Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT)

General Description

This multicenter open-label study was designed to evaluate the safety and efficacy of standardized initial therapy using either mesalamine or corticosteroids then mesalamine for the treatment of children and adolescents newly diagnosed with ulcerative colitis. The study investigated the hypothesis that response to the initial 4 weeks of therapy as well as specific clinical, genetic, and immune parameters determined during the initial course of therapy predicted severe disease as reflected by need for escalation of medical therapy or surgery.

Participants were assigned to one of two initial therapeutic plans (mesalamine only or prednisone/liquid equivalent prednisolone followed by mesalamine) depending upon initial disease severity determined by the validated multi-dimensional Pediatric Ulcerative Colitis Activity Index (PUCAI). Biospecimens were obtained at diagnosis, and subsequently following the initiation of therapy at weeks 4, 12, and 52 (blood and stool at weeks 4 and 12; blood, stool, and colonic tissue at week 52). Follow-up clinic visits were conducted for a minimum of 1 year to a maximum of 5 years depending on when the participant enrolled. Adherence to mesalamine dosing was monitored using a state of the art electronic Medication Event Monitoring System (MEMS®).

The primary publication associated with the PROTECT study can be found here: Clinical and Biological Predictors of Response to Standardised Paediatric Colitis Therapy: A Multicentre Inception Cohort Study.

Objectives

The objectives of this study were to determine a standardized way of administering ulcerative colitis medications, and to identify biomarkers for ulcerative colitis in order to develop treatment models.

Outcome Measure

The primary outcome measures of the study were:

• Number of participants with corticosteroid (CS) free remission measured at 52 weeks with PUCAI < 10 and no corticosteroids for 28 days without additional therapy or colectomy
• Number of participants who needed additional therapy or colectomy therapy including Anti-Tumor Necrosis Factor alpha (TNFα), Calcineurin inhibitor, and Immunomodulator (IM)

The secondary outcome measure of the study was the number of participants receiving a colectomy within 52 weeks.

Criteria

Inclusion criteria:

• Age ≥ 4 years and ≤ 17 years at initiation of therapy
• 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)
• 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), Clostridium difficile toxin, and enteric parasites (ova and parasites)
• Ability to remain in follow-up for a minimum of one year from diagnosis
• Female patients of childbearing age must have a negative urine pregnancy test, practice acceptable contraception, and must not be lactating

Exclusion criteria:

• Clinical, endoscopic, radiologic, or histologic evidence suggesting Crohn's disease (CD) consistent with Paris and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) criteria
• A previous diagnosis of inflammatory bowel disease for which treatment was given
• Evidence of any active enteric infection at the time of study entry
• Use of any oral CS for non-gastrointestinal indication within the past 4 weeks (e.g., asthma)
• 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, any 5-aminosalicylate, or any investigational drug within the past 4 weeks
• Pregnant
• 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 Alkaline phosphatase (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)

Outcome

A minority of children (38%) participating in the study achieved the ideal clinical outcome of CS-free remission with mesalamine alone at 52 weeks post-diagnosis. A strong predictor of Week 52 outcome was early response to mesalamine ± CS and achieving clinical remission by Week 4. Additional medical therapies were common, including use of thiopurines, and 6% of participants required colectomy within one year of diagnosis.