Combination of orthokeratology lens with 0.01% atropine in slowing axial elongation in children with myopia: a randomized double-blinded clinical trial

Study design

This study was conducted in two phases. All children who had been wearing the OK lenses successfully for 2 months were randomly assigned in a 1:1 ratio to the combination group (combination of OK lens and 0.01% atropine eye drops) and the control group (combination of OK lens and placebo) for 1 year in phase 1 (Fig. 1). At the beginning of the second year in phase 2, the combination group would be crossed over to the control group, and the control group would be crossed over to the combination group. The current study reported the 1-year phase 1 results. This trial was approved by the Human Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Number: 2020-KY-223) and registered in the Chinese Clinical Trial Registry. This study conformed to the tenets of the Declaration of Helsinki. Written informed consent was obtained from the parents or guardians before the procedures, and the possible risks were fully explained before treatment initiation.

Fig. 1figure 1

Subject recruitment and randomization flowchart

Study Population

Sixty Chinese myopic children (Han nationality) who visited the First Affiliated Hospital of Zhengzhou University between June 2020 and September 2020 were recruited for this trial. The inclusion criteria were: 8–12 years of age, cycloplegic spherical equivalent refraction (SER) from − 1.00 to -4.00D, astigmatism less than 1.50D, anisometropia of less than 1.00D, monocular best corrected visual acuity of 20/20 or better, intraocular pressures not greater than 21 mmHg, no other eye diseases and surgery, no eye and systemic organic changes affecting vision acuity. The exclusion criteria were as follows: poor OK lens fit, congenital myopia (myopia present at birth) and pathological myopia, preterm birth, low-weight infants at birth, inability to comply with the study visit schedule, previous use of atropine or pirenzepine, peripheral defocus contact lenses and spectacles, and OK lenses to control myopia progression.

Randomization and masking

A stratified block randomization method was used to control for age and SER at baseline (2 months after wearing lenses). Specifically, children were divided into four subgroups, by age (8.0–10.0 years and 10.1–12.0 years) and by SER (-1.00 to -2.50 D and − 2.51 to -4.0 D), then, the children in each subgroup were randomly allocated into combination and control groups.

The 0.01% atropine and placebo eye drops were packaged in identical bottles; thus, neither the examiner nor the participants were able to identify the contents. All the eye drops were maintained and distributed by the same doctor. The data analysts were blinded to reduce observational bias.

Eye drops and OK lenses

The 0.01% atropine eye drops (pH = 5.4–5.6, 3 mL sealed bottle, 15–25 °C room temperature storage, discarded eye drops after opening the bottle for 1 month) were prepared by diluting atropine sulfate powder (Shaoxing Minsheng Medical Co., Ltd., Zhejiang, China) with normal saline under sterile conditions and subsequently, adding a preservative (0.3 mg/mL ethylparaben). The 0.01% atropine eye drops showed minimal degradation (approximately 1.8%) after opening the eye drop bottle for one month, and its properties were stable. A blank solvent without atropine was used as a placebo eye drops. All children were instructed to use 0.01% atropine or placebo eye drops by instilling one drop in both eyes once nightly 10 min before OK lens insertion.

The OK lenses used in this trial were four-zoned reverse-geometry lenses (Boston EM Material, Alpha Corp., Nagoya, Japan) with a Dk of 100 × 10–11 cm2/s (mL/O2/mL × mmHg). All children were fitted with lenses using trial lenses by the same ophthalmologist focusing on optometric eye care, according to the manufacturer’s instructions. The patients were advised to wear the lenses every night for at least 8 consecutive hours. The patients were also required to attend routine aftercare (1 day, 1 week, 2 months, and every 4 months after lens delivery) and unscheduled visits whenever necessary to ensure good ocular response and health. Lenses were routinely replaced about every 1.5 years, but if the residual SER was found to be more than 0.50 D at any visit after stabilization of treatment, lenses would be reordered. As the central corneal thickness stabilizes after wearing the OK lens for 1–2 months [24, 25], axial length (AL) measurement after wearing the OK lens for 2 months was used as the baseline value. Further, due to disruptions caused by COVID-19, with long inspection time of imported goods and slow delivery speed, it would take the participants approximately 1.5 months from fitting to wearing the OK lens. Therefore, the children in the two groups started to use 0.01% atropine or placebo once nightly at approximately 3.5 months (as baseline) after enrollment. All adverse events were recorded.

Each child was given four bottles of eyedrops at the randomization visit and the subsequent 4 monthly follow-up visits. These four bottles of atropine were collected at follow-up visits to track and monitor children’s compliance. Compliance was assessed based on the remaining amount of eye drop. One drop of the solution was approximately 0.04 ml, and each child would have used more than 2.4 ml each month. If the child’s remaining eye drops in any bottle exceeded 10% (about 1 ml) of the total amount in each bottle, then their compliance was not good. We carefully checked and recorded the OK lenses, lens case, lens suction holder, and care solutions at each visit. Specifically, the average weekly use of eye drops and wearing of OK lenses was assessed using a paper questionnaire at each follow-up visit. To improve compliance, we adopted the following methods: (1) We explained to the children and their parents the importance of using eye drops and wearing the OK lens correctly daily for myopia control. (2) A WeChat group was set up for all parents of the children, and two colleagues of the research group answered all kinds of questions encountered by the children during the trial. (3) Parents were asked to set a reminder before sleeping for applying eye drops before wearing the OK lens because both procedures had to be performed daily.

Study procedures

The details of the examination method for the observation items have been published elsewhere and are briefly described here [7, 15]. AL, corneal power, and anterior chamber depth (ACD) were evaluated using a non-contact partial coherence interferometer (IOLMaster; Carl Zeiss Meditec AG, Germany). Five successive measurements were taken on each occasion, and their means were used for analysis. Pupil diameter was measured with an autorefractor (NIDEK, AR-1, Japan) under bright light indoors. The light in the examination room was maintained at constant illumination of 300–310 lx (TES-1332 A illumination photometer). The children had to adapt to ambient light in the examination room for 10 min before the measurement. Three consecutive measurements were performed, and the average values were recorded. The AMP was measured monocularly using the push-up technique. The children wore their fully corrected spectacle prescription and focused on the previous line of best-corrected visual acuity in the right eye while the left eye was occluded. The children were instructed to focus on one letter as the chart moved closer. They were told to keep the letter as clear as possible until they could no longer be held in clear focus. The inverse of the final distance in meters was recorded as the AMP of the child. The AMP was recorded three times, and the average was used for analysis. Discomfort symptoms in the experimental groups were assessed using a written questionnaire during each follow-up visit. Cycloplegic autorefraction was performed using four drops of compound tropicamide eye drops (0.5% tropicamide and 0.5% neo-synephrine) (Santen, Japan) administered to both eyes at an interval of 10 min [26, 27]. Ten minutes after the last drop, cycloplegic autorefraction was measured thrice using an autorefractor (Topcon RM 8000 A, CA), and the readings, all within a difference of 0.25 D, were averaged for analysis. SER was calculated as the sphere plus half of the cylindrical power.

Sample size and data analysis

The sample size was calculated based on the results of previous studies [16,17,18]. We assumed that 90% power was required to detect at least 0.10 mm AL difference between the combination and control groups, with significance at the two-sided 5% level and standard deviation of 0.15 mm. Thus, this cross-over trial required overall 48 participants in the two groups. Considering a dropout rate of 20%, a total of 60 participants would be adequate.

Both eyes were treated and tested, but only right eye data from subjects who completed the 12-month follow-up were used for the analysis. The data was analyzed on a per-protocol basis. That is, subjects with poor compliance were not included in the statistical analysis. Normal distributed continuous variables were expressed as mean ± standard deviation (SD) and evaluated using Student t-test. Nonnormally distributed continuous variables were presented as medians with first and third quartiles [Q1, Q3] (95% CI) and evaluated using non-parametric rank-sum test. Categorical variables, such as sex and parental myopia status, were expressed as percentages (%) and evaluated using the chi-square test. Two-factor repeated measures ANOVA were performed for the AL, PD and AMP at each time point with treatment group (combination and control groups), time, and interaction of time and group included in the model setup. Multivariate linear regression analyses were used to compare AL changes between combination and control groups and assess the relationship between age, baseline SER and AL, changes in PD, and axial elongation at the 12-month visit. Statistical significance was set at p < 0.05. All statistical analyses were performed using Empower(R) software (WWW.EMPOWERSTATS. COM, X & Y Solutions Inc., Boston, MA, USA) and R (http://www.R-project.org).

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