LAMP study Phase 4: early and continued treatment is key

Paper title: Five-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression (LAMP) Study: Phase 4 Report

Authors: Zhang, XJ (1,8); Zhang, Y (1); Yip, BHK (5); Kam, KW (1,3); Tang, F (1); Ling, X (1); Ng, MPH (1); Young, AL (1,3); Wu, P-C (6); Tham, CC (1,2,3,4,7); Chen, LJ (1,3,7); Pang, CP (1,7,8); Yam, JC (1,2,3,4,7,8)

1. Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong[Link to open access paper]
2. Hong Kong Eye Hospital, Hong Kong
3. Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong
4. Department of Ophthalmology, Hong Kong Children’s Hospital, Hong Kong
5. Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong
6. Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
7. Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong
8. Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, China

Date: Sep 2024

References: Zhang XJ, Zhang Y, Yip BHK, Kam KW, Tang F, Ling X, Ng MPH, Young AL, Wu PC, Tham CC, Chen LJ, Pang CP, Yam JC. Five-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression (LAMP) Study: Phase 4 Report. Ophthalmology. 2024 Sep;131(9):1011-1020

This paper is the latest extended phase of the Low-Concentration Atropine for Myopia Progression (LAMP) study, which examines long-term efficacy of low-dose (0.05%) atropine over 5yrs.

In the original LAMP study (2019), 438 children aged 4-12yrs with myopia of at least -1.00D, with no more than -2.50D astigmatism, were randomised to receive either 0.05%, 0.025%, 0.01% atropine or a placebo eyedrop. All concentrations were well-tolerated and reduced myopia progression compared to the placebo in a dose-dependent effect. Atropine 0.05% was most effective with mean changes in spherical equivalent refraction (SE) and axial length (AL) of -0.27D and 0.20mm (exceeding 50% efficacy).

In Phase 2 of the LAMP study (2020), placebo group participants were switched to receive 0.05% atropine. Those already using atropine continued for a further year. Second-year efficacy for 0.05% concentration was double that of 0.01%. For the original placebo group, 0.05% atropine significantly slowed SE and AL progression from 0.82D and 0.43mm (with placebo drop) to 0.18D and 0.15mm with 0.05% atropine.

Phase 3 (2022) investigated continued use and rebound effects during yr3. The atropine groups were halved, with participants randomised to continue or have a wash-out period. The previous placebo group continued with 0.05% atropine. Progression was faster for those in the washout groups and although the original 0.05% group showed a greater rebound effect, it was deemed clinically insignificant. Faster rebound was associated with younger age (6-8yr old) and higher concentration atropine. The most effective concentration over 3yrs was 0.05%. 

The purpose of Phase 4 was to evaluate long-term efficacy of low dose atropine over 5yrs, the proportion of children who may require re-treatment after ceasing treatment and the efficacy of pro re nata (PRN) 0.05% atropine re-treatment for children showing progression after ceasing use. 

All atropine treatment groups from Phase 3 were switched to receive 0.05% atropine for Phase 4. Participants in the washout periods were monitored for changes in SER. If changes of -0.50D or more were seen over 1yr, they resumed atropine treatment at 0.05% on PRN basis (pro re nata, as needed). 

Comprehensive eye examinations were performed at each visit which included cycloplegic auto-refraction and AL measurement. Parents completed a Visual Function questionnaire at the end of yrs 4 and 5 and answered questions regarding their child’s outdoor and near work time. 

Of the original LAMP study cohort (n = 438), 270 were followed for 5yrs. Cumulative mean SE and AL progression of -1.34D, -1.97D and -2.34D and 0.79mm, 1.11mm and 1.24mm for the 0.05, 0.025 and 0.01% groups, respectively. In the PRN re-treatment group (n = 107), 94 children progressed by -0.50D or more and re-started 0.05% atropine. SE and AL progressions for continued treatment and the PRN groups were -0.97D and -1.00D and 0.51mm and 0.49mm, respectively. 

Light sensitivity was the most commonly reported adverse response, with most responses from the 0.05% atropine group. No changes in vision-related quality of life were seen.

This study showed that the higher the concentration of atropine, the more myopia control and that the dose dependent effect was sustained over 5yrs.

• Although restarting treatment showed similar efficacy to continued use, uninterrupted 0.05% atropine treatment was more beneficial than restarting or switching treatment concentration.
• However, the efficacy of the PRN treatment was better than for the switchover group who had originally received a placebo.

This indicates that commencing treatment at an earlier age when progression is faster is beneficial and that children at risk of myopia progression may benefit from having continuous long-term treatment.

Most children restarted treatment after 2yrs of stopping and younger children were more likely to require re-treatment.

• Therefore, re-treatment should be considered in practice for children who show progression after ceasing atropine treatment.

The amount of children showing more than -1.25D, -2.00D or -2.50D progression after 5yrs treatment in this study was 54.55, 78.79 and 87.88%. Response to treatment was similar across all concentration groups. The ATOM2 study reported re-treatment rates of 24, 59 and 68% for 0.01, 0.1 and 0.5% atropine, respectively.⁴

• The re-treatment rates may appear higher in the LAMP study due featuring more high-risk younger children liable to faster progression and to different cut-off points for re-starting treatment.

Over the 5yr period of the LAMP study, there were a higher than anticipated drop-out rate. This may have introduced bias and reduced the statistical power of the results.

• However, the drop-out rate from the 3^rd year was not highest in the 0.05% treatment group, suggesting the side-effects were tolerable.  

The long-term efficacy of 0.025 and 0.01% atropine couldn’t be assessed after the participants in these groups were switched to use 0.05% atropine. This was an ethical decision after observing the previous reduction in progression seen with 0.05% concentration and it allowed for the assessment of long-term use of 0.05% atropine.

• However, this meant there was no control group to compare 5yr efficacy.

Further research could clarify long-term efficacy and safety of high and low dose atropine and investigate the rate and degree of typical progression rates after cessation of each concentration. This could inform approaches to reducing treatments to limit rebound effects.

Phase 5 of the LAMP study will incorporate a longitudinal observational period in order to maximise treatment effects and consider approaches to stopping treatment.

Title: Five-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression (LAMP) Study: Phase 4 Report

Authors: Xiu Juan Zhang, Yuzhou Zhang, Benjamin H K Yip, Ka Wai Kam, Fangyao Tang, Xiangtian Ling, Mandy P H Ng, Alvin L Young, Pei-Chang Wu, Clement C Tham, Li Jia Chen, Chi Pui Pang, Jason C Yam

Purpose: To evaluate (1) the long-term efficacy of low-concentration atropine over 5 years, (2) the proportion of children requiring re-treatment and associated factors, and (3) the efficacy of pro re nata (PRN) re-treatment using 0.05% atropine from years 3 to 5.

Methods: 

Design: Randomized, double-masked extended trial.

Participants: Children 4 to 12 years of age originally from the Low-Concentration Atropine for Myopia Progression (LAMP) study.

Methods: Children 4 to 12 years of age originally from the LAMP study were followed up for 5 years. During the third year, children in each group originally receiving 0.05%, 0.025%, and 0.01% atropine were randomized to continued treatment and treatment cessation. During years 4 and 5, all continued treatment subgroups were switched to 0.05% atropine for continued treatment, whereas all treatment cessation subgroups followed a PRN re-treatment protocol to resume 0.05% atropine for children with myopic progressions of 0.5 diopter (D) or more over 1 year. Generalized estimating equations were used to compare the changes in spherical equivalent (SE) progression and axial length (AL) elongation among groups.

Main outcomes measures: (1) Changes in SE and AL in different groups over 5 years, (2) the proportion of children who needed re-treatment, and (3) changes in SE and AL in the continued treatment and PRN re-treatment groups from years 3 to 5.

Results: Two hundred seventy (82.8%) of 326 children (82.5%) from the third year completed 5 years of follow-up. Over 5 years, the cumulative mean SE progressions were -1.34 ± 1.40 D, -1.97 ± 1.03 D, and -2.34 ± 1.71 D for the continued treatment groups with initial 0.05%, 0.025%, and 0.01% atropine, respectively (P = 0.02). Similar trends were observed in AL elongation (P = 0.01). Among the PRN re-treatment group, 87.9% of children (94/107) needed re-treatment. The proportion of re-treatment across all studied concentrations was similar (P = 0.76). The SE progressions for continued treatment and PRN re-treatment groups from years 3 to 5 were -0.97 ± 0.82 D and -1.00 ± 0.74 D (P = 0.55) and the AL elongations were 0.51 ± 0.34 mm and 0.49 ± 0.32 mm (P = 0.84), respectively.

Conclusions: Over 5 years, the continued 0.05% atropine treatment demonstrated good efficacy for myopia control. Most children needed to restart treatment after atropine cessation at year 3. Restarted treatment with 0.05% atropine achieved similar efficacy as continued treatment. Children should be considered for re-treatment if myopia progresses after treatment cessation.

[Link to open access paper]