Effect of Wearing Peripheral Focus-out Glasses on Emmetropization in Chinese Children Aged 6-8 Years: Study Protocol For a 2-year, Randomized, Controlled Intervention Trial.

doi:10.21203/rs.3.rs-3122169/v1

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Research Article

Effect of Wearing Peripheral Focus-out Glasses on Emmetropization in Chinese Children Aged 6-8 Years: Study Protocol For a 2-year, Randomized, Controlled Intervention Trial.

https://doi.org/10.21203/rs.3.rs-3122169/v1

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published 22 Nov, 2023

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Background Myopia is one of the most common eye diseases causing visual impairment and blindness, and the high prevalance in adolescents remains a major public health concern. Based on clinical studies using optical defocus to regulate ocular growth and refractive changes through visual feedback, we hypothesize that early wearing of peripheral myopic defocusing spectacles in children at high risk of myopia may slow the process of emmetropization and even prevent the onset of myopia by inducing more peripheral myopic defocus. The aim of this study is to investigate whether the wearing of peripheral focus-out glasses can be effective in delaying emmetropization in non-myopic children aged 6- 8 years.

Methods The study is a 2-year, randomized, controlled trial. A total of 160 subjects will be randomized to the experimental or the control group. The experimental group will be fitted with Direct Emmetropia with Focus-out Glasses (DEFOG) to guide the emmetropization process. The control group will not receive any treatment and will serve as a blank control group. The primary aim is to determine whether non-myopic children wearing DEFOG lenses are superior to those who do not receive any intervention on progression of cycloplegic objective refraction over 2 years.

Discussion This is the first randomized controlled trial aiming at myopic prevention by non-invasive intervention in non-myopic children. This study aims to initially investigate whether wearing peripheral focus-out glasses can effectively delay the process of emmetropization in children aged 6-8 year at high risk of myopia, which might give potential clues for further exploration on early prevention of myopia.

Trial registration NCT05689567 (https://clinicaltrials.gov/ct2/manage-recs/register, registered on 10 January 2023).

Emmetropization

Myopia

Myopia defocus

Myopia prevention

Spectacle lens.

Myopia is one of the most common eye diseases causing visual impairment and blindness. The high rate of myopia in young people is also a major public health problem. It is predicted that 50% of the world's population will suffer from myopia by 2050[1]. Because the aetiology and pathogenesis of myopia is not fully understood, there is a lack of safe methods for myopia prevention and treatment.

Studies in animal models have shown that retinal defocus triggers a signaling cascade that causes numerous cellular and biochemical changes in the retina and retinal pigment epithelium that signal to the choroid and sclera, causing changes in the overall growth and refractive state of the eye. Wearing a certain degree of concave lens in immature animals causes hyperopia optical focus on the retina form[2]. This experimental myopia animal model has been utilized in a variety of animal experiments. It is considered that peripheral hyperopia optical focus can stimulate the growth of the eye and lead to the formation of central myopia, which is a risk factor for the development of myopia[3]. A number of studies have shown that in the process of hyperopic focusing or after inducing experimental myopia, the use of a certain amount of myopic focusing can prevent the onset of experimental myopia or partially reverse myopia that has already occurred[4, 5]. Experiments in laboratory animals demonstrate that ocular growth and emmetropization are mediated by local retinal mechanisms and that foveal vision is not essential for many vision-dependent aspects of refractive development. However, the peripheral retina, in isolation, can effectively regulate emmetropization and mediate many of the effects of vision on the eye’s refractive status[6].

An RCT study in Canada showed that children with rapid myopia progression were treated with bifocal spectacle lens (the lower lens added + 1.50D for close viewing) had myopia progression of -1.25D in 3 years, while the control group with single vision spectacle lens − 2.06D[7].

BLINK study was an RCT study designed to investigate the effects of multi-focal soft contact lens on the control of myopia progression in children. The three groups of myopic children were fitted with single-vision soft lens,multi-focal soft lens with medium add power (+ 1.50 D) and multi-focal soft lens with high add power (+ 2.50 D). Adjusted 3-year myopia progression was − 0.60 D for high add power, -0.89 D for medium add power, and − 1.05 D for single-vision contact lens. The high add power group decreased the myopia progression by approximately 43% compared with the single vision soft lens group[8].

In another RCT study, children were randomly assigned to wear Defocus Incorporated Multiple Segments(DIMS)or single vision spectacle lenses (SV). Myopia progressed 52% more slowly for children in the DIMS group compared with those in the SV group. Likewise, children in the DIMS group had less axial elongation by 62% than those in the SV group. The result showed that simultaneous clear vision with constant myopic defocus can slow myopia progression[9].

Additionally, a number of prospective studies of refractive changes in refractive accommodative esotropic children with full correction of hyperopia have revealed that the decrease in hyperopic refraction and the axial elongation were significantly lower than in children with under-correction of hyperopia[10, 11].

In humans and animals, the developmental process from hyperopia at birth to emmetropia or myopia is called emmetropization, and too fast or too slow process leads to the occurrence of myopia or hyperopia[12]. Emmetropization in this higher primate, as in a number of other species, is an active process that is regulated by optical defocus associated with the eye's effective refractive state[3]. Due to the influence of environmental factors and the changes in lifestyle habits, the myopia rate of kindergarten children in some parts of China has reached 12%, and the overall myopia rate of primary school students has exceeded 69%, showing an early onset, rapid growth and a deep degree[13]. This means that most children are now completing the process of emmetropization too fast, and thus inevitably experience early onset of myopia. The proportion of high myopia has also increased significantly.

Current myopia control measures are mainly aiming at children who are already myopic, by using low-concentration atropine[14], orthokeratology[15], peripheral myopic defocusing spectacles[9] and soft multi-focal contact lenses[16, 17]. LAMP2 study showed that among children aged 4 to 9 years without myopia, nightly use of 0.05% atropine eyedrops compared with placebo resulted in a significantly lower incidence of myopia and lower percentage of participants with fast myopic shift at 2 years, but long-term safety of using eyedrops in nonmyopic children is debatable[18]. And there is still a lack of evidence-based preventative strategies for children who are not yet myopic. To our knowledge, we believe the only way to truly reduce myopia rates is to find effective preventative tools for children who are not myopic through early intervention, where slowing down the process of emmetropization in children may be the key point behind the current gap.

On the basis of the clinical researches on optical defocus, which regulates ocular growth and refractive changes through visual signal feedback, and the above-mentioned bifocal and multi-focal lens, we believe that the early use of peripheral myopic defocus glasses in 6–8 aged children can slow down the process of emmetropization and even prevent the onset of myopia by producing more myopic defocus and reducing near-use accommodation.

To the best of our knowledge, randomized trial aiming at prevention of myopia by non-invasive method is lacking. The prevalence of myopia is very high in Chinese school-age children, up to 70 ~ 80%[19] which support the ethnic, rationale and acceptability of using an intervention approach for preventing myopia in children population.

Aim of study

This study aims to investigate whether DEFOG lens can effectively delay the process of emmetropization in non-myopic children aged 6–8 years. The primary aim is to determine whether non-myopic children wearing DEFOG lenses are effective on delaying progression of myopia drift over 2 years compared with those who do not. Other changes such as axial length (AL), amplitude of accommodation (AMP), subfoveal choroidal thickness (ChT) and peripheral retinal refraction will also be compared during the study period.

Study setting

The site of this study is Department of Ophthalmology, a tertiery pediatric hospital of Shanghai, China.

Study design and recruitment

This is a randomized, controlled, superiority trial. A total of 160 children (aged 6–8 years) will be recruited and followed up for 2 years.

Potential participants will be recruited primarily via: (1) offline advertising in outpatient clinics (2) online propaganda through domestic social media platforms.

The researchers will explain the purpose and content of the trial to the potential participants and their guardians, so as to be fully informed about the study content. Written consents of guardians will be obtained before enrollment. All the identifying information will be confidential and will be kept in locked cabinets that only be accessible to the principle investigator and project director (Dr. Chenhao Yang and Dr Weiming Yang). The protocol was approved by institutional IRB on Nov/2022[approval NO.(2022)315].

Eligibility criteria

The following eligibility criteria for this trial is modified from those provided by the International Myopia Institute (IMI) and related studies[20, 21]: non-myopia children at high risk will be recruited.

1. Age: ≥6 and ≤ 8 years at enrollment.

2. At least one parent' s spherical equivalent refraction≤-3.00D.

3. Spherical equivalent refraction(SER) under cycloplegia: +0.50 to + 1.50 diopters (D).

4. Astigmatism ≤ 1.00 D .

5. Anisometropia ≤ 1.00 D.

6. Best Corrected Visual Acuity (BCVA) : 1.0 or better.

7. Provision of consent written by subject's legal guardian.

8. Willing and able to participate in all required activities of the study.

Exclusion criteria: one will be excluded if any of the following criteria is met:

1. Any of the following abnormalities on the ocular surface: such as trachoma, pemphigoid, chemical injury, thermal burn, radiation damage, etc.

2. Eyelid abnormalities (such as entropion, ectropion, tumor, edema, blepharospasm, incomplete eyelid closure, severe trichiasis, severe ptosis), which might affect eyelid function in either eye.

3. Eye diseases such as strabismus, amblyopia, anisometropia, fundus diseases, and accommodation abnormality, etc.

4. Prior treatment of myopia prevention and control in either eye within 3 months before enrollment, including but not limited to atropine eye ointment, low concentration atropine eye drops, orthokeratology, low-level red-light therapy, etc.

5. Noncompliance with measurement at enrollment.

Intervention

1. Experimental group (DEFOG group): The experimental group will wear DEFOG lenses during the whole study period. Shanghai Guan Zhi Medical Technology Company will provide DEFOG glasses for this study. The bespoke company is commissioned by the researchers, who have no competing interest with the company, and the company will not be involved in this study itself during the whole process. The DEFOG lens is a custom-made plastic spectacle lens. It comprises a central plane optical zone and an asymmetrical peripheral myopic defocus zone with multiple segments of a positive power. This design simultaneously introduces myopic defocus on the peripheral retina and provides a clear vision for the wearers at all viewing distances. Baseline data including visual acuity, cycloplegic objective refraction, axial length, amplitude of accommodation, strabismus examination, pupil size, choroidal thickness and peripheral retinal refraction will be measured at enrollment. The subjects are required to wear DEFOG lenses for at least 8 hours a day, 5 days a week, and will be followed and examined at 6, 12, 18 and 24 months from baseline. In addition to ocular examinations, compliance and behavioral questionnaires will be recorded at any follow-up visit. During the follow-up period, if the cycloplegic SER≦ -0.50D, the subject should stop wearing DEFOG lenses and start using other myopia prevention and control methods such as single focal glasses, low-concentration atropine eye drops, myopic focus-out glasses, orthokeratology, multi-focus soft glasses, etc.

2. Control group: The control group will receive no intervention but general education about healthy reading and writing habits and will be a blank control, with follow-up schedule and measurements as identical as the experimental group. Behavioral questionnaires will be assessed at each follow-up visit, including changes in reading and writing habits. If cycloplegic SER≦ -0.50D during the follow-up period, other myopia prevention and control methods will be initiated to control myopia progression.

3. Adherence

The adherence monitoring of DEFOG will be undertaken at every follow-up visit by interviewing the participant and guardians. The average time of wearing DEFOG will be recorded through follow-up questionnaire by trained clinicians. Participants will be assessed whether they adhere to the intervention well or not according to the following rationale: 1) high compliance: the average wearing time ≥ 5 days/week and 8 hours/day; 2) moderate compliance: the average wearing time of 3–4 days/week or 6–7 hours/day; 3) poor compliance: the average wearing time of < 3days/week or < 6 hours/day. For those with mild or poor compliance, investigators will communicate with the subjects and their guardians to consider any safety concern of wearing DEFOG, such as adverse events.

Main adverse events like decrease in visual clarity, dizziness and discomfort will be recorded to evaluate the safety of wearing DEFOG at every follow-up visit, or subjectively reported by subjects or their guardians throughout the study period. Investigators will address the signs and symptoms of the subjects in a timely manner, and consider withdraw subjects with severe adverse events from the study if necessary.

Study outcomes

Rationale for outcome chosen

Myopia is an eye disorder characterized by light focusing in front of the retina due to excessive axial elongation of the eyeball. The evaluation of myopia is influenced by several factors, and in clinical settings, objective refraction (reflected by SER) under cycloplegia is considered more relevant for assessing changes in individuals with myopia. To avoid binocular interaction bias, only right eye will be chosen for analysis of the study outcomes.

Primary outcome :

The primary outcome is overall changes of cycloplegic objective refraction (reflected by SER) (right-eye only, D) of DEFOG group and the control group at 24 months from baseline. Objective refraction data will be examined by AUTO REF/KERATOMETER. SER is calculated by adding the sum of the sphere power with half of the cylinder power. Baseline data will be measured at enrollment. Other measurements obtained at follow-up visits are considered secondary outcome measures.

Secondary outcomes:

1. Changes of cycloplegic objective refraction (D)

Changes of cycloplegic objective refraction (reflected by SER) at different follow-up time (6, 12, 18 months) from the baseline time (right-eye only). Objective refraction data will be examined by AUTO REF/KERATOMETER.

2. Cycloplegic objective refraction (D)

Cycloplegic objective refraction (reflected by SER) at 6, 12, 18 and 24 months (right-eye only). Objective refraction data will be examined by AUTO REF/KERATOMETER.

3. The occurrence of myopia

Cycloplegic SER ≦-0.50D at 6, 12, 18 and 24 months (right-eye only). Objective refraction data will be examined by AUTO REF/KERATOMETER.

4. Changes of axial length (AL) (mm)

Changes of axial length (AL) at different follow-up time (6, 12, 18 and 24 months) from the baseline time (right-eye only). AL will be examined by IOL Master.

5. Axial length (AL) (mm)

Axial length (AL) at 6, 12, 18 and 24 months (right-eye only). AL will be examined by IOL Master.

6. Amplitude of accommodation (AMP) (D)

Amplitude of accommodation (AMP) at 6, 12, 18 and 24 months (right-eye only). AMP will be examined by the lens test.

7. Visual acuity

The BCVA at 6, 12, 18 and 24 months (right-eye only).

8. Strabismus examination(△)

Strabismus examination at 6, 12, 18 and 24 months by SYNOPTOPHORE.

9. Changes of choroidal thickness (ChT) (um)

Changes of choroidal thickness (ChT) at different follow-up time (6, 12, 18 and 24 months) from the baseline time (right-eye only). ChT will be examined by OPTICALCOHERENCETOMOGRAPHY.

10. Pupil size (mm)

Pupil size at 6, 12, 18 and 24 months (right-eye only).

11. Peripheral retinal refraction (D)

Peripheral retinal refraction at 6, 12, 18 and 24 months (right-eye only). Peripheral Retinal Refraction will be examined by AUTO FUNDUS CAMERA.

Cycloplegia protocol

All of the refraction measurements will be obtained by a standard cycloplegia protocol. Ciliary muscle paralysis will be performed by using 1% cyclopentanone eye drops 2 doses in each eye, with an interval of 5 minutes between doses. The pupil size and light reflex will be examined after 30 minutes, and if the pupil is dilated to ≥ 6 mm and a light reflex is absent, cycloplegia will be deemed complete. Otherwise, the third drop of 1% cyclopentanone will be dropped in each eye. The optometry will be performed with AUTO REF/KERATOMETER.

Participants timeline

In this study, primary and secondary outcomes will be evaluated during the follow-up period according to the pre-determined schedule (Fig. 1 and Table 1).

Table 1

Schedule of activities
Procedure/Measurements	Enrolment (-2 to 0 weeks)	Allocation (0)	6 Months (± 14days)	12 Months (± 21days)	18 months (± 28days)	24 months (± 35days)
Informed consent	X
Randomization	X
Demographic data and medical history	X
Allocation		X
Compliance and behavior Habits			X	X	X	X
Visual acuity	X		X	X	X	X
Slit-lamp microscopic examination	X		X	X	X	X
Cycloplegic objective refraction	X		X	X	X	X
Axial length	X		X	X	X	X
Amplitude of accommodation	X		X	X	X	X
Strabismus examination	X		X	X	X	X
Pupil size	X		X	X	X	X
Fundus examination	X		X	X	X	X
Optical coherence tomography	X		X	X	X	X
Peripheral retinal refraction	X		X	X	X	X

Sample size calculation

The primary outcome is the change in cycloplegic objective refraction (as measured by SER), as the rationale specified above. However, as this is the first preventative trial targeting non-myopic children by wearing lens, there is a lack of reference information on the preventative effect on refraction changes which is relevant to our study population. Considering changes in refraction are proportional to changes in axial length, the sample size calculation is alternatively referenced from a previous large trial in China, by using average change in axial length for non-myopic children aged 6–8 years over 24 months[22].it is estimated that the axial length of the control group will increase by 0.6mm ± 0.4mm at the 24th month, and that of the experimental group will increase by 0.4mm at the 24th month. Therefore, the value of Cohen’s D for sample size calculation is referred as the estimated effect between group divided by baseline standard deviation in control group, that is, (0.6 − 0.4)/0.4 = 0.5, which will be subsequently converted into a suspected effect of change in refraction in this study. According to previous experience and the latest 2-year large trial in Shanghai, China[23], we conservatively assume an average change in refraction of -1.00D ± 1.00D (i.e. 0.6mm increase in axial length specified in the same study) over 2 years in children aged 6-8years with baseline refraction of 1.00D ± 1.00D in the control group. Thus, the estimated effect will be 0.5×1.00+(-1.00)=-0.50D for change in refraction in the experimental group. This means that the sample size is fulfilled for us to observe at least − 0.50D change between group to reject the null hypothesis of no difference.

The sample size is calculated by using STATA15.1(Stata Corp, Texas, USA). Assuming a power of 0.80, a two-sided alpha of 0.05, and a 1:1 ratio between the experimental group and the control group, the estimated sample size for each group is 64 subjects. With an expected dropout rate of 20%, the estimated sample size for each group is 80 subjects (i.e. 160 subjects in total).

Randomization and masking

Block randomization with a block size of 4 and 1:1 ratio will be used to assign either DEFOG or blank control to enrolled subjects. The randomization sequence is generated by the independent statistic team at the Clinical Trials Unit of Children’s Hospital of Fudan University, using Stata 16.1 software (random seed number: 20230316). To ensure allocation concealment, each allocation sequence was placed in small, opaque, and sealed envelopes numbered and marked in order from one to four and were enclosed in a larger, opaque, and sealed envelope marked with the block number. The clinicians involved in this trial assess eligibility, enroll the subject after obtaining informed consent, and then contact the clinic coordinator who is independent of other research processes to obtain the allocation protocol for that subject. Block envelopes and the four enclosed small envelopes will be opened in order by the clinic coordinator.

The trial is unblinded due to the nature of the intervention. Subjects, and clinicians responsible for enrollment and compliance assessment are aware of the group assignment. To minimize the risk of observer bias due to unblinding, all ocular measurements will be performed by masked assessors (i.e. assessment-masked), who will not be aware of the allocation of the subjects, and will not be involved in the intervention throughout the study. To avoid accidental unmasking, other assessment-masked strategies will also be included: 1) participants and guardians will be told not to reveal or talk about their group assignment with assessors during examination; 2) for experimental group, DEFOG lens will be taken off in advance before they meet masked assessors, and kept in unmasked clinicians until all examination are done.

Data collection and management

All the data of this trial, including collection of outcomes will be originally recorded in clinical record forms and then entered into Microsoft ACCESS database. Double data entry and check will be completed on a wireless-enabled laptop by two trained operators who will not be involved in other procedures during the trial. The database will be coded and stored in the safe location that is only accessible to personnels involved in data collection. In ACCESS database, there are modules that allow for the identification of missing data, as well as quality assurance mechanisms. The data will be checked for data quality routinely and locked up when the last patient completes follow-up to achieve outcomes (i.e. 24 months follow-up). An internal data monitoring committee (DMC) will be established and will consist of ophthalmologists who are not involved in the trial and statistical experts for monitoring data completeness, safety information, adverse events, and so forth. No auditing will be performed through a professional organization.

Once the subjects are enrolled, retention efforts will be made to minimize loss-to follow-up during the study, such as 1) All the examinations will be free charged for all participants during the study period. 2) To develop a well-defined process in which all subjects will complete all examinations within one hour, reducing the burden of follow-up visits. 3) To train and inform subjects and their families about the hazards associated with myopia, understanding how this trial may help their children, and increase the confidence of subjects and their families to complete the trial. 4)To maintain a positive relationship with the subjects, using various means of communication such as WeChat, SMS, and telephone. Regular contact should be kept with a friendly attitude to establish a harmonious and trustworthy relationship. Additionally, it is necessary to strengthen supervision and management of the subjects.

Statistical analysis

Baseline characteristics of subjects will be presented as mean ± standard deviation (approximately normal distribution) or median ± interquartile range (skewed distribution), while categorical variables (e.g. gender) will be described as proportions.

In the present study, the primary analysis will be performed following intention-to-treat analysis (ITT) strategy, which includes all randomized subjects regardless of protocol adherence. Repeated measures analysis will be used to determine changes from baseline over time and between the two study groups for both primary outcome and secondary continuous outcomes, by using generalized linear mixed model (GLMM). The maximum likelihood method is used to estimate the mean difference between the two groups and their 95% CI, with Gaussian distribution and identity link function, group (group), time point (visit) and group × visit interaction as fixed effects, as well as with subjectid as the random effect. Data from the right eye will be used for the analysis. To compare the prevalence rate of myopia between group, multivariable poisson regression model will be applied to obtain the risk ratio and its 95% CI for myopia at the 24th month. Other strategies for additional analyses and missing data handling will be described in statistical analysis plan and uploaded before the completion of this trial on ClinicalTrials.gov (NCT05689567).

Statistical analyses will be performed using R4.1.2 (Vienna, Austria) and Stata 16.1 software (Stata Corp, Texas, USA), and all statistical tests will be two-sided, with an alpha level of 0.05 and P < 0.05 will be considered a statistically significant difference.

Ethics and dissemination:

The trial protocol (V.2.0, 22 November 2022) is following the principles of the Declaration of Helsinki, and has been approved by the research ethics board of Children's Hospital of Fudan University [No.(2022)315]. It has been registered on 10 January 2023 at ClinicalTrials.gov (NCT05689567). Any modifications to the protocol will be reported. Informed consent will be obtained from potential participants by a senior doctor in the trial team, who has GCP certification. Trial results will be published in peer-reviewed journals and will be disseminated to the media and the general public.

Reporting of research protocol

This protocol is reported according to the SPIRIT 2013 reporting guidelines[24]. The checklist is filled out in the supplementary information of additional file 1.

The myopia rate of kindergarten children in some parts of China has reached 12%, and the overall myopia rate of primary school students has exceeded 69%, showing an early onset, rapid growth and a deep degree[13]. However, this huge crisis seemed not effectively be kept under control until the myopia has already occured. Driven by previous evidence that any correcting lens design that imposes peripheral myopic defocus such as orthokeratology, myopic focus-out glasses and soft multi-focal contact lenses will be effective in slowing the rate of myopia progression and ocular axial growth, how to slow down the process of emmetropization in non-myopic children may become the key point. In this way, this research will become a pioneering work that figure out a potential solution that might help narrow the gap in terms of myopia prevention. Given the high prevalence and dramatic increase in myopia rate of Chinese children, it might benefit a large number of people if the efficacy of DEFOG will have been proved.

The following are further considerations on the trial design:

1. The criteria of participants

Recent population studies have indicated that myopia is less prevalent in children under 6 years old (< 5%), but increases significantly after the age of 8 (30%) and can be as high as 50% by 10 years old[25–27]. Furthermore, there is a prospective study showing that there is no significant change in SER among kindergarten children aged 3–5 years old through 1-year period, and there is no significant difference in SER between the 3-, 4-, and 5-years-old groups[28]. In a recent cross-sectional study, compared with 2020 ( after COVID-19 home isolation), the prevalence of myopia among children aged 6 to 8 years in the 2021 screenings decreased, and the mean SER returned to pre-pandemic level. The refractive development in children aged 6 to 8 years may be most susceptible to environmental changes[29]. These remind us that 6–8 years old may be the key age range for our intervention in delaying emmetropization.

In this trial, we recruit non-myopic children who are at a high risk of having myopia within a short term as the inclusion criteria of parental myopia of SER≤ -3.00DS, which differs from the previous cluster RCT of non-myopic children[30, 31]. Parental myopia has a significant positive association with a child's risk of developing myopia, as summarized in a recent meta-analysis[32]. Thus, these children will more likely to benefit from DEFOG intervention. High adherence to the trial will be more likely to be achieved due to high willingness to prevent myopia from their guardians.

2. The two-year follow-up

Longitudinal analyses showed that became-myopic eyes were clearly different from emmetropic eyes 2 to 4 years before the onset of myopia in terms of refractive error, axial length, relative peripheral refractive error. Eyes of became-myopic children differed in their rates of change between years and the fastest interval for change in all three components was during the year before onset of myopia. Became-myopic children had more myopia compared with emmetropes through 5 years after onset[33]. This suggests that there may be an opportunity for timely intervention in this short window.

This is the first randomized controlled study in delaying the process of emmetropization in non-myopic but at-high-risk children. Furthermore, this trial might not only provide reliable evidence to reflect the efficacy of DEFOG design, but also give potential clues for further exploration on early prevention of myopia, by comparing the myopia onset between groups over 2 years.

DEFOG: Direct emmetropia with focus-out glasses; AL: Axial length, AMP: Amplitude of accommodation, ChT: Subfoveal choroidal thickness; IMI: International Myopia Institute; SER: Spherical equivalent refraction; BCVA: Best corrected visual acuity; ITT: intention-to-treat analysis; PP: per-protocol analysis; GLM: generalized linear model; GLMM: Generlised Linear Mixed Model.

Ethical approval has been obtained from Children’s hospital of Fudan University[protocol number (2022)315, V2.0; dated 22 November 2022]. Recruitment of this trial started on 23 March 2023 and the approximate date when recruitment will be completed is 23 March 2024.

Availability of data and materials Not applicable. Data sharing is not applicable to this article, because no datasets have been generated or analyzed in the current study.

Author details The Department of Ophthalmology of Children’s Hospital of Fudan University. The Clinical Trials Center of Children’s Hospital of Fudan University.

Authors' contributions Li Shen and Wennan He contributed equally to this work and are considered co-first authors. Chenhao Yang and Weili Yan contributed equally to this work and are considered co-corresponding authors. CY, WY, LS ,WH and WY conceptualized the project and developed the protocol. WH provided additional expertise in the statistical analysis. LS, WY ,WH and CY drafted the manuscript. All authors discussed, read, revised the manuscript and all approved the publication of this.

Funding statement This trial will be conducted with no external funding. All of the examinations will be free for the participants and funded by the Department of Ophthalmology.

Competing interests statement None declared. Shanghai Guan Zhi Medical Technology Company will provide DEFOG glasses for free for this study. The bespoke company is commissioned by the researcher, who has no competing interest in the company, and the company will not be involved in this study itself during the whole process.

Patient consent for publication Not applicable.

Provenance and peer review Not commissioned; externally peer review.

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published 22 Nov, 2023

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Editorial decision: Major revision
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Reviewers invited by journal
17 Jul, 2023
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16 Jul, 2023
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Effect of Wearing Peripheral Focus-out Glasses on Emmetropization in Chinese Children Aged 6-8 Years: Study Protocol For a 2-year, Randomized, Controlled Intervention Trial.

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