Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT)

• Corticosteroid free remission (SFR) [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
  Relative to other patients, those who have a PUCAI<10 at 4 weeks from start of therapy will be more likely to be in corticosteroid free remission (PUCAI<10) at 52 weeks while receiving the aminosalicylate mesalamine only as maintenance therapy without the need for rescue therapy with IM, CI, anti-TNFα, or surgery.
  
  

• Corticosteroid free remission [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]

  The secondary endpoints are defined relative to start of therapy:

  • PUCAI <10 at 4 weeks
  • SFR at 12 weeks without the need for rescue therapy
  • SFR at 26 weeks without the need for rescue therapy
  • SFR at 104 weeks without the need for rescue therapy
  • Endoscopic response (Mayo score reduced by ≥1) and being 0,1 at week 52
  • Endoscopic remission (Mayo score 0) at week 52
  • IMPACT - III at 52 and 104 weeks
  • Colectomy free status during the follow-up period
  
  

Ulcerative Colitis (UC) denotes a phenotype of chronic inflammatory bowel disease (IBD), where inflammation is localized to the colonic mucosa, and extends from the rectum proximally in varying extents. The disorder is thought to result from an inappropriate activation of the mucosal immune system by antigens derived from both the host epithelium and the enteric flora, in genetically susceptible individuals. UC is strikingly heterogeneous with respect to age of onset, anatomical extent and disease course, with some experiencing chronically active severe disease, while others have intermittent periods of clinical remission and disease exacerbation. Patients' therapeutic responses vary. The reasons underlying such variability are not well understood. Although it has been widely hypothesized that several genes may influence the development of UC, and modify its phenotypic expression and severity, to date there are few confirmed examples of such relationships.

It has been postulated that the 5-aminosalicylate drugs exert their anti-inflammatory effect locally at the intestinal mucosa. Mechanisms likely include inhibition of 5-lipoxygenase resulting in decreased production of leukotriene B4, scavenging of reactive oxygen metabolites, prevention of up-regulation of leukocyte adhesion molecules, and inhibition of IL-1 synthesis. Though multiple studies have shown the efficacy of aminosalicylates in inducing and maintaining remission in adults with UC, there are few data in children.

Corticosteroids have been the mainstay of treatment of severe UC since efficacy was first demonstrated in the 1955 randomized controlled trial by Truelove and Witts. Recent practice guidelines developed in adults support their use because of rapid onset of action and significant efficacy though CS dependency is noted. Though no controlled data on their use have been reported in children they are frequently used in this population. A recent report from investigators leading the prospective Pediatric IBD Collaborative Research Group Registry described 97 subjects with a diagnosis of UC and a minimum of 1 year follow-up; 79% received CS. At diagnosis 81% of CS treated patients had moderate/severe disease, and 81% had pancolitis. Clinically inactive disease, determined by physician global assessment, was noted in 60% at 3 months following CS therapy, but by one year 45% were considered CS dependent despite the frequent use of IM. Among those children with initially moderate to severe disease in clinical remission at 3 months, about two-thirds had stopped the CS by one year.