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Comparative Effectiveness of Anti-TNF in Combination with Low Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial
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Comparative Effectiveness of Anti-TNF in Combination with Low Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial

Michael D. Kappelman, David A. Wohl, Hans H. Herfarth, Ann M. Firestine, Jeremy Adler, Rana F. Ammoury, Jeanine E. Aronow, Dorsey M. Bass, Julie A. Bass, Keith Benkov, …
Social Science Research Network : SSRN
Elsevier BV
03/01/2023
DOI: 10.2139/ssrn.4352561
url
https://doi.org/10.1053/j.gastro.2023.03.224 View
Published (Version of record)This article has now been published in a journal and has been peer-reviewed by subject experts. This version may differ significantly from the preprint version. Access restricted to faculty, staff and students
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https://doi.org/10.2139/ssrn.4352561View
Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

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Abstract

Background: Anti-Tumor Necrosis Factor inhibitors (TNFi), including infliximab and adalimumab, are a mainstay of pediatric Crohn’s disease (PCD) therapy; however, non-response and loss of response is common. As combination therapy with methotrexate may improve response, we performed a multi-center, randomized, double-blind, placebo-controlled pragmatic trial to compare the effectiveness of TNFi in combination with low dose oral methotrexate to TNFi monotherapy in children with PCD. Methods: PCD patients initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for a minimum of 12 months and maximum of 36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included development of anti-drug antibodies (ADA) and patient reported outcomes (PROs) of pain interference and fatigue. Adverse events (AEs) and Serious AEs (SAEs) were collected. Findings: Of 297 participants (mean age 13.9 years, 35% female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). Overall, a non-significant trend towards reduced treatment failure was observed among combination therapy users (HR 0.69, 95% CI 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (HR 0.93, 95% CI 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (HR 0.40, 95% CI 0.19-0.81). A trend towards lower ADA development in the combination therapy arm was not significant. [(infliximab OR 0.72 (0.49-1.07); adalimumab OR 0.71 (0.24-2.07)]. No differences in PROs were observed. Combination therapy resulted in more AEs but fewer SAEs. Interpretation: Among adalimumab but not infliximab initiators, PCD patients treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure. Overall, these findings suggest improved effectiveness of combination therapy in adalimumab-treated patients with a tolerable safety profile.
 Hepatology Gastroenterology

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