The latest research on atropine: efficacy, ideal candidates, and safety

Topical low-dose atropine has been extensively researched for its myopia controlling capabilities and is currently the only pharmacological agent that can consistently slow progression.¹ However, as it is not approved for myopia management, it is used off-label and must be obtained from compounding pharmacies.²

The Childhood Atropine for Myopia Progression (CHAMP) trial is a randomized controlled trial that aimed to investigate the efficacy and safety profile of NVK002 0.01% and 0.02% atropine.³ The trial was conducted in 26 clinical sites in North America and 5 countries in Europe, involving 576 children of various ethnicities who used placebo, NVK002 0.01% atropine or 0.02% atropine topically over 3 years.

NVK002 is a novel formulation of topical low-dose atropine eyedrops developed by Vyluma, Inc. to be preservative free, shelf-stable at room temperature for at least two years, and produced to meet global pharmaceutical manufacturing standards. This sets the product apart from compounded preparations – learn more on the latter in What’s in the atropine bottle? Q&A With Professor Mark Bullimore.

NVK002 is currently under regulatory review for consideration of approval. You can also get an overview on the CHAMP trial from its Principal Investigator in The CHAMP Trial – Q&A With Professor Karla Zadnik. As the data is further examined, this article will explore what we’ve learned from the newest analyses stemming from the CHAMP trial.

The CHAMP trial had three main efficacy endpoints, all analyzed after 36 months of nightly dosing. These were:

• Responder analysis (proportion of children whose myopia progressed less than 0.50 diopters of myopia over three years)
• Mean change from baseline in spherical equivalent refraction
• Mean change from baseline in axial length

At Month 36, compared to placebo, NVK002 0.01% increased the proportion of responders (p=0.031) and notably slowed mean SER progression (p<0.001) and axial elongation (p<0.001). NVK002 0.02% slowed mean axial elongation (p=0.005; at Months 12, 24 or 36) but did not significantly increase the proportion of responders (p=0.373) nor slow mean SER progression (p=0.101; except at Month 12).^3,4

The efficacy results of the CHAMP trial found that NVK002 0.01% had positive results in all three main efficacy endpoints. There was a positive, statistically significant, and clinically meaningful reduction in refractive and axial length progression, supportive of efficacy for NVK002 0.01%. The responder analysis showed that 28.5% of children treated with NVK002 0.01% showed less than 0.50D myopia progression over three years compared to 17.5% in the placebo group: representing a 63% relative improvement in responders in NVK002 0.01% over placebo. 

The results for NVK002 0.01%’s myopia control efficacy are consistent with the results of most previous research on low-dose atropine. This is important given the novel formulation and is consistent in terms of both refractive and biometric outcomes. In an abstract presented at the Association for Research in Vision and Ophthalmology (ARVO) 2023 meeting in New Orleans, the results of the CHAMP trial were compared to five other published randomized placebo-controlled studies of atropine 0.01% to evaluate efficacy results:⁵

When compared to these published studies, NVK002 0.01% showed a responder proportion similar to three other studies undertaken in China, India (ATOM-I trial) and Hong Kong (LAMP trial)  at Month 12.^5-8 At Month 24, the change from baseline in SER for NVK002 0.01% (0.22D)⁵ was comparable to studies undertaken in Japan (ATOM-J trial) (0.22D)⁹ and Australia (WA-ATOM trial) (0.14D).¹⁰ Axial elongation appeared to mirror the comparison of SER progression.^5,9,10 This is important as it indicates similar findings across various trial populations and locations, compared to the multi-site CHAMP trial population located in the US and Europe.  

Since the ARVO 2023 meeting, two additional 2-year studies on 0.01% atropine were published. The MOSAIC results are generally consistent with the CHAMP results at Month 24.¹¹  The MTS1 result on SER and AL progression appear to be an outlier at Month 24, showing no significant difference between 0.01% atropine and placebo.¹²

Comparisons of the CHAMP placebo group to a matched group from the CLEERE trial - which spans approximately 25 years of data gathered across multiple sites in the US - showed similarities in the mean changes from baseline in AL and SER over three years. This suggests that the CHAMP participants are a representative sample of the general population of myopic children in the US. The findings also could imply that, despite the increased prevalence of myopia, the 3-year progression rate of myopia in myopic children aged 6-10 years may not have significantly changed over the past two decades.¹³ 

In the CHAMP trial, the 26 clinical sites in North America and 5 countries in Europe captured a diverse patient demographic in the trial. Participants were: 1.2% American Indian or Alaskan Native, 19% Asian, 14.1% Black or African American, 0.7% Native Hawaiian or Other Pacific Islander, 53.8% White, and 11.2% as belonging to another racial category. 45.5% were male and 54.5% female, with an age range of 3 to <17 years of age. Myopia at baseline ranged from -0.50D to -6.00D.³ Age, sex, race, iris colour, region and baseline SER were examined in a subgroup analyses to determine if baseline characteristics influenced treatment outcomes.¹⁴ Subgroup analyses revealed that baseline characteristics, including age, sex, race, iris color, region, and baseline SER, generally supported the outcome of the full CHAMP population.^14,15  Atropine has previously been studied extensively in South and East Asian locations, and has shown significant myopia control effect.^6-9 Subgroup analysis of the CHAMP data showed comparable treatment effects observed across light and dark irises.¹⁶

The CHAMP trial assessed safety and tolerability of the atropine formulations over the course of the 3-year period, as well as efficacy.

In terms of safety, no serious ocular treatment-emergent adverse events (TEAEs) occurred with NVK002, and serious non-ocular TEAEs were only reported in 2.3% of patients, with no treatment-related serious AE in the NVK002 0.01% or 0.02%   arms as assessed by investigators.³ The incidence of any TEAE was similar across treatments, and the most common adverse events included photophobia, allergic conjunctivitis, eye irritation, and mydriasis.^17,18  As expected, photophobia was the most reported ocular TEAE,^3,19 with its reported incidence decreasing over the trial years. These findings suggest that both 0.01% and 0.02% NVK002 are safe and well-tolerated in children after 3 years of nightly dosing.^17,18

Notably, no subjects across any treatment group required photochromic spectacles to treat photophobia throughout the trial.²⁰ This suggests that NVK002’s novel formulation did not cause photophobia necessitating treatment with photochromic spectacles.

The CHAMP trial was a large-scale randomized placebo-controlled trial that involved prospective and post hoc data analyses to gain insights on the efficacy, safety, tolerability of NVK002 low-dose atropine and how it may be used for myopia control. While atropine remains as an off-label intervention for myopia management, the CHAMP trial indicates that the novel formulation NVK002 is safe, well tolerated, and effective in slowing myopia progression in children with myopia. CHAMP also stands alone as the only three-year, concurrent placebo-controlled trial with results demonstrating the consistent and cumulative benefit of NVK002 treatment for children with myopia. NVK002 is currently under regulatory review and has promise to be the first approved, commercially available, preservative free, low dose atropine product to treat myopia in children.