The CHAMP study: safety and efficacy of low-dose atropine

Paper title:  Efficacy and Safety of 0.01% and 0.02%Atropine for the Treatment of Pediatric Myopia Progression Over 3 Years

Authors: Zadnik, Karla (1); Schulman, Erica (2); Flitcroft, Ian (3); Fogt, Jennifer S (1); Blumenfeld, Louis C (4); Fong Tung M (5); Lang, Eric (5); Hemmati, Houman D (5); Chandler, Simon P (5); CHAMP Trial Group Investigators

1. The Ohio State University College of Optometry, Columbus.
2. SUNY College of Optometry, New York.
3. Centre for Eye Research, Dublin, Ireland.
4. Eye Physicians of Central Florida, Maitland.
5. Vyluma Inc, Bridgewater, New Jersey.

 Date:  June 2023

Reference: Zadnik K, Schulman E, Flitcroft I, Fogt JS, Blumenfeld LC, Fong TM, Lang E, Hemmati HD, Chandler SP; CHAMP Trial Group Investigators. Efficacy and Safety of 0.01% and 0.02% Atropine for the Treatment of Pediatric Myopia Progression Over 3 Years: A Randomized Clinical Trial. JAMA Ophthalmol. 2023 Jun 1: e232097

[Link to open access paper]

Low-dose atropine (up to 0.05%) has been shown to give a slowing effect on myopia progression in children, while providing fewer unwanted side-effects seen with higher concentrations.^1-6 It is thought to ultimately slow myopia progression by blocking receptors within the eye and limiting thinning of the choroid and scleral layers.^7,8

The LAMP and ATOM2 studies have demonstrated the efficacy of low-dose atropine.^6,8 However, atropine is not approved so far in the US and Europe as a pharmacological myopia management treatment. Many atropine preparations can cause irritation, dry eye and toxicity responses, usually from the preservatives within the solution.

This study assessed the safety and efficacy of 0.01% and 0.02% preservative-free atropine (NVK002, Vyluma) vs. a placebo to treat myopia progression.

The Childhood Atropine for Myopia Progression (CHAMP) study was a randomised, placebo-controlled clinical trial that took place across 27 clinical sites in North America and 5 European countries.

Children aged between 3 and 16yrs with spherical equivalent refractive error (SER) of between -0.50 and -6.00D and ≤-1.50D astigmatism were recruited to the study. They received either 0.01%, 0.02% atropine or placebo eye drops to use once daily for 36mths.

The primary objective was to assess myopia progression for the children and the primary outcome was the proportion of children with 0.50D or less progression at 3yrs. Secondary outcomes were change in SER and axial length (AL) from baseline for both atropine doses at the end of the 3-yr period. Cycloplegic SER and axial length were measured at 6 monthly intervals.

The intent to treat (ITT) data set included all children aged 3-16yrs who had been randomized into the treatment groups. At baseline, there were 576 in the ITT set who received placebo (n = 165), 0.01% atropine (n = 164), or 0.02% atropine (n = 247). The treatment groups comprised 573 children who received the trial treatment. The safety analysis included all participants who had been administered at least 1 dose of the trial medication. The modified to treat analysis (mITT) set included 489 children aged between 6 and 10yrs at baseline. This group was pre-defined as the primary analysis group due to the extent of study in previous literature.

The responder analysis showed the proportion of eyes that progressed less than 0.50D from baseline to 36mths was:

• 17.5% in the placebo group
• 28.5% in 0.01% atropine group
• 22.1% in 0.02% atropine group

The differences in SER at 36mths from baseline were:

• -1.25D in placebo group
• -1.04D in 0.01% group
• -1.18D in 0.02% group

Both atropine concentrations showed slower axial length elongation than placebo at 12 and 24mths intervals. At 36mths, the changes from baseline for axial length were:

• 0.81mm in placebo group
• 0.68mm in 0.01% group
• 0.73mm in 0.02% group

Compared to the placebo drop at 36mths, 0.01% atropine showed increased responders, slower mean SER progression and axial elongation. There were higher responder rates with 0.01% atropine than with placebo at all time intervals.

At the same time point, 0.02% atropine did not significantly increase the number of responders or slow mean SER progression compared to placebo, although axial length elongation was slower. The difference with 0.02% atropine v placebo was only seen at 12mth interval.

There were no serious ocular events, with both low concentrations being well tolerated. The most common adverse events found were photophobia, eye irritation, mydriasis and blurred vision.

The incidence of treatment-emergent adverse events was similar across all groups (placebo, 71.6%; 0.01% atropine, 59.8% and 0.02% atropine 66%).

The results of the CHAMP study demonstrated the efficacy and safety profile of Vyluma preservative-free 0.01% atropine formulation for children aged 6-10yrs over 3yrs. A smaller treatment effect was seen for the 0.02% concentration.

• This supports the use of 0.01% atropine as a pharmacological option for treating childhood myopia progression.

This study also confirmed findings from other studies that examined the efficacy of low-dose atropine.

• The ATOM2 study found dose-dependent effects for atropine concentrations of 0.01 – 0.5%. However, the study did not feature a placebo group.⁹
• Other placebo-controlled studies have assessed low-dose atropine efficacy over 1-2yrs. The treatment effects were generally consistent with 0.01% atropine over the same period.^2,4-6

Using low-dose 0.01% atropine for younger children experiencing myopia progression may be an important and effective early option.

• This study was sponsored by Vyluma Inc. which may provide potential bias. However, this was a double-masked, placebo-controlled, randomised clinical trial which strengthens the results.
• Results bias is possible where some study participants discontinued the trial medication and had switched to confounding treatments. There were also fewer children in the 3-5yrs and 11-17yrs ranges. Further studies could confirm the results with larger cohorts for these age groups.
• The 0.02% atropine concentration was found to under-perform in comparison to 0.01% concentration. However, it was still able to provide a difference in the proportion of responders and the mean difference in SER changes v the placebo. Also, including data on participants in the mITT set who had stopped the trial drops and commenced other treatments may have skewed the results for the 0.02% strength formula.
• The responder rate for the placebo group was higher than expected (17.5% v 7%). Other myopia therapy studies have shown similar progression rates for their control groups, including the MiSight soft contact lens trial ^3,10-12
• Atropine for younger children is often chosen for myopia control over contact lenses or spectacle treatment options as part of a risk / benefit consideration. Further studies will tell us the age ranges where efficacy is optimum for atropine alone and what age to consider combining with other treatments to achieve best results

Title: Efficacy and Safety of 0.01% and 0.02%Atropine for the Treatment of Pediatric Myopia Progression Over 3 Years

Authors:  Zadnik, Karla; Schulman, Erica; Flitcroft, Ian; Fogt, Jennifer S; Blumenfeld, Louis C; Fong Tung M; Lang, Eric; Hemmati, Houman D; Chandler, Simon P; CHAMP Trial Group Investigators

Purpose: To assess the safety and efficacy of NVK002 (Vyluma), a novel, preservative-free, 0.01% and 0.02% low-dose atropine formulation for treating myopia progression.

Methods: This was a double-masked, placebo-controlled, parallel-group, randomized phase 3 clinical trial conducted from November 20, 2017, through August 22, 2022, of placebo vs low-dose atropine, 0.01% and 0.02% (2:2:3 ratio). Participants were recruited from 26 clinical sites in North America and 5 countries in Europe. Enrolled participants were 3 to 16 years of age with -0.50 diopter (D) to -6.00 D spherical equivalent refractive error (SER) and no worse than -1.50 D astigmatism.

Once-daily placebo, low-dose atropine, 0.01%, or low-dose atropine, 0.02%, eye drops for 36 months.

The primary outcome was the proportion of participants' eyes responding to therapy (<0.50 D myopia progression at 3 years). Secondary efficacy outcomes included mean change from baseline in SER and axial length at month 36 in a modified intention-to-treat population (mITT; participants 6 to 10 years of age at baseline). Safety measurements for treated participants (3 to 16 years of age) were reported.

Results: A total of 576 participants were randomly assigned to treatment groups. Of these, 573 participants (99.5%; mean [SD] age, 8.9 [2.0] years; 315 female [54.7%]) received trial treatment (3 participants who were randomized did not receive trial drug) and were included in the safety set. The 489 participants (84.9%) who were 6 to 10 years of age at randomization composed the mITT set. At month 36, compared with placebo, low-dose atropine, 0.01%, significantly increased the responder proportion (odds ratio [OR], 4.54; 95% CI, 1.15-17.97; P = .03), slowed mean SER progression (least squares mean [LSM] difference, 0.24 D; 95% CI, 0.11 D-0.37 D; P < .001), and slowed axial elongation (LSM difference, -0.13 mm; 95% CI, -0.19 mm to -0.07 mm; P < .001). At month 36, compared with placebo, low-dose atropine, 0.02%, also showed benefit but did not significantly increase the responder proportion (OR, 1.77; 95% CI, 0.50-6.26; P = .37) or slow mean SER progression (LSM difference, 0.10 D; 95% CI, -0.02 D to 0.22 D; P = .10) but did slow mean axial elongation (LSM difference, -0.08 mm; 95% CI, -0.13 mm to -0.02 mm; P = .005). There were no serious ocular adverse events and few serious nonocular events; none were judged as associated with atropine.

Conclusions: Results of this randomized clinical trial suggest efficacy for low-dose atropine, 0.01%, across all 3 main end points compared with placebo. The efficacy and safety observed suggest that low-dose atropine may provide a treatment option for childhood myopia progression.

[Link to open access paper]