Official Title: “Phase 2 Study of the Safety and Efficacy of ß-Methyl-p-[123I]-Iodophenyl-Pentadecanoic Acid for Identification of Ischemic Myocardium Using SPECT in Adults With Symptoms Consistent With Acute Coronary Syndrome”
The purpose of this study is to:
- evaluate the performance characteristics (sensitivity & specificity) of iodofiltic acid I-123 imaging for detection of myocardial ischemia in patients that present in the Emergency Department with suspected Acute Coronary Syndrome (ACS).
- evaluate the safety of a single injection of iodofiltic acid I-123 in patients suspected of myocardial ischemia related to ACS.
- Study Type: Interventional
- Study Design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Diagnostic
- Study Primary Completion Date: February 2009
Detailed Clinical Trial Description
Annually, approximately eight million patients in the United States visit the Emergency Department (ED) with chest pain. Three million are sent home with a non-cardiac diagnosis, and the remaining five million patients are admitted to undergo further evaluation for suspected or actual acute coronary syndrome (ACS). Of these 5 million hospitalized patients, almost 3 million (58%) are determined to have a non-cardiac cause, 1 million (20%) are determined to have an acute myocardial infarctions (AMI), 1 million (20%) are diagnosed with unstable angina. It would be of great value to have a noninvasive triage tool that could accurately and rapidly distinguish non-cardiac etiologies from myocardial ischemia in ACS among patients presenting to the ED with chest pain. If sufficiently sensitive and specific, such a test could reduce significantly unnecessary hospitalization of patients with non-cardiac etiologies (responsible for approximately 1.6 million hospital days and $4 billion annually) as well as reduce the incidence (approximately 2-5%) of "missed" high-risk diagnoses (false negatives) among chest pain patients who are discharged and experience a myocardial infarction (MI) soon thereafter, approximately 16% of whom die from complications. Therefore, improved triage of ED chest pain patients would reduce health care costs as well as improve outcomes for patients. Iodofiltic acid I-123 is a novel imaging agent with the potential to rapidly detect cardiac ischemia in ACS patients presenting to the ED with chest pain.
Naturally occurring, long-chain fatty acids are the principal energy source for the myocardium, where they are rapidly metabolized by β-oxidation. [123I]-labeled analogs of long-chain fatty acids have been developed for use with planar and SPECT imaging, and these compounds have been used to differentiate areas of normal and abnormal cardiac fatty acid metabolism. Because straight chain fatty acids undergo very rapid metabolism by beta-oxidation, and rapid clearance from the myocardium, derivatives have been devised that retard the metabolism. One such derivative is iodofiltic acid I-123. Iodofiltic acid I-123 is a methyl-branched fatty acid that is labeled with radioactive iodine. It has been marketed in Japan since 1993 for use with planar or single photon emission computer tomography (SPECT) imaging for the diagnosis of a number of cardiac pathologic conditions, including AMI, cardiac viability, and cardiomyopathy. Over 500,000 patients have received iodofiltic acid I-123 in Japan with no reports of clinically significant adverse events (AEs).
β-methyl-p-[123I]-iodophenyl-pentadecanoic acid (iodofiltic acid I-123) is a methyl-branched fatty acid that does not readily undergo β-oxidation. The methyl branch slows the metabolism of the fatty acid and thereby prolongs the retention of the radiolabel in the myocardial cells. The iodine is attached to the para position of a terminal phenyl group, which prevents de-iodination by cellular enzymes. The metabolic stability of iodofiltic acid I-123 affords retention of radioactivity in the heart long enough to allow sufficient blood clearance so that high quality planar and SPECT imaging can be performed.
Iodofiltic acid I-123 imaging may have significant advantages in the diagnosis of ACS when compared with existing techniques, including reduced time to make a diagnosis, improved accuracy due to ischemic memory, reduced radiation exposure, and elimination of the need for pharmacologic or exercise-induced stress. These potential advantages of iodofiltic acid I-123 imaging may present significant diagnostic advantages in the evaluation of patients presenting with chest pain that are suspected to be experiencing a myocardial ischemic event. Rest/stress myocardial perfusion scintigraphy is the most commonly used form of imaging for detecting ischemia in patients with chronic stable coronary heart disease. Because stress testing is contraindicated in patients with unstable angina, resting Myocardial Perfusion Imaging (MPI) is often performed. The sensitivity of rest MPI for detection of significant coronary artery stenosis (with 75% or greater diameter reductions) was found to be only 31 – 54%. In a study comparing iodofiltic acid with resting thallium in patients with unstable angina it was found that the sensitivity of iodofiltic acid was 89% vs. 54% for thallium when compared against coronary angiography. Thus, iodofiltic acid I-123 imaging may be the better diagnostic agent in patients who cannot undergo stress testing or when stress is contraindicated.
The first targeted indication is to aid in the detection of myocardial ischemia in patients presented to the ED or other acute care setting with chest pain suggesting ACS. Molecular Insight has conducted three clinical studies in the United States. A Phase 1 study was conducted in 2001 in six healthy volunteers who received two injections of 6.5-7.5 mCi iodofiltic acid I-123 (one in a fasting state and the other 3-5 weeks later in a glucose-loaded state). The objectives of the study were to evaluate the safety and characterize the bio-distribution and dosimetry of the study drug. In whole-body scintigraphy, the liver and heart had the highest localization of radioactivity. Between 6 and 18% of the injected dose (ID) was recovered in urine over the first day after injection of iodofiltic acid I-123; recovery was higher in the fasting state (mean = 13.3% ID through 24 hours post-injection) than in the glucose-loaded state (mean = 9.9% ID through 24 hours post-injection). When all patients were analyzed, average doses for most organs were less than 0.10 rad/mCi, with the exception of the distal colon (0.15 rad/mCi), the proximal colon (0.13 rad/mCi), the heart wall (0.12 rad/mCi), and the bladder wall (0.12 rad/mCi). The largest single organ dose in this study was 0.22 rad/mCi to the bladder wall in one patient.
Results indicate that this experimental imaging agent was well tolerated, with no AEs of clinical significance reported. Estimated half-life values of the product indicate slow egress from tissues and disposition through excretory routes. The effective dose equivalent for iodofiltic acid I-123 is comparable with other diagnostic scintigraphic procedures, and, on a per imaging-study basis, is less than both Tl-201 and Tc-99m Sestamibi, indicating a lower radiation risk for iodofiltic acid I-123 at the 2.5-5.0 mCi level proposed in this study. The high uptake of the study drug by the heart at early postinjection time points supports its proposed use in medical imaging for the detection of cardiac ischemia. A comparison of myocardial uptake in the fasted and glucose-loaded conditions demonstrated that fasting is not required in order to obtain evaluable SPECT images.
Molecular Insight Pharmaceuticals, Inc. conducted a phase 2a study in 2002 to document the ability of iodofiltic acid I-123 imaging to demonstrate the concept of "ischemic memory". The objectives of the study were to evaluate the safety of iodofiltic acid I-123 imaging in patients with a documented recent ischemic event (positive stress portion of a Tl-201 stress/rest myocardial perfusion imaging study), to characterize the uptake and initial wash out of iodofiltic acid I-123 in the myocardium, and to compare the early uptake and initial wash out on iodofiltic acid I-123 SPECT imaging scans to the Tl-201 stress and rest myocardial perfusion images obtained within 30 hours prior to the iodofiltic acid I-123 injection. In this study, 32 patients who had evidence of treadmill stress-induced reversible myocardial ischemia by thallium stress/rest imaging were injected with 2.8-6 mCi of the fatty acid metabolic tracer iodofiltic acid I-123 up to 30 hours after the stress-induced ischemic episode. SPECT imaging of the iodofiltic acid I-123 distribution was performed beginning at approximately 10 minutes post rest injection of iodofiltic acid I-123 ("early" imaging), and again beginning 30 to 45 minutes after rest injection ("delayed" imaging). Both the thallium and the iodofiltic acid I-123 images were considered to be of generally high quality by the readers. The injection was well tolerated, and no clinically significant drug related AEs were reported. The data from this study suggest that iodofiltic acid I-123 imaging can successfully detect the suppression of fatty acid metabolism after stress-induced ischemia for at least 30 hours following the stress-induced ischemic episode. There was also good correlation between the extent and severity of the stress thallium perfusion abnormality and the extent and severity of the iodofiltic acid I-123 metabolic abnormality on both the early and delayed iodofiltic acid I-123 SPECT images.
The results of these two studies supported a Phase 2b study of iodofiltic acid I-123 imaging in patients presenting to the ED with a recent episode of acute chest pain consistent with myocardial ischemia for the determination of ACS. This study was named MIP-BP21. A total of 105 patients were enrolled, and the sensitivity population was 26 patients. Three readers read the data independently, and the Truth Standard was created by an adjudicator who read the clinical data as reported by the principal investigators. The primary endpoint was agreement > 75% for majority reader. This particular study resulted in an accuracy of < 75% however after subsequent review it was determined that improvements can be made in image data analysis and interpretation. The current trial incorporates these findings. Furthermore, this trial will incorporate the use of a semiautomated quantitation tool developed from a database of normal patients studied with iodofiltic acid I-123. Furthermore, this trial, MIP-BP23, will use a more rigorous Truth Standard and will improve reader training by having access to a greater number of training cases developed from previous studies.
Interventions Used in this Clinical Trial
- Radiation: Iodofiltic acid I-125
- Iodofiltic acid I-125 (4.0-5.0 mCi) is injected within 30 hours of the cessation of chest pain as a single injection. Single photon emission computed tomography is then performed 10-15 minutes after the injection.
Arms, Groups and Cohorts in this Clinical Trial
- Active Comparator: Stratum A
- Patients presenting with elevated cardiac biomarkers or reversible ST-segment depressions consistent with myocardial ischemia
- Active Comparator: Stratum B
- Patients with a known history of coronary artery disease presenting with typical anginal symptoms
- Active Comparator: Stratum C
- Patients with a known history of coronary artery disease presenting with atypical chest pain or patients without a history of coronary artery disease presenting with typical anginal chest pain
Outcome Measures for this Clinical Trial
- Evaluation of sensitivity and specificity of BMIPP for the detection of coronary artery disease using cardiac catheterization or SPECT perfusion imaging with tetrofosmin or sestamibi as the gold standard
- Time Frame: 30 days
Safety Issue?: No
- Time Frame: 30 days
- Evaluate for adverse events associated with administration of BMIPP in patients with suspected acute coronary syndromes
- Time Frame: 30 day
Safety Issue?: Yes
- Time Frame: 30 day
Criteria for Participation in this Clinical Trial
- Chest pain occurred within the previous 24 hours
- Provide written informed consent and are willing to comply with protocol requirements
- ≥ 40 years of age
- Are being evaluated for possible acute coronary syndrome
- Age < 40 years
- Females who are pregnant or lactating
- History of left ventricular ejection fraction (LVEF) ≤ 40%
- History of MI
- Acute ST segment elevation on ECG
- Left bundle branch block on ECG
- Known history of significant allergy to shellfish, X-ray contrast media or iodine/iodides
- Currently or formerly on medication that targets fatty acid uptake or metabolism (e.g., ranolazine [Ranexa])
- Administered radiopharmaceutical other than rubidium-82 or thallium-201 within 2 days prior to study enrollment
- Underwent cardiac stress testing of any kind within 2 days prior to study enrollment
- Serum creatinine level > 2.0 mg per dL
- Received investigational compound and/or medical device within 30 days of admission into this study
- Q-wave abnormalities consistent with previous MI
Gender Eligibility for this Clinical Trial: Both
Minimum Age for this Clinical Trial: 40 Years
Maximum Age for this Clinical Trial: N/A
Are Healthy Volunteers Accepted for this Clinical Trial: Accepts Healthy Volunteers
Clinical Trial Investigator Information
- Lead Sponsor
- Yale University
- Molecular Insight Pharmaceuticals, Inc.
- Provider of Information About this Clinical Study
- Normal LaFrance, MD/Chief Medical Officer, Molecular Insights Pharmaceuticals
- Overall Official(s)
- Norman LaFrance, MD, Study Director, Molecular Insight Pharmaceuticals, Inc.
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