Ranolazine for Incomplete Vessel Revascularization Post-Percutaneous Coronary Intervention (PCI)
Condition: Coronary Artery Disease; Angina Pectoris
MeSH terms: Coronary Artery Disease; Angina Pectoris
Intervention: Ranolazine; Placebo
Intervention description: Subjects will receive ranolazine 500 milligrams (mg) twice daily for 7 days, followed by 1000 mg administered orally twice daily for the duration of the study.
Subjects receiving a moderate CYP3A4 inhibitor will receive ranolazine 500 mg or placebo administered orally twice a day for the duration of the concomitant therapy.; Subjects will receive one tablet of matching placebo twice daily for 7 days, followed by two tablets of matching placebo twice daily for the duration of the study.
Subjects receiving a moderate CYP3A4 inhibitor will receive ranolazine 500 mg or placebo administered orally twice a day for the duration of the concomitant therapy.
Intervention MeSH terms: Ranolazine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 2651.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study will evaluate the efficacy of ranolazine as compared with placebo when used as
      part of standard medical therapy in chronic angina subjects with incomplete revascularization
      post-percutaneous coronary intervention (PCI; formerly known as angioplasty with stent) on
      the composite of ischemia-driven revascularization or ischemia-driven hospitalization without
      revascularization.
    

Eligibility criteria:

        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