Clinical trial NCT01536535: Predicting Response to Standardized Pediatric Colitis Therapy
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Ulcerative Colitis
Keywords: Ulcerative Colitis
mesalamine
corticosteroids
PROTECT
Lead sponsor: Connecticut Children's Medical Center
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2012-02-22
Enrollment: 431
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Number of Participants With Corticosteroid Free Remission (SFR)
timeFrame: 52 weeks
measure: Number of Participants Who Needed Additional Therapy or Colectomy
timeFrame: Within 52 weeks
Secondary outcomes:
measure: Number of Participants Receiving a Colectomy
timeFrame: Within 52 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Atlanta
country: United States
facility: Emory Children's Center
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Children's Hospital
state: Indiana
city: Baltimore
country: United States
facility: John Hopkins Children's Hospital
state: Maryland
city: Boston
country: United States
facility: Children's Hospital of Boston
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center
state: Minnesota
city: Morristown
country: United States
facility: Goryeb Children's Hospital / Atlantic Health
state: New Jersey
city: Buffalo
country: United States
facility: Women and Children's Hospital of Buffalo
state: New York
city: New Hyde Park
country: United States
facility: Cohen Children's Medical Center
state: New York
city: New York
country: United States
facility: Mt Sinai Hospital
state: New York
city: New York
country: United States
facility: Morgan Stanley Children's Hospital
state: New York
city: Syracuse
country: United States
facility: Golisano Children's Hospital SUNY Upstate Medical University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel HIll
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Providence
country: United States
facility: Hasbro Children's Hospital
state: Rhode Island
city: Nashville
country: United States
facility: Monroe Carell Jr. Children's Hospital at Vanderbilt
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center (University of Utah)
state: Utah
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Connecticut Children's Medical Center
name: Jeffrey Hyams, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Lee Denson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Collaborative Studies Coordinating Center - UNC-CH
name: Sonia Davis, DrPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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, Wali P, Moulton D, Evans J, Kappelman MD, Marquis A, Sylvester FA, Collins MH, Venkateswaran S, Dubinsky M, Tangpricha V, Spada KL, Britt A, Saul B, Gotman N, Wang J, Serrano J, Kugathasan S, Walters T, Denson LA. Factors associated with early outcomes following standardised therapy in children with ulcerative colitis (PROTECT): a multicentre inception cohort study. Lancet Gastroenterol Hepatol. 2017 Dec;2(12):855-868. doi: 10.1016/S2468-1253(17)30252-2. Epub 2017 Sep 20.
citation: Carmody JK, Plevinsky J, Peugh JL, Denson LA, Hyams JS, Lobato D, LeLeiko NS, Hommel KA. Longitudinal non-adherence predicts treatment escalation in paediatric ulcerative colitis. Aliment Pharmacol Ther. 2019 Oct;50(8):911-918. doi: 10.1111/apt.15445. Epub 2019 Aug 2.
citation: Hyams JS, Davis Thomas S, Gotman N, Haberman Y, Karns R, Schirmer M, Mo A, 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 PA, Strople J, Ziring D, Guthery SL, Sudel B, Benkov K, Wali P, Moulton D, Evans J, Kappelman MD, Marquis MA, Sylvester FA, Collins MH, Venkateswaran S, Dubinsky M, Tangpricha V, Spada KL, Saul B, Wang J, Serrano J, Hommel K, Marigorta UM, Gibson G, Xavier RJ, Kugathasan S, Walters T, Denson LA. Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study. Lancet. 2019 Apr 27;393(10182):1708-1720. doi: 10.1016/S0140-6736(18)32592-3. Epub 2019 Mar 29.