Combining Nutritional Therapy and Anti-TNFα Treatment in Pediatric Patients With Crohn's Disease

Open-Label Multicentre Randomized Dietary Intervention Study in Pediatric Crohn's Disease Patients Initiating Anti-TNF Therapy

Children with Crohn's disease (CD), a type of Inflammatory Bowel Disease (IBD), often face serious health challenges, including poor growth, frequent hospital stays, and long-term medication use. Although biologic drugs like infliximab, an anti-TNFα (Tumor necrosis factor α) medication, have improved treatment, they don't work for everyone: many children still experience symptoms or disease flare-ups. Nutritional therapies, especially the Crohn's Disease Exclusion Diet (CDED), may help improve treatment outcomes. This study will assess whether starting CDED at the same time as infliximab leads to better responses to treatment. The goal of this study is to improve how well children respond to therapy, reduce drug exposure, and support better long-term health.

This open-label, randomized, controlled interventional study will evaluate the effectiveness of combining nutritional therapy (modified Crohn's Disease Exclusion Diet; mCDED) with infliximab (IFX) in pediatric patients with luminal Crohn's disease (CD), compared to IFX alone.

The investigators hypothesize that initiating mCDED at the start of IFX therapy will enhance clinical response by the time the first IFX maintenance dose is given (week 12), and increase clinical and biochemical remission rates at 1 year (week 52).

Participation will last up to 16 months and includes a pre-randomization phase of up to 4 months (for baseline sample and data collection), and 12 months of intervention. After randomization (T0), participants assigned to the intervention arm will follow a standardized IFX infusion schedule and begin the mCDED with the support of a dietitian. Participants in the control arm will follow the same IFX schedule and meet with a dietitian who will review their usual eating habits, but they will not be asked to follow any dietary advice.

A total of 140 pediatric CD patients (70 per arm) will be recruited from the lead site (Vancouver) and 7-9 additional participating sites (Montreal, Ottawa, Toronto, Halifax, Calgary, Edmonton, London, Hamilton) within the Canadian Children Inflammatory Bowel Disease Network (CIDsCaNN).

The following samples and data will be collected:

1. 3-day diet record (3DDR) - Completed by both arms at weeks 1, 12, 24 and 52 to assess dietary intake differences and dietary adherence to mCDED.
2. 24-hour diet recall - Conducted by a dietitian to assess dietary adequacy of both groups at weeks 1, 2 (for intervention group only), 6, 12, and 24.
3. CDED diet habits questionnaire - Completed by both groups at weeks 1 and 52 to assess how their diet aligns with the mCDED and to evaluate any changes in dietary habits.
4. CDED adherence questionnaire - Completed by the intervention group only at weeks 2, 6, 12, and 24.
5. KIDMED questionnaire (Mediterranean Diet Quality Index in children) - Completed by both groups at weeks 1 and 52 to assess adherence to a healthy diet and good dietary habits.

7) Paediatric Yorkhill Malnutrition Score (PYMS) - At pre-randomization assessment, weeks 24 and 52, to assess malnutrition.

8) Clinical and Biochemical Data - Weighted paediatric Crohn's disease activity index (wPCDAI), physician global assessment (PGA), C-reactive protein (CRP), ESR (Erythrocyte Sedimentation Rate), Fecal calprotectin (FCP) and hematological data (Complete Blood Count [CBC]) collected at pre-randomization assessment, weeks 1, 6, 12, 24 and 52.

9) Anthropometric data (body mass index [BMI], growth velocity) - Assessed over study at pre-randomization assessment, weeks 1, 2, 6, 12, 24, 36 and 52.

10) Nutritional status (Albumin, Ferritin, B12, Vitamin D levels) - Measured in blood at weeks 1, 6, 12, 24 and 52 11) IFX trough levels - Measured in blood at weeks 6, 12, 24 and 52. 12) Optional blood sample - Participants will have the option to provide a blood sample during the pre-randomization assessment for genetic testing to investigate genetic variants that may influence response to IFX, including but not limited to HLADQA1*05 (major histocompatibility complex, class II, DQ alpha 1).

13) Magnetic Resonance Elastography (MRE) - Performed at Baseline (within 4 months prior to randomization and starting therapy) and at week 52 (±4 weeks) and/or when clinically indicated to assess disease activity.

14) Intestinal ultrasound (IUS) - Performed at Baseline (T-2, within 4 months prior to randomization and starting therapy), weeks 12 (±2 weeks), 24 (±4 weeks) and 52 (±4 weeks) to assess disease activity (transmural intestinal inflammation).

15) Colonoscopy - At Baseline (within 4 months prior to randomization and starting therapy) and at week 52 (±4 weeks) to assess disease activity (SES-CD; Simple endoscopic score for Crohn's disease). While not mandatory, it is highly encouraged. In the absence of a colonoscopy, a composite score will be generated. If a colonoscopy is performed, mucosal washes and intestinal biopsies will be collected for research purpose.

16) Fecal samples - Collected without preservatives by participants at weeks 1, 2, 6, 12, 24, and 52 for longitudinal microbiota analysis, in vitro microbiota culturing, and fecal transplantation into germ-free recipient mice.

17) IMPACT-III - Quality of life survey completed by all participants at weeks 1, 12 and 52.

Inclusion Criteria:

• Moderate-severe active luminal inflammatory (B1) pCD [wPCDAI > or = 40] ileal +/- colonic (L1, L2, L3), and in whom treating physician plans to start IFX
• OR Strong suspicion of moderate-severe active luminal inflammatory (B1) pCD ileal +/- colonic (L1, L2, L3), and in whom treating physician plans to start IFX
• Within 12-months of diagnosis (when starting IFX treatment)
• Naïve to a biologic therapy
• For patients with established disease who flare up: no response to dietary intervention or steroids within 4 weeks of commencement of these therapies.
• For newly diagnosed patients: no response to dietary intervention or steroids within 2 weeks of commencement of these therapies.
• Evidence of active inflammation: FCP level > 250 µg/g and/ or CRP > 5 mg/L or ESR > 20 mm/hr
• BMI between the 5th and 95th percentiles, adjusted for age and sex
• On steroids or EEN for less than 2 (or 4, for established disease) weeks
• Able and willing to follow dietary recommendations
• On stable dose of AZA or Methotrexate (MTX) at randomization
• Willing to enroll in the CIDsCaNN Network study

Exclusion Criteria:

• CDED, EEN, or steroids commenced more than 2 weeks prior to randomization
• Antibiotic use in the last 2 months (except short course < 1 week between 1-2 months) or laxative use within the past month (except for bowel prep for endoscopy pre commencement of anti-TNFα)
• Pre-, pro-, synbiotic supplements in the last month (food containing these products, e.g. yogurt, allowed)
• Strict vegetarians and vegans
• High risk of malnutrition as assessed by the Paediatric Yorkhill Malnutrition Score (PYMS)
• Other known GI disorders (except IBS), food intolerances or chronic diseases
• Bowel surgery prior the randomization
• Severe perianal disease (fistulizing or ulcerating), fibrostenotic (B2) or penetrating (B3) disease
• Currently on prednisone/prednisolone for > 2 weeks
• Pregnant or breastfeeding
• Participating in another study
• Inability to consent