OP04NORDTREAT: a randomised, multicentre, biomarker-strategy design, open-label, controlled trial of top-down versus clinical management in newly diagnosed IBD

Abstract Background Substantial variation exists in early inflammatory bowel disease (IBD) disease management. Biomarkers predicting disease trajectories may enable personalised treatment. The NORDTREAT strategy-trial was designed to compare “top-down” treatment with standard clinical care in patients at increased risk of an aggressive IBD course, as defined by the prognostic NORDTREAT protein signature.1 Methods NORDTREAT (NORdic inflammatory bowel disease TREATment; NCT05180175) was a randomised, multicentre, biomarker-strategy design, open-label, controlled trial conducted across 15 Nordic hospitals. Following screening, eligible adult with newly diagnosed IBD were randomised (1:1) to either access or non-access to the protein signature. In the access arm, patients displaying a high-risk profile received “top-down” (anti-TNF +/- immunomodulator) treatment, whereas low-risk patients were excluded. The non-access arm received standard care with stepwise treatment escalation at the investigator’s discretion (“clinical management”). The primary endpoint was corticosteroid-free clinical and endoscopic remission at week 52, with surgery considered treatment failure. Secondary endpoints included endoscopic remission, cumulative corticosteroid exposure, and serious adverse events. Analyses were performed in the intention to treat population. Results 313 IBD patients (CD, n = 133 and UC/IBD-unclassified, n = 180) were randomised between February 2022 and March 2024. Median time from diagnosis to enrolment was 7 days. Among access-arm patients (n = 157), 24 (15%) had a high-risk profile. In the non-access arm, 29/156 (19%) patients were found after trial completion to have had a high-risk profile at baseline and of these 16 (55%) received advanced therapy after a median period of 15 days. The primary endpoint was achieved in 10/24 (42%) “top-down” and 8/29 (27%) “clinical management” patients (absolute difference 15%; 95%CI -11-41, p = 0.26). Endoscopic remission rates at week 52 were comparable (53% vs 53%, p = 0.99). Median cumulative cortisone equivalents was 1232 mg in top-down vs 1651 mg in standard care, p = 0.07). Table 1 provides information on serious adverse events. Post-hoc analyses showed numerically higher rates of achieving the primary endpoint in CD, 50% vs 11% (p = 0.09) UC, whereas rates were comparable in UC 36% vs 35% (p = 0.97). Conclusion A biomarker-guided “top-down” approach did not increase corticosteroid-free clinical and endoscopic remission at week 52 compared with standard care. However, a possible benefit was seen in CD, suggesting that early “top-down” could improve outcomes in this subgroup of patients even in the era of widespread use of advanced therapies. Reference: 1. Rejler R, Füchtbauer JD, Davíðsdóttir LG, et al. BMJ Open. 2024 Jul 31;14(7):e083163. doi: 10.1136/bmjopen-2023-083163. Conflict of interest: Bergemalm, Daniel: DB has received fees for lectures and/or advisory board from Abbvie, Bristol Mayers Squibb, Johnson and Johnson, Pharmacosmos, Pfizer, Takeda, Tillots Pharma and Sandoz. Füchtbauer, David: travel grants from Tillotts Pharma Rejller, Martin: No conflict of interest Davíðsdóttir, Loa: No conflict of interest Fejrskov, Anja: No conflict of interest Hedin, Charlotte Rose: Grant: C. R. H. Hedin has received specific project grants from Takeda and Tillotts. Personal Fees: C. R. H. Hedin served as a speaker and/or advisory board member for AstraZeneca, Abbvie, Dr Falk Pharma and the Falk Foundation, Galapagos, Janssen, Lilly, Pfizer, Ferring, Takeda, Tillotts Pharma, and received grant support from Tillotts and Takeda. These fees are invoiced by her employer. Bache-Wiig Mathisen, Charlotte: No conflict of interest Hupperz-Hauss, Gert: No conflict of interest Carstens, Adam: No conflict of interest Kristensen, Vendel: Has served as speaker, consultant, and advisory member for or has received investigator-initiated research funding from Takeda, Janssen, Ferring and Tillotts Pharma Hjortswang, Henrik: No conflict of interest Aabrekk, Tone Bergene: No conflict of interest Carlson, Marie: Dr Carlson has received speaker’s fees from ViforPharma and AbbVie. She is the national PI for clinical trials for AstraZeneca. None of these activities have any relation to the present study. Frigstad, Svein-Oskar: Personal fees from Takeda, Galapagos, Jansen-Cilag, Abbvie, Pharmacosmos, Norgine and Bristol-Myers-Squibb. Söderholm, Johan D.: No conflict of interest Christensen, Robin: No conflict of interest Andersen, Vibeke Charlotte: Grant support: The Region of Southern Denmark “Fri og Strategisk Forskning” (J.nr.: 20/44012 and 17/18561), Innovation Fund Denmark (90569 NORDTREAT: grant number 8114-00026B). Sundhedsdonationer (2024-0379). Presenting and/or advisory board fees from: MSD/Merck and Eli Lilly Repsilber, Dirk: No conflict of interest Kjeldsen, Jens: No conflict of interest Høivik, Marte: Investigator-initiated research grants from Takeda, Pfizer,Tillotts, Ferring, and Janssen. Received speaker honorariafrom Takeda, Tillotts, Ferring, AbbVie, Galapagos, and Meda.Advisory board affiliations with Takeda, Galapagos, MSD,Lilly, Celltrion, and AbbVie Halfvarson, Jonas: Grant support: Swedish Foundation for Strategic Research (RB13-0160 to J.H.), the Swedish Research Council (2020-02021 to J.H.), the Örebro University Hospital research foundation (OLL-890291 to J.H.), NordForsk (90569 to J.H.) and Vinnova (2019-01185 to JH and 2024-01155 co-applicant), IHI, EU, INTERCEPT (Grant agreement number 101194780, co-applicant), miGut-Health, HORIZON-HLTH-2022, EU (Grant Agreement 101095470, Co-applicant), 3TR, IMI 2, EU, (Grant agreement number 831434, Co-applicant), Janssen, MSD, and Takeda. Consulting and/or advisory board fees from: AbbVie, Alfasigma, Aqilion, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Hospira, Index Pharmaceuticals, Janssen, Johnson & Johnson, MEDA, Medivir, Medtronic, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and speaker’s fees from: AbbVie, Alfasigma, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma and research grant support from Janssen, Merck Sharp & Dohme and Takeda.