The role of low-dose atropine for childhood myopia: evaluating efficacy, durability and dosing

Myopia control and low-dose atropine: recent evidence

Myopia in childhood is largely driven by axial elongation and is associated with elevated lifetime risks of myopic macular degeneration, retinal detachment, glaucoma and cataract; risk correlates with increasing myopia and longer axial length (AL) (1). As myopia prevalence increases globally (2), interventions that slow progression during the years of most rapid eye growth have become a clinical and public health priority (1).

Topical atropine has an extensive evidence base for myopia control (Table 1); however, several uncertainties remain, including the optimal concentration for treatment, the varying efficacy in different populations, the expected effect size for low-dose formulations, and what happens when treatment is reduced or stopped.

Studies in Asian populations found nightly low-concentration atropine slowed refractive progression and axial elongation in a concentration-dependent manner. Atropine for the Treatment of Myopia 1 (ATOM1) demonstrated that high-dose (1.0%) atropine, while efficacious, was associated with substantial dose-related mydriatic or cycloplegic effects (11). Subsequently Atropine for the Treatment of Myopia 2 (ATOM2) compared lower doses and reported 2-year spherical equivalent refraction (SER) progression of −0.30 diopter (D), −0.38 D, and −0.49 D, with AL increases of 0.27, 0.28, and 0.41 mm, for 0.5, 0.1 and 0.01% atropine respectively, supporting a favorable tolerability–efficacy balance for 0.01% in this cohort (3,12). The Low-Concentration Atropine for Myopia Progression (LAMP) studies found that, over 2 years, cumulative SER progression was −0.55, −0.85, and −1.12 D with AL elongation of 0.39, 0.50, and 0.59 mm for 0.05, 0.025, and 0.01% atropine, respectively, with 0.05% also showing the greatest 1-year benefit (4,13).

Recent placebo-controlled trials in non-Asian cohorts have not reached agreement. The Childhood Atropine for Myopia Progression (CHAMP) study reported efficacy signals for atropine 0.01% over 36 months (0.24 D less SER progression and 0.13 mm less AL elongation versus placebo) (6), whereas the US Pediatric Eye Disease Investigator Group (PEDIG) trial found no benefit of atropine 0.01% versus placebo over 24 months (8). In Europe, The Myopia Outcome Study of Atropine in Children (MOSAIC) observed no statistically significant effect on SER at 24 months but reported reduced AL growth (−0.07 mm; P=0.007) with 0.01% atropine (7,14). The Western Australia-Atropine for the Treatment of Myopia (WA-ATOM) study reported modest myopia-control effect, with an apparent decrease in efficacy between months 18 and 24 (0.25 D less SER progression and 0.10 mm less AL elongation at 18 months; 0.14 D and 0.05 mm at 24 months) (5). In the recent randomized, double-masked, vehicle-controlled STudy of Atropine to Reduce (STAR) trial, nightly atropine sulfate 0.01% or 0.03% significantly slowed myopia progression through 24 months versus vehicle (mean annual progression rate −0.31 and −0.32 versus −0.44 D/year, treatment differences +0.13 and +0.12 D/year for 0.01 or 0.03% versus vehicle), with larger effects in fast progressors (9). Niklas Hansen’s group in Copenhagen, Denmark, have released data over several years from their Danish placebo-controlled trials, showing that low-dose atropine produced only modest slowing at 12 months (0.19–0.24 D less SER progression and 0.07–0.10 mm less axial elongation, not significant after multiplicity adjustment versus placebo), while at 24 months continuous 0.01% atropine showed a small but statistically significant benefit (0.26 D less progression and 0.10 mm less axial elongation versus placebo) and the 0.1% loading regimen did not provide a clear added advantage (15,16).

Objective of Hansen et al.

Hansen et al. report prespecified 3-year outcomes from an investigator-initiated, placebo-controlled, double-blind, randomized clinical trial in Danish children aged 6–12 years with myopia. The stated aim was to examine the safety and efficacy of nightly low-dose atropine given for 24 months, followed by a 12-month washout, and specifically to determine whether treatment effects were sustained after cessation and whether a 6-month atropine 0.1% “loading dose” followed by 18 months of atropine 0.01% improved final outcomes compared with continuous atropine 0.01% or placebo (10).

Findings of Hansen et al. from the 3-year study of low-dose atropine

Ninety-seven children were randomized (1:1:1) to atropine 0.01% nightly for 24 months, atropine 0.1% nightly for 6 months followed by atropine 0.01% nightly for 18 months, or placebo nightly for 24 months; all groups then underwent a 12-month washout without study drops. Ninety-one participants completed all visits. Primary endpoints were AL (non-cycloplegic) and SER (cycloplegic) assessed after washout. Analyses used constrained linear mixed models (intention-to-treat) with multiplicity adjustment; responder-eye analyses (myopia progression <0.50 D from baseline) used Fisher’s exact test (10).

At 36 months, mean AL was 25.28 mm in the loading-dose group, 25.25 mm in the 0.01% group and 25.33 mm in the placebo group. Compared with placebo, the reported mean AL differences were −0.06 mm [95% confidence interval (CI): −0.18 to 0.07; adjusted P=0.86] for the loading-dose regimen and –0.09 mm (95% CI: −0.21 to 0.04; adjusted P=0.78) for atropine 0.01%. Mean SER at 36 months was –4.45 D (0.1% loading-dose arm), −4.26 D (continuous 0.01% arm), and −4.43 D (placebo arm). The reported mean SER differences were −0.02 D (95% CI: −0.30 to 0.26; adjusted P=0.94) and +0.17 D (95% CI: −0.11 to 0.45; adjusted P=0.82) in the 0.1% loading-dose arm and the continuous 0.01% atropine arm, respectively, versus placebo. Responder proportions were not statistically different between groups at year 1, year 2, or year 3 (10).

During washout, the authors report near and distance best-corrected visual acuity, pupil diameters and accommodation amplitude that were similar to baseline and comparable between groups; intraocular pressure increased versus baseline but remained within normal parameters. Seven adverse events were reported during washout, and no serious adverse events occurred. The authors conclude that there was no difference in myopia progression between groups following washout, that a 6-month 0.1% loading phase did not improve efficacy compared with 0.01% monotherapy, and that the loading-dose regimen showed a rebound effect after dose switching (10).

The authors highlight the randomized, double-blind, placebo-controlled design and low dropout rate (6%) as key strengths that reduce selection bias. They also describe excellent adherence, supported by parental dosing records and by pupil diameter changes during active treatment. In terms of study limitations, the authors note that additional head-to-head concentration comparisons would have been desirable but were not feasible. Further, the study was powered for a large (≥50%) difference in SER progression based on an assumed progression rate of approximately −1.0 D/year, whereas observed progression was closer to 0.5 D/year, potentially leaving the trial underpowered to detect smaller between-group effects. Additional limitations noted include the constrained duration of a randomized trial and the lack of evaluation of potential modifiers of progression (e.g., parental myopia, outdoor exposure and near work) (10).

Considerations on the methodology and outcomes of Hansen et al.

This was a relatively small (97 patients across three arms) study in three hospital centers; however, it builds on findings from two previous consecutive years of study. The different inclusion criteria between age groups (those aged 6–9 years required at least one negative spherical diopter in one eye and those aged 9–12 years of age required at least two negative spherical diopters in one eye to be included) may have influenced efficacy results, especially in patients around 9 years of age; it would be interesting to hear the authors’ thoughts on this detail. As the authors note, the study was potentially underpowered for the detection of small between-group differences in effect, and it was acknowledged other risk factors were not evaluated. A longer duration of study may help further elucidate the effect of low-dose atropine in the treatment of myopia. However, this recent work by Hansen et al. is a welcome addition to the expanding evidence base for low-dose atropine use in children with myopia.

In context with other pediatric myopia trials with atropine treatment

Across contemporary trials, the clinical benefits of atropine are most apparent during active treatment, while discontinuation can be followed by myopia worsening, termed ‘rebound effect’. Rebound patterns have been described after stopping higher atropine concentrations in ATOM2 and after cessation of lower doses in LAMP and WA-ATOM (17-19), and this provides context for the loss of effect separation after a universal washout year and for the post–dose-reduction acceleration seen after step-down from 0.1 to 0.01% described by Hansen et al (10). ATOM2 observed the smallest rebound effect with 0.01% atropine versus 0.1 and 0.5% (17).

Low-dose atropine produces modest average effect sizes, with trial-to-trial heterogeneity. CHAMP and STAR demonstrated that small but statistically significant on-treatment differences can be detected in large, well-controlled studies (6,9), while MOSAIC and WA-ATOM reinforced that effects may attenuate over time and/or vary across subgroups and settings (5,14).

Endpoint selection can play a role in demonstrating efficacy with expected small effect sizes. Several trials report that AL can show clearer separation than cycloplegic SER at 0.01% (7,14), supporting the use of AL as a sensitive biomarker when pharmacologic effects are small. Effect modification is a recurring theme. STAR reported larger treatment effects in prespecified faster-progressing strata (9), and MOSAIC observed variation by ethnicity and degree of COVID-19 restriction exposure (7,14), supporting the clinical intuition that baseline risk (age, prior progression, environmental context) may influence the observed response.

A broad dose–response relationship remains supported when concentrations are separated sufficiently (most clearly in the ATOM and LAMP studies), with higher concentrations producing greater on-treatment control but at the cost of more dose-related visual side effects and greater rebound risk on cessation (3,11-13,17).

The most prominent disagreement in the literature concerns the consistency of efficacy of 0.01% atropine in non-Asian cohorts. CHAMP and STAR report statistically significant on-treatment separation versus placebo/vehicle (6,9), whereas PEDIG reported no benefit during 24 months of treatment (8), WA-ATOM showed time-varying and ultimately non-significant separation by 24 months (5). Hansen et al, reported a small but statistically significant 24-month on-treatment benefit with continuous 0.01% atropine versus placebo (16), although no statistically significant between-group differences were observed after the subsequent 12-month washout period (10).

Trials also differ in how concentration–response relationships manifest at low doses. In LAMP and ATOM, higher concentrations clearly outperformed 0.01% for both SER and AL endpoints (3,13). By contrast, CHAMP’s 0.02% arm did not meet its prespecified primary endpoint despite efficacy signals with 0.01% atropine (6), and STAR reported limited separation between 0.01% and 0.03% on its primary outcome (9), highlighting that concentration alone may not predict outcomes when doses are similar, formulations differ, or the endpoint is defined as an annualized rate.

Hansen et al. raises a ‘step-down’ variant of the rebound question. Whereas ATOM, LAMP and WA-ATOM primarily characterized rebound after complete cessation, the data from Hansen et al. suggest that reducing concentration mid-course (0.1 to 0.01%) may be accompanied by an adverse change in trajectory even before treatment stops. Whether tapering mitigates or exacerbates rebound remains unclear with current trial evidence.

The loading-dose question: how this study challenges a proposed strategy

A plausible clinical hypothesis is that an initial higher concentration could quickly suppress progression, followed by de-escalation to a lower concentration to improve tolerability and mitigate rebound. Hansen et al. provide a placebo-controlled test of such a strategy: atropine 0.1% nightly for 6 months followed by 0.01% nightly for 18 months, compared with continuous 0.01% and placebo, with an additional 12 months off treatment. The authors report no improvement in the final 3-year outcome versus continuous 0.01% and describe a rebound pattern after reducing the concentration at 6 months, challenging the assumption that a 0.1% loading phase and taper to 0.01% is advantageous when the maintenance dose is very low (10).

Next steps: evidence gaps and study approaches to address them

Despite the growing body of evidence supporting low-dose atropine for childhood myopia control, several important gaps remain (20). One of the most pressing uncertainties concerns the optimal dose for non-Asian children, as trial results in European, North American, and Australian cohorts have been less consistent than those observed in Asian populations. Determining whether differences in response reflect ethnicity, environmental exposures, study design, or pharmacologic factors remains an important priority. These considerations are particularly relevant because the expected effect size of atropine 0.01% in non-Asian populations appears modest and may be strongly dependent on baseline progression risk. When background progression is relatively slow, detection of small treatment effects becomes more challenging and requires larger sample sizes and minimization of heterogeneity, particularly with respect to age and baseline risk. This issue is illustrated by Hansen et al., where the study was powered on an assumed progression rate of approximately −1.00 D/year, whereas observed progression was closer to −0.50 D/year, potentially reducing power to detect smaller treatment effects. By contrast, progression rates in Asian cohorts are often higher, reflecting not only ethnicity but also environmental, behavioural and social determinants such as educational intensity, near-work exposure, outdoor time and other contextual factors; consequently, statistically significant treatment differences may be easier to demonstrate. This raises the possibility of overtreatment in lower-risk Caucasian or other non-Asian children if efficacy assumptions are extrapolated directly from Asian populations without considering individual progression risk, age, AL trajectory and environmental context.

Long-term safety and durability of effect also require further clarification. Most randomized trials have been limited to two or three years of treatment, often followed by relatively short washout periods. Given that myopia progresses over many years, longer observation is needed to understand whether treatment benefits persist, whether cumulative effects emerge over time, and how discontinuation influences long-term refractive and axial outcomes.

Another unresolved issue is the optimal strategy for treatment cessation or dose modification. Evidence suggests that both abrupt discontinuation and concentration reduction may be associated with rebound progression, yet it remains unclear whether tapering mitigates this effect or whether continuation at a maintenance dose provides superior long-term control. Carefully designed trials comparing continuation, tapering, and abrupt cessation at different ages or axial-length thresholds are needed to establish evidence-based discontinuation protocols.

There is also a need to better identify which children are most likely to benefit from low-dose atropine. Treatment effects appear modest on average, and heterogeneity in response suggests that baseline risk factors, such as age, prior progression rate, ethnicity, genetic predisposition, and environmental exposures, may influence outcomes. Distinguishing potential responders from non-responders would allow for the development of personalized, and therefore more efficient, treatment strategies.

Finally, inconsistency in endpoints and reporting across trials complicates interpretation and comparison. Some studies demonstrate clearer separation in AL than in cycloplegic SER, while others use different definitions of progression or annualized rates. Standardization of primary and secondary outcomes would enhance comparability and strengthen the cumulative evidence base.

Looking ahead, future research should prioritize large, multicenter trials that are adequately powered to detect small but clinically meaningful differences. Studies should incorporate longer follow-up periods, ideally 5 years or more, to capture sustained effects and post-treatment trajectories. AL should serve as a primary efficacy endpoint, with cycloplegic refraction as a complementary measure. Trials should also be stratified by baseline risk characteristics and explicitly designed to evaluate dosing algorithms, including initiation thresholds, escalation strategies, tapering approaches, and cessation timing. Harmonization of outcome measures and reporting standards across studies will be essential to enable meaningful cross-trial comparisons.

In addition to traditional randomized trials, pragmatic studies embedded within routine clinical care could accelerate translation of research findings into practice. Such real-world investigations may help refine individualized treatment pathways and support the development of practical, evidence-based dosing strategies for childhood myopia control.

Acknowledgments

Medical writing was provided by Colin Griffin PhD (Griffin Scientific Ltd, UK), which was funded by Santen.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0033/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0033/coif). A.G. reports grants from Alcon, Bausch & Lomb, CooperVision, Essilor, Hoya, Johnson & Johnson, Polpharma, Viatris, Teleon, Thea, and Zeiss; lecture fees from Alcon, Essilor, Eyerising, Polpharma, Santen, Thea and Viatris; and serves on Advisory Boards for Eyerising, Santen, and Thea. The author has no other conflicts of interest to declare.

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