June 15, 2023
By Dwight Akerman, OD, MBA, FAAO, FBCLA, FIACLE
In a new study recently published in JAMA Ophthalmology, a novel preservative-free eye drop (NVK002, Vyluma) containing 0.01% or 0.02% atropine led to significant improvements in several markers of myopia in children who received the experimental therapy. Being the first to include a placebo control for three years and involving a large and diverse population recruited from multiple clinical sites, the study adds robustness to the research conducted on low-dose atropine.
The groundbreaking randomized controlled trial, known as the CHAMP study (Childhood Atropine for Myopia Progression), has demonstrated the potential of topical low-dose atropine to slow myopia Rx and axial length progression in North American and European children and adolescents. The results are a significant breakthrough for myopia care because no pharmacologic therapy is currently approved in the U.S., Canada, or Europe for treating myopia progression in children.
METHODOLOGY
- The CHAMP study was a double-masked, placebo-controlled, randomized phase 3 trial conducted between November 20, 2017, and August 22, 2022, that involved children at 26 sites in North America and five centers in Europe.
- Participants were randomly assigned in a 2:2:3 ratio to receive placebo (vehicle), atropine, 0.01%, or atropine, 0.02%, respectively, dosed one time per day in each eye at bedtime.
- Patients at the time of enrollment were ages 3 to 16 years. They demonstrated a spherical equivalent refractive error (SER) of −0.50D to −6.00D, with astigmatism no worse than −1.50D.
- Of these patients, 573 were included in a safety analysis, and 489 were included in a modified intention-to-treat analysis.
TRIAL ENDPOINTS
- The primary efficacy endpoint was the proportion of participants’ eyes that showed less than 0.50D myopia progression from baseline (responder analysis) at month 36 for atropine 0.02% vs. placebo.
- Secondary endpoints were defined as the responder analysis for atropine 0.01% and change from baseline for SER and axial length for both doses at month 36.
- Primary and secondary efficacy analyses were performed in the modified intention-to-treat (mITT) data set, which included all participants aged 6 to 10 years at baseline. The mITT set was predefined as the primary analysis population because this age group has been widely studied in the literature.
RESULTS
- After 36 months, the 0.01% dose of atropine was associated with a significantly lower responder proportion as well as slower progression of SER and axial elongation.
- Paradoxically, the effect of the 0.02% dose on responder proportion and SER progression was not statistically significant, but the treatment was associated with slower axial elongation.
- The researchers observed no serious ocular adverse events and few serious non-ocular events, none of which was determined to be associated with the treatment.
The treatment effect observed with atropine 0.01% is clinically meaningful as reflected in the increased number of responders to therapy compared with placebo (28.5% vs. 17.5%; a difference of 11%; 95% CI, 3%-18.5%). Although no reference exists to show that this difference is clinically meaningful, the predefined threshold for a responder eye was myopia progression of less than 0.50D SER from baseline at three years. This is a stringent criterion for defining myopia control and indicates clinically negligible progression or stable myopia. Compared with placebo, atropine, 0.01%, resulted in a greater proportion of responders at months 12, 24, and 36 and reduced mean SER progression at months 24 and 36 compared with placebo. Although atropine 0.02% slowed axial elongation compared with placebo, the responder analysis and SER progression were not statistically significant compared to placebo.
The researchers concluded that from a risk/benefit perspective, the efficacy and safety observed suggest that low-dose atropine may provide a treatment option for children aged 3 to 17 years with myopia progression, which may lead to less frequent or delayed change in spectacles, progression to less severe correction, and potentially reduce long-term sequelae, which could lead to vision loss later in life, such as myopic maculopathy.
Abstract
Efficacy and Safety of 0.01% and 0.02% Atropine for the Treatment of Pediatric Myopia Progression Over 3 Years: A Randomized Clinical Trial
Karla Zadnik, OD, PhD; Erica Schulman, OD; Ian Flitcroft, MA, MBBS, DPhil; Jennifer S. Fogt, OD, MS; Louis C. Blumenfeld, MD; Tung M. Fong, PhD; Eric Lang, MD; Houman D. Hemmati, MD, PhD; Simon P. Chandler, PhD; for the CHAMP Trial Group Investigators
Importance: The global prevalence of myopia is predicted to approach 50% by 2050, increasing the risk of visual impairment later in life. No pharmacologic therapy is approved for treating childhood myopia progression.
Objective: 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.
Design, Setting, and Participants: 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 five countries in Europe. Enrolled participants were 3 to 16 years of age with −0.50 diopter (D) to −6.00D spherical equivalent refractive error (SER) and no worse than −1.50D astigmatism.
Interventions: Once-daily placebo, low-dose atropine, 0.01%, or low-dose atropine, 0.02%, eye drops for 36 months.
Main Outcomes and Measures: The primary outcome was the proportion of participants’ eyes responding to therapy (<0.50D myopia progression at three 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 (three 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 non-ocular events; none were judged as associated with atropine.
Conclusions and Relevance: Results of this randomized clinical trial suggest efficacy for low-dose atropine, 0.01%, across all three main endpoints compared with placebo. The efficacy and safety observed suggest that low-dose atropine may provide a treatment option for childhood myopia progression.
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 June 1: e232097. Epub ahead of print.
DOI: 10.1001/jamaophthalmol.2023.2097
