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Microvascular abnormalities secondary to radiation therapy in neovascular age-related macular degeneration: findings from the INTREPID clinical trial
  1. Florentina Joyce Freiberg1,
  2. Stephan Michels1,2,
  3. Alyson Muldrew3,
  4. Jason Slakter4,
  5. Denis O’Shaughnessy5,
  6. Alan Czeszynski6,
  7. Linda Danielson7,
  8. Timothy L Jackson8,
  9. Usha Chakravarthy9
  1. 1 Department of Ophthalmology, City Hospital Triemli, Zurich, Switzerland
  2. 2 Augenklinik, University of Zurich, Zurich, Switzerland
  3. 3 Central Angiographic Resource Facility, Queen’s University of Belfast, Belfast, UK
  4. 4 Retina Vitreous Consultants of New York, Digital Angiography Reading Center, New York City, New York, USA
  5. 5 Clinical Development, Aura, 85 Bolton Street, Cambridge, Massachussetts, USA
  6. 6 Department of Research and Development, Neurovision Imaging LLC, 1395 Garden Highway, Sacramento, California 95833, USA
  7. 7 The International Drug Development Institute, Louvain-la-Neuve, Belgium
  8. 8 Ophthalmology, King’s College London, London, UK
  9. 9 Centre for Experimental Medicine, Queen’s University of Belfast, Belfast, UK
  1. Correspondence to Dr Usha Chakravarthy, Center for Experimental Medicine, Queen’s University of Belfast, Belfast BT12 6BA, UK; u.chakravarthy{at}


Purpose To report the incidence and features of retinal microvascular abnormalities (MVAs) occurring secondary to stereotactic radiotherapy (SRT) in a randomised double-masked sham-controlled clinical trial at 21 European sites.

Methods Two hundred and thirty participants with neovascular age-related macular degeneration (AMD) treated with at least three intravitreal antivascular endothelial growth factor (anti-VEGF) injections prior to enrolment, and demonstrating a continuing need for re-treatment. Interventions: 16 Gy, 24 Gy or sham SRT. All three groups received pro re nata anti-VEGF injections if the lesion was judged to be active at review visits. Colour fundus images from baseline and 6 months and fluorescein angiograms from baseline and annual visits were graded for measures of morphological outcome and safety using a prespecified protocol with accompanying definitions to distinguish RT-related MVA from non-specific retinal vessel abnormalities that are known to occur in neovascular AMD. The main outcome measure was MVA detected by months 12, 24 and 36 after enrolment.

Results The frequency of MVAs in the combined SRT arms was 0% in year 1, 13.1% in year 2 and 30.3% in year 3. The area of MVA was small and the mean change in visual acuity in year 2 was similar in a subset of SRT eyes with MVAs, versus those without MVAs. MVA was considered to have possibly contributed to vision loss in 2 of 18 cases with MVA in year 2, and 5 of 37 cases in year 3.

Conclusion Treatment with SRT is associated with development of subtle MVAs that have little or no impact on visual outcome. These findings can help clinicians recognise the retinal MVAs that occur in response to SRT.

  • macula
  • neovascularisation
  • degeneration

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  • Contributors TLJ, UC, DOS, AC were substantial contributors to the conception and design of the work. AM UC JS DO AC TLJ SM and LD were involved in the acquisition and interpretation of data. The analysis was undertaken by IDDI (LD) who were the sponsor’s assigned data management and statistical provider . FJF TJ, SM and UC drafted the manuscript and all authors revised it for intellectual content. All authors gave final approval of the version published.

  • Funding This study was funded and sponsored by Oraya Therapeutics. The sponsor was responsible for the design and conduct of the study. The sponsor played no role in the development of the reading center grading protocols.

  • Competing interests UC and TLJ have received honoraria for attendance at advisory boards and have acted as consultants to Oraya therapeutics. AM has no conflicts to report. JS, FF and SM report compensations for their time. DOS and AC were employees of Oraya Therapeutics at the time of this study. 

  • Patient consent Obtained.

  • Ethics approval NHS Research Ethics Committee, 10/NIR02/40.

  • Provenance-and-peer-review Not commissioned; externally peer reviewed.

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