Exclusive Enteral Nutrition in Patients With Ileocaecal Crohn's Disease

Study Overview
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Brief Summary
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Inflammatory bowel diseases are chronic and progressive entities, triggered by exposure to environmental factors in individuals with a genetic background. One of the most common environmental factors is the type of diet which is a key influencer on pathogenesis. Nutrients alter the intestinal microbiota, thus changing the intestinal permeability. The Western-type diet encompasses sugar, fat, and protein-rich products that have some deleterious effects on the intestinal microbiome compared to the plant-based Mediterranean-type diet. Based on this fact, diet-based therapeutic efforts have been used extensively in pediatric Crohn's disease patients and there is strong evidence that exclusive enteral nutrition (EEN) is as effective as corticosteroids to induce both clinical and endoscopic remission but this treatment strategy is underutilized in adults.

Official Title
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Exclusive Enteral Nutrition in Patients With Ileocaecal Crohn's Disease (XENIC): an Open-label, Multicenter, Prospective, Randomized Clinical Trial

Conditions
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Crohn Disease, Nutrient; Excess, Remission/Regression

Intervention / Treatment
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* Dietary Supplement: EEN (Nestle Modulen®)
* Drug: Standart of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects, aged between 18-75 years with a diagnosis of ileocolonic Crohn's disease (CD) confirmed using endoscopy and/or imaging technology at most 3 months prior. Participant or his/her legal representative have voluntarily signed and dated an informed consent approved by and compliant with the requirements of this study protocol which has been approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Adequate cardiac, renal, and hepatic function as determined by the Principal Investigator and demonstrated by Screening laboratory evaluations, questionnaires, and physical examination results that do not indicate an abnormal clinical condition that would place the participant at undue risk preclude participation in the study. Participant must be able to orally administer study medication/nutrient or have a designee or Healthcare Professional who can assist Exclusion Criteria: Previous or current use of any medication for Crohn's disease such as biologics, immunomodulators (e.g., methotrexate, azathioprine, 6-mercaptopurine, JAK inhibitor, alpha-integrin), and corticosteroids Presence of complications (Fistula, abscess, fibrotic disease, imminent risk of surgery) Participants with a poorly controlled medical condition such as uncontrolled diabetes with a documented history of recurrent infections, unstable ischemic heart disease, moderate to severe congestive heart failure (New York Heart Association [NYHA] class III or IV), recent cerebrovascular accident, and any other condition which, in the opinion of the Investigator or the sponsor, would put the participant at risk by participation in the protocol Participants with positive C. difficile stool assay at screening. Rescue therapy with steroids, depending on the severity of the disease will be initiated for patients in the EEN group who do not respond clinically and will be excluded from the study. If the number of clinically unresponsive patients was greater than 25% of the total EEN population, the study will be stopped. Criteria for clinical response are described in the Outcome Measures section.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is an open-label, randomized, multicenter, interventional, parallel-group study, designed to evaluate the efficacy and tolerability of EEN in inducing clinical remission at 12 weeks in subjects with ileocaecal CD. Patients will receive EEN for 8 weeks, initially building up to the full required volume of formula over the first 3 to 4 days, depending on tolerance and side effects After the completion of the period of EEN, foods will be reintroduced slowly and supplementary enteral nutrition will be continued for another 4 weeks. A total of 256 patients with ileocaecal CD will be randomized in a 1:1 ratio to receive steroids and EEN. Each of the treatment arms will comprise 128 subjects. In order to make the groups comparable, randomization will be stratified according to the severity of the disease according to Crohn's Disease Activity Index (CDAI): CDAI between 150-220 --> Mild CDAI between 220-450 --> Moderate CDAI>450 --> Severe
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exclusive Enteral Nutrition<br>35kcal/kg/day EEN (Nestle Modulen®) - Subjects will take medicine and EEN solution orally themselves. | Dietary Supplement: EEN (Nestle Modulen®)<br>* 35kcal/kg/day for every patient<br>|
| Active Comparator: Standard of care<br>Budesonide 9mg/day for mild disease Prednisolone 1mg/kg, maximum 40mg/day in decreasing doses (40mg for 4 weeks followed by a fixed taper for 6 weeks) for moderate-to-severe disease for 12 weeks. Patients with moderate-to-severe disease in the steroid group will also receive 2mg/kg azathioprine. The dose of azathioprine will be adjusted according to abnormalities of white blood cell (WBC) count, platelet count, liver function tests (LFTs; i.e. alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase), lipase, blood urea nitrogen (BUN), and serum creatinine. | Drug: Standart of care<br>* Budesonide 9mg/day for mild disease Prednisolone 1mg/kg, maximum 40mg/day in decreasing doses (40mg for 4 weeks followed by a fixed taper for 6 weeks) for moderate-to-severe disease for 12 weeks. Patients with moderate to severe disease in the steroid group will also receive 2mg/kg azathioprine. The dose of azathioprine will be adjusted according to abnormalities of white blood cell (WBC) count, platelet count, liver function tests (LFTs; i.e. alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase), lipase, blood urea nitrogen (BUN), and serum creatinine.<br>* Other names: Budesonide (Budenofalk®), Prednisolone (Deltacortril®), Azathioprine (Imuran®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with mucosal healing | Defined as Simple Endoscopic Score for Crohn's Disease (SES-CD) ≤2, at 12 weeks after randomization. The ileocolonoscopies will be evaluated by the site. SES-CD is an index for determining the severity of Crohn's disease. The SES-CD considers size of ulcerations, ulcerated surface, effected surface and the presence of narrowings, evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The score ranges from 0 to 60 where higher scores indicate more severe endoscopic activity. | 12 weeks | 
| Percentage of patients that tolerate the EEN by week 12 | Defined as withdrawal from the study from randomization through 12 weeks after randomization | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endoscopic response | Defined as decrease in SES-CD > 50% from baseline at 12 weeks after randomization | 12 weeks | 
| Mean change from baseline in SES-CD at 12 weeks after randomization | Mean change from baseline in SES-CD | 12 weeks | 
| Mean change from baseline in CDAI over time (Time Frame: Baseline, 4, 8 and 12 weeks after randomization) | The Crohn's Disease Activity Index (CDAI) is a research tool used to quantify the symptoms of patients with Crohn's disease. Participants were asked to record the frequency of stools, abdominal pain and general well-being on a daily basis. In addition to the diary data, the investigator assessed the following for the calculation of CDAI: presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. The CDAI is the sum of the products of each item multiplied by a weighting factor and generally ranges from 0 up to 600, where remission of Crohn's disease is defined as CDAI < 150, and severe disease is defined as CDAI > 450. A negative change from baseline indicates improvement. | 12 weeks | 
| Time to clinical remission (Time frame: from randomization through 12 weeks after randomization) | Clinical remission was defined as: CDAI < 150 PRO-2 abdominal pain (AP) score≤1 (7 day average) and liquid/very soft stool frequency (SF) score≤3 (7 day average) Two-item Patient Reported Outcome (PRO-2) is a health outcome directly reported by the patient to quantify a treatment's efficacy that is derived from CDAI diary card. Participants were asked to record daily number of liquid or very soft stools and the severity of abdominal pain (defined as; 0=none, 1=mild, 2=moderate 3=severe). PRO-2 is the sum of the products of each item multiplied by a weighing factor. PRO-2 scores that correspond to CDAI thresholds are: Mild Moderate Severe CDAI 150 220 450 PRO-2 8 14 34 | 12 weeks | 
| Time to clinical response (Time frame: from randomization through 12 weeks after randomization) | Clinical response was defined as: CDAI reduction ≥100 from baseline PRO-2 reduction ≥8 from baseline | 12 weeks | 
| Mean change from baseline in C-reactive protein (CRP) over time (Time Frame: 4, 8 and 12 weeks after randomization) | Changes in CRP levels | 12 weeks | 
| Mean change from baseline in fecal calprotectin (FC) over time (Time Frame: 4, 8 and 12 weeks after randomization) | Changes in fecal calprotectin levels | 12 weeks | 
| Mean change from baseline in PRO-2 (Time Frame: Baseline and 12 weeks after randomization) | Two-item Patient Reported Outcome (PRO-2) is a health outcome directly reported by the patient to quantify a treatment's efficacy that is derived from CDAI diary card. Participants were asked to record daily number of liquid or very soft stools and the severtiy of abdominal pain (defined as; 0=none, 1=mild, 2=moderate 3=severe). PRO-2 is the sum of the products of each item multiplied by a weighing factor. PRO-2 scores that correspond to CDAI thresholds are: Mild Moderate Severe CDAI 150 220 450 PRO-2 8 14 34 | 12 weeks | 
| Change from baseline in SIBDQ total score (Time Frame: Baseline and 12 weeks after randomization) | Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is a 10-item HrQOL questionnaire designed to quantify the changes in patients' daily activity, related to Crohn's disease symptoms. Participants were asked questions about physical, social, emotional, and systemic aspects and scored on a 7-point scale from 1 (severe problem) to 7 (no problems at all). The score ranges from 1 to 70 where higher scores indicate better HrQOL. | 12 weeks | 
| Change in Robarts Histopathology Index (RHI) (Time Frame: Baseline and 12 weeks after randomization) | RHI is a research tool used to quantify the histologic changes and to assess the degree of inflammation in the mucosa. RHI= 1xchronic inflammatory infiltrate level (4 levels) 2 x lamina propria neutrophils (4 levels) 3 x neutrophils in epithelium (4 levels) 5 x erosion or ulceration (4 levels) The total score ranges from 0 (no disease activity) to 33 (severe disease activity). RHI≤3 corresponds to histologic remission. | 12 weeks | 
| Number of Crohn's disease-related hospitalizations after randomization (Time Frame: From randomization through 12 weeks after randomization) | Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. Hospitalization due to emergency was defined as a hospitalization admitted through the emergency department. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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enteral nutrition, induction of remission, Crohn's disease