Elsevier

Ophthalmology Retina

Volume 3, Issue 12, December 2019, Pages 1026-1034
Ophthalmology Retina

Original Article
Secondary and Exploratory Outcomes of the Subthreshold Nanosecond Laser Intervention Randomized Trial in Age-Related Macular Degeneration: A LEAD Study Report

https://doi.org/10.1016/j.oret.2019.07.008Get rights and content

Purpose

To evaluate the secondary and exploratory outcomes of the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study, a 36-month trial of a subthreshold nanosecond laser (SNL) treatment for slowing the progression to late age-related macular degeneration (AMD) in its early stages.

Design

Multicenter, randomized, sham-controlled trial.

Participants

Two-hundred ninety-two patients with bilateral large drusen.

Methods

Participants were randomly assigned to receive SNL or sham treatment to the study eye at 6-month intervals.

Main Outcome Measures

The secondary outcome measure of the LEAD study was the time to development of late AMD, defined by multimodal imaging in the non–study eye. The exploratory outcome measures were the rate of change in best-corrected visual acuity (BCVA), low-luminance visual acuity, microperimetric mean sensitivity, drusen volume in the study and non–study eyes, and participant-reported outcomes based on the Night Vision Questionnaire and Impact of Vision Impairment questionnaire.

Results

Progression to late AMD in the non–study eye was not significantly delayed with SNL treatment (hazard ratio, 0.83; 95% confidence interval, 0.40–1.71; P = 0.611). There was no evidence of effect modification based on the coexistence of reticular pseudodrusen; interaction P = 0.065). There was no significant difference between study groups in the rate of change of low-luminance visual acuity, microperimetric mean sensitivity, and drusen volume in the study or non–study eyes, and Night Vision Questionnaire and Impact of Vision Impairment questionnaire scores (all P ≥ 0.167). The rate of BCVA decline was slightly higher for participants in the SNL group compared with the sham treatment group in the study eye (–0.54 and 0.23 letters/year, respectively; P < 0.001) but not the non–study eye (–0.48 and –0.56 letters/year, respectively; P = 0.628).

Conclusions

Subthreshold nanosecond laser treatment of one eye did not have an effect on delaying progression to late AMD in the fellow eye and did not, in general, have an impact on the exploratory structural, functional, and participant-reported outcomes.

Section snippets

Methods

Details of the design of the LEAD study have been reported in detail previously.5 The LEAD study was a randomized, sham-controlled clinical trial conducted at 5 sites in Australia and one site in Northern Ireland. This study is registered with the Australian New Zealand Clinical Trials Registry (identifier, ACTRN12612000704897) and clinicaltrials.gov (identifier, NCT01790802), and it was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical

Results

In the LEAD study, 292 participants were randomly assigned to receive SNL or sham treatment; these participants were on average 70 years old, were primarily female (74%), and of white descent (90%), and 47% were past or current smokers; the full details of the characteristics of these participants have been described in detail previously.5, 9

Discussion

This article presents findings for the secondary and exploratory outcomes of the LEAD study. We observed that SNL treatment of one eye did not have a significant effect on the rate of progression to late AMD based on MMI in the fellow untreated eye. In addition, we did not detect any significant difference in the rate of change in the exploratory outcome measures between the treatment groups, except for a slightly faster rate of decline in BCVA in the study eye of the SNL group compared with

Conclusions

Subthreshold nanosecond laser treatment did not delay progression to late AMD significantly in the non-treated, fellow eyes of individuals with bilateral large drusen. However, there was some weak evidence of effect modification by the coexistence of RPD at baseline in the fellow eye, in a similar manner as noted previously in the treated study eye.9 These findings suggest that direct treatment of an eye may be necessary to harness the full potential effect of the SNL treatment. Furthermore,

References (25)

  • A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS Report No. 8

    Arch Ophthalmol

    (2001)
  • Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration

    JAMA

    (2013)
  • Cited by (31)

    • Reticular Pseudodrusen on the Risk of Progression in Intermediate Age-Related Macular Degeneration

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      Understanding RPD and their role in vision loss in AMD remains important, even if there is not a significant association between their presence and disease progression in the early stages of AMD. We recently reported in a post hoc analysis that the presence of RPD was a potentially significant treatment effect modifier in the Laser Intervention in the Early Stages of AMD (LEAD) Study.28,43 Namely, those without coexistent RPD showed a 4-fold reduction in the rate of progression to late AMD with novel subthreshold nanosecond laser treatment, whereas those with coexistent RPD showed a more than 2-fold increase in the rate of developing late AMD, in individuals with bilateral large drusen.28

    • Reticular pseudodrusen: A critical phenotype in age-related macular degeneration

      2022, Progress in Retinal and Eye Research
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      We consider this possibility by reviewing the evidence available from treatment studies that have examined the impact of RPD. The LEAD Study is a 36-month multicenter, randomized-controlled trial that evaluated the efficacy of a subthreshold nanosecond laser (SNL) intervention for slowing the development of late AMD complications in the early stages of AMD (Guymer et al., 2019; Lek et al., 2017; Wu et al., 2019). Evaluating 292 participants with bilateral large drusen, we observed in the LEAD study that overall, there was no significant difference in the rate of progression to late AMD between those who were randomized to the SNL and sham treatment groups.

    • Subthreshold Nanosecond Laser in Age-Related Macular Degeneration: Observational Extension Study of the LEAD Clinical Trial

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      Longer-term follow-up in this extension study revealed that statistically significant differences in the change in BCVA of the study eye from baseline at the 60-month visit between the two groups no longer existed, nor did significant differences in the rate of BCVA change over time during visits where late AMD had not developed (albeit in a similar trend). This is an important and reassuring finding, and it is consistent with our previous findings that the significant between-group difference in BCVA of the study eye in the LEAD study was not reflected in differences seen with other visual function measures (e.g., microperimetric sensitivity or low-luminance visual acuity).21 However, we found in this extension study that although BCVA decreased over time in the non-study eye, the amount of change from baseline at 60 months for the SNL group was significantly less (2.1 letters on average) than the change from baseline seen in the sham group.

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    Supplemental material available at www.ophthalmologyretina.org.

    Financial Disclosure(s): R.H.G.: Personal fees -- Bayer, Novartis, Roche Genentech, and Apellis outside the submitted work; Research grant -- Bayer outside the submitted work.

    F.K.C.: Personal fees -- Bayer, Novartis, Allergan, Heidelberg Engineering, Alcon, and Pfizer outside the submitted work; Research grant -- Novartis and Bayer outside the submitted work.

    U.C.: Personal fees --Bayer, Novartis, and Roche outside the submitted work; Research grant -- Bayer, Novartis, and Roche outside the submitted work.

    J.J.A.: Personal fees from Allergan, Bayer, and Novartis.

    C.A.H.: Personal fees -- Novartis, Bayer, and Allergan and a director of Avalanche Australia outside the submitted work.

    S.S.W.: Personal fees -- Allergan and Bayer outside the submitted work.

    W.J.H.: Personal fees -- Alcon, Bayer, and Novartis outside the submitted work.

    R.P.F.: Personal fees -- Novartis, Bayer, Santen, Opthea, Novelion, Retina Implant, Oxford Innovation; Research grant -- Novartis outside the submitted work.

    Supported by National Health & Medical Research Council of Australia (project grant APP1027624 [R.H.G. and C.D.L.], and fellowship grant GNT1103013 (R.H.G.), APP1104985 [Z.W.], APP1054712 [F.K.C.], APP1142962 [F.K.C.] and GNT1128343 [S.S.W.]), and BUPA Health Foundation (Australia) (R.H.G. and 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 (REDCap) 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.

    HUMAN SUBJECTS: Human subjects were included in this study. This study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the tenets of the Declaration of Helsinki. Institutional review board approval was obtained at all sites, and all participants provided written informed consent.

    No animal subjects were used in this study.

    Author Contributions:

    Research design: Wu, Luu, Hodgson, Caruso, Brassington, Tindill, Aung, Harper, Wickremashinghe, Sandhu, McGuinness, Chen, Chakravarthy, Arnold, Heriot, Cohn, Baglin, Sharangan, Guymer

    Data acquisition and/or research execution: Wu, Luu, Hodgson, Caruso, Brassington, Tindill, Aung, Harper, Wickremashinghe, Sandhu, McGuinness, Chen, Chakravarthy, Arnold, Heriot, Durkin, Cohn, Baglin, Sharangan, Guymer

    Data analysis and/or interpretation: Wu, Luu, Harper, Wickremashinghe, Sandhu, McGuinness, Chen, Chakravarthy, Arnold, Heriot, Durkin, Wintergerst, Gorgi Zadeh, Schultz, Finger, Guymer

    Obtained funding: Luu, Guymer

    Manuscript preparation: Wu, Luu, Hodgson, McGuiness, Chen, Chakravarthy, Arnold, Heriot, Wintergerst, Schultz, Finger, Guymer

    LEAD Study Group authors are listed in Supplementary Material 1 (available at www.ophthalmologyretina.org).

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