Longitudinal Observational Study of Diabetic Retinopathy Progression in Type 2 Diabetes Patients

Official title

IMaging Pre-PrOlifeRative sTAge of Diabetic retiNopaThy to Guarantee Timely Treatment - IMPORTANT

Overview

The purpose of this clinical study is to explore imaging, functional and systemic biomarkers of diabetic retinopathy (DR) progression, in Type 2 Diabetes (T2D) patients with moderate to severe non-proliferative diabetic retinopathy (NPDR) and mild proliferative diabetic retinopathy (PDR) using state of the art methodologies, commonly applied in clinical practice, over a period of two years. This study will provide longitudinal data to better understand retinal changes in moderate to severe diabetic retinopathy and early proliferative diabetic retinopathy and help guide timely interventions to prevent vision loss.

Detailed description

Diabetes Mellitus (DM) is an important public health problem, affecting about 589 million people in the world, and expected to reach 853 million by 2050. Active screening for DR is important because most patients may be asymptomatic until the very late stages. Nonproliferative diabetic retinopathy (NPDR) itself may be associated with reduced visual function and quality of life measures (Willis et al., 2017).

The molecular pathophysiology of DR is complex, and a complete model of the disease is still being elucidated. The oxidative stress in diabetes upregulates multiple cytokines and chemokines, such as vascular endothelial growth factor (VEGF), angiopoietins, tumour necrosis factor (TNF), interleukins (ILs) and matrix metalloproteinases (MMPs) that leads to breakdown of the blood-retinal-barrier (BRB). Also, retinal capillary obstruction (leukostasis) or dropout (apoptosis of vascular cells) in diabetes leads to tissue ischemia and hypoxia causing increased retinal VEGF expression through transcriptional regulation by hypoxia-inducible factor 1 alpha (HIF-1α) (Arjamaa \& Nikinmaa, 2006; Whitehead et al., 2019).

The risk of developing DR complications increases over time, with increasing areas of capillary nonperfusion underpinning progression to more severe forms and development of complications as PDR or diabetic macular edema (DME), driven by hypoxia and hyperexpression of proangiogenic growth factors. However, this risk varies widely, independently of metabolic control. Differentiating patients with higher risk of progression and development of vision-threatening complications (VTC; DME and PDR) is of paramount importance for efficient treatment of the disease in order to prevent vision disability and achieve better visual outcomes. Recent developments in terms of retina imageology, namely Optical Coherence Tomography (OCT) and OCT Angiography (OCTA), have improved the understanding of DR pathophysiology and evolution, with a better characterization of venous abnormalities including occlusion, tortuosity, dilatation, looping or beading. OCTA examination is faster and safer compared to examination with fluorescein angiography (FA), and it can visualise the retinal vasculature in any layer of the retina. OCTA has the potential to become the examination of choice to identify eyes at risk of progression and development of VTC.

The purpose of this observational, non-interventional, prospective, and longitudinal clinical study is to explore imaging, functional and systemic biomarkers of DR progression, in T2D patients with moderate to severe NPDR and mild PDR - Diabetic Retinopathy Severity Scale (DRSS) levels 43, 47, 53, and 61 - using state of the art methodologies, commonly applied in clinical practice.

Follow-up visits will be performed every 6 months for 2 years with a total of 5 visits. Participants will undergo the following assessments: multimodal retinal imaging, including OCT, OCTA, ultra-widefield (UWF) fundus fluorescein angiography (FFA) and fundus photography (FP), and color fundus photography (CFP); functional testing: best corrected visual acuity (BCVA) and microperimetry (Macular Integrity Assessment, MAIA); collection of systemic health variables, including glycated hemoglobin (HbA1c), blood pressure, diabetes duration, and relevant comorbidities.

Primary outcome measures

• Changes in capillary skeletonized vessel density (SVD) [Time frame: Baseline to 24 months]
• Changes in capillary perfusion density (PD) using OCTA [Time frame: Baseline to 24 months]
• Foveal Avascular Zone (FAZ) area [Time frame: Baseline to 24 months]
• Foveal Avascular Zone (FAZ) perimeter [Time frame: Baseline to 24 months]
• Foveal Avascular Zone (FAZ) circularity [Time frame: Baseline to 24 months]
• Changes in retinal ischemic area using UWF FFA [Time frame: Baseline to 24 months]
• Changes in central retinal thickness (CRT) [Time frame: Baseline to 24 months]
• Changes in central intraretinal fluid [Time frame: Baseline to 24 months]
• Changes in Disorganisation of Retinal Inner Layers (DRIL) [Time frame: Baseline to 24 months]
• Changes in Disorganisation of Retinal Outer Layers (DROL) [Time frame: Baseline to 24 months]

Secondary outcome measures (5)

• Changes in DRSS levels [Time frame: Baseline to 24 months]
• Changes in Best Corrected Visual Acuity (BCVA) [Time frame: Baseline to 24 months]
• Retinal sensitivity using MAIA Microperimetry [Time frame: Baseline to 24 months]
• Changes in Intraretinal Microvascular Abnormalities (IRMAs) [Time frame: Baseline to 24 months]
• Changes in neovascularization (NV) [Time frame: Baseline to 24 months]

Eligibility criteria

Inclusion criteria

• Type 2 diabetes mellitus (T2D) according to 1985 World Health Organization (WHO) criteria.
• Age between 35 and 80 years.
• Best-corrected visual acuity (BCVA) ≥ 69 letters (20/40).
• Refraction with a spherical equivalent less than 5 diopters.
• Non-proliferative diabetic retinopathy (NPDR; DRSS levels 43, 47, 53) or mild proliferative diabetic retinopathy (PDR; DRSS level 61: Neovascularization Elsewhere (NVE) < ½ disc area in ≥ 1 quadrant, no Neovascularization of the Disc (NVD), no vitreous or sub-hyaloid hemorrhage), in which panretinal photocoagulation (PRP) and/or intravitreal anti-VEGF treatment can safely be deferred for at least 6 months, based on consensus between patient and investigator - using ETDRS criteria, 7-field equivalent area on ultra-widefield fundus imaging.
• Ability to understand and sign the written Informed Consent Form (ICF).

Exclusion criteria

• Central subfield thickness (CST) > 400 μm (fluid allowed if CST ≤ 400 μm and foveal contour is normal, as determined by the Central Reading Centre, and treatment is not immediately required).
• Any sign of retinal fibrovascular proliferation.
• Uncontrolled glaucoma (intraocular pressure > 25 mmHg regardless of concomitant IOP-lowering medications) or neovascular glaucoma.
• Any sign of iris neovascularization, vitreous, or pre-retinal hemorrhage.
• Other retinal vascular diseases (ocular ischemic syndrome, retinal arterial or venous occlusion, exudative age-related macular degeneration, etc.).
• Previous panretinal photocoagulation (PRP) or intravitreal injection treatment.
• Any eye surgery within 6 months prior to the inclusion visit.
• Significant media opacities including severe cataract, corneal scarring or edema, or vitreous hemorrhage that precludes fundus evaluation.
• Pupil dilation < 5 mm.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Portugal · 1 center

• AIBILI-CEC (AIBILI-Clinical Trial Centre) — Coimbra

Publications

• Arjamaa O, Nikinmaa M. Oxygen-dependent diseases in the retina: role of hypoxia-inducible factors. Exp Eye Res. 2006 Sep;83(3):473-83. doi: 10.1016/j.exer.2006.01.016. Epub 2006 Jun 5. PMID 16750526
• Willis JR, Doan QV, Gleeson M, Haskova Z, Ramulu P, Morse L, Cantrell RA. Vision-Related Functional Burden of Diabetic Retinopathy Across Severity Levels in the United States. JAMA Ophthalmol. 2017 Sep 1;135(9):926-932. doi: 10.1001/jamaophthalmol.2017.2553. PMID 28750122
• Whitehead M, Osborne A, Widdowson PS, Yu-Wai-Man P, Martin KR. Angiopoietins in Diabetic Retinopathy: Current Understanding and Therapeutic Potential. J Diabetes Res. 2019 Aug 14;2019:5140521. doi: 10.1155/2019/5140521. eCollection 2019. PMID 31485452

Identifiers

NCT: NCT07458516 · 4C-2025-17

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗