Ophthalmology science · 2026
Novel Clinical Trial Designs for Intermediate Age-Related Macular Degeneration.
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Berni Alessandro, Shen Mengxi, Liu Jeremy, Kastner James D, El-Mulki Omar S, Beqiri Sara, Herrera Gissel, Trivizki Omer, Waheed Nadia K, Usner Dale W, Levy Brian, O'Brien Robert, Gregori Giovanni, Rosenfeld Philip J
Аннотация
PURPOSE: To develop and model clinical trial designs for intermediate age-related macular degeneration (iAMD) using OCT-based structural biomarkers to define inclusion criteria and estimate sample size requirements for detecting treatment effects over 2 years.
DESIGN: Retrospective study of a prospectively acquired swept-source OCT cohort.
SUBJECTS: Patients with iAMD enrolled in a prospective natural history imaging study.
METHODS: Two clinical trial designs were modeled. The first included eyes with drusen volume (DV) ≥0.20 mm3 and any hyperreflective foci (HRF). The second included eyes with an area of HRF ≥0.07 mm2, regardless of DV. Eyes were followed from the time of eligibility and monitored for the onset and growth of large hypertransmission defects (hyperTDs). Power and sample size simulations were performed based on the expected treatment effects.
MAIN OUTCOME MEASURES: Annual square root growth rates of large hyperTDs and incidence of new large hyperTDs over 2 years.
RESULTS: In 76 eyes with DV ≥0.20 mm3 and HRF, the mean annual growth rate of large hyperTDs was 0.153 mm/year (standard deviation [SD] = 0.188), and 35.5% of these iAMD eyes developed hyperTDs by 2 years. In the 79 eyes with HRF area ≥0.07 mm2, the mean annual growth rate was 0.161 mm/year (SD = 0.172), and 40.5% developed hyperTD by 2 years. With a 2-sided alpha of 0.1, a 50% reduction in the growth rate could be detected with 80% power using ≥89 eyes per arm in the first group and ≥64 eyes per arm in the second group.
CONCLUSIONS: The growth rate of large hyperTDs is a continuous and reproducible structural endpoint for iAMD trials, influenced by both lesion onset and progression. Drusen volume or the area of HRF serves as high-risk biomarkers for enrolling iAMD eyes. This design allows for a study duration of 1-2 years with no more than 100 subjects per arm.
FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
DESIGN: Retrospective study of a prospectively acquired swept-source OCT cohort.
SUBJECTS: Patients with iAMD enrolled in a prospective natural history imaging study.
METHODS: Two clinical trial designs were modeled. The first included eyes with drusen volume (DV) ≥0.20 mm3 and any hyperreflective foci (HRF). The second included eyes with an area of HRF ≥0.07 mm2, regardless of DV. Eyes were followed from the time of eligibility and monitored for the onset and growth of large hypertransmission defects (hyperTDs). Power and sample size simulations were performed based on the expected treatment effects.
MAIN OUTCOME MEASURES: Annual square root growth rates of large hyperTDs and incidence of new large hyperTDs over 2 years.
RESULTS: In 76 eyes with DV ≥0.20 mm3 and HRF, the mean annual growth rate of large hyperTDs was 0.153 mm/year (standard deviation [SD] = 0.188), and 35.5% of these iAMD eyes developed hyperTDs by 2 years. In the 79 eyes with HRF area ≥0.07 mm2, the mean annual growth rate was 0.161 mm/year (SD = 0.172), and 40.5% developed hyperTD by 2 years. With a 2-sided alpha of 0.1, a 50% reduction in the growth rate could be detected with 80% power using ≥89 eyes per arm in the first group and ≥64 eyes per arm in the second group.
CONCLUSIONS: The growth rate of large hyperTDs is a continuous and reproducible structural endpoint for iAMD trials, influenced by both lesion onset and progression. Drusen volume or the area of HRF serves as high-risk biomarkers for enrolling iAMD eyes. This design allows for a study duration of 1-2 years with no more than 100 subjects per arm.
FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.