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

Abstract

ImportanceThe 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.ObjectiveTo 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 ParticipantsThis 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.InterventionsOnce-daily placebo, low-dose atropine, 0.01%, or low-dose atropine, 0.02%, eye drops for 36 months.Main Outcomes and MeasuresThe 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.ResultsA 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 and relevanceResults 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.Trial RegistrationClinicalTrials.gov Identifier: NCT03350620

Atropine Eye Drops for Myopia Control in Childhood—More Long-Term Data, Please

“…Nonetheless, the observation of increased risks for MMD with atropine concentrations of 0.1% and 0.5% deserves additional research. Of note, the 0.01% concentration used in many current studies did not show any increase in adverse events …”

“…These initial study results led to the widespread administration and rapid adoption of nightly administration of low-dose atropine eye drops (0.01% to 0.05%) to young children with low myopia (−1 diopter [D] to −6 D) to slow progression of the myopia and axial elongation of the eye. More recently completed studies in Australia, North American, and Europe have found smaller or no effects of the low concentrations studied (0.01% and 0.02%) in terms of slowing myopia progression . Each of these randomized clinical trials was launched recognizing that the primary and secondary outcomes would necessarily be short term and thus would be unable to provide the long-term outcomes needed to completely assess efficacy and safety.…”

Topical Atropine for Childhood Myopia Control

“…However, other similar randomized clinical trials by the National Eye Institute-sponsored Pediatric Eye Disease Investigator Group did not show a benefit of 0.01% atropine compared with placebo and suggested evaluation of the use of higher concentrations . While a Cochrane meta-analysis further supports that low dose atropine (less than 0.1%) had a mean treatment difference of 0.24 D with equivalence criteria being less than 0.25 D, these studies do not incorporate the recent lack of an effect for the primary 0.02% atropine trial by Zadnik et al nor the lack of an effect of the 0.01% atropine dose in the Pediatric Eye Disease Investigator Group.…”

“…After stopping atropine for 2 years, there was a reverse concentration-related effect suggested with greater rebound noted, especially in higher concentrations and younger children, which negated the initial benefits of atropine use . Zadnik et al also recently reported reduction in myopia progression in their secondary outcome of 0.01% atropine compared with placebo but not for the primary outcome of 0.02% atropine over 3 years of treatment. However, other similar randomized clinical trials by the National Eye Institute-sponsored Pediatric Eye Disease Investigator Group did not show a benefit of 0.01% atropine compared with placebo and suggested evaluation of the use of higher concentrations .…”

“…Over the past decades, topical administration of atropine eye drops has been demonstrated to be a safe and effective intervention in slowing the onset of myopia and reducing myopia progression in children . However, a recent clinical trial of 0.01% low-dose atropine eye drops did not slow myopia progression or axial elongation in US children .…”