Among patients with pediatric Crohn disease (PCD), antitumor necrosis factor (TNF) combination therapy with low-dose methotrexate was more effective in decreasing treatment failure than anti-TNF monotherapy for those treated with adalimumab but not infliximab, according to a study in Gastroenterology.
The randomized, double-blind, multicenter, pragmatic clinical trial (ClinicalTrials.gov Identifier: NCT02772965) compared the effectiveness and safety of anti-TNF in combination with low-dose oral methotrexate vs monotherapy in children with Crohn disease.
Participants who were aged younger than 21 years, weighed at least 20 kg, diagnosed with PCD by standard criteria, and initiated infliximab or adalimumab (or biosimilars) were enrolled from 35 US centers from October 2018 to December 2021.
The primary intervention was oral methotrexate or an identically matched placebo, with participants randomly assigned 1:1. For those in the active arm, oral methotrexate was administered in a weekly weight-dependent dose.
The primary outcome was failure to achieve or maintain steroid-free remission. The patients were followed for 104 weeks or until study termination in April 2021, after the last participant completed 52 weeks of follow-up.
A total of 297 patients were included in the modified intent-to-treat analysis — 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 were assigned to placebo (102 infliximab initiators and 39 adalimumab initiators). Their mean age was 13.9 years, 35% were female, and 82% were White. The median follow-up was 751 days in the methotrexate group and 737 days in the placebo group.
Among the cohort, 30% had study-defined treatment failure (27% of infliximab initiators and 36% of adalimumab initiators). Treatment failure occurred in 26% of patients in the combination therapy group and 34% in the monotherapy group.
Overall, a nonsignificant trend toward lower event rates was observed in the combination therapy group in Kaplan Meier analysis (hazard ratio [HR], 0.69; 95% CI, 0.45-1.05; P =.08). The infliximab initiators had no difference between combination therapy and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P =.78). For adalimumab initiators, combination therapy was significantly more effective than monotherapy (HR, 0.40; 95% CI, 0.19-0.81; P =.01).
Among the 151 infliximab users (71%) who had serum available, 61 (40%) had positive anti-drug antibodies (ADA). The differences between groups (47% monotherapy vs 34% combination therapy) were not statistically significant (risk ratio [RR], 0.72; 95% CI, 0.49-1.07). Infliximab users who had a positive ADA vs a negative ADA were no more likely to have treatment failure (44% vs 39%, P =.71).
Among combination therapy patients, 76% had 1 or more adverse events vs 68% of monotherapy patients; 44% of combination therapy patients had an AE that was possibly or definitely related to treatment vs 33% of monotherapy patients. Monotherapy group participants were more likely to have a serious adverse event (16% vs 12%).
The main limitation is that slow recruitment as well as the COVID-19 pandemic prevented the researchers from achieving their recruitment target, and so failure to detect a difference between combination and monotherapy in the overall study population may reflect type 2 error. Also, adherence was encouraged but not strictly monitored, and colonoscopy was not required before enrollment.
“Our study findings suggest strong consideration of using combination therapy for PCD patients initiating adalimumab but not infliximab,” the study authors noted. “Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of de-implementation of combination therapy in infliximab-treated patients.”
Disclosure: Biosample supplies and shipping costs and anti-drug antibody testing were provided in kind by Progenika Biopharma, a Grifols Company. Anti-drug antibody testing also was provided in kind by Esoterix Specialty Laboratory, Labcorp. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Kappelman MD, Wohl DA, Herfarth HH, et al. Comparative effectiveness of anti-TNF in combination with low dose methotrexate vs anti-TNF monotherapy in pediatric Crohn’s disease: a pragmatic randomized trial. Gastroenterology. Published online March 31, 2023. doi:10.1053/j.gastro.2023.03.224