Visual Function Metrics in Early and Intermediate Dry Age-related Macular Degeneration for Use as Clinical Trial Endpoints

doi:10.1016/j.ajo.2018.02.012

American Journal of Ophthalmology

Volume 189, May 2018, Pages 127-138

https://doi.org/10.1016/j.ajo.2018.02.012 Get rights and content

Purpose

To evaluate and quantify visual function metrics to be used as endpoints of age-related macular degeneration (AMD) stages and visual acuity (VA) loss in patients with early and intermediate AMD.

Design

Cross-sectional analysis of baseline data from a prospective study.

Methods

One hundred and one patients were enrolled at Duke Eye Center: 80 patients with early AMD (Age-Related Eye Disease Study [AREDS] stage 2 [n = 33] and intermediate stage 3 [n = 47]) and 21 age-matched, normal controls. A dilated retinal examination, macular pigment optical density measurements, and several functional assessments (best-corrected visual acuity, macular integrity assessment mesopic microperimety, dark adaptometry, low-luminance visual acuity [LLVA] [standard using a log 2.0 neutral density filter and computerized method], and cone contrast test [CCT]) were performed. Low-luminance deficit (LLD) was defined as the difference in numbers of letters read at standard vs low luminance. Group comparisons were performed to evaluate differences between the control and the early and intermediate AMD groups using 2-sided significance tests.

Results

Functional measures that significantly distinguished between normal and intermediate AMD were standard and computerized (0.5 cd/m²) LLVA, percent reduced threshold and average threshold on microperimetry, CCTs, and rod intercept on dark adaptation (P < .05). The intermediate group demonstrated deficits in microperimetry reduced threshhold, computerized LLD2, and dark adaptation (P < .05) relative to early AMD.

Conclusions

Our study suggests that LLVA, microperimetry, CCT, and dark adaptation may serve as functional measures differentiating early-to-intermediate stages of dry AMD.

Section snippets

Study Participants

The single-center, prospective, exploratory observational study was registered on the National Institute of Health–maintained public database ClinicalTrials.gov (registration number NCT01822873, location Duke Eye Center, Durham, North Carolina, USA). This study was approved by the Duke University Health System Institutional Review Board and was conducted in accordance with Good Clinical Practice using the guidance documents and practices offered by the International Conference on Harmonization

Results

A total of 101 participants were enrolled in the study (80 AMD subjects and 21 healthy controls) and underwent all study assessments. Participant characteristics are listed in Table 1. Of the subjects with AMD, 33 had diagnosed AREDS 2 (early AMD) and 47 had diagnosed AREDS 3 (intermediate AMD). Four of 21 study eyes in the control group had fewer than 5 drusen < 65 μm. There was no overall significant intergroup variation in age, sex, race, ethnicity, or smoking history (P > .63 for all).

Discussion

The paucity of treatment options for patients with dry AMD is a significant clinical problem. This clinical unmet need promises only to worsen over time, as a significant portion of the global population enters the sixth and seventh decades of life.²¹ Substantial barriers limiting the ability to effectively develop new treatments are a lack of markers of disease severity and relevant clinical trial endpoints.

To meet this need, several studies have been performed to understand the functional

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The NIGHT study aimed to assess the natural history of choroideremia (CHM), an X-linked inherited chorioretinal degenerative disease leading to blindness, and determine which outcomes would be the most sensitive for monitoring disease progression.
A prospective, observational, multicenter cohort study.
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A total of 220 participants completed the study. The mean BCVA was stable over 20 months. Most participants (81.4% in the worse eye and 77.8% in the better eye) had change from baseline > −5 ETDRS letters at Month 20. Interocular symmetry was low overall. Reductions from baseline to Month 12 were observed (worse eye, better eye) for retinal sensitivity (functional outcome; −0.68 dB, −0.48 dB), central EZ area (anatomical outcome; −0.276 mm², −0.290 mm²), and total area of FAF (anatomical outcome; −0.605 mm², −0.533 mm²). No assessment-related serious adverse events occurred.
Retinal sensitivity, central EZ area, and total area of FAF are more sensitive than BCVA in measuring the natural progression of CHM.
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Geographic atrophy is a leading cause of progressive, irreversible vision loss. The objectives of OAKS and DERBY were to assess the efficacy and safety of pegcetacoplan compared with sham treatment in patients with geographic atrophy.
OAKS and DERBY were two 24-month, multicentre, randomised, double-masked, sham-controlled, phase 3 studies, in which patients aged 60 years and older with geographic atrophy secondary to age-related macular degeneration were enrolled at 110 clinical sites and 122 clinical sites worldwide, respectively. Patients were randomly assigned (2:2:1:1) by central web-based randomisation system to intravitreal 15 mg per 0·1 mL pegcetacoplan monthly or every other month, or sham monthly or every other month using stratified permuted block randomisation (stratified by geographic atrophy lesion area at screening, history or presence of active choroidal neovascularisation in the eye not under assessment, and block size of six). Study site staff, patients, reading centre personnel, evaluating physicians, and the funder were masked to group assignment. Sham groups were pooled for the analyses. The primary endpoint was the change from baseline to month 12 in the total area of geographic atrophy lesions in the study eye based on fundus autofluorescence imaging, in the modified intention-to-treat population (ie, all patients who received one or more injections of pegcetacoplan or sham and had a baseline and at least one post-baseline value of lesion area). Key secondary endpoints (measured at 24 months) were change in monocular maximum reading speed of the study eye, change from baseline in mean functional reading independence index score, change from baseline in normal luminance best-corrected visual acuity score, and change from baseline in the mean threshold sensitivity of all points in the study eye by mesopic microperimetry (OAKS only). Safety analyses included patients who were randomly assigned and received at least one injection of pegcetacoplan or sham. The now completed studies are registered with ClinicalTrials.gov, NCT03525613 (OAKS) and NCT03525600 (DERBY).
Between Aug 30, 2018, and July 3, 2020, 1258 patients were enrolled in OAKS and DERBY. The modified intention-to-treat populations comprised 614 (96%) of 637 patients in OAKS (202 receiving pegcetacoplan monthly, 205 pegcetacoplan every other month, and 207 sham) and 597 (96%) of 621 patients in DERBY (201 receiving pegcetacoplan monthly, 201 pegcetacoplan every other month, and 195 sham). In OAKS, pegcetacoplan monthly and pegcetacoplan every other month significantly slowed geographic atrophy lesion growth by 21% (absolute difference in least-squares mean –0·41 mm², 95% CI –0·64 to –0·18; p=0·0004) and 16% (–0·32 mm², –0·54 to –0·09; p=0·0055), respectively, compared with sham at 12 months. In DERBY, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth, although it did not reach significance, by 12% (–0·23 mm², –0·47 to 0·01; p=0·062) and 11% (–0·21 mm², –0·44 to 0·03; p=0·085), respectively, compared with sham at 12 months. At 24 months, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth by 22% (–0·90 mm², –1·30 to –0·50; p<0·0001) and 18% (–0·74 mm², –1·13 to –0·36; p=0·0002) in OAKS, and by 19% (–0·75 mm², –1·15 to –0·34; p=0·0004) and 16% (–0·63 mm², –1·05 to –0·22; p=0·0030) in DERBY, respectively, compared with sham. There were no differences in key secondary visual function endpoints at 24 months. Serious ocular treatment-emergent adverse events were reported in five (2%) of 213, four (2%) of 212, and one (<1%) of 211 patients in OAKS, and in four (2%) of 206, two (1%) of 208, and two (1%) of 206 patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. New-onset exudative age-related macular degeneration was reported in 24 (11%), 16 (8%), and four (2%) patients in OAKS, and in 27 (13%), 12 (6%), and nine (4%) patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months.
Pegcetacoplan, the first treatment approved by the US Food and Drug Administration for geographic atrophy, slowed geographic atrophy lesion growth with an acceptable safety profile.
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Biologically Guided Optimization of Test Target Location for Rod-mediated Dark Adaptation in Age-related Macular Degeneration: Alabama Study on Early Age-related Macular Degeneration 2 Baseline
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We evaluate the impact of test target location in assessing rod-mediated dark adaptation (RMDA) along the transition from normal aging to intermediate age-related macular degeneration (AMD). We consider whether RMDA slows because the test locations are near mechanisms leading to or resulting from high-risk extracellular deposits. Soft drusen cluster under the fovea and extend to the inner ring of the ETDRS grid where rods are sparse. Subretinal drusenoid deposits (SDDs) appear first in the outer superior subfield of the ETDRS grid where rod photoreceptors are maximal and spread toward the fovea without covering it.
Cross-sectional.
Adults ≥ 60 years with normal older maculas, early AMD, or intermediate AMD as defined by the Age-Related Eye Disease Study (AREDS) 9-step and Beckman grading systems.
In 1 eye per participant, RMDA was assessed at 5° and at 12° in the superior retina. Subretinal drusenoid deposit presence was identified with multi-modal imaging.
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In 438 eyes of 438 persons, RIT was significantly longer (i.e., RMDA is slower) at 5° than at 12° for each AMD severity group. Differences among groups were bigger at 5° than at 12°. At 5°, SDD presence was associated with longer RIT as compared to SDD absence at early and intermediate AMD but not in normal eyes. At 12°, SDD presence was associated with longer RIT in intermediate AMD only, and not in normal or early AMD eyes. Findings were similar in eyes stratified by AREDS 9-step and Beckman systems.
We probed RMDA in relation to current models of deposit-driven AMD progression organized around photoreceptor topography. In eyes with SDD, slowed RMDA occurs at 5° where these deposits typically do not appear until later in AMD. Even in eyes lacking detectable SDD, RMDA at 5° is slower than at 12°. The effect at 5° may be attributed to mechanisms associated with the accumulation of soft drusen and precursors under the macula lutea throughout adulthood. These data will facilitate the design of efficient clinical trials for interventions that aim to delay AMD progression.
Proprietary or commercial disclosure may be found after the references.
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Retinal microperimetry (MP) is a procedure that assesses the retinal sensitivity while the fundus is directly observed, and an eye tracker system is active to compensate for involuntary eye movements during testing. With this system, the sensitivity of a small locus can be accurately determined, and it has become an established ophthalmic test for retinal specialists. Macular diseases are characterized by chorioretinal changes; therefore, the condition of the retina and choroid requires careful and detailed evaluations to perform effective therapy. Age-related macular degeneration is a representative retinal disease in which the macular function has been evaluated by the visual acuity throughout the course of the disease process. However, the visual acuity represents the physiological function of only the central fovea, and the function of the surrounding macular area has not been sufficiently evaluated throughout the different stages of the macula disease process. The new technique of MP can compensate for such limitations by being able to test the same sites of the macular area repeatedly. This is especially useful in the recent management of age-related macular degeneration or diabetic macular edema during anti-vascular endothelial growth factor treatments because MP can assess the effectiveness of the treatment. MP examinations are also valuable in diagnosing Stargardt disease as they can detect visual impairments before any abnormalities are found in the retinal images. The visual function needs to be carefully assessed along with morphologic observations by optical coherence tomography. In addition, the assessment of retinal sensitivity is useful in the presurgical or postsurgical evaluations.
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The use of LL AULCSF and certain features of FAF should be considered in clinical trials of intermediate age-related macular degeneration. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
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Age-related macular degeneration (AMD) is the leading cause of blindness for the elderly in high-income countries. Although multivitamin antioxidant nutrients can slow the progression of intermediate “dry” or nonneovascular AMD, no treatment can halt or reverse any stage of dry disease. Multiple biologic pathways have been implicated in AMD pathobiology, including the complement pathway. These pathways have been targeted by various approaches in clinical trials. To date, no treatment has reached their prespecified primary end point in 2 phase III trials, a requirement by the US Food and Drug Administration for a new drug approval. Here, we describe perspectives on the failures and possible successes of various clinical trials that will guide further investigation. These perspectives will also discuss clinical trial design issues to consider in future investigations, and how recent insights into AMD pathobiology might both provide additional explanation for trials not reaching the prespecified primary end points and offer direction for identifying prioritized treatment targets.

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Original articleVisual Function Metrics in Early and Intermediate Dry Age-related Macular Degeneration for Use as Clinical Trial Endpoints

Purpose

Design

Methods

Results

Conclusions

Section snippets

Study Participants

Results

Discussion

Lancet Glob Health

Ophthalmology

Am J Ophthalmol

Ophthalmology

Am J Ophthalmol

Trends Neurosci

Ophthalmology

Am J Ophthalmol

Exp Eye Res

Ann Thorac Surg

Ophthalmology

Ophthalmology

Vision Res

Vision Res

Free Radic Biol Med

Arch Biochem Biophys

Am J Clin Nutr

Ophthalmology

Development of a questionnaire to assess vision problems under low luminance in age-related maculopathy

Invest Ophthalmol Vis Sci

Psychometric properties of the National Eye Institute Visual Function Questionnaire (NEI-VFQ). NEI-VFQ Field Test Investigators

Arch Ophthalmol

Original article
Visual Function Metrics in Early and Intermediate Dry Age-related Macular Degeneration for Use as Clinical Trial Endpoints