Diagnostic and Targeted Therapy Approach for Abdominal Aortic Aneurysm

No longer recruiting at 1 trial location

Overseen By Laura McDonald, RN, BSN

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Washington University School of Medicine

Disqualifiers: Chronic renal failure, Allergy, Pregnancy, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: 4 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks new methods to diagnose and treat abdominal aortic aneurysms (AAAs), which are bulges in the large blood vessel that can burst without warning. Researchers aim to identify markers in the body that indicate disease activity, potentially allowing for tailored treatments. The trial includes several groups, such as those with a confirmed AAA and those without, using a special imaging technique to study the condition. Participants should be 40 or older, have an AAA diagnosed by a CT scan, or have been screened and confirmed not to have an AAA. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking medical advancements.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you have certain conditions like coronary disease, cancer, or autoimmune diseases, you may be excluded from participating.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the 64Cu-DOTA-ECL1i tracer used in this study has been promising in spotting inflammatory cells in abdominal aortic aneurysms (AAA) in past animal studies. These studies found the tracer effective and accurate in detecting these cells, which could aid in diagnosing AAA. However, since this trial is in the early stages, information on human reactions to this tracer remains limited. Early trials typically focus on safety, so researchers will closely monitor any side effects or reactions. Therefore, the treatment is still being tested for safety in humans, and participants should consider this when deciding to join the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores new ways to diagnose and treat abdominal aortic aneurysms (AAA) by targeting a specific type of inflammatory cell, known as CCR2+ cells, using a radiotracer called 64Cu-DOTA-ECL1i. Unlike traditional treatments that typically focus on surgical repair and monitoring, this approach could help identify and target inflammation in aneurysms more precisely. By using PET/CT imaging and analyzing tissue samples, the trial aims to better understand the role of these inflammatory cells in AAA development, potentially leading to more targeted and effective treatments in the future.

What evidence suggests that this trial's treatments could be effective for abdominal aortic aneurysm?

Research has shown that focusing on the CCR2 receptor might offer a promising way to treat abdominal aortic aneurysms (AAA). Studies with rats demonstrated that a CCR2 blocker can help predict and prevent AAA from bursting. In these studies, the treatment slowed aneurysm growth and reduced the chances of deadly ruptures. This approach proved especially effective in female rats, who face a higher risk of rupture. In this trial, participants in the AAA Group (Aim 3A) and AAA Group (Aim 3B-Reproducibility) will undergo PET/CT scans using the 64Cu-DOTA-ECL1i tracer to detect CCR2+ inflammatory cells. Early tests in humans have shown promise in spotting AAA using CCR2 PET/CT scans. Although human studies remain limited, these findings suggest that targeting CCR2 could help manage and possibly prevent AAA from rupturing. ^{1 6 7 8 9}

Who Is on the Research Team?

Mohamed M. Zayed, MD

Principal Investigator

Washington University of Medicine

Are You a Good Fit for This Trial?

This trial is for men over 65 and women with abdominal aortic aneurysms (AAA) that are asymptomatic, measured by CT angiogram. It includes smokers and non-smokers who can follow study instructions. Non-AAA volunteers without AAA or significant atherosclerotic disease can also join. People unable to lie flat for an hour, those with unstable conditions, severe kidney failure, allergies to iodine/shellfish, pregnant/lactating women, or inflammatory diseases cannot participate.

Inclusion Criteria

Whether or not you currently smoke.

I am 40 years old or older.

I have a large abdominal aortic aneurysm but no symptoms.

Exclusion Criteria

You have a proven allergy to iodinated contrast dye or shellfish.

Patients with an unstable clinical condition that in the opinion of the principal investigators or designee precludes participation in the study

I cannot lie flat for 60 minutes with my arms by my side.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Imaging and Diagnosis

Participants undergo PET/CT imaging to detect CCR2+ inflammatory cells and assess AAA inflammation

10-14 days

2 visits (in-person)

Treatment

Participants receive 64Cu-DOTA-ECL1i tracer for targeted imaging and potential therapeutic assessment

4 years

Follow-up

Participants are monitored for safety and effectiveness after imaging and treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• AAA Group (Aim 3A)
• AAA Group (Aim 3B-Reproducibility)
• Ex Vivo Human AAA Specimens
• Non-AAA Group

Trial Overview

The NIH CCR2 AAA Study aims to develop new diagnostic methods and targeted treatments for AAA by studying the relationship between a radiotracer and CCR2 expression in patients with AAAs compared to those without. The study will involve imaging tests like PET/CT scans on different groups including people with AAAs and controls without it.

How Is the Trial Designed?

Group I: Radiotracer and CCR2 (Aim 2B) Experimental Treatment 1 Intervention

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.

Group II: Non-AAA Group Experimental Treatment 1 Intervention

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.

Group III: Ex Vivo Human AAA Specimens (Aim 2A) Experimental Treatment 1 Intervention

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.

Group IV: AAA Group (Aim 3B-Reproducibility) Experimental Treatment 1 Intervention

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.

Group V: AAA Group (Aim 3A) Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Published Research Related to This Trial

The study successfully cloned and characterized rabbit CCR2, showing it shares 80% identity with human CCR2b, which is important for understanding inflammatory diseases in rabbit models.

Rabbit CCR2 is a functional chemotactic receptor for MCP-1, and the CCR2 antagonist TAK-779 effectively inhibits its activity, providing a valuable tool for future toxicology and efficacy studies in inflammatory disease research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cloning and functional characterization of the rabbit C-C chemokine receptor 2. Lu, D., Yuan, XJ., Evans, RJ., et al.[2018]

Novel alkylsulfones have been developed as potent CCR2 antagonists, showing reduced activity on the hERG channel, which is important for heart safety, and improved pharmacokinetics compared to earlier compounds.

Two specific alkylsulfones demonstrated oral efficacy in an animal model of inflammation, indicating their potential as effective treatments for conditions involving inflammatory recruitment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alkylsulfone-containing trisubstituted cyclohexanes as potent and bioavailable chemokine receptor 2 (CCR2) antagonists. Cherney, RJ., Mo, R., Yang, MG., et al.[2021]

CCR2 antagonists have shown promise in reducing inflammation in various diseases, such as rheumatoid arthritis and multiple sclerosis, and are progressing into clinical development.

A new approach to designing CCR2 antagonists involves modifying the chemical structure to reduce unwanted hERG binding, which is important for improving drug safety and pharmacokinetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel series of N-(azetidin-3-yl)-2-(heteroarylamino)acetamide CCR2 antagonists. Subasinghe, NL., Lanter, J., Markotan, T., et al.[2013]

New CCR1 antagonists have been identified that are highly effective, showing sub-nanomolar potency in blocking MIP-1α-induced calcium flux in cells expressing CCR1, which is important for leukocyte activation and migration.

Further preclinical studies are necessary to evaluate the potential of these CCR1 antagonists in treating human inflammatory diseases like multiple sclerosis and rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-aryl pyrazoles, indazoles and azaindazoles as antagonists of CC chemokine receptor 1: patent cooperation treaty applications WO2010/036632, WO2009/134666 and WO2009/137338. Carter, PH., Hynes, J.[2013]

Compound 3 is a novel hydroxyethylene peptide isostere that effectively inhibits CCL3 binding to its receptor CCR1 at micromolar concentrations, indicating potential therapeutic relevance.

The initial studies confirm that compound 3 is a promising lead for further medicinal chemistry optimization, paving the way for developing new treatments targeting CCR1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The discovery of structurally novel CCR1 antagonists derived from a hydroxyethylene peptide isostere template. Kath, JC., DiRico, AP., Gladue, RP., et al.[2007]

In a study involving 54 male BABL/c mice, the use of a CCR3 antagonist significantly reduced corneal neovascularization compared to the control group, indicating its potential efficacy in treating this condition.

Despite the reduction in neovascularization, the CCR3 antagonist did not significantly alter the expression levels of VEGF, suggesting that the CCR3 pathway may play a crucial role in corneal neovascularization that requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Inhibited experimental mouse corneal neovascularization by CCR3 antagonist]. Liu, G., He, X., Zhou, W., et al.[2014]

Targeting the CCR2 receptor is promising for treating various diseases like autoimmune disorders and metabolic diseases due to its key role in monocyte migration.

Despite the potential, developing effective CCR2 antagonists has faced challenges, including poor activity in rodent models and selectivity issues with other receptors, which complicates their therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CCR2 antagonists. Struthers, M., Pasternak, A.[2019]

CCR1 is a promising target for treating autoimmune and inflammatory diseases due to its role in inflammation, with numerous antagonists being developed to block its activity.

Recent advancements in CCR1 antagonists have shown improved potency and efficacy in animal models, although some earlier compounds were withdrawn from clinical trials due to insufficient effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CCR1 antagonists. Cheng, JF., Jack, R.[2021]

A new class of CCR2 antagonists was developed, featuring a unique 2-aminooctahydrocyclopentalene-3a-carboxamide structure, which showed promising potency in preclinical studies.

One specific compound, referred to as compound 51, demonstrated a favorable pharmacokinetic profile in both dogs and monkeys, and effectively reduced inflammation in a model using human CCR2 knock-in mice when administered orally.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel 2-aminooctahydrocyclopentalene-3a-carboxamides as potent CCR2 antagonists. Cai, C., Kang, FA., Hou, C., et al.[2016]

The dual CCR3 and H1-receptor antagonist AZD3778 significantly reduced symptoms of allergic rhinitis and improved nasal peak inspiratory flow (PIF) compared to a placebo and antihistamine (loratadine) during allergen challenges in patients with seasonal allergic rhinitis.

AZD3778 also decreased levels of eosinophil-related markers (ECP) in nasal lavages, suggesting its effectiveness in targeting allergic inflammation through CCR3 antagonism, which may be a key mechanism in alleviating symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a dual CCR3 and H1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis. Greiff, L., Ahlström-Emanuelsson, C., Bahl, A., et al.[2021]

The study successfully constructed a recombinant eukaryotic expression vector for murine Ccr2, which was then stably transfected into RAW264.7 cells, indicating a successful method for gene expression in these immune cells.

The expression of Ccr2 was confirmed through multiple techniques, including RT-PCR and Western blot, showing that the CCR2 protein is present on the cell membrane, which is crucial for its function in immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Construction of eukaryotic expression vector of murine chemokine (C-C motif) receptor 2 (Ccr2) and establishment of its stably transfected RAW264.7 cell line]. Zhao, W., Lu, XH., Pei, XY.[2010]

The study identified that the cyclohexane linker in a CCR3 antagonist could be effectively replaced with an acyclic syn-alpha-methyl-beta-hydroxypropyl linker, which maintains the drug's efficacy.

The compound alpha-methyl-beta-hydroxypropyl urea demonstrated a very low IC(50) of 38 pM for eosinophil chemotaxis, indicating strong potential for clinical development in treating asthma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis. Santella, JB., Gardner, DS., Yao, W., et al.[2014]

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