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

Summary

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.

Timeline

Start

2024-07-15

Primary completion

2026-12-31

Completion

2027-07-31

Publications

• Background 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.
• Background 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.
• Background 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, McKinney EF, Lyons PA, Lindsay JO, Kennedy NA, Smith KGC, Parkes M; PROFILE Study Group. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial. Lancet Gastroenterol Hepatol. 2024 May;9(5):415-427. doi: 10.1016/S2468-1253(24)00034-7. Epub 2024 Feb 22.
• Background 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.
• Background 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.
• Background 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 Disease. N Engl J Med. 2016 Nov 17;375(20):1946-1960. doi: 10.1056/NEJMoa1602773.
• Background 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.
• Background 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.
• Background Haider SA, Yadav A, Perry C, Su L, Akanbi O, Kudaravalli P, Tripathi N, Hashim MA, Abdelsalam M, Hussein M, Elkheshen A, Patel V, Ali SE, Lamb L, Ingram K, Mayne C, Stuffelbeam AB, Flomenhoft D, Stromberg A, Barrett TA. Ustekinumab dose escalation improves clinical responses in refractory Crohn's disease. Ther Adv Gastroenterol. 2020 Oct 13;13:1756284820959245. doi: 10.1177/1756284820959245. eCollection 2020.
• Background Bermejo F, Jimenez L, Algaba A, Vela M, Bastida G, Merino O, Lopez-Garcia A, Melcarne L, Rodriguez-Lago I, de la Maza S, Bouhmidi A, Barreiro-de Acosta M, Lopez-Serrano P, Carrillo-Palau M, Mesonero F, Orts B, Bonillo D, Granja A, Guerra I. Re-induction With Intravenous Ustekinumab in Patients With Crohn's Disease and a Loss of Response to This Therapy. Inflamm Bowel Dis. 2022 Jan 5;28(1):41-47. doi: 10.1093/ibd/izab015.
• Background Privitera G, Pugliese D, Lopetuso LR, Scaldaferri F, Neri M, Guidi L, Gasbarrini A, Armuzzi A. Novel trends with biologics in inflammatory bowel disease: sequential and combined approaches. Ther Adv Gastroenterol. 2021 Apr 27;14:17562848211006669. doi: 10.1177/17562848211006669. eCollection 2021.
• Background Yang E, Panaccione N, Whitmire N, Dulai PS, Vande Casteele N, Singh S, Boland BS, Collins A, Sandborn WJ, Panaccione R, Battat R. Efficacy and safety of simultaneous treatment with two biologic medications in refractory Crohn's disease. Aliment Pharmacol Ther. 2020 Jun;51(11):1031-1038. doi: 10.1111/apt.15719. Epub 2020 Apr 24.
• Background Gold SL, Steinlauf AF. Efficacy and Safety of Dual Biologic Therapy in Patients With Inflammatory Bowel Disease: A Review of the Literature. Gastroenterol Hepatol (N Y). 2021 Sep;17(9):406-414.
• Background Penagini F, Lonoce L, Abbattista L, Silvera V, Rendo G, Cococcioni L, Dilillo D, Calcaterra V, Zuccotti GV. Dual biological therapy and small molecules in pediatric inflammatory bowel disease. Pharmacol Res. 2023 Oct;196:106935. doi: 10.1016/j.phrs.2023.106935. Epub 2023 Sep 23.
• Background Feng Z, Kang G, Wang J, Gao X, Wang X, Ye Y, Liu L, Zhao J, Liu X, Huang H, Cao X. Breaking through the therapeutic ceiling of inflammatory bowel disease: Dual-targeted therapies. Biomed Pharmacother. 2023 Feb;158:114174. doi: 10.1016/j.biopha.2022.114174. Epub 2022 Dec 31.
• Background Fenster M, Alayo QA, Khatiwada A, Wang W, Dimopoulos C, Gutierrez A, Ciorba MA, Christophi GP, Hirten RP, Ha C, Beniwal-Patel P, Cohen BL, Syal G, Yarur A, Patel A, Colombel JF, Pekow J, Ungaro RC, Rubin DT, Deepak P. Real-World Effectiveness and Safety of Tofacitinib in Crohn's Disease and IBD-U: A Multicenter Study From the TROPIC Consortium. Clin Gastroenterol Hepatol. 2021 Oct;19(10):2207-2209.e3. doi: 10.1016/j.cgh.2020.10.025. Epub 2020 Oct 14.
• Background Stalgis C, Deepak P, Mehandru S, Colombel JF. Rational Combination Therapy to Overcome the Plateau of Drug Efficacy in Inflammatory Bowel Disease. Gastroenterology. 2021 Aug;161(2):394-399. doi: 10.1053/j.gastro.2021.04.068. Epub 2021 May 4. No abstract available.
• Background Loftus EV Jr, Panes J, Lacerda AP, Peyrin-Biroulet L, D'Haens G, Panaccione R, Reinisch W, Louis E, Chen M, Nakase H, Begun J, Boland BS, Phillips C, Mohamed MF, Liu J, Geng Z, Feng T, Dubcenco E, Colombel JF. Upadacitinib Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med. 2023 May 25;388(21):1966-1980. doi: 10.1056/NEJMoa2212728.
• Background Lee SD, Singla A, Harper J, Barahimi M, Jacobs J, Kamp KJ, Clark-Snustad KD. Safety and Efficacy of Tofacitinib in Combination With Biologic Therapy for Refractory Crohn's Disease. Inflamm Bowel Dis. 2022 Feb 1;28(2):309-313. doi: 10.1093/ibd/izab176.
• Background Alayo QA, Khatiwada A, Patel A, Zulfiqar M, Gremida A, Gutierrez A, Rood RP, Ciorba MA, Christophi G, Deepak P. Effectiveness and Safety of Combining Tofacitinib With a Biologic in Patients With Refractory Inflammatory Bowel Diseases. Inflamm Bowel Dis. 2021 Oct 18;27(10):1698-1702. doi: 10.1093/ibd/izab112. No abstract available.
• Background Alayo QA, Fenster M, Altayar O, Glassner KL, Llano E, Clark-Snustad K, Patel A, Kwapisz L, Yarur AJ, Cohen BL, Ciorba MA, Thomas D, Lee SD, Loftus EV Jr, Fudman DI, Abraham BP, Colombel JF, Deepak P. Systematic Review With Meta-analysis: Safety and Effectiveness of Combining Biologics and Small Molecules in Inflammatory Bowel Disease. Crohns Colitis 360. 2022 Feb 10;4(1):otac002. doi: 10.1093/crocol/otac002. eCollection 2022 Jan.
• Background Yerushalmy-Feler A, Olbjorn C, Kolho KL, Aloi M, Musto F, Martin-de-Carpi J, Lozano-Ruf A, Yogev D, Matar M, Scarallo L, Bramuzzo M, de Ridder L, Kang B, Norden C, Wilson DC, Tzivinikos C, Turner D, Cohen S. Dual Biologic or Small Molecule Therapy in Refractory Pediatric Inflammatory Bowel Disease (DOUBLE-PIBD): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN. Inflamm Bowel Dis. 2024 Feb 1;30(2):159-166. doi: 10.1093/ibd/izad064.

Drugs

Indications