The Efficacy and Safety of Infliximab Combination With Azathioprine in Crohn's Disease in Children

Official title

Study on the Efficacy and Safety of Infliximab Monotherapy or in Combination With Azathioprine in the Treatment of Crohn's Disease in Children

Overview

The goal of this clinical trial is to investigate whether there are significant differences in the efficacy of infliximab monotherapy and combined azathioprine therapy in treating pediatric Crohn's disease, as well as whether there are differences in the safety of these two treatment regimens during long-term use. The main questions it aims to answer are: Is infliximab combined with azathioprine superior to monotherapy in inducing and maintaining remission of Crohn's disease in children? In long-term treatment, can infliximab combined with azathioprine more effectively reduce disease activity and the occurrence of complications, but the incidence of adverse reactions is not higher than that of monotherapy? Researchers will compare the treatment of infliximab combined with azioprine with that of infliximab monotherapy to assess the efficacy and safety of both in inducing and maintaining remission of Crohn's disease in children. Participants will: Take drug ABC or a placebo every day for 4 months Experimental group: Infliximab, administered intravenously at 5mg/kg every 8 weeks at weeks 0, 2, 6 and thereafter, along with azathioprine, taken orally at 1.5-2.5mg/kg daily. Control group: Infliximab (Remicade), administered intravenously at 5mg/kg every 8 weeks at weeks 0, 2, 6 and thereafter. A comprehensive disease assessment will be conducted at the hospital in the 14th and 54th weeks. Record their symptoms, signs and test results.

Detailed description

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD). In recent years, the incidence of CD in children has shown a significant upward trend globally, and it has also increased significantly in Chinese children. According to epidemiological studies, the incidence of CD in Chinese children is approximately 2.5 to 11 cases per 100,000 people per year. CD in children is usually more severe and can significantly affect the psychological and social functions as well as physical development of patients. Infliximab (IFX), as the first tumor necrosis factor-α (TNF-α) antagonist approved for the treatment of CD, specifically binds and neutralizes TNF-α, inhibiting intestinal inflammatory responses and promoting mucosal healing. In the field of pediatric CD, several studies have preliminarily confirmed that IFX monotherapy can effectively induce clinical remission, promote growth and development, and reduce hormone dependence. However, a considerable proportion (37.8% to 43.3%) of CD patients treated with anti-TNF-α therapy will develop secondary adaptive responses (LOR). Therefore, they need dose intensification, switching to other anti-TNF drugs, or switching to drugs with different mechanisms of action for intervention. Multiple studies have shown that the combination of anti-TNF-α drugs with immunomodulators may reduce the production of anti-drug antibodies and improve efficacy, thereby maintaining remission. The most commonly used immunomodulators for IBD are thiopurine drugs, such as azathioprine or 6-mercaptopurine. Some previous studies suggest that combination therapy may be superior to monotherapy in adult CD, but its efficacy and safety for this special group of children remain controversial: on the one hand, the immune system of children is not yet fully developed, and combined therapy may further increase the risks of infection and bone marrow suppression; on the other hand, children have urgent needs for growth and development, and the effectiveness and safety of combined therapy in improving growth retardation and promoting mucosal healing still require more high-quality evidence to support. Currently, there are limited clinical studies on the use of IFX monotherapy or IFX combined with azathioprine for pediatric CD in both domestic and international settings, and most of them are small-sample retrospective studies, lacking large-sample prospective randomized controlled trial (RCT) data. At the same time, there is also a lack of evidence on the optimal timing of combined therapy, dose adjustment strategies, and long-term follow-up safety (such as long-term tumor risk, fertility impact, etc.) for combined therapy, which cannot provide sufficient evidence for clinical decision-making. Based on the above background, this study aims to compare the efficacy and safety of IFX monotherapy and IFX combined with azathioprine in treating pediatric CD, in order to clarify the differences in efficacy of the two treatment regimens in inducing remission, maintaining remission, mucosal healing, and growth and development of pediatric CD, and to comprehensively analyze their short-term and long-term safety characteristics, in order to provide more reliable evidence-based medical evidence for individualized treatment of pediatric CD, optimize clinical treatment pathways, and ultimately improve the long-term prognosis and quality of life of children.

Interventions

• Drug Infliximab combined with azathioprine therapy
  Infliximab is administered intravenously at 5mg/kg every 8 weeks at weeks 0, 2, 6 and thereafter. Simultaneously, azathioprine is taken orally at 1.5 - 2.5mg/kg daily.
• Drug Infliximab monotherapy
  Infliximab is administered intravenously at 5mg/kg every 8 weeks at weeks 0, 2, 6 and thereafter.

Primary outcome measures

• The clinical remission rates（(Pediatric Crohn's Disease Activity Index）in the 14th week and the 54th week [Time frame: the 14th week and the 54th week]

Secondary outcome measures (3)

• Comparison of adverse reactions between the two treatment regimens within 54 weeks [Time frame: within 54 weeks]
• The mucosal healing rates （Simple Endoscopic Score for Crohn's Disease）in the 14th week and the 54th week [Time frame: the 14th week and the 54th week]
• Patient-reported outcomes（PRO2） for the 14th week and the 54th week [Time frame: the 14th week and the 54th week]

Eligibility criteria

Inclusion criteria

• Diagnose Crohn's disease based on the 2019 Expert Consensus for the Diagnosis and Treatment of Pediatric Inflammatory Bowel Disease.
• The baseline Pediatric Crohn's Disease Activity Index (PCDAI) value is ≥ 30.
• None of the patients had received treatment with azathioprine, 6-mercaptopurine, or anti-TNF biological agents before.
• Patients who received the following adjunctive treatments also meet the participation criteria: acid-suppressing drugs (if the dose was stable for at least 2 weeks before enrollment, it is applicable), enteral nutrition (with a stable plan for 2 weeks). Rectal, intravenous, or oral corticosteroids are not allowed, and they must be discontinued at least 2 weeks before enrollment.

Exclusion criteria

• Suffering from short bowel syndrome, ostomy surgery, symptomatic stenosis, abscess, or a recent history of abdominal surgery (within 6 months)
• History of tuberculosis or other granulomatous infections, positive chest imaging or positive tuberculin skin test
• Recent opportunistic infection history (within 6 months), active hepatitis B or C infection, human immunodeficiency virus infection
• Multiple sclerosis, cancer
• Homozygous mutations in NUDT15 or TPMT genes, or heterozygous mutations in at least one of the above genes

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 4 centers

• The First People's Hospital of Yunnan — Kunming
• The Children's Hospital of Zhejiang University School of Medicine — Hangzhou
• JinHua Maternal & Child Health Care Hospital — Jinhua
• Second Affiliated Hospital of Wenzhou Medical University — Wenzhou

Publications

• Kappelman MD, Wohl DA, Herfarth HH, Firestine AM, Adler J, Ammoury RF, Aronow JE, Bass DM, Bass JA, Benkov K, Tobi CB, Boccieri ME, Boyle BM, Brinkman WB, Cabera JM, Chun K, Colletti RB, Dodds CM, Dorsey JM, Ebach DR, Entrena E, Forrest CB, Galanko JA, Grunow JE, Gulati AS, Ivanova A, Jester TW, Kaplan JL, Kugathasan S, Kusek ME, Leibowitz IH, Linville TM, Lipstein EA, Margolis PA, Minar P, Molle- PMID 37004887

Identifiers

NCT: NCT07424040 · CHZJU2025IIT017

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗