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J. G. Edwards, G. R. Jackson; Dark Adaptation as a Clinical Trial Endpoint in AMD. Invest. Ophthalmol. Vis. Sci. 2009;50(13):728.
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© ARVO (1962-2015); The Authors (2016-present)
This paper reports on investigation of dark adaptation as a new clinical trial endpoint for age-related macular degeneration (AMD). The ultimate goal is to facilitate clinical trials for development of early-stage interventions by validating dark adaptation as a surrogate marker for future vision loss in AMD.
It has previously been shown that dark adaptation speed is a sensitive biomarker for AMD from its earliest stages, and that the amount of dark adaptation impairment closely correlates with disease severity. We have developed a dark adaptometer specifically tailored for use as a clinical trial endpoint measure. Like other dark adaptometers, our AdaptRx provides for photobleaching of the retina with subsequent measurement of sensitivity recovery. However, it also allows precise control of the primary variables affecting dark adaptation kinetics: intensity of the bleaching light and location of the stimulus for recovery measurements. Furthermore, we have developed a clinically useful parameter for characterizing dark adaptation speed called the rod intercept (the time after bleaching when the patient has recovered to a criterion sensitivity). The rod intercept provides a uniform method for characterizing dark adaptation speed regardless of disease severity.
The macula is not uniformly affected by AMD. Impairment decreases with eccentricity. Thus, dark adaptation is faster at the edge of the macula compared to the fovea. In pilot experiments with two early and two intermediate AMD patients, dark adaptation was measured at 5° (adjacent to the fovea) and 12° (just outside the macula). Their rod intercepts were on average 4.75 minutes faster at 12° vs. 5° (p<0.001). Similarly, dark adaptation speed is proportional to bleaching intensity. Reducing the bleaching intensity shortens the recovery time. In pilot experiments, intermediate AMD patients who exhibited essentially no dark adaptation in 20 minutes when bleached with a relatively strong flash (≥ 82% effective bleach) had a rod intercept ≤ 20 minutes when bleached with a weaker flash (≤ 56% equivalent bleach). This paper will provide the results of an ongoing systematic investigation of bleaching intensity and stimulus location to identify an optimum protocol.
Our preliminary findings suggest a high probability of success for achieving the desired clinical trial endpoint characteristics. The next steps are confirmation that our protocol reproducibly discriminates dark adaptation speed across the full range of early and intermediate AMD patients, followed by a multi-year prospective study of AMD patients to validate that dark adaptation impairment predicts imminent visual acuity loss.
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