Onset of End-Stage Atrophic Age-Related Macular Degeneration as an End Point-A Delphi Study: Classification of Atrophy Meetings Report 7

Abstract

Purpose: To investigate whether consensus can be reached on the acceptability of end-stage atrophy onset as a clinical end point in early intervention trials of age-related macular degeneration (AMD), and the criteria for defining such an end point.

Design: A modified Delphi study.

Participants: International panel of experts in AMD, retinal imaging, and histopathology that are part of the Classification of Atrophy Meetings group.

Methods: A modified Delphi study was undertaken to determine if there is consensus on the acceptability of the onset of end-stage atrophic AMD as a clinical end point to evaluate early interventions and the criteria for defining such an end point. Two initial rounds of online surveys were conducted. Aggregate results and anonymized comments were provided after each round, followed by a face-to-face meeting before a final survey round was completed.

Main outcome measures: Statements where consensus was reached, defined as ≥80% of responses within the 3-point bracket for agreement or disagreement based on a 9-point Likert rating scale, from a total of 33 statements included in the final round of the survey.

Results: Consensus was reached for the statement that the onset of end-stage atrophic AMD was an appropriate clinical end point to evaluate early interventions (82% responses in agreement). Consensus was also reached for the statement that such an end point should be defined based on anatomical changes that have been previously shown in clinical studies to be associated with marked, but not necessarily complete, functional loss (95% responses in agreement). Consensus was nearly reached for the specific criterion that ≥90% of such atrophic AMD lesions should have ≥1 test location that was ≤10 decibels on 2 microperimetry tests (77% responses in agreement).

Conclusions: There was expert group consensus that the onset of end-stage atrophy is an appropriate clinical end point to evaluate early interventions in AMD, and that such an end point should show evidence of marked functional loss in prior clinical studies. We believe these findings will help to define incident clinical end points that are acceptable to regulatory authorities.

Financial disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Age-related macular degeneration; Delphi; Drusen; Geographic atrophy; Microperimetry.

Figure 1

Three examples illustrating the different specific functional criteria evaluated in this study, based on the results from repeated targeted, high-density microperimetry tests (top row), with visual sensitivity thresholds (in decibels [dB]) at each location shown. The first criterion (left) required ≥1 location that was <0 dB (or an absolute scotoma) to be present on both tests, the second criterion (middle) required ≥1 location to be <0 dB on 1 test and ≤10 dB (marked, but not complete, loss of visual sensitivity) on the other test, and the third criterion (right) required ≥1 location to be ≤10 dB on both tests. The location where targeted, high-density microperimetry testing was performed is shown on the near-infrared reflectance image (middle row; indicated by the dashed square). The OCT B-scan through the region tested is shown for interest (bottom row; its location is indicated by the dashed horizontal lines on the near-infrared reflectance image).