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

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.

Study Overview

• Status: Recruiting
• Conditions: Crohn Disease (CD)
• Intervention / Treatment: Drug: Upadacitinib; Drug: Standard-Dose infliximab; Drug: Standard-Dose Adalimumab; Drug: Infliximab Dose Intensification; Drug: Adalimumab Dose Intensification

• Study Type: Interventional
• Enrollment (Estimated): 312
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Wei Wang, MD; Phone Number: 86-18702046420; Email: wangw239@mail.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Recruiting
      • The Sixth Affiliated Hospital, Sun Yat-sen University
      • Contact: Wei Wang, MD; Phone Number: 86-18702046420; Email: wangw239@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for enrollment:

1. Age 18-65 years, regardless of sex.
2. 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.
3. 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.
4. 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.

Exclusion Criteria:

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

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. History of gastrointestinal malignancy, or presence of any other malignant disease that may significantly affect study safety or efficacy assessment.
10. Pregnant or breastfeeding women, or women planning pregnancy who are unwilling to use effective contraception during the study period.
11. Severe psychiatric or neurologic disorders that may impair the ability to provide informed consent, adhere to treatment, or complete study follow-up.
12. 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.
13. Any other condition that, in the investigator's judgment, makes the participant unsuitable for enrollment in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard-Dose TNFi Plus Low-Dose Upadacitinib; Participants will continue their current standard-dose TNF inhibitor therapy and receive oral upadacitinib. Standard-dose TNF inhibitor therapy includes infliximab 5 mg/kg intravenously every 8 weeks or adalimumab 40 mg subcutaneously every 2 weeks, with no dose intensification or switching during the study. Upadacitinib will be initiated at 15 mg orally once daily for 14 weeks. If inflammatory biomarkers such as 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 protocol.	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: 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.
Active Comparator: TNFi Dose Intensification; Participants will continue their current TNF inhibitor with protocol-defined dose intensification. For infliximab, the dosing interval will be shortened from every 8 weeks to every 4 weeks at 5 mg/kg intravenously. For adalimumab, the dose will be increased from 40 mg every 2 weeks to 80 mg every 2 weeks by subcutaneous injection. No switching to another TNF inhibitor, no additional biologic therapy, and no new JAK inhibitor will be permitted during the intervention period. The treatment period is 14 weeks.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical remission rate	The proportion of participants achieving clinical remission at Week 14, defined as a Crohn's Disease Activity Index (CDAI) score <150.	Week 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	Weeks 14 and 52
Endoscopic response rate	The proportion of participants achieving endoscopic response, defined as a ≥50% reduction in SES-CD from baseline.	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.	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.	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).	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.	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.	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.	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.	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.	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	Weeks 14 and 52

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Week 14, and Week 52
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.	Baseline, Week 14, and Week 52
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.	Baseline, Week 14, and Week 52
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.	Baseline, Week 14, and Week 52

Collaborators and Investigators

• Sponsor: Sixth Affiliated Hospital, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: March 29, 2026
• First Submitted That Met QC Criteria: March 29, 2026
• First Posted (Actual): April 3, 2026

Study Record Updates

• Last Update Posted (Actual): April 22, 2026
• Last Update Submitted That Met QC Criteria: April 18, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Upadacitinib; Crohn Disease; Infliximab; Adalimumab; TNF inhibitor; Multicenter randomized controlled trial; Dual-target therapy; Dose intensification
• Additional Relevant MeSH Terms: Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Inflammatory Bowel Diseases; Crohn Disease; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Adalimumab; Infliximab; upadacitinib
• Other Study ID Numbers: 2026ZSLYEC-158

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) will not be shared because this is a multi-center study involving detailed clinical, imaging, endoscopic, surgical, and pathology data from patients with complicated Crohn's disease, and there is a potential risk of participant re-identification despite de-identification. Data sharing is also subject to local ethics approval, institutional policy, and participant consent.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No