NIH CCR2 AAA Study

Brief Title

NIH CCR2 AAA Study

Official Title

CCR2 Targeted Molecular Imaging and Treatment of Abdominal Aortic Aneurysms

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.
    

Study Phase

Early Phase 1

Study Type

Interventional

Primary Outcome

Determine the binding characteristics of 64Cu-DOTA-ECL1i in ex vivo human AAA specimens and correlate with associated histopathological features

Condition

Abdominal Aortic Aneurysm (AAA)

Intervention

AAA Group (Aim 3A)

Study Arms / Comparison Groups

 AAA Group (Aim 3A)

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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Diagnostic Test

Estimated Enrollment

50

Start Date

February 17, 2021

Completion Date

June 2025

Primary Completion Date

June 2025

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.
      

Gender

All

Ages

40 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Mohamed M. Zayed, MD, (314) 362-6257, [email protected]

Location Countries

United States

Location Countries

United States

NCT ID

NCT04586452

Organization ID

202008190

Responsible Party

Sponsor

Study Sponsor

Washington University School of Medicine

Study Sponsor

Mohamed M. Zayed, MD, Principal Investigator, Washington University of Medicine

Verification Date

July 2022