A Phase 2 interventional study of 99mTc-rhAnnexin V-128 in Carotid Artery Plaque, sponsored by Advanced Accelerator Applications. Terminated at 1 site in Canada. Open to participants aged 18 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2020-10-09.
Sponsored by Advanced Accelerator Applications · Phase 2, Interventional, and Diagnostic
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.
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.
339 studies on the registry are indexed under Carotid Stenosis; 81 are open to participants now.
This study's enrollment of 39 is below the median of 106 across 182 interventional studies indexed under Carotid Stenosis.
Browse Carotid Stenosis studies →Advanced Accelerator Applications is the lead sponsor of 17 studies on the registry; none are open to participants now.
Of its 6 completed or terminated interventional studies of FDA-regulated products, 4 (67%) have results posted.
Counted across the registry records on this site, refreshed daily.
For all participants:
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 the most recent US imaging within 8 weeks prior to 99mTc-rhAnnexin V-128 administration
For control participants:
Exclusion Criteria:
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).
Radiation: 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).
Radiation: 99mTc-rhAnnexin V-128
Number of Participants Evaluated for Imaging Feasibility
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.
Time frame: Day 0
Percentage of Participants With Prevalence of Abnormal 99mTc-rhAnnexin V-128 SPECT/CT Imaging (Phase II Step)
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.
Time frame: At 60 and 120 minutes post injection on Day 0
Left Carotid Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)
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).
Time frame: At 60 and 120 minutes post injection on Day 0
Right Carotid Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)
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).
Time frame: At 60 and 120 minutes post injection on Day 0
Ascending Aorta Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)
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).
Time frame: At 60 and 120 minutes post injection on Day 0
Descending Aorta Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)
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).
Time frame: At 60 and 120 minutes post injection on Day 0
Aortic Arch Uptake Correlation Imaging Assessment as Measured by Target to Background Ratio (TBR)
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).
Time frame: At 60 and 120 minutes post injection on Day 0
Left Carotid Uptake Imaging Assessment as Measure by Target to Background Ratio (TBR) by Ultrasound Grade of Plaque Echolucency/Echogenicity
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.
Time frame: At 60 and 120 minutes post injection on Day 0
Right Carotid Uptake Imaging Assessment as Measure by Target to Background Ratio (TBR) by Ultrasound Grade of Plaque Echolucency/Echogenicity
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.
Time frame: At 60 and 120 minutes post injection on Day 0
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs and Death
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.
Time frame: From Day 0 post injection up to Day 30
Number of Participants With Clinically Significant Abnormal Laboratory Values
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.
Time frame: From Day 0 post injection up to Day 30
The study was conducted at single center in Canada.
| Milestone | Carotid Atherosclerotic Plaque (CAD) Participants | Healthy Participants |
|---|---|---|
| Started | 27 | 12 |
| Dosed participants | 26 | 10 |
| Full analysis set population (fas) | 25 | 10 |
| Completed | 26 | 10 |
| Not completed | 1 | 2 |
| Withdrew: Withdrawal by subject | 1 | 0 |
| Withdrew: Other reason | 0 | 2 |
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.
| Participants | CAD Participants | Healthy Participants |
|---|---|---|
| Number of Participants Evaluated for Imaging Feasibility | 15 | 5 |
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.
| Participants | CAD Participants | Healthy Participants |
|---|---|---|
| 60 mins after injection — Positive (abnormal) | 8 | 0 |
| 60 mins after injection — Negative (normal) | 16 | 10 |
| 60 mins after injection — Missing | 1 | 0 |
| 120 mins after injection — Positive (abnormal) | 8 | 0 |
| 120 mins after injection — Negative (normal) | 17 | 10 |
| 120 mins after injection — Missing | 0 | 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).
| Target to Background Ratio (TBR) | CAD Participants | Healthy Participants |
|---|---|---|
| 60 Minutes | 1.171 ± 0.764 | 0.697 ± 0.222 |
| 120 Minutes | 1.208 ± 0.486 | 0.827 ± 0.205 |
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).
| Target to Background Ratio (TBR) | CAD Participants | Healthy Participants |
|---|---|---|
| 60 Minutes | 1.252 ± 0.745 | 0.768 ± 0.209 |
| 120 Minutes | 1.220 ± 0.550 | 0.928 ± 0.217 |
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).
| Target to Background Ratio (TBR) | CAD Participants | Healthy Participants |
|---|---|---|
| 60 Minutes | 2.054 ± 0.656 | 1.574 ± 0.252 |
| 120 Minutes | 1.616 ± 0.294 | 1.381 ± 0.190 |
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).
| Target to Background Ratio (TBR) | CAD Participants | Healthy Participants |
|---|---|---|
| 60 Minutes | 2.159 ± 0.865 | 1.590 ± 0.164 |
| 120 Minutes | 1.520 ± 0.245 | 1.341 ± 0.131 |
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).
| Target to Background Ratio (TBR) | CAD Participants | Healthy Participants |
|---|---|---|
| 60 Minutes | 1.986 ± 0.679 | 1.606 ± 0.279 |
| 120 Minutes | 1.628 ± 0.380 | 1.294 ± 0.174 |
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.
| Ratio | CAD Participants |
|---|---|
| Predominantly echolucent: 60 Minutes | 1.490 ± 0.756 |
| Predominantly echolucent: 120 Minutes | 1.014 ± 0.309 |
| Predominantly echogenic: 60 Minutes | 0.945 ± 0.287 |
| Predominantly echogenic: 120 Minutes | 1.096 ± 0.186 |
| Echogenic: 60 Minutes | 0.950 ± 0.245 |
| Echogenic: 120 Minutes | 1.387 ± 0.496 |
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.
| Ratio | CAD Participants |
|---|---|
| Echolucent: 60 Minutes | 0.619 ± 0.000 |
| Echolucent: 120 Minutes | 0.820 ± 0.000 |
| Predominantly echolucent: 60 Minutes | 0.955 ± 0.192 |
| Predominantly echolucent: 120 Minutes | 1.126 ± 0.311 |
| Predominantly echogenic: 60 Minutes | 1.593 ± 1.174 |
| Predominantly echogenic: 120 Minutes | 1.294 ± 0.851 |
| Echogenic: 60 Minutes | 1.180 ± 0.206 |
| Echogenic: 120 Minutes | 1.149 ± 0.438 |
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.
| Participants | CAD Participants | Healthy Participants |
|---|---|---|
| Treatment Emergent Adverse Events (TEAEs) | 7 | 0 |
| Treatment Emergent Adverse Drug Reactions | 2 | 0 |
| Treatment Emergent Serious Adverse Events (TESAEs) | 1 | 0 |
| Treatment Emergent Serious Adverse Drug Reactions | 0 | 0 |
| TEAEs leading to Withdrawal | 0 | 0 |
| TEAEs leading to Deaths | 0 | 0 |
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.
| Participants | CAD Participants | Healthy Participants |
|---|---|---|
| Blood Chemistry — Abnormal non clinical relevant | 26 | 10 |
| Blood Chemistry — Abnormal clinically relevant | 0 | 0 |
| Hematology — Abnormal non clinical relevant | 15 | 4 |
| Hematology — Abnormal clinically relevant | 0 | 0 |
| Urinalysis — Abnormal non clinical relevant | 10 | 4 |
| Urinalysis — Abnormal clinically relevant | 0 | 0 |
Collected over Adverse events were collected from Day 0 up to Day 30. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| CAD Participants | 0/26 (0%) | 1/26 (3.8%) | 7/26 (26.9%) |
| Healthy Participants | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) |
| Event | CAD Participants | Healthy Participants |
|---|---|---|
| BradycardiaCardiac disorders | 1/26 | 0/10 |
| Event | CAD Participants | Healthy Participants |
|---|---|---|
| PalpitationsCardiac disorders | 1/26 | 0/10 |
| AccidentInjury, poisoning and procedural complications | 1/26 | 0/10 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 1/26 | 0/10 |
| Muscle spasmsMusculoskeletal and connective tissue disorders | 1/26 | 0/10 |
| Musculoskeletal painMusculoskeletal and connective tissue disorders | 1/26 | 0/10 |
| ClaustrophobiaPsychiatric disorders | 1/26 | 0/10 |
| Sinus headacheRespiratory, thoracic and mediastinal disorders | 1/26 | 0/10 |
Safety Population Set
| Age, Continuous(years) | CAD Participants | Healthy Participants | Total |
|---|---|---|---|
| Mean | 70.9 ± 6.6 | 58.4 ± 12.1 | 67.4 ± 10.1 |
| Sex: Female, Male(Participants) | CAD Participants | Healthy Participants | Total |
|---|---|---|---|
| Female | 5 | 5 | 10 |
| Male | 21 | 5 | 26 |
| Race/Ethnicity, Customized(Participants) | CAD Participants | Healthy Participants | Total |
|---|---|---|---|
| Caucasian | 26 | 9 | 35 |
| Other | 0 | 1 | 1 |
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Plan to share: Yes — Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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