Abstract
Background & Aims: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. Methods: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12–36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. Results: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45–1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55–1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19–0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49–1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24–2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. Conclusions: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. ClinicalTrials.gov, Number: NCT02772965.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 149-161.e7 |
| Journal | Gastroenterology |
| Volume | 165 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 2023 |
Funding
Funding This study was funded by grants from the Patient Centered Outcomes Research Institute (PCS-1406-18643), the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases (U19AR069525). Biosample supplies and shipping costs and anti-drug antibody testing were provided in kind by Progenika Biopharma, a Grifols Company. Anti-drug antibody testing was also provided in kind by Esoterix Specialty Laboratory, Labcorp. Funding This study was funded by grants from the Patient Centered Outcomes Research Institute (PCS-1406-18643), the Helmsley Charitable Trust , and National Institute of Arthritis and Musculoskeletal and Skin Diseases ( U19AR069525 ). Biosample supplies and shipping costs and anti-drug antibody testing were provided in kind by Progenika Biopharma, a Grifols Company. Anti-drug antibody testing was also provided in kind by Esoterix Specialty Laboratory, Labcorp. Conflicts of interest These authors disclose the following: Michael D. Kappelman has consulted for Abbvie, Janssen, Pfizer, Takeda, and Lilly, is a shareholder in Johnson & Johnson, and has received research support from Pfizer, Takeda, Janssen, Abbvie, Lilly, Genentech, Boehringer Ingelheim, Bristol Myers Squibb, Celtrion, and Arenapharm. Hans H. Herfarth has consulted for Alivio, BMS, Boehringer, ExeGi Pharma, Finch, Fresenius Kabi, Gilead, Janssen, Otsuka, Pfizer, Pure Tech, and Ventyx and has received research support form Allakos, Artizan, NovoNordisk, and Pfizer. William B. Brinkman has common stock holdings in the following publicly traded companies: Pfizer, Merck, Abbott Laboratories, Viatris, and Johnson & Johnson. Richard B. Colletti has consulted for Janssen Research & Development and is a member of the scientific advisory board for Janssen Biotech. Traci W. Jester has received research support from Abbvie. Ellen A. Lipstein has received research support from Pfizer, Inc. Jonathan Moses is on the Speaker’s Bureau for Abbvie and on the scientific medical advisory board for PSI Inc. Dinesh S. Pashankar has received research support from Janssen and Abbvie. Shehzad A. Saeed is a member of the advisory board for Abbvie, Inc. Athos Bousvaros has consulted for Takeda, Best Doctors, Eli Lilly, Fresenius Kabi, and has received research support from Janssen, Abbvie, Takeda, Buhlmann, Arena, Eli Lilly, Bristol Myers Squibb, and PROCISE diagnostics. The remaining authors disclose no conflicts.
Keywords
- Adalimumab
- Anti-Tumor Necrosis Factor–α
- Children
- Crohn's Disease
- Infliximab
- Methotrexate
ASJC Scopus subject areas
- Hepatology
- Gastroenterology
