Intermediate AMD (iAMD) is the most high-risk AMD stage for progressing to late AMD. This article gives the report of the MACUSTAR study. A wide range of assessments were conducted across 20 sites in seven European countries, in accordance with established guidelines. This prospective European multicentre cohort study validates the structural, functional, and patient-reported iAMD endpoints for use in future trials. The structural assessments encompassed evaluations, such as colour fundus photography, fundus autofluorescence and OCT. Additionally, functional tests were conducted, including assessments of best-corrected and low-luminance visual acuity (VA), Moorfields acuity, contrast sensitivity, reading speed, mesopic and scotopic microperimetry, and dark adaptometry. Moreover, patient-reported outcome assessments, specifically the Vision Impairment in Low Luminance questionnaire, were also incorporated into the evaluation process. Associations between variables were investigated using Phi coefficients, Pearson correlation coefficients and age-corrected regression models. Five-hundred eighty-five individuals with iAMD and 133 in the control group were included in the study. Participants were on average 72 ±7 years and more than two-thirds were female. Forty-nine percent had pigmentary abnormalities, 27% had reticular pseudodrusen; 10% and 9% had incomplete and complete retinal pigment epithelium and outer retinal atrophy at baseline, respectively. Mean best-corrected VA, low-luminance VA and mesopic average threshold on microperimetry at baseline were 0.03 ±0.11logMAR, 0.24 ±0.16logMAR, and 23.3 ±3.7dB. Mean vision impairment in low luminance (VILL) subscale scores at baseline were 2 ±2 to 2 ±3 logits. Phi coefficients between structural assessments ranged between 0.17 and 0.22 (median 0.21); correlation coefficients between function tests ranged between 0.07 and 0.69 (median 0.34) and between VILL scores ranged between 0.21 and 0.68 (median 0.23). The study suggests that the disease spectrum is diverse and heterogeneous and further efforts from the MACUSTAR consortium and other international collaborations are required to better understand this spectrum. Age-related macular degeneration reclassification efforts, development of enrichment criteria and endpoints are required for future iAMD trials. These will hopefully work towards the unmet need in preventing the visual loss of late stages of AMD. Strengths include the large phenotype cohort, image reading by central reading centre, continuous data quality checks and independent monitoring. Additional strengths include engagement of trained and certified clinical staff using standardised operating procedures (SOPs) for data acquisition and the use of valid and reliable tests such as the VLL questionnaire from previous independent studies. Limitations: limited number of analyses of available structural biomarkers.
