Nicotinamide for Retinal Protection in Primary Open-Angle Glaucoma (NADIR Trial)

Glaucoma causes progressive and irreversible loss of retinal ganglion cells (RGCs), often continuing despite adequate intraocular pressure control. Mitochondrial dysfunction and depletion of NAD+ (nicotinamide adenine dinucleotide) are increasingly recognized as central contributors to RGC vulnerability. Nicotinamide (NAM), a commercially available form of vitamin B3 and potent NAD+ precursor, has demonstrated robust neuroprotection in preclinical glaucoma models and early clinical trials outside the United States.

NADIR is the first IND-regulated, prospective, randomized Phase 2a trial in the United States to evaluate high-dose oral nicotinamide as adjunctive neuroprotective therapy in adults with mild to moderate POAG, using macular ganglion cell layer imaging (SD-OCT) as the primary structural biomarker detectable within 12 months. Ocular vascular perfusion imaging (OCT-A) is included as an exploratory endpoint.

Inclusion criteria

• Age 40 to 80 years, inclusive
• Diagnosis of primary open-angle glaucoma (POAG) in at least one eye, confirmed by a licensed ophthalmologist or optometrist based on characteristic optic nerve head changes and/or visual field defects with an open anterior chamber angle
• Mild to moderate glaucoma severity in the study eye: Humphrey Visual Field 24-2 mean deviation (MD) between -2.0 and -12.0 dB on at least one reliable test (fixation losses 33% or less, false positive rate 15% or less)
• Best-corrected visual acuity (BCVA) of 20/40 or better (Snellen equivalent) in the study eye
• Confirmed glaucomatous structural damage on SD-OCT (average GCIPL and/or RNFL below age-adjusted normative mean on device-generated classification) and/or a reproducible visual field defect on Humphrey Visual Field 24-2 consistent with glaucoma, as confirmed by the enrolling glaucoma specialist at screening
• Macular GCIPL and peripapillary RNFL above device-specific SD-OCT floor effect in the study eye
• Currently receiving stable intraocular pressure-lowering therapy (topical medications and/or prior selective laser trabeculoplasty) for at least 4 months prior to enrollment, with no planned changes to glaucoma therapy at the time of enrollment
• Intraocular pressure of 21 mmHg or less on current therapy at the screening visit in the study eye
• Established patient receiving ongoing glaucoma care at University of Chicago Medicine Duchossois Center for Advanced Medicine Eye Clinic
• Willing and able to provide written informed consent and comply with all study visit schedules and procedures

Exclusion criteria

• Advanced glaucoma: visual field MD worse than -12.0 dB or BCVA worse than 20/40 in the study eye
• Significant retinal disease affecting macular structure or visual field, including advanced age-related macular degeneration, diabetic retinopathy greater than mild non-proliferative, clinically significant diabetic macular edema, major retinal vein occlusion, or non-glaucomatous optic neuropathy
• Ocular surgery other than uncomplicated cataract extraction or selective laser trabeculoplasty within the past 6 months
• Hepatic dysfunction at baseline: AST or ALT greater than 2 times the upper limit of normal, or total bilirubin greater than 1.5 times the upper limit of normal
• Renal dysfunction: eGFR less than 30 mL/min/1.73 m2
• Current use of, or unwillingness to abstain from: NAD+/nicotinamide supplements, high-dose niacin or vitamin B3, Ginkgo biloba, CoQ10, isoniazid, pyrazinamide, carbamazepine, phenobarbital, primidone, or sustained-release niacin or nicotinamide formulations
• Poorly controlled diabetes mellitus: HbA1c greater than 9.0% at screening
• Normal tension glaucoma with documented intraocular pressure consistently 21 mmHg or less without hypotensive therapy
• Participation in another investigational drug trial within 30 days of screening
• Pregnancy, lactation, or intent to become pregnant during the study period
• Significant cognitive impairment or inability to comply with study requirements
• Clinically significant media opacity (corneal, lenticular, or vitreal) sufficient to degrade OCT signal quality below device-minimum thresholds, even if BCVA of 20/40 or better is preserved
• Active or recent uveitis or intraocular inflammation in the study eye within the past 3 months
• Any condition that, in the investigator's judgment, would preclude safe participation or confound result interpretation