Comparing the Safety and Effectiveness of Medicines to Treat Crohn's Disease in Children and Adolescents – The COMBINE Trial [Internet]

Excerpt

Background: Comparing anti-tumor necrosis factor (TNF) monotherapy to combination therapy with an immunomodulator in patients with Crohn disease (CD) is a pressing research need, particularly among pediatric and newly diagnosed patients.

Objectives:

1. To determine whether, in children with moderate to severe CD, low-dose oral methotrexate in combination with anti-TNF biological therapy is more effective than anti-TNF monotherapy in the induction and subsequent maintenance of steroid-free remission for up to 3 years.

2. To compare patient-reported outcomes that have been prioritized by pediatric patients with CD and their caregivers in patients receiving anti-TNF combination therapy with low-dose oral methotrexate vs anti-TNF monotherapy.

3. To describe the investigator-reported adverse events in pediatric patients with CD treated with anti-TNF monotherapy and anti-TNF combination therapy with low-dose oral methotrexate.

4. To prospectively collect and bank serum from trial participants in order to facilitate future studies to evaluate whether anti-TNF combination therapy with low-dose oral methotrexate compared with anti-TNF monotherapy is associated with decreased anti-TNF antibody formation and higher anti-TNF trough levels.

Methods: We performed a randomized, double-blind, placebo-controlled, pragmatic trial to compare low-dose oral methotrexate with placebo in children with CD initiating anti-TNF therapy with infliximab or adalimumab. Eligible participants were randomly assigned 1:1 and followed for a minimum of 12 months and maximum of 36 months in the context of routine clinical care. The primary outcome was a composite of indicators of treatment failure or toxicity. Secondary outcomes included patient-reported outcomes of pain interference and fatigue. Safety events were also recorded and analyzed.

Results: We recruited 297 participants across 35 centers. A total of 162 patients were assigned to the methotrexate (combination therapy) group (114 infliximab initiators and 46 adalimumab initiators), and 144 were assigned to the placebo (monotherapy) group (103 infliximab initiators and 41 adalimumab initiators). Overall, 40 of 156 participants (26%) in the combination therapy group and 48 of 141 participants (34%) in the monotherapy group experienced a primary event. A trend toward lower event rates in the combination therapy group was not statistically significant (hazard ratio [HR], 0.69; 95% CI, 0.45-1.05; P = .08). We performed a prespecified stratification by the specific anti-TNF agent (infliximab and adalimumab; P = .05 for interaction). Among infliximab initiators, there were no differences between combination therapy and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). Among adalimumab initiators, combination therapy significantly outperformed monotherapy (HR, 0.40; 95% CI, 0.19-0.81; P = .01). No significant differences in either patient-reported outcome were observed. The combination therapy group had a higher number of adverse events overall, including nausea and vomiting and elevated liver enzymes, but a lower number of serious adverse events.

Conclusions: In the largest double-blind, randomized trial to date in pediatric patients with CD, we observed an overall trend toward lower treatment failure among those treated with an anti-TNF agent in combination with low-dose oral methotrexate vs anti-TNF monotherapy that was not statistically significant. Among adalimumab-treated patients, combination therapy was associated with a 2-fold reduction in the occurrence of events indicating treatment failure, loss of response, or toxicity. Among infliximab initiators, there were no differences between combination therapy and monotherapy. Although we observed a slightly higher number of adverse events in the combination therapy group, including the expected symptoms of nausea and vomiting and elevation of liver enzymes, patients in the combination therapy group experienced fewer serious adverse events. Additionally, patients in the combination therapy group did not require treatment discontinuation for toxicity more frequently than in the monotherapy group. We did not see any difference in our prespecified secondary end points of patient-reported outcomes of pain interference and fatigue. Overall, these findings suggest improved effectiveness of combination therapy in adalimumab-treated patients with a tolerable safety profile.

Limitations: We did not reach our full enrollment target, raising the possibility of a type 2 error. In this pragmatic trial, we were only able to include outcomes measured in the context of routine clinical care, which limited our ability to evaluate outcomes of mucosal healing.