Photocoagulation or sham laser in addition to conventional anti-VEGF therapy in macular edema associated with TelCaps due to diabetic macular edema or retinal vein occlusion (TalaDME): a study protocol for a multicentric, French, two-group, non-commercial, active-control, observer-masked, non-inferiority, randomized controlled clinical trial

Abstract

Background: Macular edema (ME) results from hyperpermeability of retinal vessels, leading to chronic extravasation of plasma components into the retina and hence potentially severe visual acuity loss. Current standard of care consists in using intravitreal injections (IVI), which results in a significant medical and economic burden. During diabetic retinopathy (DR) or retinal vein occlusion (RVO), it has recently been shown that focal vascular anomalies (capillary macro-aneurysms, also termed TelCaps) for telangiectatic capillaries may play a central role in the onset, early recurrence, and/or persistence of ME. Since targeted photocoagulation of TelCaps may improve vision, identification, and photocoagulation of TelCaps, it may represent a way to improve management of ME.

Objective: The Targeted Laser in (Diabetic) Macular Edema (TalaDME) study aims to evaluate whether ICG-guided targeted laser (IGTL), in association with standard of care by IVI, allows reducing the number of injections during the first year of treatment compared with IVI only, while remaining non-inferior for visual acuity.

Methods: TalaDME is a French, multicentric, two-arms, randomized, sham laser-controlled, double-masked trial evaluating the effect of photocoagulation of TelCaps combined to IVI in patients with ME associated with TelCaps. Patients with vision loss related to center involved ME secondary to RVO or DR and presenting TelCaps are eligible. Two hundred and seventy eyes of 270 patients are randomized in a 1:1 ratio to standard care, i.e., IVI of anti-VEGF solely (control group) or combined with IGTL therapy (experimental group). Stratification is done on the cause of ME (i.e., RVO versus diabetes). Anti-VEGF IVI are administered to both groups monthly for 3 months (loading dose) and then with a pro re nata regimen with a monthly follow-up for 12 months. The primary endpoint will be the number of IVI and the change in visual acuity from baseline to 12 months. Secondary endpoints will be the changes in central macular thickness, impact on quality of life, cost of treatment, and incremental cost-utility ratio in each groups.

Key safety: Rare but severe AE linked to the use of IVI and laser, and previously described, are expected. In the sham group, rescue laser photocoagulation may be administered by the unmasked investigator if deemed necessary at month 3.

Discussion: The best management of ME associated with TelCaps is debated, and there have been no randomized study designed to answer this question. Given the fact that TelCaps may affect 30 to 60% of patients with chronic ME due to DR or RVO, a large number of patients could benefit from a specific management of TelCaps. TalaDME aims to establish the clinical and medico-economic benefits of additional targeted laser. The results of TalaDME may raise new recommendations for managing ME and impact healthcare costs.

Trial registration: EudraCT: 2018-A00800-55/ NCT03751501. Registration date: Nov. 23, 2018.

Keywords: Diabetic retinopathy; Laser; Macular edema; Photocoagulation; Retinal vein occlusion; Telangiectatic capillaries (TelCaps).

Fig. 1

TelCaps before and after targeted laser photocoagulation. Left: A large TelCaps is visible on B-scan, with adjacent cystic edema, and characterized by a late ICG staining, located at the center of the macular thickening. Right: 2 months after targeted laser, the TelCaps is closed, leaving a hyper reflectivity on OCT B-scan. No ICG staining is visible, confirming the complete closure of the TelCaps, and associated with a complete resolution of macular edema

Fig. 2

OCT map showing the 4 macular zones used to locate from the fovea and example of a TelCaps’ aggregate. A Color fundus photograph showing circinate exudates. B Late frame ICG (12 mn) showing multiple lesions located within a 1000-μm-diameter circle. Note the contrast between the background fluorescence and the TelCaps and the hypofluorescence of vessels. C ETDRS map showing the 4 macular zones used for TelCaps location. Zone 1: inside a 1-mm-diameter circle (< 500 μm of the center of the macula). Zone 2: inside a 3-mm-diameter circle (between 500 and 1500 μm of the center of the macula). Zone 3: inside a 6-mm-diameter circle (between 1500 and 3000 μm of the center of the macula). Zone 4: outside a 6-mm-diameter circle (beyond 3000 μm of the center of the macula. D Inter-papillomacular area (inside broken lines) represents the exclusion zone for photocoagulation

Fig. 3

OCT acquisition protocol. Upper row: macular cube centered on the macula (30 × 25°, spacing minimal 60 and maximum 120 μm, HR, ART 1). Bottom row: Macular cube performed on the intermediate ICG frame ( 5 mn) with measurement of TelCaps size and distance to fovea

Fig. 4

Scheme of the treatment arms

Fig. 5

Illustration of different presentations of telangiectatic capillaries by optical coherence tomography. Top row, a 76-year-old man; bottom row, case 2, a 65-year-old man. Note the presence of intraluminal material (arrow), as a hypo-reflective croissant, narrowing the passage of blood flow (from Castro Farias D et al., Br J Ophthalmol 2019)