Stereotactic Radiotherapy for Wet AMD (STAR)

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 National Health Service (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.

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 bevacizumab 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.

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 of 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.