This secondary analysis of the 3-year results of the 24-Month Myopia Outcome Study of Atropine in Children (MOSAIC) randomized clinical trial investigates the efficacy and safety of different atropine eye drop regimens, 0.05% and 0.01%, in treating myopia progression in European eyes.
Key Points
Question
What is the efficacy and safety of different atropine eye drop regimens, 0.05% and 0.01%, in treating myopia progression in European eyes?
Findings
In this secondary analysis of the 3-year results of the 24-Month Myopia Outcome Study of Atropine in Children (MOSAIC) randomized clinical trial including 199 children and adolescents, among 66 participants switched from placebo to nightly 0.05% atropine eye drops in year 3, approximately 20% experienced transient blurred near vision or photophobia but no treatment discontinuation. The group receiving nightly 0.05% atropine eye drops exhibited less 12-month axial eye growth than participants switched from nightly 0.01% atropine eye drops to either placebo or tapering of 0.01% atropine eye drops.
Meaning
These findings support consideration of treatment of childhood myopia with 0.05% atropine eye drops despite more adverse events in this group.
Abstract
Importance
Additional data are required regarding atropine treatment regimens for control of myopia progression.
Objective
To investigate the efficacy and safety of different atropine regimens for myopia in children.
Design, Setting, and Participants
This was a secondary analysis of the 3-year results of the 24-Month Myopia Outcome Study of Atropine in Children (MOSAIC) trial, called the MOSAIC2 trial. The MOSAIC trial was an investigator-led, double-masked, randomized clinical trial of different atropine concentrations and regimens. The MOSAIC2 study took place at the Centre for Eye Research Ireland, in Dublin, Ireland, and included children and adolescents with myopia from the MOSAIC trial. Data analysis was conducted from November 2023 to February 2024.
Interventions
Participants were randomly assigned to the following cohorts: group 1, nightly placebo for 2 years then 0.05% atropine eye drops for 1 year and group 2, nightly 0.01% atropine eye drops for 2 years then rerandomization to placebo nightly, tapering placebo, or tapering of 0.01% atropine eye drops for 1 year.
Main Outcomes and Measures
Observed changes in cycloplegic spherical equivalent refraction and axial length from month 24, or baseline, to month 36.
Results
A total of 199 children with myopia (mean [SD] age, 13.9 [2.4] years; 121 female [60.8%]) of the 250 children and adolescents from the MOSAIC trial were included in the MOSAIC2 trial analysis. Of 83 participants assigned to group 1, 66 (79.5%) reconsented to year 3, and 61 (73.5%) completed the trial. Of 167 participants assigned to group 2, 133 (79.6%) continued to year 3, and 121 (72.5%) completed the trial (0.01% atropine, then nightly placebo: n = 31 and n = 29 [93.5%]; 0.01% atropine, then tapering placebo: n = 29 and n = 25 [86.2%]; 0.01% atropine then tapering 0.01% atropine: n = 73 and n = 67 [91.8%], respectively). Compared with the group taking placebo then 0.05% atropine, the combined atropine then placebo groups had more spherical equivalent progression (adjusted difference, −0.13 diopters [D]; 95% CI, −0.22 to −0.04 D; P = .01) and axial elongation (adjusted difference, 0.06 mm; 95% CI, 0.02-0.09 mm; P = .008), and the group taking 0.01% atropine then tapering 0.01% atropine had more axial elongation (adjusted difference, 0.04 mm; 95% CI, 0.009-0.07 mm; P = .04). In the group taking placebo then 0.05% atropine, 15% (n = 10) and 8% (n = 5) reported blurred near vision and photophobia, respectively, during year 3, compared with 3% (n = 2) and 0%, respectively, in the group taking 0.01% atropine then tapering 0.01% atropine, and no reports in both placebo groups.
Conclusions and Relevance
Despite more adverse events, participants using 0.05% atropine during year 3 had no differences in treatment completion rates and exhibited 0.13-D less myopia progression and 0.06-mm less axial elongation, compared with participants using placebo, supporting consideration of treatment as given to the group taking 0.05% atropine in this European population.
Trial Registration
isrctn.org Identifier: ISRCTN36732601
Introduction
The increasing prevalence and severity of myopia1 represents a major public health concern due to its potential to cause vision2 and economic loss,3 several optical4,5,6 and pharmaceutical interventions7,8,9 are being pursued in childhood and adolescence to reduce the magnitude of myopia and risk of permanent vision loss among treated individuals.10
Atropine, a nonselective muscarinic antagonist, has been shown in some but not all clinical trials to slow the progression of myopia in a dose-dependent manner.11 However, high-concentration atropine poses challenges including blurred near-vision, pupil dilation, and increased photosensitivity.8
Over the past 2 years, 0.01% atropine eye drops have been investigated in children of European descent,12,13,14 including in the 24-Month Myopia Outcome Study of Atropine in Children (MOSAIC) clinical trial results.13 However, efficacy on myopia progression varied, from no significant effect at the primary end point14,15 to an effect on axial length,12,13 or spherical equivalent progression.12 The multicenter Childhood Atropine for Myopia Progression (CHAMP) study found no dose-response effect, with results suggesting that the 0.01% atropine group achieved better myopia control than the 0.02% atropine group, which showed no effect on spherical equivalent refractive error.12
Atropine studies in Asian countries have shown 0.01% atropine eye drops to consistently reduce myopia progression.9,16,17,18 Additionally, the Low-concentration Atropine for Myopia Progression (LAMP) study in Hong Kong9 and the Atropine Treatment Of Myopia (ATOM) study in Singapore11 suggested dose-dependent relationships between atropine concentration, myopia control efficacy, and rebound myopia progression after cessation.8 In this study, rebound myopia progression was defined as myopia progression faster than an age-matched, treatment-naive control group.19 The LAMP study identified that 0.05% atropine eye drops appeared to have a greater myopia control effect relative to lower concentrations, with an increase in reported adverse effects; however, tolerability of 0.05% atropine eye drops has not been established in European populations, where lighter iris colors could be associated with more adverse effects due to lower levels of melanin-bound atropine in the eye.20
Building on the results of the first 2 years of the MOSAIC trial (baseline to 24 months) and months 24 to 36 of the MOSAIC trial (called the MOSAIC2 trial), we aimed to explore (1) the change in myopia progression after ceasing 0.01% atropine eye drops or reducing its frequency in a tapering regimen and (2) the safety and efficacy of 0.05% atropine eye drops in a European population of treatment-naive participants.
Methods
The 3-year investigator-led, double-masked, placebo-controlled MOSAIC randomized clinical trial was designed to assess the safety, tolerability, and mechanism of action of low concentration atropine in managing childhood myopia in a European population (Supplement 1).21 The initial protocol examined only 0.01% atropine eye drops as the intervention,21 but due to emerging evidence, the protocol was updated to incorporate a planned analysis of the safety and efficacy of 0.05% atropine eye drops from month 24 to 36. The study was approved by research ethics committees at the Mater Misericordiae University Hospital, Dublin, Ireland, and Technological University Dublin. Participants and guardians provided written informed assent and consent before enrollment at the Centre for Eye Research Ireland, Dublin, Ireland. At the 24-month visit, participants could opt for a third year, requiring reconsent and/or reassent, as applicable, to the updated protocol. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (eTable 1 in Supplement 2).22
Eligibility criteria for the MOSAIC trial were age 6 to 16 years with spherical equivalent less than or equal to −0.50 diopters (D), no prior myopia therapy, no significant comorbidities, and no contraindications to atropine. The recruited 250 participants (from July 2019 to September 2020) were randomly assigned in a 2:1 ratio to either preservative-free 0.01% atropine or placebo eye drops nightly in both eyes for 24 months (MOSAIC). Participants did not receive compensation or incentives to participate.
The third year of the MOSAIC trial (MOSAIC2) is a randomized trial of 2 groups from the MOSAIC trial. In group 1, participants were assigned to use placebo nightly for 2 years followed by 0.05% atropine eye drops for 1 year (placebo then 0.05% atropine group). In group 2, participants were assigned to use 0.01% atropine nightly for 2 years and were then rerandomized using block randomization in a 1:1:2 ratio to use one of the following: (1) placebo nightly (atropine then nightly placebo group), (2) tapering placebo (atropine then tapering placebo group), or (3) tapering 0.01% atropine eye drops (0.01% atropine then tapering 0.01% atropine group) for 1 year. The tapering regimen involved using 1 eye drop in both eyes every second night from month 25 to 27, then twice weekly from month 28 to 30, followed by once weekly from month 31 to 33 before ceasing eye drops entirely from month 34 to 36.
A carer or parents of participants reported their child’s race with the following options: Asian, Black, Hispanic, multiracial, White, and other, which included a free-text space for parents to specify further. These data were collected to investigate racial interactions between myopia progression and low-concentration atropine treatment efficacy. Of the children identified as other race, the specified races were Indian and Russian.
Intervention
Single-use preservative-free eye drops in disposable ampules, identical packaging, with labels revealing kit number, expiration, and batch (Vyluma) were dispensed. In the MOSAIC2 trial, the treatment regimen provided some information about the treatment concentration (ie, placebo, 0.01% atropine, or 0.05% atropine), eg, participants using eye drops nightly in the third year could only be using placebo or 0.05% atropine eye drops. Some study members were unmasked to the treatment regimen, not the concentration, explaining it to participants and handling dispensing, accountability (counting used vials), and recording expected adverse events. Other study members, masked to both treatment regimen and concentration, conducted the remaining study examinations. Participants and parents were masked to treatment assignments, but not regimens, throughout the full 3 years of the MOSAIC trial, with unmasking occurring after the 36-month visit.
Sample Size
The sample size calculation for the MOSAIC trial was based on the 24-month primary end point.21 An a priori sample size calculation was not performed for the current analysis of a secondary end point.
Examinations
Examinations occurred every 6 months, but the 6-month visit was disrupted and abandoned due to the COVID-19 pandemic. Each examination included cycloplegic autorefraction. Before cycloplegia, visual acuity at distance and near (MultiQuity MIQ 720 [Sightrisk]), binocular accommodative amplitude (Royal Air Forces rule, a binocular gauge used to measure convergence and accommodation), accommodative facility (number of ±2 D flipper cycles cleared in 1 minute), and monocular accommodative lag (at 33 cm; WAM-5500 autorefractor [Grand Seiko]) were measured. Iris color was assessed at baseline using a slitlamp and published grading system.23 Ocular biometry, including axial length, corneal radius, and pupil diameter (photopic and mesopic conditions), was measured using a partial coherence interferometer and pupillometer (Aladdin [Topcon]). Cycloplegia was achieved with 0.5% proxymetacaine hydrochloride followed by 1% cyclopentolate, and dark-eyed participants received a second eye drop of cyclopentolate 5 minutes after the first. Autorefraction, measured with the WAM-5500 autorefractor (Grand Seiko), was performed at least 30 minutes after the last cyclopentolate drop, with a mean of 5 readings recorded. Parents completed the Amblyopia Treatment Index (ATI) survey, assessing eye drop acceptability, and participants responded to 6 ocular symptom questions at each visit. Treatment compliance was evaluated by dividing the number of returned used vials by the expected number, with 75% or greater defining adequate compliance.
Statistical Analysis
We performed an intention-to-treat analysis on participants reconsented to the MOSAIC2 trial. For analysis of outcomes, the atropine then nightly placebo group and atropine then tapering placebo group were combined (labeled atropine then placebo) because of the following: (1) both received 0.01% atropine treatment for 2 years followed by inactive treatment for 1 year, and (2) the sole rationale for administering placebo in tapering vs nightly regimens was to facilitate masking. Outcome changes (ie, cycloplegic spherical equivalent and axial length changes) were calculated relative to the 24-month visit, with the placebo tapered and nightly arms combined as a single treatment arm. To examine differences in categorical, continuous parametric, or nonparametric variables, χ2, 1-way analysis of variance, or Kruskal-Wallis tests, respectively, were performed at a single visit.
To assess treatment effects, linear mixed models were used to model change in the outcome parameter against visit and treatment arm, and an interaction between visit arm and treatment covariates, which included sex, age, and the value of the outcome at the MOSAIC trial baseline or 24-month visit as appropriate. Where change in an ocular parameter from month 24 onward was modeled, we additionally adjusted for change in that parameter from baseline to the 24-month visit. A random-intercept term for eye nested within participant was included to account for within-participant correlations. Estimated marginal means, generated using the R package emmeans (R Project for Statistical Computing), facilitated pairwise comparisons. To investigate factors associated with treatment response, data were limited to the 36-month visit and an interaction between the factor of interest and treatment arm included in the model. R, version 4.3.0 (R Project for Statistical Computing), was used for statistical analysis. All P values were 2-sided, and a P value <.05 was considered statistically significant. Tukey P value adjustments were made for pairwise comparison of multiple treatment groups but not comparison of multiple outcomes. Data analysis was conducted from November 2023 to February 2024.
Results
A total of 199 children with myopia (mean [SD] age, 13.9 [2.4] years; 121 female [60.8%]; 78 male [39.2%]) of the 250 children and adolescents from the MOSAIC trial were included in the MOSAIC2 trial analysis. Participants self-identified with the following races and ethnicities: 15 Asian (7.5%), 4 Black (2.0%), 1 Hispanic (0.5%), 11 multiracial (5.5%), 166 White (83.4%), 2 other (1.0%). Of 250 participants enrolled in the MOSAIC trial, 83 (33.3%) and 167 (67.7%) were assigned to group 1 (placebo) and group 2 (0.01% atropine) at baseline, respectively. In group 1, 66 participants (79.5%) reconsented to the MOSAIC2 trial at the 24-month visit, and 61 (73.5%) completed the 36-month visit. In group 2, 133 participants (79.6%) reconsented to the MOSAIC2 trial, and 121 (72.5%) completed the 36-month visit, including 31 and 29 (93.5%), respectively, in the atropine then nightly placebo group; 29 and 25 (86.2%), respectively, in the atropine then tapering placebo group; and 73 and 67 (91.8%), respectively, in the atropine then tapering 0.01% atropine group. No differences in rates of discontinuation from baseline, and from month 24, were detected among the 4 groups. A flowchart of recruitment and retention is shown in Figure 1 and Table 1 displays the characteristics of participants in the MOSAIC2 trial during their 24-month visit. Notably, pupil diameter was greater in users of 0.01% atropine at the 24-month visit, with otherwise well-balanced characteristics across treatment arms. Baseline characteristics showed no differences between those who did and did not reconsent to the MOSAIC2 trial, except for slightly higher accommodative facility in the MOSAIC2 reconsent group (median [IQR], 5 [3-7] vs 4 [2-5] cycles per minute; P = .03). Study treatment compliance, defined as using 75% or greater of expected doses, was equally good across all the groups: atropine then tapering placebo (90%), atropine then nightly placebo (81%), atropine then tapering 0.01% atropine (83%), and placebo then 0.05% atropine (81%) (P = .81).
Figure 1. Consolidated Standards of Reporting Trials Flow Diagram for the 24-Month Myopia Outcome Study of Atropine in Children (MOSAIC) Trial.
Participants or legal carers were invited to reconsent to participate in the third year of the MOSAIC. The tapering regimen involving using 1 eye drop in both eyes every second night for 3 months, then twice weekly for 3 months, followed by once weekly for 3 months and participants ceased eye drop use entirely for the 3 months before the 36-month visit.
Table 1. Characteristics of the 24-Month Myopia Outcome Study of Atropine in Children, Months 24 to 36 (MOSAIC2) Participants at the 24-Month Visita.
| Treatment arm | 0.01% Atropine then placebo | 0.01% Atropine then taper 0.01% atropine | Placebo then 0.05% atropine | P value |
|---|---|---|---|---|
| No. | 60 | 73 | 66 | |
| Age, mean (SD), y | 13.66 (2.60) | 14.21 (2.32) | 13.71 (2.19) | .32 |
| Sex, No. (%) | ||||
| Female | 36 (60.0) | 43 (58.9) | 42 (43.6) | .79 |
| Male | 24 (40.0) | 30 (41.1) | 24 (36.4) | |
| No. of parents with myopia, No. (%) | ||||
| 0 | 8 (13.3) | 17 (23.3) | 12 (18.2) | .27 |
| 1 | 33 (55.0) | 44 (60.3) | 37 (56.1) | |
| 2 | 19 (31.7) | 12 (16.4) | 17 (25.8) | |
| Race, No. (%) | ||||
| Asian | 6 (10.0) | 5 (6.8) | 4 (6.1) | .65 |
| Black | 2 (3.3) | 1 (1.4) | 1 (1.5) | |
| Hispanic | 0 (0.0) | 1 (1.4) | 0 (0.0) | |
| Multiracial | 6 (10.0) | 3 (4.1) | 2 (3.0) | |
| White | 46 (76.7) | 62 (84.9) | 58 (87.9) | |
| Otherb | 0 | 1 (1.4) | 1 (1.5) | |
| Iris color, No. (%) | ||||
| Blue | 29 (48.3) | 35 (47.9) | 36 (54.5) | .52 |
| Brown | 18 (30.0) | 16 (21.9) | 12 (18.2) | |
| Green | 13 (21.7) | 22 (30.1) | 18 (27.3) | |
| Final visit attended, No. (%) | ||||
| 24-mo | 4 (6.7) | 5 (6.8) | 4 (6.1) | .94 |
| 30-mo | 2 (3.3) | 1 (1.4) | 1 (1.5) | |
| 36-mo | 54 (90.0) | 67 (91.8) | 61 (92.4) | |
| Spherical equivalent, median (IQR), D | −4.04 (−4.84 to −3.11) | −3.62 (−5.06 to −2.50) | −3.98 (−4.69 to −2.60) | .49 |
| Axial length, mean (SD), mm | 25.12 (0.99) | 25.27 (1.08) | 25.29 (1.17) | .62 |
| Change in SER from baseline to 24-mo, mean (SD), D | −0.60 (0.50) | −0.48 (0.55) | −0.63 (0.62) | .26 |
| Change in axial length from baseline to 24-mo, mean (SD), mm | 0.36 (0.28) | 0.30 (0.24) | 0.40 (0.30) | .12 |
| Photopic pupil diameter, mean (SD), mm | 4.47 (0.78) | 4.29 (0.71) | 3.92 (0.53) | <.001 |
| Mesopic pupil diameter, mean (SD), mm | 5.30 (0.76) | 5.30 (0.73) | 4.91 (0.64) | .002 |
| Amplitude of accommodation, median (IQR), D | 19.00 (14.75 to 20.00) | 18.00 (13.50 to 20.00) | 20.00 (14.62 to 20.00) | .36 |
| Accommodative facility, median (IQR), cycles/min | 5.00 (3.00 to 7.25) | 6.00 (4.00 to 8.00) | 7.00 (4.25 to 8.88) | .14 |
| Accommodative lag, median (IQR), D | 1.06 (0.84 to 1.48) | 0.96 (0.66 to 1.26) | 0.87 (0.50 to 1.20) | .07 |
Abbreviations: D, diopter; SER, spherical equivalent refraction.
Ocular data are the mean of both eyes. The placebo group contains combined data from both the atropine then nightly placebo group and the atropine then tapering placebo group. Tests for P value are either χ2, 1-way analysis of variance or Kruskal-Wallis for categorical, continuous parametric (described with mean) or continuous nonparametric (described by median), respectively.
Other race includes Indian and Russian.
Efficacy Outcomes
Figure 2, Table 2, and eTable 2 in Supplement 2 depict changes in cycloplegic spherical equivalent and axial length from the 24-month visit across the 3 treatment arms (placebo then 0.05% atropine, atropine then placebo, and atropine then tapering 0.01% atropine). eTable 3 and eFigures 1 and 2 in Supplement 2 list the separate comparisons of atropine then nightly placebo and atropine then tapering placebo and changes relative to baseline. From the 24- to 36-month visit, the atropine then placebo group had more spherical equivalent (adjusted difference, −0.13 D; 95% CI, −0.22 to −0.04 D; P = .01) and axial length (adjusted difference, 0.06 mm; 95% CI, 0.02-0.09 mm; P = .008) progression compared with the placebo then 0.05% atropine group. The atropine then tapering 0.01% atropine group had more axial eye growth compared with the placebo then 0.05% atropine group (adjusted difference, 0.04 mm; 95% CI, 0.009-0.07 mm; P = .04), after adjusting for age, sex, the outcome value at baseline and the baseline to 24-month change in the outcome. The proportion of participants in the placebo, 0.01% atropine, and 0.05% atropine groups, separately, that met defined spherical equivalent refraction progression thresholds for slower, medium, and faster myopia progression is shown in eFigure 3 in Supplement 2.
Figure 2. Mean Change (SE) in Spherical Equivalent Refractive Error and Axial Length Relative to 24-Month Visit.
The placebo group contains combined data from both the atropine then nightly placebo group and atropine then tapering placebo group. AL indicates axial length.
Table 2. Change in Ocular Parameters From Either Baseline to 24-Month, 24-Month to 36-Month, or Baseline to 36-Month in Participants That Reconsented to 24-Month Myopia Outcome Study of Atropine in Children, Months 24 to 36 (MOSAIC2)a.
| MOSAIC2 treatment | Atropine then placebo (group 1) | 0.01% Atropine then taper atropine, 0.01% (group 2) | Placebo then 0.05% atropine (group 3) | Adjusted pairwise differences (95% CI) | Pairwise comparisons | |||
|---|---|---|---|---|---|---|---|---|
| Mean (SD) | No. (%) | Mean (SD) | No. (%) | Mean (SD) | No. (%) | |||
| Spherical equivalent, D | ||||||||
| Change from baseline to 24 mo | −0.60 (0.55) | 358 (99.4) | −0.48 (0.58) | 436 (99.5) | −0.63 (0.65) | 390 (98.5) | 1 vs 2: −0.07 (−0.22 to 0.08) | 1 vs 2: P = .62 |
| 1 vs 3: 0.03 (−0.12 to 0.18) | 1 vs 3: P = .92 | |||||||
| 2 vs 3: 0.10 (−0.04 to 0.24) | 2 vs 3: P = .36 | |||||||
| Change from 24-36 mo | −0.23 (0.34) | 212 (88.3) | −0.18 (0.26) | 264 (90.4) | −0.11 (0.30) | 242 (91.7) | 1 vs 2: −0.04 (−0.12 to 0.04) | 1 vs 2: P = .63 |
| 1 vs 3: −0.13 (−0.22 to −0.04) | 1 vs 3: P = .01 | |||||||
| 2 vs 3: −0.09 (−0.17 to −0.005) | 2 vs 3: P = .10 | |||||||
| Change from baseline to 36 mo | −0.85 (0.73) | 570 (95.0) | −0.60 (0.61) | 700 (95.9) | −0.78 (0.77) | 632 (95.8) | 1 vs 2: −0.13 (−0.30 to 0.04) | 1 vs 2: P = .26 |
| 1 vs 3: −0.10 (−0.27 to 0.07) | 1 vs 3: P = .49 | |||||||
| 2 vs 3: 0.04 (−0.13 to 0.20) | 2 vs 3: P = .90 | |||||||
| Axial length, mm | ||||||||
| Change from baseline to 24 mo | 0.36 (0.29) | 358 (99.4) | 0.30 (0.25) | 436 (99.5) | 0.40 (0.31) | 390 (98.5) | 1 vs 2: 0.02 (−0.05 to 0.09) | 1 vs 2: P = .83 |
| 1 vs 3: −0.05 (−0.11 to 0.02) | 1 vs 3: P = .35 | |||||||
| 2 vs 3: −0.07 (−0.13 to −0.002) | 2 vs 3: P = .10 | |||||||
| Change from 24-36 mo | 0.14 (0.17) | 212 (88.3) | 0.10 (0.11) | 264 (90.4) | 0.09 (0.14) | 242 (86.0) | 1 vs 2: 0.01 (−0.02 to 0.05) | 1 vs 2: P = .76 |
| 1 vs 3: 0.06 (0.02 to 0.09) | 1 vs 3: P = .008 | |||||||
| 2 vs 3: 0.04 (0.009 to 0.07) | 2 vs 3: P = .04 | |||||||
| Change from baseline to 36 mo | 0.49 (0.40) | 570 (95.0) | 0.38 (0.30) | 700 (95.9) | 0.51 (0.39) | 632 (95.8%) | 1 vs 2: 0.05 (−0.03 to 0.12) | 1 vs 2: P = .43 |
| 1 vs 3: −0.004 (−0.08 to 0.07) | 1 vs 3: P = .99 | |||||||
| 2 vs 3: −0.05 (−0.12 to 0.02) | 2 vs 3: P = .35 | |||||||
| Photopic pupil diameter, mm | ||||||||
| Change from baseline to 24 mo | 0.18 (0.97) | 329 (91.4) | 0.09 (0.72) | 424 (96.8) | −0.23 (0.59) | 366 (92.4%) | 1 vs 2: 0.15 (−0.05 to 0.35) | 1 vs 2: P = .31 |
| 1 vs 3: 0.52 (0.30 to 0.74) | 1 vs 3 P < .001 | |||||||
| 2 vs 3: 0.37 (0.17 to 0.57) | 2 vs 3 P < .001 | |||||||
| Change from 24-36 mo | −0.49 (0.79) | 188 (78.3) | −0.38 (0.72) | 248 (84.9) | 1.33 (0.99) | 227 (86.0%) | 1 vs 2: −0.08 (−0.33 to 0.18) | 1 vs 2: P = .84 |
| 1 vs 3: −1.53 (−1.80 to −1.26) | 1 vs 3 P < .001 | |||||||
| 2 vs 3: −1.46 (−1.72 to −1.21) | 2 vs 3 P < .001 | |||||||
| Change from baseline to 36 mo | −0.38 (0.58) | 517 (86.2) | −0.34 (0.84) | 672 (92.5) | 1.09 (0.95) | 592 (89.8%) | 1 vs 2: 0.03 (−0.19 to 0.25) | 1 vs 2: P = .95 |
| 1 vs 3: −1.34 (−1.55 to −1.12) | 1 vs 3 P < .001 | |||||||
| 2 vs 3: −1.37 (−1.59 to −1.15) | 2 vs 3 P < .001 | |||||||
| Mesopic pupil diameter, mm | ||||||||
| Change from baseline to 24 mo | 0.20 (0.86) | 328 (91.1) | 0.18 (0.85) | 425 (97.0) | −0.15 (0.73) | 369 (93.2%) | 1 vs 2: 0.02 (−0.18 to 0.22) | 1 vs 2: P = .98 |
| 1 vs 3: 0.40 (0.20 to 0.60) | 1 vs 3 P < .001 | |||||||
| 2 vs 3: 0.38 (0.18 to 0.58) | 2 vs 3 P < .001 | |||||||
| Change from 24-36 mo | 0.44 (1.10) | 194 (80.8) | 0.61 (0.66) | 250 (85.6) | 2.01 (0.95) | 234 (88.6%) | 1 vs 2: −0.22 (−0.48 to 0.04) | 1 vs 2: P = .26 |
| 1 vs 3: −1.60 (−1.89 to −1.31) | 1 vs 3 P < .001 | |||||||
| 2 vs 3: −1.38 (−1.65 to −1.11) | 2 vs 3 P < .001 | |||||||
| Change from baseline to 36 mo | −0.29 (0.70) | 522 (87.0) | −0.29 (0.69) | 675 (92.5) | 0.91 (0.97) | 603 (91.4%) | 1 vs 2: −0.03 (−0.25 to 0.19) | 1 vs 2: P = .96 |
| 1 vs 3: −1.11 (−1.33 to −0.90) | 1 vs 3 P < .001 | |||||||
| 2 vs 3: −1.08 (−1.30 to −0.86) | 2 vs 3 P < .001 | |||||||
| Accommodative amplitude, D | ||||||||
| Change from baseline to 24 mo | −1.85 (4.95) | 230 (63.9) | −1.99 (4.75) | 290 (66.2) | −0.77 (5.26) | 262 (66.2%) | 1 vs 2: −0.03 (−1.27 to 1.21) | 1 vs 2: P = .99 |
| 1 vs 3: −0.87 (−2.12 to 0.38) | 1 vs 3: P = .36 | |||||||
| 2 vs 3: −0.84 (−2.04 to 0.36) | 2 vs 3: P = .35 | |||||||
| Change from 24-36 mo | −1.22 (4.22) | 208 (86.7) | 0.42 (4.69) | 264 (90.4) | −1.28 (4.17) | 240 (90.0%) | 1 vs 2: −1.52 (−2.72 to −0.32) | 1 vs 2: P = .04 |
| 1 vs 3: −0.28 (−1.50 to 0.94) | 1 vs 3: P = .89 | |||||||
| 2 vs 3: 1.24 (0.08 to 2.40) | 2 vs 3: P = .10 | |||||||
| Change from baseline to 36 mo | −3.26 (5.53) | 422 (87.9) | −1.60 (4.48) | 554 (75.9) | −2.12 (5.29) | 502 (76.1) | 1 vs 2: −1.72 (−3.01 to −0.43) | 1 vs 2: P = .03 |
| 1 vs 3: −0.82 (−2.13 to 0.49) | 1 vs 3: P = .44 | |||||||
| 2 vs 3: 0.90 (−0.35 to 2.15) | 2 vs 3: P = .34 | |||||||
| Accommodative lag, D | ||||||||
| Change from baseline to 24 mo | −0.08 (0.67) | 222 (61.7) | −0.05 (0.63) | 278 (63.5) | −0.15 (0.71) | 262 (66.2) | 1 vs 2: 0.10 (−0.07 to 0.26) | 1 vs 2: P = .51 |
| 1 vs 3: 0.16 (−0.009 to 0.33) | 1 vs 3: P = .16 | |||||||
| 2 vs 3: 0.06 (−0.10 to 0.22) | 2 vs 3: P = .71 | |||||||
| Change from 24-36 mo | 0.11 (0.60) | 200 (83.3) | −0.03 (0.52) | 257 (88.0) | 0.06 (0.66) | 242 (91.7) | 1 vs 2: 0.19 (0.04 to 0.34) | 1 vs 2: P = .04 |
| 1 vs 3: 0.16 (0.01 to 0.31) | 1 vs 3: P = .08 | |||||||
| 2 vs 3: −0.02 (−0.16 to 0.12) | 2 vs 3: P = .95 | |||||||
| Change from baseline to 36 mo | 0.03 (0.76) | 422 (70.3) | −0.06 (0.56) | 535 (75.9) | −0.07 (0.73) | 504 (76.4) | 1 vs 2: 0.21 (0.04 to 0.38) | 1 vs 2: P = .04 |
| 1 vs 3: 0.23 (0.06 to 0.40) | 1 vs 3: P = .02 | |||||||
| 2 vs 3: 0.02 (−0.14 to 0.18) | 2 vs 3: P = .98 | |||||||
| Accommodative facility, cycles/min | ||||||||
| Change from baseline to 24 mo | 1.27 (3.13) | 230 (63.9) | 1.14 (3.06) | 290 (66.2) | 1.83 (3.17) | 262 (66.2) | 1 vs 2: −0.15 (−1.01 to 0.71) | 1 vs 2: P = .94 |
| 1 vs 3: −0.68 (−1.56 to 0.20) | 1 vs 3: P = .29 | |||||||
| 2 vs 3: −0.53 (−1.37 to 0.31) | 2 vs 3: P = .43 | |||||||
| Change from 24-36 mo | −0.03 (2.08) | 208 (86.7) | 0.26 (2.38) | 264 (90.4) | −0.27 (2.5) | 240 (90.9) | 1 vs 2: −0.26 (−1.02 to 0.50) | 1 vs 2: P = .77 |
| 1 vs 3: 0.06 (−0.72 to 0.84) | 1 vs 3: P = .99 | |||||||
| 2 vs 3: 0.33 (−0.42 to 1.08) | 2 vs 3: P = .66 | |||||||
| Change from baseline to 36 mo | 1.28 (2.76) | 438 (73.0) | 1.54 (3.08) | 554 (75.9) | 1.57 (3.46) | 502 (76.1) | 1 vs 2: −0.5 (−1.36 to 0.36) | 1 vs 2: P = .48 |
| 1 vs 3: −0.43 (−1.31 to 0.45) | 1 vs 3: P = .60 | |||||||
| 2 vs 3: 0.08 (−0.74 to 0.90) | 2 vs 3: P = .98 | |||||||
Abbreviation: D, diopter.
The raw mean and SD changes in spherical equivalent, axial length, pupil and accommodative outcomes between MOSAIC phase 2 treatment groups. Observations are from both eyes across all visits and presented as number (percentage). The placebo group contains combined data from both the atropine then nightly placebo group and atropine then tapering placebo group. Accommodative outcomes were not measured at the 12-month visit, due to the COVID-19 pandemic, hence there are fewer observations. The adjusted means, CIs, and P values are generated from linear mixed model analysis of the 24- or 36-month visit adjusting for age at baseline, sex, the outcome value at the baseline visit and, for models investigating change between the 24-month and 36-month visits, the change in the outcome value from the baseline to the 24-month visit. Differences, 95% CIs, and P values are generated using the emmeans package in R (R Project for Statistical Computing) and are averaged over the levels of sex (ie, males and females). The P values represent pairwise comparisons and are adjusted for the 3-way pairwise comparison of treatment groups using the Tukey method.
Factors Associated With Treatment Response
Analysis of myopia progression from the 24- to 36-month visit revealed no interactions between treatment and age, sex, or ethnicity at baseline (eTable 3 in Supplement 2).
Rebound Myopia Progression
There was no obvious rebound myopia progression among participants ceasing 0.01% atropine eye drops, with mean myopia progression slower during the MOSAIC2 trial compared with the MOSAIC trial, in both the atropine then placebo group (MOSAIC vs MOSAIC2, spherical equivalent: −0.30 D per year vs −0.23 D per year; axial length: 0.18 mm per year vs 0.14 mm per year) and the atropine then tapering 0.01% atropine group (MOSAIC vs MOSAIC2, spherical equivalent: −0.24 D per year vs −0.18 D per year, axial length: 0.15 mm per year vs 0.10 mm per year). Myopia progression in participants ceasing 0.01% atropine was additionally not faster than mean myopia progression in participants using placebo eye drops during the MOSAIC trial (spherical equivalent: −0.31 D per year, axial length: +0.20 mm per year).
Pupil and Accommodation Outcomes
Pupil diameter increased in the placebo then 0.05% atropine group after the 24-month visit showing mean (SD) increases of +1.3 (1.0) mm and +2.0 (1.0) mm in photopic and mesopic conditions, respectively (eTable 2 in Supplement 2). In the atropine then placebo and atropine then tapering 0.01% atropine groups, photopic pupil diameter slightly decreased (mean [SD], −0.49 [0.79] mm and −0.38 [0.72] mm, respectively) whereas mesopic pupil diameter slightly increased (+0.44 [1.1] mm and +0.61 [0.66] mm, respectively). Differences in accommodative variables were not noted (Table 2 and eTable 2 in Supplement 2).
Acceptability
The parent-reported ATI score was similar across the atropine then placebo group (median [IQR], 1.71 [1.59-2.13]), the atropine then tapering 0.01% atropine group (median [IQR], 1.71 [1.60-1.91]), and the placebo then 0.05% atropine group (median [IQR], 1.74 [1.61-2.25]) at the 36-month visit (P = .44). In the placebo then 0.05% atropine group, participants reported higher likelihood of their eyes feeling a little or very sore in light at the 30-month visit (placebo then 0.05% atropine, 19 of 58 participants [32.8%]; atropine then tapering 0.01% atropine, 9 of 65 participants [13.8%]; atropine then placebo, 8 of 53 participants [15.1%]; P = .05) and a lower likelihood of having no difficulty reading and writing at the 36-month visit (placebo then 0.05% atropine, 19 of 55 participants [80.0%]; atropine then tapering 0.01% atropine, 56 of 66 participants [84.8%]; atropine then placebo, 48 of 62 participants [77.4%]; P = .04), and no differences in other self-reported symptoms (blurring, itching, stinging) were noted. At the 36-month visit, 168 of 181 parents (92.8%) and 139 of 181 participants (76.8%) reported they would be happy to continue using their currently assigned eye drops.
Adverse Events and Treatment Discontinuation
There was a higher rate of possibly, probably, or definitely related adverse events in the placebo then 0.05% atropine group (17 of 60 [26%]), compared with the other treatment arms (atropine then tapering 0.01% atropine, 2 of 73 [3%]; atropine then placebo, 1 of 60 [2%]; P < .001) (Table 3). Common adverse events included blurred vision, photophobia, and noted pupil dilation. Three of 10 participants who experienced blurred near vision opted to use varifocal spectacles; none opted for photochromic lenses to relieve photophobia. All events of blurred near vision or photophobia resolved on medication cessation at the 36-month visit. Of the 66 participants in the placebo then 0.05% atropine group, 15% (n = 10) and 8% (n = 5) reported blurred near vision and photophobia, respectively, during year 3, compared with 3% (n = 2) and 0%, respectively, in the group taking atropine then tapering 0.01% atropine and no reports in both placebo groups. In addition, in the placebo then 0.05% atropine group, 12 participants (18%) experienced an adverse event of blurred near vision, photophobia, or pupil dilation, and 3 (5%) required varifocal glasses. Rates of these adverse events were slightly higher among blue-eyed participants (9 of 36 [25%]) and green-eyed participants (3 of 18 [17%]) compared with brown-eyed participants (0 of 12). Despite adverse events, no one stopped treatment, with no difference in discontinuation rates across arms (Table 3). Only 1 serious adverse event occurred during the MOSAIC2 trial involving hospitalization for an appendectomy and was judged unrelated to treatment by a masked investigator.
Table 3. The 24-Month Myopia Outcome Study of Atropine in Children, Months 24 to 36 (MOSAIC2) Adverse Events and Treatment Discontinuation Reasons; Medication-Related Events Graded as Possibly, Probably, or Definitely Relateda.
| Variable | Treatment arm | ||
|---|---|---|---|
| Atropine then placebo (n = 60) | 0.01% Atropine then taper 0.01% atropine (n = 73) | Placebo then 0.05% atropine (n = 66) | |
| Adverse event, No. (%) | |||
| Blurred near vision | 0 | 2 (2.7) | 10 (15.2) |
| Pupil dilation | 0 | 0 | 1 (1.5) |
| Photophobia | 0 | 0 | 5 (7.6) |
| Discomfort with eye drops | 0 | 0 | 1 (1.5) |
| Swelling/inflammation of the eyelids | 1 (1.7) | 0 | 0 |
| Total | 1 | 2 | 17 |
| Treatment discontinuation reason, No. (%) | |||
| External advice to stop | 0 | 1 (1.4) | 0 |
| Lost to follow-up | 4 (6.7) | 3 (4.1) | 5 (7.6) |
| Personal reason | 1 (1.7) | 1 (1.4) | 0 |
| Seeking other myopia control treatment | 0 | 1 (1.4) | 0 |
| Tired of eye drops | 1 (1.7) | 0 | 0 |
| Total | 6 (10) | 6 (8.2) | 5 (7.6) |
Percentages in parentheses are the proportion of events relative to the treatment arm sample size. No participant in year 3 reported the same adverse event twice on separate occasions. Proportions are not given for the adverse events totals as some participants reported multiple, separate adverse events. The placebo group contains combined data from both the atropine then nightly placebo group and atropine then tapering placebo group.
Discussion
This randomized clinical trial investigated different atropine regimens, including 0.01% and 0.05% atropine eye drops, for managing myopia progression in a predominantly White, European population. Over the duration of the MOSAIC2 trial, participants assigned to use 0.05% atropine eye drops had less myopia progression than participants using placebo eye drops and less axial elongation compared with participants using either placebo or 0.01% atropine. The unadjusted treatment effect of 0.05% atropine in year 3 was approximately 1.5 to 2 times that of 0.01% atropine in years 1 and 2 of the MOSAIC study (+0.12 D per year vs +0.05 D per year; −0.05 mm per year vs −0.04 mm per year). This represents an important finding as the placebo then 0.05% atropine group was effectively 2 years older by the time active treatment was initiated. After month 24, myopia progression in the atropine then placebo group did not increase, relative to treated progression rates, and was consistent with an age-related slowing. Although the MOSAIC2 trial did not have an age-matched treatment-naive control group to fully assess myopia rebound, myopia progression in both then atropine then placebo group and atropine then tapering 0.01% atropine group was similar to, or slower than, untreated control participants in the Western Australia Atropine Treatment of Myopia (WA-ATOM) study (spherical equivalent, −0.29 D per year; axial length, 0.13 mm per year),24 who have a comparable age-profile to the MOSAIC trial.
Although the placebo then 0.05% atropine group had higher treatment-related adverse events, participants generally tolerated the symptoms without discontinuing treatment with 92% completing the 36-month visit and 81% adhering to the treatment regimen. Only 5% of participants using 0.05% atropine required varifocal lenses to manage their symptoms. Our study shows that 0.05% atropine eye drops are tolerated without treatment-related symptoms in approximately 80% of European children and adolescents, whereas 15% experience symptoms but require no additional treatment, and the remaining 5% tolerate 0.05% atropine with management of their associated symptoms. In comparison, 0.01% atropine was more easily tolerated, with low rates of treatment-related adverse events (approximately 2%-3%), all not requiring additional treatment.
Comparison With Other Studies
The absolute treatment effect was smaller than that noted in the younger LAMP study cohort (+0.54 D per year and −0.21 mm per year for spherical equivalent and axial length, respectively).9 However, untreated myopia progression was lower in the MOSAIC trial (MOSAIC trial years 1 and 2: −0.31 D per year; MOSAIC trial year 3: −0.23 D per year; LAMP study: −0.84 D per year), associated with the relative treatment effects (spherical equivalent, 52.2% vs 66.7%; axial length, 35.7% vs 51.3%). Therefore, low-concentration atropine eye drops may have a proportional treatment effect that is relative to the expected untreated myopia progression. Clinically, this implies that patients who are likely to have the most myopia progression will get the greatest absolute treatment benefits from atropine treatment, although it is possible that this greater effect is seen when starting from a higher level of myopia at baseline. This may be one explanation for the modest 0.01% atropine efficacies found in clinical trials in slower-progressing European populations.12,15,24 The WA-ATOM and Myopia Treatment Study 1 (MTS1) studies failed to detect treatment effects of 0.01% atropine, which may be attributable, in part, to reduced power to detect a true effect when effect sizes are small.
Recent reports from Hong Kong,25 Japan,26 and China27 also have not found evidence of rebound myopia progression after ceasing 0.01% atropine eye drops. These results contrast with the WA-ATOM study, which did find a rebound progression among participants ceasing 0.01% atropine eye drops, relative to a treatment-naive control group, despite not finding a treatment effect at 24 months. Rebound myopia progression on ceasing atropine eye drops and its effect on long-term myopia outcomes remain a concern,25 with the LAMP study finding that more than 80% of children continued to have myopia progression after ceasing low-concentration atropine eye drops28 and a 20-year follow-up of the Singaporean ATOM studies showing no difference in long-term myopia outcomes among placebo and treatment groups.29 There is a theoretical basis for tapering atropine eye drops to prevent myopia rebound; however, further investigations are required to show a definite benefit.
Compared with the Hong Kong–based LAMP study,9 rates of photophobia with 0.05% atropine eye drops were lower in the MOSAIC trial (8% vs 34% in the LAMP study at 2 weeks), but rates of blurred near vision requiring varifocal lenses were higher (4.5% vs 0.9% in the LAMP study). There was some suggestion iris color influenced this, with brown eyes less affected in the MOSAIC2 trial. It is possible that Irish children may experience lower rates of photophobia, compared with other countries, due to lower ambient sunshine (eg, 1542 hours of annual sunshine in Ireland30 vs 1835 hours in Hong Kong31). Notably, 12-month pupil diameter changes in the 0.05% atropine group during the MOSAIC2 trial were higher than that noted in the LAMP study (respectively, photopic: +2.0 mm vs +0.90 mm; mesopic: +1.3 mm vs +0.56 mm).
Strengths and Limitations
This study has several strengths. One strength is the study’s predominantly White European participants, providing additional safety and efficacy data for 0.05% atropine in this population. The inclusion of children and adolescents across a broad age range is notable; however, the older age of participants in the MOSAIC2 trial, relative to other studies,9,12 in whom myopia progression will be slowing, may be a weakness.32
This study also has limitations. Limitations include the smaller sample sizes across treatment arms in year 3 of the study and potential carry-over effects (ie, a potential continued treatment benefit from the MOSAIC trial) for participants transitioning from 0.01% atropine to placebo or 0.01% atropine tapered. Due to the lack of a totally untreated control group, we could only assess rebound myopia progression on the basis of the likely third-year myopia progression from the MOSAIC trial placebo group. The age of the participants during the third year may also have impacted the study’s ability to detect rebound progression. The MOSAIC trial myopia progression rates may be further complicated by the COVID-19 pandemic, which may have altered myopia progression rates and 0.01% atropine treatment efficacy.13 Three-year retention in MOSAIC (73%) was similar to that of the LAMP study33 (74%) but, nevertheless, represents a relatively large loss to follow-up. Although sample sizes within the 3 randomized subgroups of group 2 were relatively small, when combining the 2 groups using placebo eye drops the number of participants per group was 54 to 67. Although the MOSAIC trial was overpowered initially, this will have reduced power to detect true effects and also could have biased the change in outcome estimates should probability of dropout be related to outcome change. However, no differences in rates of discontinuation were detected across the four treatment arms, suggesting that dropout was not related to treatment assignment.
Conclusions
In the MOSAIC2 randomized clinical trial, no rebound effect on myopia progression was observed in participants switching from 0.01% atropine to placebo or tapering 0.01% atropine eye drops. Despite a higher frequency of blurred near vision and photophobia with 0.05% atropine eye drops, the symptoms associated with treatment were not associated with discontinuation. Recognizing a 2-year delay in treatment initiation in the group of children originally assigned to placebo, 0.05% atropine eye drops slowed both myopia progression and axial eye growth over the course of a 1-year period. Despite more adverse events, participants using 0.05% atropine during year 3 had no differences in treatment completion rates and exhibited 0.13-D less myopia progression and 0.06-mm less axial elongation, compared with participants using placebo, supporting consideration of treatment as given to the 0.05% atropine group in this European population.
Trial Protocol.
eTable 1. CONSORT Checklist
eTable 2. Mean (SD) of Ocular Outcomes at the Baseline, 24-Month, and 36-Month Visits
eTable 3. Spherical Equivalent and Axial Length Mean (SD) Progression From the 24 to the 36-Month by Age, Sex, Ethnicity, and COVID-19 Impact Subgroups
eTable 4. Change in Spherical Equivalent and Axial Length Between Treatment Arms, Maintaining the Placebo Tapering and Placebo Nightly Groups Separate
eFigure 1. Mean Change (SE) in Spherical Equivalent Refractive Error and Axial Length by MOSAIC2 Treatment Arm, Relative to 24-Month Visit
eFigure 2. Mean Changes (SE) in Spherical Equivalent Refraction and Axial Length From Baseline to 36 Months and From 24 to 36 Months by Treatment Arm
eFigure 3. Bar Plot Illustrating the Proportion of Participants in the Placebo Group, Atropine, 0.01%, Group, and Atropine, 0.05%, Group, Separately, That Met Defined Spherical Equivalent Refraction Progression Thresholds for Slower, Medium, and Faster Myopia Progression
Data Sharing Statement.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol.
eTable 1. CONSORT Checklist
eTable 2. Mean (SD) of Ocular Outcomes at the Baseline, 24-Month, and 36-Month Visits
eTable 3. Spherical Equivalent and Axial Length Mean (SD) Progression From the 24 to the 36-Month by Age, Sex, Ethnicity, and COVID-19 Impact Subgroups
eTable 4. Change in Spherical Equivalent and Axial Length Between Treatment Arms, Maintaining the Placebo Tapering and Placebo Nightly Groups Separate
eFigure 1. Mean Change (SE) in Spherical Equivalent Refractive Error and Axial Length by MOSAIC2 Treatment Arm, Relative to 24-Month Visit
eFigure 2. Mean Changes (SE) in Spherical Equivalent Refraction and Axial Length From Baseline to 36 Months and From 24 to 36 Months by Treatment Arm
eFigure 3. Bar Plot Illustrating the Proportion of Participants in the Placebo Group, Atropine, 0.01%, Group, and Atropine, 0.05%, Group, Separately, That Met Defined Spherical Equivalent Refraction Progression Thresholds for Slower, Medium, and Faster Myopia Progression
Data Sharing Statement.
