Efficacy of Multifocal Soft Contact Lenses in Reducing Myopia Progression Among Taiwanese Schoolchildren: A Randomized Paired-Eye Clinical Trial

This prospective, randomized, double-blind, placebo-controlled study was conducted at three sites at two medical centers in Taiwan (National Taiwan University Hospital and Chang Gung Memorial Hospital, Linkou and Taipei branches). Eligible participants were randomly assigned to receive either the multifocal soft contact lens (test lens) or the single-vision soft contact lens (control lens), worn in the left or right eye. Such a paired-eye design could mitigate variations associated with myopia progression among participants, including differences in lifestyle or genetic susceptibility, leading to a balanced comparison between the treatment and control groups. The study spanned 50 weeks, encompassing a 2-week screening phase, followed by a 48-week treatment period involving ten visits. A schematic rendition of the study design is presented in Supplement Fig. S1.

The study recruited schoolchildren aged 6–15 years, irrespective of sex, presenting with a spherical equivalent (SE) refractive error ranging from − 1.00 D to − 10.00 D in both eyes. Inclusion criteria encompassed a minimum visual acuity of 0.8 with contact lenses in each eye, astigmatism equal to or below 1.50 D, anisometropia less than or equal to 1.00 D, and willingness to adhere to the assigned contact lens usage and study protocol. Participants were excluded if they had amblyopia, strabismus, pathologically dry eyes, aphakia, ongoing ocular infections or inflammation, severe ocular allergies, anterior segment abnormalities, corneal vascularization exceeding 1 mm, or a history of herpetic keratitis. Additional exclusion conditions included the use of atropine, orthokeratology, or other myopia control treatments within the previous month; presence of systemic diseases affecting vision or contact lens wear; surgically altered eyes; and long-term use of certain medications that might disrupt contact lens wear, tear production, or refractive state (e.g., pseudoephedrine, antihistamine).

A permuted block randomization approach with a 1:1 ratio was employed to allocate participants into two distinct arms, structured as follows: (A) left eye as treatment and right eye as control, or (B) left eye as control and right eye as treatment. The treatment group wore multifocal soft contact lenses, whereas the control group wore single-vision soft contact lenses in the opposite eye. Utilizing SAS 9.4 software, randomization code lists were produced at each study site by an independent code programmer. The randomized data remained inaccessible to all study personnel, preserving the integrity of the blinding process. The corresponding study group for each participant was securely documented within sealed envelopes, maintaining confidentiality until the data lock point.

Randomized participants were assigned to wear a multifocal soft contact lens (Largan Myopia Control Soft Lens) as the intervention in one eye, and a single-vision soft contact lens (Largan 1-Day Soft Contact Lens) as the control in the other eye. Before the formal study phase, eligible participants received Largan 1-Day Soft Contact Lens pairs during the screening visit to facilitate lens fitting and familiarity with wearing. The multifocal soft contact lens, the investigational product, had specific attributes including a composition of 45% HEMA copolymer, 55% water content, oxygen permeability of 18 × 10^–11 (cm²/s) (mlO₂/ml × mmHg) @ 35 °C, a blue tint, UV blocking with Benzophenone UV absorbing monomer, diameter ranging from 10.0 to 16.0 mm, and base curve ranging from 6.5 to 10.8 mm. Being available in powers from − 10.00 D to + 0.00 D, it offered a peripheral progressive add power ranging from + 3.00 to + 5.50 D. The lenses were subjected to daily disposable wear. Both the intervention and control lenses were supplied by Largan Medical Co., Ltd., and the study kits were prepared, packaged, and distributed by the same company. Lens power was prescribed based on the data of cycloplegic refraction and over-refraction. The participants were instructed to wear the lens for at least 8 h per day, 6 days a week. However, during the adaptation period, wearing them for less than 8 h per day was acceptable. The participants were also instructed to avoid overnight use, as this would increase the risk of complications. Lenses were re-prescribed during the study period if the subject’s visual acuity with the contact lenses was < 20/25.

Participants were eligible for withdrawal from the study under various circumstances, including voluntary consent withdrawal, loss of interest in contact lens wear, inability to comply with the protocol (e.g., not wearing lenses for a cumulative 10 weeks), experiencing discomfort or unsatisfactory vision with the lenses, encountering adverse reactions that rendered them unfit for lens wear, facing persistent difficulties in lens handling despite training, and receiving other treatments affecting study efficacy, as decided by the investigator. In line with ethical considerations, participants displaying rapid myopia progression within the initial 6 months of the study (defined as an increase of 1.00 D accompanied by axial elongation) were also withdrawn. The participants were subsequently offered alternative myopic control treatments.

This study encompassed two primary outcomes: changes in cycloplegic spherical equivalent and changes in axial length between the two eyes over the entire study period (48 weeks). Cycloplegia was induced using three consecutive drops of 1.0% tropicamide separated by 5-min intervals. Measurements were taken 15 min after the third drop of tropicamide. The devices used to measure refraction and axial length at each study site are listed in Supplementary Table S1. The identical instruments were consistently used for all the initial assessment and follow-up visits for each study participant. Secondary outcomes included tracking these changes at 12, 24, and 36 weeks, treatment compliance rates, and participants’ self-assessment of visual symptoms. The treatment compliance rate was calculated as the number of days of actual wearing hours of at least 8 h/288 days (6 days/week for 48 weeks).

For the safety evaluation, adverse events (AEs) were reported with a detailed breakdown, including count and percentage metrics. These data included participants with AEs, total AE occurrences, AEs linked to the study product, and their severity. Serious AEs were defined as those resulting in fatality, life-threatening scenarios, a substantial decline in best-corrected visual acuity by two lines, or necessitating hospitalization. Severe AEs included incapacitating or sight-threatening occurrences, whereas moderate AEs included interference with daily activities and/or treatment with prescription medications.

The study's sample size determination was based on a two-sided alpha level of 0.05 for a superiority t test, a robust 90% power, and a mean change difference of − 0.22 ± 0.36 D in cycloplegic refractive error at week 48 between treatment and control groups [10]. This translated into 47 eyes per arm (94 eyes in total). Factoring in an estimated 20% dropout rate, the adjusted enrolment was set at 59 eyes per arm (118 eyes in total). Similarly, an assumed − 0.10 ± 0.13 mm difference in mean axial length change at week 48 between treatment and control groups [11], warranted 30 eyes per arm (60 eyes total) for 90% power at a two-sided alpha of 0.05. Accounting for a 20% dropout rate, the adjusted enrollment target was 38 eyes per arm (76 eyes in total). To ensure the robustness of both clinical parameters, 118 eyes (59 patients) were selected for enrollment.

Paired t tests were used to demonstrate the primary outcome differences between the treated and control eyes. A two-sided significance level of 0.05 was considered as statistically significant. For other secondary outcomes, paired t test and McNemar’s test were used for continuous and categorical variables, respectively. All statistical analyses and graph drawing were performed using SAS version 9.4 and R statistical software, version 4.1.2.

This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. The study protocol was approved by the institutional review boards of both medical centers, and registered on ClinicalTrials.gov. (IRB approval No.: 201709029DSA [NTUH], 201701288A0D001 [CGMH]; Clinical trial registry No.: NCT03413085). Written informed consent was secured from parents or legal guardians, and participants provided written assent too.

The mean change in SE from baseline at week 48 was − 0.73 ± 0.40 D in the treatment lens group and − 0.85 ± 0.51 D in the control lens group (mean difference:

− 0.12 ± 0.34 D, 95% confidence interval [CI] − 0.22, − 0.03, p = 0.012) (Fig. 2A). The treatment lens group demonstrated a 52.3% reduction in myopia progression compared with the control lens group. The mean change in axial length from baseline at week 48 was 0.25 ± 0.14 mm in the treatment lens group and 0.33 ± 0.17 mm in the control lens group (mean difference: 0.08 ± 0.10 mm, 95% CI 0.05, 0.11, p < 0.001) (Fig. 2B). The treatment lens group demonstrated a 25.1% reduction in axial length elongation compared with the control lens group.

The mean change in SE from baseline at week 12, week 24, and week 36 were − 0.35 ± 0.28 D, − 0.47 ± 0.29 D, and − 0.59 ± 0.33 D in the test lens group, and − 0.29 ± 0.28 D, − 0.48 ± 0.35 D, and − 0.60 ± 0.38 D in the control lens group, respectively. No significant differences were noted between the groups at these points in time (Fig. 2A). The mean change in axial length from baseline at week 12, week 24, and week 36 were 0.07 ± 0.07 mm, 0.13 ± 0.09 mm, and 0.20 ± 0.12 mm in the test lens group, and 0.10 ± 0.07 mm, 0.18 ± 0.11 mm, and 0.25 ± 0.16 mm in the control lens group, respectively. Significant differences were noted between the groups at these time points (all p < 0.05) (Fig. 2B).

The mean compliance rate to the protocol-specified wearing time was 95.0 ± 16.6%. Owing to the paired-eye design, the compliance rate remained consistent for both the treatment and control eyes within each participant. Supplement Table S2 presents the outcomes of the participants' self-assessments of visual symptoms. In summary, 96.1% of the participants expressed being either "very comfortable" or "comfortable" in their overall assessment of comfort of the treated eyes. Participants reported a modest occurrence of mild symptoms such as sensations of dryness, burning, itching, photophobia, tearing, and unstable vision (ranging from 1.9 to 13.5%). However, no substantial differences were observed between the treated and control eyes. Notably, none of the participants reported glare, halo, or reading difficulties with the treated eye.

The results of subgroup analyses for the two primary endpoints (differences of change in SE and axial elongation between treatment and control lens group at week 48) based on baseline age group (6–12 and 13–15 years), gender, baseline spherical equivalent (< − 3.00 D and ≥ − 3.00 D), the compliance rate (> 90% and ≤ 90%), and whether the treatment lens was applied on dominant eye (yes and no), are presented in Fig. 3. Statistical significance was observed in the difference in SE change among subgroups with younger age, female sex, higher baseline myopia, better compliance rates, and treatment lens assigned to dominant eye. Similarly, the difference in axial elongation was statistically significant within the subgroups of younger age, both male and female, low and high baseline myopia, better compliance rates, and treatment lens assigned to dominant and non-dominant eye.

Throughout the study period, the average daily lens wearing hours was comparable between treatment and control eyes (11.50 ± 1.68 vs. 11.52 ± 1.68, p = 0.12). Eighteen of the 59 participants (30.5%) experienced at least one eye-related AE. All of them were mild. None of the participants experienced severe AE. The reported eye-related AEs in the test lens group were hordeolum (n = 5, 8.5%), allergic conjunctivitis (n = 4, 6.8%), acute conjunctivitis (n = 4, 6.8%), corneal epithelial defect (n = 2, 3.4%), chalazion (n = 1, 1.7%), and subjectively-reported unstable vision (n = 1, 1.7%). The most frequently reported eye-related AEs in the control lens group were acute conjunctivitis (n = 4, 6.8%), allergic conjunctivitis (n = 3, 5.1%), corneal epithelial defect (n = 2, 3.4%), hordeolum (n = 1, 1.7%), chalazion (n = 1, 1.7%), and subjectively reported unstable vision (n = 1, 1.7%). Among these, only five (8.5%) AE were judged to be treatment-related (one hordeolum, three allergic conjunctivitis, and one subjectively reported unstable vision). All patients recovered after receiving the corresponding ophthalmic treatment, with or without transient discontinuation of treatment lens or control lens wearing.

At week 48, three participants experienced anisomyopia greater than 1.00 D, but none exceeded 1.25 D. There was no significant difference between treatment and control eyes in the mean change of horizontal corneal curvature, intraocular pressure, and other ophthalmologic findings from baseline, except that the mean change of vertical corneal curvature in the treatment eyes was significantly larger than the control eyes (0.17 ± 0.33 D vs. − 0.02 ± 0.37 D, p < 0.001) (Table 2). This was also observed at 12, 24, and 36 weeks. However, the mean vertical corneal curvature at each visit was comparable between the groups. Based on the final ophthalmological findings, these changes did not lead to corneal disorders and were not clinically significant.