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NIH CCR2 AAA Study

Primary Purpose

Abdominal Aortic Aneurysm (AAA), No Abdominal Aortic Aneurysm (Non-AAA)

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
AAA Group (Aim 3A)
Non-AAA Group
Ex Vivo Human AAA Specimens (Aim 2A)
Relationship between radiotracer and CCR2 (Aim 2B)
AAA Group (Aim 3B-Reproducibility)
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Abdominal Aortic Aneurysm (AAA)

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 40 years old and above
  • With or without active tobacco use
  • Asymptomatic patients with known AAAs by CT angiogram (men ≥ 5.5 cm, women ≥ 5.0cm).
  • Non-AAA volunteers will have a documented absence of AAA by exam and recent screening ultrasound (US).
  • Able to comprehend and willing to follow instructions for the study procedures as called for by the protocol

Exclusion Criteria:

  • Inability to receive and sign informed consent.
  • Patients with Stage ≥ 4 chronic renal failure (calculated by modification of diet in renal disease eGFR equation [to minimize confounding imaging variables])
  • Documented allergy to iodinated contrast and/or shellfish.
  • Patients with an unstable clinical condition that in the opinion of the principal investigators or designee precludes participation in the study.
  • Inability to tolerate 60 minutes in a supine position with arms down at sides, as necessary for PET/CT.
  • Positive pregnancy test or lactating.
  • Other conditions such as symptomatic/recently treated coronary disease, cancer requiring oncologic management, or autoimmune/inflammatory diseases (e.g., rheumatoid arthritis or multiple sclerosis) that are known to have increased associated CCR2 expression.
  • Non-AAA volunteers may not carry a diagnosis of aortoiliac occlusive disease, as documented by their treating vascular surgeon, as significantly progressed atherosclerotic disease may demonstrate exaggerated, associated CCR2 expression.

Sites / Locations

  • Washington University School of MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Other

Other

Experimental

Arm Label

AAA Group (Aim 3A)

Non-AAA Group

Ex Vivo Human AAA Specimens (Aim 2A)

Radiotracer and CCR2 (Aim 2B)

AAA Group (Aim 3B-Reproducibility)

Arm Description

40 (20 men; 20 women) participants with a diagnosis of AAA (above 40 years) will undergo a PET/CT scan prior to their scheduled surgical repair of their condition. The radiotracer, 64Cu-DOTA-ECL1i, will be injected to detect CCR2+ inflammatory cells. A dosage range of 8-10 mCi (296-370 MBq) is planned for 64Cu-DOTA-ECL1i. A PET-certified medical professional will draw and administer the 64Cu-DOTA-ECL1i tracer. The dosage will be assayed in a dose calibrator before and after the administration.

10 (5 men; 5 women) participants will have a documented absence of AAA by screening ultrasound that was previously obtained as part of standard of care. A dosage range of 8-10 mCi (296-370 MBq) is planned for 64Cu-DOTA-ECL1i. A PET-certified medical professional will draw and administer the 64Cu-DOTA-ECL1i tracer. The dosage will be assayed in a dose calibrator before and after the administration.

Tissue samples obtained from an existing tissue bank as well as discarded tissue obtained from participants in this study will be examined to assess the sensitivity and specificity of 64Cu-DOTA-ECL1i binding to ex vivo to human AAA specimens.

Tissue samples obtained from an existing tissue bank as well as discarded tissue obtained from participants in this study will be examined to better understand the relationship between the levels of CCR2+ inflammatory cells and the inflammatory and clinical status of AAA, to gain insight into the importance of proinflammatory monocytes/macrophages in the development of AAA disease at the time of elective AAA repair.

20 (10 men; 10 women) will receive a second PET/CT imaging study performed 10-14 days after the first PET/CT in order to determine the ability to reproduce the uptake results. A dosage range of 8-10 mCi (296-370 MBq) is planned for 64Cu-DOTA-ECL1i. A PET-certified medical professional will draw and administer the 64Cu-DOTA-ECL1i tracer. The dosage will be assayed in a dose calibrator before and after the administration.

Outcomes

Primary Outcome Measures

Determine the binding characteristics of 64Cu-DOTA-ECL1i in ex vivo human AAA specimens and correlate with associated histopathological features
Perform histopathological evaluation of human AAA specimens and categorize them based on clinical status (e.g, diameter) and degree of inflammation. The investigators will consider healthy, nonatherosclerotic aorta as negative controls, and non-aneurysmal aortas from patients that have undergone surgery for aortoiliac occlusive disease as positive controls. Disease severity will be graded as mild, moderate, and severe based on the degree of VSMC loss and elastic layer disruption (<25%, 25-75%, and >75% compared to normal aorta). The presence of atherosclerotic changes, intraluminal thrombus and degree and location of associated inflammation will be documented. The degree of inflammation will be scored in three tiers: absent/minimal (rare scattered inflammatory cecells), moderate (small clusters of inflammatory cells), and severe (easily identified with scanning magnification).
Determine the relationship between 64Cu-DOTA-ECL1i binding, regional CCR2 gene expression, cytokine profiles and local matrix metalloproteinase (MMP) activity.
Tissue will be collected from patients who undergo surgery and tissue will be collected from a repository at our institution. Investigators will correlate level of MMP expression, activity and cytokine profiles of each specimen, with associated histopathological features. To address the concern of tissue heterogeneity, investigators will perform spatial transcriptomics assays for quantitative measurement of regional CCR2 gene expression on human AAA sections. Since clinical status and aneurysmal anatomic features on preop imaging of each patient is known, investigators will explore correlation of standard of care imaging findings with those from Aim 2A and this sub-aim to determine the role of CCR2 in AAA pathogenesis and its potential as a biomarker for human AAA disease.
Assess the 64Cu-DOTA-ECL1i imaging characteristics in AAA patients undergoing open repair and non-AAA volunteers to determine the relationship between tracer uptake and molecular characterization of prospectively collected AAA tissues.
Investigators will determine retention of 64Cu-DOTA-ECL1i in abdominal aorta of non-AAA volunteers (n=10, 5 women and 5 men). Investigators will image AAA patients pre-operatively and collect tissue at the time of open repair in an attempt to demonstrate ex-vivo tissue corroboration of our imaging findings (n=20, 10 women and 10 men).
Assess imaging reproducibility of 64Cu-DOTA-ECL1i PET/CT in non-surgical AAA patients.
Reproducibility group - Aim 3B, We will demonstrate consistent 64Cu-DOTAECL1i uptake by performing repeated imaging studies in a separate group of non-surgical AAA patients (n=20, 10 women and 10 men). Completion of this sub-aim will provide support for the use of 64Cu-DOTA-ECL1i PET for evaluating AAA disease in a reliable fashion.

Secondary Outcome Measures

Full Information

First Posted
September 29, 2020
Last Updated
July 14, 2023
Sponsor
Washington University School of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT04586452
Brief Title
NIH CCR2 AAA Study
Official Title
CCR2 Targeted Molecular Imaging and Treatment of Abdominal Aortic Aneurysms
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 17, 2021 (Actual)
Primary Completion Date
June 2025 (Anticipated)
Study Completion Date
June 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Abdominal aortic aneurysm (AAA) is a degenerative vascular disease, which is typically asymptomatic until rupture, resulting in high mortality. AAAs are more prevalent in men over age 65, though rupture is disproportionately higher in women. Due to nonlinear and unpredictable aortic dilatation, it is challenging to predict the AAA rupture using clinical diagnostics based on morphology. No medical therapy is used clinically to treat AAA, and there is an unmet need for clinically translatable, molecular biomarkers of AAA disease activity for surveillance and patient-specific management. The goal of this proposal is to develop a new approach for the diagnosis and targeted therapy of AAA.
Detailed Description
This project addresses the absence of a reliable diagnostic modality and medical therapy to prevent abdominal aortic aneurysm (AAA) growth and rupture in patients, leading to high mortality in those over the age of 65 years old. Due to the pathogenic role of the monocyte chemoattractant protein-1 / C-C chemokine receptor type 2 (MCP-1/CCR2) axis in AAA, we propose to study the ability of 64Cu-DOTA-ECL1i PET/CT to predict the murine AAA rupture and serve as a companion diagnostic to assess CCR2 molecular therapy of murine AAA. We will perform the first-in-patient evaluation of 64Cu-DOTA-ECL1i PET/CT to image and detect AAA inflammation in a preoperative setting and acquire key biological information from AAA specimens collected at the time of open AAA repair, in order to assess the potential of 64Cu-DOTA-ECL1i PET in the management of AAA patients. Preclinical and clinical research demonstrated that monocyte chemotactic protein-1/ chemokine (C-C motif) receptor 2 (MCP-1/CCR2) plays an important role in the pathogenesis of AAAs. This axis specifically promotes AAA formation and development by mediating the recruitment of circulating LY6Chigh monocytes and infiltration of macrophages, which leads to the degradation of elastic and collagen. In AAA mouse models, the genetic depletion or specific inhibition of CCR2 significantly decreased the production of matrix metalloproteinases (MMPs) and formation of aneurysms, suggesting the potential of CCR2 as a biomarker for AAA imaging and pre-screening for targeted intervention. We have developed a specific CCR2 binding radiotracer, 64Cu-DOTA-ECL1i, for targeted imaging of CCR2 positive pro-inflammatory monocytes/macrophages, in multiple animal inflammatory models using positron emission tomography (PET). This investigational PET tracer is being used under Exploratory IND 137620 for research imaging studies in human subjects. In patients with inflammatory diseases, 64Cu-DOTA-ECL1i PET revealed specific detection of CCR2+ cells in inflammatory tissues. In a rat AAA model, 64Cu-DOTA-ECL1i PET revealed specific localization within the aneurysm, as well as sensitive detection of CCR2+ inflammatory cells. Human AAA specimens demonstrated specific binding of 64Cu-DOTA-ECL1i to CCR2 by autoradiography. Thus, we hypothesize that 64Cu-DOTA-ECL1i detect CCR2+ cells mediated aneurysmal activity and can be utilized for AAA molecular imaging. We propose to assess the potential of 64Cu-DOTA-ECL1i as a biomarker for AAA patients imaging.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Abdominal Aortic Aneurysm (AAA), No Abdominal Aortic Aneurysm (Non-AAA)

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Model Description
There are two (2) groups in the study. AAA Group: 40 (20 men; 20 women) participants who will have a PET/CT imaging study performed and a subset of 20 participants who will have an additional PET/CT imaging study performed. Non-AAA Group: 10 without AAA (5 men; 5 women), above the age of 40, with or without active tobacco use
Masking
None (Open Label)
Allocation
Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
AAA Group (Aim 3A)
Arm Type
Experimental
Arm Description
40 (20 men; 20 women) participants with a diagnosis of AAA (above 40 years) will undergo a PET/CT scan prior to their scheduled surgical repair of their condition. The radiotracer, 64Cu-DOTA-ECL1i, will be injected to detect CCR2+ inflammatory cells. A dosage range of 8-10 mCi (296-370 MBq) is planned for 64Cu-DOTA-ECL1i. A PET-certified medical professional will draw and administer the 64Cu-DOTA-ECL1i tracer. The dosage will be assayed in a dose calibrator before and after the administration.
Arm Title
Non-AAA Group
Arm Type
Experimental
Arm Description
10 (5 men; 5 women) participants will have a documented absence of AAA by screening ultrasound that was previously obtained as part of standard of care. A dosage range of 8-10 mCi (296-370 MBq) is planned for 64Cu-DOTA-ECL1i. A PET-certified medical professional will draw and administer the 64Cu-DOTA-ECL1i tracer. The dosage will be assayed in a dose calibrator before and after the administration.
Arm Title
Ex Vivo Human AAA Specimens (Aim 2A)
Arm Type
Other
Arm Description
Tissue samples obtained from an existing tissue bank as well as discarded tissue obtained from participants in this study will be examined to assess the sensitivity and specificity of 64Cu-DOTA-ECL1i binding to ex vivo to human AAA specimens.
Arm Title
Radiotracer and CCR2 (Aim 2B)
Arm Type
Other
Arm Description
Tissue samples obtained from an existing tissue bank as well as discarded tissue obtained from participants in this study will be examined to better understand the relationship between the levels of CCR2+ inflammatory cells and the inflammatory and clinical status of AAA, to gain insight into the importance of proinflammatory monocytes/macrophages in the development of AAA disease at the time of elective AAA repair.
Arm Title
AAA Group (Aim 3B-Reproducibility)
Arm Type
Experimental
Arm Description
20 (10 men; 10 women) will receive a second PET/CT imaging study performed 10-14 days after the first PET/CT in order to determine the ability to reproduce the uptake results. A dosage range of 8-10 mCi (296-370 MBq) is planned for 64Cu-DOTA-ECL1i. A PET-certified medical professional will draw and administer the 64Cu-DOTA-ECL1i tracer. The dosage will be assayed in a dose calibrator before and after the administration.
Intervention Type
Diagnostic Test
Intervention Name(s)
AAA Group (Aim 3A)
Intervention Description
The primary goal is to relate preoperative 64Cu-DOTA-ECL1i AAA uptake with CCR2+ cell activity in AAA tissue collected at the time of open repair. We will image AAA patients pre-operatively and collect tissue at the time of open repair in an attempt to demonstrate ex-vivo tissue corroboration of our imaging findings (n=20, 10 women and 10 men). Participants with AAA will undergo routine clinical evaluation including ultrasound, CT scan and scheduling of open surgical repair. We will record age and tobacco use. If a renal function blood test has not been performed within the past 90 days, we will draw ~2 teaspoons of blood for a creatinine test. A contrast dye will be used for the CT portion of the PET-CT scan. Those having open surgery, their PET/CT imaging will be within 7-14 of the surgery and if available, collection of discarded aortic tissue at the time of surgery.
Intervention Type
Diagnostic Test
Intervention Name(s)
Non-AAA Group
Intervention Description
We will determine the retention of 64Cu-DOTA-ECL1i in abdominal aorta of non-AAA volunteers (n=10, 5 women and 5 men). This group of participants will have a documented absence of AAA by screening ultrasound that was previously obtained as part of standard care. Both men and women, above the age of 40, with or without active tobacco use will be considered for participation.
Intervention Type
Other
Intervention Name(s)
Ex Vivo Human AAA Specimens (Aim 2A)
Intervention Description
The primary objective of this sub-aim is to assess the sensitivity and specificity of 64Cu-DOTA-ECL1i binding to ex vivo to human AAA specimens from the Washington University Vascular Surgery Biobank (VS-BB). We will first perform a histopathological evaluation of human AAA specimens (n=75, including samples from this study) and categorize them based on clinical status (e.g, diameter) and degree of inflammation. We will consider healthy, nonatherosclerotic aorta (n=25) as negative controls, and non-aneurysmal aortas (n=25) from patients that have undergone surgery for aortoiliac occlusive disease as positive controls.
Intervention Type
Other
Intervention Name(s)
Relationship between radiotracer and CCR2 (Aim 2B)
Intervention Description
The objective of this sub-aim is to better understand the relationship between the levels of CCR2+ inflammatory cells and the inflammatory and clinical status of AAA, to gain insight into the importance of proinflammatory monocytes/macrophages in the development of AAA disease at the time of elective AAA repair. We will correlate the level of MMP expression and activity, as well as cytokine profiles, of each specimen, with the associated histopathological features. The relationship between 64Cu-DOTA-ECL1i binding and CCR2 expression in tissues with different degrees of disease severity will be evaluated using Pearson or Spearman correlation coefficients. This will allow us to speculate as to how tracer uptake will perform in vivo and what that uptake represents in regard to disease severity.
Intervention Type
Diagnostic Test
Intervention Name(s)
AAA Group (Aim 3B-Reproducibility)
Other Intervention Name(s)
Reproducibility
Intervention Description
We will demonstrate consistent 64Cu-DOTAECL1i uptake by performing repeated imaging studies in a separate group of non-surgical AAA patients (n=20, 10 women and 10 men). Completion of this sub-aim will provide support for the use of 64Cu-DOTA-ECL1i PET for evaluating AAA disease in a reliable fashion. These participants will have another PET/CT imaging study performed 10-14 days after the first PET/CT in order to determine the ability to reproduce the uptake results of Cu-64-DOTA-ECL1i. The physician will assess the participant's willingness and eligibility to have a second PET/CT scan.
Primary Outcome Measure Information:
Title
Determine the binding characteristics of 64Cu-DOTA-ECL1i in ex vivo human AAA specimens and correlate with associated histopathological features
Description
Perform histopathological evaluation of human AAA specimens and categorize them based on clinical status (e.g, diameter) and degree of inflammation. The investigators will consider healthy, nonatherosclerotic aorta as negative controls, and non-aneurysmal aortas from patients that have undergone surgery for aortoiliac occlusive disease as positive controls. Disease severity will be graded as mild, moderate, and severe based on the degree of VSMC loss and elastic layer disruption (<25%, 25-75%, and >75% compared to normal aorta). The presence of atherosclerotic changes, intraluminal thrombus and degree and location of associated inflammation will be documented. The degree of inflammation will be scored in three tiers: absent/minimal (rare scattered inflammatory cecells), moderate (small clusters of inflammatory cells), and severe (easily identified with scanning magnification).
Time Frame
4 years
Title
Determine the relationship between 64Cu-DOTA-ECL1i binding, regional CCR2 gene expression, cytokine profiles and local matrix metalloproteinase (MMP) activity.
Description
Tissue will be collected from patients who undergo surgery and tissue will be collected from a repository at our institution. Investigators will correlate level of MMP expression, activity and cytokine profiles of each specimen, with associated histopathological features. To address the concern of tissue heterogeneity, investigators will perform spatial transcriptomics assays for quantitative measurement of regional CCR2 gene expression on human AAA sections. Since clinical status and aneurysmal anatomic features on preop imaging of each patient is known, investigators will explore correlation of standard of care imaging findings with those from Aim 2A and this sub-aim to determine the role of CCR2 in AAA pathogenesis and its potential as a biomarker for human AAA disease.
Time Frame
4 years
Title
Assess the 64Cu-DOTA-ECL1i imaging characteristics in AAA patients undergoing open repair and non-AAA volunteers to determine the relationship between tracer uptake and molecular characterization of prospectively collected AAA tissues.
Description
Investigators will determine retention of 64Cu-DOTA-ECL1i in abdominal aorta of non-AAA volunteers (n=10, 5 women and 5 men). Investigators will image AAA patients pre-operatively and collect tissue at the time of open repair in an attempt to demonstrate ex-vivo tissue corroboration of our imaging findings (n=20, 10 women and 10 men).
Time Frame
4 years
Title
Assess imaging reproducibility of 64Cu-DOTA-ECL1i PET/CT in non-surgical AAA patients.
Description
Reproducibility group - Aim 3B, We will demonstrate consistent 64Cu-DOTAECL1i uptake by performing repeated imaging studies in a separate group of non-surgical AAA patients (n=20, 10 women and 10 men). Completion of this sub-aim will provide support for the use of 64Cu-DOTA-ECL1i PET for evaluating AAA disease in a reliable fashion.
Time Frame
4 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 40 years old and above With or without active tobacco use Asymptomatic patients with known AAAs by CT angiogram (men ≥ 5.5 cm, women ≥ 5.0cm). Non-AAA volunteers will have a documented absence of AAA by exam and recent screening ultrasound (US). Able to comprehend and willing to follow instructions for the study procedures as called for by the protocol Exclusion Criteria: Inability to receive and sign informed consent. Patients with Stage ≥ 4 chronic renal failure (calculated by modification of diet in renal disease eGFR equation [to minimize confounding imaging variables]) Documented allergy to iodinated contrast and/or shellfish. Patients with an unstable clinical condition that in the opinion of the principal investigators or designee precludes participation in the study. Inability to tolerate 60 minutes in a supine position with arms down at sides, as necessary for PET/CT. Positive pregnancy test or lactating. Other conditions such as symptomatic/recently treated coronary disease, cancer requiring oncologic management, or autoimmune/inflammatory diseases (e.g., rheumatoid arthritis or multiple sclerosis) that are known to have increased associated CCR2 expression. Non-AAA volunteers may not carry a diagnosis of aortoiliac occlusive disease, as documented by their treating vascular surgeon, as significantly progressed atherosclerotic disease may demonstrate exaggerated, associated CCR2 expression.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ashley Cosentino, RN, BSN
Phone
(314) 362-6257
Email
ashley.cosentino@wustl.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Laura McDonald, RN, BSN
Phone
(314) 747-7828
Email
m.laura@wustl.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mohamed M. Zayed, MD
Organizational Affiliation
Washington University of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Julie Wilson, RN
Phone
314-747-7828
Email
wilsonj@wustl.edu
First Name & Middle Initial & Last Name & Degree
Ashley Burgess, RN, BSN
Phone
(314) 362-6257
Email
ashley.burgess@wustl.edu
First Name & Middle Initial & Last Name & Degree
Sean English, M.D.

12. IPD Sharing Statement

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NIH CCR2 AAA Study

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