Comparison of Azathioprine to Methotrexate in Combination Therapy With Adalimumab in Crohn's Disease: an Open-label Randomized Controlled Trial (COMET)

Combination therapy, the association of an anti-Tumor Necrosis Factor (TNF) to an immunosuppressant, is recognized as the most effective treatment during Crohn's disease (CD). Several mechanisms have been proposed to explain the superiority of combination therapy over monotherapy, the additive effect of two effective drugs or the prevention of anti-TNF immunogenicity. As the best combination therapy is unknown, both azathioprine (AZA) and methotrexate (MTX) are used. Some retrospective studies suggest a higher effectiveness of AZA. MTX may have an advantage in terms of safety.

The investigators hypothesize that AZA is more effective than MTX as combination therapy with adalimumab to improve short-term endoscopic, clinical and pharmacological outcomes in CD patients.

Study Overview

• Status: Recruiting
• Conditions: Crohn Disease; Methotrexate; Azathioprine
• Intervention / Treatment: Drug: AZA capsules; Biological: blood sample; Drug: MTX

• Study Type: Interventional
• Enrollment (Estimated): 166
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mathurin Fumery, Pr; Phone Number: 03 22 08 88 51; Email: Fumery.mathurin@chu-amiens.fr

Study Locations

• France
  • Amiens, France, 80480
    • Recruiting
    • CHU Amiens
    • Principal Investigator: Benjamin Pariente, Pr
    • Principal Investigator: Guillaume Savoye, Pr
    • Principal Investigator: Vanessa Bonjemah, MD
    • Principal Investigator: Duveau Nicolas, MD
    • Principal Investigator: Painchart, MD
    • Principal Investigator: Tavernier Noemie, MD
    • Principal Investigator: Laurent Peyrin-Biroulet, Pr
    • Principal Investigator: Yoram Bouhnik, Pr
    • Principal Investigator: David Laharie, Pr
    • Principal Investigator: Arnaud Boureille, Pr
    • Principal Investigator: Antony Buisson, MD
    • Principal Investigator: Xavier Roblin, Pr
    • Principal Investigator: Lucine Vuitton, MD
    • Principal Investigator: Romain Altwegg, MD
    • Principal Investigator: Clea Rouillon, MD
    • Contact: Mathurin Fumery, Pr; Phone Number: 03 22 08 88 51; Email: Fumery.mathurin@chu-amiens.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female patients with age > 18 years
• Crohn's disease for at least 6 weeks,
• Clinically active with CDAI > 150
• Active inflammation by endoscopy (CDEIS > 4) at baseline
• Not responder to conventional therapy or are intolerant to or have medical contraindications for such therapies and initiating treatment with adalimumab
• Patient followed in a center belonging to the GETAID network
• Fertile men and women of childbearing potential included in the protocol should use adequate methods of contraception according to study drug SMPCs.
• Written consent

Exclusion Criteria:

• Short bowel syndrome, ostomy, symptomatic stricture, abscess, recent history of abdominal surgery (<3 months)
• Non-passable colonic stricture
• Previous intolerance to thiopurines or MTX
• Previous exposition to adalimumab
• Contra-indication to immunosuppressants or anti-TNF
• Others serious simultaneous illness that could interfere with study participation
• Planning pregnancy, pregnancy or lactation or absence of contraception
• Known substance abusers
• Use of any investigational drug within 30 days
• Adults protected by law

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZA group; Combination of sub-cutaneous administration of adalimumab at a dose of 160mg(W0)-80mg(W2)-40mg(W6) and then 40mg EOW and oral AZA capsules at a daily dose of 2.5 mg/kg	Drug: AZA capsules; oral AZA capsules at a daily dose of 2.5 mg per kilogram,; Biological: blood sample; The lab tests are: serum albumin, C-reactive protein, thrombocytosis and haemoglobin.
Experimental: MTX group; Combination of sub-cutaneous administration of adalimumab at a dose of 160mg (week (W) 0)-80mg(W2)-40mg(W6) and then 40mg EOW and sub-cutaneous MTX 25mg once a week	Biological: blood sample; The lab tests are: serum albumin, C-reactive protein, thrombocytosis and haemoglobin.; Drug: MTX; MTX 25 mg SC once a week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variation of the endoscopic response between AZA and MTX groups	Variation of the endoscopic response to AZA in combination with adalimumab and to MTX in combination with adalimumab in patients with CD. The endoscopic reference score (EREFS) is used to determine severity of 5 endoscopic findings: edema, rings, exudates, furrows, and structures. The EREFS classification system rates the severity of edema (0-2), rings (0-3), exudates (0-2), furrows (0-2), and strictures (0-1)	26 weeks

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire, Amiens
• Collaborators: Hospices Civils de Lyon; University Hospital, Montpellier; University Hospital, Bordeaux; University Hospital, Clermont-Ferrand; Centre Hospitalier Universitaire de Besancon; Nantes University Hospital; Henri Mondor University Hospital; Hopitaux Civils de Colmar; CHU Toulouse; AP-HP - HU BEAUJON; CHU REIMS; CHRU LILLE; CHU Rennes,France; CHU ROUEN - HOPITAL DE BOIS-GUILLAUME; CHRU TOURS; CHU NICE; CHU NANCY; CHU CAEN; CHU SAINT-ETIENNE; CH TOURCOING; CH COTE BASQUE; CH ROUBAIX; CHI CRETEIL; CHI TOULON LA SEYNE; CH VALENCE; CMC Ambroise Paré, Pierre Cherest, Hartmann

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2021
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: August 26, 2021
• First Submitted That Met QC Criteria: September 7, 2021
• First Posted (Actual): September 10, 2021

Study Record Updates

• Last Update Posted (Actual): May 28, 2025
• Last Update Submitted That Met QC Criteria: May 22, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: methotrexate; Crohn Disease; azathioprine; Combinations of therapy; anti-Tumor Necrosis Factor
• Additional Relevant MeSH Terms: Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Inflammatory Bowel Diseases; Crohn Disease
• Other Study ID Numbers: PI2021_843_0080

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
• product manufactured in and exported from the U.S.: No