Use of Composite End Points in Early and Intermediate Age-Related Macular Degeneration Clinical Trials: State-of-the-Art and Future Directions

The slow progression of early AMD stages to advanced AMD requires the use of surrogate endpoints in clinical trials. The use of combined endpoints may allow for shorter and smaller trials due to increased precision. We performed a literature search for the use of composite endpoints as primary outcome measures in clinical studies of early AMD stages. PubMed was searched for composite endpoints used in early/intermediate AMD studies published during the last 10 years. A total of 673 articles of interest were identified. After reviewing abstracts and applicable full-text articles, 33 articles were eligible and thus included in the qualitative synthesis. The main composite endpoint categories were: Combined structural and functional endpoints, combined structural endpoints, combined functional endpoints and combined multi-categorical endpoints. The majority of the studies included binary composite endpoints. There was a lack of sensitivity analyses of different endpoints against accepted outcomes (i.e. progression) in the literature. Various composite outcome measures have been used but there is a lack of standardization. To date no agreement on the optimal approach to implement combined endpoints in clinical studies of early stages of AMD exists and no surrogate endpoints have been accepted for AMD progression

Test-Retest Variability and Discriminatory Power of Measurements From Microperimetry and Dark Adaptation Assessment in People With Intermediate Age-Related Macular Degeneration – A MACUSTAR Study Report

Purpose: The purpose of this study was to assess test-retest variability and discriminatory power of measures from macular integrity assessment (S-MAIA) and AdaptDx. // Methods: This is a cross-sectional study of 167 people with intermediate age-related macular degeneration (iAMD), no AMD (controls; n = 54), early AMD (n = 28), and late AMD (n = 41), recruited across 18 European ophthalmology centers. Repeat measures of mesopic and scotopic S-MAIA average (mean) threshold (MMAT decibels [dB] and SMAT [dB]) and rod intercept time (RIT [mins]) at 2 visits 14 (±7) days apart were recorded. Repeat measures were assessed by Bland-Altman analysis, intra-class correlation coefficients (ICCs) and variability ratios. Secondary analysis assessed the area under the receiver operating characteristic curves (AUC) to determine the ability to distinguish people as having no AMD, early AMD, or iAMD. // Results: Data were available for 128, 131, and 103 iAMD participants for the mesopic and scotopic S-MAIA and AdaptDx, respectively. MMAT and SMAT demonstrate similar test-retest variability in iAMD (95% confidence interval [CI] ICC of 0.79–0.89 and 0.78–0.89, respectively). ICCs were worse in RIT (95% CI ICC = 0.55–0.77). All tests had equivalent AUCs (approximately 70%) distinguishing between subjects with iAMD and controls, whereas early AMD was indistinguishable from iAMD on all measures (AUC = <55%). A learning effect was not seen in these assessments under the operating procedures used. // Conclusions: MMAT, SMAT, and RIT have adequate test-retest variability and are all moderately good at separating people with iAMD from controls. // Translational Relevance: Expected levels of test-retest variability and discriminatory power of the AdaptDx and MAIA devices in a clinical study setting must be considered when designing future trials for people with AMD

Disease-specific assessment of Vision Impairment in Low Luminance (VILL) in age-related macular degeneration – a MACUSTAR study report

Background/Aims: To further validate the Vision Impairment in Low Luminance (VILL) questionnaire, which captures visual functioning and vision-related quality of life under low luminance, low contrast conditions relevant to age-related macular degeneration (AMD). Methods: The VILL was translated from German into English (UK), Danish, Dutch, French, Italian and Portuguese. Rasch analysis was used to assess psychometric characteristics of 716 participants (65% female, mean age 72±7 years, 82% intermediate AMD) from the baseline visit of the MACUSTAR study. In a sub-set of participants (n=301), test-retest reliability (intra-class correlation coefficient, ICC; coefficient of repeatability, CoR) and construct validity were assessed. Results: Four items were removed from the VILL-37 due to misfit. The resulting VILL-33 has three subscales with no disordered thresholds and no misfitting items. No differential item functioning and no multidimensionality were observed. Person reliability and person separation index were 0.91 and 3.27 for the reading subscale (VILL-R), 0.87 and 2.58 for the mobility subscale (VILL-M) and 0.78 and 1.90 for the emotional subscale (VILL-E). ICC and CoR were 0.92 and 1.9 for VILL-R, 0.93 and 1.8 for VILL-M and 0.82 and 5.0 for VILL-E. Reported visionrelated quality of life decreased with advanced AMD stage (p<0.0001) and was lower in the intermediate AMD group than in the no AMD group (p≤0.0053). Conclusion: The VILL is a psychometrically sound patient-reported outcome instrument and the results further support its reliability and validity across all AMD stages. We recommend the shortened version of the questionnaire with three subscales (VILL-33) for future use. Trial registration number NCT03349801

Using the Rate of Global and Pointwise Microperimetry Change to Predict Structural Conversion in Intermediate Age-Related Macular Degeneration

Purpose Studies evaluating functional change in age-related macular degeneration (AMD) using microperimetry often measure the difference in global mean sensitivity at interval time points versus baseline. We evaluate the rate of global and pointwise microperimetry change in intermediate AMD (iAMD) in the multicenter MACUSTAR (Registration NCT03349801) study and assess their prognostic value in structural conversion to late-stage AMD. Design Prospective study. Subjects Four hundred forty-seven subjects with iAMD (Beckman classification) from 20 European sites. Methods Subjects that underwent mesopic microperimetry on ≥3 follow-up visits were included. Two methods of assessing functional progression were evaluated: (1) global mean sensitivity regression and (2) pointwise sensitivity regression at fastest progressing N number of locations (N from 1 to 10). Rates of microperimetry progression were then evaluated in an initial series of visits prior to structural conversion to late-stage AMD. Main Outcome Measures Area under the receiving operating characteristic (AUC) curves and Cox proportional hazard models were used to assess risk of structural conversion based on rate of functional progression. Results The mean age of subjects was 72 (standard deviation 7) years. The median number of visits and duration of follow-up was 6 visits and 3 years, respectively. Structural conversion to late-stage AMD was observed in 80 (17.9%) eyes. In the visits prior to conversion, there was a greater rate of global mean sensitivity loss in eyes that eventually developed late-stage AMD compared with those that did not (–1.05 vs. –0.30 decibels/year, P < 0.001). The AUC for classifying structural conversion versus no conversion was 0.72 for global sensitivity progression and 0.75–0.76 for between 1 and 10 fastest progressing N pointwise locations. The rate of global (hazard ratio 1.7, confidence interval [CI] 1.4–2.0) and pointwise (hazard ratio 1.2, CI 1.2–1.3) microperimetry progression in the initial series of visits was significantly associated with structural conversion (P < 0.0001). Conclusions In the analysis of longitudinal microperimetry data from the MACUSTAR study, the rate of global and pointwise sensitivity change was significantly greater and strongly prognostic of eyes that developed structural conversion. Our findings support use of these trend-based pointwise analysis methods in assessing functional progression in iAMD. Financial Disclosure(s) Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article

Relative ellipsoid zone reflectivity and its association with disease severity in age-related macular degeneration: a MACUSTAR study report

Quantification of the relative ellipsoid zone reflectivity (rEZR) might be a structural surrogate parameter for an early disease progression in the context of age-related macular degeneration (AMD). Within the European multicenter, cross-sectional MACUSTAR study, we have devised an automatic approach to determine the mean rEZR [arbitrary units, AU] at two independent visits in SD-OCT volume scans in study participants. Linear mixed-effects models were applied to analyze the association of AMD stage and AMD associated high-risk features including presence of pigmentary abnormalities, reticular pseudodrusen (RPD), volume of the retinal-pigment-epithelial-drusenoid-complex (RPEDC) with the rEZR. Intra-class correlation coefficients (ICC) were determined for rEZR reliability analysis. Within the overall study cohort (301 participants), we could observe decreased rEZR values (coefficient estimate ± standard error) of - 8.05 ± 2.44 AU (p = 0.0011) in the intermediate and of - 22.35 ± 3.28 AU (p < 0.0001) in the late AMD group. RPD presence was significantly associated with the rEZR in iAMD eyes (- 6.49 ± 3.14 AU; p = 0.0403), while there was a good ICC of 0.846 (95% confidence interval: 0.809; 0.876) in the overall study cohort. This study showed an association of rEZR with increasing disease severity and the presence of iAMD high-risk features. Further studies are necessary to evaluate the rEZR's value as a novel biomarker for AMD and disease progression

Risk of Epilepsy and Factors Associated With Time to Seizure Remission in Anti-LGI1 Encephalitis:Long-Term Outcome in 236 Patients

BACKGROUND AND OBJECTIVES: Autoimmune encephalitis (AIE) with anti-leucine-rich glioma-inactivated 1 (LGI1) antibodies typically manifests with subacute cognitive deficits, seizures, and psychiatric symptoms, mostly in older adults. Immunotherapy (IT) leads to the cessation of seizures in most patients, yet some develop AIE-associated epilepsy (AEAE) and persistent cognitive deficits. The aim of this large multicentric retrospective observational cohort study was to assess long-term outcomes of patients with anti-LGI1 encephalitis regarding seizures and AEAE and to identify associated factors. METHODS: We included patients with anti-LGI1 encephalitis from 3 national referral centers/consortia meeting the following inclusion criteria: (I) definite LGI1 limbic encephalitis (Graus criteria); (II) occurrence of seizures; and (III) follow-up period ≥24 months. We aimed to (1) determine the risk of seizure recurrence (ROSR) on remission, (2) investigate clinical and paraclinical biomarkers for an effect on time to seizure remission using Cox proportional hazard modeling (n = 188), and (3) assess the risk of AEAE and determine associated factors (n = 236). RESULTS: AEAE was observed in 5.9% (16/271) of the full cohort. Both AEAE (16/16 vs 129/215, p = 0.001) and longer time to seizure remission (OR 1.36 per year, p = 0.025) were associated with persistent cognitive impairment. Patients with pilomotor seizures had a lower rate of seizure remission (hazard ratio [HR] 0.58, 95% CI 0.55-0.60, p &lt; 0.001) while patients under IT administration had a higher rate of seizure remission over time (HR 12.4, 95% CI 9.67-16.0, p &lt; 0.001). In addition, patients receiving second-line IT tended to achieve earlier seizure remission (log-rank test, p = 0.019). The ROSR at 12, 60, and 120 months on seizure remission was 9% (95% CI 4.5%-13%), 20% (95% CI 11%-28%), and 53% (95% CI 14%-74%), respectively. DISCUSSION: In conclusion, our results demonstrate that AEAE in anti-LGI1 encephalitis is rare and suggest that the diagnosis of epilepsy is inappropriate in patients reaching seizure remission because of a relatively low ROSR. Accordingly, on seizure remission, the diagnosis of acute symptomatic seizures would be appropriate. Moreover, we validate and quantify the importance of IT for seizure remission and identify biomarkers associated with lower rates of seizure remission. Late remission of seizures and AEAE were associated with persistent cognitive impairment.</p

Comparability of automated drusen volume measurements in age-related macular degeneration: a MACUSTAR study report

Drusen are hallmarks of early and intermediate age-related macular degeneration (AMD) but their quantification remains a challenge. We compared automated drusen volume measurements between different OCT devices. We included 380 eyes from 200 individuals with bilateral intermediate (iAMD, n = 126), early (eAMD, n = 25) or no AMD (n = 49) from the MACUSTAR study. We assessed OCT scans from Cirrus (200 × 200 macular cube, 6 × 6 mm; Zeiss Meditec, CA) and Spectralis (20° × 20°, 25 B-scans; 30° × 25°, 241 B-scans; Heidelberg Engineering, Germany) devices. Sensitivity and specificity for drusen detection and differences between modalities were assessed with intra-class correlation coefficients (ICCs) and mean difference in a 5 mm diameter fovea-centered circle. Specificity was > 90% in the three modalities. In eAMD, we observed highest sensitivity in the denser Spectralis scan (68.1). The two different Spectralis modalities showed a significantly higher agreement in quantifying drusen volume in iAMD (ICC 0.993 [0.991–0.994]) than the dense Spectralis with Cirrus scan (ICC 0.807 [0.757–0.847]). Formulae for drusen volume conversion in iAMD between the two devices are provided. Automated drusen volume measures are not interchangeable between devices and softwares and need to be interpreted with the used imaging devices and software in mind. Accounting for systematic difference between methods increases comparability and conversion formulae are provided. Less dense scans did not affect drusen volume measurements in iAMD but decreased sensitivity for medium drusen in eAMD. Trial registration: ClinicalTrials.gov NCT03349801. Registered on 22 November 2017

Challenges, facilitators and barriers to screening study participants in early disease stages-experience from the MACUSTAR study

BACKGROUND: Recruiting asymptomatic participants with early disease stages into studies is challenging and only little is known about facilitators and barriers to screening and recruitment of study participants. Thus we assessed factors associated with screening rates in the MACUSTAR study, a multi-centre, low-interventional cohort study of early stages of age-related macular degeneration (AMD). METHODS: Screening rates per clinical site and per week were compiled and applicable recruitment factors were assigned to respective time periods. A generalized linear mixed-effects model including the most relevant recruitment factors identified via in-depth interviews with study personnel was fitted to the screening data. Only participants with intermediate AMD were considered. RESULTS: A total of 766 individual screenings within 87 weeks were available for analysis. The mean screening rate was 0.6 ± 0.9 screenings per week among all sites. The participation at investigator teleconferences (relative risk increase 1.466, 95% CI [1.018-2.112]), public holidays (relative risk decrease 0.466, 95% CI [0.367-0.591]) and reaching 80% of the site's recruitment target (relative risk decrease 0.699, 95% CI [0.367-0.591]) were associated with the number of screenings at an individual site level. CONCLUSIONS: Careful planning of screening activities is necessary when recruiting early disease stages in multi-centre observational or low-interventional studies. Conducting teleconferences with local investigators can increase screening rates. When planning recruitment, seasonal and saturation effects at clinical site level need to be taken into account. TRIAL REGISTRATION: ClinicalTrials.gov NCT03349801 . Registered on 22 November 2017

Heterogenous visual function deficits in intermediate age-related macular degeneration – A MACUSTAR report

Objective To examine the extent to which visual function in Beckman age-related macular degeneration (AMD) disease stages differ from age similar peers with no AMD and using reference limits derived from those with no AMD, test the hypothesis that people with intermediate AMD (iAMD) have heterogenous visual function deficits. Design Cross-sectional analyses of a range of baseline visual function measures from the MACUSTAR study; an international, multi-center (n=20), non-interventional clinical trial. Participants 585 participants with iAMD (67% female, mean [standard deviation] age 72 [7] years) were recruited alongside 56 with no AMD (59% female, 68 [6]), 34 with early AMD (79% female, 72 [6]) and 43 with late AMD (49% female, 75 [6]). Methods Participants performed best-corrected visual acuity (BCVA), low luminance visual acuity (LLVA), Moorfields acuity test (MAT), Pelli-Robson contrast sensitivity (PR-CS), Small Print Standardized International Reading Speed Test (SPS), mesopic and scotopic Average Threshold (MesAT and ScoAT; Macular Integrity Assessment, iCare,) and Rod Intercept Time (RIT; AdaptDx, Lumithera). Main Outcome Measures Relationship between each visual function measure and disease classification was examined by linear regression adjusted for age, sex and phakic status. No AMD data were used to estimate normal reference limits for each visual function test. iAMD scores were dichotomised against reference limits and proportion worse than each limit calculated. Results Relative to no AMD, SPS was significantly worse in early AMD (p = 0.001), all measures except SPS were significantly reduced in iAMD (p<0.02) and all measures were markedly reduced in late AMD (p<0.0001). 31% of iAMD participants breached reference limits for PR-CS, 29% for RIT, 24% for LLVA, 23% for MAT, 21% for BCVA, 20% for MesAT, 18% for ScoAT and 13% for SPS. 69.6% and 42.7% of iAMD participants breached ≥1 and ≥2 reference limits respectively, whereas 33.6% and 5.7% would be expected by chance. Conclusions A large proportion of people with structurally defined iAMD exhibit heterogenous visual function deficits outside normal reference limits. This observation may be relevant for the design and inclusion criteria of future interventional trials