Diagnostic and Targeted Therapy Approach for Abdominal Aortic Aneurysm

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

50 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the idea that Diagnostic and Targeted Therapy Approach for Abdominal Aortic Aneurysm is an effective treatment?

The available research does not provide specific data on the effectiveness of the Diagnostic and Targeted Therapy Approach for Abdominal Aortic Aneurysm. The studies mentioned focus on different conditions and treatments, such as inflammation and allergic reactions, rather than directly addressing the treatment of abdominal aortic aneurysms. Therefore, there is no direct evidence from the provided information to support the effectiveness of this treatment for abdominal aortic aneurysms. ^{1 2 3 4 5}

What data supports the effectiveness of the drug CCR2 inhibitor RS504393 for treating abdominal aortic aneurysm?

Research on CCR2 inhibitors shows they can reduce inflammation in animal models, which might help in conditions like abdominal aortic aneurysm where inflammation plays a role. ^{1 2 3 4 5}

What safety data exists for the treatment of abdominal aortic aneurysm?

The safety data for the treatment of abdominal aortic aneurysm, particularly involving CCR2 inhibitors like RS504393, is primarily derived from studies on CCR2 antagonists. These studies indicate that CCR2 antagonists have been efficacious in animal models of inflammatory diseases and have been advanced into clinical development. However, specific safety data for the use of CCR2 inhibitors in abdominal aortic aneurysm treatment is not detailed in the provided research. The research does highlight efforts to improve pharmacokinetics and reduce hERG channel activity, which are important for safety profiles. For Endovascular Aneurysm Repair (EVAR) and Open Surgical Repair (OSR), these are established procedures with existing safety data from clinical practice, but specific safety data from the research provided is not mentioned. ^{2 6 7 8 9}

Is the drug for the trial titled 'Diagnostic and Targeted Therapy Approach for Abdominal Aortic Aneurysm' a promising treatment?

The drug is promising because it targets specific receptors involved in inflammation, which is a key factor in many diseases. By blocking these receptors, the drug could potentially reduce inflammation and help treat conditions like abdominal aortic aneurysm. ^{2 3 10 11 12}

Research Team

Mohamed M. Zayed, MD

Principal Investigator

Washington University of Medicine

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. China pubmed.ncbi.nlm.nih.gov

[Inhibited experimental mouse corneal neovascularization by CCR3 antagonist]. [2014]

2. England pubmed.ncbi.nlm.nih.gov

Cloning and functional characterization of the rabbit C-C chemokine receptor 2. [2018]

3. England pubmed.ncbi.nlm.nih.gov

The discovery of structurally novel CCR1 antagonists derived from a hydroxyethylene peptide isostere template. [2007]

4. England pubmed.ncbi.nlm.nih.gov

Novel 2-aminooctahydrocyclopentalene-3a-carboxamides as potent CCR2 antagonists. [2016]

5. England pubmed.ncbi.nlm.nih.gov

Effects of a dual CCR3 and H1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis. [2021]

6. Netherlands pubmed.ncbi.nlm.nih.gov

CCR1 antagonists. [2021]

7. China 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]. [2010]

8. England pubmed.ncbi.nlm.nih.gov

Alkylsulfone-containing trisubstituted cyclohexanes as potent and bioavailable chemokine receptor 2 (CCR2) antagonists. [2021]

9. England pubmed.ncbi.nlm.nih.gov

A novel series of N-(azetidin-3-yl)-2-(heteroarylamino)acetamide CCR2 antagonists. [2013]

10. England 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. [2014]

11. United Arab Emirates pubmed.ncbi.nlm.nih.gov

CCR2 antagonists. [2019]

12. England 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. [2013]