99mTc-rhAnnexin V-128 Imaging for Carotid Atherosclerosis

Phase 2

Terminated

Conditions: Carotid Artery Plaque

Interventions: Radiation: 99mTc-rhAnnexin V-128

Registration Number: NCT02667457

Lead Sponsor: Advanced Accelerator Applications

Brief Summary: This was a single-center, single-dose, study comprising a Proof of Concept (PoC) part and a subsequent Phase II part. The study was being done to assess the ability of the radiotracer 99mTc-rhAnnexin V-128 to image atherosclerotic plaque that might rupture and break off artery walls. This is caused by apoptosis or cell death in the plaque. These ruptured plaques can block blood circulation in the arteries causing a lack of oxygen to the tissues. Atherosclerotic plaques can build up on any artery in the body.

Detailed Description: The sponsor decided to terminate the study earlier than planned due to strategic decisions to focus the AAA development portfolio on oncology theragnostics and not based on safety concerns. Novartis acquired Advanced Accelerator Applications SA.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 39

Inclusion Criteria

For all participants:

Males and females age 18 years or greater
Able and willing to comply with the study procedures
Negative pregnancy test for women of childbearing potential at screening and on the day of administration of 99mTc-rhAnnexin V-128.

For participants with carotid artery disease:
Evidence of 50% or more carotid stenosis in one or more carotid arteries on carotid ultrasound within 2 years;
Evidence of 50% or more carotid stenosis in the most recent US imaging within 8 weeks prior to 99mTc-rhAnnexin V-128 administration

For control participants:
No significant carotid artery disease on carotid ultrasound;
No clinically significant abnormalities in baseline laboratory values.

Exclusion Criteria

Previous carotid stending, endarterectomy or stroke;
Diagnosis of vasculitis, dissection, or non-atherosclerotic carotid disease (Ehlers-Danlos, Marfans);
Pregnancy or lactation;
History of any disease or relevant physical or psychiatric condition or abnormal physical finding which may interfere with the study objectives at the investigator judgment;
Know hypersensitivity to the investigational product or any of its components;
Claustrophobia or inability to lie still in a supine position;
Participation in another clinical trial within 4 weeks before study inclusion, except for patients who have participated or who are currently participating in a study without any study drug administration;
Unwillingness to provide consent.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CAD Participants	99mTc-rhAnnexin V-128	Participants with asymptomatic or previously symptomatic with TIA only carotid atherosclerotic plaque with evidence of 50% or more carotid stenosis in one or more carotid arteries on carotid ultrasound within 2 years, received a single intravenous bolus of 350 MBq ± 10 % of 99mTc-rhAnnexin V-128 via an intraveneous (IV) catheter in an antecubital vein, followed by a saline flush on screening (Day 0).
Healthy Participants	99mTc-rhAnnexin V-128	Healthy participants with no significant carotid artery disease on carotid ultrasound, received a single intravenous bolus of 350 MBq ± 10 % of 99mTc-rhAnnexin V-128 via an IV catheter in an antecubital vein, followed by a saline flush on screening (Day 0).

Primary Outcome Measures

Name	Time	Method
Number of Participants Evaluated for Imaging Feasibility	Day 0	The frequency and severity of abnormal carotid scans was determined in the CAD participants and control groups by review of the number, localization, length and uptake intensity grade of each plaque to define a positive or negative scan at each time point. The feasibility of imaging apoptotic activity in CAD using 99mTc-rhAnnexin V-128 was assessed by the data monitoring committee (visual image review and consensus). The three reviewers of the DMC did an independent visual assessment of the images using a 1 to 4 point grading system: each observer reviewed the images of each patient and scored either 1 or 2 (uptake was less than or equal to blood pool), these images were considered normal; 3 was equivocal and four equalled abnormal. Only descriptive analysis performed.
Percentage of Participants With Prevalence of Abnormal 99mTc-rhAnnexin V-128 SPECT/CT Imaging (Phase II Step)	At 60 and 120 minutes post injection on Day 0	The prevalence of apoptotic activity was defined as the percentage of participants with "abnormal" Single-Photon Emission Computed Tomography (SPECT) imaging scans (also described as positive scans). The overall result of 99mTc-rhAnnexin V-128 imaging was unique: participants with at least one SPECT imaging as positive result (after 60 min or after 120 min from 99mTc-rhAnnexin V-128 injection) were considered as abnormal, participants with SPECT/CT images as negative were considered as normal. All images were acquired with a dual head SPECT/CT gamma camera with low-energy high-resolution collimators. Only descriptive analysis performed.

Secondary Outcome Measures

Name	Time	Method
Descending Aorta Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)	At 60 and 120 minutes post injection on Day 0	Quantitative analysis of planar images was carried out by placing a region of interest in the carotid areas and over a background area placed in the subclavian regions representing venous and arterial activity (target-to-background). Carotid artery uptake measured as TBR data for right and left carotids at 1 and 2 hours was compared between normal control and carotid artery disease groups. Quantitative analysis of the SPECT 1 and 2 hour images was done with regions of interest placed over the arterial target (right carotid, left carotid, ascending aorta, arch and descending aorta) and adjacent vein (internal jugular, SVC or IVS) using transaxial slices. TBR was calculated as arterial max / venous mean (the average of 3 slices centered on the slice with the highest TBR value).
Aortic Arch Uptake Correlation Imaging Assessment as Measured by Target to Background Ratio (TBR)	At 60 and 120 minutes post injection on Day 0	Quantitative analysis of planar images was carried out by placing a region of interest in the carotid areas and over a background area placed in the subclavian regions representing venous and arterial activity (target-to-background). Carotid artery uptake measured as TBR data for right and left carotids at 1 and 2 hours was compared between normal control and carotid artery disease groups. Quantitative analysis of the SPECT 1 and 2 hour images was done with regions of interest placed over the arterial target (right carotid, left carotid, ascending aorta, arch and descending aorta) and adjacent vein (internal jugular, SVC or IVS) using transaxial slices. TBR was calculated as arterial max / venous mean (the average of 3 slices centered on the slice with the highest TBR value).
Left Carotid Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)	At 60 and 120 minutes post injection on Day 0	Quantitative analysis of planar images was carried out by placing a region of interest in the carotid areas and over a background area placed in the subclavian regions representing venous and arterial activity (target-to-background). Carotid artery uptake measured as TBR data for right and left carotids at 1 and 2 hours was compared between normal control and carotid artery disease groups. Quantitative analysis of the SPECT 1 and 2 hour images was done with regions of interest placed over the arterial target (right carotid, left carotid, ascending aorta, arch and descending aorta) and adjacent vein (internal jugular, SVC or IVS) using transaxial slices. TBR was calculated as arterial max / venous mean (the average of 3 slices centered on the slice with the highest TBR value).
Right Carotid Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)	At 60 and 120 minutes post injection on Day 0	Quantitative analysis of planar images was carried out by placing a region of interest in the carotid areas and over a background area placed in the subclavian regions representing venous and arterial activity (target-to-background). Carotid artery uptake measured as TBR data for right and left carotids at 1 and 2 hours was compared between normal control and carotid artery disease groups. Quantitative analysis of the SPECT 1 and 2 hour images was done with regions of interest placed over the arterial target (right carotid, left carotid, ascending aorta, arch and descending aorta) and adjacent vein (internal jugular, SVC or IVS) using transaxial slices. TBR was calculated as arterial max / venous mean (the average of 3 slices centered on the slice with the highest TBR value).
Ascending Aorta Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)	At 60 and 120 minutes post injection on Day 0	Quantitative analysis of planar images was carried out by placing a region of interest in the carotid areas and over a background area placed in the subclavian regions representing venous and arterial activity (target-to-background). Carotid artery uptake measured as TBR data for right and left carotids at 1 and 2 hours was compared between normal control and carotid artery disease groups. Quantitative analysis of the SPECT 1 and 2 hour images was done with regions of interest placed over the arterial target (right carotid, left carotid, ascending aorta, arch and descending aorta) and adjacent vein (internal jugular, SVC or IVS) using transaxial slices. TBR was calculated as arterial max / venous mean (the average of 3 slices centered on the slice with the highest TBR value).
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs and Death	From Day 0 post injection up to Day 30	An AE is defined as any untoward medical occurrence in a participant and which does not necessarily have a causal relationship with the investigational product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease, temporally associated with the use of an investigational product, whether or not causally related to the investigational product. Treatment emergent adverse events that emerge after the 99mTc-rhAnnexin V-128 injection and up to 30 days after the injection that were absent before it or worsen relative to the pre-treatment state. A serious AE is defined as any untoward medical occurrence that at any dose results in death; is life-threatening; results in persistent or significant disability or incapacity; results in congenital anomaly or birth defect; or requires inpatient hospitalization or prolongation of hospitalization. Only descriptive analysis performed.
Number of Participants With Clinically Significant Abnormal Laboratory Values	From Day 0 post injection up to Day 30	Laboratory data was analysed with respect to the normal ranges of values provided by the local laboratory and with respect to levels of change and significance in these values. The evaluation of the "Clinically Significant Abnormal Laboratory Values" was at the discretion of the Principal Investigator and noted as such in patient files, where necessary. Participants with abnormal laboratory values were analyzed based on clinical relevance. Only descriptive analysis performed.
Left Carotid Uptake Imaging Assessment as Measure by Target to Background Ratio (TBR) by Ultrasound Grade of Plaque Echolucency/Echogenicity	At 60 and 120 minutes post injection on Day 0	B-mode and color Doppler ultrasound studies were acquired of both carotid arteries and performed with an ultrasound scanner equipped with a 5- to 7-MHz transducer. Plaque morphology, as echogenicity, defined as reflectance of the emitted ultrasound signal, were assessed and graded from 1 to 4 as echolucent, predominantly echolucent, predominantly echogenic, or echogenic. The vessel lumen was used as the reference structure for defining echolucency, and the bright echo zone produced by the media-adventitia interface in the far wall was used as the reference structure for defining echogenicity. Uptake was reported as the ratio of the uptake in the region of interest (target) to the uptake in the blood pool (background). Only descriptive analysis performed.
Right Carotid Uptake Imaging Assessment as Measure by Target to Background Ratio (TBR) by Ultrasound Grade of Plaque Echolucency/Echogenicity	At 60 and 120 minutes post injection on Day 0	B-mode and color Doppler ultrasound studies were acquired of both carotid arteries and performed with an ultrasound scanner equipped with a 5- to 7-MHz transducer. Plaque morphology, as echogenicity, defined as reflectance of the emitted ultrasound signal, were assessed and graded from 1 to 4 as echolucent, predominantly echolucent, predominantly echogenic, or echogenic. The vessel lumen was used as the reference structure for defining echolucency, and the bright echo zone produced by the media-adventitia interface in the far wall was used as the reference structure for defining echogenicity. Uptake was reported as the ratio of the uptake in the region of interest (target) to the uptake in the blood pool (background). Only descriptive analysis performed.