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.

• Citicoline 500 MG (Optigen) for 4 months (Dietary supplement): one citicoline tablet per day for 4 months
• citicoline 500 mg + nicotinamide 54 mg + PQQ 5 mg + Homotaurine 50 mg fixed combination tablet (Neuprozin mito) (Dietary supplement): one fixed combination tablet per 4 months

Primary outcomes

• Unravelling the effects of Nicotinamide/Pyrroloquinolone Quinone /Citicoline/Homotaurine fixed combination on reading performance in glaucoma [From enrollment to the end of treatment at 8 months]: Evaluate whether the intake of NEUPROZIN MITO and OPTIGEN induces changes in reading speed in patients with pharmacologically controlled POAG, and whether there are differences between the two groups at 4 and 8 months. Reading speed is assessed using the MNREAD App. The MNREAD chart uses standardized sentences consisting of 10 words (60 characters) to determine reading speed across print sizes that decrease logarithmically in 0.1 log-unit steps.
• Unravelling the effects of Nicotinamide/Pyrroloquinolone Quinone /Citicoline/Homotaurine fixed combination on contrast sensitivity, [From enrollment to the end of treatment at 8 months]: Evaluate whether the intake of NEUPROZIN MITO and OPTIGEN induces changes in contrast sensitivity in patients with pharmacologically controlled POAG, and whether there are differences between the two groups at 4 and 8 months. SPARCS test is a contrast sensitivity test. The range of contrast tested is from 100% to 0.45% (log contrast sensitivity from 0.00 to 2.35), with an approximately 0.15-log-unit decrease between contrast levels.
• 1. Unravelling the effects of Nicotinamide/Pyrroloquinolone Quinone /Citicoline/Homotaurine fixed combination on quality of life. [From enrollment to the end of treatment at 8 weeks]: Evaluate whether the intake of NEUPROZIN MITO and OPTIGEN induces changes in quality of life in patients with pharmacologically controlled POAG, and whether there are differences between the two groups at 4 and 8 months. Assessment of quality of life using the "Glaucoma Quality of Life 15" (GQL-15). This test consists of 15 questions, each assigned a score. The normal score ranges from 0 to 75 points, while higher scores indicate a poorer quality of life.

Secondary outcomes

• effects of neuroprotection correlated to glaucoma stage [From enrollment to the end of treatment at eight months]: Evaluate potential differences in response in patients with glaucoma at different stages of disease progression. Determination of the functional stage of the disease based on the mean deviation (MD) obtained through standard automated perimetry (HFA; Carl Zeiss Meditec, Dublin, CA, USA) using the 24-2 SITA-Fast strategy. The visual field defect is classified according to the Hodapp-Parrish-Anderson criteria as mild when MD > -6 dB, moderate when MD ranges from -6 dB to -12 dB, advanced when MD < -12 dB, and severe when MD < -20 dB.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age over 18 years
* Good knowledge of the Italian language and good reading skills
* Manifest primary open-angle glaucoma (POAG) in the early to moderate stage (MD > -12 dB). The stage of glaucoma is determined by measuring the mean defect (MD, dB) using standard automated perimetry (HFA II/III; Carl Zeiss Meditec, Dublin, CA, USA, program 24/2).
* Patients able to provide written informed consent
* Pharmacologically controlled IOP: average values of 3 measurements (9 AM) <18 mmHg
* Stable perimetry in the year prior to enrollment

Exclusion Criteria:

* Illiteracy
* Severe-stage glaucoma (MD < -12 dB)
* Previous surgical treatment for glaucoma or other ocular surgeries (except for cataract surgery performed more than 6 months earlier)
* Concomitant ocular diseases, previous ocular trauma, or high myopia
* Neurodegenerative diseases of the central nervous system, dysarthria, dyslexia, psychiatric disorders
* Pregnancy/breastfeeding