The Phase II APPLE study for low-dose atropine in Singapore

Paper title: Atropine Ophthalmic Solution to Reduce Myopia Progression in Pediatric Subjects: The Randomized, Double-Blind Multicenter Phase II APPLE Study

Authors: Chia, Audrey (1), Ngo, Cheryl (2), Choudry, Nozhat (3), Yamakawa, Yutaka (4), Tan, Donald (1,2,5)

1. Singapore National Eye Centre, Singapore, Singapore.

2. Department of Ophthalmology, National University Hospital, Singapore, Singapore.
3. Santen Canada Inc., Toronto, ON, Canada.
4. Santen Pharmaceuticals Co. Ltd, Osaka, Japan.
5. Eye and Retina Surgeons, Camden Medical Center, Singapore, Singapore.

Date: Jul-Aug 2023

[Link to open access paper]Reference: Chia A, Ngo C, Choudry N, Yamakawa Y, Tan D. Atropine Ophthalmic Solution to Reduce Myopia Progression in Pediatric Subjects: The Randomized, Double-Blind Multicenter Phase II APPLE Study. Asia Pac J Ophthalmol (Phila). 2023 Jul-Aug 01;12(4):370-376

[Link to open access paper]

Atropine is commonly used for myopia control and has been shown to have a dose-dependent efficacy in slowing myopia progression.^1-5 Although research has discovered low-dose atropine (as low as 0.01%) is effective in slowing myopia progression in children, a minimum efficacy threshold yet to be established.

The aim of this randomised, multicentre, double-blind phase II study was to assess the dose-dependent effects and safety of low-dose atropine for slowing myopia progression in children.

Participants were 100 children aged 6 to 11yrs with spherical equivalent myopia between -1.00 to -6.00D, astigmatism of no more than 1.50D and with progression of at least -0.50D in the year prior to recruitment. They were stratified by age group (6-7, 8-9 and 10-11yrs) and randomised to receive atropine in 0.0025 (n = 24), 0.005 (n = 24) or 0.01% (n = 25) concentration or a placebo drop (n = 26).

All groups instilled one drop at bedtime and were followed for a year. The primary endpoint was changes in spherical equivalent (SE) over 12mths. Secondary endpoints were changes in axial length and near logMAR, visual acuity and incidence of adverse effects.

• Of the 99 participants, 87.9% were ethnic Chinese.
• Mean baseline values for SE and AL were -3.50D ± 1.2 D and 24.64 ± 0.79 mm, respectively.
• After 12mths, mean changes from baseline for SE were -0.55D, -0.55D, -0.33D and -0.39D for the placebo, 0.0025%, 0.005% and 0.01% groups, respectively. The mean differences between the placebo group and the 0.0025%, 0.005%, and 0.01% atropine groups were 0.11D, 0.23D, and 0.25D, respectively.
• Axial length changes at 12 months were 0.35mm, 0.30mm, 0.27mm and 0.25mm for the placebo, 0.0025%, 0.005% and 0.01% groups, respectively. The mean differences between the placebo group and the 0.0025%, 0.005% and 0.01% atropine groups were –0.06 mm, −0.09 mm, and −0.10 mm, respectively, with the 0.0025% being a non-significant difference. 
• Lower progression rates were seen in the older age group (10-11yrs) and for those with high baseline myopia (SE greater than 4D and AL of 25mm or more).

No significant changes were seen over the study period for near visual acuity for any of the atropine groups and changes in amplitude of accommodation and IOP were minimal. There were no pupil size changes seen in the placebo and 0.0025% groups. The 0.005% and 0.01% atropine groups showed 0.26 and 0.31mm changes in pupil size, respectively.

Previous atropine studies (ATOM2, LAMP AND ATOM-J) found doses of 0.01-0.5% were able to reduce myopia progression.^6,7,8 This study established that 0.0025% atropine (1/4 strength of 0.01%) had an insignificant effect on slowing progression but the very low dose 0.005% (half strength of 0.01%) and 0.01% had small and similar effects, with minimal impacts on pupil size or accommodation. 

Younger children showed poorer responses to atropine than older children, confirming findings from previous studies.⁶ Efficacy was seen to be better in older children and for those with higher baseline myopia.

The effect of baseline myopia severity on efficacy of atropine is currently unclear, but may be associated with a child’s age. This study found greater reductions in axial elongation with older children and higher myopia. 

• A retrospective study found 0.01% atropine efficacy was associated with higher myopia for Chinese children, although this may have been due to the children being older.⁹
• The LAMP study (Hong Kong) found younger children needed higher doses to achieve the efficacy seen for older children using lower doses.⁶
• However, the ATOM-J study (Japan) found there was no association between atropine efficacy and baseline myopia.⁸

Limitations to this study include the relatively small number of children in each dose category (approximately 25), which may make extrapolating to a larger population inaccurate; and the short-term data. It is important to note that there are no other studies investigating 0.005% atropine (half strength of 0.01%). 

Title: Atropine Ophthalmic Solution to Reduce Myopia Progression in Pediatric Subjects: The Randomized, Double-Blind Multicenter Phase II APPLE Study

Authors: Chia, Audrey; Ngo, Cheryl; Choudry, Nozhat; Yamakawa, Yutaka; Tan, Donald

Purpose: The purpose of this study was to assess the dose-response effects of low-dose atropine on myopia progression and safety in pediatric subjects with mild-to-moderate myopia.

Methods: This phase II, randomized, double-masked, placebo-controlled study compared the efficacy and safety of atropine 0.0025%, 0.005%, and 0.01% with placebo in 99 children, aged 6–11 years, with mild-to-moderate myopia. Subjects received 1 drop in each eye at bedtime. The primary efficacy endpoint was change in spherical equivalent (SE), while secondary endpoints included changes in axial length (AL) and near logMAR (logarithm of the minimum angle of resolution) visual acuity and adverse effects.

Results: The mean±SD changes in SE from baseline to 12 months in the placebo and atropine 0.0025%, 0.005%, and 0.01% groups were −0.55±0.471, −0.55±0.337, −0.33±0.473, and −0.39±0.519 D, respectively. The least squares mean differences (atropine−placebo) in the atropine 0.0025%, 0.005%, and 0.01% groups were 0.11 D (P=0.246), 0.23 D (P=0.009), and 0.25 D (P=0.006), respectively. Compared with placebo, the mean change in AL was significantly greater for atropine 0.005% (−0.09 mm, P=0.012) and 0.01% (−0.10 mm, P=0.003). There were no significant changes in near visual acuity in any of the treatment groups. The most common ocular adverse events were pruritus and blurred vision, each occurring in 4 (5.5%) atropine-treated children. Changes in mean pupil size and amplitude of accommodation were minimal.

Conclusions: Atropine doses of 0.005% and 0.01% effectively reduced myopia progression in children but no effect was noted with 0.0025%. All doses of atropine were safe and well tolerated.

[Link to open access paper]