Analysis of DR Progression to Identify Risks and Need for Treatment (ALERT)

February 27, 2026 updated by: Association for Innovation and Biomedical Research on Light and Image

The goal of this observational study is to understand whether vascular and structural changes in the eyes caused by diabetes can help predict which people are more likely to experience worsening diabetic retinopathy (a diabetes-related eye disease) and how these eye changes are related to cardiovascular complications.

The study will include about 1,000 people with type 2 diabetes, aged 35 to 90 years, and will take place over twelve months. It may also include a retrospective component, where existing medical and imaging data collected from previous visits (within the last 1 to 5 years) will be analyzed.

The main questions it aims to answer are:

  • Can eye vessel and tissue changes, observed through modern imaging techniques and clinical data, help better describe and predict which cases of diabetic retinopathy will become more severe?
  • Can these same eye changes help predict the presence and risk of cardiovascular problems-such as heart disease or stroke-in people living with type 2 diabetes?

Study Overview

Status

Recruiting

Conditions

Detailed Description

Diabetic Retinopathy (DR) is a leading cause of vision loss in adults with type 2 diabetes (T2D) and is associated with systemic complications, including cardiovascular disease. Early identification of patients at high risk of DR progression and cardiovascular events is critical to optimizing clinical management. Retinal imaging biomarkers, combined with clinical and demographic data, provide an opportunity to better understand disease mechanisms, predict progression of DR and associated cardiovascular complications, and guide personalized interventions.

The aim of this study is to investigate the influence of central versus peripheral retinal lesions on DR progression and staging, characterize associations between retinal biomarkers and cardiovascular risk factors and major adverse cardiovascular events (MACE), and contribute to the understanding of pathophysiological mechanisms underlying DR in T2D patients. The study will also generate a high-quality, harmonized database to support the development of artificial intelligence (AI) models.

This study aims to determine the extent to which central and peripheral retinal lesions, together with quantitative imaging biomarkers, contribute to the progression and staging of DR and the occurrence of cardiovascular complications in patients with T2D. Additionally, in the scope of the ALERT project (supported by Fundação para Ciência e Tecnologia (FCT); COMPETE2030-FEDER-00921900), the data of this clinical study will be used to create a harmonized, high-quality database for the development of exploratory interpretable artificial intelligence models for predicting DR progression and stage as well as predict the values of cardiovascular risk factors, and the risk of developing cardiovascular complications.

Study Type

Observational

Enrollment (Estimated)

1000

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Portugal
    • Coimbra District
      • Portugal, Coimbra District, Portugal, 3000-548
        • Recruiting
        • AIBILI-Clinical Trial Centre
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

1.000 participants with T2D will be included in this study, in a recruitment period of 12 months.

Description

Inclusion Criteria:

  • Diagnosed with type 2 diabetes according to the 1985 WHO criteria.
  • Age between 35 and 90 years.
  • Retrospective visit or referenced patients. For the retrospective visit, a documented follow-up of 1-5 years is required, with at least one clinical visit. For the referenced patients, it is required that they have either diabetic retinopathy at the baseline visit, the presence of at least one cardiovascular risk factor at the baseline visit, or cardiovascular complications at the baseline visit.
  • Signed informed consent.

Exclusion Criteria:

  • Previous laser photocoagulation or intravitreal injections (consider if corticosteroids were administered).
  • Presence of clinically significant macular edema (CSME) with vision loss or requiring immediate treatment.
  • Proliferative diabetic retinopathy.
  • Any ocular surgery within the previous 3 months.
  • Renal Replacement Therapy (Hemodialysis, Peritoneal Dialysis).
  • Severe systemic illness, subject to investigator's judgment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Diabetic Retinopathy Staging
Time Frame: Baseline to 12 months
Change in score on the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS DRSS; range 10-85; higher scores indicate worse severity), measured on Optos Ultra-Widefield Fundus Photography.
Baseline to 12 months
Diabetic Retinopathy (DR) Progression, measured on the OPTOS Ultra-widefield Fundus Photography (UWF-FP)
Time Frame: Baseline to 12 months
Defined as a ≥2-step worsening on the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS DRSS)
Baseline to 12 months
Proportion of participants with ≥15-letter loss in ETDRS Best-Corrected Visual Acuity (BCVA)
Time Frame: Baseline to 12 months
≥15-letter loss on the ETDRS BCVA chart (measured with Snellen or LogMAR charts converted to the ETDRS scale).
Baseline to 12 months
Incidence of Major Adverse Cardiovascular Events (MACE)
Time Frame: Baseline to 12 months
Incidence of myocardial infarction, ischemic stroke, or hospitalization for heart failure, extracted from medical history and confirmed by investigator.
Baseline to 12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of microaneurysms in the central ETDRS area (90°)
Time Frame: Baseline to 12 months
Count of microaneurysms within the central ETDRS grading area (90 degrees), assessed by human graders on Optos Ultra-Widefield Fundus Photography images.
Baseline to 12 months
Number of microaneurysms in the peripheral retina (90-200°)
Time Frame: Baseline to 12 months
Count of microaneurysms in the peripheral retinal area (between 90 and 200 degrees), assessed by human graders on Optos Ultra-Widefield Fundus Photography images.
Baseline to 12 months
Presence of hemorrhages in the central ETDRS area
Time Frame: Baseline to 12 months
Presence of retinal hemorrhages within the central ETDRS grading area (90 degrees), identified by human graders on Optos Ultra-Widefield Fundus Photography. Reported as the percentage of affected eyes.
Baseline to 12 months
Presence of peripheral retinal hemorrhages (90-200°)
Time Frame: Baseline to 12 months
Presence of retinal hemorrhages in the peripheral retina (90-200 degrees), assessed through human grading of Optos Ultra-Widefield Fundus Photography images. Reported as the percentage of affected eyes.
Baseline to 12 months
Presence of exudates in the retina
Time Frame: Baseline to 12 months
Presence of hard exudates identified by human graders on Optos Ultra-Widefield Fundus Photography. Reported as the percentage of eyes displaying ≥1 exudate.
Baseline to 12 months
Presence of cotton wool spots in the retina
Time Frame: Baseline to 12 months
Presence of cotton wool spots identified by human graders on Optos Ultra-Widefield Fundus Photography. Reported as the percentage of affected eyes.
Baseline to 12 months
Correlation between retinal microaneurysm count and glycated hemoglobin (HbA1c)
Time Frame: Baseline to 12 months
Correlation between the number of microaneurysms identified on Optos Ultra-Widefield Fundus Photography and (HbA1c) levels obtained through clinical laboratory testing. Reported as a correlation coefficient (r).
Baseline to 12 months
Retinal vessel density
Time Frame: Baseline to 12 months
Quantitative vessel density measured using Optical Coherence Tomography Angiography. Expressed in inverse millimeters (mm-1)
Baseline to 12 months
Correlation between retinal vessel density and systolic blood pressure
Time Frame: Baseline to 12 months
Correlation between vessel density quantified using Optical Coherence Tomography Angiography and systolic blood pressure collected during clinical evaluation. Reported as a correlation coefficient (r).
Baseline to 12 months
Abnormal intercapillary spaces (AIS) in the retina
Time Frame: Baseline to 12 months
Count of abnormal intercapillary spaces assessed using Optical Coherence Tomography Angiography automated analysis tools. Expressed as the percentage of pixels associated with the presence of abnormal intercapillary spaces relative to the total number of pixels in the slab.
Baseline to 12 months
Correlation between abnormal intercapillary spaces (AIS) and major adverse cardiovascular events (MACE)
Time Frame: Baseline to 12 months
Correlation between the number of abnormal intercapillary spaces measured on Optical Coherence Tomography Angiography and the occurrence of (MACE). Reported as a correlation coefficient (r).
Baseline to 12 months
Retinal venous calibre
Time Frame: Baseline to 12 months
Mean venous calibre measured in micrometers (μm) through automated analysis of Color Fundus Photography images.
Baseline to 12 months
Microaneurysm turnover (MAT) over one year
Time Frame: Baseline to 12 months
Number of microaneurysms appearing and disappearing over a one-year period, quantified through automated analysis of sequential Color Fundus Photography images.
Baseline to 12 months
Retinal fractal dimension
Time Frame: Baseline to 12 months
Fractal dimension of the retinal vascular network, calculated using an automated feature extraction applied to Color Fundus Photography images.
Baseline to 12 months
Foveal Avascular Zone (FAZ) metrics
Time Frame: Baseline to 12 months
Area of the foveal avascular zone measured in square millimeters (mm²) using Optical Coherence Tomography Angiography automated segmentation tools.
Baseline to 12 months
Retinal vascular tortuosity
Time Frame: Baseline to 12 months
Vascular tortuosity calculated from Color Fundus Photography images using validated image analysis algorithms.
Baseline to 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Association for Innovation and Biomedical Research on Light and Image

Collaborators

Fundação para a Ciência e a Tecnologia

Investigators

  • Study Director: Luís Mendes, PhD, Association for Innovation and Biomedical Research on Light and Image

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 3, 2025

Primary Completion (Estimated)

November 1, 2026

Study Completion (Estimated)

November 1, 2027

Study Registration Dates

First Submitted

November 19, 2025

First Submitted That Met QC Criteria

February 10, 2026

First Posted (Actual)

February 18, 2026

Study Record Updates

Last Update Posted (Actual)

March 2, 2026

Last Update Submitted That Met QC Criteria

February 27, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 4C-2025-16

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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