Examining the LEAD trial

The LEAD study or Laser Intervention in early stages of age-related macular degeneration (AMD) trial was a world-first study into the safety and efficacy of the 2RT laser as a possible treatment for people with earlier stages of AMD to slow or prevent progression to late-stage AMD.


Owned by AlphaRET (a subsidiary of Nova Eye Medical, formerly Ellex), the 2RT laser is a novel, ultra-low energy nanosecond laser. In the LEAD trial the 2RT ‘retinal rejuvenation therapy’ treatment showed promise as an effective intervention in selected cases of intermediate AMD, in which patients exhibit large drusen (a form of waste deposit associated with retinal disease) and no signs of cell death, said its parent company in a press statement at the time. “Although the trial did not meet its primary endpoint for the patient population as a whole, the treatment effect of Ellex 2RT was found to differ based on the clinical classification of AMD. Specifically, there was a four-fold reduction in the rate of disease progression in patients without coexistent reticular pseudodrusen (RPD), a key biomarker of retinal dysfunction, which characterised 76% of the trial population.”


However, given that nearly a quarter of trial patients, those with RPD showed a higher rate of disease progression, the main conclusion was one of caution.


“The results of the LEAD trial showed encouraging outcomes in reducing progression to late-stage AMD in carefully selected patients,” said Macular Disease Foundation of Australia (MDFA) CEO Dee Hopkins. “At this stage, until further studies into the long-term efficacy and safety are available, the MDFA only recommends use of the 2RT laser within a well-conducted clinical trial setting.”


In a case study review published last year*, Dr Leo Sheck, an ophthalmologist specialising in medical retina, said, “It is my personal opinion that 2RT laser treatment should not be offered to patients with reticular pseudodrusen as there is evidence of harm. But a careful discussion on 2RT laser, especially regarding the LEAD trial results, is warranted for those with drusen without reticular pseudodrusen.”


Hamilton-based ophthalmologist Dr David Worsley has employed the 2RT laser since 2013 for patients with AMD and very high-risk characteristics for disease progression. "These patients are at the cliff end of the spectrum and face a very grim outlook,” he said.


The LEAD study confirmed 2RT to be very safe, but any treatment benefits were confounded by study design around RPD disease, said Dr Worsley. “When LEAD was designed, the importance of RPD in risk of progression was poorly understood. If LEAD were designed based on what we now know, RPD would have been part of the randomisation process and the results may well have been definitive. Instead, the massive 76% risk reduction for eyes without RPD was shown in a secondary effect modification analysis of LEAD data.”  


Dr Worsley said in his opinion, and given his patient experience, there is good reason to be optimistic that a large AMD risk reduction with the 2RT laser will be confirmed by a further study of eyes without RPD. In the meantime, he agrees with Dr Sheck and currently only offers treatment for patients without significant RPD. “From my practice audit of the outcomes of very high-risk eyes without RPD, the rate of progression to late AMD appears to be much lower than I would expect from natural history; that is, real-world experience appears to mirror LEAD.”


Dr Worsley’s three-year follow up data is currently being analysed by senior statistician Dr Jennie Louise from the University of Adelaide, with the intention of publishing a real-world experience. “Hopefully, this will give a little further insight - but we definitely need the new phase three study,” he said.




With additional reporting by Lesley Springall


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