Comparisons of NAD Precursors for Neuroenhancement in Glaucoma Patients

Official title

Comparisons of Nicotinamide Adenine Dinucleotide (NAD) Precursors for Neuroenhancement in Glaucoma Patients

Overview

The goal of this clinical trial is to determine whether oral supplementation with different nicotinamide adenine dinucleotide (NAD) precursors can improve visual function in adults with primary open-angle glaucoma. The main questions it aims to answer are: 1. Does daily oral administration of equimolar doses of nicotinamide riboside (NR), nicotinamide (NAM), nicotinamide mononucleotide (NMN), or nicotinic acid (NA) improve visual field sensitivity in glaucoma patients over the short term? 2. How do plasma NAD+ metabolite profiles change after administration of each precursor, and do these changes relate to improvements in visual function? Researchers will compare NR, NAM, NMN, NA, and placebo groups to see if any of the NAD precursors lead to greater improvements in visual field sensitivity or changes in blood NAD+ metabolite levels compared to placebo. Participants will: Be randomly assigned to receive one of the four NAD precursors or placebo daily for two weeks. Undergo comprehensive eye examinations, including visual field testing and optical coherence tomography, at baseline and after two weeks. Provide blood samples before and after the intervention for measurement of NAD+ metabolites. Have safety monitored through clinical examination. This study will help identify whether boosting NAD+ levels with specific precursors offers functional benefit in glaucoma, and which blood metabolites may mediate these effects.

Detailed description

This prospective randomized, double-blind, placebo-controlled clinical trial evaluates four nicotinamide adenine dinucleotide (NAD) precursors for neuroenhancement in 138 adults with primary open-angle glaucoma. Participants are randomly assigned to receive daily oral supplementation for one week with equimolar doses of nicotinamide riboside (300 mg), nicotinamide (125 mg), nicotinamide mononucleotide (350 mg), nicotinic acid (125 mg), or placebo. The study assesses short-term changes in visual field sensitivity using Humphrey Field Analyzer 24-2 testing and measures NAD+ metabolite profiles through liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis of plasma and peripheral blood mononuclear cells collected at baseline, pre-dose, and post-dose timepoints.

Secondary objectives include comparing pattern electroretinogram nerve fiber layer thickness measurements before and after treatment and analyzing correlations between systemic NAD+ metabolite elevations and functional visual improvements. Blood samples undergo standardized processing with Lymphoprep separation, snap-freezing, and derivatization protocols prior to mass spectrometry analysis using Agilent and Thermo Fisher systems with predefined NAD+ metabolite inclusion lists.

Statistical analysis employs linear mixed models to compare within-group and between-group changes, with intention-to-treat principles. The study design addresses gaps in comparative NAD precursor bioavailability data by testing equimolar doses in a targeted glaucoma population, while maintaining double-blinding through computer-generated randomization and masked outcome assessment.

Interventions

• Dietary supplement Nicotinamide Riboside
  Oral supplementation of 300mg Nicotinamide Riboside (NR) daily for 2 weeks
• Dietary supplement Nicotinamide
  Oral supplementation of 125mg Nicotinamide/Niacinamide (NAM) daily for 2 weeks
• Dietary supplement Nicotinamide Mononucleotide
  Oral supplementation of 350mg Nicotinamide Mononucleotide (NMN) daily for 2 weeks
• Dietary supplement Nicotinic Acid
  Oral supplementation of 350mg Nicotinic Acid (NA) daily for 2 weeks
• Other Placebo (Corn Starch)
  Oral supplementation of 300mg Placebo daily for 2 weeks
• Other Placebo (Corn Starch)
  Oral supplementation of 300mg Placebo daily for 2 weeks

Primary outcome measures

• Change in visual field sensitivity [Time frame: 2 weeks]

Secondary outcome measures (3)

• Blood NA and NAD+ metabolome [Time frame: 2 weeks]
• Change in pattern ERG measurements [Time frame: 2 weeks]
• Retinal nerve fiber layer thickness and defect imaging by optical coherence tomography [Time frame: 2 weeks]

Eligibility criteria

Inclusion criteria

• glaucoma patients
• age ≥ 18 years
• best corrected VA ≥20/40
• IOP <21 mmHg
• visual field mean deviation better than -24 dB on standard automated perimetry 24-2 SITA standard

Exclusion criteria

• pathological myopia
• diseases that may cause visual field loss or optic disc abnormalities other than glaucoma
• inability to perform reliable visual field
• suboptimal quality of OCT images
• diabetic retinopathy/maculopathy
• history of abnormal liver function within 12 months
• known allergy to NAD precursor supplement(s)
• pregnancy or lactation
• use of NAD precursor supplements 14 days prior to baseline.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Hong Kong · 1 center

• HKU Eye Centre — Wong Chuk Hang

Publications

• Allison K, Patel D, Alabi O. Epidemiology of Glaucoma: The Past, Present, and Predictions for the Future. Cureus. 2020 Nov 24;12(11):e11686. doi: 10.7759/cureus.11686. PMID 33391921
• Bengtsson B, Lindgren A, Heijl A, Lindgren G, Asman P, Patella M. Perimetric probability maps to separate change caused by glaucoma from that caused by cataract. Acta Ophthalmol Scand. 1997 Apr;75(2):184-8. doi: 10.1111/j.1600-0420.1997.tb00121.x. PMID 9197570
• Bledi Petriti, Alessandro Rabiolo, Pete Williams, Kai-Yin Chau, Gerassimos Lascaratos, David F Garway-Heath; Primary open angle glaucoma patients have lower systemic mitochondrial function, associated with lower systemic nicotinamide adenine dinucleotide (NAD) levels, compared to Controls. Invest. Ophthalmol. Vis. Sci. 2023;64(8):483.
• Bledi Petriti, Gerassimos Lascaratos, David Chau, Williams Peter, David F Garway-Heath; Preliminary data show Normal Tension Glaucoma patients have lower systemic nicotinamide adenine dinucleotide (NAD+) levels and mitochondrial function compared to Controls. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1765.
• Capuzzi DM, Guyton JR, Morgan JM, Goldberg AC, Kreisberg RA, Brusco OA, Brody J. Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. Am J Cardiol. 1998 Dec 17;82(12A):74U-81U; discussion 85U-86U. doi: 10.1016/s0002-9149(98)00731-0. PMID 9915666
• Christopher Kai-Shun Leung, Philip Guo, Marco Yu, Gilda Lai; Nicotinamide Riboside for Progressing Glaucoma: A Double-blind, Parallel Group, Randomized, Placebo-controlled Trial - A Report on Neuroenhancement. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4349.
• Cros C, Cannelle H, Laganier L, Grozio A, Canault M. Safety evaluation after acute and sub-chronic oral administration of high purity nicotinamide mononucleotide (NMN-C(R)) in Sprague-Dawley rats. Food Chem Toxicol. 2021 Apr;150:112060. doi: 10.1016/j.fct.2021.112060. Epub 2021 Feb 12. PMID 33587977
• De Moraes CG, John SWM, Williams PA, Blumberg DM, Cioffi GA, Liebmann JM. Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma: A Phase 2 Randomized Clinical Trial. JAMA Ophthalmol. 2022 Jan 1;140(1):11-18. doi: 10.1001/jamaophthalmol.2021.4576. PMID 34792559

Identifiers

NCT: NCT06991712 · H029

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗