Atropine (0.05%) for rapid progressive childhood myopia (ARM study)

Abstract

Purpose:

This study aims to assess the effectiveness of atropine 0.05% for myopia control among children exhibiting (documented) rapid myopia progression (>0.75D/year).

Methods:

This prospective interventional single-arm clinical trial included children aged between 6–12 years, spherical equivalent refractive (SER) error between − 2 and − 6D, and having documented myopia progression of >0.75D in the preceding year. All participants were administered atropine 0.05% in both eyes once at bedtime for 1 year. The primary outcome measure was a change in the rate of myopia progression (D/year) and change in SER and axial length (AL) at 1 year and documentation of any adverse effects related to therapy.

Results:

Forty children were enrolled with a mean age of 8.5 ± 2.2 years. (45% male) The mean SER 1 year before starting atropine treatment was −3.53 ± 0.78D. At baseline, the mean SER was −4.58 ± 1.03D, which increased to −4.98 ± 0.97D after 1-year follow-up. The study reported a 62% reduction in the rate of myopia progression after 1 year of atropine 0.05% treatment (−1.05 ± 0.21D/year [baseline] to − 0.4 ± 0.14D/year[1-year follow-up] [P < 0.001]). The mean AL increased from 24.98 ± 2.43 mm (baseline) to 25.21 ± 2.32 mm (1 year). There was no significant correlation between changes in AL and SER (r: 0.57; P: 0.063). The study observed the response to treatment was independent of the age at baseline, baseline refractive error, baseline rate of progression, gender, and family history of myopia. No adverse effects from atropine 0.05% were reported.

Conclusions:

Atropine 0.05% could be an effective treatment for children with rapidly progressing myopia with no significant side effects.

Myopia has emerged as a worldwide public health issue and is one of the ocular conditions identified as immediate priority by the World Health Organization.[1] Although, the prevalence of myopia varies by region, age, and ethnicity; it is a major cause of visual impairment in both developing and developed world.[2,3,4,5,6,7,8,9,10]

Although various strategies have been tried for myopia control, including orthokeratology,[11] bifocal contact lenses,[12] specially segmented spectacles,[13] etc.; atropine eye drops continue to be the most widely used.[14,15,16,17,18,19] Various concentrations of atropine have been used to evaluate the better treatment-to-side effect ratio.[14,15] Previously, low-dose atropine (0.01%) has been shown to provide effective myopia control with few side effects in various studies conducted worldwide,[15,16] including India.[17,18] However, recent studies suggest that 0.05% is the optimum concentration in controlling myopia progression.[14,19,20]

Most of the studies assessing various interventions for myopia control had overlooked previous myopia progression or primarily focused on mild to moderate progressive myopic cohorts.[11,12,13,14,15,16,17] A recent study investigating the impact of atropine 0.01% in myopia prevention emphasized the necessity of exploring higher doses for rapid progressors.[18] Limited evidence is available from a small case series[21] involving four subjects; and a recent retrospective study[22] examined the role of atropine 0.05% in combination therapy among rapid progressors. To best of our knowledge, no prospective interventional study has evaluated the efficacy of myopia prevention interventions specifically targeting rapid progressors, defined as those experiencing more than 0.75D/year of progression. Therefore, the present prospective study aims to assess the effectiveness of atropine 0.05% in controlling myopia progression among children exhibiting rapid myopia progression (>0.75D/year).

Methods

This prospective interventional study registered at clinical trial registry in India was conducted in accordance with the principles outlined in the Declaration of Helsinki. The study received ethical approval from the Institute Ethics Committee (IEC552/2022), and informed consent was taken from all parents/guardians before enrollment.

The study comprised of a cohort of children aged between 6 and 12 years, with myopia at presentation between −2 to −6D and having documented myopia progression of greater than 0.75D in the preceding year. Moreover, participants were required to have astigmatism equal to or less than 1.5D, anisometropia of no more than 1D, and distance best-corrected visual acuity (DBCVA) of 20/40 or better. Exclusion criteria encompassed any ocular pathology such as amblyopia, strabismus, or glaucoma, as well as a history of prior ocular surgeries or the utilization of myopia control therapies, such as multifocal lenses, orthokeratology, or atropine eye drops. The children were treatment naïve (unintentionally untreated during the preceding year of enrollment) before presenting to us and had rapid progression defined as above.

Baseline evaluation included anterior and posterior segment examination and assessment of best-corrected visual acuity using the early treatment diabetic retinopathy study chart at 4 m (converted to the logarithm of the minimum angle of resolution scale), distance-corrected near vision using Snellen’s near vision chart at 33 cm. At baseline, cycloplegic autorefraction was performed 45 minutes after instilling homatropine 2% drops thrice with intervals of 10 minutes. Care was taken to see that the pupils were dilated at least 6 mm and that no pupillary reflex was present post dilatation. The automated refraction was measured using NIDEK ARK-1 autorefractor. The final correction prescribed was based on subjective acceptance and was recorded for the analysis. For this study, the refractive error was expressed and noted as spherical equivalent refractive error (SER). Furthermore, the axial length (AL) was measured using partial coherence interferometry based biometer (IOL master^® 700, Carl Zeiss, Meditec AG).

All the enrolled children were administered atropine 0.05% eye drops in both eyes once at bedtime for 1 year. Atropine 0.05% (isotonic atropine sulfate 0.05% with stabilized oxychloro complex as preservative) prepared at our in-house pharmacy compiled with good laboratory practice. After the initial visit measurements, the parents/guardians were instructed on how to administer the medication, i.e., placing a single drop in both eyes before bedtime in the supine position and pulling down the lower eyelid. They were also informed about the potential side effects, which include photophobia, blurred vision, and rashes. Next, bottles of 0.05% atropine sulfate eye drops were dispensed. Each bottle was advised to be used for no longer than a month once opened. Patients were scheduled for follow-up visits at 6 and 12 months. They were instructed to bring the empty bottles (to monitor compliance) to each scheduled follow-up, whereupon new bottles were dispensed. At each follow-up, an optometrist reassessed BCVA, cycloplegic refraction, and ocular biometry. A new prescription for glasses was provided if myopia progressed by more than 0.50D or if there was a decrease in distance BCVA. Parents were asked to self-report any side effects with topical therapy and subsequently directly asked about the symptoms.

The primary outcome measure was a change in the rate of myopia progression, change in SE and AL at 1 year and documentation of any adverse effects related to therapy.

Statistical analysis was performed using SPSS 25.0 (IBM Corp., Armonk, NY). Clustered data from both eyes of the same patient were pooled using robust standard error.[23] The statistical significance was evaluated within the group using a paired sample t-test assuming equal variance unless specified otherwise. Linear mixed effect models were used to address missing data at random. P value less than 0.05 was considered statistically significant.

To detect at least a 50% difference in myopia progression, within group SD of 0.5D, a sample size of at least 34 participants is needed to achieve 90% power with a two-sided test of 5% (0.05 significance level). Considering the attrition rate of 15%, a total sample size of 40 children was required.

Result

Forty children were enrolled with a mean age of 8.5 ± 2.2 years (45% male). The mean SER error 1 year before starting atropine treatment was −3.53 ± 0.78D. At baseline, the mean SER was −4.58 ± 1.03D, which increased to − 4.98 ± 0.97D after 1 year of atropine treatment [Table 1].

Table 1.

Comparison of mean SER and AL during the study period

(n=40)	1 year before treatment (−1 year)	Baseline	1 year on atropine	P (baseline vs 1 year)
Mean Sph. equivalent ref. error (D)	−3.53±0.78	−4.58±1.03	−4.98±0.97	<0.001
Rate of myopia progression (D/year)		−1.05±0.21	−0.4±0.14	<0.001
Axial length (mm)		24.98±2.43	25.21±2.32	0.012

The mean myopia progression rate in the previous year of enrollment (myopia at baseline minus myopia at 1 year before enrollment) was −1.05D ± 0.21D. A significant reduction in myopia progression rate to − 0.4 ± 0.14D (P < 0.001) was observed. The mean AL at baseline was 24.98 ± 2.43 mm, and it increased to 25.21 ± 2.32 after 1 year of treatment. The change in AL after 1 year of treatment was 0.23 ± 0.08 mm, which was found to be statistically significant. No correlation was found between the change in AL and change in SER (r: 0.57; P: 0.063). No change in distance as well as near visual acuity was observed at baseline and 1 year follow-up. The adverse effect related to use of atropine 0.05% among study subjects was neither clinically observed nor reported by parents and/or children.

Gender-based analysis revealed no significant disparity in the rate of myopia progression pre- and post-treatment [Table 2]. The study cohort was stratified into two age brackets: younger (ages 6–9 years) and older (ages 10–12 years). Younger participants exhibited notably higher rates of myopia progression across all assessment points compared to their older counterparts. Nevertheless, no direct association was observed between age and the response to atropine treatment. Among children whose parents did not have myopia, the myopia progression rate was − 1.03 ± 0.22D in the year preceding enrollment and − 0.41 ± 0.14D 1 year after treatment. Similarly, children with one or both myopic parents showed comparable progression (−1.09 ± 0.19D at baseline; and − 0.4 ± 0.11D 1 year after treatment). Our findings indicate that parental myopia did not influence the rate of myopia progression before or after treatment [Table 2].

Table 2.

Comparison of mean myopia progression during the study period based on gender, age, and parental myopia

Mean myopia progression	−1 to 0 years	0 to 1 years	P
Gender
Male (n=18)	−1.01±0.18	−0.38±0.12	<0.001
Female (n=22)	−1.09±0.2	−0.41±0.14	<0.001
P (unpaired t-test)	0.1	0.14
Age
6–9 year (n=25)	−1.11±0.24	−0.42±0.14	<0.001
10–12 year (n=15)	−0.97±0.2	−0.38±0.11	<0.001
P (unpaired t-test)	0.043	0.091
No. of myopic parents
0 (n=17)	−1.03±0.22	−0.41±0.14	<0.001
1 and 2 (n=23)	−1.09±0.19	−0.4±0.11	<0.001
P (unpaired t-test)	0.11	0.14

Myopia progression of <0.5D/year was seen in 24 cases (60%) after 1 year of treatment with atropine 0.05%, while 16 out of 40 cases (40%) showed myopia progression of ≥ 0.5D. Three children (7.5%) continued to show progression of > 0.75/D/year on 0.05% atropine. No direct correlation was found between treatment response and baseline refractive error (r: 0.43; P: 0.11) and between treatment response and rate of baseline progression (r: 0.47, P: 0.08). A moderate correlation between the rate of progression and baseline myopic refractive error was observed (r: 0.73, P: 0.041). It was observed that the response to treatment was independent of the age at baseline, baseline refractive error, baseline rate of progression, gender, and family history of myopia [Table 3].

Table 3.

Analysis based on treatment response to atropine

Myopia progression (D/year)	<0.5D (n=24)	≥0.5D (n=16)	P
Age at baseline (yr)	8.7±1.8	8.2±2.1	0.07
Baseline refractive error (D)	−4.51±0.98	−4.65±1.01	0.12
Baseline rate of progression	−1.01±0.18	−1.08±0.17	0.14
Gender (% male)	46% (11/24)	44% (7/16)	0.38
Parental myopia (% no myopic parent)	42% (10/24)	44% (7/16)	0.44

Discussion

Atropine 0.01% is now commercially available in various countries across Europe and Asia and has been adopted for the control of myopia progression by many pediatric ophthalmologists worldwide,[19,24] including India.[25] LAMP phase 3 study evaluated the efficacy and safety of low-concentration atropine eye drops at 0.05%, 0.025%, and 0.01% and found that 0.05% atropine remained the optimal concentration effective in controlling SER progression and AL elongation over 3 years in Chinese children.[20]

Notably, 9.3% of patients in ATOM 2 (≥1.5D) at 2 years[26] and 19.2% of patients in the LAMP study (>2D) at 2 years[16] showed progression of more than 0.75D/year with 0.01% atropine. In pan India multicentric retrospective study, 17.4% of children progressed more than 0.75D/year after 2 years of 0.01% atropine therapy.[18] It has been observed that the children showing rapid myopia progression are usually younger and have higher baseline myopia than the mild and moderate progressors,[14,15,18] and they might be candidates for more aggressive interventions like higher concentration atropine (e.g., 0.05%, 0.025%) and/or combination therapy. This study evaluated the effect of 0.05% atropine on change in SER error and AL of rapidly progressive myopic children and found a 62% reduction in the rate of myopia progression at 1-year follow-up compared to baseline.

A retrospective study from Taiwan including 21 subjects aged 6 to 12 years receiving 0.05% atropine found a myopia progression rate of −0.28 ± 0.26D/year.[27] A myopia progression rate of −0.27 ± 0.61D/year was observed in the patients receiving 0.05% atropine in the LAMP study.[14] In our study, mean progression with atropine 0.05% was −0.4 ± 0.14D/year; this difference can be attributed to our exclusive inclusion cohort of rapid progressors. We found a mean AL elongation of 0.23 ± 0.08 mm after 1 year of treatment. Similar AL elongation of 0.20 ± 0.25 mm/year was reported in the LAMP study in the 0.05% atropine subgroup.[14]

No gender difference was found in myopia progression before or after the treatment with atropine therapy as documented in prior studies.[14,15,18] We also found that younger children showed higher myopia progression rates as compared to the older group. However, no direct correlation was observed between age and treatment response to atropine therapy.

A study on school children in Singapore found that the children with no myopic parents had an average myopia progression rate of 0.42D per year, compared to those with one or two myopic parents who had a progression rate of 0.63D per year.[28] However, in our study, we found similar myopia progression rates before and after treatment, irrespective of parental myopia.

A retrospective study reported combining 0.05% atropine and peripheral defocus contact lenses exhibited high effectiveness in controlling myopia.[22] In our study, 7.5% of children (n = 3) did not respond to atropine (continued > 0.75D/year of progression) 0.05% therapy, suggesting the need for combination therapies in these children. Similar results were reported in the LAMP study where 9.5% of children on atropine 0.05% did not respond to the treatment.[16] No adverse effects of 0.05% atropine were reported in our study.

This study has certain limitations. Firstly, being a non-randomized trial, there is a potential for biases when compared to blinded randomized controlled trials. Secondly, the sample size is modest; a larger cohort studied with longer follow-up would offer deeper insights into the drug’s efficacy and safety. However, this study stands out as pioneering research documenting the efficacy of atropine 0.05% among rapidly progressive myopes, setting a foundation for future studies. A key strength of our study is the inclusion of documented rapidly progressive myopic children (greater than 0.75D per year). To our current understanding, this is the first study prospectively evaluating the effect of any myopia prevention intervention on rapidly progressing myopia.

Conclusion

Our study concludes that atropine 0.05% could be an effective treatment for children with rapidly progressing myopia with no significant side effects.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.