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Microvascular Coronary Disease In Women: Impact Of Ranolazine

Sponsor
Cedars-Sinai Medical Center (Other)
Overall Status
Completed
CT.gov ID
NCT00570089
Collaborator
CV Therapeutics (Industry)
20
Enrollment
1
Location
2
Arms
32
Duration (Months)
0.6
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

  1. To evaluate the impact of ranolazine extended-release tablets in women with subendocardial ischemia due to microvascular endothelial dysfunction on myocardial ischemia (Cardiac Magnetic Resonance (CMR) extent, severity.

  2. To evaluate the impact of ranolazine extended-release tablets in women with subendocardial ischemia due to microvascular endothelial dysfunction on the outcomes of angina (Seattle Angina Questionnaire (SAQ), WISE angina frequency, Duke Activity Status Inventory(DASI) and SF-36).

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Interested women will be considered for the study if they meet inclusion and exclusion criteria including review of baseline CMR, ECG and blood work (liver and kidney function). The baseline CMR must be completed within 12 months previous to enrollment.

Eligible women with angina and CMR subendocardial perfusion abnormalities, defined as CMR qualitative perfusion abnormalities of greater than or equal to 10% reported as abnormal following blind review per protocol, will be consented and enrolled. The women will complete baseline demographic and health history questionnaires, including the SAQ, Women's Ischemic Syndrome Evaluation (WISE) angina frequency, DASI and SF-36.

This study is a double-blind, placebo controlled, cross-over design in which treatment order to ranolazine and placebo will be randomly assigned. Note: The participant's usual medication regimen will be continued throughout study participation. Following enrollment into the study, participants will be randomized to treatment #1 (either placebo or ranolazine). Ranolazine will be dosed as 500 mg orally twice daily for 2 weeks and, assuming tolerance, followed by 1000 mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500 mg twice daily for the second 2 week interval. The first end of treatment CMR (CMR 1) will be scheduled at the end of the 4th week of treatment, approximately 4 hours after the morning dose of study drug. At this visit (Vis 2), concurrent medications, symptoms, and adverse events will be reviewed. Clinical measurements will be taken (weight, BP, waist and hip circumference) and questionnaires will be completed (SAQ, WISE angina frequency, DASI and SF-36).

After the first course of study treatment, the patient will undergo a two week wash-out with no study drug while continuing usual medication regimen. Following the washout period, study participants will start the second cycle of study drug treatment (i.e., the other study drug not received in treatment 1). At visit 3, participants will undergo baseline 2 measurements which include concurrent medication and symptom assessment, clinical measurements (weight, BP, waist and hip circumference) and will complete baseline 2 questionnaires (SAQ, WISE angina frequency, DASI and SF-36). Study drug treatment #2 will follow the same escalation of study drug dose as described above for treatment 1. The final study CMR (CMR 2) will be scheduled at the end of the 4th week of treatment 2, approximately 4 hours after the morning dose of study drug. At this visit (Vis 4), concurrent medications, symptoms, and adverse events will be reviewed. Clinical measurements will be taken (weight, blood pressure, waist and hip circumference) and questionnaires will be completed (SAQ, WISE angina frequency, DASI and SF-36). [See Table 1 for a listing of all study procedures by visit.] The two post study drug treatment CMRs will be performed at the same time of day, replicating temperature, fasting state, adenosine dosing and infusion, magnet settings and using the same over-reader. The dose of adenosine will be consistent for all study CMR tests: 140 mcg/kg over 5 minutes.

Study Design

Study Type:
Interventional
Actual Enrollment :
20 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
Microvascular Coronary Disease In Women: Impact Of Ranolazine
Study Start Date :
Apr 1, 2007
Actual Primary Completion Date :
Dec 1, 2009
Actual Study Completion Date :
Dec 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Experimental: Study Drug Ranexa, Then Placebo

Participants first received study drug Ranexa, 500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval. After a washout period of 2 weeks, they then received Placebo tablet (matching Ranexa tablet).

Drug: Ranolazine
500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.
Other Names:
  • Ranexa

    • Drug: Placebo
    Placebo, 500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.
    Experimental: Placebo, Then Study Drug Ranexa(Ranolazine)

    Participants first received Placebo tablet (matching Ranexa tablet) for two weeks. After washout period of 2 weeks, they then received Ranexa 500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.

    Drug: Ranolazine
    500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.
    Other Names:
  • Ranexa

    • Drug: Placebo
    Placebo, 500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.

    Outcome Measures

    Primary Outcome Measures

    1. Cardiac Magnetic Resonance (CMRs) [4 weeks and 10 weeks]

      Cardiac Magnetic Resonance (CMRs) (CMR 1 and CMR 2) end of the 4th week of treatment 1 and treatment 2 respectively, 4 hours after the morning dose of study drug was performed to measure myocardial perfusion defect in percentage.

    Secondary Outcome Measures

    1. Seattle Angina Questionnaire (SAQ) [4 weeks and 10 weeks]

      Questionnaires will be completed (SAQ - Seattle Angina Questionnaire) at the end of each treatment period. The Seattle Angina Questionnaire (SAQ) is a self-administered, 19-item questionnaire, a cardiac disease-related quality-of-life measure. The SAQ is well validated and sensitive to clinical changes. It has five subscales: physical limitation, angina stability, angina frequency, treatment satisfaction, and disease perception. The possible range of scores for each of the five subscales is 0 to 100, with higher scores indicating better quality of life. A change of 10 points in any of the subscales is considered to be clinically important. Each final SAQ domain ranges from 0-100, where higher is a better outcome score. Subscales are not combined. Median, SD and range are calculated for each domain.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 AHSP Los Angeles California United States 90048

    Sponsors and Collaborators

    • Cedars-Sinai Medical Center
    • CV Therapeutics

    Investigators

    • Principal Investigator: Noel Bairey-Merz, MD, Cedars-Sinai Medical Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Noel Bairey Merz, Director, Cedars-Sinai Medical Center
    ClinicalTrials.gov Identifier:
    NCT00570089
    Other Study ID Numbers:
    • IRB 10465
    First Posted:
    Dec 10, 2007
    Last Update Posted:
    Jun 10, 2019
    Last Verified:
    Jun 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by Noel Bairey Merz, Director, Cedars-Sinai Medical Center
    Ranolazine
    Myocardial ischemia
    Double blinded
    Placebo controlled
    Additional relevant MeSH terms:
    Coronary Disease
    Coronary Artery Disease
    Myocardial Ischemia
    Ischemia
    Ranolazine

    Study Results

    Participant Flow

    Recruitment Details 20 subjects were recruited at Cedars-Sinai Medical Center Cardiology outpatient clinic.
    Pre-assignment Detail This is a cross-over study. 20 subjects (10 in study drug arm and 10 in placebo arm) completed period 1. In period 2, the 10 subjects who were on study drug in period 1 were on placebo arm in period 2, and the 10 subjects who were on placebo arm in period 1 were on study drug arm in period 2. The 20 subjects had a 2-week wash out in between.
    Arm/Group Title Study Drug Ranexa Then Placebo Placebo Then Study Drug Ranexa
    Arm/Group Description 20 subjects (10 in study drug arm and 10 in placebo arm) completed period 1. In period 2, the 10 subjects who were on study drug in period 1 were on placebo arm in period 2, and the 10 subjects who were on placebo arm in period 1 were on study drug arm in period 2. The 20 subjects had a 2-week wash out in between. 20 subjects (10 in study drug arm and 10 in placebo arm) completed period 1. In period 2, the 10 subjects who were on study drug in period 1 were on placebo arm in period 2, and the 10 subjects who were on placebo arm in period 1 were on study drug arm in period 2. The 20 subjects had a 2-week wash out in between.
    Period Title: Period 1
    STARTED 10 10
    COMPLETED 10 10
    NOT COMPLETED 0 0
    Period Title: Period 1
    STARTED 10 10
    COMPLETED 10 10
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title All Study Participants
    Arm/Group Description Participants who were randomized to receive either Study drug Ranexa or Placebo.
    Overall Participants 20
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    14
    70%
    >=65 years
    6
    30%
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    57
    Sex: Female, Male (Count of Participants)
    Female
    20
    100%
    Male
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    20
    100%

    Outcome Measures

    1. Primary Outcome
    Title Cardiac Magnetic Resonance (CMRs)
    Description Cardiac Magnetic Resonance (CMRs) (CMR 1 and CMR 2) end of the 4th week of treatment 1 and treatment 2 respectively, 4 hours after the morning dose of study drug was performed to measure myocardial perfusion defect in percentage.
    Time Frame 4 weeks and 10 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Study Drug Ranexa - CMRs (10 CMR 1 and 10 CMR 2) Placebo - CMRs (10 CMR 1 and 10 CMR 2)
    Arm/Group Description CMRs (CMR 1 and CMR 2) were performed to test the efficiency of the treatment of the study drug. CMRs (CMR 1 and CMR 2) were performed to test the efficiency of the treatment of the study drug.
    Measure Participants 20 20
    Median (Full Range) [Percentage of ischemic myocardium]
    11.7
    16.0
    2. Secondary Outcome
    Title Seattle Angina Questionnaire (SAQ)
    Description Questionnaires will be completed (SAQ - Seattle Angina Questionnaire) at the end of each treatment period. The Seattle Angina Questionnaire (SAQ) is a self-administered, 19-item questionnaire, a cardiac disease-related quality-of-life measure. The SAQ is well validated and sensitive to clinical changes. It has five subscales: physical limitation, angina stability, angina frequency, treatment satisfaction, and disease perception. The possible range of scores for each of the five subscales is 0 to 100, with higher scores indicating better quality of life. A change of 10 points in any of the subscales is considered to be clinically important. Each final SAQ domain ranges from 0-100, where higher is a better outcome score. Subscales are not combined. Median, SD and range are calculated for each domain.
    Time Frame 4 weeks and 10 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Study Drug Placebo
    Arm/Group Description Study drug Ranexa arm Placebo arm
    Measure Participants 20 20
    Physical Functioning
    91.7
    83.3
    Angina Stability
    75
    50
    Angina Frequency
    80
    75
    Treatment Satisfaction
    87.5
    93.8
    Quality of Life
    75
    66.7

    Adverse Events

    Time Frame 10 weeks
    Adverse Event Reporting Description
    Arm/Group Title Study Drug Placebo
    Arm/Group Description Study drug Ranexa arm Placebo arm
    All Cause Mortality
    Study Drug Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Study Drug Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/20 (0%) 0/20 (0%)
    Other (Not Including Serious) Adverse Events
    Study Drug Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/20 (0%) 0/20 (0%)

    Limitations/Caveats

    This was a pilot study.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title C. Noel Bairey Merz, MD
    Organization Cedars-Sinai Medical Center
    Phone 310-423-9680
    Email merz@cshs.org
    Responsible Party:
    Noel Bairey Merz, Director, Cedars-Sinai Medical Center
    ClinicalTrials.gov Identifier:
    NCT00570089
    Other Study ID Numbers:
    • IRB 10465
    First Posted:
    Dec 10, 2007
    Last Update Posted:
    Jun 10, 2019
    Last Verified:
    Jun 1, 2019