This multicenter, randomized, controlled trial aims to evaluate the efficacy and safety of standard-dose tumor necrosis factor inhibitor (TNFi) plus low-dose upadacitinib compared with TNFi dose intensification in patients with moderate-to-severe Crohn's disease who have a suboptimal response to standard-dose TNFi therapy. Eligible participants are adults with active Crohn's disease receiving standard-dose infliximab or adalimumab who remain inadequately controlled despite ongoing treatment. Participants will be randomly assigned in a 1:1 ratio to either continue standard-dose TNFi with oral upadacitinib 15 mg once daily, or receive TNFi dose intensification according to the protocol. Clinical assessments will be performed at baseline and during follow-up, with the primary endpoint assessed at Week 14. The primary outcome is the proportion of participants achieving clinical remission, defined as a Crohn's Disease Activity Index (CDAI) score \<150 at Week 14. Secondary outcomes include clinical response, endoscopic response and remission, changes in inflammatory biomarkers such as C-reactive protein and fecal calprotectin, quality of life, and safety outcomes including adverse events and serious adverse events. Participants will continue follow-up after Week 14 to evaluate treatment durability and longer-term safety. This study is designed to determine whether a dual-target strategy with standard-dose TNFi plus low-dose upadacitinib provides superior short-term efficacy and acceptable safety compared with conventional TNFi intensification in Crohn's disease patients with insufficient benefit from standard-dose TNFi therapy.
Age 18-65 years, regardless of sex.
Established diagnosis of Crohn's disease (CD) based on a comprehensive assessment including clinical manifestations, imaging, endoscopy, histopathology, and other relevant evaluations, and meeting currently accepted domestic and international diagnostic criteria.
Prior exposure to TNFα inhibitors (including infliximab, adalimumab, or its biosimilars) for at least 12 weeks, and currently receiving a standard-dose treatment regimen. After comprehensive evaluation by the investigators, the participant is considered to have partial response to TNFα inhibitor therapy with residual room for optimization. This is defined as failure to achieve the prespecified treatment target after standard induction and/or maintenance therapy, while still being considered by the investigator to have potential for further optimization. Eligible participants should meet either of the following: (1)Loss of response (LOR): The participant previously achieved clinical remission and/or objective improvement after TNFα inhibitor treatment, but subsequently developed recurrent disease activity during the maintenance phase. Based on the prior response trajectory, current objective evidence of disease activity, treatment adherence, and available reactive therapeutic drug monitoring (TDM) results, the investigator judges that the participant has not developed complete pharmacodynamic failure to TNFi, and still has room for further therapeutic optimization. (2)Primary inadequate response: After completion of standard induction therapy, the participant achieved some but insufficient improvement compared with pretreatment baseline, defined as meeting at least one of the following: ①CDAI decrease of ≥100 points, but CDAI remains ≥150, ②SES-CD decrease of ≥50%, but active ulcerative lesions persist or endoscopic remission has not been achieved, ③CRP and/or FCP decrease of ≥50%, but inflammatory markers have not normalized (e.g., FCP ≥250 μg/g), ④Based on a comprehensive assessment of symptoms, endoscopy, inflammatory biomarkers, and imaging, the investigator determines that the participant has achieved partial response to TNFi but has not reached the anticipated treatment target, with further room for optimization.
Active Crohn's disease with objective evidence of active inflammation, defined as meeting all of the following: 150 ≤ CDAI < 450; at least one of the following objective indicators of active inflammation: (1)Endoscopy showing active ulcerative lesions, (2)Elevated inflammatory markers such as C-reactive protein (CRP), (3)Fecal calprotectin (FCP) ≥250 μg/g, (4)Imaging evidence of active intestinal inflammation, such as CTE, MRE, or intestinal ultrasound.
No improvement at all after adequate induction therapy with a TNFα inhibitor, with investigator judgment indicating clear mechanistic non-response and minimal likelihood of benefit from further optimization.
Documented immunogenic clearance confirmed by therapeutic drug monitoring (TDM), defined as positive anti-drug antibodies against a TNFα inhibitor with extremely low or undetectable trough drug levels, and judged by the investigator to be unsuitable for continued treatment with the original TNFα inhibitor.
Current symptoms are judged, after comprehensive evaluation, to be caused primarily by non-inflammatory factors, with no objective evidence of active inflammation, such as irritable bowel syndrome, bile acid diarrhea, small intestinal bacterial overgrowth, or other non-inflammatory causes.
Prior exposure to JAK inhibitors (including but not limited to upadacitinib), known hypersensitivity to any component of the investigational treatment, or other clear contraindications to study treatment.
Parallel
Upadacitinib
DrugUpadacitinib will be administered orally in combination with ongoing standard-dose TNF inhibitor therapy in the experimental arm. The initial dose is 15 mg once daily for 14 weeks. If inflammatory biomarkers, including C-reactive protein or fecal calprotectin, do not decrease by at least 30% from baseline at Week 4 and treatment is well tolerated, the dose may be increased to 30 mg once daily according to the study protocol
Infliximab Dose Intensification
DrugIn the active comparator arm, infliximab dose intensification will be performed by shortening the dosing interval from every 8 weeks to every 4 weeks at 5 mg/kg, according to the study protocol.
Adalimumab Dose Intensification
DrugIn the active comparator arm, adalimumab dose intensification will be performed by increasing the dose from 40 mg every 2 weeks to 80 mg every 2 weeks, according to the study protocol.
Standard-Dose infliximab
DrugIn the experimental arm, participants will continue standard-dose infliximab at 5 mg/kg every 8 weeks.
Standard-Dose Adalimumab
DrugIn the experimental arm, participants will continue standard-dose adalimumab at 40 mg every 2 weeks.
Clinical remission rate
The proportion of participants achieving clinical remission at Week 14, defined as a Crohn's Disease Activity Index (CDAI) score \<150.
Clinical response rate
Clinical response is defined as a decrease of at least 100 points from baseline in the Crohn's Disease Activity Index (CDAI) score.
Endoscopic remission rate
The proportion of participants achieving endoscopic remission, defined as a Simple Endoscopic Score for Crohn's Disease (SES-CD) \<3.
Endoscopic response rate
The proportion of participants achieving endoscopic response, defined as a ≥50% reduction in SES-CD from baseline.
Mucosal healing rate
The proportion of participants achieving mucosal healing, defined as complete absence of ulceration in all examined bowel segments. This outcome will be evaluated among participants who undergo ileocolonoscopy at the specified time points.
Change in gut microbiome characteristics
Gut microbiome characteristics will be assessed among participants with available stool samples at baseline, Week 14, and Week 52. Analyses will include microbial composition, alpha and beta diversity, and the relative abundance of key taxa, in order to explore associations between microbiome changes and treatment response.
Change in metabolomic profiles
Metabolomic profiles will be assessed among participants with available stool and/or blood samples at baseline, Week 14, and Week 52. Analyses will include candidate biomarkers such as inflammation-related metabolites, bile acids, and lipid metabolites, to explore associations between metabolic changes and treatment response.
Change in transcriptomic and inflammation-related molecular biomarkers
Transcriptomic and inflammation-related molecular biomarkers will be assessed among participants with available blood and/or tissue samples at baseline, Week 14, and Week 52, when samples are available. Analyses will focus on pathways related to TNF, JAK-STAT, IL-6, and other inflammatory signaling mechanisms, to explore the molecular basis of treatment response.
Anti-TNF trough level change and target attainment rate
Anti-TNF trough levels will be assessed among participants with available blood samples at baseline, Week 14, and Week 52. This outcome will evaluate changes in trough levels over time and the proportion of participants achieving pre-defined target trough concentrations, and will be used to explore the relationship between drug exposure and clinical, endoscopic, and biomarker outcomes.
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