Clinical, Imaging, and Endoscopic Outcomes of Children Newly Diagnosed With Crohn's Disease

Study Overview
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Brief Summary
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Crohn's disease (CD) is a condition that causes inflammation (swelling, redness) of the lining and wall of the small intestine, large intestine, or both. CD may be associated with abdominal cramps/pain, diarrhea, blood in the stool, weight loss, or delayed growth in children. While the exact cause of CD is not certain it is thought that the immune system located in the intestine reacts abnormally to the large number of bacteria contained there. The investigators think that diet, exposure to antibiotics early in life, and having a family history of CD puts people at increased risk for developing CD. In order to decrease the inflammation doctors use what is called biologic therapy with anti-TNF molecules that can be given through an intravenous or shots. TNF is a chemical made by white blood cells that is involved in inflammation. When this type of treatment is given early after diagnosis it is more effective than when it is given later. The investigators have learned that it is important to give the optimum (ideal) amount of this medicine guided by certain blood tests. The investigators also know that not everyone responds to this therapy but do not understand the reasons for this variability between people. The CAMEO study has been started to help understand what factors are important in determining whether a child with CD completely heals the inflammation after anti-TNF therapy. The investigators will do that by measuring certain markers of inflammation in the blood and stool and by looking at a person's genes (DNA) and how inflammation is controlled in the intestine. These inflammation tests will be done before, during, and after one year of anti-TNF therapy. The investigators will determine how much healing has taken place by comparing the results of the colonoscopy and a special type of MRI that are both done before anti-TNF and then again one year later. The goal in treating CD is to heal both the lining and the wall of the intestine. Children ages 6-17 years who are thought to have CD and are about to undergo their diagnostic colonoscopy are eligible to be enrolled. If they are found to indeed have CD and start an anti-TNF medicine within 6 months they can continue in the study. There are no increased risks of participating in this study beyond those normally associated with having CD and its treatment. By better understanding why the bowel does or does not heal, doctors will be better able to provide personalized care.

Detailed Description
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Study Sites: Approximately 27 pediatric clinical centers in North America Study Period: Planned enrollment period - 3 years Planned duration of the study: 5 years Primary Study Objective: Identify clinical, radiologic, genomic, immune, microbial and transcriptomic factors associated with complete intestinal healing (CH) in the context of optimized anti-TNF therapy in children with newly diagnosed CD Secondary Study Objective: Identify clinical, radiologic, genomic, immune, microbial and transcriptomic factors associated with endoscopic healing only, transmural healing by MRE only, endoscopic response only, transmural response only, clinical remission, fecal calprotectin normalization, in the context of optimized anti-TNF therapy in children with newly diagnosed CD Study Design: Prospective multicenter open label single arm clinical trial with 2-phase enrollment Sample Size: Phase 1: 900; Phase 2: 550

Official Title
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Clinical, Imaging, and Endoscopic Outcomes of Children Newly Diagnosed With Crohn's Disease

Conditions
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Crohn Disease

Intervention / Treatment
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* Biological: infliximab, adalimumab


Participation Criteria
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Eligibility Criteria
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Phase 1 Inclusion Criteria (all must be fulfilled) Age ≥ 6 years and < 18 years at enrollment Suspected diagnosis of CD Stool culture if performed that is negative for routine enteric pathogens (Salmonella, Shigella, Campylobacter, E. coli 0157:H7) and Clostridium difficile toxin in patients presenting with diarrhea. If history of C. difficile then a minimum of 6 weeks duration from treatment start and negative repeat stool for C. difficile toxin. Parent/guardian consent and patient assent Ability to remain in follow-up for up to 6 months of initial observation followed by a minimum of 52 weeks after possible start of anti-TNF therapy Phase 1 Exclusion Criteria Diagnosis of CD following abdominal resectional surgery/appendectomy at initial presentation Investigator judgment that patient has high likelihood (>50%) of needing bowel resection within 3 months of diagnosis (i.e., presentation with perforation, bowel obstruction from stricture) Use of any oral corticosteroid (CS) for non-gastrointestinal indication within the four weeks prior to diagnostic assessment and biosampling (e.g., asthma) Use of any investigational drug within the past four weeks prior to diagnostic assessment and sampling Pregnancy Patients with poorly controlled medical conditions (e.g. diabetes, congestive heart failure) Previous treatment with immunomodulators or anti-TNF therapy for other medical conditions (e.g., juvenile idiopathic arthritis) at any time prior to enrollment Previous treatment with non-anti TNF biologics or small molecules for non-IBD indications in the past 6 months Phase 2 Inclusion Criteria (all must be fulfilled) Met all eligibility criteria for Phase 1 and participated in Phase 1 Diagnosed with active luminal CD involving the terminal ileum and/or colon by endoscopic and/or radiographic evidence Magnetic Resonance Enterography (MRE) imaging within 6 weeks of ileocolonoscopy and no more than 4 weeks after starting initial therapy. A limited 'research protocol' MRE is acceptable in participants who have undergone a clinical CTE during their initial diagnostic evaluation; see Manual of Procedures for details. Received at least one of the following as initial therapy upon diagnosis: Corticosteroids Immunomodulator Defined nutritional therapy Anti-TNF (adalimumab or infliximab) Commenced adalimumab or infliximab anti-TNF therapy guided by ROADMAB™ CDST as first therapy or within 180 days of first therapy, with or without concomitant immunomodulator Had ileal and rectal biopsies Parent/guardian re-consent and patient re-assent Ability to remain in follow-up for a minimum of 52 weeks after start of anti-TNF therapy Phase 2 Exclusion Criteria Diagnosis of CD using video capsule endoscopy only with normal ileocolonoscopy and normal MRE Orofacial CD only Esophageal, gastric, duodenal, and/or jejunal CD only Severe complex fistulizing perianal disease +/- abscess, or perianal disease requiring surgical intervention or likely to require on-going surgical intervention possibly including diversion Perianal CD only with no evidence of luminal disease Internal fistulizing disease at diagnosis Initial inflammatory bowel disease (IBD) treatment with non-anti-TNF biologic or small molecule therapy Received any anti-TNF agent other than adalimumab or infliximab Investigator judgment that patient unlikely to return for clinical, endoscopic or MRE follow-up Inability to have MRE because of claustrophobia or other reasons Incomplete lower endoscopic diagnostic evaluation where the investigation is terminated prior to intubation of the ileum Video of baseline endoscopy not available for central reading Underwent bowel resection within 3 months of initial therapy

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Anti-tumor necrosis factor (TNF)<br>Patients newly diagnosed with pediatric-onset Crohn's disease starting anti-TNF therapy within 6 months of diagnosis | Biological: infliximab, adalimumab<br>* Anti-TNF therapy guided by therapeutic drug monitoring<br>* Other names: Remicade, Inflectra, Renflexis, Avsola, Humira, Amgevita, Hulio, Hadlima, Hyrimoz, Idacio;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete healing (CH) | The achievement of complete healing (CH) 52 weeks after initiation of anti-TNF therapy guided by ROADMAB™ (therapeutic drug monitoring) as evidenced by a composite of all of the following four features below: Endoscopic healing (EH) determined by centrally read ileocolonoscopy (total SES-CD score <3) Transmural healing (TH) determined by centrally read MRE (no segmental MaRIAs score of ≥1) Corticosteroid free for a minimum of 4 weeks The absence of either intestinal resection or the addition of a nutritional, biological or small molecule therapeutic agent other than anti-TNF± concomitant IM | 52 weeks from anti-TNF start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endoscopic mucosal healing only | Following approximately 52 weeks of anti-TNF therapy guided by the ROADMAB™ Clinical Decision Support Tool (CDST), with a minimum of 4 weeks of being corticosteroid free, and in the absence of either intestinal resection or the addition of a biological or small molecule therapeutic agent other than anti-TNF± concomitant IM: Endoscopic mucosal healing only (total Simple Endoscopic Score - Crohn's Disease (SES-CD) <3) | 52 weeks | 
| Transmural healing only | Following approximately 52 weeks of anti-TNF therapy guided by the ROADMAB™ Clinical Decision Support Tool (CDST), with a minimum of 4 weeks of being corticosteroid free, and in the absence of either intestinal resection or the addition of a biological or small molecule therapeutic agent other than anti-TNF± concomitant IM: Transmural healing only (no segmental simplified magnetic resonance index of activity (MaRIAs) score ≥1) | 52 weeks | 
| Clinical remission | Following approximately 52 weeks of anti-TNF therapy guided by the ROADMAB™ Clinical Decision Support Tool (CDST), with a minimum of 4 weeks of being corticosteroid free, and in the absence of either intestinal resection or the addition of a biological or small molecule therapeutic agent other than anti-TNF± concomitant IM: Clinical remission (weighted Pediatric Crohn's Disease Activity Index (wPCDAI) < 12.5) | 52 weeks | 
| Fecal calprotectin | Following approximately 52 weeks of anti-TNF therapy guided by the ROADMAB™ Clinical Decision Support Tool (CDST), with a minimum of 4 weeks of being corticosteroid free, and in the absence of either intestinal resection or the addition of a biological or small molecule therapeutic agent other than anti-TNF± concomitant IM: Fecal calprotectin <250 ug/g | 52 weeks | 
| Endoscopic response | Following approximately 52 weeks of anti-TNF therapy guided by the ROADMAB™ Clinical Decision Support Tool (CDST), with a minimum of 4 weeks of being corticosteroid free, and in the absence of either intestinal resection or the addition of a biological or small molecule therapeutic agent other than anti-TNF± concomitant IM: Endoscopic response: 50% reduction in SES-CD | 52 weeks | 
| Transmural response | Following approximately 52 weeks of anti-TNF therapy guided by the ROADMAB™ Clinical Decision Support Tool (CDST), with a minimum of 4 weeks of being corticosteroid free, and in the absence of either intestinal resection or the addition of a biological or small molecule therapeutic agent other than anti-TNF± concomitant IM: Transmural response: 50% reduction in MaRIAs | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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crohn disease, children, pediatric, anti-TNF therapy, therapeutic drug monitoring, intestinal microbiome, inflammatory bowel disease, gene expression, genomic DNA