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Intensified- vs Standard-Dose Infliximab Induction Therapy for Steroid-Refractory Acute Severe Ulcerative Colitis
TAKE-HOME MESSAGE
- The PREDICT-UC trial is a randomised controlled trial comparing intensified dose with standard dose infliximab rescue strategies in patients with steroid-refractory acute severe ulcerative colitis. There was no significant difference in clinical response by day 7 between the 10 mg/kg (65%) and 5 mg/kg (61%; P = .62) groups. In patients with hypoalbuminaemia (<25 g/L) or high C-reactive protein levels (≥50 mg/L), there was a numerically higher proportion of patients with clinical response at day 7 in the 10 mg/kg group than in the 5 mg/kg group; however, this did not reach statistical significance. Patients in the 5 mg/kg group were further randomised into a standard or accelerated induction strategy. At 3 months, there was no significant difference in clinical remission, steroid-free remission, or colectomy rates among the intensified, accelerated, and standard induction groups.
- This study indicates that infliximab is a safe and effective rescue therapy for acute severe ulcerative colitis.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
The optimal dosing strategy for infliximab in steroid-refractory acute severe ulcerative colitis (ASUC) is unknown. We compared intensified and standard dose infliximab rescue strategies and explored maintenance therapies following infliximab induction in ASUC.
METHODS
In this open-label, multicentre, randomised controlled trial, patients aged 18 years or older from 13 Australian tertiary hospitals with intravenous steroid-refractory ASUC were randomly assigned (1:2) to receive a first dose of 10 mg/kg infliximab or 5 mg/kg infliximab (randomisation 1). Block randomisation was used and stratified by history of thiopurine exposure and study site, with allocation concealment maintained via computer-generated randomisation. Patients in the 10 mg/kg group (intensified induction strategy [IIS]) received a second dose at day 7 or earlier at the time of non-response; all patients in the 5 mg/kg group were re-randomised between day 3 and day 7 (1:1; randomisation 2) to a standard induction strategy (SIS) or accelerated induction strategy (AIS), resulting in three induction groups. Patients in the SIS 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. Patients in the AIS 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 no response. The primary outcome was clinical response by day 7 (reduction in Lichtiger score to <10 with a decrease of ≥3 points from baseline, improvement in rectal bleeding, and decreased stool frequency to ≤4 per day). Secondary endpoints assessed outcomes to day 7 and exploratory outcomes compared induction regimens until month 3. 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 as a cohort study up to month 12. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02770040, and is completed.
FINDINGS
Between July 20, 2016, and Sept 24, 2021, 138 patients were randomly assigned (63 [46%] female and 75 [54%] male); 46 received a first dose of 10 mg/kg infliximab and 92 received 5 mg/kg infliximab. After randomisation 1, we observed no significant difference in the proportion of patients who had a clinical response by day 7 between the 10 mg/kg and 5 mg/kg groups (30 [65%] of 46 vs 56 [61%] of 92, p=0·62; risk ratio adjusted for thiopurine treatment history, 1·06 [95% CI 0·94-1·20], p=0·32). We found no significant differences in secondary endpoints including time to clinical response or change in Lichtiger score from baseline to day 7. Two patients who received 10 mg/kg infliximab underwent colectomy in the first 7 days compared with no patients in the 5 mg/kg group (p=0·21). Three serious adverse events occurred in three patients in both the 10 mg/kg group and 5 mg/kg group. After randomisation 2, the proportions of patients with clinical response at day 14 (34 [74%] of 46 in the IIS group, 35 [73%] of 48 in the AIS group, and 30 [68%] of 44 in the SIS group, p=0·81), clinical remission at month 3 (23 [50%], 25 [52%], 21 [48%], p=0·92), steroid-free remission at month 3 (19 [41%], 20 [42%], 18 [41%], p=1·0), endoscopic remission at month 3 (21 [46%], 22 [46%], 21 [48%], p=0·98), and colectomy at month 3 (three [7%] of 45, nine [19%] of 47, five [12%] of 43, p=0·20) were not significantly different between groups. Between day 8 and month 3, the proportion of patients with at least one infectious adverse event possibly related to infliximab was two (4%) of 46 in the IIS group, eight (17%) of 48 in the AIS group, and eight (18%) of 44 in the SIS group (p=0·082). No deaths occurred in the study.
INTERPRETATION
Infliximab is a safe and effective rescue therapy in ASUC. In steroid-refractory ASUC, a first dose of 10 mg/kg infliximab was not superior to 5 mg/kg infliximab in achieving clinical response by day 7. Intensified, accelerated, and standard induction regimens did not result in a significant difference in clinical response by day 14 or in remission or colectomy rates by month 3.
FUNDING
Australian National Health and Medical Research Council, Gastroenterology Society of Australia, Gandel Philanthropy, Australian Postgraduate Award, Janssen-Cilag.
Additional Info
Disclosure statements are available on the authors' profiles:
Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial
Lancet Gastroenterol Hepatol 2024 Nov 01;9(11)981-996, MC Choy, CFD Li Wai Suen, D Con, K Boyd, R Pena, K Burrell, O Rosella, D Proud, R Brouwer, A Gorelik, D Liew, WR Connell, EK Wright, KM Taylor, A Pudipeddi, M Sawers, B Christensen, W Ng, J Begun, G Radford-Smith, M Garg, N Martin, DR van Langenberg, NS Ding, L Beswick, RW Leong, MP Sparrow, P De CruzFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Acute severe ulcerative colitis (ASUC) is associated with significant morbidity and mortality, with colectomy rates approaching 30% within 3 months.1–5 Infliximab (IFX) has been touted as a rescue therapy, although the longitudinal benefit over therapies such as cyclosporine are debated.6–8 The optimal dosing of IFX in ASUC is unclear. High induction doses have been proposed by experts despite a lack of randomised controlled trial data to support this approach.
Choy et al sought to address this knowledge gap via a randomised controlled trial of several IFX dosing strategies in ASUC. They conducted a prospective, open-label, multicentre superiority trial to compare intensified IFX rescue therapy (10 mg/kg) with a standard induction strategy (SIS; 5 mg/kg) in Australian adults with steroid-refractory ASUC. Participants in the SIS arm were then re-randomised between days 3 and 7 to either an accelerated induction strategy (AIS) or continued standard induction. In the AIS arm, further doses of IFX were given at weeks 1 and 3. The second dose was also increased to 10 mg/kg and was given earlier for those who did not respond to the first dose. In those continuing SIS, further 5 mg/kg IFX doses were given at weeks 2 and 6, with the second dose again given earlier for non-response. The primary outcome was clinical response by day 7, defined as a Lichtiger score of less than 10 with at least a 3-point reduction from baseline, improved rectal bleeding, and reduced stool frequency to four or fewer per day.
At day 7, 65% of patients in the intensified group achieved clinical response compared with 61% in the standard dose group. Adjusting for thiopurine treatment, there was no significant difference between the groups. Additionally, there were fewer severe adverse events in the intensified group. There was also no significant difference in the secondary outcomes of remission at 90 days or colectomy-free survival.
There are several factors that merit consideration when interpreting the results. Although varying initial doses of IFX were assessed across the three arms, the study did not evaluate the effect of sustained administration of a 10 mg/kg dose of infliximab in the AIS arm. This is an issue requiring further investigation as it remains unclear whether sustained dose intensification for initial non-responders will improve outcomes. Additionally, stratification by individual factors such as hypoalbuminaemia that may require intensified therapy will require further study. Lastly, non-significant findings in this superiority trial do not confirm equivalence between the groups. While the efforts of the investigators here are to be commended, further research will be required regarding sustained dose escalation and uniquely at-risk subpopulations to better understand the role of dose escalation of IFX in ASUC.
References