S1127 A Randomized, Double-Blind, Placebo-Controlled Trial of Vedolizumab With and Without Upadacitinib in Adults With Crohn’s Disease: Design and Rationale for the VICTRIVA Study

Introduction: Remission rates in patients with Crohn’s disease (CD) suggest a therapeutic ceiling when treated with a single advanced targeted treatment (ATT) or ATT plus immunomodulator, representing an unmet need for alternative strategies. Dual targeted therapy (DTT)/advanced combination therapy has potential to provide an additive or synergistic benefit by targeting >1 pathway. Vedolizumab (VDZ) and upadacitinib (UPA) are treatments for moderate to severe CD with different mechanisms of action, and in silico models suggest their combination could modulate a high number of pathways relevant to the pathophysiology of CD. The VICTRIVA trial aims to compare the efficacy and safety of induction with VDZ + UPA vs VDZ alone. Methods: The primary objective of VICTRIVA (NCT06227910), a randomized, double-blind, controlled, phase 3b trial in biologic experienced and biologic naïve adult patients with CD, is to assess whether induction with VDZ + UPA improves rates of clinical remission and endoscopic response at week(W) 12 vs VDZ alone. Patients will be randomized 1:1 to 12 week induction with VDZ + UPA (Group 1) or VDZ + placebo (Group 2) (Figure 1). W12 responders will enter the maintenance arm from W13-52 (VDZ monotherapy every 8 weeks [every 8 weeks] to W52; possible every 4 weeks escalation if needed). W12 nonresponders will enter prolonged induction Substudy 1 (VDZ + UPA to W24, followed by VDZ monotherapy). Patients who lose response during maintenance will be escalated to every 4 weeks, or enter rescue treatment Substudy 2 (DTT for 12 weeks, then VDZ every 4 weeks). Assessments include Crohn’s Disease Activity Index (CDAI) and patient reported outcomes at W2,6,12 during induction and in the maintenance and substudies through W52, Simple Endoscopic Score for Crohn’s Disease (SES-CD) at screening, W12 and 52, and safety at each visit. Results: 396 patients (198 in Groups 1 and 2) will be enrolled globally. Co-primary endpoints will be CDAI clinical remission (score < 150) and SES-CD endoscopic response ( >50% score reduction) at W12. Key secondary endpoints include PRO2 clinical remission at W12, and CDAI clinical remission, SES-CD endoscopic response and PRO2 clinical remission at W52. Safety endpoints will include adverse events and adverse events of special interest. Conclusion: The VICTRIVA trial is designed to evaluate the efficacy and safety of VDZ in combination with UPA relative to VDZ monotherapy in an attempt to break the current therapeutic ceiling for inducing remission in CD and improve long-term outcomes.Figure 1.: A) VDZ IV 300 mg at Weeks 0, 2, 6, and 10. B) UPA oral 45 mg once daily. C) VDZ IV 300 mg every 8 weeks, possible escalation to every 4 weeks. D) VDZ IV 300 mg every 4 weeks. eUPA oral 30 mg once daily for patients initially assigned to Group 1, 45 mg once daily for patients initially assigned to Group 2. CDAI, Crohn’s Disease Activity Index; PRO2, Patient Reported Outcome; SES-CD, Simple Endoscopic Score for Crohn’s Disease; UPA, upadacitinib; VDZ, vedolizumab; IV, intravenous; every 4 weeks, every 4 weeks.

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