Evaluate Established Anti-DEFA5 mAbs Diagnostic Efficacy and Safety in IBD

Sponsor

Meharry Medical College (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05663671

Collaborator

(none)

230

Enrollment

Location

Anticipated Duration (Months)

9.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Investigators propose to validate efficacy and safety of the detection of DEFA5 in the diagnosis of the colonic IBD using longitudinal vs. cross-sectional studies of known patient clinical data to correlate with their endoscopy biopsy data. 30% of colonic IBD patients cannot be accurately diagnosed (CC vs. UC) in a timely manner even when a state-of-the-art classification system of combined clinical, endoscopic, radiologic and histologic tools are used. When the diagnostic classification for these two diseases is inconclusive, the condition is termed indeterminate colitis (IC). Here, the central medical challenge is the discrimination of IBD into the specific subtypes with high accuracy, as it greatly effects surgical care of patients. Diagnostic accuracy of IC into either authentic UC or CC is of utmost importance when determining a patient's candidacy for RPC-IPAA surgery, the standard curative surgical procedure for UC. Further, incorrect diagnosis and treatment carry potential morbidity from inappropriate and unnecessary surgery and costs. The success outcomes of RPC-IPAA surgery and convalescence depend on correct diagnosis. To address IBD diagnosis ambiguity and delays in IBD clinical settings, investigators developed a proteomic signature to discriminate between UC and CC patients that also will predict the outcome of IC patients for their eventual progress to either UC or CC. Our published data has shown robust evidence supporting presence of human alpha-defensin 5 (DEFA5) in areas of the colon mucosa with aberrant expression of apparent Paneth cell-like cells (PCLCs) or crypt cell-like cells (CCLCs), which identifies an area of colonic ileal metaplasia, consistent with the diagnosis of CC. DEFA5 bioassay discriminated CC and UC in a cohort of all IC patients with accuracy. A fit logistic model with group CC and UC as the outcome and the DEFA5 as independent variable differentiator with a positive predictive value of 96%. These findings were obtained solely from colectomy specimens for both the discovery and validation analyses. Investigators believe that use of endoscopy biopsies would be indifferent, which is the purpose of this prospective patient centered clinical study. Investigators propose to demonstrate that UC and CC, the two unsolved medical subtypes of pathology with no drugs for a cure, can accurately be distinguished molecularly by examining CCLCs-secreted DEFA5 in colonic endoscopy biopsies instantly. Our proposal is highly innovative, as it highlights the robustness of DEFA5 and its clinical relevance to IBD is both in science and the anticipated impact, as investigators seek to better understand difficulty to determine 'subtypes" and translate that to improve diagnosis, treatment, clinical outcomes, and quality of life for patients and the realm of clinical care. DEFA5 immunoreactivity in colonic endoscopy biopsies could be a rapid potential diagnostic signature to resolve IC into authentic UC and CC with a first clinic endoscopy biopsy. IC is likely to be eliminated for good.

Condition or Disease	Intervention/Treatment	Phase
Inflammatory Bowel Diseases Ulcerative Colitis Crohn Colitis Indeterminate Colitis	Diagnostic Test: Diagnostic Test

Detailed Description

The clinical relevance of this proposed screen is that it would lead to the elusive and accurate diagnosis to circumvent the inexact IC patients into authentic CC and UC with a first clinic endoscopy biopsy. The central medical challenge in endoscopic medicine and colorectal surgery is the discrimination of colonic IBD into the subtypes with high accuracy because it greatly affects surgical care of patients. Incorrect diagnosis and surgery carry potential morbidity from inappropriate and unnecessary surgery and cost. Our published data has shown robust evidence supporting presence of human alpha-defensin 5 (DEFA5) in areas of the colon mucosa with aberrant expression of apparent Paneth cell-like cells (PCLCs) / crypt cell-like cells (CCLCs), which identifies an area of colonic ileal metaplasia, consistent with the diagnosis of CC. Investigators propose to demonstrate that UC and CC, the two unsolved medical subtypes of GI pathology with no drugs for a cure, may accurately be distinguished molecularly by examining CCLCs-secreted DEFA5 in colonic endoscopy biopsies instantly. Our proposal is highly innovative, as it highlights the robustness efficacy and safety of DEFA5 and its clinical relevance in IBD diagnostics. The goal of this proposal is to develop a clinical approach to circumvent diagnostic ambiguity and delay, as well as permit timely, and accurate diagnosis of colonic IBD. DEFA5 immunoreactivity in colonic endoscopy biopsies could be a potential diagnostic signature that accurately diagnoses CC and provides the basis to resolve ambiguity in the diagnosis of IBD to not only circumvent diagnostic delay, but also permit timely, accurate diagnosis and timely prescription of appropriate treatment options, an Affordable, Sensitive, Specific, User-friendly, Robust and Rapid, Equipment-free, and Deliverable (ASSURED) bioassay that may delineate subtypes of IBD during the first clinic endoscopy biopsy visit. This bioassay is specific, sensitive, linear, affordable, low risk, and less invasive. Investigators hypothesize that aberrant expression of DEFA5 secreting CCLCs in colonic crypt of IBD patients may be exploited as a reliable diagnostic signature to highly differentiate CC from UC in otherwise IC patients during the first clinic visit endoscopy biopsy without delay. Investigators foresee no issues pertaining to this proposal as an established sampling error by endoscopic biopsy making it does not interfere with results and apropos of this project that each biopsy has complement CCLCs with co-localized DEFA5 clearly restricted in areas of the mucosa with aberrant CCLCs identifies a ubiquitously colonic ileal metaplasia that is consistent with the diagnosis of authentic CC. If successful, widespread use of this approach would not only revolutionize provide accurate diagnoses and the correct treatment regimens for IBD patients, but also it will improve health outcomes and patient quality of life, while reducing medical complications and/or unnecessary drugs, surgeries, & costs.

Study Design

Study Type:

Observational

Anticipated Enrollment :

230 participants

Observational Model:

Cohort

Time Perspective:

Cross-Sectional

Official Title:

Evaluate Established Anti-DEFA5 mAbs Diagnostic Efficacy and Safety in IBD

Anticipated Study Start Date :

Jun 1, 2023

Anticipated Primary Completion Date :

May 31, 2025

Anticipated Study Completion Date :

Jun 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Crohn's colitis Correlate patient longitudinal study of clinical data and their biopsy data. Investigators will determine DEFA5 levels from endoscopy biopsies from known authentic CC patients.	Diagnostic Test: Diagnostic Test 30% of IBD patients are misdiagnosed. This affects surgical care of patients. Investigators have unveiled a signature discriminator between UC&CC that also predicts the outcome of IC patients into authentic UC/CC. This is a bioassay that is specific, sensitive, linear, affordable, minimal risk, non-invasive and constitutes an inexpensive, simple to use, point-of-care test format. Investigators published data which have shown robust presence of DEFA5 in the colon crypt mucosa with aberrant expression of apparent crypt-cell-like cells (CCLCs) in areas identified with ectopic colon ileal metaplasia consistent with CC. Investigators propose to validate that UC/CC, the two unsolved medical sub-types of pathology can accurately be distinguished among IC patients by examining CCLCs secreted DEFA5 levels in endoscopy biopsies instantly. Diagnostics relies on the expression/localization/activation of DEFA5 and the ectopic CCLCs in the mucosal crypt of CC patients.
Ulcerative colitis Correlate patient longitudinal study of clinical data and their biopsy data. Investigators will determine DEFA5 levels from endoscopy biopsies from known authentic UC patients.	Diagnostic Test: Diagnostic Test 30% of IBD patients are misdiagnosed. This affects surgical care of patients. Investigators have unveiled a signature discriminator between UC&CC that also predicts the outcome of IC patients into authentic UC/CC. This is a bioassay that is specific, sensitive, linear, affordable, minimal risk, non-invasive and constitutes an inexpensive, simple to use, point-of-care test format. Investigators published data which have shown robust presence of DEFA5 in the colon crypt mucosa with aberrant expression of apparent crypt-cell-like cells (CCLCs) in areas identified with ectopic colon ileal metaplasia consistent with CC. Investigators propose to validate that UC/CC, the two unsolved medical sub-types of pathology can accurately be distinguished among IC patients by examining CCLCs secreted DEFA5 levels in endoscopy biopsies instantly. Diagnostics relies on the expression/localization/activation of DEFA5 and the ectopic CCLCs in the mucosal crypt of CC patients.
Indeterminate colitis Correlate patient longitudinal study of clinical data and their biopsy data. Investigators will determine DEFA5 levels from endoscopy biopsies from known IC patients (into authentic UC and CC)	Diagnostic Test: Diagnostic Test 30% of IBD patients are misdiagnosed. This affects surgical care of patients. Investigators have unveiled a signature discriminator between UC&CC that also predicts the outcome of IC patients into authentic UC/CC. This is a bioassay that is specific, sensitive, linear, affordable, minimal risk, non-invasive and constitutes an inexpensive, simple to use, point-of-care test format. Investigators published data which have shown robust presence of DEFA5 in the colon crypt mucosa with aberrant expression of apparent crypt-cell-like cells (CCLCs) in areas identified with ectopic colon ileal metaplasia consistent with CC. Investigators propose to validate that UC/CC, the two unsolved medical sub-types of pathology can accurately be distinguished among IC patients by examining CCLCs secreted DEFA5 levels in endoscopy biopsies instantly. Diagnostics relies on the expression/localization/activation of DEFA5 and the ectopic CCLCs in the mucosal crypt of CC patients.
Diverticulitis Correlate patient longitudinal study of clinical data and their biopsy data. Investigators will determine DEFA5 levels from endoscopy biopsies from known diverticulitis.	Diagnostic Test: Diagnostic Test 30% of IBD patients are misdiagnosed. This affects surgical care of patients. Investigators have unveiled a signature discriminator between UC&CC that also predicts the outcome of IC patients into authentic UC/CC. This is a bioassay that is specific, sensitive, linear, affordable, minimal risk, non-invasive and constitutes an inexpensive, simple to use, point-of-care test format. Investigators published data which have shown robust presence of DEFA5 in the colon crypt mucosa with aberrant expression of apparent crypt-cell-like cells (CCLCs) in areas identified with ectopic colon ileal metaplasia consistent with CC. Investigators propose to validate that UC/CC, the two unsolved medical sub-types of pathology can accurately be distinguished among IC patients by examining CCLCs secreted DEFA5 levels in endoscopy biopsies instantly. Diagnostics relies on the expression/localization/activation of DEFA5 and the ectopic CCLCs in the mucosal crypt of CC patients.
Ileum Positive control	Diagnostic Test: Diagnostic Test 30% of IBD patients are misdiagnosed. This affects surgical care of patients. Investigators have unveiled a signature discriminator between UC&CC that also predicts the outcome of IC patients into authentic UC/CC. This is a bioassay that is specific, sensitive, linear, affordable, minimal risk, non-invasive and constitutes an inexpensive, simple to use, point-of-care test format. Investigators published data which have shown robust presence of DEFA5 in the colon crypt mucosa with aberrant expression of apparent crypt-cell-like cells (CCLCs) in areas identified with ectopic colon ileal metaplasia consistent with CC. Investigators propose to validate that UC/CC, the two unsolved medical sub-types of pathology can accurately be distinguished among IC patients by examining CCLCs secreted DEFA5 levels in endoscopy biopsies instantly. Diagnostics relies on the expression/localization/activation of DEFA5 and the ectopic CCLCs in the mucosal crypt of CC patients.

Outcome Measures

Primary Outcome Measures

Evaluate Established Anti-DEFA5 mAbs Diagnostic Efficacy and Safety in IBD [Six moths]
Using Western blot (WB) technology investigators will evaluate our newly established Anti-DEFA5 mAbs by measuring and quantifying DEFA5 protein levels in colonic biopsies from IBD and non-IBD patients. Anti-DEFA5 monoclonal antibodies (mAbs), i.e., clones 1A8 & 4FD efficacy. Anti-DEFA5 mAbs specificity and sensitivity to the DEFA5 protein which is diagnostic for colonic Crohn's disease

Secondary Outcome Measures

Evaluate Established Anti-DEFA5 mAbs Diagnostic Efficacy and Safety in IBD [Six months]
Our two newly developed mAbs will be tested by measuring detection sensitivity specific to peptide DEFA5 protein. DEFA5 detection level between the mAbs will determine the most effective Anti-DEFA5 mAb to be used to develop bioassay kit for DEFA5.
Evaluate Established Anti-DEFA5 mAbs Diagnostic Efficacy and Safety in IBD [12 months]
Using immunohistochemistry (IHC) technology investigators will evaluate diagnostic efficacy and safety of DEFA5 bioassay using colonic IBD biopsies. The DEFA5 protein, which is diagnostic in IBD will be measured and quantified in the colonic biopsies. Investigators will use colon tissue biopsies from patients with UC, CC, IC, diverticulitis, normal (diverticilosis),& ileum as positive control and compare between different pathologies.