scholarly journals Use of composite endpoints in early and intermediate age-related macular degeneration clinical trials – state-of-the-art and future directions

2020 ◽  
Author(s):  
Jan Henrik Terheyden ◽  
Steffen Schmitz-Valckenberg ◽  
David P. Crabb ◽  
Hannah Dunbar ◽  
Ulrich F. O. Luhmann ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Outcome Measures ◽  
Clinical Studies ◽  
Composite Endpoint ◽  
Age Related Macular Degeneration ◽  
Sensitivity Analyses ◽  
Surrogate Endpoints ◽  
Qualitative Synthesis ◽  
Age Related ◽  
Composite Endpoints

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.

scholarly journals Selection of Endpoints for Clinical Studies of Ophthalmic Drugs

2021 ◽  
Vol 11 (3) ◽  
pp. 167-173
Author(s):  
M. O. Komarova
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Studies ◽  
Age Related Macular Degeneration ◽  
Surrogate Endpoints ◽  
Social Significance ◽  
Ophthalmic Drugs ◽  
Clinical Endpoints ◽  
Age Related ◽  
Selection Of

Until now, there have been no effective treatments for some ophthalmic diseases that have high social significance. Development of therapeutic approaches to such diseases may be complicated due to challenges in diagnosis and selection of clinical trial endpoints. The aim of the study was to analyse current approaches to selection of endpoints in clinical trials of ophthalmic drugs. Clinical efficacy studies of new medicinal products use surrogate endpoints in addition to clinical endpoints. However, currently used surrogate endpoints are not always relevant and do not fully reflect changes in the status of patients with chronic or progressive diseases. The study analysed published approaches to the selection of endpoints in clinical studies of ophthalmic drugs intended for the treatment of glaucoma, uveitis, dry eye syndrome, and age-related macular degeneration. It was demonstrated that the choice of surrogate endpoints in a clinical trial should take into account specific aspects of a particular disease. The assessment of dynamic patterns of changes in visual functions generally requires a complex approach for a comprehensive characterisation of the eye condition in a particular disease. The paper analyses the possibility of using potential surrogate endpoints in studies of the most common eye diseases, and highlights that none of them has been recommended for use in clinical trials or routine clinical practice.

scholarly journals AI-based structure-function correlation in age-related macular degeneration

Eye ◽  
2021 ◽  
Author(s):  
Leon von der Emde ◽  
Maximilian Pfau ◽  
Frank G. Holz ◽  
Monika Fleckenstein ◽  
Karsten Kortuem ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Clinical Trials ◽  
Visual Acuity ◽  
Structure Function ◽  
Macular Degeneration ◽  
Outcome Measures ◽  
Multimodal Imaging ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Function Correlation

AbstractSensitive and robust outcome measures of retinal function are pivotal for clinical trials in age-related macular degeneration (AMD). A recent development is the implementation of artificial intelligence (AI) to infer results of psychophysical examinations based on findings derived from multimodal imaging. We conducted a review of the current literature referenced in PubMed and Web of Science among others with the keywords ‘artificial intelligence’ and ‘machine learning’ in combination with ‘perimetry’, ‘best-corrected visual acuity (BCVA)’, ‘retinal function’ and ‘age-related macular degeneration’. So far AI-based structure-function correlations have been applied to infer conventional visual field, fundus-controlled perimetry, and electroretinography data, as well as BCVA, and patient-reported outcome measures (PROM). In neovascular AMD, inference of BCVA (hereafter termed inferred BCVA) can estimate BCVA results with a root mean squared error of ~7–11 letters, which is comparable to the accuracy of actual visual acuity assessment. Further, AI-based structure-function correlation can successfully infer fundus-controlled perimetry (FCP) results both for mesopic as well as dark-adapted (DA) cyan and red testing (hereafter termed inferred sensitivity). Accuracy of inferred sensitivity can be augmented by adding short FCP examinations and reach mean absolute errors (MAE) of ~3–5 dB for mesopic, DA cyan and DA red testing. Inferred BCVA, and inferred retinal sensitivity, based on multimodal imaging, may be considered as a quasi-functional surrogate endpoint for future interventional clinical trials in the future.

scholarly journals Future Perspectives of Therapeutic, Diagnostic and Prognostic Aptamers in Eye Pathological Angiogenesis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1455
Author(s):  
Emilio Iturriaga-Goyon ◽  
Beatriz Buentello-Volante ◽  
Fátima Sofía Magaña-Guerrero ◽  
Yonathan Garfias
Keyword(s):  
Clinical Trials ◽  
Macular Degeneration ◽  
Small Molecules ◽  
Inflammatory Diseases ◽  
Age Related Macular Degeneration ◽  
Future Perspectives ◽  
Whole Cells ◽  
Pathological Angiogenesis ◽  
Age Related ◽  
Viral Particles

Aptamers are single-stranded DNA or RNA oligonucleotides that are currently used in clinical trials due to their selectivity and specificity to bind small molecules such as proteins, peptides, viral particles, vitamins, metal ions and even whole cells. Aptamers are highly specific to their targets, they are smaller than antibodies and fragment antibodies, they can be easily conjugated to multiple surfaces and ions and controllable post-production modifications can be performed. Aptamers have been therapeutically used for age-related macular degeneration, cancer, thrombosis and inflammatory diseases. The aim of this review is to highlight the therapeutic, diagnostic and prognostic possibilities associated with aptamers, focusing on eye pathological angiogenesis.

scholarly journals The role of future treatments in the management of neovascular age-related macular degeneration in Europe

2021 ◽  
pp. 112067212110183
Author(s):  
Laurent Kodjikian ◽  
Carl Joe Mehanna ◽  
Salomon-Yves Cohen ◽  
François Devin ◽  
Sam Razavi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Phase Iii ◽  
Vascular Endothelial ◽  
Real World Data ◽  
Phase Iii Clinical Trials ◽  
Age Related ◽  
Injection Frequency ◽  
Endothelial Growth Factor

Anti-vascular endothelial growth factor (VEGF) agents have transformed the management of patients with neovascular age-related macular degeneration (nAMD) over the past two decades. However, as more long-term real-world data become available, it is clear that treatment outcomes are inferior to those reported in large, controlled clinical trials. This is largely driven by undertreatment, that is, not maintaining a consistent injection frequency to achieve sustained VEGF suppression, whether due to patient non-compliance, an important injection burden, or non/incomplete anatomical response. Newer therapeutic advances under evaluation hold promise in achieving more, for less. We review the latest drugs currently in or having successfully finished phase III clinical trials, and determine their potential place in the management of patients with nAMD in Europe.

scholarly journals Eyes that Do Not Meet the Eligibility Criteria of Clinical Trials on Age-Related Macular Degeneration: Proportion of the Real-World Patient Population and Reasons for Exclusion

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Jae Hui Kim ◽  
Jong Woo Kim ◽  
Chul Gu Kim
Keyword(s):  
Clinical Trials ◽  
Visual Acuity ◽  
Real World ◽  
Age Related Macular Degeneration ◽  
Subretinal Hemorrhage ◽  
Neovascular Amd ◽  
Eligibility Criteria ◽  
Type 3 Neovascularization ◽  
Age Related ◽  
Type 3

Background. To evaluate the proportion of eyes that do not meet the eligibility criteria of clinical trials on neovascular age-related macular degeneration (AMD) and the reasons for exclusion. Methods. This retrospective, observational study included 512 eyes of 463 patients diagnosed with treatment-naïve neovascular AMD. The proportion of eyes that did not meet the eligibility criteria of the Vascular Endothelial Growth Factor Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) studies were evaluated. The two most common reasons for exclusion were also evaluated in each subtype of neovascular AMD (typical neovascular AMD, polypoidal choroidal vasculopathy (PCV), and type 3 neovascularization). Results. Among the 512 eyes, 229 (44.7%) did not meet the eligibility criteria. In all the included eyes, the most common reasons for exclusion were good or poor visual acuity (169 eyes, 33.0%), followed by the presence of subretinal hemorrhage (47 eyes, 9.5%). Moreover, good or poor visual acuity was the most common reason for exclusion in all three subtypes of neovascular AMD. The second most common reason was a fovea-involving scar or fibrosis in typical neovascular AMD, subretinal hemorrhage in PCV, and other vascular diseases affecting the retina in type 3 neovascularization. Conclusions. Among the included cases, 44.7% did not meet the eligibility criteria for VIEW study, suggesting that the conclusion derived from clinical trials may not directly reflect the real-world outcomes. Additionally, the reasons for ineligibility differed among the different subtypes of neovascular AMD.

scholarly journals Saffron (Crocus sativus L.) in Ocular Diseases: A Narrative Review of the Existing Evidence from Clinical Studies

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 649 ◽  
Author(s):  
Rebekka Heitmar ◽  
James Brown ◽  
Ioannis Kyrou
Keyword(s):  
Clinical Studies ◽  
Wide Spectrum ◽  
Narrative Review ◽  
Age Related Macular Degeneration ◽  
Crocus Sativus ◽  
Ocular Diseases ◽  
Neuroprotective Effects ◽  
Age Related ◽  
Underlying Mechanisms ◽  
Crocus Sativus L

Saffron (Crocus sativus L.) and its main constituents, i.e., crocin and crocetin, are natural carotenoid compounds, which have been reported to possess a wide spectrum of properties and induce pleiotropic anti-inflammatory, anti-oxidative, and neuroprotective effects. An increasing number of experimental, animal, and human studies have investigated the effects and mechanistic pathways of these compounds in order to assess their potential therapeutic use in ocular diseases (e.g., in age related macular degeneration, glaucoma, and diabetic maculopathy). This narrative review presents the key findings of published clinical studies that examined the effects of saffron and/or its constituents in the context of ocular disease, as well as an overview of the proposed underlying mechanisms mediating these effects.

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