Vitrectomy, subretinal Tissue plasminogen activator and Intravitreal Gas for submacular haemorrhage secondary to Exudative Age-Related macular degeneration (TIGER): study protocol for a phase 3, pan-European, two-group, non-commercial, active-control, observer-masked, superiority, randomised controlled surgical trial

Abstract

Background: Neovascular (wet) age-related macular degeneration (AMD) can be associated with large submacular haemorrhage (SMH). The natural history of SMH is very poor, with typically marked and permanent loss of central vision in the affected eye. Practice surveys indicate varied management approaches including observation, intravitreal anti-vascular endothelial growth factor therapy, intravitreal gas to pneumatically displace SMH, intravitreal alteplase (tissue plasminogen activator, TPA) to dissolve the clot, subretinal TPA via vitrectomy, and varying combinations thereof. No large, published, randomised controlled trials have compared these management options.

Methods: TIGER is a phase 3, pan-European, two-group, active-control, observer-masked, superiority, randomised controlled surgical trial. Eligible participants have large, fovea-involving SMH of no more than 15 days duration due to treatment-naïve or previously treated neovascular AMD, including idiopathic polypoidal choroidal vasculopathy and retinal angiomatous proliferation. A total of 210 participants are randomised in a 1:1 ratio to pars plana vitrectomy, off-label subretinal TPA up to 25 μg in 0.25 ml, intravitreal 20% sulfahexafluoride gas and intravitreal aflibercept, or intravitreal aflibercept monotherapy. Aflibercept 2 mg is administered to both groups monthly for 3 doses, then 2-monthly to month 12. The primary efficacy outcome is the proportion of participants with best-corrected visual acuity (BCVA) gain of ≥ 10 Early Treatment Diabetic Retinopathy (ETDRS) letters in the study eye at month 12. Secondary efficacy outcomes (at 6 and 12 months unless noted otherwise) are proportion of participants with a BCVA gain of ≥ 10 ETDRS letters at 6 months, mean ETDRS BCVA, Radner maximum reading speed, National Eye Institute 25-item Visual Function Questionnaire composite score, EQ-5D-5L with vision bolt-on score, Short Warwick and Edinburgh Mental Wellbeing score, scotoma size on Humphrey field analyser, and presence/absence of subfoveal fibrosis and/or atrophy and area of fibrosis/atrophy using independent reading centre multimodal image analysis (12 months only). Key safety outcomes are adverse events, serious adverse events, and important medical events, coded using the Medical Dictionary for Regulatory Activities Preferred Terms.

Discussion: The best management of SMH is unknown. TIGER aims to establish if the benefits of SMH surgery outweigh the risks, relative to aflibercept monotherapy.

Trial registration: ClinicalTrials.gov NCT04663750 ; EudraCT: 2020-004917-10.

Keywords: Aflibercept; Alteplase; Anti-vascular endothelial growth factor (anti-VEGF); Cost-effectiveness; Economic analysis; Gas tamponade; Neovascular age-related macular degeneration; Pars plana vitrectomy; Quality-adjusted life year (QALY); Randomised controlled trial; Submacular haemorrhage; Surgery; Tissue plasminogen activator.

Conflict of interest statement

TJ has no conflicts of interests in relation to the IMP under evaluation, or SMH. His employer has received site payments from Bayer for participants enrolled on commercial clinical trials of aflibercept. He serves as a consultant for Opthea, a company investigating a novel treatment for wet AMD. His employer has received payments for trials of other novel and licensed treatments for wet AMD, and he has received research grants from commercial organisations for treatments of wet AMD. RD and CNL’s employer has received payments for trials of novel and licensed treatments for wet AMD, including commercial trials of Eylea. CB’s post is part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London; the views she expresses are her own and not necessarily those of the NIHR or the Department of Health and Social Care. JvM was on the Board of Euretina when it commissioned Fight for Sight to run the call for funding but left the Board in 2019 before the grant was awarded and was not an applicant on the bid.

© 2022. The Author(s).

Figures

Fig. 1

Trial Participant Flow Diagram

Fig. 2

Recruitment Projection Diagram

Fig. 3

TIGER Study Organisation