Diagnostic and Targeted Therapy Approach for Abdominal Aortic Aneurysm
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase < 1
Waitlist Available
Sponsor: Washington University School of Medicine
No Placebo Group
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.
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.
12345What 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.
26789Is 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.
23101112Eligibility 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.
+2 more
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.
+5 more
Participant Groups
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.
5Treatment groups
Experimental Treatment
Group I: Radiotracer and CCR2 (Aim 2B)Experimental Treatment1 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 GroupExperimental Treatment1 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 Treatment1 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 Treatment1 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 Treatment1 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Washington University School of MedicineSaint Louis, MO
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Who Is Running the Clinical Trial?
Washington University School of MedicineLead Sponsor
References
[Inhibited experimental mouse corneal neovascularization by CCR3 antagonist]. [2014]To explore the effect of CCR3 antagonist on the development of experimental corneal neovascularization.
Cloning and functional characterization of the rabbit C-C chemokine receptor 2. [2018]CC-family chemokine receptor 2 (CCR2) is implicated in the trafficking of blood-borne monocytes to sites of inflammation and is implicated in the pathogenesis of several inflammatory diseases such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. The major challenge in the development of small molecule chemokine receptor antagonists is the lack of cross-species activity to the receptor in the preclinical species. Rabbit models have been widely used to study the role of various inflammatory molecules in the development of inflammatory processes. Therefore, in this study, we report the cloning and characterization of rabbit CCR2. Data regarding the activity of the CCR2 antagonist will provide valuable tools to perform toxicology and efficacy studies in the rabbit model.
The discovery of structurally novel CCR1 antagonists derived from a hydroxyethylene peptide isostere template. [2007]The present manuscript details the discovery and early fundamental structure-activity relationship studies involving compound 3, a novel hydroxyethylene peptide isostere derived molecule that provides micromolar inhibition of CCL3 binding to its receptor CCR1. Initial studies established this screening hit as a legitimate lead for further medicinal chemistry optimization.
Novel 2-aminooctahydrocyclopentalene-3a-carboxamides as potent CCR2 antagonists. [2016]Novel CCR2 antagonists with a novel 2-aminooctahydrocyclopentalene-3a-carboxamide scaffold were designed. SAR studies led to a series of potent compounds. For example, compound 51 had a good PK profile in both dog and monkey, and exhibited excellent efficacy when dosed orally in an inflammation model in hCCR2 KI mice. In addition, an asymmetric synthesis to the core structures was developed.
Effects of a dual CCR3 and H1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis. [2021]The CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation.
CCR1 antagonists. [2021]CCR1 (CC Chemokine receptor 1) is a widely studied G protein-coupled receptor target expressed on multiple types of leukocytes. It is implicated in initiating and exacerbating inflammatory conditions and thus is viewed as a good target for autoimmune and inflammatory therapeutic applications. Numerous CCR1 antagonists have been reported. Although some early CCR1 antagonists lacked the species cross reactivity that made in vivo animal model study difficult, efforts have been made to improve the compound potency in rodents. Recent identification of new and improved CCR1 antagonists has resulted in promising, in vivo efficacy in a variety of animal models of disease. While several early compounds have been withdrawn from clinical trials due to lack of efficacy, work continues to evaluate CCR1 antagonists in preclinical and clinical settings.
[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]To construction of eukaryotic expression vector of murine Ccr2 and establishment of its stable transfected RAW264.7 cell line.
Alkylsulfone-containing trisubstituted cyclohexanes as potent and bioavailable chemokine receptor 2 (CCR2) antagonists. [2021]We describe novel alkylsulfones as potent CCR2 antagonists with reduced hERG channel activity and improved pharmacokinetics over our previously described antagonists. Several of these new alkylsulfones have a profile that includes functional antagonism of CCR2, in vitro microsomal stability, and oral bioavailability. With this improved profile, we demonstrate that two of these antagonists, 2 and 12, are orally efficacious in an animal model of inflammatory recruitment.
A novel series of N-(azetidin-3-yl)-2-(heteroarylamino)acetamide CCR2 antagonists. [2013]The inflammatory response associated with the activation of C-C chemokine receptor CCR2 via it's interaction with the monocyte chemoattractant protein-1 (MCP-1, CCL2) has been implicated in many disease states, including rheumatoid arthritis, multiple sclerosis, atherosclerosis, asthma and neuropathic pain. Small molecule antagonists of CCR2 have been efficacious in animal models of inflammatory disease, and have been advanced into clinical development. The necessity to attenuate hERG binding appears to be a common theme for many of the CCR2 antagonist scaffolds appearing in the literature, presumably due the basic hydrophobic motif present in all of these molecules. Following the discovery of a novel cyclohexyl azetidinylamide CCR2 antagonist scaffold, replacement of the amide bond with heterocyclic rings was explored as a strategy for reducing hERG binding and improving pharmacokinetic properties.
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]Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
CCR2 antagonists. [2019]Inhibition of CCR2 has been considered as a target for multiple therapeutic diseases including autoimmune disease, atherosclerosis, pain, and metabolic disease, based in part on the critical role this receptor plays on monocyte migration. Numerous companies have reported programs to identify CCR2 antagonists. Common challenges to the development of CCR2 agents have included poor activity at the rodent receptor and selectivity for both other chemokine receptors and ion channels. This review summarizes the rationale for targeting CCR2 in disease, the recent progress in the identification of potent and select CCR2 antagonists, and the current status of clinical trials for CCR2 agents.
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]CC chemokine receptor 1 (CCR1) is a GPCR involved in the migration and activation of leukocytes. A number of studies have highlighted a role for CCR1 in preclinical animal models of inflammatory diseases, including MS and rheumatoid arthritis.