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New AMD clinical endpoints

Roibeard O’hEineachain

Posted: Tuesday, September 1, 2020

Dr Giuliana Silvestri (left), Clinical Director for Ophthalmic Services, Belfast Health and Social Care Trust and Dr Cathy Cukras, Clinical
Researcher, National Eye Institute, USA, pictured at the Fighting Blindness Retina 2019 international conference in Dublin, Ireland

Changes in the speed of dark adaptation (DA) appear to correlate with changes in disease status in patients with early and intermediate age-related macular degeneration (AMD), and could therefore be useful clinical endpoints in trials of treatments for the condition, according to the findings of a longitudinal study presented by Cathy Cukras MD, PhD, at Retina 19, a meeting sponsored by Fighting Blindness, a patient-led charity.

“In our longitudinal analysis we generally observed a decline in DA function over time, which correlated with patient-reported functional deficits, and is accelerated in eyes with greater AMD severity, especially in eyes with reticular pseudodrusen,” said Dr Cukras, Head, Unit on Clinical Investigation of Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.

The ongoing single-centre study involves more than 100 patients with early-to-intermediate AMD. The study’s investigators monitored the responses to DA over four years, using a measure called the rod-intercept time (RIT). Dr Cukras noted that they defined RIT as the time taken after a photobleach for visual sensitivity to recover detection of a 5×10 -3cd/m2 stimulus, a decrease of three log units.

The investigators assigned participants to AMD severity groups based on fundus characteristics drusen, pigmentary changes, and subretinal drusenoid deposits (SDDs). In addition, the mean rate of change was computed and correlations with ocular and patient features measures, such as visual acuity, and structural features obtained through multimodal imaging were evaluated, she noted.

The mean change in DA function over time was calculated using the slope of linear regression fits of longitudinal RIT data. Furthermore, patients provided responses to a Low Luminance Questionnaire (LLQ), which were given at baseline and yearly. Non-parametric statistical testing was performed on all comparisons, she explained.

DA correlates with objective and subjective AMD parameters.

Dr Cukras noted that the analysis revealed that higher rates of RIT prolongation correlated significantly with AMD severity group assignment at baseline (p=0.026) and at year four (p=0.0011). In addition, eyes that developed SDD during follow-up demonstrated higher rates of RIT prolongation relative to those that did not (p<0.0001). Overall, higher rates of RIT prolongation were significantly correlated with greater four-year decreases in LLQ scores (total mean score, p=0.0032).

Furthermore, an analysis of covariance demonstrated that the variables that correlated with DA measures included age, AMD group and the presence of reticular pseudodrusen. The study also showed that patient-reported functional deficits correlated with both reduced DA and reduced choroidal thickness.

VISUAL ACUITY NOT A SENSITIVE INDICATOR OF DISEASE PROGRESSION
Dr Cukras noted that visual acuity has long been used as the primary endpoint for clinical trials of AMD treatment. However, visual acuity is unchanged early in disease and late in disease the floor effect makes any changes difficult to measure.

“The lack of a broadly applicable treatment for geographic atrophy may be attributed to an incomplete understanding of the mechanisms resulting in photoreceptor dysfunction and death, and uncertainty about the outcomes measures needed to facilitate the discovery of potential treatments in interventional clinical trials,” Dr Cukras said.

Clinical endpoints reflecting disease progression over earlier stages of disease could potentially increase the feasibility of clinical trials and allow for the identification of eyes with more severe cell dysfunction within early and intermediate categories of AMD.

She added that examination of pathologic features in eyes with intermediate AMD demonstrate preferential loss of rod cells in the macula even in eyes with early disease, compared with age-matched controls.

“Dark adaptation is one measure of visual function that has been identified to reveal abnormalities in non-advanced stages of AMD. The RIT prolongation as a measure of changing DA function may be a useful functional outcome measure in AMD clinical studies,” Dr Cukras added.