Determining the Optimal Concentration of Atropine

Authors: Jason C. Yam, Yuning Jiang, Shu Min Tang, Anthony K.P. Law, Joyce J. Chan, Emily Wong, Simon T. Ko, Alvin L. Young, Clement C. Tham, Li Jia Chen, Chi Pui Pang.

Date: January 2019

Reference: Ophthalmology. 2019;126:113-124. [Link to open access paper]

Despite being used for myopia management for many years, significant controversy exists in both literature and clinical optometric practice regarding the optimal concentration of atropine, a non-selective muscarinic antagonist, with decision making largely based on striking a balance between efficacy, safety and side effects. 

The current study reported the first-year (Phase 1) results of a randomised controlled trial, which evaluated both the efficacy and safety of various concentrations of atropine eye drops. The results provide new evidence supporting that 0.05%, 0.025% and 0.01% atropine reduce myopia progression along a concentration-dependent response. All concentrations were well tolerated without apparent adverse effect on the quality of life. Of the three concentrations used, 0.05% was the most effective in controlling myopic progression and axial length elongation over a one-year period.

All three concentrations of atropine reduced myopia progression when compared with placebo. The results demonstrated a concentration-dependant response, meaning efficacy increased with increasing concentration.

• At one-year, in comparison to placebo, there was a percentage reduction in: 
  • Spherical Equivalent Refraction of 67% (-0.27D) for 0.05%, 43% (-0.46D) for 0.025%  and 27% (-0.59D) for 0.01% 
  • Axial Length of 51% for 0.05%, 29% for 0.025% and 12% for 0.01% 
• 0.05% atropine produced the greatest reduction in myopia progression and axial length elongation at the one-year period. Interestingly, previous studies (ATOM 1 and 2) did not report a concentration-dependant result.

0.01% atropine did not result in a statistically significant reduction in axial length at one-year. 

• These results are interesting, as 0.01% atropine is commonly prescribed, following the promising results of its efficacy in ATOM21. 
• However, the majority of the efficacy in axial length reduction in ATOM 2 was gained in year 2, not year 1. Hence, the results from this studies' second year follow up were vital. Similar to the phenomenon observed in ATOM 2, Phase 2 of this study indicated a mild improvement in efficacy in year 2
  • Read further about The Latest and Greatest Research on Atropine, including a summary of Phase 2 of this study
• The lack of correlation between axial and refractive outcomes with atropine indicate the importance of myopia studies including axial length as a primary outcome to gain a comprehensive understanding of efficacy.

One of the main concerns that deters the use of higher-concentration atropine is pupil mydriasis, leading to photophobia, risk of cataract and loss of accommodation resulting in blurry vision2. However, all three concentrations were well tolerated by the children in pupil dilation, accommodative loss, near vision and best-corrected distance vision. 

• Reductions in accommodative amplitude in all groups were small 
• Near vision and BCVA in all groups was unaffected
• Only a few subjects required Progressive Addition Spectacle Lenses (PALs), which was similar in all groups 
• Pupil dilation was statistically significant between groups; however, the effect was small (1mm for 0.05%, 0.8mm for 0.025% and 0.5mm for 0.01%)
• The vision related quality of life was similar between treatment and placebo groups
• Consequently, previous hesitancies regarding the use of 0.05% atropine due to intolerable side effects may be misfounded.

The results from this study differ to those obtained in ATOM 2

• The efficacy of 0.01% atropine observed in this study was less than reported in ATOM 2 (SER 0.43D and axial length of 0.24mm), while the efficacy of 0.05% atropine was greater than in ATOM 2 (similar to 0.1%, but with better tolerance)
• There are numerous parameters of the study designs that could contribute to these differences. The age range at the commencement of each study was different, as well as the cohort characteristics (ethnicity, baseline refractive error). 
• Hence, while it is interesting to compare results obtained from the two studies, the different populations make it impossible to make a direct comparison. This indicates the importance of further research being conducted in this area.

The differences in outcomes between the LAMP study reported on here and the previous ATOM studies reveal that there are many questions regarding atropine eye drops that remain without a clear answer. Further research is required to determine:

• The anti-myopia mechanism of low-concentration atropine.³ 
• The percentage that generates superior efficacy with a low side effect profile. Further evidence is required to determine if atropine is concentration dependent, as this study indicates. 
• The nature of the rebound effect observed with atropine, and whether it should be discontinued once the myopia progression is under control or continued. 

This randomised placebo-controlled trial aimed to evaluate the efficacy and safety of low concentration atropine eye drops at 0.05%, 0.025% and 0.01% compared with placebo over a 1-year period.

This study reported the first year (Phase 1) results of a total 5-year study. 

PHASE 1: 1 year of treatment of 0.05%, 0.025% and 0.01% and placebo.

PHASE 2: Placebo group crossed over to the optimal group from phase 1 (due to ethical reasons) for 1 year. The other treatment groups continue for 1 year (hence 2 years of atropine use in total).

PHASE 3: Washout period of 1 year for 0.05%, 0.025%, 0.01% to determine rebound phenomenon. The crossed-over group will continue with atropine drops.  

PHASE 4: Extended phase to determine the long-term effects of low concentration atropine. Atropine resumed in children whom have progressed more than 0.50D in Phase 3, and change-over group continued without pause.

The study was conducted from January 2016 to November 2017 in Hong Kong, China. 438 children aged 4-12 years, with myopia of at least -1.00D and <-2.50D astigmatism and documented progression of at least 0.50D in the past one year were included in the study. Participants were randomly allocated to receive either 0.05%, 0.025% or 0.01% eye drops, or placebo eyes drops, once nightly to both eyes for one year. Cycloplegic auto-refraction, axial length, accommodative amplitude, pupil size (mesopic and photopic), near VA and BCVA were measured at baseline, 2 weeks, 4 months, 8 months and 12 months. Visual Function Questionnaire was administered at the one year visit. 

A diary on the trial medication was kept for each subject. Compliance level of each subject was classified according to the mean number of using atropine drops per week as reported by participants over the first one year. Subjects with 75% compliance (mean of 5.25 days/week) were considered to have good compliance. Any adverse events, regardless of whether they appeared relevant to atropine use, were documented at all follow-up visits.

Importantly, there was no statistically significant difference in the compliance of atropine use between groups. As aforementioned, 0.01% atropine did not cause a statistically significant reduction in axial length at one year in comparison to placebo. 

Secondary Ocular Parameter Outcomes

Changes in both accommodation amplitude and pupil size followed a concentration-dependant response. The mean accommodative amplitudes were different among all four groups. Similar changes in accommodation were observed in placebo and 0.01%, but significant differences in comparisons among the other groups. These changes remained stable over time. At 12 months, the mean amplitude of accommodation for the 0.05% group was 10.59D, while the placebo group was 11.65D (difference of 1.06D), which is unlikely to be clinically relevant. Both near vision (p=0.25) and mean distance BCVA (p=0.82) in all groups was not affected significantly. At the 2 week visit, there was a difference between groups in reports of photophobia, however this reduced over time. 31.2% of  the 0.05% group reported photophobia at 2 weeks, decreasing to 7.8% at 1 year. Interestingly, at the 2 week visit 12.6% of the placebo group reported photophobia, and 4.3% at the 1 year visit. Mean IOP was similar among all treatment groups. Occurrence of allergic conjunctivitis was similar among all groups (p=0.57). 

There was no difference in the vision-related quality of life among all groups. In all 11 domains (including general vision, ocular pain, near vision, distance vision), the 4 groups had similar scores.

The results of this study describe Phase 1 of a four-phase randomised clinical trial that aims to determine the optimal concentration of atropine eye drops for myopia control. The results indicate that 0.05%, 0.025% and 0.01% atropine reduce myopia progression in a concentration-dependant response, and all concentrations are well tolerated. 0.05% atropine was the most effective in reducing myopic progression, while 0.01% did not cause a statistically significant reduction in axial length. Many unanswered questions remain regarding the use of atropine eye drops. Further research is required to determine the rebound effect across varying concentrations, as well as the mechanism of action in reducing myopic progression.

Title: Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control

Authors: Jason C. Yam, Yuning Jiang, Shu Min Tang, Anthony K.P. Law, Joyce J. Chan, Emily Wong, Simon T. Ko, Alvin L. Young, Clement C. Tham, Li Jia Chen, Chi Pui Pang.

Purpose: Low-concentration atropine is an emerging therapy for myopia progression, but its efficacy and optimal concentration remain uncertain. Our study aimed to evaluate the efficacy and safety of low-concentration atropine eye drops at 0.05%, 0.025%, and 0.01% compared with placebo over a 1-year period.

Methods: Participants were randomly assigned in a 1:1:1:1 ratio to receive 0.05%, 0.025%, and 0.01% atropine eye drops, or placebo eye drop, respectively, once nightly to both eyes for 1 year. Cycloplegic refraction, axial length (AL), accommodation amplitude, pupil diameter, and best-corrected visual acuity were measured at baseline, 2 weeks, 4 months, 8 months, and 12 months. Visual Function Questionnaire was administered at the 1-year visit.

Results: After 1 year, the mean SE change was −0.27±0.61 D, −0.46±0.45 D, −0.59±0.61 D, and −0.81±0.53 D in the 0.05%, 0.025%, and 0.01% atropine groups, and placebo groups, respectively (P < 0.001), with a respective mean increase in AL of 0.20±0.25 mm, 0.29±0.20 mm, 0.36±0.29 mm, and 0.41±0.22 mm (P < 0.001). The accommodation amplitude was reduced by 1.98±2.82 D, 1.61±2.61 D, 0.26±3.04 D, and 0.32±2.91 D, respectively (P < 0.001). The pupil sizes under photopic and mesopic conditions were increased respectively by 1.03±1.02 mm and 0.58±0.63 mm in the 0.05% atropine group, 0.76±0.90 mm and 0.43±0.61 mm in the 0.025% atropine group, 0.49±0.80 mm and 0.23±0.46 mm in the 0.01% atropine group, and 0.13±1.07 mm and 0.02±0.55 mm in the placebo group (P < 0.001). Visual acuity and vision-related quality of life were not affected in each group.

Conclusion: The 0.05%, 0.025%, and 0.01% atropine eye drops reduced myopia progression along a concentration-dependent response. All concentrations were well tolerated without an adverse effect on vision-related quality of life. Of the 3 concentrations used, 0.05% atropine was most effective in controlling SE progression and AL elongation over a period of 1 year.

[Link to open access paper]