Efficacy and Safety of Standard-Dose TNF Inhibitor Plus Low-Dose Upadacitinib Versus TNF Inhibitor Intensification for Crohn's Disease With Suboptimal Response to Standard-Dose TNF Inhibitors: A Multicenter, Randomized, Controlled Trial
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.
• Participants must meet all of the following criteria to be eligible for enrollment:
⁃ 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:
• CDAI 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;
‣ CRP and/or FCP decrease of ≥50%, but inflammatory markers have not normalized (e.g., FCP ≥250 μg/g).
∙ Based 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.
∙ 5\. 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.
∙ 5\. At enrollment, the participant must simultaneously meet both requirements: Partial response to TNFα inhibitor therapy with residual room for optimization, and 6. Objective evidence of active inflammation at the current active stage of CD. Baseline TDM and pharmacokinetic assessment are feasible at enrollment, and relevant results may be used for baseline stratification, efficacy analysis, and exploratory research.
∙ 7\. The participant fully understands the study objectives, procedures, and potential risks, voluntarily agrees to participate, and has signed the written informed consent form.