Retinal Ganglion Cell Neuroprotection Under Prostaglandin Analogues

Official title

Retinal Ganglion Cell Neuroprotection Under Prostaglandin Analogues: NEUROPA - a Retrospective Cohort Study

Overview

The goal of this observational study is to evaluate whether prostaglandin analogue eye drops have a direct neuroprotective effect on retinal ganglion cells - beyond their intraocular pressure (IOP)-lowering effect - in adult patients with glaucoma or ocular hypertension. The study includes individuals diagnosed with glaucoma (any sex/gender, adult age groups) undergoing standard clinical treatment. The main questions it aims to answer are: * Do prostaglandin analogues provide a neuroprotective effect on retinal ganglion cells that is independent of their IOP-lowering properties? * Should prostaglandin analogues be promoted/favoured over other IOP-lowering compounds for long-term glaucoma management? Researchers will compare an interventional group, which consist of 750 eyes treated with prostaglandin analogues (e.g., latanoprost, travoprost, tafluprost, bimatoprost, unoprostone), with a control group, which consist of 750 eyes treated with non-prostaglandin IOP-lowering compounds (e.g., timolol, dorzolamide, brimonidine, netarsudil) to see if treatment with prostaglandin analogues is associated with better retinal ganglion cell survival over a period of 3 years (36 months). Data will be collected from individuals who had at least 36 months of documented follow-up, with clinical data available at approximately 3, 6, 12, 24, and 36 months. Eligible individuals must have been treated with either prostaglandin analogues or other intraocular pressure (IOP)-lowering agents as part of routine clinical care. The data to be obtained from medical records will include at least: * Intraocular pressure readings * Visual field testing * OCT measures * Visual acuity * Adverse events * Treatment adherence/compliance * Additional glaucoma interventions

Detailed description

Glaucoma is among the most prevalent causes of irreversible blindness and is characterized by a progressive, irreversible degeneration of the retinal ganglion cells. Elevated intraocular pressure (IOP) is the most important glaucoma risk factor and the only risk factor that is readily modifiable with established treatment options, which include pharmacological approaches, laser treatment, and surgery. However, in many patients the disease progresses even after IOP is effectively lowered. Hence, neuroprotective treatment approaches that go beyond IOP lowering are needed.

Prostaglandin analogue eye drops reduce IOP by increasing uveoscleral outflow and are a well-established treatment option in ocular hypertension and glaucoma. Animal studies suggest that prostaglandin analogues may have a direct neuroprotective effect on retinal ganglion cells in addition to the effect mediated by IOP lowering. Proposed mechanisms of action include inhibiting of caspase-3 and cyclooxygenase as well as activation of polypeptide 2B1 and Klotho protein. However, this proposed additional, direct neuroprotective effect has not yet been tested in human patients. The viability and functional status of the retinal ganglion cells in glaucoma can be assessed by morphological readings, the standard nowadays being various optical coherence tomography modalities, and by visual field testing. Detection of Apoptosing Retinal Cells (DARC) is another, relatively novel technology that allows for quantification of retinal ganglion cell death, presumably on a much shorter time scale.

This is an observational, retrospective and longitudinal clinical study, according to the normal clinical practice.

This study aims to evaluate prostaglandin analogues neuroprotective effect on retinal ganglion cells apart from intraocular pressure (IOP)-lowering over a period of 3 years (36 months) and whether treatment of ocular hypertension and glaucoma participants with prostaglandin analogues should be promoted/ favoured over other IOP-lowering compounds. It will have a follow-up at 3, 6, 12, 24, and 36 months in eyes with glaucoma treated with prostaglandin analogues or a different topically applied compound.

Primary outcome measures

• Intraocular pressure (IOP), measured using a Goldmann applanation tonometer, an iCare tonometer, or similar. Change in IOP value (mmHg). [Time frame: 6 months]
• Visual field (VF) - Mean Deviation, measured by automated perimetry testing devices, such as Haag-Streit Octopus, Zeiss Humphrey, or similar [Time frame: 6 months]
• Visual Field - Pattern Standard Deviation, measured by automated perimetry testing devices, such as Haag-Streit Octopus, Zeiss Humphrey, or similar. [Time frame: 6 months]
• Visual Field - Glaucoma Progression Analysis (GPA), measured by automated perimetry testing devices, such as Haag-Streit Octopus, Zeiss Humphrey, or similar. [Time frame: 6 months]
• Optical Coherence Tomography - Change in Average GCL+IPL Thickness, measured by Heidelberg Spectralis, Zeiss Cirrus, or similar. [Time frame: 6 months]
• Optical Coherence Tomography - Average RNFL Thickness, measured by Heidelberg Spectralis, Zeiss Cirrus, or similar. [Time frame: 6 months]
• Optical Coherence Tomography - Disc Rim Area, measured by Heidelberg Spectralis, Zeiss Cirrus, or similar. [Time frame: 6 months]
• Optical Coherence Tomography - Cup-to-disc Ratio, measured by Heidelberg Spectralis, Zeiss Cirrus, or similar. [Time frame: 6 months]
• Optical Coherence Tomography - Central Subfield Thickness, measured by Heidelberg Spectralis, Zeiss Cirrus, or similar. [Time frame: 6 months]

Secondary outcome measures (4)

• 10 Visual Acuity, measured by Best Corrected Visual Acuity (BCVA) score, using Snellen and/or LogMar charts. [Time frame: 6 months]
• Adverse Events, as reported in patient's medical history. [Time frame: 6 months]
• Adherence to Study Treatment [Time frame: 6 months]
• Additional Glaucoma Interventions [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• Age 18+ years
• Established glaucoma diagnosis (primary open-angle glaucoma, normal tension Glaucoma, pseudoexfoliation glaucoma, pigmentary dispersion glaucoma) in either eye
• Visual field mean deviation (MD; location-weighted mean difference from average age-corrected visual field sensitivity) of 2 visual fields differing by no more than 3 dB, for a mean deviation of better than -6.0 dB, or by no more than 4 dB, for a mean deviation worse than -6.0 dB, as measured using Humphrey perimetry (or equivalent Haag-Streit / Octopus; in at least one eye; analogous to The United Kingdom Glaucoma Treatment Study)
• Treatment with either prostaglandin analogues only or another topically applied IOP-lowering compound only for at least 3 years
• Documented follow-up period of at least 3 years
• At least 6 patient visits documented over the follow-up period with readings of IOP, visual field, OCT
• No additional glaucoma intervention apart from laser trabeculoplasty and/or cataract surgery during the observational period

Exclusion criteria

• Follow-up period < 3 years
• Number of patient visits <6 visits
• Number of OCT, visual field readings during the observation period < 6
• Low compliance/therapy interruption
• Beginning of combination therapy of prostaglandin analogues and other IOP lowering eye drops during the observation period
• In case of glaucoma diagnosis in both eyes: different topical IOP-lowering treatment regimes (e.g. prostaglandin analogues in one eye and beta-adrenergic blocking agents in the fellow eye)
• Additional glaucoma intervention during the observational period other than laser trabeculoplasty and/or cataract surgery

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United Kingdom · 3 centers

• Clinical Eye Research Centre - St. Paul's Eye Unit, Royal Liverpool University Hospital — Liverpool
• ICORG - Imperial College Ophthalmologic Research Group — London
• NIHR Moorfields Clinical Research Facility, Moorfields Eye Hospital, NHS Foundation Trust — London

Germany · 2 centers

• Department of Ophthalmology University of Bonn — Bonn
• University Eye Hospital Leipzig — Leipzig

Italy · 2 centers

• Centre for Clinical Trials at San Paolo Hospital University of Milan — Milan
• Eye Unit, University Hospital Maggiore della Carità — Novara

Spain · 2 centers

• Centro de Oftalmologia Barraquer — Barcelona
• Retina Unit, Department of Ophthalmology, Bellvitge University Hospital — Barcelona

Switzerland · 1 center

• University Hospital Basel — Basel

Publications

• Jonas JB, Aung T, Bourne RR, Bron AM, Ritch R, Panda-Jonas S. Glaucoma. Lancet. 2017 Nov 11;390(10108):2183-2193. doi: 10.1016/S0140-6736(17)31469-1. Epub 2017 May 31. PMID 28577860
• Leske MC, Heijl A, Hyman L, Bengtsson B, Dong L, Yang Z; EMGT Group. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology. 2007 Nov;114(11):1965-72. doi: 10.1016/j.ophtha.2007.03.016. Epub 2007 Jul 12. PMID 17628686
• Peters D, Bengtsson B, Heijl A. Lifetime risk of blindness in open-angle glaucoma. Am J Ophthalmol. 2013 Oct;156(4):724-30. doi: 10.1016/j.ajo.2013.05.027. Epub 2013 Aug 7. PMID 23932216
• Chang EE, Goldberg JL. Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology. 2012 May;119(5):979-86. doi: 10.1016/j.ophtha.2011.11.003. Epub 2012 Feb 18. PMID 22349567
• Lee HP, Tsung TH, Tsai YC, Chen YH, Lu DW. Glaucoma: Current and New Therapeutic Approaches. Biomedicines. 2024 Sep 3;12(9):2000. doi: 10.3390/biomedicines12092000. PMID 39335514
• Yamamoto K, Sato K, Yukita M, Yasuda M, Omodaka K, Ryu M, Fujita K, Nishiguchi KM, Machida S, Nakazawa T. The neuroprotective effect of latanoprost acts via klotho-mediated suppression of calpain activation after optic nerve transection. J Neurochem. 2017 Feb;140(3):495-508. doi: 10.1111/jnc.13902. Epub 2016 Dec 27. PMID 27859240
• Yamagishi R, Aihara M, Araie M. Neuroprotective effects of prostaglandin analogues on retinal ganglion cell death independent of intraocular pressure reduction. Exp Eye Res. 2011 Sep;93(3):265-70. doi: 10.1016/j.exer.2011.06.022. Epub 2011 Jul 26. PMID 21791206
• Kanamori A, Naka M, Fukuda M, Nakamura M, Negi A. Latanoprost protects rat retinal ganglion cells from apoptosis in vitro and in vivo. Exp Eye Res. 2009 Mar;88(3):535-41. doi: 10.1016/j.exer.2008.11.012. Epub 2008 Dec 3. PMID 19084521

Identifiers

NCT: NCT07074782 · ECR-GLC-2025-18

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗