Crohn Disease
Conditions
Keywords
crohn disease, children, pediatric, anti-TNF therapy, therapeutic drug monitoring, intestinal microbiome, inflammatory bowel disease, gene expression, genomic DNA
Brief summary
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
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
Interventions
DRUGAnti-TNF therapy
Use of anti-TNF therapy for children and adolescents with newly diagnosed Crohn's disease guided by a clinical decision support tool
Sponsors
Connecticut Children's Medical Center
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Emory University
Children's Hospital Medical Center, Cincinnati
University of North Carolina, Chapel Hill
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Phase 1 Inclusion Criteria 1. Age ≥ 6 years and \< 18 years at enrollment 2. Suspected diagnosis of CD 3. 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. 4. Parent/guardian consent and patient assent 5. 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
1. Diagnosis of CD following abdominal resectional surgery/appendectomy at initial presentation 2. 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) 3. Use of any oral CS for non-gastrointestinal indication within the four weeks prior to diagnostic assessment and biosampling (e.g., asthma) 4. Use of any investigational drug within the past four weeks prior to diagnostic assessment and sampling 5. Pregnancy 6. Patients with poorly controlled medical conditions (e.g. diabetes, congestive heart failure) 7. Previous treatment with immunomodulators within one year of enrollment or anti-TNF therapy within two years of enrollment for other medical conditions (e.g., juvenile idiopathic arthritis) 8. Previous treatment with non-anti TNF biologics or small molecules for non-IBD indications in the past 6 months, with the exception of dupilumab (Dupixent) for asthma, eczema, or eosinophilic esophagitis 9. Inability to have MRE because of claustrophobia or other reasons Phase 2 Inclusion Criteria 1. Met all eligibility criteria for Phase 1 and participated in Phase 1 2. Diagnosed with macroscopic CD involving the terminal ileum and/or colon by endoscopic evaluation and/or MRE 3. MRE imaging within 6 weeks of ileocolonoscopy and no more than 4 weeks after starting initial therapy (TT). 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. 4. Received at least one of the following as initial therapy upon diagnosis: 1. Corticosteroids 2. Immunomodulator 3. Aminosalicylic acids (5-ASA) 4. Defined nutritional therapy 5. Anti-TNF (adalimumab or infliximab) 5. Commenced adalimumab or infliximab anti-TNF therapy guided by ROADMAB™ CDST as first therapy or within 180 days of diagnosis (TD), with or without concomitant immunomodulator 6 a. Had ileal and rectal biopsies, OR b. Ileal biopsies are not obtained secondary to inflammatory or structural changes at the ileocecal valve or distal ileum that prevent ileal intubation. To be acceptable for Phase 2, the following additional criteria must be met: b1. Gross inflammation or obvious narrowing at the IC valve or distal ileum as documented by the video colonoscopy, AND b2. MRE documentation of TI inflammation with or without narrowing, OR c. Ileal biopsies are not obtained secondary to inflammatory or structural changes due to colonic CD. 7\. Parent/guardian consent and patient assent 8. Ability to remain in follow-up for a minimum of 52 weeks after start of anti-TNF therapy Phase 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete healing (CH) | 52 weeks from anti-TNF start | 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: 1. Endoscopic healing (EH) determined by centrally read ileocolonoscopy (total SES-CD score \<3) 2. Transmural healing (TH) determined by centrally read MRE (no segmental MaRIAs score of ≥1) 3. Corticosteroid free for a minimum of 4 weeks 4. The absence of either intestinal resection or the addition of a nutritional, biological or small molecule therapeutic agent other than anti-TNF± concomitant IM |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Endoscopic mucosal healing only | 52 weeks | 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) |
| Transmural healing only | 52 weeks | 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) |
| Clinical remission | 52 weeks | 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) |
| Fecal calprotectin | 52 weeks | 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 |
| Endoscopic response | 52 weeks | 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 |
| Transmural response | 52 weeks | 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 |
Countries
Canada, United States
Contacts
CONTACTDena E Hopkins, MPH, CCRP
CONTACTJeffrey S Hyams, MD
PRINCIPAL_INVESTIGATORJeffrey S Hyams, MD
Connecticut Children's Medical Center
PRINCIPAL_INVESTIGATORSubra Kugathasan, MD
Emory University
PRINCIPAL_INVESTIGATORLee Denson, MD
Children's Hospital Medical Center, Cincinnati
Outcome results
None listed