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

Crohn's Disease Clinical Trial

— TOPIC  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06244849
• Other study ID #: 69HCL22_1172
• Status: Not yet recruiting
• Phase: N/A
• Start date: March 1, 2024
• Est. completion date: November 1, 2025

Study information

• Verified date: December 2023
• Source: Hospices Civils de Lyon
• Contact: NANCEY Stéphane, Pr
• Phone: 0478861289
• Email: Stephane.nancey[@]chu-lyon.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 170
• Est. completion date: November 1, 2025
• Est. primary completion date: November 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

--- Inclusion Criteria :

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
• Stable doses of oral prednisone (=30 mg per day) or budesonide (=9 mg per day), mesalamine, concomitant immunosuppressive agents, biologics including anti-TNF agents, vedolizumab or ustekinumab are allowed at stable dose for at least three months before inclusion.
• 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
• Exclusion Criteria * :

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
• Serious secondary illnesses of an acute or chronic nature, which in the opinion of the investigator renders the patient unsuitable for inclusion into 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 will be exposed to antibiotics 4 weeks prior the inclusion, given the potential impact on the detection of AIEC colonization in ileal biopsies
• Patients who denied the protocol, not ability to accept or sign consent of the protocol
• Subject involved in another interventional research with an exclusion period still in progress at inclusion
• Pregnant women, women in labor or breastfeeding women*.
• Persons deprived of their liberty by a judicial or administrative decision
• Persons under psychiatric care
• Persons admitted to a health or social institution for purposes other than research
• Adults subject to a legal protection measure (guardianship, curatorship)
• Subject involved in another clinical trial

Related Conditions & MeSH terms

• Crohn Disease
• Crohn's Disease

Intervention

Biological:
• Blood samples
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
• Stool simple
A fresh stool sample will be collected and conserved at room temperature until shipment
• Ileocolonic biopsies
An ileo-colonoscopy with 10 ileal biopsies scheduled in their regular medical follow-up will be performed

Locations

Country	Name	City	State
France	CHU Estaing	Clermont-Ferrand
France	Centres Hospitalier Lyon Sud	Pierre-Bénite

Sponsors (2)

Lead Sponsor	Collaborator
Hospices Civils de Lyon	Centre International de Recherche en Infectiologie (CIRI)

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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).	Qualitative and/or quantitative comparative analysis of content of the autophagosomal cargos between CD patients expressing the CD-associated autophagy related variants and WT gene-expressing non-IBD controls.	Baseline and the day of ileocolonoscopy
Secondary	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).	Qualitative and/or quantitative comparative analysis of content of the exosomal proteome cargos between CD patients expressing the CD-associated autophagy related variants and WT gene-expressing non-IBD controls.	Baseline and the day of ileocolonoscopy