Michael Kappelman, MD, on Combination Therapy With Anti-TNFs and Methotrexate in Pediatric Patients With IBD

Dr Kappelman reviews the results of the COMBINE trial, in which the efficacy of combined therapy using antitumor necrosis factor therapies with low-dose methotrexate was compared to anti-TNF monotherapy in pediatric patients with inflammatory bowel disease.

Michael Kappelman, MD, is a professor of pediatrics at the University of North Carolina at Chapel Hill.

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TRANSCRIPT:

Hi, this is Michael Kappelman. I am a professor of pediatrics at the University of North Carolina at Chapel Hill, and I spoke at DDW 2023 on results from the COMBINE trial, which stands for Clinical Outcomes of Methotrexate, Binary Treatment with Infliximab or Adalimumab in Practice. By way of background, anti-TNF therapy is the most effective FDA approved treatment for Pediatric Crohn's disease, yet primary and secondary non-response are common.

We have learned through the Sonic trial that combination therapy with infliximab and azathioprine can improve treatment response and longevity in adult patients. However, there is reluctance to use thiopurine analogs in pediatrics due to concern of malignancy and other side effects. Combination therapy with methotrexate may be a safer alternative, and indeed there was an adult trial looking at combination infliximab plus methotrexate, and that trial showed the combination therapy was associated with reduced immunogenicity but did not find any difference in the primary efficacy endpoints.

Clearly, this is an area where pediatric data are urgently needed because the magnitude of treatment response or side effects of any therapy may be very different in children compared to adults. And of equal importance, second line treatments for adults with Crohn's disease are not yet FDA approved or widely available for pediatric patients. And so maximizing the initial biologic anti TNF agent is of paramount importance. The objective of the COMBINE trial was to compare the effectiveness and safety of anti-tumor necrosis factor alpha in combination with low dose oral methotrexate versus anti-TNF monotherapy alone. The study designed was a randomized double-blind, multi-center placebo controlled pragmatic trial, and it's worth emphasizing the pragmatic trial design, which is a design that is conducted to maximize the ability to measure effectiveness, or what is a realistic expectation of the benefit of an intervention under real world conditions. This is in contrast to traditional clinical trials, which are designed to optimize the ability to evaluate efficacy of an intervention or the ideal benefit under perfectly controlled circumstances.

In our COMBINE trial, we identified participants with Crohn's disease less than 21 years of age, who were starting on an anti-TNF agent either infliximab or adalimumab, and had no contraindication to methotrexate. After enrollment, participants were randomized to receive either low dose oral methotrexate or placebo and were followed in the context of routine clinical care for a period between one and three years. The primary outcome included induction and maintenance of remission. And secondary outcomes included patient reported outcomes, anti-TNF antibody development and safety endpoints as well. The infliximab and adalimumab were managed at the discretion of each participant's treating physician, including a fair amount of flexibility to select the initial dose and interval, and adjust the dose and interval as time went on, and indeed therapeutic drug monitoring of the anti-TNF agent was allowed throughout the course of the COMBINE trial.

The study medication was oral methotrexate. We used a 15 milligram dose for the larger children and we scaled the dose down on a weight-based basis for smaller children. Those assigned to combination therapy received concomitant ondansetron before and possibly after the methotrexate as needed, as well as folic acid.

Participants assigned to the monotherapy group received a placebo equivalent of methotrexate and ondansetron as well as open-label folic acid.

The primary outcome was a composite outcome of a number of clinical parameters that would indicate treatment failure. Secondary outcomes included patient reported outcomes and the proportion of patients with a positive anti-TNF antibody.

Overall, we enrolled 297 participants in the study. It is worth noting that we did not achieve our original plan sample size of 425 patients due to slow recruitment in general, and recruitment that was severely compromised by the COVID-19 pandemic. Across our 297 participants, 212 of them were initiating infliximab and 85 initiating adalimumab. The breakdown of active or combination therapy versus placebo or monotherapy was 156 participants in the combination group, and 141 participants in the placebo group.

Across demographic characteristics, clinical characteristics, and other baseline measures of disease activity. The study population overall was well-balanced between combination and monotherapy assigned groups.

Our overall analysis was a time to treatment failure analysis for which we used Cox Proportional-Hazards Models. What we found overall is a numeric decrease in time to treatment failure amongst combination therapy treated patients, versus monotherapy treated patients with a hazard ratio of 0.69. This was however not statistically significant with a P-value of 0.08. We did have a pre-planned stratification by the anti-TNF agent that was utilized either infliximab or adalimumab. When we stratified by this agent, we really saw no difference between combination and monotherapy amongst infliximab initiators with a hazard's ratio of 0.93. In contrast, amongst adalimumab initiator's, combination therapy was strongly associated with longer time to treatment failure with an observed hazard ratio of 0.4 and a P-value of 0.01.

In terms of secondary endpoints, we saw no differences in patient reported outcomes of pain interference or fatigue either overall, or at week 52 and week 104. When we compared combination therapy treated participants to monotherapy participants. An additional secondary outcome was the development of anti-drug antibodies of 151 infliximab treated patients for which serum was available, antibodies were detected in 47% of the monotherapy group versus 34% of the combination therapy group. The relative risk was 0.72, but this was not statistically significant with odds ratios crossing one.

Amongst adalimumab users, there were 61 participants with available serum, and we found the presence of anti-drug antibodies to be 21% in the monotherapy group and 15% in the combination therapy arm. The relative risk was similar, 0.71, but again, this trend was not statistically significant, after adjustment.

Looking at safety endpoints, we found a slightly higher proportion of patients with reported adverse events in the combination therapy group compared to the monotherapy group, 73% versus 67%. However, when looking at serious adverse events, those were more common amongst monotherapy participants with 15% in the monotherapy group compared with 11% in the combination therapy group. Among adverse events as expected, nausea, vomiting, elevated liver enzymes and infection were all more common in the combination therapy group compared to the monotherapy group. Whereas, in contrast, gastrointestinal symptoms in general were more prevalent in the monotherapy arm.

Overall, nine patients on methotrexate and seven patients on placebo needed to stop therapy due to toxicity. Fortunately, we observed no deaths or malignancies over the course of our study.

And so in summary, we observed it amongst adalimumab initiators. Combination therapy resulted in a 50% reduction in treatment failure amongst infliximab initiators, there were no differences between combination versus monotherapy. We did observe a trend towards reduced anti-drug antibodies associated with combination therapy in both the infliximab and adalimumab groups, but this was not statistically significant, and overall combination therapy appeared to be reasonably well tolerated.

As with any study, I think there are a number of clinical implications and future research needs. For now, we believe that there is no role for low-dose oral methotrexate amongst infliximab initiators with Pediatric Crohn's disease. However, adalimumab initiators likely will benefit from the addition of low-dose methotrexate, and we recommend shared decision making with patients and family members, amongst those starting their journey on adalimumab.

There are a number of future research needs, including how long to continue combination therapy if and when started. There's also the question of whether more aggressive, proactive, therapeutic drug monitoring, particularly amongst the adalimumab treated patients and higher adalimumab dosing, could lead to further benefits or possibly replace the role of combination therapy with methotrexates.

And finally, this study was not designed to directly compare infliximab to adalimumab. Those comparisons will need to be the study of future research. Thank you very much, and I appreciate the opportunity to share our study findings with you.

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