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COMBINE: Clinical Outcomes of Methotrexate Binary Therapy

A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Pragmatic Clinical Trial to Evaluate the Effectiveness of Low Dose Oral Methotrexate in Patients with Pediatric Crohn's Disease Initiating Anti-TNF Therapy

Crohn's disease (CD) is a chronic inflammatory disorder that primarily affects the gastrointestinal tract. Pediatric cases commonly begin in late middle childhood and adolescence. When active, the disease can be debilitating, embarrassing, and socially isolating.  Typical experiences include pain, frequent and bloody diarrhea, fatigue and emotional distress. Children with CD experience negative side effects on their physical well-being, emotions and mood. Compared with adult counterparts, pediatric CD patients present with more extensive distribution of psychosocial difficulties, problems with academic performance and altered pubertal development and growth. Approximately 8% of children require intestinal resection during the year following diagnosis.

The Anti-TNF Combination trial provides a unique opportunity to evaluate PROMIS measures in pediatric CD. Children under 18 years old with pediatric Crohn's disease (both genders, all race and ethnicities) with moderate to severe disease activity who are initiating their first anti-TNF agent will constitute the study population.

The trial will occur in the offices of pediatric gastroenterologists who participate in ImproveCareNow, a learning health system. ImproveCareNow was formed in 2007 to transform health, care and costs for all children and adolescents with Crohn's disease and ulcerative colitis by building sustainable collaborative chronic care network that enables patients, families, clinicians and researchers to work together to accelerate innovation, discovery and application of new knowledge.

BACKGROUND

  • To determine whether, in children with moderate-severe CD, low-dose oral methotrexate, in combination with anti-TNF biological therapy, is more effective than anti-TNF alone in the induction and subsequent maintenance of steroid-free remission for a period of up to two years

  • To evaluate the content validity, clinical meaning, responsiveness and longitudinal construct validity of four PROMIS pediatric instruments (pain interference, fatigue, IBD GI symptoms, and positive affect) in 425 children with Crohn's disease.

STUDY AIMS

  • Content Validity:

    • We enrolled 50 children and 79 parents (Summer 2016) to participate in an online card sorting activity, semi-structured interviews and cognitive interviews.

    • The data that was collected allowed researchers to create a Crohn's specific PRO measure for Fatigue and Pain Interference.

    • These new condition-specific measures are now being evaluated in the COMBINE trial.

  • Clinical Validity:

    • Longitudinal construct validity of PROMIS PRO measures of experienced wellbeing for Crohn's disease patients is being tested by 1) evaluating the associations between change in disease phenotype and experienced wellbeing, and 2) evaluating the longitudinal change for presence of response shift in clinical status and PRO scores

    • The COMBINE trial started to recruit patients in October 2016. There are currently 146 enrolled patients and 40 active sites that are ready to enroll new patients

    • This is a multi-center trial with an estimated 50 sites participating

GOALS & RESULTS