Study of Colchicine Resistance in Familial Mediterranean Fever (COLCHI-RESIST)

Study Of Colchicine Resistance In Familial Mediterranean Fever

Five to 10% of familial mediterranean patients are considered colchicine-resistant (i.e. patients with a persistent inflammatory syndrome, despite taking the maximum tolerated dose of colchicine daily). The recommended treatment in this case is a subcutaneous anti-interleukin 1 biotherapy (anakinra or canakinumab). These treatments are expensive (1,000 to 12,000 euros/month).

However, for a patient to be considered colchicine-resistant, compliance with the treatment must be verified. Furthermore specific activation of the pyrin inflammasome by Clostrioides difficile toxin and the overrepresentation of these bacteria in the stools of our patients led us to systematically search for them in our resistant patients. The demonstration of the involvement of C. difficile in the imbalance of the disease has not yet been published.

The colchiresist study aim to better characterize colchicine-resistance by confirming good compliance to treatment with colchicine hair measurement and by looking for clostrioides infection or intestinal dysbiosis.

Study Overview

• Status: Completed
• Conditions: Colchicine Resistance; Mediterranean Fever
• Intervention / Treatment: Biological: Capillary colchicine dosage in colchicine-resistant Familial Mediterranean Fever patients.

Detailed Description

Patients meeting the criteria for colchicine resistance will be included in a follow-up visit.

• Adherence to colchicine therapy will be assessed by the Girerd questionnaire completed by the patient at the inclusion visit.
• A blood test is performed including a haemogram, CRP and SAA, creatinine and proteinuria.
• a standard stool analysis on site to look for C. difficile toxin.

For research purposes, samples of:

• Stool.
• A strand of hair with the diameter of a pencil and a minimum length of 2 cm, in the region of the posterior vertex, where the growth and integration are relatively constant to avoid variability.
• In patients with baldness or bleached hair only: pubic and/or axillary hair will be taken, The samples will then be processed without segmentation.
• Additional blood (5ml) and urine (2ml) samples for colchicine dosage. The patient's participation ends after this visit

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Léa SAVEY, MD; Phone Number: 0033156017431; Email: lea.savey@aphp.fr
• Study Contact Backup: Name: Sophie Georgin-Lavialle, PD, PhD; Phone Number: 0033156017431; Email: sophie.georgin-lavialle@aphp.fr

Study Locations

• France
  • Paris, France, 75020
    • Service de Médecine Interne. Hôpital Tenon, 4 Rue de la Chine
    • Contact: Léa SAVEY, MD; Phone Number: 0033156016791; Email: lea.savey@aphp.fr
    • Contact: Sophie Georgin-Lavialle, MD, PhD; Phone Number: 0033156017431; Email: sophie.georgin-lavialle@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Inclusion Criteria Age ≥ 12 years with no upper age limit -Patients with familial Mediterranean fever (FMF) meeting international criteria for the disease (Livneh criteria) and carrying 2 pathogenic mutations in the MEFV gene.

Patients considered colchicine-resistant according to EULAR criteria reviewed by an expert consensus:

• Persistence of signs of activity (at least one attack per month for at least 3 months) despite taking the maximum tolerated dosage of colchicine.
• Persistence of a biological inflammatory syndrome after exclusion of other causes and despite taking a maximum tolerated dosage of colchicine.
• Signature of an informed consent by the patient (or his parents if under 18 years of age)
• Patients affiliated to a social security system

Exclusion Criteria:

- Patients participating in another interventional trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Colchicine-resistant Familial Mediterranean Fever patients

Biological: Capillary colchicine dosage in colchicine-resistant Familial Mediterranean Fever patients.; Adherence to colchicine therapy will be assessed by the Girerd questionnaire (6 questions ) completed by the patient at the inclusion visit.; A blood sample (8ml) is taken, including a haemogram, CRP and creatinine and proteinuria.; Standard on-site stool analysis for C. difficile toxin. For research purposes, samples of: Stool. If the patient is unable to produce stools on the day of the visit, a collection kit with 2 tubes containing a preservative will be given to him/her as well as a stamped envelope to take the sample at home and send it by post within 10 days according to a validated procedure.; A strand of hair with the diameter of a pencil and a minimum length of 2 cm, in the region of the posterior vertex.; In patients with baldness or bleached hair only: pubic and/or axillary hair, a pencil-sized strand.; Additional blood (5ml) and urine (2ml) samples for colchicine determination.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amount of colchicine measured in the first 2 cm of hair from the scalp of an FMF patient considered colchicine resistant or from pubic hair in patients with bald or colored hair, which corresponds to the average compliance of the last 2 months of intake	To assess 2-month compliance with colchicine in patients with FMF considered resistant via capillary drug dosage	Through study completion, an average of 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between the amount of colchicine measured in the hair and the blood and urine levels of colchicine attesting to the last days' intake.	To study blood and urine colchicine dosage in FMF patients considered resistant to colchicine	Through study completion, an average of 18 months
Correlation between capillary colchicine dosage and colchicine compliance assessed with the 6-item GIRERD	Compare hair dosing to self-reported compliance	Through study completion, an average of 18 months
Composition of the fecal microbiota (search for an overrepresentation of clostridiae) in colchicine-resistant patients patients with colchicine resistance	Studying the composition of the fecal microbiota in colchicine-resistant FMF patients	Through study completion, an average of 18 months
Testing for clostridioides difficile toxin B in colchicin-resistant patients	Testing colchicine-resistant FMF patients for clostridioides difficile toxin to rule out chronic asymptomatic carriage	Through study completion, an average of 18 months
Dosage of proinflammatory cytokines IL1, IL6, IL18, TNFa and il1Ra.	Study blood levels of proinflammatory cytokines in colchicine-resistant patients, in particular IL1 and il1RA	Through study completion, an average of 18 months
Percentage of patients for whom a prescription of anti-IL-1 biotherapy could have been avoided (i.e. poor compliance with Colchicine and/or Clostrioides Difficile infection)	Determine the percentage of patients labeled colchicine resistant who were actually noncompliant or chronically infected with pyrin-activating bacteria like clostridioides difficile	Through study completion, an average of 18 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Léa SAVEY, MD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2022
• Primary Completion (Actual): July 4, 2023
• Study Completion (Actual): October 27, 2023

Study Registration Dates

• First Submitted: June 10, 2022
• First Submitted That Met QC Criteria: June 10, 2022
• First Posted (Actual): June 14, 2022

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Microbiota; Drug resistance; interleukin-1; Drug compliance; Familial mediterranean fever; Colchicin-resistant; clostrioides difficile; second-line therapy.
• Additional Relevant MeSH Terms: Skin Diseases; Infections; Genetic Diseases, Inborn; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Skin Diseases, Genetic; Body Temperature Changes; Fever; Brucellosis; Familial Mediterranean Fever; Hereditary Autoinflammatory Diseases; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gout Suppressants; Colchicine
• Other Study ID Numbers: APHP211442

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No