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

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.

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.