The COMBINE Trial
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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
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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 perfomance and altered pubertal development and growth. Approximately 8% of children require intestinal resection during the year following diagnosis.
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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's primary aim is 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 steriod-free remission for a period of up to two years. 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.
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The purpose of this research project is 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.
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Current Status:
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Content Validity (Aim 1) 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. (Three questions were changed to reflect Crohn's patients' experiences for each measure). These new condition-specific measures are now being evaluated in the COMBINE trial.
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Clinical Validity (Aims 2-4) Longitudinal construct validity of PROMIS PRO measures of experienced wellbeing for Crohn's disease patients will be 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.
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CCFA Partners Kids and Teens Cohort
Crohn’s disease (CD) and ulcerative colitis (UC) affect nearly 1.2 million Americans with estimated direct costs of $6 billion annually. Typical symptoms (e.g., abdominal pain, bloody diarrhea) result in substantial morbidity, including hospitalization and surgery, missed work and school, and diminished HRQOL. Approximately 20% of IBD cases begin in childhood and 10% of cases are in children or adolescents under the age of 17. Despite this, much of the evidence used to formulate treatment recommendations stems from placebo-controlled trials in adults.
In July 2013, Crohn’s and Colitis Foundation of America (CCFA) Partners (an ongoing partnership of over 10,000 patients with IBD) launched CCFA Partners Kids & Teens, a parallel study of childhood IBD. Nearly 25% of individuals with IBD are diagnosed during childhood or adolescence. The needs of these young patients are different, as they are undergoing rapid physical and mental growth and development while coping with this illness, so we formed a dedicated research partnership for this special group. By joining, kids and their parents will complete online surveys twice a year, and receive feedback directed at the specific quality of life issues affecting kids and teens with IBD. Both CCFA Partners and CCFA Partners Kids & Teens are sponsored by The Crohn’s & Colitis Foundation.
Real world, population-based clinical effectiveness and comparative effectiveness research in children are required to better understand the risks and benefits of IBD therapies for pediatric populations. As with clinical studies in children with other chronic illnesses, generally accepted endpoints do not adequately reflect patients’ well-being. In contrast, PROs evaluate what is most important to patients and caregivers about IBD and its treatment--symptoms, signs, functional status, and perceptions. Studies of PROMIS instruments developed to assess health domains in children indicate that they discriminate well among known groups of disease activity and severity. However, much remains to be learned about the performance of PROMIS measures in children with IBD. The current PEPR project with the CCFA Kids and Teens cohort aims to enhance the clinical meaningfulness and usefulness of these PROMIS measures.