Efficacy of EVP 1001-1 (SeeMore) in the Assessment of Myocardial Viability in Patients With Cardiovascular Disease
Condition: ISCHEMIC CARDIOMYOPATHY
MeSH terms: Cardiovascular Diseases; Cardiomyopathies
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The investigator hopes to introduce a novel MRI contrast agent with SeeMore ™ that directly
      defines viable myocardium. Identifying viable myocardium non-invasively using cardiac MRI is
      still a moving target and a question we plan to answer more definitively with the SeeMore ™
      contrast. Though well tested in small and large animals and Phase I & II clinical trials, the
      investigators would like to determine the efficacy of the SeeMore contrast further in a
      clinical setting.

      SeeMore is a new manganese (Mn)-based intravenous imaging agent being developed to enhance
      magnetic resonance imaging (MRI). While Mn has long been known to have desirable magnetic and
      kinetic properties for MRI, use in humans was not initially possible due to cardiovascular
      depression and electrocardiogram (ECG) changes, including prolongation of PR and QTc
      intervals, associated with intravenous administration [1-5]. SeeMore provides Mn in a form
      that maintains the desired magnetic and kinetic properties while overcoming the
      cardiovascular toxicity of Mn. SeeMore is taken up into heart cells (primarily via addition
      of calcium to avoid cardiotoxic effects; please refer to US patent #5,980,863). The potential
      to distinguish healthy heart tissue from unhealthy heart tissue based on a specific sustained
      pattern of enhancement provides a basis for evaluating the performance of SeeMore in heart
      patients. It may be possible to enhance the utility of MRI for heart disease through the use
      of an imaging agent that is specifically taken up into heart cells. SeeMore is the only
      cardiac-specific agent being developed for this purpose. Unlike nuclear perfusion agents,
      SeeMore is not radioactive and does not require special handling, shielding, transport or
      storage. In addition, the specific pattern of enhancement achieved in the heart muscle
      persists over time, offering potential benefits over the nonspecific extracellular agents
      currently available for MRI or X-ray/CT procedures. This feature allows full use of the high
      resolution of MRI, since there is not a trade-off of high spatial resolution for temporal
      (first-pass) resolution. It is anticipated the features offered by SeeMore along with the
      high resolution, three dimensional attributes of MRI will result in higher accuracy than is
      available with other current modalities in practice, including stress echocardiograms,
      cardiac MRI using gadolinium contrast and nuclear studies such as SPECT and PET. This will be
      evaluated in this study and serve as the basis for pivotal registration studies.

      All components of SeeMore™ are USP and are approved for use as drugs in man, orally and/or
      intravenously.
    

Detailed description: 
      This is an open-label, baseline-controlled study. An initial cohort study of patients to
      conduct safety evaluation will be conducted before proceeding with the additional patients.
      In this initial cohort, a patient will be dosed based on the Phase 1 and 2 clinical trial
      data evaluation completed by Eagle Vision Pharmaceutical, Inc.

      Starting 30 minutes before the cardiac MRI scan (CMR), the subjects will take a 4 mg tablet
      of ondansetron by mouth. CMR will subsequently take place and SeeMore™ will then be
      administered approximately 15 minutes into the scan for contrast enhanced images. SeeMore™
      will be administered intravenously over approximately one minute. The subjects will each
      receive 0.28 mL/kg of SeeMore™. All subjects will be monitored closely from before
      ondansetron administration until their discharge from the imaging center. If positive
      delayed-enhanced MRI is detected, the subject will undergo MEMRI within 1 week. The
      investigators plan to perform imaging with CMR and SeeMore™ within a week after standard
      gadolinium-based delayed enhanced imaging by CMR (performed as clinically indicated within
      Stanford Hospital by the patient's physician) to directly compare the two different contrast
      enhanced images (SeeMore vs Gadolinium in determining viable myocardium).

      Parameters to be Measured:

      A standard physical examination will be performed within 24 hours prior to dosing and at the
      end of experimental MEMRI imaging (approximately 1 hour post dosing). A standard 12-lead EKG
      will be performed both before the experimental MR study and after the experimental MR study
      to assure no significant EKG changes have occurred. HR will be measured before and after the
      study. After the study, the patient will have another standard 12-lead EKG performed to
      compare with the pre-MRI 12-lead EKG. The patient's symptoms will be reassessed 1 hour and 1
      year after infusion of the SeeMore contrast. Adverse events (AEs) and discomforts will be
      recorded until discharge from the imaging center. Any clinically relevant changes from
      baseline in vital signs, ECG rhythm, clinical chemistries or physical condition and all AEs
      will be followed until resolution or until the outcome is known. Primary efficacy will be
      based on determining whether the heart is normal or abnormal and if abnormal whether there is
      an infarction, ischemia or both. This provides the basis for calculating sensitivity,
      specificity, accuracy and predictive values. In addition, the location, size, conspicuity and
      associated confidence for any disease will be recorded.

      The study will be stopped for any significant adverse cardiovascular event including
      cardiovascular death, myocardial infarction, ventricular arrhythmia, ICD firing, congestive
      heart failure, hospitalization, or syncope.
    

Intervention name(s): 'SEEMORE' - MANGANESE-ENHANCED MRI CONTRAST REAGENT
Intervention type(s): Drug
Intervention description(s): EACH SUBJECT UNDERWENT 2 CARDIAC MRI PROCEDURES: ONE WITH MAGNEVIST (GADOLINIUM), ONE WITH SEEMORE (MANGANESE) REAGENT
CARDIAC MRI USING STANDARD DOSE OF 0.2mMOL/KG MAGNEVIST IV (IN THE VEIN)
CARDIAC MRI USING SEEMORE REAGENT, DOSE: 0.35CC/KG IV (IN THE VEIN) 1 WEEK AFTER GADOLINIUM MRI
Intervention MeSH terms: Manganese
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
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