TNFi plus low-dose upadacitinib versus TNFi dose intensification for Crohn's disease with suboptimal response

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 trial tests whether adding low-dose upadacitinib to a standard TNF blocker helps adults with moderate-to-severe Crohn's disease who haven't responded well to standard-dose infliximab or adalimumab, compared with increasing the TNFi dose.

Quick facts

• Phase: Phase 4
• Study type: Interventional
• Enrollment: 312 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: Sixth Affiliated Hospital, Sun Yat-sen University (Academic / other)
• Drugs / interventions: infliximab, adalimumab, upadacitinib
• Locations: 1 site (Guangzhou, Guangdong)
• Trial ID: NCT07510191 on ClinicalTrials.gov

What this trial studies

This randomized, multicenter, phase 4 trial enrolls adults with active Crohn's disease who have had a suboptimal response to at least 12 weeks of standard-dose infliximab or adalimumab. Participants are randomized 1:1 to either continue standard-dose TNFi and add oral upadacitinib 15 mg once daily or to undergo TNFi dose intensification per protocol. Clinical assessments occur at baseline and during follow-up, with the primary endpoint being clinical remission (CDAI <150) at Week 14. Safety and secondary clinical outcomes are also monitored throughout the study.

Who should consider this trial

Good fit: Adults aged 18–65 with established Crohn's disease who have been on standard-dose infliximab or adalimumab for at least 12 weeks and are judged to have a partial or suboptimal response are the intended participants.

Not a fit: Patients who are primary nonresponders to TNFi, have contraindications to JAK inhibitors, have severe complications requiring alternate care, or who are outside the 18–65 age range are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could help more patients achieve clinical remission without switching biologics by adding a low-dose oral JAK inhibitor to their current TNFi.

How similar studies have performed: JAK inhibitors including upadacitinib have shown efficacy for Crohn's disease in prior trials, but directly combining low-dose upadacitinib with ongoing TNFi instead of switching is a relatively novel approach with limited direct evidence.

Eligibility criteria

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.

Where this trial is running

Guangzhou, Guangdong

• The Sixth Affiliated Hospital, Sun Yat-sen University — Guangzhou, Guangdong, China (Recruiting)

Study contacts

• Study coordinator: Wei Wang, MD

Conditions Crohn Disease; TNF inhibitor; Infliximab; Adalimumab; Upadacitinib; Dose intensification; Dual-target therapy; Multicenter randomized controlled trial