StereoTactic radiotherapy for wet Age-Related macular degeneration (STAR): A randomised, double-masked, sham- controlled, clinical trial comparing low-voltage X-ray irradiation with as needed ranibizumab, to as needed ranibizumab monotherapy

Aim: To determine the safety and efficacy of stereotactic radiotherapy (SRT) for wet (neovascular) AMD. Design: Randomised, double-masked, sham-controlled, multi-centre, pivotal clinical trial. Population: Older adults of either sex receiving anti-VEGF therapy for active, chronic, wet AMD. Intervention: Participants will be allocated in a 2:1 ratio to either 16 Gray SRT (IRay, Oraya, Newark, USA) delivered in a single session, or sham SRT. Both arms will receive intravitreal injections of 0.5 mg ranibizumab (Lucentis)at baseline, and then administered 'as required' (PRN) up to monthly, if predefined retreatment criteria are met. Outcomes: The primary efficacy outcome is the number of ranibizumab injections over 24 months. The secondary efficacy outcome is Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity at 24 months. Other efficacy measures include: •Percentage of participants losing fewer than 15 ETDRS letters •Percentage of participants gaining greater than or equal to 0 ETDRS letters •Percentage of participants gaining greater than or equal to 15 ETDRS letters •Mean total lesion area by fluorescein angiography •Mean total choroidal neovascularisation area by fluorescein angiography •Mean foveal thickness measured using optical coherence tomography (OCT) •Cost per quality adjusted life year (QALY) gained Safety outcome measures will include adverse events and serious adverse events. We will specifically report the incidence of microvascular abnormalities/radiation retinopathy and arteriothrombotic events. Assessments: Participants will be treated with 16 Gray or sham SRT at baseline, with an intravitreal ranibizumab injection. Thereafter they will attend every 28 days for two years for visual acuity, fundus examination, and OCT, with an intravitreal injection of ranibizumab admistered PRN, based on predefined retreatment criteria. Retreatment criteria are as reported in a large study comparing bevacizumab and ranibizumab (CATT; clinicaltrials.gov: NCT 00593450). A safety visit will occur at year 3 and year 4. Fluorescein angiography will be undertaken at baseline, year 1, 2, 3, and 4. Indocyanine green angiography will be undertaken at baseline. Sample size: 411 participants. Statistical analysis: The primary analysis population will be on an intent-to-treat basis. The primary analysis will look at the number of injections (primary outcome) in both arms at 24 months with the analysis being conducted using a regression approach where the baseline value is included in the model as a covariate. The secondary outcome, visual acuity, will be tested statistically for non-inferiority using the same methods. Economic benefit: Data from patient questionnaires will be used to help determine if SRT provides value for money and produces an improvement in patients' quality of vision and quality of life. Participants will complete the National Eye Institute Visual Function Questionnaire (VFQ-25) and the EuroQol EQ5D (with vision bolt on) questionnaires at enrolment, and years 1, 2, 3 and 4. These will allow us to compare results (in terms of vision) against other trials and within the trial, based on a widely used and widely reported vision-specific measure. It will also provide an accepted, generic quality of life measure that can be scored to produce utility values. These will be used to derive QALYs associated with each arm of the trial.