Predicting Response to Standardized Pediatric Colitis Therapy

Ulcerative Colitis Clinical Trial

— PROTECT  

Official title:

Multicenter Open-label Study Evaluating the Safety and Efficacy of Standardized Initial Therapy Using Either Mesalamine or Corticosteroids Then Mesalamine to Treat Children and Adolescents With Newly Diagnosed Ulcerative Colitis.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01536535
• Other study ID #: U01DK095745-01
• Secondary ID: 1U34DK090804
• Status: Completed
• Phase: Phase 4
• Start date: July 10, 2012
• Est. completion date: April 30, 2018

Study information

• Verified date: September 2019
• Source: Connecticut Children's Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multi-center, open-label study to determine the safety and effectiveness (how well it works) of two standardized treatments called "mesalamine" (Pentasa®) and "prednisone" in children with newly diagnosed Ulcerative Colitis (UC). Standardized treatments are types of treatments agreed upon and used by many qualified doctors. The medications being used in this study are considered "standard of care". Currently the ways in which these medicines are used (doses, frequency of dosing) may vary from site to site. This study will determine response to a standardized way of giving these medicines.

This study will also identify biomarkers for ulcerative colitis. Biomarkers are things that doctors can find in blood, stool, or bowel tissue that indicate how much inflammation there is in the bowel, how the inflammation is produced, and whether the inflammation is responding to treatment. Collecting response and remission (free of symptoms) information on these standardized treatments and the "biomarkers" can possibly help doctors create a model, or plan to know which children with UC may respond quickly, or which children may develop complications.

Description:

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 Interleukin 1 (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 (CS) 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 immunomodulators (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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 431
• Est. completion date: April 30, 2018
• Est. primary completion date: April 30, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years to 17 Years

Eligibility

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 Crohn's disease (CD) consistent with Paris and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (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 entry

• Use 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-TNFa 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 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).

• 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.

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer
• Ulcerative Colitis

Intervention

Drug:
• Mesalazine
Mesalazine (Pentasa) comes in 500mg capsules, and doses will need to be rounded to the nearest 500mg increment, with a maximum dose of 76 mg/kg/day. The average dose for the pediatric population will be approximately 70 mg/kg/day. Patients will be allowed to escalate to the final dose over 4 days to minimize side-effects such as headache.
• IV Corticosteroid
Treatment with IV Corticosteroid
• Oral Corticosteroids
Treatment with oral corticosteroids

Other:
• Additional Therapies
Anti-TNFa, Calcineurin inhibitor, Immunomodulator

Procedure:
• Colectomy
Colectomy

Locations

Country	Name	City	State
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Hospital for Sick Children	Toronto	Ontario
United States	Emory Children's Center	Atlanta	Georgia
United States	John Hopkins Children's Hospital	Baltimore	Maryland
United States	Children's Hospital of Boston	Boston	Massachusetts
United States	Women and Children's Hospital of Buffalo	Buffalo	New York
United States	University of North Carolina at Chapel HIll	Chapel Hill	North Carolina
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	UT Southwestern	Dallas	Texas
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Riley Children's Hospital	Indianapolis	Indiana
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	UCLA Medical Center	Los Angeles	California
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota Medical Center	Minneapolis	Minnesota
United States	Goryeb Children's Hospital / Atlantic Health	Morristown	New Jersey
United States	Monroe Carell Jr. Children's Hospital at Vanderbilt	Nashville	Tennessee
United States	Cohen Children's Medical Center	New Hyde Park	New York
United States	Morgan Stanley Children's Hospital	New York	New York
United States	Mt Sinai Hospital	New York	New York
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Hasbro Children's Hospital	Providence	Rhode Island
United States	Primary Children's Medical Center (University of Utah)	Salt Lake City	Utah
United States	University of California at San Francisco	San Francisco	California
United States	Golisano Children's Hospital SUNY Upstate Medical University	Syracuse	New York

Sponsors (2)

Lead Sponsor	Collaborator
Connecticut Children's Medical Center	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Hyams JS, Davis S, Mack DR, Boyle B, Griffiths AM, LeLeiko NS, Sauer CG, Keljo DJ, Markowitz J, Baker SS, Rosh J, Baldassano RN, Patel A, Pfefferkorn M, Otley A, Heyman M, Noe J, Oliva-Hemker M, Rufo P, Strople J, Ziring D, Guthery SL, Sudel B, Benkov K, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Corticosteroid Free Remission (SFR)	Week 52 CS-free remission: Number of participants with a PUCAI < 10 and no corticosteroids (CS) for 28 days without additional therapy or colectomy. Participants in both groups received corticosteroids, biologics, or colectomies, if symptomatic.; The Pediatric Ulcerative Colitis Activity Index (PUCAI) is a non-invasive disease activity index. The index measures include abdominal pain, rectal bleeding, stool consistency, number of stools per 24 hours, nocturnal stools, and activity level. A total score less than 10 indicates remission, Mild disease activity is 10-30, Moderate 35-60, Severe disease activity 65-85.	52 weeks
Primary	Number of Participants Who Needed Additional Therapy or Colectomy	Number of participants who needed additional therapy or colectomy. Additional therapy included Anti-Tumour Necrosis Factor alpha (TNFa), Calcineurin inhibitor, Immunomodulator	Within 52 weeks
Secondary	Number of Participants Receiving a Colectomy	Number of participants who received a colectomy within 52 weeks	Within 52 weeks

External Links

•   PROTECT Study Homepage