Microvascular Coronary Dysfunction (MCD)
Conditions
Keywords
Microvascular Coronary Dysfunction (MCD)
Brief summary
This research study is designed to test the use of ranolazine in patients with angina (chest discomfort due to reduced blood supply to the heart) due to microvascular coronary dysfunction (MCD; abnormalities in the small blood vessels of the heart). This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. The FDA has approved this drug based on studies primarily on patients with chronic angina with major blockages of the arteries.
Detailed description
This is a randomized, double-blinded, placebo- controlled, and cross-over clinical trial. 147 subjects will be enrolled at two clinical sites, with projected 9-10% dropout and anticipated 134 completed subjects. To maintain blinding of the investigators, the study randomization table will be kept in Pharmacy Service. The sponsor will ship the study drug directly to the Pharmacy Service. The pharmacy service will also be responsible for dispersing the study drug. There are 4 study visits (2 visits in each study period) in this study. Subjects will be in this study for about 6 weeks from Week 0 - baseline visit to Week 6 - exit visit. Besides the procedure of study medication mentioned above, other study procedures include informed consent, physical exam, questionnaires, EKG for safety assessment, blood collection for laboratory testing, cardiac MRI, and follow-up events. In sum, participants will be asked to undergo 2 cardiac MRI's and fill out questionnaires 4 times. They will be asked to participate for 6 weeks with two 2-week courses (with a treatment window period of 5 days), one with ranolazine and the other with placebo (without knowing which they are taking). There is a 2-week washout period between treatments. The participants will otherwise remain on all their usual medications. The physicians will also be blinded to which medication the subject is receiving. Participation in this study will be approximately 6 weeks, which consists of two 2-week study periods and in between a 2-week washout period: 1. During the first 2-week period: Subjects will be randomized to first receive either the ranolazine or a placebo pill (sugar pill with no active medicine). Subjects will take the extended-release ranolazine or a placebo pill for a total of 2 weeks. Subjects will take 500 mg twice daily for the first 1 week and then 1000 mg twice daily for an additional 1 week. Subjects who are unable to take the higher dose due to side effects will remain on 500 mg twice daily for the entire study period. After the 2 weeks, the participant will have a Cardiac MRI and complete study questionnaires. These tools will allow us to evaluate if the participant is doing better on the medication. 2. 2-week washout period: Subject will then be asked to go 2 weeks without any study medication (ranolazine or placebo). 3. During the second 2-week period: Subject will then be given either extended release ranolazine or placebo depending on which was received the first time for a total of 2 weeks. Subjects will take 500 mg twice daily for the first 1 week and then 1000 mg twice daily for an additional 1 week. Subjects who are unable to take the higher dose due to side effects will remain on 500 mg twice daily for entire study period. This 2-week period will again be followed by a final Cardiac MRI and questionnaire completion.
Interventions
DRUGRanolazine
This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. 500-1,000 mg po bid for 2 weeks
DRUGPlacebo
500-1,000 mg po bid for 2 weeks
Sponsors
University of Florida
Cedars-Sinai Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men or women age \>18 from diverse racial/ethnic groups; 2. Competent to give informed consent; 3. Patients with chronic angina or its equivalent; 4. Coronary angiogram revealing MCD with no obstructive CAD (epicardial coronary stenosis \<50% luminal diameter stenosis); 5. Left ventricular ejection fraction \> or = 45%; 6. Objective evidence of ischemia by noninvasive methods such as exercise stress test, stress Echo, MRI, or SPECT; 7. Patients with 10% myocardial ischemia by Cardiac magnetic resonance imaging (CMRI) myocardial perfusion reserve index ≤ 2.0 or abnormal coronary reactivity testing (CFR \< 2.5, or ACH response of no dilation or constriction, determined by local site read).
Exclusion criteria
1. Acute coronary syndrome (defined by WHO), cardiogenic shock or requiring inotropic or intra-aortic balloon support; 2. Planned percutaneous coronary intervention or CABG or established obstructive CAD with ischemia eligible for revascularization, acute MI; 3. Prior non-cardiac illness with an estimated life expectancy \<4 years; 4. Unable to give informed consent; 5. Allergy or contra-indication to CMRI testing, including renal failure, claustrophobia, and asthma, uncontrolled moderate hypertension (sitting blood pressure \>160/95mmHg with measurements recorded on at least 2 occasions), conditions likely to influence outcomes: Severe lung, creatinine \>1.8 or CrCl ≤ 50ml/min) or hepatic disease; 6. Surgically uncorrected significant congenital or valvular heart disease and other disease likely to be fatal or require frequent hospitalization within the next six months; 7. Adherence or retention reasons; 8. Unwilling to complete follow-up evaluation including repeat testing, documented obstructive hypertrophic cardiomyopathy; 9. Aortic stenosis (valve area \<1.5cm); 10. LV dysfunction (ejection fraction ≤35%); 11. History of significant cocaine or amphetamine abuse; 12. Taking potent CYP3A4 inhibitors (ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir); 13. Women who are pregnant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Seattle Angina Questionnaire (SAQ) | 2 weeks (first intervention) and 6 weeks (second intervention) | 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 quality of life. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac Magnetic Resonance (CMRs) | 2 weeks (first intervention) and 6 weeks (second intervention) | Cardiac Magnetic Resonance (CMRs) (CMR 1 and CMR 2) end of the 2nd week of treatment 1 and treatment 2 respectively, 4 hours after the morning dose of study drug was performed to measure myocardial perfusion reserve index. Myocardial perfusion reserve index (MPRI) was assessed using the first-pass perfusion intensity curves during stress and rest cardiac magnetic resonance imaging. First-pass perfusion images were analysed using CAAS MRV CMRI analysis software Version 3.3 (Pie Medical Imaging B.V., Maastricht, the Netherlands). Global MPRI was calculated as the ratio of stress/rest relative perfusion upslope, corrected for LV cavity upslope. Higher MPRI represents better myocardial perfusion reserve. Since MPRI is an index, there is no unit. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ranolazine/Placebo 147 subjects will be enrolled at two clinical sites, with projected 9-10% dropout and anticipated 134 completed subjects.
For Ranolazine first group, subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing.
For Placebo first group, subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing. | 142 |
| Total | 142 |
Baseline characteristics
| Characteristic | Ranolazine/Placebo |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 142 Participants |
| Age, Continuous | 55.2 years STANDARD_DEVIATION 9.8 |
| Region of Enrollment United States | 142 Participants |
| Sex: Female, Male Female | 135 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 14 / 142 | 11 / 142 |
| other Total, other adverse events | 8 / 142 | 10 / 142 |
| serious Total, serious adverse events | 6 / 142 | 1 / 142 |
Outcome results
Primary
Seattle Angina Questionnaire (SAQ)
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 quality of life. 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.
Time frame: 2 weeks (first intervention) and 6 weeks (second intervention)
Population: Not all participants answered every question in the SAQ, thus the numbers are different for each question.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranolazine | Seattle Angina Questionnaire (SAQ) | Physical Limitation | 68.09 Units on scale | Standard Deviation 23.34 |
| Ranolazine | Seattle Angina Questionnaire (SAQ) | Angina Frequency | 63.91 Units on scale | Standard Deviation 26.09 |
| Ranolazine | Seattle Angina Questionnaire (SAQ) | Angina Stability | 58.4 Units on scale | Standard Deviation 26.11 |
| Ranolazine | Seattle Angina Questionnaire (SAQ) | Treatment Satisfaction | 74.16 Units on scale | Standard Deviation 21.23 |
| Ranolazine | Seattle Angina Questionnaire (SAQ) | Quality of Life | 56.05 Units on scale | Standard Deviation 23.09 |
| Ranolazine | Seattle Angina Questionnaire (SAQ) | SAQ Overall | 62.49 Units on scale | Standard Deviation 19.32 |
| Placebo | Seattle Angina Questionnaire (SAQ) | Quality of Life | 54.17 Units on scale | Standard Deviation 23.31 |
| Placebo | Seattle Angina Questionnaire (SAQ) | Physical Limitation | 66.7 Units on scale | Standard Deviation 23.34 |
| Placebo | Seattle Angina Questionnaire (SAQ) | Treatment Satisfaction | 74.17 Units on scale | Standard Deviation 21.08 |
| Placebo | Seattle Angina Questionnaire (SAQ) | SAQ Overall | 60.97 Units on scale | Standard Deviation 20.11 |
| Placebo | Seattle Angina Questionnaire (SAQ) | Angina Stability | 51.17 Units on scale | Standard Deviation 27.68 |
| Placebo | Seattle Angina Questionnaire (SAQ) | Angina Frequency | 62.73 Units on scale | Standard Deviation 25.95 |
Secondary
Cardiac Magnetic Resonance (CMRs)
Cardiac Magnetic Resonance (CMRs) (CMR 1 and CMR 2) end of the 2nd week of treatment 1 and treatment 2 respectively, 4 hours after the morning dose of study drug was performed to measure myocardial perfusion reserve index. Myocardial perfusion reserve index (MPRI) was assessed using the first-pass perfusion intensity curves during stress and rest cardiac magnetic resonance imaging. First-pass perfusion images were analysed using CAAS MRV CMRI analysis software Version 3.3 (Pie Medical Imaging B.V., Maastricht, the Netherlands). Global MPRI was calculated as the ratio of stress/rest relative perfusion upslope, corrected for LV cavity upslope. Higher MPRI represents better myocardial perfusion reserve. Since MPRI is an index, there is no unit.
Time frame: 2 weeks (first intervention) and 6 weeks (second intervention)
Population: Out of 142 randomized, there were 10 dropouts and 4 missing treatment periods. Therefore 128 was included in analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Cardiac Magnetic Resonance (CMRs) | 1.98 myocardial perfusion reserve index | Standard Deviation 0.46 |
| Placebo | Cardiac Magnetic Resonance (CMRs) | 1.96 myocardial perfusion reserve index | Standard Deviation 0.42 |