Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 4, Randomized, Double-Blind, Placebo-Controlled, Parallel Study of Ranolazine in Subjects With Chronic Stable Angina and Coronary Artery Disease With a History of Type 2 Diabetes Mellitus
Brief Summary: This study will evaluate the effect of ranolazine compared to placebo on the average weekly angina frequency in subjects with chronic stable angina and coronary artery disease (CAD) who have a history of type 2 diabetes mellitus (T2DM), and whether ranolazine can reduce the frequency of angina (chest pain) attacks, compared to a placebo. Subjects will be asked to record their daily angina episodes in a diary at the end of each study day. Ranolazine is approved for the treatment of chronic angina, and is not approved for the treatment of T2DM.


Options:
A: Inclusion Criteria:

* Written informed consent
* Males and females aged at least 18 years
* At least a 3-month history of chronic stable angina triggered by physical effort and relieved by rest and/or sublingual nitroglycerin
* CAD documented by one or more of the following:

  1. Angiographic evidence of ≥ 50% stenosis of one or more major coronary arteries
  2. History of myocardial infarction (MI) documented by positive myocardial muscle creatine kinase (CK-MB) enzymes, troponins, or electrocardiogram (ECG) changes
  3. Cardiac imaging study or exercise test diagnostic for CAD
* Treatment with up to 2 antianginal therapies at a stable dose for at least 2 weeks prior to the Qualifying Period.
* Documented history of T2DM
* Willing to maintain stable tobacco usage habits throughout the study
* Willing to maintain stable activity levels throughout the study
* Females of childbearing potential must agree to utilize highly effective contraception methods from Screening throughout the duration of study treatment and for 14 days following the last dose of study drug.

Exclusion Criteria:

* New York Heart Association (NYHA) Class III and IV
* Acute coronary syndrome in the prior 2 months or planned coronary revascularization during the study period
* Stroke or transient ischemic attack within 6 months prior to Screening
* QTc \> 500 milliseconds
* Uncontrolled hypertension (seated systolic blood pressure \> 180 mmHg or diastolic blood pressure \> 110 mmHg)
* Systolic blood pressure \< 100 mmHg
* Clinically significant hepatic impairment
* Prior treatment with ranolazine, or known hypersensitivity or intolerance to ranolazine
* Females who are breastfeeding
* Positive serum pregnancy test
* Participation in another investigational drug or device study within 1 month prior to Screening
* Current treatment with trimetazidine, ivabradine, or nicorandil. Subjects will need to discontinue these medications 2 weeks prior to the Qualifying Period.
* Current treatment with potent inhibitors of cytochrome (CYP)3A (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir)
* Current treatment with CYP3A and P glycoprotein (Pgp) inducers (eg, rifampicin/rifampin, carbamazepine, and St. John's wort \[Hypericum perforatum\])
* Current treatment with CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporine, tacrolimus, and sirolimus)
* Subjects taking simvastatin who cannot reduce the dose to 20 mg once daily or who cannot switch to another statin
* Current treatment with Class I or III antiarrhythmic medications
* History of illicit drug use or alcohol abuse within 1 year of Screening
* Any other conditions that, in the opinion of the investigator, are likely to prevent compliance with the study protocol or pose a safety concern if the subject participates in the study
B: Inclusion Criteria:

1. Written informed consent
2. Males and females aged 18 years and older
3. History of chronic angina defined as at least 2 episodes of anginal pain or discomfort in the chest, jaw, shoulder, back, neck, or arm that is precipitated by exertion or emotional stress, and relieved by rest or sublingual nitroglycerin, which occurred on at least 2 separate days and at least 14 days prior to PCI (in the case of staged PCI procedures, at least 14 days prior to the first PCI in the series). Participants may or may not have additional angina episodes within the 14 days prior to their first PCI in the series, as well as any time prior to Randomization.
4. PCI for any indication (ACS or non-ACS). For the purposes of stratification at randomization, ACS will be defined as hospitalization for anginal pain or discomfort within the previous 24 hours to their hospitalization with any one (or more) of the following criteria:

   i. Elevated troponin or creatinine kinase-MB (CK-MB) consistent with myocardial infarction (MI), as reported by local laboratory and measured prior to index PCI ii. Electrocardiographic changes (including transient changes) comprising new or presumably new ST segment depression ≥ 0.1 mV (≥ 1 mm), or ST segment elevation ≥ 0.1 mV (≥ 1 mm) in at least 2 contiguous leads, or new or presumably new Left Bundle Branch Block
5. Randomization within 14 days post-PCI. In the case of staged PCI procedures, randomization has to occur within 14 days of the last PCI in the series. Participants may be randomized starting on the day of PCI and anytime during the following 14 days. PCI is defined as an attempt to cross the lesion with a wire with the intention of performing revascularization.
6. Post-PCI (post the last PCI for staged procedures) evidence of incomplete revascularization defined as the presence of one or more visually estimated ≥ 50% stenoses in one or more coronary arteries with reference vessel diameter of at least 2.0 mm, whether in the target vessel or in a non-target vessel regardless of the presence or absence of coronary collaterals. In the case of a participant post-coronary artery bypass grafting (CABG), incomplete revascularization is defined as the presence of one or more visually estimated ≥ 50% stenoses in an unbypassed epicardial vessel with a reference diameter of ≥ 2.0 mm, or one or more visually estimated ≥ 50% stenoses in a bypass graft supplying an otherwise unrevascularized myocardial territory.
7. Clinically stable post-PCI. Participants randomized in-hospital on day of planned discharge or in clinic are considered stable. Participants randomized in-hospital prior to day of planned discharge must meet all of the following criteria:

   i. CK-MB \< 3 times the upper limit of normal (ULN) at least 3 hours post-PCI, or if ≥ 3 times the ULN with evidence of decreasing CK-MB (decreased by at least 20% from the prior measurement) as reported by local laboratory. If CK-MB is not available, a participant must have evidence of normal or decreasing troponin levels (by at least 20% from the prior measurement) at least 3 hours post-PCI, as reported by local laboratory.

   ii. Systolic blood pressure ≥ 90 mm Hg and not receiving pressors or inotropes iii. No current requirement for an intra-aortic balloon pump (IABP) or any left ventricular assist device iv. No current requirement for intravenous (IV) nitroglycerin
8. Ability and willingness to comply with all study procedures during the course of the study
9. Females of childbearing potential must have a negative pregnancy test at Screening (unless surgically sterile or post-menopausal) and must agree to use highly effective contraception methods from Screening throughout the duration of study treatment and for 14 days following the last dose of study drug.

Exclusion Criteria:

1. Any future planned revascularization (including staged procedures) or possible planned revascularization (ie, planned stress test to assess the imminent need for additional revascularization). Future planned stress tests for purposes of monitoring are permitted but strongly discouraged. Participants may be enrolled after the last PCI in the staged series or once a decision is made not to perform a follow up PCI, as long as Randomization occurs within 14 days from the last PCI. If a participant has had a stress test post-PCI and prior to Randomization and no further intervention is planned, the participant may be enrolled within 14 days from the last PCI.
2. Unrevascularized left main coronary artery stenosis ≥ 50%. Participants with a history of CABG to the left coronary system will be considered to have a revascularized left main if at least one graft is patent.
3. Major complication during or after the index PCI (in the case of staged PCI, the last in the series) including:

   i. Major bleeding (TIMI Bleeding classification or any bleeding requiring blood transfusion of ≥ 2 units of red blood cells) ii. Coronary perforation requiring treatment iii. Procedural complication requiring surgery (including CABG or peripheral vascular surgery)
4. Stroke within 90 days prior to Randomization, or any history of stroke with permanent major neurologic disability (eg, aphasia or significant motor dysfunction)
5. Cardiogenic shock within 90 days prior to Randomization (transient decreases in blood pressure without clinical sequelae are not considered to be cardiogenic shock)
6. New York Heart Association (NYHA) Class III or IV heart failure
7. Severe renal insufficiency as assessed by an estimated glomerular filtration rate \< 30 mL/min/1.73m2 using the 4 variable modification of diet in renal disease (MDRD) equation per local laboratory (based on the last available measurement prior to Randomization, collected within 1 month prior to the index PCI \[in the case of staged PCI, the last in the series\])
8. Liver cirrhosis
9. Use of Class Ia, Ic, or Class III antiarrhythmics, except for amiodarone
10. Current treatment with strong inhibitors of CYP3A
11. Current treatment with CYP3A4 inducers or P-gp inducers
12. Participants taking \> 20 mg simvastatin daily or \> 40 mg lovastatin daily who cannot reduce the dose to 20 mg once daily for simvastatin or 40 mg once daily for lovastatin, or who cannot switch to another statin
13. Participants taking greater than a total of 1000 mg daily of metformin who cannot reduce the dose to a maximum total of 1000 mg daily (additional anti-diabetic medications may be added as clinically indicated to allow participants to decrease their metformin dose and maintain glycemic control)
14. Previous treatment with ranolazine for \> 7 consecutive days within 30 days prior to Randomization, or known hypersensitivity or intolerance to ranolazine or to any of the excipients
15. Participation in another investigational drug or investigational device study within 30 days prior to Randomization (participation in registries is allowed)
16. Women who are pregnant or breast feeding
17. Non-coronary artery disease comorbid conditions (eg, advanced malignancy, severe aortic stenosis) which are likely to result in death within 2 years of Randomization
18. Any condition that in the opinion of the investigator would preclude compliance with the study protocol
C: Inclusion Criteria:

* Hospitalized with non-ST elevation acute coronary syndrome
* Ischemic symptoms (more than or equal to 5 minutes) at rest within 48 hours of study entry
* At least one additional risk factor (e.g., elevated cardiac enzymes, ST-depression, diabetes)

Exclusion Criteria:

* Persistent acute ST-segment elevation
* Successful revascularization during the qualifying hospitalization, prior to study entry
* Acute pulmonary edema, hypotension, or evidence of cardiogenic shock
* Clinically significant liver disease
* End stage kidney disease requiring dialysis
* Concomitant use of drugs known to prolong the QT interval, or any digitalis drugs
* Use at study entry of drugs that are strong inhibitors of cytochrome P450 3A4
* Pregnant or lactating women, or women of child bearing potential not using an acceptable form of birth control

Additional study entry criteria will be evaluated during initial screening.
D: Inclusion Criteria:

1. Women with signs and symptoms of myocardial ischemia (chest pain, abnormal stress testing, abnormal noninvasive testing) in the absence of obstructive coronary artery disease (epicardial coronary stenosis \<50% luminal diameter stenosis).
2. Women with ≥10% myocardial ischemia by CMR perfusion.

Exclusion Criteria:

1. Contraindications to withholding nitrates, beta-blockers, calcium channel agents, ACE/ARB agents for 48 hours prior to testing.
2. Contraindications in CMR including AICD, pacemaker, untreatable claustrophobia or known angio-edema.
3. Contraindications to ranolazine including hepatic insufficiency, prolonged QT, renal failure.
4. Women taking drugs that inhibit CYP3A such as diltiazem, verapamil, ketoconazole, macrolides or HIV protease inhibitors.
5. Women less than 18 years of age.
6. Women on drugs that prolong the QT interval such as Class Ia or III antiarrhythmic agents, erythromycin, certain antipsychotics.
7. Pregnancy or breast feeding.
8. Life expectancy less than 6 months.

Answer: A