Introduction

In patients admitted for an acute severe ulcerative colitis (ASUC) episode responding to intravenous (IV) steroids, the most effective treatment regimen is unknown. The benefit of early infliximab (IFX) therapy remains to be established in this indication.

Aims & Methods

In this French multicentre, parallel group, open-label randomised controlled trial, thiopurine and biologics-naïve adults admitted for ASUC defined by a Lichtiger score >10 were included between December 2016 and June 2021 if they responded to IV steroids. Response to IV steroids was defined according to the absence of Oxford criteria. They were randomly assigned to receive an early combination therapy with IFX (5 mg/kg IV at week 0, 2 and 6 and then every 8 weeks) and azathioprine (AZA) (2 and 2.5 mg/kg/day) with a quick steroid discontinuation of AZA (2 and 2.5 mg/kg/day) and standardized steroid tapering regimen (AZA arm). Steroids use was prohibited after day 7 in the IFX+AZA arm and after week 14 in the AZA arm.
The primary endpoint was treatment failure at week 52 (w52), defined as absence of steroid-free clinical remission according to total Mayo Clinic score (≤2 with no individual subscore >1) at w52, absence of endoscopic response (Mayo endoscopic subscore of 0 or 1 according to local reading) at w52, or use of a prohibited treatment for relapse (partial Mayo score >5), severe adverse event leading to interruption of any of the allocated treatment, colectomy or death during the study period.
A sample size of 73 patients per group was calculated to detect 24%-difference between both group with a 1:1 randomization ratio, a 80% power and a 5% two-sided alpha risk. Due to challenges in recruiting patient, the steering committee decided to prematurely terminate the study in September 2019 blindly of any study results, after including 64 patients.

Results

64 were randomised (32 males, median age of 34.5 [IQR 26.3-50.3] years, 38% with pancolitis, Lichtiger score of 13.0 [95%CI 12-14], CRP of 29.0 [12.8-96.8] mg/L and serum albumin of 31.2 [27.7-35.6] g/L at baseline): 32 were assigned to IFX+AZA arm and 32 to AZA arm. Components of the composite primary endpoint are given in table 1.

	IFX + AZA arm (n=32)	AZA arm (n=32)
Death	0	0
Colectomy	0	0
use of a prohibited treatment for relapse	6 (18.8%)	10 (31.2%)
severe adverse event leading to interruption of any of the allocated treatment	5 (15.6%)	3 (9.4%)
Retracted consent	1 (3.1%)	0
Absence of steroid-free clinical remission at w52	5 (15.6%)	8 (25.0%)
Mayo endoscopic subscore ≥2	6 (18.8%)	8 (25.0%)

In the ITT population, treatment failure at w52 was observed in 81.5% in the AZA arm versus 53.3% in the IFX+AZA arm (OR 3.85, 95%CI [1.15-12.88], p=0.03). In the PP population, treatment failure at week 52 was observed in 81.5% (22/27) in the AZA arm versus 50.0% (13/26) in the IFX + AZA arm (OR 4.40, 95%CI [1.28-15.18], p=0.02). In total 121 treatment emergent adverse events (AE) were reported in 40 patients including 23 serious AE in 18 patients (11 in the IFX + AZA arm vs 7 in the AZA arm, p=0.24). Serious AE included infectious AE in 6 cases (1 vs 5, p=0.20) and UC relapse in 9 (4 vs 5, p=0.60). No deaths were reported.

Conclusion

At w52, combination therapy with IFX + AZA and quick steroids discontinuation was more effective than AZA with standard steroids tapering regimen to prevent treatment failure in patients with ASUC responding to IV steroids. In routine practice, pre-emptive use of early combination therapy with IFX + AZA should be encouraged in ASUC patients responding to IV steroids (EudraCT 2014-005212-42).

Disclosure

this study was funded by Pfizer