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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
312
Upadacitinib 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
In 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.
In 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.
In the experimental arm, participants will continue standard-dose infliximab at 5 mg/kg every 8 weeks.
In the experimental arm, participants will continue standard-dose adalimumab at 40 mg every 2 weeks.
The Sixth Affiliated Hospital, Sun Yat-sen University
Guangzhou, Guangdong, China
RECRUITINGClinical remission rate
The proportion of participants achieving clinical remission at Week 14, defined as a Crohn's Disease Activity Index (CDAI) score \<150.
Time frame: Week 14
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.
Time frame: Weeks 14 and 52
Endoscopic remission rate
The proportion of participants achieving endoscopic remission, defined as a Simple Endoscopic Score for Crohn's Disease (SES-CD) \<3.
Time frame: Weeks 14 and 52
Endoscopic response rate
The proportion of participants achieving endoscopic response, defined as a ≥50% reduction in SES-CD from baseline.
Time frame: Weeks 14 and 52
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.
Time frame: Weeks 14 and 52
C-reactive protein (CRP) response rate
The proportion of participants achieving a ≥50% reduction in CRP levels from baseline or normalization to within the upper limit of normal.
Time frame: Weeks 14 and 52
Fecal calprotectin (FCP) response rate
The proportion of participants achieving a ≥50% reduction in fecal calprotectin levels from baseline or normalization (\<250 μg/g).
Time frame: Weeks 14 and 52
Imaging response rate
Cross-sectional imaging response is defined as improvement from baseline on CTE or MRE in the affected bowel segment, including at least one of the following: a ≥25% reduction in bowel wall thickness, reduction in mural hyperenhancement or mural edema, or reduction in associated inflammatory changes.
Time frame: Weeks 14 and 52
Imaging remission rate
Proportion of participants achieving radiologic remission at Week 12, assessed primarily by CTE and, when available, MRE, defined as minimal or absent active transmural inflammatory findings on cross-sectional imaging, including absence or near-complete resolution of mural hyperenhancement, mural stratification and/or mural edema, comb sign, and perienteric inflammatory change, without radiologic progression or new penetrating inflammatory complications. In participants undergoing MRE, radiologic remission may additionally be defined as a MaRIA score \<7.
Time frame: Weeks 14 and 52
Bowel ultrasound response rate
Proportion of participants achieving bowel ultrasound response at Week 12, defined as a reduction in bowel wall thickness and/or a decrease in bowel wall vascularity (Limberg score) compared with baseline.
Time frame: Weeks 14 and 52
Incidence of adverse events and serious adverse events
Safety will be assessed by the incidence of adverse events (AEs) and serious adverse events (SAEs) during the study period. All AEs and SAEs will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
Time frame: Weeks 14 and 52
Proportion of participants discontinuing study treatment due to adverse events
Treatment tolerability will be assessed by the proportion of participants who discontinue study treatment due to adverse events during the study period.
Time frame: Weeks 14 and 52
Incidence of treatment-related adverse events
Treatment-related adverse events will be assessed during the study period based on investigator attribution
Time frame: Weeks 14 and 52
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