Elsevier

Ophthalmology

Volume 126, Issue 6, June 2019, Pages 829-838
Ophthalmology

Original Article
Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration: The LEAD Randomized Controlled Clinical Trial

https://doi.org/10.1016/j.ophtha.2018.09.015Get rights and content
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open access

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.

Abbreviations and Acronyms

AMD
age-related macular degeneration
BCVA
best-corrected visual acuity
BM
Bruch’s membrane
CI
confidence interval
ECM
extracellular matrix
HR
hazard ratio
iAMD
intermediate age-related macular degeneration
MMP
matrix metalloproteinase
nAMD
neovascular age-related macular degeneration
LEAD
Laser Intervention in Early Stages of Age-Related Macular Degeneration
MMI
multimodal imaging
RPD
reticular pseudodrusen
SNL
subthreshold nanosecond laser
2RT®
retinal rejuvenation therapy

Cited by (0)

See Commentary on page 839.

Supplemental material available at www.aaojournal.org.

Financial Disclosure(s): The author(s) have made the following disclosure(s): R.H.G.: Financial support – Bayer, Novartis, Roche Genentech.

F.K.C.: Financial support – Bayer, Novartis, Allergan, Heidelberg Engineering, Alcon, Pfizer.

U.C.: Financial support – Bayer, Novartis, Roche.

J.J.A.: Financial support – Allergan, Bayer, Novartis.

C.A.H.: Financial support – Novartis, Bayer, Allergan; Director – Avalanche Australia.

Supported by the National Health & Medical Research Council of Australia (project grant no.: APP1027624 [R.H.G., C.D.L.]; and fellowship grant nos.: GNT1103013 [R.H.G.], APP1104985 [Z.W.], APP1054712 [F.K.C.], and APP1142962 [F.K.C.]); and Bupa Health Foundation, Australia (R.H.G., C.D.L.). The Centre for Eye Research Australia receives operational infrastructure support from the Victorian Government. Ellex R&D Pty Ltd, Adelaide, Australia, provided partial funding of the central coordinating center and the in-kind provision of Ellex 2RT® laser systems, ongoing support of those systems, and the Macular Integrity Assessment microperimeters for the duration of the study. The web-based Research Electronic Data Capture application and open-source platform OpenClinica allowed secure electronic data capture. The study is sponsored by the Centre for Eye Research Australia, an independent medical research institute and a not-for-profit company. The funders of this study had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. All authors had full access to all the data in the study and approved the final version and the corresponding author had the final responsibility for the decision to submit for publication.

HUMAN SUBJECTS: Human subjects were included in this study. This study was conducted according to the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki, with the protocol approved at all sites by the local institutional review boards. All participants provided informed consent.

No animal subjects were included in this study.

Author Contributions:

Conception and design: Guymer, Wu, Hodgson, Caruso, Brassington, Tindill, Aung, McGuinness, Fletcher, Chen, Chakravarthy, Arnold, Heriot, Durkin, Lek, Harper, Wickremasinghe, Sandhu, Baglin, Sharangan, Luu

Analysis and interpretation: Guymer, Wu, McGuinness, Fletcher, Chen, Chakravarthy, Arnold, Heriot, Durkin, Harper, Braat, Luu

Data collection: Guymer, Wu, Hodgson, Caruso, Brassington, Tindill, Aung, McGuinness, Chen, Chakravarthy, Arnold, Heriot, Durkin, Harper, Wickremasinghe, Sandhu, Baglin, Sharangan, Luu

Obtained funding: Guymer, Luu

Overall responsibility: Guymer, Wu, Hodgson, McGuinness, Fletcher, Chen, Chakravarthy, Arnold, Heriot, Durkin, Braat, Luu

∗

A complete listing of the members of the Laser Intervention in Early Stages of Age-Related Macular Degeneration Study Group is available at www.aaojournal.org.

© 2018 by the American Academy of OphthalmologyThis is an open access article under the CC BY-NC-ND license (<inter-ref xlink: href=http://creativecommons.org/licenses/by-nc-nd/4.0/>http://creativecommons.org/licenses/by-nc-nd/4.0/</inter-ref>).