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Nicotinamide Riboside in Ulcerative Colitis

Primary Purpose

Ulcerative Colitis

Status
Not yet recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Nicotinamide Riboside Chloride
Placebo
Standard of Care
Sponsored by
University of Pittsburgh
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Ulcerative Colitis focused on measuring NAD

Eligibility Criteria

undefined - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • UPMC Children's Hospital of Pittsburgh

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Daily oral therapy with Nicotinamide Riboside Chloride (Niagen) + Standard Therapy

Daily oral therapy with placebo + Standard Therapy

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.
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.
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.
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.

Full Information

First Posted
September 13, 2022
Last Updated
October 3, 2023
Sponsor
University of Pittsburgh
Collaborators
Crohn's and Colitis Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT05561738
Brief Title
Nicotinamide Riboside in Ulcerative Colitis
Official Title
Nicotinamide Riboside in Ulcerative Colitis
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
November 1, 2023 (Anticipated)
Primary Completion Date
October 31, 2024 (Anticipated)
Study Completion Date
October 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Pittsburgh
Collaborators
Crohn's and Colitis Foundation

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ulcerative Colitis
Keywords
NAD

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Daily oral therapy with Nicotinamide Riboside Chloride (Niagen) + Standard Therapy
Arm Type
Experimental
Arm Description
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).
Arm Title
Daily oral therapy with placebo + Standard Therapy
Arm Type
Experimental
Arm Description
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).
Intervention Type
Dietary Supplement
Intervention Name(s)
Nicotinamide Riboside Chloride
Intervention Description
The intervention consists of 6 months to 1 year of daily oral therapy with Nicotinamide Riboside Chloride (Niagen) in addition to standard therapy.
Intervention Type
Dietary Supplement
Intervention Name(s)
Placebo
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Standard of Care
Intervention Description
Standard of Care
Primary Outcome Measure Information:
Title
Number of patients screened
Description
The investigators will report the number of overall patients screened for enrollment.
Time Frame
2 years
Title
Proportion of patients screened who meet inclusion/exclusion criteria
Description
The investigators will report the number of patients screened who meet inclusion/exclusion criteria.
Time Frame
2 years
Title
Enrollment percentage
Description
The investigators will report the proportion of eligible patients who enroll in the study per month.
Time Frame
2 years
Title
Completion percentage
Description
The investigators will report the proportion of enrolled subjects who complete the study.
Time Frame
2 years
Title
Reasons for exclusion
Description
The investigators will report the reasons that patients are excluded from the study.
Time Frame
2 years
Title
Dropout rate
Description
The investigators will report the percentage of subjects who drop out per month.
Time Frame
2 years
Title
Reasons for dropout
Description
The investigators will log reasons for dropout.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Changes in mitochondrial structure from baseline to 6-12 months
Description
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.
Time Frame
Baseline 6-12 months
Title
Changes in mitochondrial function from baseline to 6-12 months
Description
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.
Time Frame
Baseline 6-12 months
Title
Changes in the PGC1α-Sirt1 axis from baseline to 6-12 months
Description
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.
Time Frame
Baseline 6-12 months
Title
Changes in cellular metabolism from baseline to 6-12 months
Description
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.
Time Frame
Baseline 6-12 months

10. Eligibility

Sex
All
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Min Shi
Phone
412-692-6272
Email
shim@upmc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kevin Mollen
Organizational Affiliation
University of Pittsburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
UPMC Children's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Min Shi
Email
shim@upmc.edu
First Name & Middle Initial & Last Name & Degree
Kevin P Mollen, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
IPD Sharing Time Frame
6 months after publication of the results of the study. Date will be available for 1 year.
IPD Sharing 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.
Citations:
PubMed Identifier
26484345
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.
Results Reference
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Citation
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.
Results Reference
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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.
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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.
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Nicotinamide Riboside in Ulcerative Colitis

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