A standard induction regimen of infliximab as a rescue therapy for acute severe ulcerative colitis is just as effective as intensified and accelerated regimens for clinical response and remission rates, Australian gastroenterologists have found.

However, findings published in the Lancet Gastroenterology & Hepatology [link here] indicated that although remission was similar between the groups at three months, remission might be achieved earlier with more aggressive dosing.

The PREDICT-UC study was an open-label randomised controlled trial involving 138 adult patients (54% male) from 13 Australian hospitals with intravenous steroid-refractory acute severe ulcerative colitis (ASUC), who were randomly assigned (1:2) to receive a first dose of 10 mg/kg or standard 5 mg/kg infliximab.

There were three induction groups: Patients in the 10 mg/kg group (intensified induction strategy) received a second dose at day 7 or earlier at the time of non-response. All other patients were re-randomised between day 3 and day 7 to a standard induction strategy (SIS) or accelerated induction strategy (AIS) group.

In terms of the regimens, patients in the standard induction strategy group received 5 mg/kg infliximab at weeks 0, 2, and 6, with an extra 5 mg/kg dose between day 3 and day 7 if no response to the first dose. The accelerated group received 5 mg/kg infliximab at weeks 0, 1, and 3, with the week 1 dose increased to 10 mg/kg and given between day 3 and day 7 if there was no response.

From month 3, maintenance therapy was selected based on treatment experience, with use of thiopurine monotherapy, combination infliximab and thiopurine, or infliximab monotherapy, with follow-up to month 12.

Findings showed no significant difference in clinical response by day 7 between the 10 mg/kg and 5 mg/kg infliximab dosing groups (65% of patients vs 61%).

There were also no significant differences in secondary endpoints including time to clinical response or change in Lichtiger score from baseline to day 7.

Two patients treated with 10 mg/kg infliximab underwent colectomy in the first 7 days compared with no patients in the 5 mg/kg group. Three serious adverse events occurred in three patients in both the 10 mg/kg and 5 mg/kg groups.

The proportions of patients with clinical response at day 14 following the second randomisation were also not significantly different between the groups (74% in the IIS group, 73% in the AIS group, and 68% in the SIS group).

This was also the case for clinical remission at month 3 (50%, 52%, 48%), steroid-free remission at month 3 (41%, 42%, 41%), endoscopic remission at month 3 (46%, 46%, 48%), and colectomy at month 3 (7%, 19%, 12% respectively).

Between day 8 and month 3, the proportion of patients with at least one infectious adverse event possibly related to infliximab was 4%, 17% and 18% in the IIS, AIS and SIS groups, respectively. No deaths occurred throughout the study.

“We theorise that the absence of difference in our primary outcome is due to infliximab being a highly potent therapy in ASUC, and thus identifying small potential differences in efficacy among subgroups with greater disease severity might require an unfeasibly large sample size,” wrote the authors, led by gastroenterologists at the Austin Health, Melbourne.

“In our study, although a post-hoc analysis and not statistically significant, a numerically higher proportion of patients with low albumin (<25 g/L) and high CRP (≥50 mg/L) who received 10 mg/kg as the index dose had a clinical response by day 7, versus those who received 5 mg/kg. Hypoalbuminaemia and high CRP concentration correlate with increased infliximab clearance and are known negative prognostic markers of response to infliximab.”

In the maintenance cohort, patients with a Ulcerative Colitis Endoscopic Index of Severity of 0–1 at month 3 were more likely to be in combined clinical and endoscopic remission at month 12 on univariable analysis.

On multivariable analysis, use of infliximab during maintenance was associated with combined clinical and endoscopic remission at month 12.

Writing in an accompanying comment [link here], gastroenterologists from All India Institute of Medical Sciences, New Delhi, said the PREDICT-UC study potentially signalled the end of accelerated or intensified dosing strategies for infliximab as rescue therapy for ASUC, which should prompt new strategic approaches.

Some suggested approaches included stratifying the inflammatory pathway at baseline and personalising the anti-inflammatory therapy or identifying predictors of response to second-line therapy based on prospective, not retrospective, data.

Janssen-Cilag provided funding for the drug supply and clinical trial coordination.