Clinical trial NCT04586452: NIH CCR2 AAA Study
Official title: CCR2 Targeted Molecular Imaging and Treatment of Abdominal Aortic Aneurysms
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Abdominal Aortic Aneurysm (AAA)
No Abdominal Aortic Aneurysm (Non-AAA)
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2020-10-14
Enrollment: 50
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: DIAGNOSTIC

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.

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.

Primary outcomes:
measure: Determine the binding characteristics of 64Cu-DOTA-ECL1i in ex vivo human AAA specimens and correlate with associated histopathological features
timeFrame: 4 years
measure: Determine the relationship between 64Cu-DOTA-ECL1i binding, regional CCR2 gene expression, cytokine profiles and local matrix metalloproteinase (MMP) activity.
timeFrame: 4 years
measure: 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.
timeFrame: 4 years
measure: Assess imaging reproducibility of 64Cu-DOTA-ECL1i PET/CT in non-surgical AAA patients.
timeFrame: 4 years
Secondary outcomes:
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University of Medicine
name: Mohamed M. Zayed, MD
role: PRINCIPAL_INVESTIGATOR
References: