Treatment With Ranolazine in Microvascular Coronary Dysfunction (MCD): Impact on Angina Myocardial Ischemia (RWISE)

Study Description

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Brief Summary:

This research study is designed to test the use of ranolazine in patients with angina (chest discomfort due to reduced blood supply to the heart) due to microvascular coronary dysfunction (MCD; abnormalities in the small blood vessels of the heart). This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. The FDA has approved this drug based on studies primarily on patients with chronic angina with major blockages of the arteries.

Condition or disease	Intervention/treatment	Phase
Microvascular Coronary Dysfunction (MCD)	Drug: Ranolazine; Drug: Placebo	Not Applicable

Detailed Description:

This is a randomized, double-blinded, placebo- controlled, and cross-over clinical trial. 147 subjects will be enrolled at two clinical sites, with projected 9-10% dropout and anticipated 134 completed subjects. To maintain blinding of the investigators, the study randomization table will be kept in Pharmacy Service. The sponsor will ship the study drug directly to the Pharmacy Service. The pharmacy service will also be responsible for dispersing the study drug.

There are 4 study visits (2 visits in each study period) in this study. Subjects will be in this study for about 6 weeks from Week 0 - baseline visit to Week 6 - exit visit. Besides the procedure of study medication mentioned above, other study procedures include informed consent, physical exam, questionnaires, EKG for safety assessment, blood collection for laboratory testing, cardiac MRI, and follow-up events. In sum, participants will be asked to undergo 2 cardiac MRI's and fill out questionnaires 4 times. They will be asked to participate for 6 weeks with two 2-week courses (with a treatment window period of 5 days), one with ranolazine and the other with placebo (without knowing which they are taking). There is a 2-week washout period between treatments. The participants will otherwise remain on all their usual medications. The physicians will also be blinded to which medication the subject is receiving.

Participation in this study will be approximately 6 weeks, which consists of two 2-week study periods and in between a 2-week washout period:

1. During the first 2-week period: Subjects will be randomized to first receive either the ranolazine or a placebo pill (sugar pill with no active medicine). Subjects will take the extended-release ranolazine or a placebo pill for a total of 2 weeks. Subjects will take 500 mg twice daily for the first 1 week and then 1000 mg twice daily for an additional 1 week. Subjects who are unable to take the higher dose due to side effects will remain on 500 mg twice daily for the entire study period. After the 2 weeks, the participant will have a Cardiac MRI and complete study questionnaires. These tools will allow us to evaluate if the participant is doing better on the medication.
2. 2-week washout period: Subject will then be asked to go 2 weeks without any study medication (ranolazine or placebo).
3. During the second 2-week period: Subject will then be given either extended release ranolazine or placebo depending on which was received the first time for a total of 2 weeks. Subjects will take 500 mg twice daily for the first 1 week and then 1000 mg twice daily for an additional 1 week. Subjects who are unable to take the higher dose due to side effects will remain on 500 mg twice daily for entire study period. This 2-week period will again be followed by a final Cardiac MRI and questionnaire completion.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	142 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	Treatment With Ranolazine in Microvascular Coronary Dysfunction (MCD): Impact on Angina Myocardial Ischemia
Actual Study Start Date :	May 2011
Actual Primary Completion Date :	December 2016
Actual Study Completion Date :	December 2016

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Ranolazine; 147 subjects, with projected 9-10% dropout and anticipated 134 completed subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing.	Drug: Ranolazine; This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. 500-1,000 mg po bid for 2 weeks; Other Name: Ranexa
Placebo Comparator: Placebo; 147 subjects, with projected 9-10% dropout and anticipated 134 completed subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing.	Drug: Placebo; 500-1,000 mg po bid for 2 weeks

Outcome Measures

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Primary Outcome Measures :

1. Seattle Angina Questionnaire (SAQ) [ Time Frame: 2 weeks (first intervention) and 6 weeks (second intervention) ]

   Questionnaires will be completed (SAQ - Seattle Angina Questionnaire) at the end of each treatment period.

   The Seattle Angina Questionnaire (SAQ) is a self-administered, 19-item questionnaire, a cardiac disease-related quality-of-life measure. The SAQ is well validated and sensitive to clinical changes. It has five subscales: physical limitation, angina stability, angina frequency, treatment satisfaction, and quality of life. The possible range of scores for each of the five subscales is 0 to 100, with higher scores indicating better quality of life. A change of 10 points in any of the subscales is considered to be clinically important.

Secondary Outcome Measures :

1. Cardiac Magnetic Resonance (CMRs) [ Time Frame: 2 weeks (first intervention) and 6 weeks (second intervention) ]

   Cardiac Magnetic Resonance (CMRs) (CMR 1 and CMR 2) end of the 2nd week of treatment 1 and treatment 2 respectively, 4 hours after the morning dose of study drug was performed to measure myocardial perfusion reserve index.

   Myocardial perfusion reserve index (MPRI) was assessed using the first-pass perfusion intensity curves during stress and rest cardiac magnetic resonance imaging. First-pass perfusion images were analysed using CAAS MRV CMRI analysis software Version 3.3 (Pie Medical Imaging B.V., Maastricht, the Netherlands). Global MPRI was calculated as the ratio of stress/rest relative perfusion upslope, corrected for LV cavity upslope.

   Higher MPRI represents better myocardial perfusion reserve. Since MPRI is an index, there is no unit.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Men or women age >18 from diverse racial/ethnic groups;
2. Competent to give informed consent;
3. Patients with chronic angina or its equivalent;
4. Coronary angiogram revealing MCD with no obstructive CAD (epicardial coronary stenosis <50% luminal diameter stenosis);
5. Left ventricular ejection fraction > or = 45%;
6. Objective evidence of ischemia by noninvasive methods such as exercise stress test, stress Echo, MRI, or SPECT;
7. Patients with 10% myocardial ischemia by Cardiac magnetic resonance imaging (CMRI) myocardial perfusion reserve index ≤ 2.0 or abnormal coronary reactivity testing (CFR < 2.5, or ACH response of no dilation or constriction, determined by local site read).

Exclusion Criteria:

1. Acute coronary syndrome (defined by WHO), cardiogenic shock or requiring inotropic or intra-aortic balloon support;
2. Planned percutaneous coronary intervention or CABG or established obstructive CAD with ischemia eligible for revascularization, acute MI;
3. Prior non-cardiac illness with an estimated life expectancy <4 years;
4. Unable to give informed consent;
5. Allergy or contra-indication to CMRI testing, including renal failure, claustrophobia, and asthma, uncontrolled moderate hypertension (sitting blood pressure >160/95mmHg with measurements recorded on at least 2 occasions), conditions likely to influence outcomes: Severe lung, creatinine >1.8 or CrCl ≤ 50ml/min) or hepatic disease;
6. Surgically uncorrected significant congenital or valvular heart disease and other disease likely to be fatal or require frequent hospitalization within the next six months;
7. Adherence or retention reasons;
8. Unwilling to complete follow-up evaluation including repeat testing, documented obstructive hypertrophic cardiomyopathy;
9. Aortic stenosis (valve area <1.5cm);
10. LV dysfunction (ejection fraction ≤35%);
11. History of significant cocaine or amphetamine abuse;
12. Taking potent CYP3A4 inhibitors (ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir);
13. Women who are pregnant.

Contacts and Locations

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Locations

United States, California
127 S. San Vicente Blvd, Suite A9303
Los Angeles, California, United States, 90048
United States, Florida
University of Florida
Gainesville, Florida, United States, 32610

Sponsors and Collaborators

Cedars-Sinai Medical Center

University of Florida

Investigators

Principal Investigator:	C. Noel Bairey Merz, MD	Cedars-Sinai Medical Center

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Birkeland K, Khandwalla RM, Kedan I, Shufelt CL, Mehta PK, Minissian MB, Wei J, Handberg EM, Thomson LE, Berman DS, Petersen JW, Anderson RD, Cook-Wiens G, Pepine CJ, Bairey Merz CN. Daily Activity Measured With Wearable Technology as a Novel Measurement of Treatment Effect in Patients With Coronary Microvascular Dysfunction: Substudy of a Randomized Controlled Crossover Trial. JMIR Res Protoc. 2017 Dec 20;6(12):e255. doi: 10.2196/resprot.8057.

Bairey Merz CN, Handberg EM, Shufelt CL, Mehta PK, Minissian MB, Wei J, Thomson LE, Berman DS, Shaw LJ, Petersen JW, Brown GH, Anderson RD, Shuster JJ, Cook-Wiens G, Rogatko A, Pepine CJ. A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. Eur Heart J. 2016 May 14;37(19):1504-13. doi: 10.1093/eurheartj/ehv647. Epub 2015 Nov 27.

Responsible Party:	Noel Bairey Merz, Director, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier:	NCT01342029 History of Changes
Other Study ID Numbers:	IN-US-259-0124 - RWISE
First Posted:	April 26, 2011
Results First Posted:	December 12, 2017
Last Update Posted:	January 19, 2018
Last Verified:	December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes

Keywords provided by Noel Bairey Merz, Cedars-Sinai Medical Center:

Microvascular Coronary Dysfunction (MCD)

Additional relevant MeSH terms:

Ischemia; Myocardial Ischemia; Coronary Artery Disease; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases	Coronary Disease; Arteriosclerosis; Arterial Occlusive Diseases; Ranolazine; Sodium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action