99mTc-rhAnnexin V-128 Imaging for Carotid Atherosclerosis

• Sponsor: Advanced Accelerator Applications (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02667457
• Collaborator: (none)
• Enrollment: 39
• Location: 1
• Arms: 2
• Actual Duration (Months): 28.9
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Carotid Artery Plaque	Radiation: 99mTc-rhAnnexin V-128	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: 99mTc-rhAnnexin V-128 Planar and SPECT Imaging of Apoptosis in Asymptomatic Or Previously Symptomatic With TIA Patients With Carotid Atherosclerotic Plaque
• Actual Study Start Date: Jun 23, 2016
• Actual Primary Completion Date: Nov 12, 2018
• Actual Study Completion Date: Nov 19, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CAD Participants 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
Experimental: Healthy Participants 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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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

1. 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).

2. 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).

3. 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).

4. 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).

5. 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).

6. 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.

7. 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.

8. 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.

9. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

For all participants:

1. Males and females age 18 years or greater

2. Able and willing to comply with the study procedures

3. 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:

1. Evidence of 50% or more carotid stenosis in one or more carotid arteries on carotid ultrasound within 2 years;

2. 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:

1. No significant carotid artery disease on carotid ultrasound;

2. No clinically significant abnormalities in baseline laboratory values.

Exclusion Criteria:

1. Previous carotid stending, endarterectomy or stroke;

2. Diagnosis of vasculitis, dissection, or non-atherosclerotic carotid disease (Ehlers-Danlos, Marfans);

3. Pregnancy or lactation;

4. 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;

5. Know hypersensitivity to the investigational product or any of its components;

6. Claustrophobia or inability to lie still in a supine position;

7. 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;

8. Unwillingness to provide consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Ottawa Heart Institute	Ottawa	Ontario	Canada	K1Y 4W7

Sponsors and Collaborators

• Advanced Accelerator Applications

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Feb 2, 2018
• Statistical Analysis Plan - May 24, 2019

More Information

Publications

None provided.

• Responsible Party: Advanced Accelerator Applications
• ClinicalTrials.gov Identifier: NCT02667457
• Other Study ID Numbers: AAA-Annexin-04; CAAA113A32201
• First Posted: Jan 29, 2016
• Last Update Posted: Oct 9, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Advanced Accelerator Applications: Carotid Stenosis; Carotid Artery Narrowing; Carotid Artery Plaque; Carotid Artery Stenosis; Carotid Artery Ulcerating Plaque; Carotid Ulcer; Common Carotid Artery Stenosis; External Carotid Artery Stenosis; Internal Carotid Artery Stenosis; Plaque, Ulcerating, Carotid Artery; Stenosis, Common Carotid Artery; Stenosis, External Carotid Artery; Ulcerating Plaque, Carotid Artery
• Additional relevant MeSH terms: Carotid Stenosis

Study Results

Participant Flow

Recruitment Details	The study was conducted at single center in Canada.
Pre-assignment Detail	A total of 39 participants were screened and enrolled to the study, of which only 36 participants were administered with investigational imaging product. All 36 treated participants completed the study.

Arm/Group Title	Carotid Atherosclerotic Plaque (CAD) Participants	Healthy Participants
Arm/Group Description	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 Day 0.	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 Day 0.
Period Title: Overall Study
STARTED	27	12
Dosed Participants	26	10
Full Analysis Set Population (FAS)	25	10
COMPLETED	26	10
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	CAD Participants	Healthy Participants	Total
Arm/Group Description	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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.	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 Day 0.	Total of all reporting groups
Overall Participants	26	10	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.9 (6.6)	58.4 (12.1)	67.4 (10.1)
Sex: Female, Male (Count of Participants)
Female	5 19.2%	5 50%	10 27.8%
Male	21 80.8%	5 50%	26 72.2%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	26 100%	9 90%	35 97.2%
Other	0 0%	1 10%	1 2.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Evaluated for Imaging Feasibility
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set population (FAS)

Arm/Group Title	CAD Participants	Healthy Participants
Arm/Group Description	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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.	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 Day 0.
Measure Participants	25	10
Count of Participants [Participants]	15 57.7%	5 50%

2. Primary Outcome

Title	Percentage of Participants With Prevalence of Abnormal 99mTc-rhAnnexin V-128 SPECT/CT Imaging (Phase II Step)
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set population (FAS)

Arm/Group Title	CAD Participants	Healthy Participants
Arm/Group Description	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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.	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 Day 0.
Measure Participants	25	10
Positive (abnormal)	8 30.8%	0 0%
Negative (normal)	16 61.5%	10 100%
Missing	1 3.8%	0 0%
Positive (abnormal)	8 30.8%	0 0%
Negative (normal)	17 65.4%	10 100%
Missing	0 0%	0 0%

3. Secondary Outcome

Title	Left Carotid Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Only participants with Left Carotid Uptake Imaging Assessment included in the analysis.

Arm/Group Title	CAD Participants	Healthy Participants
Arm/Group Description	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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.	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 Day 0.
Measure Participants	25	10
60 Minutes	1.171 (0.764)	0.697 (0.222)
120 Minutes	1.208 (0.486)	0.827 (0.205)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CAD Participants, Healthy Participants
	Comments	Timepoint = 60 minutes
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0095
	Comments	p-value is based on t-test with unequal variances (Satterthwaite) if p-value of F-test for Equality of variances is significant (p<0.05) otherwise p-value is based on t-test with equal variances.
	Method	t-test, 1 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CAD Participants, Healthy Participants
	Comments	Timepoint = 120 minutes
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0029
	Comments	p-value is based on t-test with unequal variances (Satterthwaite) if p-value of F-test for Equality of variances is significant (p<0.05) otherwise p-value is based on t-test with equal variances.
	Method	t-test, 1 sided
	Comments

4. Secondary Outcome

Title	Right Carotid Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Only participants with Right Carotid Uptake Imaging Assessment included in the analysis.

Arm/Group Title	CAD Participants	Healthy Participants
Arm/Group Description	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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.	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 Day 0.
Measure Participants	25	10
60 Minutes	1.252 (0.745)	0.768 (0.209)
120 Minutes	1.220 (0.550)	0.928 (0.217)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CAD Participants, Healthy Participants
	Comments	Timepoint = 60 minutes
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0066
	Comments	p-value is based on t-test with unequal variances (Satterthwaite) if p-value of F-test for Equality of variances is significant (p<0.05) otherwise p-value is based on t-test with equal variances.
	Method	t-test, 1 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CAD Participants, Healthy Participants
	Comments	Timepoint = 120 minutes
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0334
	Comments	p-value is based on t-test with unequal variances (Satterthwaite) if p-value of F-test for Equality of variances is significant (p<0.05) otherwise p-value is based on t-test with equal variances.
	Method	t-test, 1 sided
	Comments

5. Secondary Outcome

Title	Ascending Aorta Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Only participants with Ascending Aorta Uptake Imaging Assessment included in the analysis.

Arm/Group Title	CAD Participants	Healthy Participants
Arm/Group Description	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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.	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 Day 0.
Measure Participants	25	10
60 Minutes	2.054 (0.656)	1.574 (0.252)
120 Minutes	1.616 (0.294)	1.381 (0.190)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CAD Participants, Healthy Participants
	Comments	Timepoint = 60 minutes
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0066
	Comments	p-value is based on t-test with unequal variances (Satterthwaite) if p-value of F-test for Equality of variances is significant (p<0.05) otherwise p-value is based on t-test with equal variances.
	Method	t-test, 1 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CAD Participants, Healthy Participants
	Comments	Timepoint = 120 minutes
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0301
	Comments	p-value is based on t-test with unequal variances (Satterthwaite) if p-value of F-test for Equality of variances is significant (p<0.05) otherwise p-value is based on t-test with equal variances.
	Method	t-test, 1 sided
	Comments

6. Secondary Outcome

Title	Descending Aorta Uptake Imaging Assessment as Measured by Target to Background Ratio (TBR)
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Only participants with Descending Aorta Uptake Imaging Assessment included in the analysis.

Arm/Group Title	CAD Participants	Healthy Participants
Arm/Group Description	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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.	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 Day 0.
Measure Participants	25	10
60 Minutes	2.159 (0.865)	1.590 (0.164)
120 Minutes	1.520 (0.245)	1.341 (0.131)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CAD Participants, Healthy Participants
	Comments	Timepoint = 60 minutes
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0066
	Comments	p-value is based on t-test with unequal variances (Satterthwaite) if p-value of F-test for Equality of variances is significant (p<0.05) otherwise p-value is based on t-test with equal variances.
	Method	t-test, 1 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CAD Participants, Healthy Participants
	Comments	Timepoint = 120 minutes
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0387
	Comments	p-value is based on t-test with unequal variances (Satterthwaite) if p-value of F-test for Equality of variances is significant (p<0.05) otherwise p-value is based on t-test with equal variances.
	Method	t-test, 1 sided
	Comments

7. Secondary Outcome

Title	Aortic Arch Uptake Correlation Imaging Assessment as Measured by Target to Background Ratio (TBR)
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Only participants with Aortic Arch Uptake Correlation Imaging Assessment included in the analysis.

Arm/Group Title	CAD Participants	Healthy Participants
Arm/Group Description	Participants with asymptomatic carotid atherosclerotic plaque or previously symptomatic with TIA only 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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.	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 Day 0.
Measure Participants	25	10
60 Minutes	1.986 (0.679)	1.606 (0.279)
120 Minutes	1.628 (0.380)	1.294 (0.174)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CAD Participants, Healthy Participants
	Comments	Timepoint = 60 minutes
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0359
	Comments	p-value is based on t-test with unequal variances (Satterthwaite) if p-value of F-test for Equality of variances is significant (p<0.05) otherwise p-value is based on t-test with equal variances.
	Method	t-test, 1 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CAD Participants, Healthy Participants
	Comments	Timepoint = 120 minutes
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments	p-value is based on t-test with unequal variances (Satterthwaite) if p-value of F-test for Equality of variances is significant (p<0.05) otherwise p-value is based on t-test with equal variances.
	Method	t-test, 1 sided
	Comments

8. Secondary Outcome

Title	Left Carotid Uptake Imaging Assessment as Measure by Target to Background Ratio (TBR) by Ultrasound Grade of Plaque Echolucency/Echogenicity
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Only participants with left carotid with stenosis >=50% are taken into account.

Arm/Group Title	CAD Participants
Arm/Group Description	Participants with asymptomatic carotid atherosclerotic plaque or previously symptomatic with TIA only 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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.
Measure Participants	25
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)

9. Secondary Outcome

Title	Right Carotid Uptake Imaging Assessment as Measure by Target to Background Ratio (TBR) by Ultrasound Grade of Plaque Echolucency/Echogenicity
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Only participants with right carotid with stenosis >=50% are taken into account.

Arm/Group Title	CAD Participants
Arm/Group Description	Participants with asymptomatic carotid atherosclerotic plaque or previously symptomatic with TIA only 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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.
Measure Participants	25
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)

10. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs and Death
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population Set

Arm/Group Title	CAD Participants	Healthy Participants
Arm/Group Description	Participants with asymptomatic carotid atherosclerotic plaque or previously symptomatic with TIA only 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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.	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 Day 0.
Measure Participants	26	10
Treatment Emergent Adverse Events (TEAEs)	7 26.9%	0 0%
Treatment Emergent Adverse Drug Reactions	2 7.7%	0 0%
Treatment Emergent Serious Adverse Events (TESAEs)	1 3.8%	0 0%
Treatment Emergent Serious Adverse Drug Reactions	0 0%	0 0%
TEAEs leading to Withdrawal	0 0%	0 0%
TEAEs leading to Deaths	0 0%	0 0%

11. Secondary Outcome

Title	Number of Participants With Clinically Significant Abnormal Laboratory Values
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population Set. Only participants with abnormal laboratory values are taken into account.

Arm/Group Title	CAD Participants	Healthy Participants
Arm/Group Description	Participants with asymptomatic carotid atherosclerotic plaque or previously symptomatic with TIA only 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 IV catheter in an antecubital vein, followed by a saline flush on Day 0.	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 Day 0.
Measure Participants	26	10
Abnormal non clinical relevant	26 100%	10 100%
Abnormal clinically relevant	0 0%	0 0%
Abnormal non clinical relevant	15 57.7%	4 40%
Abnormal clinically relevant	0 0%	0 0%
Abnormal non clinical relevant	10 38.5%	4 40%
Abnormal clinically relevant	0 0%	0 0%

Adverse Events

Time Frame	Adverse events were collected from Day 0 up to Day 30
Adverse Event Reporting Description	Analysis was performed in the safety population defined as all participants who received the administration of 99mTc-rhAnnexin V-128.
Arm/Group Title	CAD Participants		Healthy Participants
Arm/Group Description	Participants with asymptomatic carotid atherosclerotic plaque or previously symptomatic with TIA only 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 IV catheter in an antecubital vein, followed by a saline flush on screening (Day 0).		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).
All Cause Mortality
	CAD Participants		Healthy Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/10 (0%)
Serious Adverse Events
	CAD Participants		Healthy Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/26 (3.8%)		0/10 (0%)
Cardiac disorders
Bradycardia	1/26 (3.8%)	1	0/10 (0%)	0
Other (Not Including Serious) Adverse Events
	CAD Participants		Healthy Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/26 (26.9%)		0/10 (0%)
Cardiac disorders
Palpitations	1/26 (3.8%)	1	0/10 (0%)	0
Injury, poisoning and procedural complications
Accident	1/26 (3.8%)	1	0/10 (0%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/26 (3.8%)		0/10 (0%)	0
Muscle spasms	1/26 (3.8%)	1	0/10 (0%)	0
Musculoskeletal pain	1/26 (3.8%)	1	0/10 (0%)	0
Psychiatric disorders
Claustrophobia	1/26 (3.8%)	1	0/10 (0%)	0
Respiratory, thoracic and mediastinal disorders
Sinus headache	1/26 (3.8%)	1	0/10 (0%)	0

Limitations/Caveats

The study was prematurely terminated on 19-Mar-2019 due to strategic decisions to focus the AAA development portfolio on oncology theragnostics, and not based on any safety concerns.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.