The Diabetic Retinopathy Study (DRS) and Early Treatment Diabetic Retinopathy Study (ETDRS) were two groundbreaking clinical trials that brought a paradigm shift to our management of diabetic retinopathy (DR).1,2 Stemming from these trials, stage-based treatment protocols of non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) were established.3 Panretinal photocoagulation (PRP) and macular focal laser photocoagulation became critical in preventing vision loss in diabetic macular edema (DME) and PDR.4

PRP still stands as the gold standard for the treatment of PDR.5 These trials further led to the United Kingdom Prospective Diabetes Study (UKPDS), which helped establish that the best treatment for mild to moderate NPDR is through tight glycemic control.6 Although, to counter diabetic macular edema, at any point in the spectrum of DR, intravitreal agents with vascular endothelial growth factor (VEGF) inhibitors are currently used as first-line treatment.7

Modern diagnostic tools serve as a backbone to determining DR staging and have evolved significantly. Staging is essential as most treatment protocols are stage-dependent. In the recent past, disease staging was predominantly dependent on clinical exam, which has limitations due to various patient and physician factors–such as the lighting of the equipment, type of the handheld lenses used, patient’s palpebral fissure size, sensitivity to light, and level of cooperation.8

However, with the advent of Optical Coherence Tomography (OCT), subtle anatomical changes can be detected straightforwardly.9 Intravenous fluorescein angiography (IVFA) is the gold standard test to study the fundus microvasculature;10 many ophthalmologists are trending towards OCT-angiography (OCTA) because of some advantages over IVFA. OCTA is quicker, noninvasive, and harbors no risk of allergic reaction (no intravenous fluorescein infusion) as well as the ability to visualize structural morphology and microvasculature in one test.11

Intelligent Evaluation of Diabetic Retinopathy (EviRed) is a European clinical trial that aims to test if AI can be effectively trained to aid ophthalmologists to diagnose stages of DR.12

EviRed Project’s existing details

The primary objective of the EviRed Project is to develop and validate a system aiding the ophthalmologist by improving the decision-making during DR follow-up.13 It intends to replace the current classification of DR, which provides an insufficient prediction precision, as it involves some degree of subjectivity among ophthalmologists. It anticipates that AI will be able to properly integrate data provided by modern fundus imaging devices with other patient medical data.

A cohort of 5000 diabetic patients has been recruited and followed for an average of two years to collect data to train and validate the new prediction system.

Study description

The study will be recruiting a cohort of 5,000 diabetic patients with different stages of DR and following them for an average of 2 years. Each year, general data as well as ophthalmological data will be collected. Retinal images and videos of both eyes will be obtained using different imaging modalities, including ultra-widefield photography, OCT, and OCTA.

The EviRed cohort will be split into two groups: one group of 1,000 patients (validation cohort) will be randomly selected during the inclusion period by an unbalanced draw to be representative of the general diabetic population.14 Their data will be used for the validation of the algorithms. The results of the remaining 4000 patients (training cohort) will be used to train the algorithms.

The primary objective will be the validation of the prognostic tool and evaluation of how accurately the algorithm can predict progression to severe retinopathy in the following year. Secondary objectives will be to evaluate how accurately the algorithm can assess DR severity and individual components of DR complications as well as to compare prediction by algorithm to that made by ophthalmologists based on the current DR classification.

Study design

Actively recruiting observational prospective cohort study involving 5000 participants. The official title of the study is Intelligent Evaluation of Diabetic Retinopathy, and the commencement date was 21 December 2020, with an estimated primary completion date of 21 May 2024.

Outcome measures

The primary outcome measure is progression to severe diabetic retinopathy within a study duration of twelve months. The secondary outcome measure is algorithm performance within a time frame of three years, where algorithms will be evaluated for their automaticity to assess the components of DR and will be compared with human evaluators.15

At each patient’s visit, study investigators will evaluate the risk of DR progression based on the current DR classification and their clinical experience. The clinician will express the risk of DR and its estimated probability of progression as a continuous variable or as a semi-quantitative variable. The performance of the human prediction will be compared to the algorithm using sensitivity, specificity, and area under the curve (AUC).

Study population

The study is targeted towards patients of all sexes who are 18 years or older have either type 1 or type 2 diabetes mellitus (DM) or other rarer forms of DM. The study’s goal is to train the algorithms to predict the progression of DR at one year and exclude DM patients with no risk of progression.16 This cohort of patients will include 10% of patients without DR or minimal NPDR and 90% of patients with moderate or severe NPDR.

Subjects will be excluded from the study if they have a history of vitrectomy, ungradable retinal imaging (IVFA/OCT/OCTA), if unwilling or unable to comply with study procedures, and/or considered part of a vulnerable population (minors, legally detained, incarcerated, patients under legal protection). With this study design, it is estimated that all DR stages will be represented; however, there will be a greater proportion of patients with moderate or severe stages of DR who are at higher risk of DR progression.

The results of this trial are pending at the time of this publication.

Importance of the EviRed Project

In 2018, the FDA permitted the marketing of AI-based devices, such as IDx-DR, to detect specific DM-related eye problems.17 The EviRed study can potentially change the future of diagnosis and treatment of DR, similar to the DRS and ETDRS studies. Integration of AI in clinical practice can change the outlook of the ophthalmic practice in the future. Algorithms in the future devices will be fully automated. Human operators with minimal training can be deployed at ophthalmic and primary care practices to make the early diagnosis of DR easier and more efficient.18

References

This content was originally published here.