Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT)

September 4, 2019 updated by: Connecticut Children's Medical Center

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.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

431

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3K6R8
        • IWK Health Centre
    • Ontario
      • Ottawa, Ontario, Canada, K1H8L1
        • Children's Hospital of Eastern Ontario
      • Toronto, Ontario, Canada, M5G1X8
        • Hospital for Sick Children
  • United States
    • California
      • Los Angeles, California, United States, 90095
        • UCLA Medical Center
      • San Francisco, California, United States, 94143
        • University of California at San Francisco
    • Connecticut
      • Hartford, Connecticut, United States, 06106
        • Connecticut Children's Medical Center
    • Florida
      • Jacksonville, Florida, United States, 32207
        • Nemours Children's Clinic
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory Children's Center
    • Illinois
      • Chicago, Illinois, United States, 60611-2605
        • Ann & Robert H. Lurie Children's Hospital of Chicago
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Riley Children's Hospital
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • John Hopkins Children's Hospital
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Children's Hospital of Boston
    • Minnesota
      • Minneapolis, Minnesota, United States, 55454
        • University Of Minnesota Medical Center
    • New Jersey
      • Morristown, New Jersey, United States, 07962
        • Goryeb Children's Hospital / Atlantic Health
    • New York
      • Buffalo, New York, United States, 14222
        • Women and Children's Hospital of Buffalo
      • New Hyde Park, New York, United States, 11040
        • Cohen Children's Medical Center
      • New York, New York, United States, 10032
        • Morgan Stanley Children's Hospital
      • New York, New York, United States, 10029
        • Mt Sinai Hospital
      • Syracuse, New York, United States, 13210
        • Golisano Children's Hospital SUNY Upstate Medical University
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • University of North Carolina at Chapel Hill
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Cincinnati Children's Hospital Medical Center
      • Columbus, Ohio, United States, 43205
        • Nationwide Children's Hospital
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Children's Hospital of Philadelphia
      • Pittsburgh, Pennsylvania, United States, 15224
        • Children's Hospital of Pittsburgh of UPMC
    • Rhode Island
      • Providence, Rhode Island, United States, 02903
        • Hasbro Children's Hospital
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Monroe Carell Jr. Children's Hospital at Vanderbilt
    • Texas
      • Dallas, Texas, United States, 75235
        • UT Southwestern
    • Utah
      • Salt Lake City, Utah, United States, 84132
        • Primary Children's Medical Center (University of Utah)
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • Medical College of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 years to 17 years (CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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-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 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Mild UC

Mild = Initiated on mesalazine, or on oral CS with Pediatric Ulcerative Colitis Activity Index (PUCAI) < 45

Patients can be treated with any of the therapies noted below:

Mesalazine: doses is rounded to the nearest 500mg increment, maximum dose of 75 mg/kg/day Oral corticosteroids:1-1.5 mg/kg/day, rounded up to the nearest 5 mg value

IV corticosteroids:

Additional Therapies:

Calcineurin inhibitor (cyclosporine, tacrolimus) or anti-Tumour Necrosis Factor alpha (TNFα) therapy: These therapies may also be instituted if in the judgment of the attending physician is needed.

Immunomodulator or biologic therapy: thiopurine then dosing of azathioprine:2.5-3 mg/kg/day; 6-MP at 1-1.5 mg/kg/day Colectomy
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.
Other Names:
  • Pentasa
Drug: IV Corticosteroid
Treatment with IV Corticosteroid
Other Names:
  • Prednisone
Drug: Oral Corticosteroids
Treatment with oral corticosteroids
Other Names:
  • Prednisone
Other: Additional Therapies
Anti-TNFα, Calcineurin inhibitor, Immunomodulator
Procedure: Colectomy
Colectomy
EXPERIMENTAL: Moderate to Severe UC

Moderate/Severe = Initiated on IV CS, or oral CS with PUCAI ≥45

Patients can be treated with any of the therapies noted below:

Mesalazine: doses is rounded to the nearest 500mg increment, maximum dose of 75 mg/kg/day Oral corticosteroids:1-1.5 mg/kg/day, rounded up to the nearest 5 mg value

IV corticosteroids:

Additional Therapies:

Calcineurin inhibitor (cyclosporine, tacrolimus) or anti-TNFα therapy: These therapies may also be instituted if in the judgment of the attending physician is needed.

Immunomodulator or biologic therapy: thiopurine then dosing of azathioprine:2.5-3 mg/kg/day; 6-Mercaptopurine (MP) at 1-1.5 mg/kg/day Colectomy
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.
Other Names:
  • Pentasa
Drug: IV Corticosteroid
Treatment with IV Corticosteroid
Other Names:
  • Prednisone
Drug: Oral Corticosteroids
Treatment with oral corticosteroids
Other Names:
  • Prednisone
Other: Additional Therapies
Anti-TNFα, Calcineurin inhibitor, Immunomodulator
Procedure: Colectomy
Colectomy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Corticosteroid Free Remission (SFR)
Time Frame: 52 weeks

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
Number of Participants Who Needed Additional Therapy or Colectomy
Time Frame: Within 52 weeks
Number of participants who needed additional therapy or colectomy. Additional therapy included Anti-Tumour Necrosis Factor alpha (TNFα), Calcineurin inhibitor, Immunomodulator
Within 52 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants Receiving a Colectomy
Time Frame: Within 52 weeks
Number of participants who received a colectomy within 52 weeks
Within 52 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Connecticut Children's Medical Center

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

  • Principal Investigator: Jeffrey Hyams, MD, Connecticut Children's Medical Center
  • Principal Investigator: Sonia Davis, DrPH, Collaborative Studies Coordinating Center - UNC-CH

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 10, 2012

Primary Completion (ACTUAL)

April 30, 2018

Study Completion (ACTUAL)

April 30, 2018

Study Registration Dates

First Submitted

February 16, 2012

First Submitted That Met QC Criteria

February 16, 2012

First Posted (ESTIMATE)

February 22, 2012

Study Record Updates

Last Update Posted (ACTUAL)

September 20, 2019

Last Update Submitted That Met QC Criteria

September 4, 2019

Last Verified

September 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • U01DK095745-01 (NIH)
  • 1U34DK090804 (NIH)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Data will be shared 6 months after the primary publication of the manuscript appears on line.

IPD Sharing Time Frame

Data will be shared 6 months after the primary publication of the manuscript appears on line.

IPD Sharing Access Criteria

NIH repository list serve to be determined

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ANALYTIC_CODE
  • CSR

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Ulcerative Colitis

Clinical Trials on Mesalazine

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Uzbekistan

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe