Nicotinamide Riboside in Ulcerative Colitis

• ClinicalTrials.gov Identifier: NCT05561738
• Recruitment Status: Recruiting
• First Posted: September 30, 2022
• Last Update Posted: March 5, 2024
• Sponsor: University of Pittsburgh
• Collaborator: Crohn's and Colitis Foundation
• Information provided by (Responsible Party): Kevin Mollen, University of Pittsburgh

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Ulcerative Colitis	Dietary Supplement: Nicotinamide Riboside Chloride; Dietary Supplement: Placebo; Other: Standard of Care	Not Applicable

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Nicotinamide Riboside in Ulcerative Colitis
• Actual Study Start Date: February 28, 2024
• Estimated Primary Completion Date: December 31, 2024
• Estimated Study Completion Date: December 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Daily oral therapy with Nicotinamide Riboside Chloride (Niagen) + Standard Therapy; 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; The intervention consists of 6 months to 1 year of daily oral therapy with Nicotinamide Riboside Chloride (Niagen) in addition to standard therapy.; Other: Standard of Care; Standard of Care
Experimental: Daily oral therapy with placebo + Standard Therapy; 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; 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

Outcome Measures

Primary Outcome Measures :

1. Number of patients screened [ Time Frame: 2 years ]
   The investigators will report the number of overall patients screened for enrollment.
2. Proportion of patients screened who meet inclusion/exclusion criteria [ Time Frame: 2 years ]
   The investigators will report the number of patients screened who meet inclusion/exclusion criteria.
3. Enrollment percentage [ Time Frame: 2 years ]
   The investigators will report the proportion of eligible patients who enroll in the study per month.
4. Completion percentage [ Time Frame: 2 years ]
   The investigators will report the proportion of enrolled subjects who complete the study.
5. Reasons for exclusion [ Time Frame: 2 years ]
   The investigators will report the reasons that patients are excluded from the study.
6. Dropout rate [ Time Frame: 2 years ]
   The investigators will report the percentage of subjects who drop out per month.
7. Reasons for dropout [ Time Frame: 2 years ]
   The investigators will log reasons for dropout.

Secondary Outcome Measures :

1. Changes in mitochondrial structure from baseline to 6-12 months [ Time Frame: Baseline 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.
2. Changes in mitochondrial function from baseline to 6-12 months [ Time Frame: Baseline 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.
3. Changes in the PGC1α-Sirt1 axis from baseline to 6-12 months [ Time Frame: Baseline 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.
4. Changes in cellular metabolism from baseline to 6-12 months [ Time Frame: Baseline 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.

Eligibility Criteria

• Ages Eligible for Study: up to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Min Shi; 412-692-6272; shim@upmc.edu

Locations

United States, Pennsylvania

UPMC Children's Hospital of Pittsburgh; Recruiting

Pittsburgh, Pennsylvania, United States, 15224

Contact: Min Shi shim@upmc.edu

Principal Investigator: Kevin P Mollen, MD

Sponsors and Collaborators

University of Pittsburgh

Crohn's and Colitis Foundation

Investigators

• Principal Investigator: Kevin Mollen; University of Pittsburgh

More Information

Publications:

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.

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.

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.

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.

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.

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.

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.

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.

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.

• Responsible Party: Kevin Mollen, Associate Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT05561738
• Other Study ID Numbers: STUDY22060104
• First Posted: September 30, 2022
• Last Update Posted: March 5, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified data and samples may be shared with the funding agent, other researchers or federal repositories in the future under and approved agreement.
• Supporting Materials: Study Protocol; Clinical Study Report (CSR)
• Time Frame: 6 months after publication of the results of the study. Date will be available for 1 year.

Access Criteria

Prior to any sharing of any data, the research data/documents will be coded and all subject identifiers will be completely removed. Only the PI and co-investigators will have access to the coding. All others will have access to the completely deidentified data only.

A data use agreement will be obtained and finalized prior to any of the data leaving the institution, and prior to any access by outside entities.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Kevin Mollen, University of Pittsburgh:

NAD

Additional relevant MeSH terms:

Colitis; Colitis, Ulcerative; Ulcer; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Intestinal Diseases; Pathologic Processes; Inflammatory Bowel Diseases; Niacinamide; Niacin; Nicotinic Acids; Vitamin B Complex; Vitamins; Micronutrients; Physiological Effects of Drugs; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Vasodilator Agents