Title: 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
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: Age-related macular degeneration (AMD) leads more people to go blind than all other eye diseases combined. 'Wet' AMD occurs when abnormal new blood vessels grow into the macula. The macula is an area inside the back of the eye, which is tightly packed with the light-sensitive cells that give fine central vision for driving, reading, facial recognition etc. Most patients are treated with repeated injections of ranibizumab (Lucentis), bevacizumab (Avastin) , or aflibercept (Eylea) into the eye (these drugs suppresses the new vessel growth). Unsurprisingly, the need for hospital visits every 1-2 months, and regular injections into the eye, is not favoured by patients. The proposed study investigates the use of radiation to treat wet AMD. Radiation preferentially damages proliferating cells, such as those forming the abnormal new blood vessels. It has the potential to kill off the abnormal cells, unlike the injections which just suppress the disease. The radiation is delivered using a robotically controlled device that aims three beams of radiation in through the white of eye, to overlap at the macula. Initial studies of stereotactic radiotherapy (SRT) were promising, and established the best dose of radiation. They showed that radiation has the potential to significantly reduce the need for injections. Each injection costs the NHS approximately £600, hence the potential cost savings are substantial. For those who respond well, disease activity is reduced, and injections can be eliminated or greatly reduced. Eye charities have run focus groups of people with wet AMD to help set priorities, and participants identified the burden of treating wet AMD as one of their most pressing concerns, as it greatly restricts their freedom and quality of life. Repeated injections also carry risks of rare but blinding complications, and long term they may possibly lead to other eye diseases such as glaucoma and atrophy of the macula. The preliminary SRT studies were not designed to determine if the visual outcome was the same, better, or worse than standard injection therapy, and follow up was too short to determine long term risks. A larger study is therefore required to confirm that SRT reduces the number of injections and to determine if the visual outcomes are acceptable. There is also a need for longer term safety monitoring, as radiation damage typically has a delayed onset. The aim of the proposed study is to determine if SRT can maintain vision in the context of fewer eye injections. SRT is not designed to replace anti-VEGF therapy in all patients, but to reduce the frequency of anti-VEGF therapy. STAR will use ranibizumab as the anti-VEGF agent in both the treatment and control arms. Ranibizumab was chosen over bevacizumab as it is licensed for use in the eye, and at present bevacizumab is used in only a small minority of NHS hospitals, such that the results with may be less generalisable. Bevacizumab may slow recruitment if prospective participants are anxious about swapping to an off label treatment, and preliminary discussions with prospective sites indicated some investigators would prefer to use ranibizumab. Further, ranibizumab was used in the phase II INTREPID study (detailed below), which helps inform the STAR statistical analysis. Aflibercept’s mandated dosing in year 1 means it is not possible to determine if radiation reduces the need for anti-VEGF treatment, the primary outcome measure. Whereas the early studies tested a range of doses, this study will only test the dose shown to have the best balance of safety and effectiveness (16 Gray). Participants will be randomly allocated to dummy SRT (0 Gray dose) or live SRT (16 Gray). Neither the treating doctor nor participant will know if a 0 or 16 Gray dose was given. SRT will be performed in approximately 3 national treatment centres, but 25 NHS recruiting hospitals will refer patients for SRT, and then review them afterwards, treating them with ranibizumab as needed. Participants will attend for examination monthly for two years. They will then revert to standard NHS care, but with two further study visits - one at the end year 3 and one at the end of year 4. These two late safety visits are to exclude delayed radiation damage. At the 24 monthly visits participants will have their vision tested on an eye chart, and a laser scan (OCT) of their macula. If the vision drops or the OCT shows disease activity, then they will receive an injection of ranibizumab. Participants will have imaging of the blood vessels in the macula (angiography) at baseline and yearly thereafter for 4 years. The images will be interpreted by an independent, specialist reading centre to quantify the effect of treatment, to study the interaction of radiation and wet AMD, to look for subtle radiation damage, and to subclassify disease to determine who responds best to SRT. We predict that SRT will produce a similar, or possibly better vision than ranibizumab alone, but with fewer injections. With 411 participants we will have 90% certainty that our results are valid. Participants will provide feedback using established questionnaires about how acceptable they found SRT, their visual function, and their overall quality of life. Experienced health economists will then look at the cost of treatment in relation to any improvement in quality of life, to see if SRT is cost-effective. The main outcomes we will monitor are the number of eye injections and visual function on an eye chart, but several other observations will be made. In particular, we will monitor the safety of treatment, any collateral damage caused by radiation, and the interactions between radiation and diseased eye tissue. If proven to be effective, SRT has the potential to save the NHS money, but more importantly, it may reduce the burden of care faced by more than 250,000 people with wet AMD.

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: EYE