Effect of Ranolazine on Myocardial Perfusion Assessed by Serial Quantitative Exercise SPECT Imaging

A Phase 4, Randomized, Double-Blind, Placebo-Controlled, Cross-over Trial to Evaluate the Effects of Ranolazine on Myocardial Perfusion Assessed by Serial Quantitative Exercise SPECT Imaging

This study enrolled participants with documented exercise-induced myocardial ischemia in order to evaluate whether ranolazine, when taken prior to exercise, can improve blood flow to the heart (myocardial perfusion), as assessed by exercise-induced myocardial perfusion defect size (PDS) and total perfusion deficit (TPD), using gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI).

This was a 2-period crossover study. The last dose of each period must have been taken 3-4 hours prior to conduct of the exercise SPECT MPI. After the research exercise SPECT MPI was performed at the end of Period 1, participants discontinued the treatment they were randomized to for that period and began the other treatment in Period 2.

Study Overview

• Status: Completed
• Conditions: Myocardial Ischemia; Myocardial Perfusion Imaging
• Intervention / Treatment: Drug: Ranolazine; Drug: Placebo to match ranolazine; Procedure: SPECT MPI; Behavioral: Exercise

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4W7
      • University of Ottawa Heart Institute
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7P2
      • ECOGENE-21 Clinical Trial Center, Chicoutimi Hospital
    • Montreal, Quebec, Canada, H1T 1C8
      • Montreal Heart Institute
    • Montreal, Quebec, Canada, H2W 1T8
      • CHUM Hôtel Dieu
• Czech Republic
  • Praha 10, Czech Republic, 100 34
    • University Hospital Kralovske Vinohrady
  • Praha 5, Czech Republic, 150 06
    • University Hospital Motol
• Finland
  • Turku, Finland, 20520
    • Turku University Hospital
• Israel
  • Ashkelon, Israel, 78278
    • Barzilai Medical Center
  • Beer Sheva, Israel, 84101
    • Soroka Medical Center
  • Haifa, Israel, 31096
    • Rambam Health Care Campus
  • Rehovot, Israel, 76100
    • Kaplan Medical Center
  • Tel Aviv, Israel, 69710
    • Assuta MC
• Italy
  • Naples, Italy, 80131
    • Federico II University
  • Naples, Italy, 80131
    • "Federico II" University
• Singapore
  • Singapore, Singapore, 119228
    • National University Health System
  • Singapore, Singapore, 168752
    • National Heart Centre Singapore
• United Kingdom
  • Middlesex, United Kingdom, HA1 3UJ
    • Northwick Park Hospital, Watford Road
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Imperial, California, United States, 92251
      • Imperial Cardiac Center
    • Lincoln, California, United States, 95648
      • Clinical Trials Research
    • Mission Viejo, California, United States, 92691
      • Mission Internal Medical Group
    • Salinas, California, United States, 93901
      • Central Coast Cardiology
  • Delaware
    • Newark, Delaware, United States, 19713
      • Alfieri Cardiology
  • Florida
    • Jacksonville, Florida, United States, 32216
      • St. Luke's Cardiology Associates
    • Miami, Florida, United States, 33173
      • Cardiovascular Research Center of South Florida
    • Orlando, Florida, United States, 32806
      • Research One
    • Wellington, Florida, United States, 33449
      • Cardiology Partners Clinical Research Institute
  • Illinois
    • Aurora, Illinois, United States, 60504
      • Fox Valley Clinical Research Center, LLC
  • Kentucky
    • Owensboro, Kentucky, United States, 42303
      • Research Integrity, LLC
  • Louisiana
    • Covington, Louisiana, United States, 70403
      • Louisiana Heart Center
    • Slidell, Louisiana, United States, 70458
      • Louisiana Heart Center
  • Maine
    • Auburn, Maine, United States, 04210
      • Androscroggin Cardiology Associates DBA Maine Research Associates
  • Maryland
    • Salisbury, Maryland, United States, 21804
      • Delmarva Heart Research Foundation, Inc
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Cardiovascular Imaging Technologies
  • New York
    • Massapequa, New York, United States, 11758
      • Dr. Michael Sacher
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Pennsylvania
    • Camp Hill, Pennsylvania, United States, 17011
      • Heritage Cardiology
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center Cardiovascular Institute
  • Tennessee
    • Jackson, Tennessee, United States, 38305
      • Kore Cardiovascular Research
  • Texas
    • Houston, Texas, United States, 77002
      • East Texas Cardiology PA
    • San Antonio, Texas, United States, 78229
      • Mercury Medical, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Exercise SPECT MPI study (stress and rest) showing at least 10% reversible myocardial ischemia (as confirmed by the core nuclear laboratory using Corridor4DM imaging software) performed not more than 12 weeks prior to screening, OR
• Exercise SPECT MPI study (stress and rest) conducted during screening (after consultation with the Medical Monitor and after informed consent was obtained) showing at least 10% reversible myocardial ischemia (as confirmed by the core nuclear laboratory)
• Stable antianginal medical therapy (excluding short-acting nitroglycerin)

Key Exclusion Criteria:

• Left bundle branch block
• Automated implantable defibrillator and/or pacemaker (selected subjects with permanent pacemakers who had an intact sinus mechanism may have been included following consultation with the Medical Monitor)
• Intervening coronary revascularization between the time of qualifying exercise SPECT MPI study and randomization
• Acute myocardial infarction (MI) within 60 days prior to screening or at any time after the qualifying exercise SPECT MPI study, or MI undergoing staged intervention during a subject's participation in the trial
• Unstable angina within 30 days prior to screening, or at any time after the qualifying exercise SPECT MPI study
• Coronary artery bypass graft surgery within 60 days prior to screening or at any time after the qualifying exercise SPECT MPI study, or percutaneous coronary intervention within 30 days prior to screening or at any time after the qualifying exercise SPECT MPI study
• Anticipated coronary revascularization during the trial period
• Cerebrovascular attack or transient ischemic attack within 90 days prior to screening
• History of serious arrhythmias
• Current atrial fibrillation or atrial flutter
• QTc interval > 500 milliseconds
• Diagnosed as having New York Heart Association Class III or IV heart failure
• Inability to exercise or exercise limitation due to other comorbidities that may have interfered with ability to perform required exercise SPECT MPI study
• Body mass index greater than or equal to 38 kg/m^2 (may have been up to 40 kg/m^2 after consultation with the Medical Monitor)
• Any absolute contraindications to exercise stress testing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ranolazine/Placebo; Participants received ranolazine from Day 1 through Day 15 (± 2 days) of Period 1, followed by an exercise SPECT MPI study, then received placebo to match ranolazine from Day 1 through Day 15 (± 2 days) of Period 2, followed by an exercise SPECT MPI study.	Drug: Ranolazine; One 500 mg tablet in the evening on Day 1 of the period; One 500 mg tablet, twice daily on Days 2-3 of the period; Two 500 mg tablets (1000 mg total), twice daily from Day 4 to the end of the period (Day 15 ± 2 days); Other Names: Ranexa®; Drug: Placebo to match ranolazine; Placebo to match ranolazine administered in the same form and frequency as the active drug.; Procedure: SPECT MPI; Gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) to confirm the presence of reversible exercise-induced left ventricular perfusion defect size (PDS) performed within 12 weeks prior to baseline or at the baseline visit, and at the end-of-period 1 and end-of-period 2 visits.; Behavioral: Exercise; Treadmill stress test
EXPERIMENTAL: Placebo/Ranolazine; Participants received placebo to match ranolazine from Day 1 through Day 15 (± 2 days) of Period 1, followed by an exercise SPECT MPI study, then received ranolazine from Day 1 through Day 15 (± 2 days) of Period 2, followed by an exercise SPECT MPI study.	Drug: Ranolazine; One 500 mg tablet in the evening on Day 1 of the period; One 500 mg tablet, twice daily on Days 2-3 of the period; Two 500 mg tablets (1000 mg total), twice daily from Day 4 to the end of the period (Day 15 ± 2 days); Other Names: Ranexa®; Drug: Placebo to match ranolazine; Placebo to match ranolazine administered in the same form and frequency as the active drug.; Procedure: SPECT MPI; Gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) to confirm the presence of reversible exercise-induced left ventricular perfusion defect size (PDS) performed within 12 weeks prior to baseline or at the baseline visit, and at the end-of-period 1 and end-of-period 2 visits.; Behavioral: Exercise; Treadmill stress test

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exercise-induced Perfusion Defect Size (PDS) Following Ranolazine and Placebo Treatment	PDS is the amount (percent) of the myocardium with decreased blood flow. A lower percentage means more of the myocardium is receiving blood flow. Measurements were obtained by gated single photon emission computed tomography (SPECT) imaging following exercise at the end of the ranolazine and placebo treatment periods.	Up to 33 days
Exercise-induced Total Perfusion Deficit (TPD) Following Ranolazine and Placebo Treatment	TPD is a score that measures the overall impact of a region of decreased myocardial blood flow, incorporating both the amount and severity of the decreased flow. TPD is measured on a scale of 0-100, with higher scores being worse and lower scores being better. Measurements were obtained by SPECT imaging following exercise at the end of the ranolazine and placebo treatment periods.	Up to 33 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perfusion Defect Severity at Baseline, End of Period 1, and End of Period 2	Perfusion defect severity was assessed for each participant as the percentage of the 17 myocardium segments with a relative perfusion defect score of 3 or 4 on a 0-4 scale. Segment scores are: 0 = normal perfusion; 1 = mild reduction in counts-not definitely abnormal; 2 = moderate reduction in counts-definitely abnormal; 3 = severe reduction in counts; 4 = absent uptake (lower scores correspond to less severity and higher scores correspond to increased severity). A lower percentage means fewer segments have severely reduced blood flow. Measurements were obtained by SPECT imaging following exercise at baseline and at the end of Periods 1 and 2.	Up to 33 days
Exercise-induced Reversible Perfusion Defect Size (PDS) at Baseline, End of Period 1, and End of Period 2	Exercise-induced reversible PDS was derived as the exercise PDS at baseline and at the end of Periods 1 and 2 minus the resting PDS at baseline. A lower percentage means more of the myocardium is receiving blood flow. Measurements were obtained by SPECT imaging at baseline both at rest and following exercise and following exercise at the end of Periods 1 and 2.	Up to 33 days
Exercise-induced Reversible Total Perfusion Deficit (TPD) at Baseline, End of Period 1, and End of Period 2	Exercise-induced reversible TPD was derived as the exercise TPD at baseline and at the end of Periods 1 and 2 minus the resting TPD at baseline. TPD is measured on a scale of 0-100, with higher scores being worse and lower scores being better. Measurements were obtained by SPECT imaging at baseline both at rest and following exercise and following exercise at the end of Periods 1 and 2.	Up to 33 days

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (ACTUAL): September 1, 2012
• Study Completion (ACTUAL): September 1, 2012

Study Registration Dates

• First Submitted: October 13, 2010
• First Submitted That Met QC Criteria: October 13, 2010
• First Posted (ESTIMATE): October 14, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): September 3, 2014
• Last Update Submitted That Met QC Criteria: August 21, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: SPECT MPI
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Ischemia; Ischemia; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Sodium Channel Blockers; Ranolazine
• Other Study ID Numbers: GS-US-259-0103