Effect of combining peripheral defocus spectacle lens wear with 0.01% atropine

Background

Myopia control mainly focuses on slowing progression of myopia and axial elongation after its onset (1). Interventions such as atropine, orthokeratology, multifocal soft contact lenses, and peripheral-defocus spectacle designs have demonstrated moderate efficacy (20–60%) in slowing myopia progression (2). However, early onset myopia is strongly associated with higher myopia and increased risk of myopia-related pathology (3). Thus, delaying the onset or preventing myopia through interventions before it starts would provide greater lifetime benefit, making pre-myopia an appealing target for intervention (4,5).

The clinical trial by Lu et al. [2025] evaluates a new spectacle lens design in the pre-myopic disease stage (6). The investigators conducted a double-masked, randomised, placebo-controlled clinical trial involving 450 treatment-naïve children aged 5 to 12 years. Participants with low hyperopia or emmetropia [spherical equivalent refraction (SER): 0.00 to 1.00 D] were randomised to receive diversified segmental defocus optimization (DSDO) spectacle lenses with placebo drops, DSDO lenses combined with nightly 0.01% atropine, or single-vision spectacles with placebo drops. After 1 year, the incidence of myopia (cycloplegic SER ≤−0.50 D) and rapid progression (myopic shift of ≥0.50 D in 1 year) was substantially lower in both DSDO and DSDO + atropine groups compared with the control group. The DSDO groups, with and without atropine, had similar outcomes. These findings suggest that the optical intervention alone may meaningfully delay the transition from pre-myopia to manifest myopia. Despite its strengths, several aspects of the study warrant careful interpretation.

Recruitment and study design

Randomisation was stratified by age, sex, and baseline refractive error using permuted blocks of varying size (3 to 6). Stratification can improve balance of baseline variables across treatment groups as these variables are strong determinants of myopia onset (7). Block randomisation helps keep the groups evenly matched as the trial is ongoing, rather than only (hopefully) balancing out by the end. Adding stratification can increase logistical complexity, and in many cases, it does not offer much extra benefit over simpler approaches such as accounting for those variables later in the analysis (8). Nevertheless, reporting the distribution of participants within each stratum across treatment arms would further assist readers in assessing baseline comparability. Stratification was performed across sex (male vs. female), age (5–8 vs. 9–12 years), and baseline SER (0.00–0.50 vs. 0.50–1.00 D), forming eight strata (2×2×2). Given the relatively large number of strata (eight), imbalances may occur in modestly sized clinical trials with power reduction below 80% (9).

Non-adjustment of covariates

Parental myopia, a combination of genetic predisposition, shared environment, and lifestyle factors (10), was not included in stratification or covariate adjustment. Parental myopia increases the risk of developing childhood myopia by 2–3 times (one parent myopic) to 5–6 times (both parents myopic) (11). Its absence limits the ability to assess the baseline risk stratification.

The study did not quantify environmental risk factors such as time spent outdoors or near work activities, both of which are known to influence the onset of myopia in children (12-14). Although randomisation should distribute these exposures across treatment groups in a large sample, residual imbalance cannot be excluded and may contribute to variability in observed treatment effects (15). Objective wearable devices, such as light sensors and activity trackers, provide more accurate and continuous measurement of these exposures compared with questionnaire-based subjective self-reporting, which is prone to parental and recall bias and masks true exposure levels (16).

Optical design

DSDO lens employs a central clear zone (9.5 mm) with 8 concentric rings of 32 micro-convex lenses (+4.0 to +3.0 D, outwards) each. The lens is designed to generate peripheral myopic defocus in the mid-peripheral retina (10–20°). The angular spacing between the microlenses increases with radius (inside out), creating a ‘starburst’ pattern design of microlenses. This is because the number of microlenses or their size does not increase proportionally, and the gaps between non-defocus clear zones will widen. As with any other segmented optical designs, the spatial distribution and density of lenslets may influence the effective retinal coverage of the defocus signal (17). Although fixation, eye movement, microsaccades, and temporal integration of defocus signals may mitigate this issue (18,19), peripheral defocus responses vary with retinal location (20). Whether differences in microlens spacing across rings alter the strength or uniformity of the inhibitory signal requires further investigation. Without a comparator myopia-control lens, the study cannot determine whether the observed benefit reflects unique features of the DSDO design or the broader effect of peripheral defocus optics.

The reported scotopic (4 lux) pupil diameter in the study population was approximately 6–7 mm, and pupil size would be expected to be smaller under typical photopic viewing conditions. Detailed optical modelling and ray-tracing analyses could therefore help clarify how effectively the DSDO design delivers peripheral myopic defocus across the retina.

Sample size and effect size

The sample size calculation was based on an expected absolute treatment difference of 0.28 D (corresponding to a relative reduction of 26%) derived from a previous clinical trial with defocus incorporated multiple segments (DIMS) lenses in myopic children (21). In the present study, however, the enrolled cohort consisted of pre-myopic children, whose overall myopic shift was substantially smaller, resulting in an observed between-group difference of approximately 0.19 D. Although this absolute effect was smaller than that assumed during power calculations, the relative treatment effect appeared larger (63%) because progression in the control group was also markedly reduced. This difference is a useful reminder that when the baseline progression is low (−0.30 D in the control group), relative reductions can appear inflated even when the actual effect is modest. In practice, absolute differences tend to matter more clinically as they quantify the magnitude of change, for example, dioptres of progression avoided or reduction in axial elongation, and the increased risk of future pathology. On the other hand, relative measures should be interpreted with caution, as they may overestimate treatment effects (22). However, they are still useful, particularly when comparing results across studies where baseline risk or progression rates are not the same, such as between cohorts of myopic and pre-myopic children.

Even though the observed absolute effect was smaller than anticipated, the study appears to be adequately powered to detect a meaningful difference between groups. This is probably because statistical power is determined not only by effect size, but also by sample size and variability. A combination of conservative assumptions in the sample size calculation and lower variability (standard deviation) in myopic shift among pre-myopic children might have increased the statistical power to detect differences between groups. Together, these factors made it easier to detect statistically significant differences, even when the treatment effect is modest. However, sample size assumptions should be based on the target population, especially in myopia control trials, as differences in baseline risk, progression rates and variability can substantially influence power and effect size estimates (23).

0.01% atropine

The inclusion of 0.01% atropine in the combination arm deserves closer scrutiny. Although this concentration is widely regarded as safe and well-tolerated, with minimal side effects, its efficacy in slowing myopia progression has been modest and inconsistent across studies (24). In particular, several trials have shown little to no meaningful reduction in axial elongation at this dose, especially when compared with higher concentrations such as 0.025% or 0.05%, which appear to exert a more robust effect (24). Against this backdrop, the lack of an additional benefit in the combination group is perhaps not unexpected. It is therefore plausible that the findings reflect the limited pharmacological effect 0.01% atropine can provide, rather than an absence of interaction between optical and pharmacological treatment strategies. This raises the possibility that the study may have effectively compared DSDO monotherapy with DSDO plus a pharmacologically weak adjunct. Future studies evaluating combination strategies may need to consider higher atropine concentrations to test potential additive or synergistic effects.

Treatment adherence

An additional consideration is the treatment adherence, which was not explicitly quantified for either spectacle wear or atropine use. Treatment adherence has been recommended as a key outcome to minimise bias and error in interpreting the outcome (25). Given that both optical and pharmacological interventions are known to be wear duration (25) and dose (26) dependent, the absence of adherence data limits interpretation of the observed treatment effects and may be particularly relevant in light of the lack of an additive effect in the DSDO + atropine combination therapy group.

Study duration

A key question when interpreting these findings is whether DSDO lenses can prevent myopia altogether or merely delay its onset. Although DSDO lenses demonstrated a lower incidence of myopia during the 1-year follow-up period, with refractive development continuing throughout childhood, a longer follow-up will be necessary to determine whether it can truly prevent myopia or only postpone its onset. This distinction is particularly relevant in light of evidence that myopia control interventions often exhibit a two-phase response, characterised by an initial rapid treatment effect partly attributed to short-term axial or choroidal changes, followed by a slower, sustained reduction in eye growth over time (22). As a result, a substantial proportion of the apparent treatment benefit may occur early, potentially amplifying perceived efficacy in short-term studies. Thus, a part of the observed reduction in incident myopia at 12 months may reflect an early shift in refractive status rather than a permanent alteration of the underlying growth trajectory. Nevertheless, even modest delays in onset remain clinically meaningful, as late onset of myopia is consistently associated with a lower lifetime risk of high myopia (3).

Definition of incident myopia

The study reports a substantial relative reduction in incident myopia using DSDO lenses alone. However, the definition of myopia introduces an important methodological consideration in interpreting these findings. As in most epidemiological studies, myopia onset was defined as cycloplegic SER of −0.50 D or less (12). While this threshold of −0.50 D reflects a clinically meaningful refractive state of the eye, Incident myopia represents a dichotomous outcome that is highly sensitive to baseline refractive distribution and measurement variability. In pre-myopic children with baseline SER close to the diagnostic threshold for myopia (0.00 D), relatively small differences in refractive change may substantially influence the proportion of participants crossing this boundary compared to children with low levels of hyperopia (0.50 to 1.00 D) where children experiencing myopic shifts of ≥0.50 D still may not have reached the −0.50 D threshold to be classified as myopic. Consequently, modest differences in mean refractive progression between groups may translate into larger proportional differences in incident myopia.

In contrast, mean SER change provides a more direct and unbiased estimate of treatment efficacy, as it captures refractive shifts across the entire cohort and is not dependent on a diagnostic threshold. Consequently, binary incidence outcomes should be interpreted alongside continuous refractive and biometric measures when evaluating efficacy.

Choroidal thickness analysis

Choroidal structural outcomes provide an opportunity to consider potential biological mechanisms underlying the effect of defocus-based myopia control. Optical interventions have largely been designed to impose mid-peripheral myopic defocus, hypothesised to modulate retinal signalling, and induce choroidal thickening, thereby influencing axial growth. Experimental studies in humans have demonstrated that short-term exposure to myopic defocus results in rapid and reversible choroidal thickening (27), with regionally localised responses corresponding to the retinal area exposed to defocus (28). Choroidal thickness changes have been proposed as a fast-responding biomarker of the ocular response to optical defocus, which could determine whether a treatment will be effective in an individual (29). They may represent the link between retinal image processing and downstream scleral remodelling, as well as the longer-term regulation of axial length.

In this context, a regional analysis of choroidal luminal and stromal components could offer valuable insight into whether these interventions preferentially affect the vascular or stromal compartments of the choroid and whether such changes vary with retinal eccentricity. They could also contribute to the evidence as to whether the efficacy of treatment in an individual could be predicted to aid with treatment selection. The methodology for deriving choroidal luminal, stromal, and total areas is insufficiently detailed. The use of ImageJ suggests manual or semi-automated segmentation; however, other key measurement aspects, such as structural boundary delineation techniques and measurement reproducibility, are not reported. Given that choroidal thickness is measured in microns (a small unit of measure) and is sensitive to image acquisition, processing, measurement technique, and diurnal variation, insufficient methodological details limit reproducibility and constrain interpretation of the findings (30-32). Drawing any mechanistic inferences regarding how this novel segmental defocus lens design influences choroidal thickness and ocular growth is limited.

Comparison with contemporary spectacle lens designs

The annualised changes in SER and axial length for DIMS lenses are derived from a 9-month pilot study in 5- to 6-year-old children with baseline SER of +0.75 to −0.50 D (33), whereas the highly aspherical lenslet (HAL) data come from a 1-year RCT in pre-myopic children aged 6 to 9.9 years with baseline SER of 0.00 to +2.00 D (34) (Table 1).

Clinical trials on myopic children using HAL lenses demonstrate a higher relative efficacy (60–67%) estimate at 1 year than for DIMS lenses, which demonstrate more modest early treatment effects, with relative reductions of slightly more than 40% at 1 year (35-38). However, longer-term follow-up or pooled analyses show higher efficacy estimates for DIMS (39), reflecting cumulative effects rather than a strong early effect.

Optical efficiency and design evolution among spectacle-based myopia-control lenses

From an optical design perspective, differences in clinical efficacy between the contemporary spectacle lenses reflect how efficiently each design delivers a consistent peripheral myopic defocus signal to the retina. The DIMS lens uses hundreds of discrete +3.50 D spherical microlenses arranged in a hexagonal grid around a central clear zone, creating multiple focal planes in the peripheral field (40,41). While this configuration produces a robust defocus stimulus, the spherical lenslets generate relatively localised defocus spots and introduce abrupt transitions between treated and untreated regions. By contrast, the highly aspherical lenslet target (HALT) design incorporates more than 1,000 HALs arranged in concentric rings that generate a continuous three-dimensional (3D) “volume of myopic defocus” rather than discrete focal points (41). Optical modelling suggests that this architecture distributes defocused light in front of the retina over a range of dioptric powers (40). This 3D shell of defocused light in front of the retina may provide a stronger inhibitory signal despite natural eye movements and variations in pupil size (41). These design differences may help explain why HALT lenses have often shown slightly greater reductions in axial elongation in randomised trials compared with earlier lenslet technologies.

Emerging evidence further suggests that the efficacy of lenslet-based interventions may not depend solely on the sign of defocus, as both positive and negative lenslet designs have been shown to slow myopia progression and axial elongation (42). This raises the possibility that modulation of retinal image quality through contrast reduction, along with spatial and temporal variation in the optical signal, may explain the mechanism of peripheral defocus on eye growth.

Conclusions

The field of myopia control is constantly evolving, and the DSDO lens represents a novel approach that modulates the spatial distribution and power of peripheral microlenses, highlighting ongoing efforts to refine how spectacle optics deliver myopia-inhibiting defocus/contrast reduction signals across the retina. At least with this optical design, combination with low-dose atropine (0.01%) did not meaningfully enhance the delay in the transition from pre-myopia to manifest myopia.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-2026-0055/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-0055/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Flitcroft I, Bullimore MA, Gifford KL, et al. Myopia Correction, Myopia Control and Myopia Management: Definitions and Recommended Usage. Invest Ophthalmol Vis Sci 2025;66:41. [Crossref] [PubMed]
2. Lawrenson JG, Shah R, Huntjens B, et al. Interventions for myopia control in children: a living systematic review and network meta-analysis. Cochrane Database Syst Rev 2023;2:CD014758. [Crossref] [PubMed]
3. Hu Y, Ding X, Guo X, et al. Association of Age at Myopia Onset With Risk of High Myopia in Adulthood in a 12-Year Follow-up of a Chinese Cohort. JAMA Ophthalmol 2020;138:1129-34. [Crossref] [PubMed]
4. Chia A, Burkill S, Ling Y, et al. Effect of low-dose atropine on young premyopic and low-myopic children: atropine treatment of myopia (ATOM3) - a randomised control trial. Br J Ophthalmol 2026;110:356-62. [Crossref] [PubMed]
5. Lee SH, Tseng BY, Wang JH, et al. Efficacy and Safety of Low-Dose Atropine on Myopia Prevention in Premyopic Children: Systematic Review and Meta-Analysis. J Clin Med 2024;13:1506. [Crossref] [PubMed]
6. Lu Y, Yang X, Zhou J, et al. Diversified segmental defocus optimization lenses with and without atropine for myopia prevention: a randomized clinical trial. JAMA Ophthalmol 2025;143:684-91. [Crossref] [PubMed]
7. Morgan IG, Wu PC, Ostrin LA, et al. IMI Risk Factors for Myopia. Invest Ophthalmol Vis Sci 2021;62:3. [Crossref] [PubMed]
8. Hemming K, Hall J, Copas A, et al. Covariate adjustment in cluster randomised trials: a practical guide. BMJ 2025;391:e084194. [Crossref] [PubMed]
9. Moseley A, LeBlanc M, Freidlin B, et al. Evaluating the impact of stratification on the power and cross-arm balance of randomized phase 2 clinical trials. Clin Trials 2025;22:361-6. [Crossref] [PubMed]
10. Enthoven CA, Tideman JWL, Polling JR, et al. Interaction between lifestyle and genetic susceptibility in myopia: the Generation R study. Eur J Epidemiol 2019;34:777-84. [Crossref] [PubMed]
11. Martínez-Albert N, Bueno-Gimeno I, Gené-Sampedro A. Risk Factors for Myopia: A Review. J Clin Med 2023;12:6062. [Crossref] [PubMed]
12. Biswas S, El Kareh A, Qureshi M, et al. The influence of the environment and lifestyle on myopia. J Physiol Anthropol 2024;43:7. [Crossref] [PubMed]
13. Karthikeyan SK, Ashwini DL, Priyanka M, et al. Physical activity, time spent outdoors, and near work in relation to myopia prevalence, incidence, and progression: An overview of systematic reviews and meta-analyses. Indian J Ophthalmol 2022;70:728-39. [Crossref] [PubMed]
14. Muralidharan AR, Lança C, Biswas S, et al. Light and myopia: from epidemiological studies to neurobiological mechanisms. Ther Adv Ophthalmol 2021;13:25158414211059246. [Crossref] [PubMed]
15. Kang M, Ragan BG, Park JH. Issues in outcomes research: an overview of randomization techniques for clinical trials. J Athl Train 2008;43:215-21. [Crossref] [PubMed]
16. Bhandari KR, Mirhajianmoghadam H, Ostrin LA. Wearable Sensors for Measurement of Viewing Behavior, Light Exposure, and Sleep. Sensors (Basel) 2021;21:7096. [Crossref] [PubMed]
17. Fernandes P, Marinho B, Alves-de-Carvalho RS, et al. Short-Term Changes in Retinal Activity With Four Myopia Control Spectacle Lenses. Transl Vis Sci Technol 2026;15:11. [Crossref] [PubMed]
18. Masquelier T, Portelli G, Kornprobst P. Microsaccades enable efficient synchrony-based coding in the retina: a simulation study. Sci Rep 2016;6:24086. [Crossref] [PubMed]
19. Zhu X. Temporal integration of visual signals in lens compensation (a review). Exp Eye Res 2013;114:69-76. [Crossref] [PubMed]
20. Qu S, Song F, Li Y, et al. Analysis of the effects of corneal and lens characteristics on peripheral defocus of the retina and its relationship with myopia. Sci Rep 2025;15:22102. [Crossref] [PubMed]
21. Huang Z, Chen XF, He T, et al. Synergistic effects of defocus-incorporated multiple segments and atropine in slowing the progression of myopia. Sci Rep 2022;12:22311. [Crossref] [PubMed]
22. Brennan NA, Toubouti YM, Cheng X, et al. Efficacy in myopia control. Prog Retin Eye Res 2021;83:100923. [Crossref] [PubMed]
23. Adamson KA, Prion S. Making sense of methods and measurement: statistical power. Clinical Simulation in Nursing 2013;9:e477-8.
24. Yam JC, Khanal S, Phillips JR. Does 0.01% atropine have a place as a myopia control therapy? Ophthalmic Physiol Opt 2025;45:929-35. [Crossref] [PubMed]
25. Dang RM, Jalbert I, Hui A, et al. Measuring Treatment Adherence in Myopia Control: Current Practices and Future Directions. Ophthalmol Sci 2026;6:100949. [Crossref] [PubMed]
26. Biswas S, Lanca C, Kynman-Sprinks D, et al. Ethnic and dose-dependent differences in atropine efficacy for myopia control: a systematic review and meta-analysis. Br J Ophthalmol 2026;110:483-91. [Crossref] [PubMed]
27. Wang D, Chun RK, Liu M, et al. Optical Defocus Rapidly Changes Choroidal Thickness in Schoolchildren. PLoS One 2016;11:e0161535. [Crossref] [PubMed]
28. Hoseini-Yazdi H, Vincent SJ, Collins MJ, et al. Regional alterations in human choroidal thickness in response to short-term monocular hemifield myopic defocus. Ophthalmic Physiol Opt 2019;39:172-82. [Crossref] [PubMed]
29. Chakraborty R, Ostrin LA, Verkicharla PK. Can short-term changes in the choroid in humans predict long-term eye growth? Ophthalmic Physiol Opt 2025;45:923-8. [Crossref] [PubMed]
30. Tan CS, Ouyang Y, Ruiz H, et al. Diurnal variation of choroidal thickness in normal, healthy subjects measured by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:261-6. [Crossref] [PubMed]
31. Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol 2009;147:811-5. [Crossref] [PubMed]
32. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496-500. [Crossref] [PubMed]
33. Yang HY, Tsai DC. Efficacy of Defocus Incorporated Multiple Segments (DIMS) Lenses in Retarding Myopic Shifts Among Pre-Myopic Preschoolers: Nine-Month Results of a Pilot Study. Invest Ophthalmol Vis Sci 2025;66:2811.
34. Zhang Z, Zeng L, Gu D, et al. Spectacle Lenses With Highly Aspherical Lenslets for Slowing Axial Elongation and Refractive Change in Low-Hyperopic Chinese Children: A Randomized Controlled Trial. Am J Ophthalmol 2025;269:60-8. [Crossref] [PubMed]
35. Liu J, Lu Y, Huang D, et al. The Efficacy of Defocus Incorporated Multiple Segments Lenses in Slowing Myopia Progression: Results from Diverse Clinical Circumstances. Ophthalmology 2023;130:542-50. [Crossref] [PubMed]
36. Bao J, Yang A, Huang Y, et al. One-year myopia control efficacy of spectacle lenses with aspherical lenslets. Br J Ophthalmol 2022;106:1171-6. [Crossref] [PubMed]
37. Lam CSY, Tang WC, Tse DY, et al. Defocus Incorporated Multiple Segments (DIMS) spectacle lenses slow myopia progression: a 2-year randomised clinical trial. Br J Ophthalmol 2020;104:363-8. [Crossref] [PubMed]
38. Guo H, Li X, Zhang X, et al. Comparing the effects of highly aspherical lenslets versus defocus incorporated multiple segment spectacle lenses on myopia control. Sci Rep 2023;13:3048. [Crossref] [PubMed]
39. D'Andrea L, Rinaldi M, Piscopo R, et al. Efficacy of spectacle lenses for myopia control: a meta-analysis of randomised controlled trials. Br J Ophthalmol 2026;110:125-32. [Crossref] [PubMed]
40. Gantes-Nuñez J, Jaskulski M, López-Gil N, et al. Optical characterisation of two novel myopia control spectacle lenses. Ophthalmic Physiol Opt 2023;43:388-401. [Crossref] [PubMed]
41. Singh NK, De Gracia P. Next-Generation Spectacle Lenses for Myopia Control: Optical Designs, Mechanisms, and Clinical Efficacy. J Clin Med 2025;14:7872. [Crossref] [PubMed]
42. Su B, Cho P, Vincent SJ, et al. Two-year results of Lenslet-ARray-Integrated spectacle lenses for myopia control in children. Eye Vis (Lond) 2025;12:45. [Crossref] [PubMed]