Predicting Response to Standardized Pediatric Colitis Therapy

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.

Inclusion Criteria:

- Age ≥ 4years and ≤17 years at initiation of therapy (achieved 4th birthday, not yet
18th)

- Weight ≥15 kg

- New diagnosis of ulcerative colitis established by standard clinical, endoscopic, and
histologic features at the PROTECT study site

- Colitis extending beyond the rectosigmoid (Paris classification E2, E3, or E4)[144].
If a patient is seriously ill and the clinician does not advance the colonoscope
beyond the sigmoid colon but the clinical condition of the patient highly suggests
more extensive disease then that patient is eligible for study.

- Disease activity by PUCAI of ≥10 at diagnosis

- No therapy previously initiated to treat the newly diagnosed ulcerative colitis

- Stool culture negative for routine enteric pathogens (Salmonella, Shigella,
Campylobacter, E. coli 0157:H7) and Clostridium difficile toxin. Recent successful
treatment for Clostridium difficile does not exclude a patient if toxin now absent.
However, the patient must be a minimum of 5 weeks from the time treatment was started
at the time toxin is absent.

- Stool study negative for enteric parasites (ova and parasites)

- Parent/guardian consent and patient assent

- Ability to remain in follow-up for a minimum of one year from diagnosis

- Female patients of child bearing age must have a negative urine pregnancy test and
practice acceptable contraception (e.g., abstinence, intramuscular or hormonal
contraception, two barrier methods (e.g., condom, diaphragm, or spermicide),
intrauterine device, verbal report of the partner with history of vasectomy, or be
surgically sterile). All female patients of childbearing potential (post-menarche)
will undergo urine pregnancy testing at screening and must not be lactating.

Exclusion Criteria:

- Clinical, endoscopic, radiologic, or histologic evidence suggesting CD consistent with
Paris and NASPGHAN criteria[144, 145]

- A previous diagnosis of inflammatory bowel disease for which treatment was given

- Evidence of any active enteric infection at the time of study entryUse of any oral CS
for non-gastrointestinal indication within the past 4 weeks (e.g., asthma). Use of
inhaled CS does not exclude a patient.

- History of use of IM or anti-TNFα agent for other medical conditions (e.g., juvenile
rheumatoid arthritis) within the past 6 months

- Use of Accutane within the past 4 weeks

- Use of any investigational drug within the past four weeks

- Use of any 5-aminosalicylate within the past 4 weeks

- Pregnancy

- Subjects with poorly controlled medical conditions (e.g. diabetes, congestive heart
failure)

- Proctitis or proctosigmoiditis only (Paris classification E1) on colonoscopic
evaluation

- Chronic renal disease (BUN and serum creatinine >1.5 times the upper normal limit)

- Hepatic disease (AST or ALP greater than 3 times the upper normal limit in the absence
of concomitant liver disease associated with IBD following full evaluation)

- History of allergy or hypersensitivity to salicylates, aminosalicylates, or any
component of the Pentasa capsule.

- History of coexisting chronic illness or evidence of significant organic or
psychiatric disease on medical history or physical examination, which, in the
Investigator's opinion, would prevent participation in the study

- History or presence of any condition causing malabsorption or an effect on
gastrointestinal (GI) motility, or history of extensive small bowel resection (greater
than half the length of the small intestine).

- The finding of Helicobacter pylori at the time of evaluation does not exclude the
patient from the study. Whether to treat this patient for Helicobacter pylori and when
will be left to the discretion of the site.