Nicotinamide Levels in Serum, Aqueous Humor, and Tear Film in Glaucoma and Correlations With Mitochondrial Damage-Associated Molecular Patterns (mtDAMPs) and Senescence-Associated Secretory Phenotype (SASP)

NCT07006194 | Not Yet Recruiting

• 1 other identifier: NAD-mtDAMPs-SASP
• Study Type: interventional
• Target: 360
• Locations: 1 country
• Sites: 3

Brief Summary

Background Glaucoma is a multifactorial, chronic, and progressive eye disease characterized by the irreversible loss of retinal ganglion cells (RGCs). It is the second leading cause of blindness globally, with approximately 76 million patients affected in 2020, a number expected to rise to 120 million in the coming decades, especially in Africa and Asia. Elevated intraocular pressure (IOP) is a significant risk factor for glaucoma, and its reduction remains the only scientifically proven approach to slowing visual function decline. However, many glaucoma patients continue to experience visual loss even with IOP values within the normal range, due to the disease's multifactorial nature. Besides IOP reduction, there is a need for direct neuroprotection to address other factors causing RGC damage. Mitochondrial dysfunction has emerged as a critical early factor in RGC damage, making glaucoma, at least in part, resemble a mitochondrial disease. Mitochondria play a key role in cellular functions such as energy production, redox metabolism, and maintaining mitochondrial function. In glaucomatous conditions, mitochondrial damage leads to the release of mitochondrial damage-associated molecular patterns (mtDAMPs), triggering chronic inflammation and tissue damage. This inflammation is exacerbated by the Senescence-Associated Secretory Phenotype (SASP), a process where senescent cells secrete bioactive molecules that contribute to cellular dysfunction and glaucoma progression. Among potential neuroprotective approaches, nicotinamide (NAM) and its precursor nicotinamide riboside (NR) are gaining attention. These compounds support mitochondrial function and NAD production, which is essential for cellular vitality. Research indicates that reductions in NAM levels correlate with glaucoma progression. For instance, studies have shown that NAD precursors may prevent or delay RGC degeneration, suggesting a promising adjunctive treatment for glaucoma patients. Study Objectives The study aims to measure NAM levels in ocular and non-ocular biological fluids (serum, aqueous humor, and tear fluid) of patients at different stages of glaucoma. The study will correlate NAM concentrations with disease severity and mitochondrial function markers. Furthermore, NAD levels in peripheral blood mononuclear cells (PBMCs) will be assessed to investigate potential biomarkers for glaucoma progression. A secondary objective is to evaluate the impact of dietary supplementation with nicotinamide and nicotinamide riboside (iNAD®) on NAD levels in pharmacologically controlled glaucoma patients. Methods This cross-sectional, case-control, multi-center study involves three universities: University of G. d'Annunzio Chieti-Pescara, University of Pisa, and University of Sassari. Biological fluid analyses will be conducted at the Animal Biology Laboratory affiliated with the University of G. d'Annunzio Chieti-Pescara. Patients will be categorized into four groups:

1. 1.Uncontrolled glaucoma patients scheduled for glaucoma surgery.
2. 2.Controlled glaucoma patients scheduled for cataract surgery.
3. 3.Healthy controls undergoing cataract surgery.
4. 4.Pharmacologically controlled glaucoma patients supplemented with iNAD®. Biological fluids (plasma, PBMCs, tear fluid, and aqueous humor) will be collected for analysis, including measures of NAD, mtDAMPs, and SASP components. These measures aim to provide insights into the molecular mechanisms underlying glaucoma and potential biomarkers for disease progression.

Conditions

Glaucoma

Keywords

glaucoma; Nicotinamide; mtDAMPs; SASP; aqueous humor; tear film; senescence

Outcome Measures

Primary Outcomes (5)

• Nicotinamide levels measurement in biologic fluids

  Measure nicotinamide levels in serum, aqueous humor, and tear fluid in open-angle glaucoma (POAG): i) in patients with decompensated glaucoma candidates for glaucoma surgery; ii) in patients with pharmacologically controlled glaucoma candidates for cataract surgery; iii) and in healthy controls candidates for cataract surgery.

  Day 1

• Nicotinamide levels clinical correlation

  Correlate NAM concentrations in the three fluids with disease stage, assessed through MD and VFI (Hodapp classification for staging) and RoP (if available).

  Day 1

• Nicotinamide levels - mtDAMPs correlation

  Correlate NAM levels with mitochondrial function indicators (mtDAMPs).

  Day 1

• Nicotinamide levels measurement in PBMCs

  Measure NAD content in PBMCs

  Day 1

• Nicotinamide levels measurement after dietary supplementation

  Measure NAD content in PBMCs from pharmacologically controlled POAG patients at baseline and after 4 weeks of dietary supplementation with a product containing nicotinamide riboside

  At enrollment and at the end of treatment at 4 weeks

Secondary Outcomes (4)

• Nicotinamide levels - IOP correlation

  Day 1

• Nicotinamide levels in different biological fluids correlation

  Day 1

• Nicotinamide levels in different OAG types

  Day 1

• Nicotinamide levels - SASP correlation

  Day 1

Study Arms (4)

OAG not pharmacologically controlled, receiving MTM and scheduled for filtering glaucoma surgery

NO INTERVENTION

Patients with open-angle glaucoma (OAG) not pharmacologically controlled, receiving maximal tolerated medical therapy and scheduled for filtering glaucoma surgery (stand-alone or combined). To this arm will be administered ophthalmological evaluation, functional stage determination, OCT imaging, sampling and analysis of biological fluids (Plasma and Peripheral Blood Mononuclear Cells (PBMCs) Isolation, Tear Film, Aqueous Humor; NAD Quantification in all biological fluids, mtDAMPS and SASP quantification in PBMCs)

Pharmacologically controlled OAG scheduled for cataract surgery

NO INTERVENTION

Patients with pharmacologically controlled OAG scheduled for cataract surgery. To this arm will be administered ophthalmological evaluation, functional stage determination, OCT imaging, sampling and analysis of biological fluids (Plasma and Peripheral Blood Mononuclear Cells (PBMCs) Isolation, Tear Film, Aqueous Humor; NAD Quantification in all biological fluids, mtDAMPS and SASP quantification in PBMCs)

Healthy individuals scheduled for cataract surgery

NO INTERVENTION

Healthy individuals scheduled for cataract surgery. To this arm will be administered ophthalmological evaluation, functional stage determination, OCT imaging, sampling and analysis of biological fluids (Plasma and Peripheral Blood Mononuclear Cells (PBMCs) Isolation, Tear Film, Aqueous Humor; NAD Quantification in all biological fluids, mtDAMPS and SASP quantification in PBMCs)

Pharmacologically controlled OAG patients scheduled for cataract surgery and treated with iNAD

EXPERIMENTAL

Pharmacologically controlled OAG patients scheduled for cataract surgery and treated with iNAD. To this arm will be administered iNAD during the month preceding surgery and ophthalmological evaluation, functional stage determination, OCT imaging, sampling and analysis of biological fluids (Plasma and Peripheral Blood Mononuclear Cells (PBMCs) Isolation, Tear Film, Aqueous Humor; NAD Quantification in all biological fluids, mtDAMPS and SASP quantification in PBMCs)

Dietary Supplement: Nicotinamide Tablet

Interventions

Nicotinamide Tablet DIETARY_SUPPLEMENT

One nicotinamide tablet per day during the month preceding surgery

Pharmacologically controlled OAG patients scheduled for cataract surgery and treated with iNAD

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \> 18 years
• Diagnosis of open-angle glaucoma (primary open-angle glaucoma)
• Uncontrolled IOP (\> 21 mmHg as the mean of three measurements between 8-10 am and 16),
• Maximal medical therapy
• Perimetric-OCT and ophthalmic optic neuropathy criteria
• Indication for standalone or combined glaucoma surgery (any surgery allowing aqueous humor sampling: MIGS, MIBS, TRABE, DS, canal surgery, drainage tube implants, revision of surgical implant)
• Age \> 18 years
• Diagnosis of open-angle glaucoma
• Controlled IOP (≤ 21 mmHg as the mean of three measurements between 8-10 am and 16) under medical therapy (excluding oral acetazolamide)
• Perimetric-OCT and ophthalmic optic neuropathy criteria.
• Age \>18 years
• IOP ≤ 21 mmHg
• Absence of perimetric-OCT and ophthalmic optic neuropathy criteria for glaucoma.

You may not qualify if:

• Conditions and systemic therapies influencing NAM levels in biological fluids
• Concomitant ocular pathologies beyond glaucoma or cataracts
• Ocular therapies beyond hypotensive eye drops
• Prior ocular surgeries
• Secondary glaucomas (uveitic, silicone oil, traumatic, neovascular)
• End-stage glaucoma or severe glaucoma (\<-20 dB)
• Pregnancy and breastfeeding.
• (only for Group 3) family history of glaucoma and transient IOP spikes

Sponsors & Collaborators

• Università degli Studi 'G. d'Annunzio' Chieti e Pescara: lead
• OFFHEALTH S.p.A.: collaborator
• Università degli Studi di Sassari: collaborator
• University of Pisa: collaborator

Study Sites (3)

Clinica Oftalmologica - Ospedale Clinicizzato SS Annunziata di Chieti

Chieti Scalo, Chieti, 66100, Italy

Location

U.O. Oculistica Universitaria

Pisa, Pisa, 56124, Italy

Location

Clinica Oculistica AOU Sassari

Sassari, Sassari, 07100, Italy

Location

MeSH Terms

Conditions

Glaucoma

Interventions

Niacinamide

Condition Hierarchy (Ancestors)

Ocular Hypertension; Eye Diseases

Intervention Hierarchy (Ancestors)

Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Central Study Contacts

Luca Agnifili, Principal Investigator

CONTACT

+390871357219; l.agnifili@unich.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Tricentric case-control cross-sectional study

Study Record Dates

• First Submitted: February 24, 2025
• First Posted: June 5, 2025
• Study Start: October 1, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: June 5, 2025

Record last verified: 2025-05

Locations

IT (3)