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Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01536535
Recruitment Status : Completed
First Posted : February 22, 2012
Last Update Posted : October 4, 2018
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Connecticut Children's Medical Center

Brief 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 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.

Condition or disease Intervention/treatment Phase
Ulcerative Colitis Drug: Mesalamine Drug: Corticosteroid Drug: Corticosteroids then mesalamine Phase 4

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 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 467 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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.
Actual Study Start Date : May 1, 2012
Actual Primary Completion Date : April 30, 2018
Actual Study Completion Date : April 30, 2018

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Mesalamine Only

mesalamine (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 sideeffects such as headache.

If a patient does not respond to mesalamine then a corticosteroid will be added to the treatment.

Drug: Mesalamine
Mesalamine (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 Name: Pentasa

Experimental: Corticosteroids then mesalamine
Patients will begin with Corticosteroids, which will be weaned as tolerated and mesalamine (Pentasa®) added.
Drug: Corticosteroids then mesalamine
Initiate treatment with prednisone, 1-1.5 mg/kg/day, (maximum 40-60 mg in a single morning dose, either as tablet or liquid equivalent), rounded up to the nearest 5 mg value. This dose will be continued for 2 weeks to assess response. If response mesalamine will be added 500 mg capsules 70-75 mg/kg per day
Other Name: Prednisone

Active Comparator: Corticosteriod
Hospitalized patients with severe UC (PUCAI≥65) will begin IV Corticosteroids followed by a corticosteroid taper.
Drug: Corticosteroid
Initiate treatment with IV Corticosteroid followed by corticosteroid taper for patients hospitalized with severe CS.
Other Name: Prednisone

Primary Outcome Measures :
  1. Corticosteroid free remission (SFR) [ Time Frame: 52 weeks ]
    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.

Secondary Outcome Measures :
  1. Corticosteroid free remission [ Time Frame: 52 weeks ]

    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

Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01536535

  Show 29 Study Locations
Sponsors and Collaborators
Connecticut Children's Medical Center
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Principal Investigator: Jeffrey Hyams, MD Connecticut Children's Medical Center
Principal Investigator: Lee Denson, MD Children's Hospital Medical Center, Cincinnati
Principal Investigator: Sonia Davis, DrPH Collaborative Studies Coordinating Center - UNC-CH

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):

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Responsible Party: Connecticut Children's Medical Center Identifier: NCT01536535     History of Changes
Other Study ID Numbers: U01DK095745-01 ( U.S. NIH Grant/Contract )
1U34DK090804 ( U.S. NIH Grant/Contract )
First Posted: February 22, 2012    Key Record Dates
Last Update Posted: October 4, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be shared 6 months after the primary publication of the manuscript appears on line.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Data will be shared 6 months after the primary publication of the manuscript appears on line.
Access Criteria: NIH repository list serve to be determined

Keywords provided by Connecticut Children's Medical Center:
Ulcerative Colitis

Additional relevant MeSH terms:
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Colitis, Ulcerative
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Intestinal Diseases
Pathologic Processes
Inflammatory Bowel Diseases
Anti-Inflammatory Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Antirheumatic Agents