Stereotactic radiotherapy for neovascular age-related macular degeneration (STAR): a pivotal, randomised, double-masked, sham-controlled device trial.

BACKGROUND

Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity.

METHODS

This pivotal, randomised, double-masked, sham-controlled trial enrolled participants with pretreated chronic active nAMD from 30 UK hospitals. Participants were randomly allocated in a 2:1 ratio to 16-Gray (Gy) SRT delivered using a robotically controlled device or sham SRT, stratified by treatment centre. Eligible participants were aged 50 years or older and had chronic active nAMD, with at least three previous anti-VEGF injections, including at least one in the last 4 months. Participants and all trial and image reading centre staff were masked to treatment allocation, except one unmasked statistician. The primary outcome was the number of intravitreal ranibizumab injections required over 2 years, tested for superiority (fewer injections). The main secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at two years, tested for non-inferiority (five-letter margin). The primary analysis used the intention-to-treat principle, and safety was analysed per-protocol on participants with available data. The study is registered with ClinicalTrials.gov (NCT02243878) and is closed for recruitment.

FINDINGS

411 participants enrolled between Jan 1, 2015, and Dec 27, 2019, and 274 were randomly allocated to the 16-Gy SRT group and 137 to the sham SRT group. 240 (58%) of all participants were female, and 171 (42%) of all participants were male. 241 participants in the 16-Gy SRT group and 118 participants in the sham group were included in the final analysis, and 409 patients were treated and formed the safety population, of whom two patients allocated to sham treatment erroneously received 16-Gy SRT. The SRT group received a mean of 10·7 injections (SD 6·3) over 2 years versus 13·3 injections (5·8) with sham, a reduction of 2·9 injections after adjusting for treatment centre (95% CI -4·2 to -1·6, p<0·0001). The SRT group best-corrected visual acuity change was non-inferior to sham (adjusted mean letter loss difference between groups, -1·7 letters [95% CI -4·2 to 0·8]). Adverse event rates were similar across groups, but reading centre-detected microvascular abnormalities occurred in 77 SRT-treated eyes (35%) and 13 (12%) sham-treated eyes. Overall, eyes with microvascular abnormalities tended to have better best-corrected visual acuity than those without. Fewer ranibizumab injections offset the cost of SRT, saving a mean of £565 per participant (95% CI -332 to 1483).

INTERPRETATION

SRT can reduce ranibizumab treatment burden without compromising vision.

FUNDING

Medical Research Council and National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme.

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests Oraya/Zeiss provided free use of the SRT device at the STAR National Treatment Centres. BCR, TP, YW, HAW, JMO, and JP declare no competing interests. TLJ is a consultant or adviser to 2CTech, Alcon, Dutch Ophthalmic Research Centre, iLumen, Opthea, Outlook Therapeutics, Oxurion, and Regeneron. He has received conference support from Roche, and an advisory board payment from Oraya in 2013. TP has participated in advisory boards for Apellis and received investigator initiated research funds paid to her institution from Boehringen Ingelheim; as well as receiving speakers fees from Heidelberg, Zeiss, and Optos. UC serves on a data monitoring committee for Adverum and is a consultant to Apellis, Boehringer Ingelheim, Isarna, Iveric, and Hoffman La Roche. JEN is an adviser to Solvemed, has received lecture fees from Novartis, and has received conference support from Dutch Ophthalmic Research Centre. HD and SW are financially supported in part by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre. CNL has undertaken contracting work for Opthea. TLJ, LR, RD, CNL, CL, PC and JEN's NHS employer receives site fees for patients enrolled on commercial retinal trials of AMD and other conditions.