TNFi Plus Low-Dose Upadacitinib vs TNFi Intensification in Crohn's Disease With Suboptimal Response

Official title

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

Overview

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.

Interventions

• Drug Upadacitinib
  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
• Drug Infliximab Dose Intensification
  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.
• Drug Adalimumab Dose Intensification
  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.
• Drug Standard-Dose infliximab
  In the experimental arm, participants will continue standard-dose infliximab at 5 mg/kg every 8 weeks.
• Drug Standard-Dose Adalimumab
  In the experimental arm, participants will continue standard-dose adalimumab at 40 mg every 2 weeks.

Primary outcome measures

• Clinical remission rate [Time frame: Week 14]

Secondary outcome measures (12)

• Clinical response rate [Time frame: Weeks 14 and 52]
• Endoscopic remission rate [Time frame: Weeks 14 and 52]
• Endoscopic response rate [Time frame: Weeks 14 and 52]
• Mucosal healing rate [Time frame: Weeks 14 and 52]
• C-reactive protein (CRP) response rate [Time frame: Weeks 14 and 52]
• Fecal calprotectin (FCP) response rate [Time frame: Weeks 14 and 52]
• Imaging response rate [Time frame: Weeks 14 and 52]
• Imaging remission rate [Time frame: Weeks 14 and 52]
• Bowel ultrasound response rate [Time frame: Weeks 14 and 52]
• Incidence of adverse events and serious adverse events [Time frame: Weeks 14 and 52]
• Proportion of participants discontinuing study treatment due to adverse events [Time frame: Weeks 14 and 52]
• Incidence of treatment-related adverse events [Time frame: Weeks 14 and 52]

Eligibility criteria

Inclusion criteria

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: 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.
• At enrollment, the participant must simultaneously meet both requirements:

Partial response to TNFα inhibitor therapy with residual room for optimization, and

• 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.
• The participant fully understands the study objectives, procedures, and potential risks, voluntarily agrees to participate, and has signed the written informed consent form.

Exclusion criteria

Participants meeting any of the following criteria will be excluded from the study:

• 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.
• Presence of severe intestinal complications rendering the participant unsuitable for this study, including but not limited to inadequately controlled active intra-abdominal abscess, intestinal perforation, severe stricture requiring urgent surgical intervention, or severe active intestinal fistula.
• Major bowel resection, stoma creation, or other major abdominal surgery within 3 months prior to enrollment, if judged by the investigator to affect efficacy assessment or safety evaluation.
• Active infection or high risk of severe infection, including but not limited to active tuberculosis, uncontrolled serious bacterial/fungal/viral infection, active herpes zoster, HBV reactivation, HIV infection, or other clinically significant immunodeficiency states.
• Severe dysfunction of major organs, such as significant hepatic impairment, severe renal insufficiency, severe cardiac insufficiency, or other serious underlying diseases judged by the investigator to make participation inappropriate.
• History of gastrointestinal malignancy, or presence of any other malignant disease that may significantly affect study safety or efficacy assessment.
• Pregnant or breastfeeding women, or women planning pregnancy who are unwilling to use effective contraception during the study period.
• Severe psychiatric or neurologic disorders that may impair the ability to provide informed consent, adhere to treatment, or complete study follow-up.
• Participation in another interventional clinical study within 30 days prior to enrollment, where the prior intervention may affect the efficacy or safety assessment of this study.
• Any other condition that, in the investigator's judgment, makes the participant unsuitable for enrollment in this study.

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 · 1 center

• The Sixth Affiliated Hospital, Sun Yat-sen University — Guangzhou

Identifiers

NCT: NCT07510191 · 2026ZSLYEC-158

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗