials. Am J Cardiol. 2007 Jan 1;99(1):11-8. Epub 2006 Nov 2.

• Responsible Party: Cardiovascular Institute of the South Clinical Research Corporation
• ClinicalTrials.gov Identifier: NCT01705509
• Other Study ID Numbers: 20121250
• First Posted: Oct 12, 2012
• Last Update Posted: Feb 18, 2020
• Last Verified: Feb 1, 2020

• Keywords provided by Cardiovascular Institute of the South Clinical Research Corporation: The Effects of Ranolazine on CPET Parameters in Ischemic; Cardiomyopathy Patients
• Additional relevant MeSH terms: Cardiomyopathies; Ranolazine

Study Results

Participant Flow

Arm/Group Title	CPET Control / CPET With Ranexa
Arm/Group Description	The initial CPET will identify patients with underlying ischemia and serve as a baseline study. Patients whose CPET results meet the criteria for ischemia will be started on Ranexa 500mg BID and advanced within one week +/-4 days to 1000mg BID. A second CPET will be performed after 4 weeks +/- 4 days of maximum therapy. CPET results before and after therapy will undergo a statistical comparison.
Period Title: Inclusion CPET
STARTED	14
COMPLETED	7
NOT COMPLETED	7
Period Title: Inclusion CPET
STARTED	7
COMPLETED	5
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	CPET Control / CPET With Ranexa
Arm/Group Description	Enrolled patients will undergo a CPET evaluation. Beta Blockers will be held day prior to and day of CPET. The initial CPET will identify patients with underlying ischemia and serve as a baseline study. Patients whose CPET results meet the criteria for ischemia will be started on Ranexa 500mg B ID and advanced within one week +/-4 days to 1000mg BID. A second CPET will be performed after 4 weeks +/- 4 days of maximum therapy. CPET results before and after therapy will undergo a statistical comparison. The initial off treatment CPET measurement will serve as the control to assess changes found during therapy. No medication changes or revascularization procedures will occur during the study.
Overall Participants	14
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 35.7%
>=65 years	9 64.3%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	68
Sex: Female, Male (Count of Participants)
Female	4 28.6%
Male	10 71.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 7.1%
White	13 92.9%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%

Outcome Measures

1. Primary Outcome

Title	Cardiopulmonary Exercise Test Parameters (CPET).
Description	CPET parameters assessed will include the peak VO2: measures the peak transport of O2 to the tissues when O2 extraction from the blood is maximal; 2) the anaerobic threshold (AT): measures the sustainable work capacity in units of VO2; 3) the O2-pulse measurements at the AT and peak VO2: estimate stroke volume at those levels of exercise; and 4) the relationship of O2 uptake to work rate (ΔVO2/ΔWR): provides information on the ability of the cardiac output to increase.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

Number of Participants who Reached CPET Milestones

Arm/Group Title	Control
Arm/Group Description	All patients who meet the criteria of ischemia will receive ranolazine after enrollment. The initial CPET will serve as the control. The second CPET after 30-days of therapy will serve as the therapy arm. CPET parameters will be assessed and compared both on and off therapy. Ranolazine: The intervention will be ranolazine therapy after the initial CPET. The initial CPET will identify patients with underlying ischemia and serve as a baseline study. Patients whose CPET results meet the criteria for ischemia will be started on Ranexa 500mg BID and advanced within one week +/-4 days to 1000mg BID. A second CPET will be performed after 4 weeks +/- 4 days of maximum therapy. CPET results before and after therapy will undergo a statistical comparison. The initial off treatment CPET measurement will serve as the control to assess changes found during therapy.
Measure Participants	14
Failed Initial CPET	5 35.7%
Withdrew Prior to CPET	2 14.3%
Screenfailed due to Ranolazine Intolerance	2 14.3%
Completed	5 35.7%

Adverse Events

Time Frame	30 days.
Arm/Group Title	CPET Control / CPET With Ranexa
Arm/Group Description	The initial CPET will identify patients with underlying ischemia and serve as a baseline study. Patients whose CPET results meet the criteria for ischemia will be started on Ranexa 500mg BID and advanced within one week +/-4 days to 1000mg BID. A second CPET will be performed after 4 weeks +/- 4 days of maximum therapy.
All Cause Mortality
	CPET Control / CPET With Ranexa
	Affected / at Risk (%)	# Events
Total	0/14 (0%)
Serious Adverse Events
	CPET Control / CPET With Ranexa
	Affected / at Risk (%)	# Events
Total	0/14 (0%)
Other (Not Including Serious) Adverse Events
	CPET Control / CPET With Ranexa
	Affected / at Risk (%)	# Events
Total	4/14 (28.6%)
Cardiac disorders
CAD (Ranexa 1000mg BID Treatment)	1/14 (7.1%)	1
General disorders
Ranexa Intolerant (Ranexa 1000mg BID Treatment)	2/14 (14.3%)	2
Headache (Ranexa 1000mg BID Treatment)	1/14 (7.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.