Patient selection criteria for pilot studies on amelioration of non-neovascular age-related macular degeneration

Abstract

Purposes: Non-neovascular age-related macular degeneration (AMD) is characterized by accumulation of macular drusen, changes in pigmentation of the retinal pigment epithelium, and geographic atrophy. The purposes of this study were to (1) measure the rate of progression of non-neovascular AMD and (2) from the rate data, to propose patient selection criteria for testing drugs to prevent progression of non-neovascular AMD.

Methods: Medical charts were searched for all AMD billing codes, consecutively reviewed, and 51 patients with a median age of 76 years were mined for severity of AMD using a standardized worsening scale from 0 to 6, visual acuity (VA, Snellen), medications or procedures to treat eye diseases, date of eye examinations, age, and sex. Individual eyes, excluding those with cataract, were grouped and compared.

Results: Using all grades, VA (logMAR) was positively correlated with AMD scores (P < 0.0001, n = 66). The median length of time to progress from AMD grade 3 or 4 to the next grade was 1.0 (n = 14) and 1.7 years (n = 7), respectively. Statistical analyses predicted that drug-treated and nontreated groups, each containing 409 grade 3 and 4 AMD eyes, could detect 50% drug inhibition (P = 0.05) in a 2-year trial.

Conclusions: VA measurements and structural AMD grades would be useful markers in clinical trials on non-neovascular AMD. Recruiting only grade 3 and 4 patients may be ideal for time- and cost-efficient pilot drug efficacy studies on moderately progressing non-neovascular AMD.

FIG. 1.

Age-related macular degeneration (AMD) scale used in the present study with representative fundus photographs and observational definitions of grades 1–6. A zero (0) score was assigned to eyes with no observable AMD pathology (not shown).

FIG. 2.

Total changes in age-related macular degeneration (AMD) grades occurring during the entire data collection period of this study. One hundred eyes were grouped according to their AMD grade at their first examination (x-axis), with the resulting number of eyes categorized into each group shown on the y-axis. Overall changes in AMD grades after the final recorded eye examination are shown in the bars as pink (no change), blue (1 grade higher), or orange (≥2 grades higher). The % within each segment of the bar indicates the proportion of eyes within a group showing a specified change. For example (*), of 8 eyes with initial AMD grade of 3, 50% (4 eyes) progressed 1 grade to AMD 4 over the entire observation period.

FIG. 3.

(A) Progressive nature of age-related macular degeneration (AMD) grades. Eyes attaining a 1–5 grade at initial or intermediate exams were grouped (x-axis), with the resulting number of eyes shown on the y-axis. By the final exam, changes in AMD are indicated by colors within the bars, as pink (no change) or blue (Δ ≥ 1 AMD score) and as % of total eyes. For example (*), 88% of 16 total eyes progressed from grade 3 to grade 4 or higher. (B) Distribution of the time (years, y-axis) for individual eyes (blue diamonds) to progress 1 grade, with median times shown as blue bars. In eyes where the AMD score increased >1 grade, the data were extrapolated back to the length of time predicted for an increase of 1 grade only.

FIG. 4.

(A) Box and whisker plot for correlation between increasing age-related macular degeneration (AMD) score (x-axis) and decreasing visual acuity (VA) (y-axis). Each point represents an individual eye. The top and bottom lines of the boxes represent the 25th and 75th percentiles, middle lines in the boxes represent the medians, and the upper and lower ends of the whiskers are at the upper and lower quartiles ± 1.5 × interquartile range, showing outlier data points and indicating a lack of normal distribution of data with advancing AMD. Nonparametric Spearman's coefficient of rank correlation (ρ) between AMD and VA was 0.57 (P < 0.0001, n = 66 using all data points). (B) Degradation of VA (y-axis) occurring in groups of eyes scoring 1–5 (x-axis) after re-testing 1 year (green bars) and 2 years (orange bars) later. At 2 years, changes in logMAR for grades 3 and 4 were 0.17 ± 0.32 (14) (equivalent to loss of ∼8.5 letters on the ETDRS chart) and 0.16 ± 0.34 (11) units, respectively.