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Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle GlaucomaA Phase 2 Randomized Clinical Trial

Educational Objective
To test the hypothesis that a combination of nicotinamide and pyruvate can improve retinal ganglion cell function in human glaucoma as measured with standard automated perimetry.
1 Credit CME
Key Points

Question  Does a combination of oral nicotinamide and pyruvate help with short-term improvement in visual function in individuals with glaucoma?

Findings  In this phase 2, randomized clinical trial, a combination of nicotinamide and pyruvate was safe and the number of improving visual field test locations was higher in the treatment group vs the placebo group over a median of 2.2 months.

Meaning  Oral nicotinamide and pyruvate can result in short-term improvement in visual function in patients with treated, manifest glaucoma.


Importance  Open-angle glaucoma may continue to progress despite significant lowering of intraocular pressure (IOP). Preclinical research has suggested that enhancing mitochondrial function and energy production may enhance retinal ganglion cell survival in animal models of glaucoma, but there is scant information on its effectiveness in a clinical setting.

Objective  To test the hypothesis that a combination of nicotinamide and pyruvate can improve retinal ganglion cell function in human glaucoma as measured with standard automated perimetry.

Design, Setting, and Participants  In this phase 2, randomized, double-blind, placebo-controlled clinical trial at a single academic institution, 197 patients were assessed for eligibility. Of these, 42 patients with treated open-angle glaucoma and moderate visual field loss in at least 1 eye were selected for inclusion and randomized. A total of 32 completed the study and were included in the final analysis. The mean (SD) age was 64.6 (9.8) years. Twenty-one participants (66%) were female. Participant race and ethnicity data were collected via self-report to ensure the distribution reflected that observed in clinical practice in the US but are not reported here to protect patient privacy. Recruitment took place in April 2019 and patients were monitored through December 2020. Data were analyzed from January to May 2021.

Interventions  Ascending oral doses of nicotinamide (1000 to 3000 mg) and pyruvate (1500 to 3000 mg) vs placebo (2:1 randomization).

Main Outcomes and Measures  Number of visual field test locations improving beyond normal variability in the study eye. Secondary end points were the rates of change of visual field global indices (mean deviation [MD], pattern standard deviation [PSD], and visual field index [VFI]).

Results  Twenty-two of 29 participants (76%) randomized to the intervention group and 12 of 13 participants (92%) randomized to placebo received their allocation, and 32 participants (32 eyes; ratio 21:11) completed the study (21 from the intervention group and 11 from the placebo group). Median (IQR) follow-up time was 2.2 (2.0-2.4) months. No serious adverse events were reported during the study. The number of improving test locations was significantly higher in the treatment group than in the placebo group (median [IQR], 15 [6-25] vs 7 [6-11]; P = .005). Rates of change of PSD suggested improvement with treatment compared with placebo (median, −0.06 vs 0.02 dB per week; 95% CI, 0.02 to 0.24; P = .02) but not MD (0.04 vs −0.002 dB per week; 95% CI, −0.27 to 0.09; P = .35) or VFI (0.09 vs −0.02% per week; 95% CI, −0.53 to 0.36; P = .71).

Conclusions and Relevance  A combination of nicotinamide and pyruvate yielded significant short-term improvement in visual function, supporting prior experimental research suggesting a role for these agents in neuroprotection for individuals with glaucoma and confirming the need for long-term studies to establish their usefulness in slowing progression.

Trial Registration Identifier: NCT03797469

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Article Information

Accepted for Publication: September 13, 2021.

Published Online: November 18, 2021. doi:10.1001/jamaophthalmol.2021.4576

Corresponding Author: Carlos Gustavo De Moraes, MD, MPH, PhD, Columbia University Irving Medical Center, 635 W 165th St, Box 69, New York, NY 10032 (

Author Contributions: Drs De Moraes and Liebmann had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: De Moraes, John, Williams, Cioffi, Liebmann.

Acquisition, analysis, or interpretation of data: De Moraes, John, Blumberg, Cioffi, Liebmann.

Drafting of the manuscript: De Moraes, Cioffi, Liebmann.

Critical revision of the manuscript for important intellectual content: De Moraes, John, Williams, Blumberg, Cioffi, Liebmann.

Statistical analysis: De Moraes.

Obtained funding: Cioffi.

Administrative, technical, or material support: Blumberg, Cioffi, Liebmann.

Supervision: De Moraes, Williams, Cioffi, Liebmann.

Conflict of Interest Disclosures: Dr De Moraes reports support from Allergan, Belite, Carl Zeiss Meditec, Galimedix, Genentech, Novartis, Ora, Thea, and Reichert outside the submitted work and from Heidelberg Engineering, the National Institutes of Health, the US Centers for Disease Control and Prevention, and Topcon during the conduct of the study. Drs John and Williams are inventors on a patent application filed by the Jackson Laboratory that covers nicotinamide- and pyruvate-based therapies in glaucoma. Dr John was employed by Howard Hughes Medical Institute during the conduct of the study. Dr Liebmann reports support from Allergan, Carl Zeiss Meditec, Genentech, and Thea outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by the Shirlee and Bernard Brown Glaucoma Genetics Initiative at the Department of Ophthalmology, Columbia University Irving Medical Center and by Research to Prevent Blindness. Dr John was an investigator of Howard Hughes Medical Institute and supported by funds from the Precision Medicine Initiative at Columbia University. Dr Williams is supported by Karolinska Institutet in the form of a board of research faculty–funded career position and by philanthropic donations from the St Erik Eye Hospital (Vetenskapsrådet 2018-02124).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

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