Nicotinamide Riboside in Ulcerative Colitis

Ulcerative Colitis Clinical Trial

Official title:

Nicotinamide Riboside in Ulcerative Colitis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05561738
• Other study ID #: STUDY22060104
• Status: Recruiting
• Phase: N/A
• Start date: February 28, 2024
• Est. completion date: December 31, 2025

Study information

• Verified date: March 2024
• Source: University of Pittsburgh
• Contact: Min Shi
• Phone: 412-692-6272
• Email: shim[@]upmc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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:

1. To establish the feasibility of an Randomized Clinical Trial (RCT) investigating the effects of NR in pediatric patients with UC.

2. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer
• Ulcerative Colitis

Intervention

Dietary Supplement:
• Nicotinamide Riboside Chloride
The intervention consists of 6 months to 1 year of daily oral therapy with Nicotinamide Riboside Chloride (Niagen) in addition to standard therapy.
• Placebo
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.

Other:
• Standard of Care
Standard of Care

Locations

Country	Name	City	State
United States	UPMC Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pittsburgh	Crohn's and Colitis Foundation

Country where clinical trial is conducted

United States, 

References & Publications (9)

Cunningham KE, Vincent G, Sodhi CP, Novak EA, Ranganathan S, Egan CE, Stolz DB, Rogers MB, Firek B, Morowitz MJ, Gittes GK, Zuckerbraun BS, Hackam DJ, Mollen KP. Peroxisome Proliferator-activated Receptor-gamma Coactivator 1-alpha (PGC1alpha) Protects against Experimental Murine Colitis. J Biol Chem. 2016 May 6;291(19):10184-200. doi: 10.1074/jbc.M115.688812. Epub 2016 Mar 11. — View Citation

Gerner RR, Klepsch V, Macheiner S, Arnhard K, Adolph TE, Grander C, Wieser V, Pfister A, Moser P, Hermann-Kleiter N, Baier G, Oberacher H, Tilg H, Moschen AR. NAD metabolism fuels human and mouse intestinal inflammation. Gut. 2018 Oct;67(10):1813-1823. doi: 10.1136/gutjnl-2017-314241. Epub 2017 Sep 6. — View Citation

Haberman Y, Karns R, Dexheimer PJ, Schirmer M, Somekh J, Jurickova I, Braun T, Novak E, Bauman L, Collins MH, Mo A, Rosen MJ, Bonkowski E, Gotman N, Marquis A, Nistel M, Rufo PA, Baker SS, Sauer CG, Markowitz J, Pfefferkorn MD, Rosh JR, Boyle BM, Mack DR, Baldassano RN, Shah S, Leleiko NS, Heyman MB, Grifiths AM, Patel AS, Noe JD, Aronow BJ, Kugathasan S, Walters TD, Gibson G, Thomas SD, Mollen K, Shen-Orr S, Huttenhower C, Xavier RJ, Hyams JS, Denson LA. Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response. Nat Commun. 2019 Jan 3;10(1):38. doi: 10.1038/s41467-018-07841-3. — View Citation

Jiang Y , Liu Y , Gao M , Xue M , Wang Z , Liang H . Nicotinamide riboside alleviates alcohol-induced depression-like behaviours in C57BL/6J mice by altering the intestinal microbiota associated with microglial activation and BDNF expression. Food Funct. 2020 Jan 29;11(1):378-391. doi: 10.1039/c9fo01780a. — View Citation

Larmonier CB, Shehab KW, Laubitz D, Jamwal DR, Ghishan FK, Kiela PR. Transcriptional Reprogramming and Resistance to Colonic Mucosal Injury in Poly(ADP-ribose) Polymerase 1 (PARP1)-deficient Mice. J Biol Chem. 2016 Apr 22;291(17):8918-30. doi: 10.1074/jbc.M116.714386. Epub 2016 Feb 24. — View Citation

Mehmel M, Jovanovic N, Spitz U. Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. Nutrients. 2020 May 31;12(6):1616. doi: 10.3390/nu12061616. — View Citation

Novak EA, Mollen KP. Mitochondrial dysfunction in inflammatory bowel disease. Front Cell Dev Biol. 2015 Oct 1;3:62. doi: 10.3389/fcell.2015.00062. eCollection 2015. — View Citation

Santos L, Escande C, Denicola A. Potential Modulation of Sirtuins by Oxidative Stress. Oxid Med Cell Longev. 2016;2016:9831825. doi: 10.1155/2016/9831825. Epub 2015 Dec 14. — View Citation

Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, Li Z, Abel ED, Migaud ME, Brenner C. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016 Oct 10;7:12948. doi: 10.1038/ncomms12948. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of patients screened	The investigators will report the number of overall patients screened for enrollment.	2 years
Primary	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
Primary	Enrollment percentage	The investigators will report the proportion of eligible patients who enroll in the study per month.	2 years
Primary	Completion percentage	The investigators will report the proportion of enrolled subjects who complete the study.	2 years
Primary	Reasons for exclusion	The investigators will report the reasons that patients are excluded from the study.	2 years
Primary	Dropout rate	The investigators will report the percentage of subjects who drop out per month.	2 years
Primary	Reasons for dropout	The investigators will log reasons for dropout.	2 years
Secondary	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
Secondary	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
Secondary	Changes in the PGC1a-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). PGC1a 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
Secondary	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