Anti-TNF Monotherapy versus Combination Therapy with Low Dose Methotrexate in Pediatric Crohn’s Disease (The COMBINE Study)

Project Summary: Crohn’s disease (CD), which affects about 600,000 Americans, causes abdominal pain and bloody diarrhea, leading to frequent hospitalizations, surgery, and decreased quality of life. Pediatric CD (PCD) affects about 38,000 children, is often progressive, and can impair both physical and emotional development. PCD treatment usually includes corticosteroids, anti-inflammatory aminosalicylates, immunosuppressives, or drugs that target tumor necrosis factor (TNF).

We will conduct a large, pragmatic clinical trial to determine whether an intervention using an anti-TNF drug plus low-dose oral methotrexate is more effective than anti-TNF therapy alone among children with moderate-to-severe PCD who have not previously had anti-TNF therapy.

Our specific aims are to:

Determine whether methotrexate, in combination with anti-TNF therapy, is more effective than anti-TNF therapy alone in the induction and subsequent maintenance of remission for 2 years.

Compare patient-reported outcomes.

Describe investigator-reported adverse events.

Collect blood serum from trial participants to facilitate future studies evaluating anti-TNF concentrations and antibody formation.

Participants, recruited through the Improve Care Now (ICN) Learning Health System, will be less than 18 years old, have moderate-to-severe PCD, and be just beginning anti-TNF therapy. Participants will be randomly assigned to receive either anti-TNF therapy and oral methotrexate (combination therapy) or anti-TNF monotherapy alone; they will be followed for 2 years.

The primary measure of effectiveness will be achieving and maintaining a symptom-free remission, without the need for steroids, hospitalization, or surgery. In addition, we will identify and prioritize a set of patient-reported outcomes that will be used as another measure of effectiveness. Finally, we will compare the occurrence of moderate or severe treatment-related side effects.

We engaged clinicians in the planning of this trial and have partnered with the Crohn’s and Colitis Foundation of America (CCFA), the nation’s leading inflammatory bowel disease advocacy organization, as well as children’s hospitals, payers, and pharmaceutical companies. An advisory board of patients, parents, the CCFA, industry, payers, and health system leaders will meet with the investigators twice yearly to review study progress, troubleshoot as needed, and help plan dissemination strategies.

This study will have substantial impact on patient decision making, care, and outcomes. Conducting this trial within ICN will allow the same network that generates the research to implement evidence into practice.

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