ISCHEMIC CARDIOMYOPATHY
Conditions
Keywords
ISCHEMIC OR CORONARY HEART DISEASE, MYOCARDIAL INFARCTION, MAGNETIC RESONANCE IMAGING, DELAYED GADOLINIUM ENHANCEMENT MRI, MANGANESE-ENHANCED MRI, INFARCT VOLUME/SIZE, ALL CAUSE MORTALITY, VENTRICULAR ARRHYTHMIAS
Brief summary
The purpose of this study is to evaluate the safety and tolerance of a new intravenous diagnostic agent, SeeMore or EVP 1001-1, in patients with Cardiovascular Disease (MEMRI scan). The initial phase of this study, NCT01989195 enrolling a total of 6 patients, has been closed. This second phase adds 10 patients in a safety cohort and 60 additional patients for a total of 70 patients.
Detailed description
This is an open-label, baseline-controlled study to be conducted. Adult male or nonpregnant female patients who have been referred for evaluation of dilated cardiomyopathy, ischemic cardiomyopathy, non-ischemic cardiomyopathy, atrial arrhythmia and also patients who have received stem cell therapy related to both ischemic and dilated cardiomyopathy (under different trials) will be recruited. An initial cohort study of 6 patients to conduct safety evaluation was conducted before proceeding with 60 additional patients. In the initial cohort, a patient was dosed based on the Phase 1 and 2 clinical trial data evaluation completed by Eagle Vision Pharmaceutical, Inc. Subjects were excluded if they had received an investigational device within 30 days prior to administration of EVP1001-1; had a history of drug abuse or alcoholism; were taking a digitalis preparation; had a history of torsades; had New York Heart Association (NYHA) Grade IV heart failure; had abnormal liver function tests or a history of liver disease; had uncontrolled hypertension; had abnormal calcium, potassium or hemoglobin values at baseline; if they develop a cardiac arrhythmia prior to or during either of the exercise tests-- EVP1001-1 was not administered. The same parameters will apply to the new group of subjects. Prior to entry into this study, all subjects will sign an Informed Consent and will undergo a physical examination including medical history, details regarding their cardiac history, prescription and over-the-counter drug questionnaire, vital signs, electrocardiogram (ECG), evaluation of the major organ systems, hematology, serum chemistries, and urinalysis. In addition, female subjects will undergo a serum pregnancy test. Starting 30 minutes before the cardiac MRI scan (CMR), the subjects will take a 16 mg tablet of ondansetron by mouth. CMR imaging will subsequently take place and then EVP1001-1 will then be administered approximately 15 minutes into the scan for contrast enhanced images. EVP1001-1 will be administered intravenously over approximately one minute. The subjects will each receive 0.28 mL/kg of EVP 1001-1. All subjects will be monitored closely from before ondansetron administration until their discharge from the imaging center. Following MEMRI, delayed-enhanced MRI (DEMRI scan) is performed using 0.2 mmol/kg. We will compare the two different contrast enhanced images (EVP1001-1 vs gadolinium (GD)) in determining the non-viable (infarct core), peri-infarct, and total infarct size of myocardial tissue.
Interventions
DRUGManganese-enhanced MRI contrast reagent
MRI using manganese-enhanced MRI contrast reagent (manganese 0.28 mL/kg).
DRUGGadolinium-enhanced MRI contrast reagent
MRI using gadolinium-enhanced MRI contrast reagent (gadolinium 0.2 mmol/kg).
Sponsors
General Electric
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
All subjects to be entered must: * be at least 18 years of age. * if female, be nonpregnant as evidenced by a serum pregnancy test and using a medically-approved method of birth control, or post-menopausal or surgically sterile * provide written informed consent after having received oral and written information about the study * be in stable health based on medical history, examination and tests
Exclusion criteria
have a positive pregnancy test (females) * received an investigational drug or device within 30 days prior to administration of SeeMore * have known hypersensitivity to ondansetron or other selective serotonin 5HT3 receptor blockers * have a history of drug abuse or alcoholism * are taking a digitalis preparation or calcium channel blocker * have a history of torsades or prolonged QT/QTc interval * have NYHA Grade IV heart failure * have abnormal liver function tests or a history of liver disease * have uncontrolled hypertension (Systolic Blood Pressure \> 140 or Diastolic BP \> 90 consistently at baseline) * have abnormal baseline potassium or calcium values or hemoglobin less than 10 g/dl * are noncompliant or otherwise unlikely to perform as required by the protocol * have pretest likelihood of CAD for which the requisite number of subjects have been entered * develop an arrhythmia prior to or during either of the exercise tests; SeeMore should not be administered.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Infarct Size of MEMRI Versus DEMRI Scans | Day of MEMRI and DEMRI scans (up to 3 hours per scan, performed on the same day or up to 7 days apart) | MEMRI is an assessment of non-viable myocardial tissue and evaluates core infarct size. DEMRI is an assessment of fibrotic tissue and evaluates the total infarct size. The difference between these two measurements evaluates the size of peri-infarct region consisting of mixed components of injured but viable cardiomyocytes and fibrosis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Diastolic Blood Pressure | Before,during, and after MEMRI scan (up to 3 hours) | Diastolic blood pressure during MEMRI scan as a measure of manganese contrast reagent safety. Normal reference range: 60-80 mmHg. |
| Heart Rate | Before,during, and after MEMRI scan (up to 3 hours) | Heart rate during MEMRI scan as a measure of manganese contrast reagent safety. Normal reference range: 60 and 100 beats per minute. |
| QT Interval | Before and after MEMRI scan (up to 3 hours) | QT interval during MEMRI scan as a measure of manganese contrast reagent safety. QT is a measurement of heart function that is dependent on heart rate, so QTc is mainly used for diagnosis rather than QT. Normal reference range was considered to be 360-450 milliseconds for this study. |
| Corrected QT (QTc) | Before and after MEMRI scan (up to 3 hours) | Corrected QT (QTc) interval during MEMRI scan as a measure of manganese contrast reagent safety. QTc is a measurement of heart function and is mainly used for diagnosis rather than QT, because QT is dependent on heart rate. Normal reference range was considered to be 360-450 milliseconds for this study. |
| Alanine Aminotransferase (ALT) | Before and after MEMRI scan (up to 3 hours) | ALT levels during MEMRI scan as a measure of manganese contrast reagent safety. ALT is a measurement of liver function. Normal reference range was considered to be \<60 U/L for this study. |
| Systolic Blood Pressure | Before, during, and after MEMRI scan (up to 3 hours) | Systolic blood pressure during MEMRI scan as a measure of manganese contrast reagent safety. Normal reference range: 90-120 mmHg. |
| Alkaline Phosphatase (ALP) | Before and after MEMRI scan (up to 3 hours) | ALP levels during MEMRI scan as a measure of manganese contrast reagent safety. ALP is a measurement of liver function. Normal reference range was considered to be \<40-130 U/L for this study. |
| Total Bilirubin | Before and after MEMRI scan (up to 3 hours) | Total bilirubin levels during MEMRI scan as a measure of manganese contrast reagent safety. Total bilirubin is a measurement of liver function. Normal reference range was considered to be \<1.4 mg/dL for this study. |
| Creatinine | Before and after MEMRI scan (up to 3 hours) | Creatinine levels during MEMRI scan as a measure of manganese contrast reagent safety. Creatinine is a measurement of kidney function. Normal reference range was considered to be 0.50-1.20 mg/dL for this study. |
| Estimated Glomerular Filtration Rate (eGFR) | Before and after MEMRI scan (up to 3 hours) | eGFR levels during MEMRI scan as a measure of manganese contrast reagent safety. eGFR is a measurement of kidney function. Normal reference range was considered to be \>60 ml/min/1.73m\^2 for this study. |
| Aspartate Aminotransferase (AST) | Before and after MEMRI scan (up to 3 hours) | AST levels during MEMRI scan as a measure of manganese contrast reagent safety. AST is a measurement of liver function. Normal reference range was considered to be \<40 U/L for this study. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Coronary Disease Patients Participants receive 2 cardiac MRI procedures: MEMRI (manganese 0.28 mL/kg as reagent); and DEMRI (gadolinium 0.2 mmol/kg as reagent). | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | Coronary Disease Patients |
|---|---|
| Age, Continuous | 63.0 years STANDARD_DEVIATION 7.6 |
| Race/Ethnicity, Customized Asian | 4 Participants |
| Race/Ethnicity, Customized Caucasian | 11 Participants |
| Race/Ethnicity, Customized Latino | 3 Participants |
| Race/Ethnicity, Customized South Asian | 6 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 33 |
| other Total, other adverse events | 14 / 33 |
| serious Total, serious adverse events | 0 / 33 |
Outcome results
Primary
Infarct Size of MEMRI Versus DEMRI Scans
MEMRI is an assessment of non-viable myocardial tissue and evaluates core infarct size. DEMRI is an assessment of fibrotic tissue and evaluates the total infarct size. The difference between these two measurements evaluates the size of peri-infarct region consisting of mixed components of injured but viable cardiomyocytes and fibrosis.
Time frame: Day of MEMRI and DEMRI scans (up to 3 hours per scan, performed on the same day or up to 7 days apart)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | Infarct Size of MEMRI Versus DEMRI Scans | DEMRI | 18.9 percentage of left ventricle | Standard Deviation 11.9 |
| Coronary Disease Patients | Infarct Size of MEMRI Versus DEMRI Scans | MEMRI | 12.2 percentage of left ventricle | Standard Deviation 7.3 |
Comparison: Comparison of infarct size using MEMRI versus DEMRI scanp-value: 0.001t-test, 2 sided
Secondary
Alanine Aminotransferase (ALT)
ALT levels during MEMRI scan as a measure of manganese contrast reagent safety. ALT is a measurement of liver function. Normal reference range was considered to be \<60 U/L for this study.
Time frame: Before and after MEMRI scan (up to 3 hours)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | Alanine Aminotransferase (ALT) | Baseline | 37.8 U/L | Standard Deviation 18.4 |
| Coronary Disease Patients | Alanine Aminotransferase (ALT) | Post MRI | 35.1 U/L | Standard Deviation 12.6 |
Secondary
Alkaline Phosphatase (ALP)
ALP levels during MEMRI scan as a measure of manganese contrast reagent safety. ALP is a measurement of liver function. Normal reference range was considered to be \<40-130 U/L for this study.
Time frame: Before and after MEMRI scan (up to 3 hours)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | Alkaline Phosphatase (ALP) | Baseline | 80.8 U/L | Standard Deviation 21.9 |
| Coronary Disease Patients | Alkaline Phosphatase (ALP) | Post MRI | 79.8 U/L | Standard Deviation 26.7 |
Secondary
Aspartate Aminotransferase (AST)
AST levels during MEMRI scan as a measure of manganese contrast reagent safety. AST is a measurement of liver function. Normal reference range was considered to be \<40 U/L for this study.
Time frame: Before and after MEMRI scan (up to 3 hours)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | Aspartate Aminotransferase (AST) | Baseline | 26.1 U/L | Standard Deviation 12.4 |
| Coronary Disease Patients | Aspartate Aminotransferase (AST) | Post MRI | 25.4 U/L | Standard Deviation 9.1 |
Secondary
Corrected QT (QTc)
Corrected QT (QTc) interval during MEMRI scan as a measure of manganese contrast reagent safety. QTc is a measurement of heart function and is mainly used for diagnosis rather than QT, because QT is dependent on heart rate. Normal reference range was considered to be 360-450 milliseconds for this study.
Time frame: Before and after MEMRI scan (up to 3 hours)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | Corrected QT (QTc) | Baseline | 435.7 milliseconds | Standard Deviation 34.5 |
| Coronary Disease Patients | Corrected QT (QTc) | Post MRI | 440.5 milliseconds | Standard Deviation 37.3 |
Secondary
Creatinine
Creatinine levels during MEMRI scan as a measure of manganese contrast reagent safety. Creatinine is a measurement of kidney function. Normal reference range was considered to be 0.50-1.20 mg/dL for this study.
Time frame: Before and after MEMRI scan (up to 3 hours)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | Creatinine | Baseline | 1.04 mg/dL | Standard Deviation 0.23 |
| Coronary Disease Patients | Creatinine | Post MRI | 1.10 mg/dL | Standard Deviation 0.19 |
Secondary
Diastolic Blood Pressure
Diastolic blood pressure during MEMRI scan as a measure of manganese contrast reagent safety. Normal reference range: 60-80 mmHg.
Time frame: Before,during, and after MEMRI scan (up to 3 hours)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | Diastolic Blood Pressure | Baseline | 71.8 mmHg | Standard Deviation 9.1 |
| Coronary Disease Patients | Diastolic Blood Pressure | During MRI | 92.6 mmHg | Standard Deviation 10.8 |
| Coronary Disease Patients | Diastolic Blood Pressure | Post MRI | 66.2 mmHg | Standard Deviation 10 |
Secondary
Estimated Glomerular Filtration Rate (eGFR)
eGFR levels during MEMRI scan as a measure of manganese contrast reagent safety. eGFR is a measurement of kidney function. Normal reference range was considered to be \>60 ml/min/1.73m\^2 for this study.
Time frame: Before and after MEMRI scan (up to 3 hours)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | Estimated Glomerular Filtration Rate (eGFR) | Post MRI | 70.5 mL/min/1.73m^2 | Standard Deviation 16 |
| Coronary Disease Patients | Estimated Glomerular Filtration Rate (eGFR) | Pre MRI | 75.4 mL/min/1.73m^2 | Standard Deviation 20.5 |
Secondary
Heart Rate
Heart rate during MEMRI scan as a measure of manganese contrast reagent safety. Normal reference range: 60 and 100 beats per minute.
Time frame: Before,during, and after MEMRI scan (up to 3 hours)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | Heart Rate | Baseline | 66.3 beats per minute | Standard Deviation 9.9 |
| Coronary Disease Patients | Heart Rate | During MRI | 82.8 beats per minute | Standard Deviation 15.1 |
| Coronary Disease Patients | Heart Rate | Post MRI | 66.2 beats per minute | Standard Deviation 10 |
Secondary
QT Interval
QT interval during MEMRI scan as a measure of manganese contrast reagent safety. QT is a measurement of heart function that is dependent on heart rate, so QTc is mainly used for diagnosis rather than QT. Normal reference range was considered to be 360-450 milliseconds for this study.
Time frame: Before and after MEMRI scan (up to 3 hours)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | QT Interval | Baseline | 414.7 milliseconds | Standard Deviation 40.1 |
| Coronary Disease Patients | QT Interval | Post MRI | 412.6 milliseconds | Standard Deviation 38.2 |
Secondary
Systolic Blood Pressure
Systolic blood pressure during MEMRI scan as a measure of manganese contrast reagent safety. Normal reference range: 90-120 mmHg.
Time frame: Before, during, and after MEMRI scan (up to 3 hours)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | Systolic Blood Pressure | Baseline | 121.8 mmHg | Standard Deviation 16.4 |
| Coronary Disease Patients | Systolic Blood Pressure | During MRI | 160.9 mmHg | Standard Deviation 24.4 |
| Coronary Disease Patients | Systolic Blood Pressure | Post MRI | 124.4 mmHg | Standard Deviation 18.3 |
Secondary
Total Bilirubin
Total bilirubin levels during MEMRI scan as a measure of manganese contrast reagent safety. Total bilirubin is a measurement of liver function. Normal reference range was considered to be \<1.4 mg/dL for this study.
Time frame: Before and after MEMRI scan (up to 3 hours)
Population: Participants who had both MEMRI and DEMRI scans are included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Coronary Disease Patients | Total Bilirubin | Baseline | 0.58 mg/dL | Standard Deviation 0.21 |
| Coronary Disease Patients | Total Bilirubin | Post MRI | 0.65 mg/dL | Standard Deviation 0.3 |