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Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT)

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ClinicalTrials.gov Identifier: NCT01536535
Recruitment Status : Completed
First Posted : February 22, 2012
Results First Posted : August 26, 2019
Last Update Posted : September 20, 2019
Sponsor:
Collaborator:
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 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.


Condition or disease Intervention/treatment Phase
Ulcerative Colitis Drug: Mesalazine Drug: IV Corticosteroid Drug: Oral Corticosteroids Other: Additional Therapies Procedure: Colectomy 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 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 431 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 : July 10, 2012
Actual Primary Completion Date : April 30, 2018
Actual Study Completion Date : April 30, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Mesalamine

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 Name: Pentasa

Drug: IV Corticosteroid
Treatment with IV Corticosteroid
Other Name: Prednisone

Drug: Oral Corticosteroids
Treatment with oral corticosteroids
Other Name: 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 Name: Pentasa

Drug: IV Corticosteroid
Treatment with IV Corticosteroid
Other Name: Prednisone

Drug: Oral Corticosteroids
Treatment with oral corticosteroids
Other Name: Prednisone

Other: Additional Therapies
Anti-TNFα, Calcineurin inhibitor, Immunomodulator

Procedure: Colectomy
Colectomy




Primary Outcome Measures :
  1. 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.


  2. 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


Secondary Outcome Measures :
  1. Number of Participants Receiving a Colectomy [ Time Frame: Within 52 weeks ]
    Number of participants who received a colectomy within 52 weeks



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

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.

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 ClinicalTrials.gov 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)
Investigators
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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
  Study Documents (Full-Text)

Documents provided by Connecticut Children's Medical Center:

Additional Information:
Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Connecticut Children's Medical Center
ClinicalTrials.gov 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
Results First Posted: August 26, 2019
Last Update Posted: September 20, 2019
Last Verified: September 2019
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
mesalamine
corticosteroids
PROTECT
Additional relevant MeSH terms:
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Colitis
Colitis, Ulcerative
Ulcer
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Intestinal Diseases
Pathologic Processes
Inflammatory Bowel Diseases
Prednisone
Mesalamine
Calcineurin Inhibitors
Immunologic Factors
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antirheumatic Agents