Efficacy and Safety of Dual-targeted Therapy With Upadacitinib and Ustekinumab Versus Intensified Ustekinumab Therapy in Crohn's Disease

Official title

Evaluation of the Efficacy and Safety of Dual-targeted Therapy With Upadacitinib and Ustekinumab Versus Intensified Ustekinumab Therapy in Crohn's Disease Patients With an Insufficient Response to Standard-dose Ustekinumab: A Randomized Controlled Trial

Overview

The goal of this clinical trial is to evaluate the efficacy and safety of dual-target therapy (Ustekinumab combined with Upadacitinib) versus intensified Ustekinumab monotherapy in patients with Crohn's disease who have an inadequate response to standard doses of Ustekinumab. The main questions it aims to answer are: Is dual-target therapy more effective than intensified Ustekinumab monotherapy in achieving endoscopic remission in Crohn's disease patients? Is dual-target therapy as safe as intensified Ustekinumab monotherapy in terms of adverse events? Participants will: Receive either dual-target therapy (Ustekinumab combined with Upadacitinib) or intensified Ustekinumab monotherapy. Attend regular clinic visits for monitoring and assessments. Complete questionnaires about their symptoms and quality of life. Undergo routine blood tests and endoscopic evaluations to assess disease activity. Researchers will compare the dual-target therapy group to the intensified Ustekinumab monotherapy group to see if dual-target therapy is more effective in achieving endoscopic remission and is as safe in terms of adverse events.

Interventions

• Drug Ustekinumab and Upadacitinib
  Participants will continue ustekinumab 90 mg administered subcutaneously every 8 weeks. In addition, upadacitinib will be administered orally once daily. During the induction period (Weeks 0-12), upadacitinib will be initiated at 15 mg or 30 mg daily, with escalation up to 45 mg daily permitted based on disease activity, clinical response, and tolerability. From Week 12 to Week 16, dose adjustment (15 0r 30 daily) will be allowed according to clinical judgment. Clinical efficacy will be assessed
• Drug Ustekinumab
  Participants will receive an additional induction dose of Ustekinumab administered intravenously at 6 mg/kg at baseline. This will be followed by subcutaneous maintenance therapy of 90 mg every 4 weeks. Clinical efficacy will be evaluated at week 16.

Primary outcome measures

• The primary endpoint of the study is the endoscopic remission rate at week 16. [Time frame: Week 16]

Secondary outcome measures (9)

• Clinical response rate at week 16 [Time frame: Week 16.]
• Endoscopic response rate at week 16 [Time frame: Week 16]
• Deep remission rate at week 16 [Time frame: Week 16]
• Biochemical remission rate at week 16 [Time frame: Week 16]
• Normalization rate of fecal calprotectin levels at week 16 [Time frame: Week 16]
• Normalization rate of intestinal wall thickness on ultrasound at week 16 [Time frame: Week 16]
• Health-related quality of life assessment using the Inflammatory Bowel Disease Questionnaire (IBDQ) [Time frame: Week 16 and around Week 52]
• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 at week 16. [Time frame: Week 16]
• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 at week 52 [Time frame: Around Week 52]

Eligibility criteria

Inclusion criteria

• Male or female participants aged 18 to 70 years at baseline (week 0).
• Active Crohn's Disease: Participants must have active Crohn's disease at baseline, defined as: CDAI > 150 and Endoscopic activity with SES-CD > 6, or SES-CD > 4 (for isolated ileal disease), excluding the contribution of the stricture component (Excluding the stricture component ensures recruitment of patients with a better chance of improvement, given the primary endpoint is endoscopic remission), and at least one of the following: CRP > 10 mg/L (upper limit of normal on local assay), Fecal calprotectin (FC) > 250 μg/g, active disease confirmed by imaging.
• Prior Ustekinumab Treatment: Participants must have had primary non-response or secondary loss of response to TNFi, and have undergone at least 16-24 weeks of standard-dose ustekinumab treatment, but still have active CD.
• Consent and Compliance: Participants must be capable and willing to provide written informed consent and comply with the requirements of the study protocol.
• General Health: The principal investigator (or designee) must determine that the participant is in good general health based on medical history, laboratory test results, physical examination, chest X-ray (CXR), and 12-lead electrocardiogram (ECG) obtained during the screening period.

Exclusion criteria

• Allergies: Participants with known allergies to UPA or UST excipients or components.
• Colonic Neoplasia: Participants with untreated or unresolved high-grade dysplasia or colon cancer.
• Active Infections: Participants with active infections at screening or baseline, including but not limited to pneumonia, pyelonephritis, or herpes zoster, or those with evidence of chronic infections that make them unsuitable for the study as per the investigator's assessment.
• Surgical Intervention: Participants who currently require or are expected to require surgical intervention for CD during the study period.
• Thrombosis: Participants with thrombosis identified through limb venous Doppler ultrasound or D-dimer screening.
• Lymphoproliferative Disorders: Participants with a history of lymphoproliferative disorders, including lymphoma, or those with signs and symptoms indicative of possible lymphoproliferative disease such as lymphadenopathy and/or splenomegaly.
• Immunodeficiency: Participants with any known congenital or acquired immunodeficiency, including common variable immunodeficiency, HIV infection, or organ transplantation.
• Pregnancy: Female participants with a positive pregnancy test at screening or baseline (week 0).
• Lactation or Pregnancy Plans: Female participants who are breastfeeding or planning to become pregnant during the study.
• Substance Abuse: Participants with a history of drug abuse (defined as the use of any illicit drug) or alcohol abuse within 1 year prior to screening.
• Investigator's Discretion: Participants deemed unsuitable for the study by the investigator for any reason.

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

Prevention

Study locations

China · 1 center

• Wei Wang — Guangzhou

Publications

• Raine T, Danese S. Breaking Through the Therapeutic Ceiling: What Will It Take? Gastroenterology. 2022 Apr;162(5):1507-1511. doi: 10.1053/j.gastro.2021.09.078. Epub 2022 Jan 4. PMID 34995533
• Schultheiss JPD, Mahmoud R, Louwers JM, van der Kaaij MT, van Hellemondt BP, van Boeckel PG, Mahmmod N, Jharap B, Fidder HH, Oldenburg B. Loss of response to anti-TNFalpha agents depends on treatment duration in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2021 Nov;54(10):1298-1308. doi: 10.1111/apt.16605. Epub 2021 Sep 24. PMID 34559428
• Noor NM, Lee JC, Bond S, Dowling F, Brezina B, Patel KV, Ahmad T, Banim PJ, Berrill JW, Cooney R, De La Revilla Negro J, de Silva S, Din S, Durai D, Gordon JN, Irving PM, Johnson M, Kent AJ, Kok KB, Moran GW, Mowat C, Patel P, Probert CS, Raine T, Saich R, Seward A, Sharpstone D, Smith MA, Subramanian S, Upponi SS, Wiles A, Williams HRT, van den Brink GR, Vermeire S, Jairath V, D'Haens GR, McKinne PMID 38402895
• Singh S, George J, Boland BS, Vande Casteele N, Sandborn WJ. Primary Non-Response to Tumor Necrosis Factor Antagonists is Associated with Inferior Response to Second-line Biologics in Patients with Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis. J Crohns Colitis. 2018 May 25;12(6):635-643. doi: 10.1093/ecco-jcc/jjy004. PMID 29370397
• Parigi TL, D'Amico F, Abreu MT, Rubin DT, Dignass A, Dotan I, Jairath V, Magro F, Peyrin-Biroulet L, Ghosh S, Danese S. Difficult-to-treat inflammatory bowel disease: results from a global IOIBD survey. Lancet Gastroenterol Hepatol. 2022 May;7(5):390-391. doi: 10.1016/S2468-1253(22)00085-1. No abstract available. PMID 35397241
• Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, Blank MA, Johanns J, Gao LL, Miao Y, Adedokun OJ, Sands BE, Hanauer SB, Vermeire S, Targan S, Ghosh S, de Villiers WJ, Colombel JF, Tulassay Z, Seidler U, Salzberg BA, Desreumaux P, Lee SD, Loftus EV Jr, Dieleman LA, Katz S, Rutgeerts P; UNITI-IM-UNITI Study Group. Ustekinumab as Induction and Maintenance Therapy for Crohn's Dise PMID 27959607
• Adedokun OJ, Xu Z, Gasink C, Jacobstein D, Szapary P, Johanns J, Gao LL, Davis HM, Hanauer SB, Feagan BG, Ghosh S, Sandborn WJ. Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn's Disease. Gastroenterology. 2018 May;154(6):1660-1671. doi: 10.1053/j.gastro.2018.01.043. Epub 2018 Feb 1. PMID 29409871
• Ollech JE, Normatov I, Peleg N, Wang J, Patel SA, Rai V, Yi Y, Singer J, Dalal SR, Sakuraba A, Cohen RD, Rubin DT, Pekow J. Effectiveness of Ustekinumab Dose Escalation in Patients With Crohn's Disease. Clin Gastroenterol Hepatol. 2021 Jan;19(1):104-110. doi: 10.1016/j.cgh.2020.02.035. Epub 2020 Feb 26. PMID 32109634

Identifiers

NCT: NCT06520397 · 2024ZSLYEC-070

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗