Title: Low-dose atropine eye drops to reduce progression of myopia in children
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: DESIGN: Multicentre, prospective, double-masked, randomized (2:1) placebo-controlled trial of topical 0.01% atropine eye drops. POPULATION: Children with myopia. INCLUSION CRITERIA: 6-12 years of age with myopia of -0.5 dioptres (D) or higher (spherical equivalent refractive error) and best corrected visual acuity (BCVA) of 0.20 logMAR or better in both eyes. INTERVENTION: Once daily 0.01% atropine eye drops to both eyes for two years. COMPARATOR: placebo eye drops. OUTCOMES: Primary outcome is change in cycloplegic spherical equivalent refractive error measured by autorefraction at 2 years (the average of both eyes). Secondary outcomes: BCVA, near VA, pupil diameter, adverse events, tolerability. Mechanistic evaluation: central and peripheral axial length, position of the lens, accommodation, peripheral retinal defocus, and macular chorio-retinal thickness. ASSESSMENTS: At baseline, and every 6 months until month 24, we will assess cycloplegic refractive error (auto-refractometer) and adverse events. At 12 and 24 months: BCVA (ETDRS), near VA (near ETDRS), pupil diameter (autorefractor), lens position (laser biometer), central and peripheral axial length (laser biometer), peripheral refractive error (auto-refractometer), and foveal chorio-retinal thickness (optical coherence tomography). Adherence with eye drops will be monitored with compliance electronic monitoring and by weighing of returned bottles every three months. Tolerability will be self-reported with a 4-level scale. Spectacle use, change in spectacle correction and time spent in near work and outdoor activity will be monitored. Long-term safety will be investigated via questionnaires to participants and optometrists at 5 years after randomisation. SAMPLE SIZE: Atropine eye drops will reduce myopia progression by at least 40%. Based on a SD=0.7 and accounting for clustering using an ICC=0.9 and variance inflation factor of 1.9 results in 97 children per group. Considering a dropout rate of 15% and a 10% rate of Chinese participants we will need 289 children (193 atropine, 75 placebo, VIF 1.9) to detect difference in a non-Chinese population with 90% power. STATISTICAL ANALYSIS: Analysis will be based on the intention to treat principle. A p-value of <0.05 will be considered statistically significant. For the primary analysis, endpoints from both eyes will be pooled in combined analysis using generalised estimating equations (GEE) to allow for the correlation between eyes within participant. Difference in myopia progression and other continuous outcomes between groups will also be tested for significance using independent t-test. Analysis of covariance will be performed to adjust for baseline characteristics. Fisher’s exact test will be used to test the difference in the proportions between the groups for the categorical variables. Exploratory subgroup analyses will be performed on the primary outcome using 99% confidence intervals and interaction terms (treatment group by subgroup) according to age and ethnicity. DURATION OF STUDY AND TIMELINE: Overall trial duration will be 48 months. 6 months: ethics approval and study set up; 15 months: recruitment; 24 months: treatment; 3 months: analysis and reporting. Including the long-term safety evaluation the duration is 84 months. EXPECTED RECRUITMENT RATE: 4 or 5 patients per month in each of 4 research centres, will be recruited through optometric practices from which we have confirmed support.

Lay abstract: Myopia (shortsightedness) causes blurry vision when looking at distant objects. Approximately 1 in 3 people in the UK suffer from myopia, and about half of those aged 25-29 have been found to have it. These proportions and the severity of myopia in the UK are increasing over time. Myopia is associated with greater use of NHS resources, including more frequent eye tests and provision of glasses. With higher myopia comes an increased risk of blinding eye conditions such as retinal detachment, glaucoma and abnormal blood vessels growth at the back of the eye (at the macula) that will have a major impact in the quality of life of the affected individuals and will be costly to the NHS. Several studies have been done to find ways to slow the worsening of myopia. The largest effects for controlling myopia have been found with anti-muscarinic medications (atropine eye drops), but we do not yet understand how they work or how best to use them. High concentration atropine eye drops are very effective but have unwelcome side effects: they sting, cause discomfort through increased light sensitivity and blurred near vision, and some people develop allergic reactions. Recent studies show that low concentration atropine drops are also effective in reducing the progression of myopia in children and have few unwanted side effects. However, all controlled studies on atropine eye drops have been done in East Asia with children of Chinese race and we do not currently know if low concentration atropine eye drops can work in UK children. We want to resolve this uncertainty by conducting a fair test of whether low dose atropine eye drops can reduce the progression of myopia in UK children. We will evaluate the efficacy, tolerability and safety of a low dose of atropine versus placebo. We will recruit 289 children with myopia between 6 and 12 years of age from local optometrists. 193 children will use atropine eye drops in each eye every day for 2 years and 96 will use placebo. We will monitor if drops are used with an electronic monitoring system. We will measure changes in myopia severity after 2 years and also how the atropine works by measuring different aspects of the eye size, shape and function which may be affected by the treatment. We will monitor long-term safety as well. We have discussed the study with parents of children with myopia. We also surveyed 35 parents. All 28 who replied were supportive of the trial but most (93%) wanted confirmation of the safety of the eye drops. They said that it was important to have a treatment that can reduce the progression of myopia. We believe atropine is safe but an independent committee will monitor possible adverse events during the trial. A reduction of myopia progression will not only be positive for individuals living with myopia but will also generate large savings for the NHS in the longer term, reducing the incidence of myopia-related eye diseases and blindness, and the frequency with which glasses (required to correct myopia) need to be changed. The research team includes statisticians, ophthalmologists and optometrists, and experts in this type of research. We will be supported by a registered Clinical Trials Unit with a portfolio of vision trials. As well as involving parents of children with myopia in preparing this proposal, two lay people and a PPI manager experienced in children's research will be on the Trial Steering Committee.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: EYE