How does low-dose atropine perform for children in Australia?

Paper title: Low-concentration atropine eyedrops for myopia control in a multi-racial cohort of Australian children: A randomised clinical trial

Authors: Samantha Sze-Yee Lee (1), Gareth Lingham (1,2), Magdalena Blaszkowska (1), Paul G Sanfilippo (3), Adrian Koay (1,4), Maria Franchina (1), Audrey Chia (5,6), James Loughman (2), Daniel Ian Flitcroft (7), Christopher J Hammond (8), Augusto Azuara-Blanco (9), Julie M Crewe (1), Antony Clark (1), David A Mackey (1,3,10)

1. Centre for Ophthalmology and Visual Sciences (incorporating the Lions Eye Institute), University of Western Australia, Perth, Western Australia, Australia.
2. Centre for Eye Research Ireland, School of Physics, Clinical and Optometric Sciences, Technological University Dublin, Dublin, Ireland.
3. Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.
4. Geraldton Eye Surgery, Geraldton, Western Australia, Australia.
5. Singapore National Eye Centre, Singapore, Singapore.
6. Singapore Eye Research Institute, Singapore, Singapore.
7. Department of Ophthalmology, Children's Health Ireland at Temple Street, Dublin, Ireland.
8. Departments of Ophthalmology and Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital, London, UK.
9. School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
10. School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.

Date: August 2022

Reference:  Lee SS, Lingham G, Blaszkowska M, Sanfilippo PG, Koay A, Franchina M, Chia A, Loughman J, Flitcroft DI, Hammond CJ, Azuara-Blanco A, Crewe JM, Clark A, Mackey DA. Low-concentration atropine eyedrops for myopia control in a multi-racial cohort of Australian children: A randomised clinical trial. Clin Exp Ophthalmol. 2022 Dec;50(9):1001-1012. [Link to open access paper]

Previous studies have explored the efficacy of low dose atropine, including the Atropine for the Treatment of Myopia (ATOM) study based in Singapore, the Low-concentration Atropine for Myopia Progression (LAMP) study from Hong Kong and the Indian-ATOM study.^1-9

These studies have featured predominantly Asian children, meaning the results may not be directly applicable to children of non-Asian ethnicity with lighter iris pigmentation.

The Western Australia (WA-ATOMA) study aimed to evaluate the safety and efficacy of 0.01% atropine for myopia control for a multi-racial cohort of Australian children. This was a double-masked, placebo-controlled, randomised trial with children aged 6 to 16yrs who had spherical equivalent (SphE) of ≤-1.50D, astigmatism of ≤1.50DC and previous myopia progression of 0.50D or more in the preceding year.

The children were classified into Europeans (around 50%), East Asians (20%), South Asians (20%), and other/mixed ancestry (10%). They were randomly assigned to receive either 0.01% atropine (n=104) or placebo eyedrops (n=49). The mean ages were 12 and 11 in the placebo and atropine groups, respectively.

The safety and tolerance of low-dose atropine was measured by changes in the distance and near best corrected visual acuity, accommodative amplitude, pupillary reactions and parental responses.

Over the study period, there was myopia and axial length progression for both groups:

• After 1 year, the mean SE and AL changes were -0.31D and 0.16mm for the atropine group and -0.53D and 0.25mm for the placebo group. These differences of -0.22D and 0.09mm treatment effect were statistically significant.
• After 2 years, the SE and AL changes were -0.64D and 0.34mm for the atropine group and -0.78D and 0.38mm in the placebo group. These differences were smaller in the second year, being only -0.14D and 0.04mm, and were not significantly different from each other. The authors suggest that a high level of dropout in the control group in the second year (25%) could have driven this limited result at 2 years, especially if the participants dropped out because of observed faster myopia progression.
• Children of East Asian and South Asian ethnicity showed no treatment effect for 0.01% atropine across the 2 years. Children of European ancestry showed around 0.11mm / 0.25D treatment effect at 12 and 18 months and children of mixed ancestry showed an even larger effect, but participant numbers in this group were small. These results indicate effectiveness of atropine 0.01% for myopia control in Australian children of European or mixed ethnicity, but not in those of East Asian or South Asian ethnicity.

The atropine group showed pupil responses which were a little slower to constrict but not to dilate. Pupils were only around 0.2mm larger in the atropin group. Both the atropine and placebo drops were well tolerated, with over 90% of parents reporting their child had not been hindered by using the eyedrops. Only 2 of the 9 adverse responses were possibly related to drop use, but not considered severe.

In this mixed-race cohort of Australian children, 0.01% atropine was well-tolerated with few side-effects but showed some varied myopia control effect:

• The effect was greater in the 1^st year, but waned before 2yrs, likely due to drop-out of faster progressors in the control group.
• The effect was moderate for children of European and other / mixed ancestries.
• However, atropine 0.01% was not effective for children of South or East Asian ancestries. This aligns with the findings of the LAMP study where 0.01% atropine was found to give minimal myopia control benefits for East Asian children in Hong Kong China.

Even though the East Asian and South Asian ethnicity children in this study lived in Australia with a potentially more outdoors-style living environment, they may still benefit from increased atropine concentration to maximise myopia control effect.

Although this study had a multi-racial cohort to reflect Australia's diverse population, future studies with a larger cohort could confirm this study's findings. The drop-out rate of the control group in the second year of the study also influenced the outcomes.

Further investigation is needed to establish if slightly higher concentrations of atropine (eg. 0.02%) could be more effective and well tolerated by Australian children of various ancestries. The authors of this study will be following-up this cohort by assessing for any rebound effect.

Limitations of this study included not assessing the participant's adherence to the eye drop usage or concentration-dependent effects. Knowing how different concentrations perform for children with varying levels of myopia risk would aid in treatment choices.

Title: Low-concentration atropine eyedrops for myopia control in a multi-racial cohort of Australian children: A randomised clinical trial

Authors: Samantha Sze-Yee Lee, Gareth Lingham, Magdalena Blaszkowska, Paul G Sanfilippo, Adrian Koay, Maria Franchina, Audrey Chia, James Loughman, Daniel Ian Flitcroft, Christopher J Hammond, Augusto Azuara-Blanco, Julie M Crewe, Antony Clark, David A Mackey

Purpose: To test the hypothesis that 0.01% atropine eyedrops are a safe and effective myopia-control approach in Australian children.

Methods: Children (6-16 years; 49% Europeans, 18% East Asian, 22% South Asian, and 12% other/mixed ancestry) with documented myopia progression were enrolled into this single-centre randomised, parallel, double-masked, placebo-controlled trial and randomised to receive 0.01% atropine (n = 104) or placebo (n = 49) eyedrops (2:1 ratio) instilled nightly over 24 months (mean index age = 12.2 ± 2.5 and 11.2 ± 2.8 years, respectively). Outcome measures were the changes in spherical equivalent (SE) and axial length (AL) from baseline.

Results: At 12 months, the mean SE and AL change from baseline were −0.31D (95% confidence interval [CI] = −0.39 to −0.22) and 0.16 mm (95%CI = 0.13-0.20) in the atropine group and −0.53D (95%CI = −0.66 to −0.40) and 0.25 mm (95%CI = 0.20-0.30) in the placebo group (group difference p ≤ 0.01). At 24 months, the mean SE and AL change from baseline was −0.64D (95%CI = −0.73 to −0.56) and 0.34 mm (95%CI = 0.30-0.37) in the atropine group, and −0.78D (95%CI = −0.91 to −0.65) and 0.38 mm (95%CI = 0.33-0.43) in the placebo group. Group difference at 24 months was not statistically significant (p = 0.10). At 24 months, the atropine group had reduced accommodative amplitude and pupillary light response compared to the placebo group.

Conclusions: In Australian children, 0.01% atropine eyedrops were safe, well-tolerated, and had a modest myopia-control effect, although there was an apparent decrease in efficacy between 18 and 24 months, which is likely driven by a higher dropout rate in the placebo group.

[Link to open access paper]