Ranolazine for Incomplete Vessel Revascularization Post-Percutaneous Coronary Intervention (PCI) (RIVER-PCI)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT01442038
First received: September 22, 2011
Last updated: June 6, 2016
Last verified: June 2016
  Purpose
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.

Condition Intervention Phase
Coronary Artery Disease
Angina Pectoris
Drug: Ranolazine
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Effects of Ranolazine on Major Adverse Cardiovascular Events in Subjects With a History of Chronic Angina Who Undergo Percutaneous Coronary Intervention With Incomplete Revascularization

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • Kaplan-Meier Estimates for Time From Randomization to First Occurrence of Ischemia-driven Revascularization or Ischemia-driven Hospitalization Without Revascularization [ Time Frame: Baseline through end of study (average 90 weeks) ] [ Designated as safety issue: No ]
    Time to event distributions were estimated by the Kaplan-Meier (KM) method. 1 month = 28 days; 1 calendar year = 365 days.


Secondary Outcome Measures:
  • Kaplan-Meier Estimates for Time From Randomization to Sudden Cardiac Death [ Time Frame: Baseline through end of study (average 90 weeks) ] [ Designated as safety issue: No ]
    Time to event distributions were estimated by the Kaplan-Meier method. 1 month = 28 days; 1 calendar year = 365 days.

  • Kaplan-Meier Estimates for Time From Randomization to Cardiovascular Death [ Time Frame: Baseline through end of study (average 90 weeks) ] [ Designated as safety issue: No ]
    Time to event distributions were estimated by the Kaplan-Meier method. 1 month = 28 days; 1 calendar year = 365 days.

  • Kaplan-Meier Estimates for Time From Randomization to Myocardial Infarction [ Time Frame: Baseline through end of study (average 90 weeks) ] [ Designated as safety issue: No ]
    Time to event distributions were estimated by the Kaplan-Meier method. 1 month = 28 days; 1 calendar year = 365 days.


Enrollment: 2651
Study Start Date: October 2011
Study Completion Date: February 2015
Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ranolazine Drug: Ranolazine

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.

Other Name: Ranexa
Placebo Comparator: Placebo Drug: Placebo

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.


  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01442038

  Show 218 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Brian McNabb, MD Gilead Sciences
  More Information

Publications:
Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT01442038     History of Changes
Other Study ID Numbers: GS-US-259-0116  2011-002507-15 
Study First Received: September 22, 2011
Results First Received: February 9, 2016
Last Updated: June 6, 2016
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
Austria: Agency for Health and Food Safety
Belgium: Federal Agency for Medicinal Products and Health Products
Czech Republic: Ethics Committee
Czech Republic: State Institute for Drug Control
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Israel: Ministry of Health
Italy: The Italian Medicines Agency
Netherlands: Medicines Evaluation Board (MEB)
Poland: Ethics Committee
Russia: Ministry of Health of the Russian Federation
Poland: The Central Register of Clinical Trials
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
Sweden: Regional Ethical Review Board
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee

Additional relevant MeSH terms:
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Angina Pectoris
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Chest Pain
Pain
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Ranolazine
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 22, 2016