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Randomized Controlled Trial
. 2023 Jul;165(1):149-161.e7.
doi: 10.1053/j.gastro.2023.03.224. Epub 2023 Mar 31.

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  1 , David A Wohl  2 , Hans H Herfarth  3 , Ann M Firestine  4 , Jeremy Adler  5 , Rana F Ammoury  6 , Jeanine E Aronow  7 , Dorsey M Bass  8 , Julie A Bass  9 , Keith Benkov  10 , Catalina Berenblum Tobi  11 , Margie E Boccieri  4 , Brendan M Boyle  12 , William B Brinkman  13 , Jose M Cabera  14 , Kelly Chun  15 , Richard B Colletti  16 , Cassandra M Dodds  17 , Jill M Dorsey  18 , Dawn R Ebach  19 , Edurne Entrena  20 , Christopher B Forrest  21 , Joseph A Galanko  22 , John E Grunow  23 , Ajay S Gulati  4 , Anastasia Ivanova  24 , Traci W Jester  25 , Jess L Kaplan  26 , Subra Kugathasan  27 , Mark E Kusek  28 , Ian H Leibowitz  29 , Tiffany M Linville  30 , Ellen A Lipstein  31 , Peter A Margolis  31 , Phillip Minar  32 , Zarela Molle-Rios  33 , Jonathan Moses  34 , Kelly K Olano  35 , Lourdes Osaba  20 , Pablo J Palomo  36 , Helen Pappa  37 , K T Park  8 , Dinesh S Pashankar  38 , Lisa Pitch  39 , Michelle Robinson  4 , Charles M Samson  40 , Kelly C Sandberg  41 , Julia R Schuchard  21 , Michael Seid  42 , Kimberly A Shelly  43 , Steven J Steiner  43 , Jennifer A Strople  44 , Jillian S Sullivan  45 , Jeanne Tung  23 , Prateek Wali  46 , Michael Zikry  15 , Morris Weinberger  47 , Shehzad A Saeed  48 , Athos Bousvaros  49
Affiliations
Randomized Controlled Trial

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 et al. Gastroenterology. 2023 Jul.

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.

Keywords: Adalimumab; Anti-Tumor Necrosis Factor–α; Children; Crohn’s Disease; Infliximab; Methotrexate.

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Conflict of interest statement

MDK 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.

DAW – no disclosures

HHF has consulted for Alivio, BMS, Boehringer, ExeGi Pharma, Finch, Fresenius Kabi, Gilead, Janssen, Otsuka, Pfizer, Pure Tech, Ventyx and has received research support form Allakos, Artizan, NovoNordisk, Pfizer.

AMF – no disclosures

JA – no disclosures

RFA – no disclosures

JEA – no disclosures

DMB – no disclosures

JAB – no disclosures

KB – no disclosures

CBT – no disclosures

MEB – no disclosures

BMB – no disclosures

WBB has common stock holdings in the following publicly traded companies: Pfizer, Merck, Abbott Laboratories, Viatris, and Johnson & Johnson.

JMC – no disclosures

KC – no disclosures

RBC has consulted for Janssen Research & Development and is a member of the scientific advisory board for Janssen Biotech.

CMD – no disclosures

JMD – no disclosures

DRE – no disclosures

EE - no disclosures

CBF – no disclosures

JAG – no disclosures

JEG – no disclosures

ASG – no disclosures

AI – no disclosures

TWJ has received research support from Abbvie.

JLK – no disclosures

SK – no disclosures

MEK – no disclosures

IHL – no disclosures

TML – no disclosures

EAL has received research support from Pfizer, Inc.

PAM – no disclosures

PM – no disclosures

ZMR – no disclosures

JM is on the Speaker’s Bureau for AbbVie and on the scientific medical advisory board for PSI Inc.

KO – no disclosures

LO - no disclosures

PJP – no disclosures

HP – no disclosures

KTP – no disclosures

DSP has received research support from Janssen and Abbvie.

LP – no disclosures

MR – no disclosures

CMS – no disclosures

KCS – no disclosures

JRS – no disclosures

MS – no disclosures

KAS – no disclosures

SJS – no disclosures

JAS – no disclosures

JSS – no disclosures

JT – no disclosures

PW – no disclosures

MZ – no disclosures

MW – no disclosures

SS is a member of the advisory board for Abbvie, Inc.

AB 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, PROCISE diagnostics.

Figures

Figure 1.
Figure 1.
Participant Flow Diagram
Figure 2:
Figure 2:
Figure 2A shows the Kaplan Meier analysis of the time-to-event in the overall population. Figure 2B shows the Kaplan Meier analysis among infliximab initiators and 2C shows the Kaplan Meier analysis among adalimumab initiators. Figure 2D shows Kaplan Meier curves broken out by both anti-TNF agent and combination versus monotherapy.
See this image and copyright information in PMC

Comment in

References

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