HLADQA1*05 Genotype and the Efficacy of Treatment With Infliximab in Chinese Population Crohn's Disease

Preemptive HLADQA1*05 Genotyping for the Use of Infliximab in Chinese Crohn's Disease：A Multicenter, Prospective, Controlled, Randomized Study

Crohn's disease (CD) is a chronic non-specific inflammatory disease of the intestine. Infliximab (IFX) is a kind of one of the anti-tumor necrosis factor agents (anti-TNF) and is the main clinical treatment drug for Crohn's disease, but approximately 30-50% of patients develop a secondary non-response to respond within one year. The main cause of secondary non-response failure is the formation of anti-IFX anti-drug antibodies (ADA). The human leukocyte antigen (HLA) gene is a complex allele that has been associated with susceptibility to a variety of diseases. Studies have shown that HLADQA1*05 allele carriage significantly increases the immunogenicity of anti-tumor necrosis factor agents (anti-TNF) and the risk of ADA formation, resulting in a significant reduction in the efficacy of IFX. Our previous retrospective study found an increased risk of ADA, IFX failure to respond and discontinuation in patients with HLADQA1*05 variants, and that IFX in combination with immunosuppression improved clinical outcomes in wild-type genotype patients, whereas combination therapy in patients with variant genotype did not optimize clinical outcomes significantly. Therefore, we believe that the impact of HLADQA1*05 on the efficacy of IFX in the Chinese population is unclear, and the combination of immunosuppressants in patients with variant HLADQA1*05 genotype remains to be validated due to insufficient sample size. We hypothesized that HLADQA1*05 wild-type CD patients would have better clinical remission when treated with IFX than HLADQA1*05 variant patients and that the combination of immunosuppressants would improve the outcome in wild-type patients but not in variant patients. By advancing this project, we hope to provide high quality evidence on the clinical use of IFX in Crohn's disease in the Chinese population and help physicians to be more selective in the use of IFX alone or in combination with azathioprine, or to switch treatment in a timely manner.

Study Overview

• Status: Not yet recruiting
• Conditions: Crohn Disease; Infliximab
• Intervention / Treatment: Drug: Infliximab; Drug: Azathioprine

• Study Type: Interventional
• Enrollment (Anticipated): 976
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants with Crohn's disease who meet the diagnostic criteria of the Consensus Opinion on the Diagnosis and Treatment of Inflammatory Bowel Disease (Beijing, 2018)
• Meet the indications for IFX use
• CDAI score of 220-450; age≥18 years, regardless of gender
• Participants or family members able to understand the study protocol and willing to participate in this study by providing written informed consent

Exclusion Criteria:

• NUDT 15 CT and TT genotypes; previous treatment with IFX and/or other anti-TNF biologics
• Participants who are proposed to have given birth and/or breastfeeding in the 12 months
• those with immunosuppressive intolerance or contraindications
• concurrent chronic diseases or factors of other systems (including severe cardiopulmonary, hepatic and renal, neurological, psychiatric, rheumatic and immune diseases, alcoholism, drug dependence, other chronic active diseases and long-term hormonal or immunosuppressive drugs)
• Excluding infectious diseases (tuberculosis, etc.)
• Excluding tumor-related diseases (lymphoma, gastrointestinal tract tumors, etc.)
• any medical condition/combined surgery/medication/other clinically significant abnormal laboratory tests which, in the judgment of the investigator, may affect the results of the test
• Known refusal or inability to follow protocol requirements for any reason (including planned clinical visits and examinations)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Infliximab; Infliximab monotherapy, the first dose of 5 mg/kg of this product is provided, followed by the same dose at weeks 2 and 6 after the first dose and every 8 weeks thereafter.	Drug: Infliximab; 5mg/kg for the first dose, and the same dose at weeks 2 and 6 after the first dose and every 8 weeks thereafter. Treatment with single Infliximab or combined azathioprine, respectively.
Active Comparator: Infliximab+azathioprine; Infliximab was given in combination with azathioprine, and Infliximab dosing was the same as in the experimental group, with azathioprine at 1-2 mg/kg/d.	Drug: Infliximab; 5mg/kg for the first dose, and the same dose at weeks 2 and 6 after the first dose and every 8 weeks thereafter. Treatment with single Infliximab or combined azathioprine, respectively.; Drug: Azathioprine; azathioprine in combination with Infliximab, with a dose of 1-2 mg/kg/d.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical remission without corticosteroid use at 102 weeks	CDAI score below 150 and no systemic corticosteroids at any dose or Budesonide ≥ 3 weeks.	102 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical response at 14 weeks	Decrease in CDAI score ≥70 or CDAI score <150	14 weeks
Positive for ADA	Transient or persistent serum ADA concentration ≥ 10 AU/mL	102 weeks
Adverse drug events	Allergies, infusion reactions, infections, tumors, liver damage, bone marrow suppression, hair loss, etc.	102 weeks
IFX discontinuation	Includes discontinuation due to IFX non-response or adverse events	102 weeks
IFX Intensive Therapy	Includes increased doses and shorter cycles due to the recurrence of disease	102 weeks
IFX Failure to Respond	Recurrence of disease during treatment with IFX with increased in CDAI score ≥ 70 or CDAI score ≥150	102 weeks

Collaborators and Investigators

• Sponsor: Sixth Affiliated Hospital, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Anticipated): April 30, 2023
• Primary Completion (Anticipated): May 31, 2026
• Study Completion (Anticipated): October 31, 2026

Study Registration Dates

• First Submitted: April 3, 2023
• First Submitted That Met QC Criteria: April 3, 2023
• First Posted (Actual): April 14, 2023

Study Record Updates

• Last Update Posted (Actual): May 9, 2023
• Last Update Submitted That Met QC Criteria: May 6, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Infliximab; Azathioprine
• Other Study ID Numbers: 2023ZSLYEC-123

Drug and device information, study documents

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