DOP056 TDM-Based Dose-Intensification of Infliximab is not Superior to Standard Dosing in Patients with Acute Severe Ulcerative Colitis: Results from the TITRATE Study

Background

Up to 40% of patients with acute severe ulcerative colitis (ASUC) do not respond to infliximab (IFX)(1). Insufficient drug exposure with low IFX serum concentrations is associated with non-response (1, 2). We investigated whether personalised TDM-driven induction dosing of IFX was superior to standard dosing.

Methods

In this prospective open-label, multi-centre randomised controlled trial (Netherlands, Norway and Ireland), hospitalised adult IFX-naïve and steroid-refractory ASUC patients were randomised 1:1 to standard (SD) or personalised dosing of IFX (PD). After an initial 5 mg/kg IFX infusion, SD consisted of 5 mg/kg IFX at week 2 and 6. In the PD group, additional 5 mg/kg IFX infusions were administered guided by a Bayesian pharmacokinetic algorithm (iDose) aiming at IFX serum concentrations >28 ug/mL from day 0-28 and >15 ug/mL from day 29-42 (measured with Quantum Blue IFX rapid test). After day 42, all patients received 5 mg/kg IFX maintenance every 8 weeks until day 182, with escalation at physician’s discretion.

The primary composite endpoint was clinical and endoscopic response at day 42 (Lichtiger score <10 and ≥3 points decrease from baseline and UCEIS ≥2 points decrease with double central endoscopy read and adjudication). Key secondary endpoints included day 42 clinical response, day 42 endoscopic response, day 182 clinical remission (Lichtiger score ≤3), day 182 endoscopic remission (UCEIS ≤1 on all components), and safety (SAEs). Endoscopies were performed at baseline, day 42 and 182.

Results

48 patients were included and received study treatment (23 PD/25 SD), 31 of whom completed treatment through week 26 (19 PD/12 SD). Median cumulative IFX dose until day 42 was 18.41 mg/kg [14.77, 20.27] for PD vs 13.79 mg/kg [10.38, 14.82] for SD (Table 1).

The primary composite endpoint of clinical and endoscopic response at day 42 was not met (13/23 (56.5%) in PD vs 11/25 (44.0%) in SD; p=0.564) (Figure 1). PD showed a higher day 42 clinical response vs SD (21/23 (91.3%) vs 16/25 (64.0%); p=0.039), Day 42 endoscopic response was observed in 13/23 (56.5%) in PD and 11/25 (44.0%) in SD (p=0.564). Numerically more patients on PD had day 182 clinical remission (14/23 (60.9%) vs 9/25 (36.0%); p=0.148) and endoscopic remission (15/23 (65.2%) vs 9/25 (36.0%); p=0.082) compared to SD. SAEs occurred in 3/23 (13.0%) of patients on PD vs 5/25 (20.0%) of patients on SD (p=0.703) and included infection (2/23 (8.7%) vs 1/25 (4.0%)), thromboembolic event (0 vs 1/25 (4.0%)), colectomy (1/23 (4.4%) vs 2/25 (8.0%)), and death (0 vs 1/25 (4.0%)). Following an interim analysis, the trial was discontinued based on futility.

Conclusion

Personalised dosing of infliximab was not superior to standard dosing in acute severe ulcerative colitis.

References

1.Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59(1):49-54.

2.Papamichael K, Van Stappen T, Vande Casteele N, Gils A, Billiet T, Tops S, et al. Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol. 2016;14(4):543-9.