Robyn H Guymer1, Zhichao Wu2, Lauren A B Hodgson2, Emily Caruso2, Kate H Brassington2, Nicole Tindill2, Khin Zaw Aung2, Myra B McGuinness2, Erica L Fletcher3, Fred K Chen4, Usha Chakravarthy5, Jennifer J Arnold6, Wilson J Heriot7, Shane R Durkin8, Jia Jia Lek9, Colin A Harper2, Sanjeewa S Wickremasinghe2, Sukhpal S Sandhu2, Elizabeth K Baglin2, Pyrawy Sharangan2, Sabine Braat10, Chi D Luu2. 1. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Ophthalmology, Department of Surgery, The University of Melbourne, Melbourne, Australia. Electronic address: rhg@unimelb.edu.au. 2. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Ophthalmology, Department of Surgery, The University of Melbourne, Melbourne, Australia. 3. Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, Australia. 4. Centre for Ophthalmology and Visual Science (incorporating the Lions Eye Institute), The University of Western Australia, and the Department of Ophthalmology, Royal Perth Hospital, Perth, Australia. 5. Belfast Health and Social Care Trust, Belfast, Northern Ireland. 6. Marsden Eye Research, Sydney, Australia. 7. Retinology Institute Victoria, Glen Iris, Australia. 8. Adelaide Eye and Retina Centre, Adelaide, Australia. 9. Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Australia. 10. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health and Melbourne Clinical and Translational Sciences, The University of Melbourne, Melbourne, Australia.
Abstract
PURPOSE: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. DESIGN: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. METHODS: Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. MAIN OUTCOME MEASURES: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. RESULTS:Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. CONCLUSIONS: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.
RCT Entities:
PURPOSE: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. DESIGN: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. METHODS:Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. MAIN OUTCOME MEASURES: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. RESULTS: Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. CONCLUSIONS: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.
Authors: Robyn H Guymer; Philip J Rosenfeld; Christine A Curcio; Frank G Holz; Giovanni Staurenghi; K Bailey Freund; Steffen Schmitz-Valckenberg; Janet Sparrow; Richard F Spaide; Adnan Tufail; Usha Chakravarthy; Glenn J Jaffe; Karl Csaky; David Sarraf; Jordi M Monés; Ramin Tadayoni; Juan Grunwald; Ferdinando Bottoni; Sandra Liakopoulos; Daniel Pauleikhoff; Sergio Pagliarini; Emily Y Chew; Francesco Viola; Monika Fleckenstein; Barbara A Blodi; Tock Han Lim; Victor Chong; Jerry Lutty; Alan C Bird; Srinivas R Sadda Journal: Ophthalmology Date: 2019-09-30 Impact factor: 12.079
Authors: Yuhua Zhang; Xiaolin Wang; Srinivas R Sadda; Mark E Clark; C Douglas Witherspoon; Richard F Spaide; Cynthia Owsley; Christine A Curcio Journal: Ophthalmol Retina Date: 2019-10-31
Authors: Susan Vitale; Elvira Agrón; Traci E Clemons; Tiarnan D L Keenan; Amitha Domalpally; Ronald P Danis; Emily Y Chew Journal: JAMA Ophthalmol Date: 2020-06-01 Impact factor: 7.389