Ischemia
Conditions
Keywords
Myocardial Perfusion, PET imaging, SPECT imaging, Coronary artery disease, Subjects that are male and nonpregnant female patients, presenting with reversible ischemia as characterized by a, rest/stress SPECT imaging study using, Technetium(99mTc)-labeled tracers
Brief summary
The main purpose of this study is to get more information on using BMS747158 (the study drug),a drug with small amounts of radioactivity to allow for heart imaging, during a PET scan which can then be compared to other images such as SPECT. The safety and quality of images will be studied.
Detailed description
The primary objectives of this study are: * To acquire data for the development of one-day rest/stress cardiac PET perfusion imaging protocols for BMS747158 with comparable diagnostic image quality to a two-day rest/stress PET protocol * To assess the safety of multiple doses of BMS747158 The secondary objectives of this study are: * To assess PET imaging parameters and image quality following administration of BMS747158 at rest and at stress (pharmacologic or exercise) same day (at different time intervals) and 16-48 hours after the rest injection * To assess feasibility of gated cardiac PET imaging with BMS747158 for left ventricular function assessment * To assess agreement of one and two day rest/stress PET imaging with BMS747158 in patients with reversible ischemia with rest/stress single photon emission computed tomography (SPECT) imaging * To perform a preliminary assessment of the diagnostic accuracy of one-day and two-day rest/stress PET perfusion imaging with BMS747158 as compared with invasive coronary angiography or computed tomography angiography (CTA) for detection of
Interventions
DRUGBMS747158
dosages at rest and at stress were not to exceed a total of 14 mCi. Cohort 1: Patients received either 2 or 3 IV bolus injections of BMS747158: 1 at rest and 1 or 2 during stress, over a 1-day or 2-day period. Cohort 2: Patients to recieve IV bolus injections of BMS747158: For the Pharmacologic (Adenosine) Stress: * Doses at rest were to range between 2.9 and 3.4 mCi. * Doses under stress were to be a factor of 2.0 to 2.4 greater than the rest dose, resulting in a range of stress doses between 5.8 and 8.2 mCi. For the Exercise Stress: * Doses at rest were to range between 1.7 and 2.0 mCi. * Doses under stress were to be a factor of 3.0 to 3.6 greater than the rest dose, resulting in a range between 5.1 and 7.2 mCi.
Sponsors
Lantheus Medical Imaging
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Provide signed IC prior to undergoing any study procedures * Be male or nonpregnant female, between the ages of 18 to 75 years, inclusive * Have:A rest/stress SPECT imaging study (either exercise or pharmacologic stress) within 21 days of enrollment, using 99mTc-labeled tracers and showing reversible ischemia * Female patients must: * be nonlactating, * no longer have child-bearing potential, either because they are post-menopausal (defined as amenorrhea ≥ 12 consecutive months, or because they have undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy)
Exclusion criteria
* Presence of any condition that may disrupt and/or increase permeability of the BBB, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, acute central nervous system (CNS) infection, CNS tumor, autoimmune disease affecting the CNS, or CNS inflammatory * Current significant illness, pathology or physical examination or vital signs measurement-findings that could potentiate any adverse pharmacological event associated with a vasodilatory drug or any pathology that, in the opinion of the investigator, might confound the interpretation of the results of the study * Known hypersensitivity to adenosine, dipyridamole or aminophylline * Presence of any contraindications to exercise stress testing * History of New York Heart Association Class III or IV Congestive Heart Failure (CHF) * Any major surgery within 4 weeks prior to enrollment or planned within 2 weeks following completion of the 2-week telephone follow-up assessment * Inability to tolerate IV medication. * History of drug or alcohol abuse within the last year * Participation in any investigational drug, device, or placebo study within 6 months prior to study enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Determination of Rest Dose: Dose Acquistion Time Product | Dosing visit | The rest flurpiridaz dose to be used for subsequent efficacy studies was determined by a modeling method that simulated a range of injected doses using a single fixed injected dose at rest in each subject and a range of acquisition durations. From this, a dose acquisition time product (DATP was determined for each subject that specified the minimal dose for a given acquisition duration that yielded an image in that subject that was negligibly affected by photon counting statistics. Descriptive statistics were used to identify an appropriate rest dose for the population. No other statistical tests were performed |
| Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Sensitivity (SN) vs SPECT MPI Sensitivity | Dosing visit | Diagnostic efficacy of one-day rest/stress BMS747158 PET MPI is measured by sensitivity as compared to single photon emission computed tomography (SPECT)MPI in the detection of coronary artery disease (CAD)using angiography or three-month cardiac events as the truth standard. |
| Cohort 1: Determination of Ratio of Stress Dose to Rest Dose | Dosing visit | The stress flurpiridaz dose for subsequent same-day rest-stress efficacy studies was determined as a multiple of the rest dose by computer modeling. Images derived only from rest flurpiridaz administration were blended using image analysis with images derived only from administration of flurpiridaz following exercise or adenosine stress. The blending fraction that resulted in negligible change in reader interpretation of defect severity was determined for each subject. The minimum value that met this criterion for all subjects was used to calculate the ratio of the stress dose to the rest dose as a function of the delay between administration of the two doses for both adenosine stress and exercise stress separately. No statistical analysis was performed. |
| Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Specificity (SP) vs SPECT MPI Specificity | Dosing Visit | Diagnostic efficacy of one-day rest/stress BMS747158 PET MPI is measured by specificity as compared to single photon emission computed tomography (SPECT)MPI in the detection of coronary artery disease (CAD)using angiography or three-month cardiac events as the truth standard. |
Countries
United States
Participant flow
Recruitment details
Cohort 1 enrolled 33 patients across 3 clinical sites. Dosing for Cohort 1 was initiated January 2009. Cohort 2 enrolled 143 patients across 21 clinical sites. Dosing for Cohort 2 was initiated July 2009
Pre-assignment details
Cohort 1: Patients showing a mild to severe reversible perfusion defect on a qualifying SPECT MPI study were considered eligible for the study Cohort 2: Patients with known or suspected cornary artery disease who presented with a broad spectrum of pre-test likelihood of CAD(very low/low, to high likelihood)were considered eligible for the study.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Dose Ranging and Dose Interval Patients received either 2 or 3 IV bolus injhections of BMS747158: 1 at rest and 1 or 2 during stress, over a 1-day or 2-day period | 33 |
| Cohort 2: Pharm Stress Patient received BMS747158 as a single IV bolus injection at rest and a single bolus injection at pharmacologic stress over a 1-day period. For patients undergoing pharmacologic stress test the dose of BMS747158 were to be a factor of 2.0 to 2.4 greater than the rest dose. | 67 |
| Cohort 2: Efficacy Exercise Stress Patient received BMS747158 as a single IV bolus injection at rest and a single bolus injection at exercise stress over a 1-day period.
For patients undergoing exercise stress test the dose of BMS747158 were to be a factor of 3.0 to 3.6 greater than the rest dose. | 76 |
| Total | 176 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Cohort 1 Dose Ranging and Dose Interval | Withdrawal by Subject | 1 | 0 |
| Cohort 2 Efficacy | Adverse Event | 0 | 1 |
| Cohort 2 Efficacy | Other | 0 | 9 |
Baseline characteristics
| Characteristic | Cohort 1 Dose Ranging and Dose Interval | Cohort 2: Pharm Stress | Cohort 2: Efficacy Exercise Stress | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 43 Participants | 24 Participants | 91 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 24 Participants | 52 Participants | 85 Participants |
| Region of Enrollment North America | 33 participants | 67 participants | 76 participants | 176 participants |
| Sex: Female, Male Female | 9 Participants | 16 Participants | 20 Participants | 45 Participants |
| Sex: Female, Male Male | 24 Participants | 51 Participants | 56 Participants | 131 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 33 | 61 / 143 |
| serious Total, serious adverse events | 0 / 33 | 2 / 143 |
Outcome results
Primary
Cohort 1: Determination of Ratio of Stress Dose to Rest Dose
The stress flurpiridaz dose for subsequent same-day rest-stress efficacy studies was determined as a multiple of the rest dose by computer modeling. Images derived only from rest flurpiridaz administration were blended using image analysis with images derived only from administration of flurpiridaz following exercise or adenosine stress. The blending fraction that resulted in negligible change in reader interpretation of defect severity was determined for each subject. The minimum value that met this criterion for all subjects was used to calculate the ratio of the stress dose to the rest dose as a function of the delay between administration of the two doses for both adenosine stress and exercise stress separately. No statistical analysis was performed.
Time frame: Dosing visit
Population: Subjects with demonstrated partially or completely reversible defects on prior SPECT who received at least one stress and one rest dose of flurpiridaz F 18, on separate days.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Dose Acquistion Time Product | Cohort 1: Determination of Ratio of Stress Dose to Rest Dose | 0.228 Fraction of rest added to stress image |
Primary
Cohort 1: Determination of Rest Dose: Dose Acquistion Time Product
The rest flurpiridaz dose to be used for subsequent efficacy studies was determined by a modeling method that simulated a range of injected doses using a single fixed injected dose at rest in each subject and a range of acquisition durations. From this, a dose acquisition time product (DATP was determined for each subject that specified the minimal dose for a given acquisition duration that yielded an image in that subject that was negligibly affected by photon counting statistics. Descriptive statistics were used to identify an appropriate rest dose for the population. No other statistical tests were performed
Time frame: Dosing visit
Population: Intent to treat, received at least one rest dose of BMS 747158
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Dose Acquistion Time Product | Cohort 1: Determination of Rest Dose: Dose Acquistion Time Product | 100 MBq X Minutes | Standard Deviation 54.7 |
Primary
Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Sensitivity (SN) vs SPECT MPI Sensitivity
Diagnostic efficacy of one-day rest/stress BMS747158 PET MPI is measured by sensitivity as compared to single photon emission computed tomography (SPECT)MPI in the detection of coronary artery disease (CAD)using angiography or three-month cardiac events as the truth standard.
Time frame: Dosing visit
Population: intent to treat, received at least one dose of BMS747158
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Dose Acquistion Time Product | Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Sensitivity (SN) vs SPECT MPI Sensitivity | PET MPI | 0.769 Proportion of True Positive Cases |
| Cohort 1: Dose Acquistion Time Product | Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Sensitivity (SN) vs SPECT MPI Sensitivity | SPECT MPI | 0.596 Proportion of True Positive Cases |
p-value: 0.0295% CI: [0.655, 0.884]McNemar
p-value: 0.0295% CI: [0.463, 0.73]McNemar
Primary
Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Specificity (SP) vs SPECT MPI Specificity
Diagnostic efficacy of one-day rest/stress BMS747158 PET MPI is measured by specificity as compared to single photon emission computed tomography (SPECT)MPI in the detection of coronary artery disease (CAD)using angiography or three-month cardiac events as the truth standard.
Time frame: Dosing Visit
Population: intent to treat, received at least one dose of BMS747158
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Dose Acquistion Time Product | Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Specificity (SP) vs SPECT MPI Specificity | PET MPI | 0.877 Proportion of True Negative Cases |
| Cohort 1: Dose Acquistion Time Product | Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Specificity (SP) vs SPECT MPI Specificity | SPECT MPI | 0.836 Proportion of True Negative Cases |
p-value: 0.31795% CI: [0.801, 0.952]McNemar
p-value: 0.31795% CI: [0.751, 0.921]McNemar