Efficacy and safety of different atropine regimens: MOSAIC2

Introduction

Early studies involving high dose atropine suggested that high dose atropine (0.5–1.0%) had a strong effect in slowing childhood myopia (1-5). It was not till the Atropine Treatment for Myopia (ATOM2) study that the potential of low doses atropine (LDA) was raised (6). Since then, there have been several RCTs involving LDA have been completed, and results published (7-27). These studies often include treatment of 1–2 years, some with a follow-up washout period (where treatment was stopped) or altered (3-4,7-11,14-17,24-27). These are set in different countries, with different racial compositions using different doses and formulations in children of different ages and baseline myopia (Table 1).

Table 1

Author [year], site Population (inclusion criteria) Intervention Change in SE and AL Loughman [2024, 2025] = MOSAIC, MOSAIC2, Ireland (24,25) N=259, 6–16 years (mean 11.7 years), SE ≤−0.5 D (mean −3.3 D) Placebo 1 year: −0.27 D, 0.24 mm; 2 years: −0.63 D, 0.40 mm A0.01 1 year: −0.24 D, 0.20 mm; 2 years: −0.53 D, 0.33 mm* Placebo to A0.05 (3rd year) 3rd year: −0.11 D, 0.09 mm* A0.01 tapered over 1 year 3rd year: −0.18 D, 0.10 mm A0.01 to placebo 3rd year: −0.23 D, 0.14 mm Randomized controlled trials with third year of intervention Chua [2006], Tong [2009] = ATOM1, SG (3,4) N=400, 6–12 years (mean 9.2 years), SE −1 to −6 D (mean −3.5 D) Placebo 1 year: −0.64 D, 0.19 mm; 2 years: −1.20 D, 0.38 mm A1.0 1 year: +0.14 D, 0.01 mm; 2 years: −0.28 D, −0.02 mm* Placebo to no treatment 3rd year: −0.38 D, 0.20 mm A1.0 to no treatment 3rd year: −1.14 D, 0.31 mm Chia [2012/2016] = ATOM2, SG (7,8) N=400, 6–12 years (mean 9.6 years), SE ≤−2 D (mean −4.7 D) A0.01 1 year: −0.43 D, 0.24 mm; 2 years: −0.49 D, 0.41 mm A0.1 1 year: −0.31 D, 0.13 mm; 2 years: −0.38 D, 0.28 mm A0.5 1 year: −0.17 D, 0.11 mm; 2 years: −0.30 D, 0.27 mm A0.01 to no treatment 3rd year: −0.28 D, 0.19 mm A0.1 to no treatment 3rd year: −0.68 D, 0.33 mm A0.05 to no treatment 3rd year: −0.87 D, 0.35 mm Yam [2019/2020/2022] = LAMP, HK (9-11) N=438, 4–12 years (mean 8.4 years), SE ≤−1 D (mean −3.8 D) Placebo to A0.05 (2nd year) 1 year: −0.81 D, 0.41 mm; 2nd year: −0.18, 0.18 mm* A0.01 1 year: −0.59 D*, 0.36 mm; 2 years: −1.12 D, 0.59 mm 3rd year: −0.38 D, 0.24 mm A0.025 1 year: −0.46 D, 0.29 mm*; 2 years: −0.73 D, 0.50 mm 3rd year: −0.35 D, 0.20 mm A0.05 1 year: −0.27 D, 0.20 mm*; 2 years: −0.55 D, 0.39 mm* 3rd year: −0.28 D, 0.17 mm A0.01 to placebo 3rd year: −0.56 D, 0.29 mm A0.025 to placebo 3rd year: −0.57 D, 0.29 mm A0.05 to placebo 3rd year: −0.68 D, 0.33 mm Hieda [2021, 2023] = ATOM-J, JP (7 sites) (14,15) N=171, 6–12 years (mean 8.9 years), SE −1 to −6 D (mean −2.9 D) Placebo 1 year: −0.77 D, 0.39 mm; 2 years: −1.48 D, 0.77 mm A0.01 1 year: −0.69 D, 0.35 mm; 2 years: −1.26 D, 0.63 mm* Placebo to no treatment 3rd year: −0.51 D, 0.28 mm A0.01 to no treatment 3rd year: −0.60 D, 0.25 mm Lee [2022, 2024] = WA-ATOM, AU (16,17) N=153, 6–16 years (mean 11.5 years), SE ≤−1.5 D (mean −3.3 D) Placebo 1 year: −0.53 D, 0.25 mm; 2 years: −0.78 D, 0.38 mm A0.01 1 year −0.31 D, 0.16 mm*; 2 years: −0.64 D, 0.34 mm Placebo to no treatment 3rd year: −0.28 D, 0.13 mm A0.01 to no treatment 3rd year: −0.41 D, 0.20 mm Zadnik [2023] = CHAMP, 26 US and 5 EU sites (26) N=576, 3–16 years (mean 8.9 years), SE −0.5 to −6 D (mean −2.4 D) Placebo 1 year: −0.57 D; 2 years −1.0 D; 3 years −1.28 D, 0.81 mm A0.01 3 years: −1.04 D*, 0.68 mm* A0.02 3 years: −1.18 D, 0.73 mm* Ohno-Matsui [2026] = ORANGE, JP, 34 sites (27) N=299, 5–15 years (mean 9.4 years), SE −1 to −6 D (mean −3.08 D) Placebo 1 year: −0.95 D; 2 years: −1.65 D, 0.74 mm 3 years: −2.04 D/0.97 mm A0.01 1 year: −0.66 D*; 2 years: −1.31 D, 0.64 mm* 3 years: −1.97 D/0.93 mm A0.025 1 year: −0.44 D*; 2 years: −1.02 D, 0.51 mm* 3 years: −1.47 D/0.72 mm Placebo to A0.01 3 years: −1.84 D/0.90 mm Placebo to A0.025 3 years: −1.87 D/0.84 mm A0.01 to placebo 3 years: −1.77 D/0.89 mm A0.025 to placebo 3 years: −1.71 D/0.82 mm Other randomized controlled trials with various doses of atropine Yen [1989], TW (1) N=96, 6–12 years (mean 10.5 years), SE −0.5 to −4.0 D (mean −1.5 D) Control 1 year: −0.91 D Cyclo 1.0 1 year: −0.58 D* A1.0 1 year: −0.22 D* Shih [1999], TW (2) N=183, 6–13 years (mean 9 years), SE −0.5 to −6.75 D (mean −4.4 D) Control 1 year: −1.06 D A0.1 1 year: −0.47 D* A0.25 1 year: −0.45 D* A0.5 1 year: −0.04 D* Yi [2015], Chongqing, CN (5) N=140, 7–12 years (mean 9.8 years), SE −0.5 to −2.0 D (mean −1.2 D) Placebo 1 year: −0.85 D/0.32 mm A1.0 1 year: +0.32 D/−0.03 mm* Wang [2017], Yan’an, CN (6) N=126, 5–10 years (8.9 years), SE −0.5 to −2 D (mean −1.2 D) Placebo 1 year: −0.8 D/0.3 mm A0.5 1 year: +0.3 D/−1.1 mm* Wei [2020/2023], Beijing, CN (12,13) N=220, 6–12 years (mean 9.6 years), SE −1 to −6 D (mean −2.5 D) with cross-over at 1 year Placebo-A0.01 1st year: −0.76 D, 0.41 mm; 2nd year: −0.56 D, 0.34 mm* A0.01-placebo 1st year: −0.49 D, 0.32 mm; 2nd year: −0.78 D, 0.39 mm* Chia [2023], = APPLE, SG (2 sites) (18) N=99, 6–12 years (mean 8.9 years), SE −1 to −6 D (mean −3.5 D) Placebo 1 year: −0.55 D, 0.36 mm A0.0025 1 year: −0.55 D, 0.31 mm A0.005 1 year: −0.33 D, 0.27 mm* A0.01 1 year: −0.39 D, 0.23 mm* Sharma [2023], IN (19) N=100, 5–12 years, SE −0.5 to −10 D (mean −3.2 D) Placebo 1 year: −0.80 D, 0.23 mm A0.01 1 year: −0.31 D, 0.11 mm* Sen [2022], IN (20) N=150, 5–15 years; SE <−2 D (mean −4 D) Placebo 1 year: −0.88 D, 0.30 mm A0.01 1 year −0.33 D, 0.11 mm* Repka [2023] = PEDIG, US (12 sites) (21) N=187, 5–12 years (mean 10.1 years), SE −1 to −6 D (mean −2.8 D) Placebo 1 year: −0.45 D, 0.25 mm; 2 years: −0.78 D, 0.41 mm A0.01 1 year: −0.39 D, 0.22 mm; 2 years: −0.74 D, 0.42 mm Hansen [2023/2025] Denmark (22,23) N=97, 6–12 years (mean 9.4 years), SE 6–9 years <−1 D, and 9–12 years <−2 (mean −3 D) Placebo 1 year: −0.70 D, 0.34 mm; 2 years −1.20 D, 0.58 mm A0.01 1 year: −0.47 D, 0.26 mm; 2 years −0.90 D, 0.46 mm* Load A0.1 6m then A.01 1 year: −0.45 D, 0.24 mm; 2 years −1.10 D, 0.48 mm Estimated from graphs

In 2025, Loughman et al. published the 3-year outcomes of the Myopia Outcome Study of Atropine in Children (MOSAIC2) study (25). In the original MOSAIC study, which was based in Dublin, Ireland, children aged 6–16 years old with bilateral cycloplegic spherical equivalent (SE) < −0.5 D were randomized to placebo (n=83) or Atropine 0.01% (n=167) (24). The majority of children were White (83%) with the rest being Asian (8.4%), Black (1.6%), Mixed (5.6%), or other (1.2%) races. Over the first 2 years, there was a small but significant treatment effect on SE up to 18 months, and on axial length (AL) up to 24 months (Table 1). Children on Atropine 0.01% were more likely to progress by <0.25 D (33.0% vs. 28.8%) and less likely to progress by >0.75 D (29.2 vs. 36.4%). Post-hoc analysis showed that this effect was seen in White but not non-White children, in blue-eyed rather than green/brown-eyed children and in older (>11 years old) compared to younger children.

In the MOSAIC2 study, children previously randomized to placebo were started on atropine 0.05% for a third year (n=66). Children previously on atropine 0.01% were randomized to placebo (either daily or tapered) (n=60) or tapered off atropine 0.01% over the year (n=73). (25) Retention rate was good (70%). From this study, authors made 2 main conclusions. First, in children randomized to no treatment (washout), subsequent mean progression in year was no greater than that noted in placebo group over first and second year, suggesting that there was no rebound when atropine was stopped (Table 1). Secondly, despite more adverse events, participants using 0.05% atropine exhibited 0.13 D less myopia progression and 0.06 mm less axial elongation, compared with participants using placebo, supporting consideration of treatment with 0.05% atropine in this European population.

Comparison with other studies

Studies to which the MOSAIC study can be compared include those with a majority White component such as the Western Australia Atropine for Treatment of Myopia (WA-ATOM) study (16,17), the Childhood Atropine for Myopia Progression (CHAMP) study (26), the Pediatric Eye Disease Interest Group (PEDIG) study (21) as well as a Denmark based study by Hansen et al. [2023, 2025] (22,23) (Table 1).

However, differences exist at baseline between studies which may influence outcome (Table 1). The baseline age in the MOSAIC study (mean age 11.7 years) was most similar to WA-ATOM (mean age 11.7 years) and both had mean baseline SE of −3.3 D (16,24). Children from the PEDIG study were slightly younger (mean age 10.1 years, mean SE −2.8 D) (21), while children from the Danish study were much younger (mean age 9.4 years, mean SE −3 D) (22). All but the WA-ATOM study was partly done during the coronavirus disease (COVID) period. In the WA-ATOM study, a treatment effect was noted in first 18 months but not by 24 months, and like in the MOSAIC study, it was better in White children than non-White children (16,24). In the CHAMP study, effect in the atropine 0.01% group was paradoxically better than in the atropine 0.02% group (26). In the PEDIG study, atropine 0.01% showed no significant treatment effect (21) while Hansen et al. noted a significant effect at 2 years but not at 1 year (22).

These findings cast doubt about whether low-dose Atropine was useful in the Western population, and if so, in which children, at what age and with which dose. Wide ranges of ages, multiple sites and races, differences in formulations and compliance, and the COVID epidemic may have influenced outcome (16,21,22,24,26). For example, the combination of younger or Asian children with faster progression (who may require higher doses), and older or Black children with little/no progression (who may not needed treatment) may have blunted overall effect (21). In the WA-ATOM study, loss of follow-up, possibly of those with more rapid progress, may have decrease effect in later years (16). Post-hoc analysis was done to try tease out groups where atropine may or may not have been effective. However, these analyses were often not adequately powered, and there was a fear that any conclusions may be biased and subject to error (16,21,24,26).

Asian studies available for comparison include the Atropine for Treatment of Myopia (ATOM1 and ATOM2) (3,4,7,8), the low-concentration atropine for myopia progression (LAMP) (9,10,11), Atropine Treatment of Myopia-Japan (ATOM-J) study (14,15) and the ORANGE study (27) based in Singapore, Hong Kong and Japan.

The mean age in the Asian randomized control trials (RCTs) was much lower than the MOSAIC, WA-ATOM and PEDIG studies, ranging from 8.4 years (LAMP), 8.9 years (ATOM-J), 9.4 years (ORANGE) to 9.6 years (ATOM2) (3,7,9,14,27). This may be relevant as myopia progression is often greater in younger children, slowing towards the mid-late teens (28,29).

Change in the placebo groups of MOSAIC study in this first year (mean −0.27 D, 0.24 mm) was much lower than all other RCTs, but by second year, change (mean −0.63 D, 0.40 mm) was quite similar to that noted in the WA-ATOM (mean −0.78 D, 0.38 mm) and PEDIG study (−0.78 D, 0.41 mm) (Table 1) (16,21,24). By contrast, mean change by 2 years in studies by Hansen et al. and the CHAMP studies, where mean age was 8.9–9.4 years, was −1.20 D, 0.58 mm and −1.0 D, respectively (22,26). Progression in these latter studies was very similar to the Singapore based ATOM and APPLE studies. However, progression in other Asian studies (i.e., from sites including Japan, India, Taiwan, Hong-Kong and mainland China) were much faster (−0.78 to −1.06 D in first year) (1,2,3,6,9,12,14,18,19,20,27), compared to Western based studies (−0.27 to −0.70 D in first year) (16,21,22,24,26). Thus, beyond age, genetic, cultural and life-style factors may also play a role in driving myopia progression in any study.

In the Asian studies, atropine 0.01% often had a significant effect at some time during the first 2 years in most studies (Table 1). When there were different doses, a dose-related effect was noted where efficacy was better with higher doses. Post-hoc analysis in the ATOM and LAMP studies suggest that younger children, those with higher progression and family history of myopia may benefit from higher doses (30,31). Higher doses, however, are associated with greater side effects (i.e., glare and near blur), and greater rebound (3,4,7,8,9,10,11,29,30).

Rebound is assumed to occur if there is progression greater than that expected for age. This is best reflected by comparison with a placebo group (4,8,15,17). However, in many studies, this information is not available as intervention was provided to placebo group prior to washout (11,25,27) Presence of a rebound then needed to graded against earlier progression or expected population norms. Rebound was important as it eroded the early benefits from treatment over time (4,8,11,32). Overall, studies suggest little or no rebound with atropine 0.01% in the MOSAIC, ATOM2, LAMP, ATOM-J and ORANGE studies (8,11,15,25,27) while some rebound was seen in WA-ATOM and by Hansen et al. (17,23). A greater rebound occurred when treatment was stopped suddenly in younger children, or those on higher dose (30,31). Rebound, however, could be blunted, such as in MOSAIC2, where children were in their mid-teens by the time medication is stopped (25).

Implications to clinical care

What dose to start

Studies done span a wide range of doses from atropine 0.01% to 1.0% (Table 1). Within the spectrum of low doses, most, except for CHAMP, suggest that higher doses were more effective (Figure 1). Based on the LAMP and MOSAIC2 studies, this dose may be atropine 0.05%. That said, individual response to any dose can be unpredictable, and some eye care practitioners may still prefer to start on a lower dose to test effect and tolerance with a plan for an incremental increase in dose when necessary.

Figure 1 Mean change in spherical equivalent and axial length at 1 and 2 years at different doses in different randomized-controlled-trials. APPLE, Atropine for the Prevention of Progression of Low myopia in Elert Children; ATOM, Atropine Treatment of Myopia; ATOM-J, Atropine Treatment of Myopia-Japan; CHAMP, Childhood Atropine for Myopia Progression; LAMP, low-concentration atropine for myopia progression; MOSAIC, Myopia Outcome Study of Atropine in Children; PEDIG, Pediatric Eye Disease Interest Group; WA-ATOM, Western Australia Atropine Treatment of Myopia.

Even better effect was seen with high dose atropine (0.5–1.0%) where a hyperopic shift can be noted in the first 2 years (1-6). Any glare and blur could be managed with photo-transition glasses with a near add. Long term adverse effects seemed minimal at least at 15-year follow-up in the ATLAS study of the ATOM subjects (32). High dose atropine may also be used part-time (e.g., 1–3× per week) to good effect (33,34).

Indeed, the eye care practitioner could base their selection of a starting dose on the child’s risk profile. High risk children (i.e., younger children, with higher baseline myopia, greater myopia progression or strong family history of myopia) may benefit from higher starting dose (30,31) while lower risk children may be started on a lower dose. The maximal optimal dose could be limited by tolerance of side effects—which seem lower in the West, than in the East (7,9,21,26).

Managing progression

Once treatment is started, it would be prudent to continue to monitor both SE and AL at 3–6 monthly intervals to check progress, compliance and manage any adverse effects (e.g., glare, near blur or allergy). A good response may be little to no change in SE or AL, or an increase which is equivalent to the emmetropic norm of the appropriate age (35). Should myopia progress, a graduated increase in atropine dose or frequency, or combination with an optical treatment may be implemented. In the LAMP2 and MOSAIC2 studies, beneficial effects were noted even at a later stage when Atropine 0.05% was started on children previously on placebo (11,25). This suggests that rescue treatment with higher doses is possible although results were much better if they were started earlier.

When and how to stop treatment

When stopping treatment, the aim is to preserve the cumulative benefits by managing rebound. There are as yet few studies focused on when and how myopia treatments should be discontinued. Until more evidence is available, current options include continuing treatment till mid-late teens, and tapering dose or frequency of atropine over time.

Conclusions

Although sometimes conflicting and confusing, studies like the MOSAIC add to the literature and help us better understand how and when to use atropine in our clinical practices. However, it also highlights gaps in our knowledge, and more RCTs or prospective cohort studies with better defined clinical subgroups (e.g., age or race), in different parts of the world, ideally in children with progressive myopia, using different doses with longer follow-up will help to better define when, how and which dose of atropine can be used in the management of childhood myopia.

Acknowledgments

None.

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-0039/coif). A.C.F. received grant support (unrelated to this paper), royalties and support/honorarium for conferences/talks. The author has no other conflicts of interest to declare.

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Cite this article as: Chia A. Efficacy and safety of different atropine regimens: MOSAIC2. Ann Transl Med 2026;14(3):43. doi: 10.21037/atm-2026-0039