TOward a Better Understanding of the autoPhagy Machinery for the Identification of Potential Novel Biomarkers and Therapeutic Targets in Crohn's Disease - TOPIC Study

NCT06244849 | Not Yet Recruiting

• 1 other identifier: 69HCL22_1172
• Study Type: interventional
• Target: 170
• Locations: 1 country
• Sites: 2

Brief Summary

Crohn's disease (CD) belongs to chronic inflammatory bowel diseases (IBD) affecting over 2 million individuals in the North America and 3.2 million in Europe with an increasing incidence rate in newly industrialized countries experiencing a westernization of lifestyle (1). This highly disabling disease affects patients' life in several ways with severe complications requiring surgery for half of them and is responsible for considerable economic burdens (2,3). Decades of research displayed that CD pathogenesis is determined by inappropriate immune responses towards luminal microbiota in genetically susceptible hosts. Genome-wide association studies (GWAS) have identified autophagy as one of the main pathways associated with susceptibility to CD (4-6). Autophagy is a dynamic process of the lysosomal catabolism, called autophagy flux, which is crucial to degrade and recycle obsolete and deleterious cytosolic components of the cell (7). Autophagy is also the main cell-autonomous process to fight intracellular microorganisms by degrading them, and by contributing to antimicrobial host immune responses. However, the functional consequences of polymorphisms affecting autophagy-associated genes on the dynamic process of autophagy and its real impact on CD pathogenesis remain largely unknown. In addition, CD is associated with a gut microbiota dysbiosis, as exemplified by the higher prevalence of AIEC (a bacterium eliminated by autophagy) in ileal mucosa of CD patients (8-10). Hence, autophagy defect, linked to autophagy SNPs, could contribute to CD-related dysbiosis and to CD activity and severity. Beyond, CD-associated abnormalities of the autophagy flux may affect the composition of the autophagic cargoes, as well as the one of other vesicular pathway, such as exosomes, known to influence autophagy. These impairments could affect at longer term both cell activities and immune responses, especially in antigen presenting cells, which drive host immune responses. The TOPIC project concerns translational research, in which we plan to generate a prospective cohort of CD patients giving up the unique opportunity to collect clinical data, to analyse simultaneously the autophagy flux, genetic variants of interest (from blood samples) and intestinal microbiota (from intestinal samples) and allowing to perform more fundamental studies. The results of the fundamental part will allow a better understanding of the pathophysiology of CD, and ultimately better management of these patients.

Conditions

Crohn's Disease

Keywords

Crohn disease; Autophagy flux; Intestinal microbiota; Biomarker; Non-inflammatory bowel diseases

Outcome Measures

Primary Outcomes (1)

• Autophagy flux

  Difference of the autophagy flux signature according to AIEC infection, autophagy related gene variants, and its relationship between CD activity and severity.

  Baseline and the day of ileocolonoscopy

Secondary Outcomes (2)

• Characterize and compare the autophagosomal proteome in CD genetic autophagicvariant expressing immune cells in ileum and in colon in CD patients from that in non IBD patients (controls).

  Baseline and the day of ileocolonoscopy

• Characterize and compare the exosomal proteome in CD genetic autophagic variant expressing immune cells in ileum and in colon in CD patients from that in non IBD patients (controls).

  Baseline and the day of ileocolonoscopy

Study Arms (2)

Patient with Crohn disease (n=150)

OTHER

CD patients requiring to undergo an ileo-colonoscopy for routine investigations (assessment of disease activity or complications as stricture or screening of colorectal cancer for CD)

Biological: Blood samples; Biological: Stool simple; Biological: Ileocolonic biopsies

Patient without Crohn disease (n=20)

OTHER

Non-IBD patients (control) requiring to undergo an ileo-colonoscopy for routine investigations (screening for colorectal cancer or diagnosis of irritable bowel syndrome for controls).

Biological: Blood samples; Biological: Stool simple; Biological: Ileocolonic biopsies

Interventions

Blood samples BIOLOGICAL

A 28 mL (5 EDTA tubes of 4 mL and 2 dry tubes) venous blood will be collected added to the standard blood analysis performed in routine

Patient with Crohn disease (n=150); Patient without Crohn disease (n=20)

Stool simple BIOLOGICAL

A fresh stool sample will be collected and conserved at room temperature until shipment

Patient with Crohn disease (n=150); Patient without Crohn disease (n=20)

Ileocolonic biopsies BIOLOGICAL

An ileo-colonoscopy with 10 ileal biopsies scheduled in their regular medical follow-up will be performed

Patient with Crohn disease (n=150); Patient without Crohn disease (n=20)

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For CD patients :
• Aged over 18 years
• Men or non-pregnant women
• Patients with a diagnosis of terminal ileum or ileocolonic CD for at least three months who requires to perform an ileocolonoscopy for routine follow-up
• Inactive and moderately to severely active CD according to the Harvey-Bradshaw index
• Informed written consent
• Beneficiary or beneficiary of a social security system
• For non IBD controls :
• Aged over 18 years
• Men or non-pregnant women
• Patients without a diagnosis of Crohn's disease who requires to perform an ileocolonoscopy for routine follow-up
• Informed written consent
• Beneficiary or beneficiary of a social security system

You may not qualify if:

• For patients and non-IBD controls :
• Existing pregnancy, lactation, or intended pregnancy within the next 15 months
• History of disease, including mental/emotional disorder that might interfere with their participation in the study
• Inability to comply with the protocol requirements
• Presence of an ileo-/colonic stoma
• Patients with known colonic stricture and exclusive or predominant anal or perineal Crohn's disease lesions
• Known previous or concurrent malignancy (other than that considered surgically cured, with no evidence for recurrence for 5 years)
• Short bowel syndrome
• Concomitant Clostridium difficile superinfection
• Indeterminate colitis
• Concomitant leukocyte apheresis
• Patients who denied the protocol, not ability to accept or sign consent of the protocol
• Pregnant women, women in labor or breastfeeding women\*.
• Persons deprived of their liberty by a judicial or administrative decision
• Persons under psychiatric care

Sponsors & Collaborators

• Hospices Civils de Lyon: lead
• Centre International de Recherche en Infectiologie (CIRI): collaborator

Study Sites (2)

CHU Estaing

Clermont-Ferrand, 63000, France

Location

Centres Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

MeSH Terms

Conditions

Crohn Disease

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Central Study Contacts

NANCEY Stéphane, Pr

CONTACT

0478861289; Stephane.nancey@chu-lyon.fr

BOSCHETTI Gilles, Pr

CONTACT

Gilles.boschetti@chu-lyon.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A case-control study from a prospective bicentric cohort of CD patients. Proof of concept and exploratory study with minimum risks (type 2)

Study Record Dates

• First Submitted: December 14, 2023
• First Posted: February 6, 2024
• Study Start: June 1, 2024
• Primary Completion: January 1, 2026
• Study Completion: January 1, 2026
• Last Updated: May 20, 2024

Record last verified: 2024-05

Locations

FR (2)