Performance of low-dose atropine in US children

Paper title: Low-Dose 0.01% Atropine Eye Drops vs Placebo for Myopia Control: A Randomized Clinical Trial

Authors: Repka, Michael X (1); Weise, Katherine K (2); Chandler, Danielle L (3); Wu, Rui (3); Melia B Michele (3); Manny, Ruth E (4); Kehler, Lori Ann F (5); Jordan, Catherine O (6); Raghuram, Aparna (7); Summers, Allison I (8); Lee, Katherine A (9); Petersen, David B (10); Erzurum, S A (11); Pang, Yi (12); Lenhart, Phoebe D (13); Ticho, Benjamin H (14); Beck, Roy W (3,15); Kraker, Raymond T (3); Holmes, Jonathan M (16); Cotter, Susan A (17); Pediatric Eye Disease Investigator Group

1. Wilmer Eye Institute, Baltimore, Maryland.
2. University of Alabama at Birmingham, Birmingham.
3. Jaeb Center for Health Research, Tampa, Florida.
4. University of Houston College of Optometry, Houston, Texas.
5. Vanderbilt University Medical Center, Nashville, Tennessee.
6. Pediatric Ophthalmology Associates, Columbus, Ohio.
7. Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
8. Casey Eye Institute, Oregon Health & Science University, Portland.
9. St Luke's Health System, Boise, Idaho.
10. Rocky Mountain Eye Care Associates, Salt Lake City, Utah.
11. Eye Care Associates Inc, Poland, Ohio.
12. Illinois College of Optometry, Chicago.
13. Emory Eye Center, Atlanta, Georgia.
14. Ticho Eye Associates, Chicago Ridge, Illinois.
15. Deputy Editor, JAMA Ophthalmology.
16. University of Arizona-Tucson, Tucson.
17. Southern California College of Optometry at Marshall B. Ketchum University, Fullerton.

Date: Aug 2023

Reference: Repka MX, Weise KK, Chandler DL, Wu R, Melia BM, Manny RE, Kehler LAF, Jordan CO, Raghuram A, Summers AI, Lee KA, Petersen DB, Erzurum SA, Pang Y, Lenhart PD, Ticho BH, Beck RW, Kraker RT, Holmes JM, Cotter SA; Pediatric Eye Disease Investigator Group. Low-Dose 0.01% Atropine Eye Drops vs Placebo for Myopia Control: A Randomized Clinical Trial. JAMA Ophthalmol. 2023 Aug 1;141(8):756-765

Link to abstract

Low-dose atropine is commonly used for managing myopia progression in children, particularly in East Asia countries where the prevalence of myopia is higher compared to Europe.

Several randomised trials have assessed the efficacy of low concentration atropine. The ATOM series of studies found concentrations of 0.01, 0.1, 0.5 and 1.0% atropine were able to reduce progression compared to a placebo control. A concentration of 0.01% gave up to 60% reduction in progression while providing fewer adverse responses and reduced rebound effect associated with higher concentrations.^1,2

There have been fewer large-scale randomised trials in the U.S. This study compared the efficacy and safety of 0.01% atropine to placebo eyedrops for slowing myopia progression in children from the U.S. It was a randomised, placebo-controlled clinical trial and was conducted from June 2018 to September 2022. Children from varied racial backgrounds aged 5-12yrs (n = 187) with spherical equivalent error (SER) between -1.00 and -6.00D and no more than 1.50D of astigmatism were included in the study. They had been recruited from 12 practices in the U.S and had no previous myopia control treatment.

Cycloplegic auto-refraction, axial length (AL), anterior chamber depth and flat corneal radius measurements were taken at baseline and repeated at each 6-monthly visit. 

The children were randomly assigned to receive either 1 drop of 0.01% atropine or placebo nightly for 24mths. The last visit was 6mths after discontinuing drops to monitor ocular changes.

The primary outcome was mean changes in SER from baseline to 24mths while using drops. Secondary outcomes included changes in SER and AL after 24mths of drops use and 6mths after stopping treatment, along with the proportion of children who experienced progression of 0.50D or more, 1D or more or 2D or more at the 12, 24 and 30mth intervals. The 30mth follow up was completed by 118 children who had received the 0.01% atropine drops and 57 having used the placebo. Their mean age was 10.1yrs with 54% female. The mean SER and AL at baseline was -2.83D and 24.4mm for the atropine and placebo groups, respectively.  At 24mths, the mean SER was -3.64D and -3.54D and 24.9mm, respectively. The adjusted mean changes in SER and AL from baseline were -0.82D and -0.80D and 0.44 and 0.45mm, respectively. At 30mths (6mths after discontinuing drops), the mean was -3.81D and -3.69D, respectively. The adjusted mean changes in SER and AL from baseline were -0.94D and -0.88D and 0.51mm and 0.49mm, respectively.

Adherence to study instructions for drop use was monitored by questionnaire and by collecting empty and unused ampules of solution. It was classed as excellent for most of the study period (76-100%).

The most common adverse events were: eye irritation when applying drops (atropine, 72% and placebo, 82%), photophobia (atropine, 26% and placebo, 27%) and blurred vision (atropine, 14% and placebo, 16%). There was little difference between the mean scores for both groups, suggesting the atropine drops were as well-tolerated as the placebo.

This study found no significant difference in the mean changes in SER for the treatment and placebo groups and therefore no evidence of slowing myopia progression or axial growth for children with low to moderate myopia.

• These results were consistent across sub-groups of iris colour, baseline SER, age, sex and ethnicity.

Although common responses of atropine use included irritation on instilling drops and photophobia, participants using atropine still continued with treatment and the drops were as well-tolerated as the placebo.

Where atropine is recommended for myopia management, this study confirms the safety profile of 0.01% concentration used nightly over 2yrs

The results of this study found 0.01% atropine did not slow myopia progression or axial length elongation after 2yrs.

Some factors may have influenced the results:

• Despite having the concentration of atropine formulation independently confirmed, it is possible it differed to that used in other studies due to a lack of standardisation.
• There were more children aged 5-7yrs in the atropine group v the placebo group. This age group typically have lower myopia and may have caused the treatment group to appear less unaffected.
• A dose-dependent effect has been observed with 0.025 and 0.05% atropine concentrations for controlling myopia progression, with the LAMP trial finding 0.01% atropine performed better for 1-year progression rates.^3,4

A different dose may be needed for US children who have different prevalence and progression rates of myopia.

• There may be ethnic differences influencing response to atropine. This study featured fewer Asian children (expected to have faster progression rates) and more Black children (thought to have slower progression rates).^5,6
• Drop usage throughout the study period may have been over-estimated by counting the empty eye drop ampules. Incorrect application or wastage may mean fewer drops were administered than expected
• The COVID-19 pandemic occurred during the treatment phase of this study. Participants were able to continue using treatment or placebo drops and had remote consultations instead of in-person visits.

However, some studies found that lifestyle changes due to home confinement and home learning during this time had a negative impact on myopia progression for some children. ^7-9

Some children may have progressed further during home confinement periods without the atropine use during the treatment phase.

The results of this study agree with the findings of other studies which also investigated the efficacy of low-dose atropine but are in contrast to others.

• The LAMP phase 2 study also found reduced responses to 0.01% atropine.

However, this was when compared to performance of higher concentrations and not a placebo control group.³

• The WA-ATOM study in Western Australia had similar age groups and refractive error range. They found the difference in myopia progression in the atropine group v placebo group was not statistically significant.

There were some participants lost to follow-up who had faster-progressing myopia, which may have contributed to a loss of treatment effect.

• A study in Japan found a mean -0.22D reduction in myopia progression with 0.01% atropine over 2yrs; one in India saw a mean -0.16D reduced SER progression over 1yr v a placebo group and one trial in China recorded a 1-yr mean difference in SER of -0.26D.^10,11,12

 Continued studies of atropine use for myopia control will confirm optimum concentrations of atropine efficacy which maintain safety and patient acceptance and provide alternative methods for ensuring patient compliance to treatment.

Title: Low-Dose 0.01% Atropine Eye Drops vs Placebo for Myopia Control: A Randomized Clinical Trial

Authors: Repka, Michael X; Weise, Katherine K; Chandler, Danielle L; Wu, Rui; Melia B Michele; Manny, Ruth E; Kehler, Lori Ann F; Jordan, Catherine O; Raghuram, Aparna; Summers, Allison I; Lee, Katherine A; Petersen, David B; Erzurum, S A; Pang, Yi; Lenhart, Phoebe D; Ticho, Benjamin H; Beck, Roy W; Kraker, Raymond T; Holmes, Jonathan M; Cotter, Susan A; Pediatric Eye Disease Investigator Group

Purpose: Controlling myopia progression is of interest worldwide. Low-dose atropine eye drops have slowed progression in children in East Asia.

To compare atropine, 0.01%, eye drops with placebo for slowing myopia progression in US children.

Methods: This was a randomized placebo-controlled, double-masked, clinical trial conducted from June 2018 to September 2022. Children aged 5 to 12 years were recruited from 12 community- and institution-based practices in the US. Participating children had low to moderate bilateral myopia (−1.00 diopters [D] to −6.00 D spherical equivalent refractive error [SER]).

Eligible children were randomly assigned 2:1 to 1 eye drop of atropine, 0.01%, nightly or 1 drop of placebo. Treatment was for 24 months followed by 6 months of observation.

Automated cycloplegic refraction was performed by masked examiners. The primary outcome was change in SER (mean of both eyes) from baseline to 24 months (receiving treatment); other outcomes included change in SER from baseline to 30 months (not receiving treatment) and change in axial length at both time points. Differences were calculated as atropine minus placebo.

Results: A total of 187 children (mean [SD] age, 10.1 [1.8] years; age range, 5.1-12.9 years; 101 female [54%]; 34 Black [18%], 20 East Asian [11%], 30 Hispanic or Latino [16%], 11 multiracial [6%], 6West/South Asian [3%], 86 White [46%]) were included in the study. A total of 125 children (67%) received atropine, 0.01%, and 62 children (33%) received placebo. Follow-up was completed at 24 months by 119 of 125 children (95%) in the atropine group and 58 of 62 children (94%) in the placebo group. At 30 months, follow-up was completed by 118 of 125 children (94%) in the atropine group and 57 of 62 children (92%) in the placebo group. At the 24-month primary outcome visit, the adjusted mean (95%CI) change in SER from baseline was −0.82 (−0.96 to −0.68) D and −0.80 (−0.98 to −0.62) D in the atropine and placebo groups, respectively (adjusted difference = −0.02 D; 95%CI, −0.19 to +0.15 D; P = .83). At 30 months (6 months not receiving treatment), the adjusted difference in mean SER change from baseline was −0.04 D (95%CI, −0.25 to +0.17 D). Adjusted mean (95%CI) changes in axial length from baseline to 24 months were 0.44 (0.39-0.50) mm and 0.45 (0.37-0.52) mm in the atropine and placebo groups, respectively (adjusted difference = −0.002 mm; 95%CI, −0.106 to 0.102 mm). Adjusted difference in mean axial elongation from baseline to 30 months was +0.009mm (95%CI, −0.115 to 0.134 mm).

Conclusions: In this randomized clinical trial of school-aged children in the US with low to moderate myopia, atropine, 0.01%, eye drops administered nightly when compared with placebo did not slow myopia progression or axial elongation. These results do not support use of atropine, 0.01%, eye drops to slow myopia progression or axial elongation in US children.

Link to abstract