Nicotinamide Riboside in Ulcerative Colitis

Study Overview
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Brief Summary
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This is a randomized, double-blind pilot study of Nicotinamide Riboside (NR) in Pediatric-onset Ulcerative Colitis (UC).

Detailed Description
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The investigators hypothesize that NR will alleviate mitochondrial dysfunction and restore metabolic homeostasis in the intestinal epithelium in pediatric patients with UC. The purpose of the study are: To establish the feasibility of an Randomized Clinical Trial (RCT) investigating the effects of NR in pediatric patients with UC. To evaluate the effects of Nicotinamide adenine dinucleotide (NAD)+ repletion on intestinal epithelial mitochondrial structure and function in human UC patients. The investigators hypothesize that daily NR supplementation will restore NAD+ levels, enhancing Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) activity and mitochondrial structure/function.

Official Title
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Nicotinamide Riboside in Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Dietary Supplement: Nicotinamide Riboside Chloride
* Dietary Supplement: Placebo
* Other: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pediatric patients (≤18yo); Diagnosis of mild to moderate ulcerative colitis as determined by Pediatric Ulcerative Colitis Activity Index (PUCAI) and endoscopic scoring (Mayo) at the time of colonoscopy; Although the investigators will target newly diagnosed patients (therefore, treatment naïve), patients with established disease will also be enrolled. Exclusion Criteria: Patients with acute severe ulcerative colitis; Concurrent gastrointestinal infection (ie. Clostridium difficile, Cytomegalovirus, etc.); A diagnosis of Crohn's disease; Indeterminate colitis/IBD-U; In general, patients that have been treated with steroids or antibiotics in the past three months. Patients on Biologic medications may be enrolled if their dose has been stable for at least three months. Final determination of eligibility will be at the discretion of the treating investigator. After the initiation of the study, subjects may receive any medication to treat their disease as dictated by their care providers; Patients who have other chronic inflammatory/autoimmune disorders or prior malignancy; Pregnant women (All women of childbearing age will be required to use contraception at the time of inclusion). Patients with existing renal or hepatic dysfunction; Per standard of care guidance, subjects with platelets <50,000 do not undergo endoscopy and, therefore, are not eligible.

Ages Eligible for Study
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Maximum Age: 18 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daily oral therapy with Nicotinamide Riboside Chloride (Niagen) + Standard Therapy<br>Nicotinamide Riboside Chloride (Niagen) 75mg or 250mg capsules provided by ChromaDex, Inc. Dosing is recommended at 12.5mg/kg/day. The dosing plan is as follows (in mg po qD): 20-25 kg 250mg; 25-30 kg 325mg; 30-35 kg 400mg; 35-40 kg 475mg; 40-45 kg 500mg; 45-50 kg 575mg; 50-55 kg 650mg; 55-60 kg 725mg; 60-65 kg 750mg; 65-70 kg 825mg; >70 kg 900mg (max dosing). | Dietary Supplement: Nicotinamide Riboside Chloride<br>* The intervention consists of 6 months to 1 year of daily oral therapy with Nicotinamide Riboside Chloride (Niagen) in addition to standard therapy.<br>Other: Standard of Care<br>* Standard of Care<br>|
| Experimental: Daily oral therapy with placebo + Standard Therapy<br>Placebo 75mg or 250mg capsules provided by ChromaDex, Inc. Dosing is recommended at 12.5mg/kg/day. The dosing plan is as follows (in mg po qD): 20-25 kg 250mg; 25-30 kg 325mg; 30-35 kg 400mg; 35-40 kg 475mg; 40-45 kg 500mg; 45-50 kg 575mg; 50-55 kg 650mg; 55-60 kg 725mg; 60-65 kg 750mg; 65-70 kg 825mg; >70 kg 900mg (max dosing). | Dietary Supplement: Placebo<br>* The intervention consists of 6 months to 1 year of daily oral therapy with placebo (Maltodextran capsules of similar size, shape and color as Niagen) in addition to standard therapy.<br>Other: Standard of Care<br>* Standard of Care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients screened | The investigators will report the number of overall patients screened for enrollment. | 2 years | 
| Proportion of patients screened who meet inclusion/exclusion criteria | The investigators will report the number of patients screened who meet inclusion/exclusion criteria. | 2 years | 
| Enrollment percentage | The investigators will report the proportion of eligible patients who enroll in the study per month. | 2 years | 
| Completion percentage | The investigators will report the proportion of enrolled subjects who complete the study. | 2 years | 
| Reasons for exclusion | The investigators will report the reasons that patients are excluded from the study. | 2 years | 
| Dropout rate | The investigators will report the percentage of subjects who drop out per month. | 2 years | 
| Reasons for dropout | The investigators will log reasons for dropout. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in mitochondrial structure from baseline to 6-12 months | Subjects will undergo colonoscopic evaluation at enrollment and after 6-12 months of treatment (per standard treatment protocols). Investigators will perform a qualitative analysis of mitochondrial structure using scanning electron microscopy and/or immunofluorescence at both timepoints. | Baseline 6-12 months | 
| Changes in mitochondrial function from baseline to 6-12 months | Subjects will undergo colonoscopic evaluation at enrollment and after 6-12 months of treatment (per standard treatment protocols). Investigators will evaluate mitochondrial function (Complex 1 and 2) via the Oroboros 2K Analyzer [oxygen consumption [(pmol/(s × mL)/μg protein] at both timepoints. | Baseline 6-12 months | 
| Changes in the PGC1α-Sirt1 axis from baseline to 6-12 months | Subjects will undergo colonoscopic evaluation at enrollment and after 6-12 months of treatment (per standard treatment protocols). PGC1α and Sirt1 levels will be evaluated in tissue biopsies using western blot (qualitative analysis of protein levels) and qRT-PCR analysis (quantitative gene expression in fold change) at both timepoints. | Baseline 6-12 months | 
| Changes in cellular metabolism from baseline to 6-12 months | Subjects will undergo colonoscopic evaluation at enrollment and after 6-12 months of treatment (per standard treatment protocols). An untargeted metabolomic analysis of the intestinal epithelium will be performed at these time points (fold change) at both timepoints. | Baseline 6-12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAD