Unravelling the Effects of Nicotinamide/Pyrroloquinolone Quinone /Citicoline/Homotaurine Fixed Combination on Contrast Sensitivity, Quality of Life, and Reading Performance in Glaucoma

Glaucoma is a chronic, progressive neuro-ophthalmic disease with a multifactorial basis, leading to irreversible retinal ganglion cell (RGC) loss. It is the second leading cause of blindness globally, and the primary cause of irreversible blindness, affecting 76 million people worldwide in 2020. This number is expected to rise to approximately 120 million by 2040, particularly in Africa and Asia. Elevated intraocular pressure (IOP) is one of the most important risk factors for the development and progression of glaucoma, and its reduction is the only scientifically proven approach to slowing visual function decline. However, despite lowering IOP, many glaucoma patients continue to experience progressive visual loss, even with IOP in the normal range. This is because glaucoma is a multifactorial disease, and reducing IOP alone does not address the other factors damaging the RGCs. Mitochondrial dysfunction appears to be one of the key and early mechanisms involved in RGC damage and death in glaucoma, prompting researchers to consider glaucoma, at least partially, as a specific form of mitochondrial disease. Consequently, there is a significant unmet need for direct neuroprotective therapies alongside IOP reduction. Several molecules with neuroprotective properties have been identified, including citicoline (CIT), homotaurine (HOMO), vitamin B3 (nicotinamide or nicotinamide riboside), and pyrroloquinoline quinone (PQQ). CIT, which provides choline and cytidine, plays a role in neuronal membrane repair and regeneration. Studies have shown CIT's positive effects on retinal and visual pathway functions. HOMO is a naturally occurring amino sulfonate compound with neuromodulatory and neuroprotective effects. It can prevent amyloid plaque formation in RGCs and modulate cortical activity, reducing neuronal excitatory responses to glutamate, which contributes to RGC death. Vitamin B3 compounds like nicotinamide (NAM) and nicotinamide riboside (NR) are precursors to nicotinamide adenine dinucleotide (NAD), a crucial cofactor in energy production and mitochondrial function. NAD deficiencies are associated with RGC degeneration in glaucoma, and supplementing NAD precursors has shown promise in preventing or delaying cell death. PQQ, a redox cofactor, stimulates new mitochondria formation, activates mitochondrial DNA repair, and serves as a potent antioxidant, protecting cells from oxidative damage. Recent evidence suggests that combining these mitochondrial-targeted compounds may offer synergistic neuroprotective effects, potentially benefiting RGCs.The study aims to evaluate the effects of an oral combination of NAM (54 mg), PQQ (5 mg), CIT (500 mg), and HOMO (50 mg) (NEUPROZIN MITO) compared to CIT alone (500 mg, OPTIGEN) on contrast sensitivity, quality of life, and reading speed in patients with primary open-angle glaucoma (POAG) and controlled IOP.This is a prospective, randomized, cross-over, monocentric study. Inclusion Criteria: Patients aged over 18, with a good understanding of the Italian language and the ability to read, diagnosed with early to moderate Primary Open-Angle Glaucoma (POAG) (Mean Deviation \[MD\] \> -12 dB). The patients must have intraocular pressure (IOP) controlled (the mean of 3 measurements \< 18 mmHg) and stable perimetry results over the past year. Exclusion Criteria: Patients who are illiterate, have severe glaucoma, have undergone ocular surgery within the past 6 months, have significant cataracts, other ocular diseases, neurodegenerative disorders, psychiatric disorders, or are pregnant or breastfeeding. Participants will be randomly assigned to receive either NEUPROZIN MITO or OPTIGEN for the first 4 months. After 4 months, participants will switch to the alternative treatment for the subsequent 4 months. Primary Outcomes: 1) Changes in contrast sensitivity: The ability to detect differences in contrast at 4 and 8 months. 2) Quality of life: Evaluated by the Glaucoma Quality of Life (GQL-15) questionnaire, comparing changes at 4 and 8 months. 3) Reading speed: Measured using the MNREAD test, comparing reading performance at 4 and 8 months. Secondary Outcomes: 1) Differences in response based on disease stage: The study will assess whether the stage of glaucoma affects the response to treatment. 2) Correlation between changes in the parameters: Examining if changes in contrast sensitivity, quality of life, and reading speed are related to one another over the study period. Sample Size Calculation: The study is designed as a cross-over trial, with half of the patients receiving NEUPROZIN MITO followed by OPTIGEN, and the other half receiving OPTIGEN followed by NEUPROZIN MITO. Based on the expected changes in the GQL-15 score and other parameters, the sample size calculation estimates that 44 patients are needed to ensure sufficient statistical power. This number accounts for a 10% dropout rate. Study Procedures: 1) Quality of Life Evaluation: The GQL-15 questionnaire is used to assess functional disability in daily activities. A normal score is between 0 and 75, with higher scores indicating a poorer quality of life. 2) Complete Ophthalmologic Evaluation: Participants will undergo best corrected visual acuity tests, Goldmann tonometry, gonioscopy, and a slit-lamp examination. 3) Functional Stage Determination: The stage of glaucoma will be assessed using automated perimetry (Mean Deviation \[MD\], Visual Field Index \[VFI\], Pattern Standard Deviation \[PSD\], and Glaucoma Hemifield Test \[GHT\]) and Optical Coherence Tomography (OCT) to measure optic nerve fiber thickness and the ganglion cell layer. 4) SPARCS Test: This is a contrast sensitivity test used to evaluate central and peripheral vision, with a contrast range from 100% to 0.45%. The test is performed on a computer screen, and the patient's ability to discern different contrast levels is evaluated. 5) Reading Speed: Reading speed will be assessed using the MNREAD test app, which measures the time taken to read sentences of decreasing font size. This test helps calculate the patient's reading speed and visual acuity based on text size and reading errors. Main Outcomes: The primary goal of the study is to assess if NEUPROZIN MITO and OPTIGEN induce changes in contrast sensitivity, quality of life, and reading speed in patients with pharmacologically controlled POAG. The results will be compared at 4 and 8 months to evaluate the effectiveness of each treatment. Secondary Outcomes: The study will also evaluate if the response to treatment varies depending on the stage of glaucoma and whether there is any significant correlation between the changes in the parameters measured (contrast sensitivity, quality of life, and reading speed). Conclusion: This study aims to provide crucial data on the potential neuroprotective benefits of mitochondrial-targeted therapies in glaucoma patients with controlled intraocular pressure (IOP). The effects of NEUPROZIN MITO and OPTIGEN on functional outcomes, such as contrast sensitivity, quality of life, and reading speed, will help to better understand how these therapies might impact the management of glaucoma.