Aim of the study
The current prospective, multicenter, randomized controlled trial will evaluated the myopia progression control efficacy of two clinical broadly used MD spectacle lenses, DIMS lenses and PALs, in 6- to 12-year-old myopic children in primary school. The primary aim is to determine whether DIMS lenses are noninferior to PALs in the combined endpoint of spherical equivalent refraction (SER) and axial length (AL) progression in myopic subjects over 3 years. Other changes will also be compared over the study period, including risk factors, ocular health, uncorrected relative peripheral refraction, binocular vision function (principally vergence), accommodation (particularly lag and amplitude), sub-foveal choroidal thickness, visual environment, and wearing experiences [15].
Study settings and responsibilities
Five trial sites will be involved, including Peking University People’s Hospital (PKUPH, PI: Dr Zhao Mingwei; and co-PI: Dr. Li Yan), Peking University International Hospital (sub-PI: Dr. Li Mingwu), Kunming City Maternal and Child Health Hospital (sub-PI: Dr. Li Na), Beijing Haidian Maternal and Child Health Hospital (sub-PI: Dr. Chen Wei), and ChuiYang Liu Hospital affiliated with Tsinghua University (sub-PI: Dr. Wang Hongxing). Each of the hospitals is a large center with ophthalmology clinics and optometrists, and data will be collected at each site. The primary investigators at each site compose the steering committee, which is under the leadership of PKUPH (Lead PI and Chair: Dr Zhao Mingwei, PKUPH). The steering committee will provide final approval of the protocol and any changes to the procedure during the clinical trial.
Among these sites, PKUPH will be in charge of supervising the conduction of the study, including staff training and assessment, protocol decisions and amendments, form development, data management, data analyses, and quality control. The reason for endowing PKUPH with this governance authority is that, PKUPH has undertaken dozens of domestic and foreign, multicenter clinical trials and thus has abundant clinical trial experience. In addition, PKUPH has a group of staff members who undertake site management organization (SMO) work, which will ensure the clinical trial protocol will be strictly implemented at different study sites.
Coordinating responsibilities, such as data collecting and recording, will be performed at all of the study sites. Subjects will be screened at each site to achieve a minimum screening percentage of 10%, and a maximum percentage not exceeding 30%. All of the centers will continue to screen subjects until the target population is achieved.
Study design and recruitment
This is designed as a 3-year, prospective, randomized, multicenter clinical trial. Recruitment is intended to begin on 30 October 2019 and is scheduled to end on 30 October 2020. A total of 600 primary school children (aged 6-12 years) will be recruited, and each of the participants will be followed for 3 years. Randomization will be performed with a random number table, and each group (DIMS, PALs) will contain 300 subjects. The final distance prescription will be determined by a masked investigator (MI) using the cycloplegic subjective refraction measured by phoropter after the objective refraction is measured by autorefraction. The lenses will be replaced with an updated prescription when the change in SER is more than 0.50 D.
Potential participants will be recruited for the clinical trials at each center through two primary processes: (1) ophthalmologist referral during daily eye disorder treatment in outpatient clinics; and (2) optometrist referral from optometry clinics during myopia treatment.
All of the potentially eligible participants and their parents/guardians will be contacted by a research coordinator who will explain the study in detail to ensure that the children and their parents/guardians understand the entire clinical trial. Once they are interested, the patients and their parents/guardians will be seen in the clinical research laboratories to sign an informed consent form. Interested participants will be invited for the eligibility and baseline assessments by the study staff. All the identifying information will be confidential. It is estimated that 10 new subjects will be recruited each month on average at each site.
Myopia defocus spectacle lens systems and spectacle prescriptions
DIMS lenses: The DIMS lenses are custom-made plastic spectacle lenses. Each lens comprises a central optical zone (9 mm in diameter) for correcting distance refractive errors and an annular multiple focal zone with multiple segments (33 mm in diameter) having a relative positive power (+3.50 D). The diameter of each segment is 1.03 mm [10].
Apollo spectacle lenses: The Apollo spectacle lenses comprise an asymmetrical MD design with a 3 MD zone, including a +2.50 D full positive power superior zone, an 80% full MD power nasal zone, and a 60% full MD power temporal zone.
Both of the spectacle lenses are designed to simultaneously provide clear distance vision for the wearer and introduce MD for the peripheral retina by providing a plane in front of the retina, resulting in signals being received as blurred images on the retina [5]. All of the children will be instructed to wear lenses all the time throughout the whole study. The use of atropine eye drops of any concentration will not be permitted for any participant during the study.
The final distance prescription of the spectacles will be determined based on cycloplegic subjective refraction by the masked optometrist. The spectacle lenses will be replaced and upgraded when the change in SER is 0.5 D or more in either eye compared with refraction while wearing spectacles.
At the initial spectacle dispensing and each follow-up visit, subjects and their guardians will receive face-to-face instruction about the purpose, use, and care of the lenses. In addition, investigators will explain the etiology and pathology of myopia, emphasize the importance of adherence to the follow-up protocol for evaluating myopia progression, and provide notifications regarding the follow-up ophthalmic examinations. In addition, the SMO from PKUPH will provide phone call reminders before each visit to enhance compliance with the present clinical trial.
Eligibility criteria
The following eligibility criteria for this trial were modified from those provided by the International Myopia Institute (IMI) and related studies [6, 10, 15]:
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Mainland Chinese, Han nationality.
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Age at enrollment: 6-12 years old.
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Cycloplegic SER: -1.00 to -4.00 D, with SER calculated as the sphere plus 0.5 x the cylinder in D. (Recommended dosage for cycloplegic refraction is 2 drops of 1% tropicamide given 5 minutes separately. Cycloplegic refraction outcomes should be measured 30-45 minutes after the first drop of tropicamide is instilled, which ensures the maximal cycloplegic effect.)
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Astigmatism: 1.50 D or less.
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Anisometropia: 1.50 D or less.
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Difference between the right and left pupil sizes: 2 mm or less.
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Monocular best-corrected visual acuity (BCVA): 20/20 (0.0 LogMAR) or better (LogMAR chart).
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Willingness to wear spectacle lenses regularly.
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Acceptance of random group allocation and the masked study design.
The exclusion criteria are as follows:
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Strabismus: checked by cover test at far and near distances.
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Any ocular and systemic diseases, including abnormalities, that might affect visual functions or refractive development.
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Previous experience with myopia control, including orthokeratology, progressive addition spectacle lenses, bifocal lenses, and pharmaceutical treatment (e.g., atropine), etc.
Study outcomes and follow-up schedule
Rational for outcome chosen: Myopia is an eye disorder in which light focuses in front of the retina but not right on the retina, and mostly because of the excessive axial elongation of the eyeball. In the clinic, two valid and reproducible indicators, subjective refraction (SER in diopters) and axial length (mm) under cycloplegia, are considered to be more relevant for evaluating changes in subjects with myopia. In addition, several influencing factors are related to the evaluation of myopia. Thus, in the present study, primary, secondary and exploratory outcomes will be evaluated during the follow-up period according to the schedule (Table 1).
Primary outcome: To determine whether DIMS lenses are noninferior to PALs for the prevention of myopia progression by evaluating the cycloplegic SER changes in two groups of subjects. For the primary outcome analyses, myopia progression over 3 years will be determined by the difference in the subjective SER between baseline and the last follow-up visit. Other measurements obtained at follow-up visits are considered secondary outcome measures.
Procedures for subjective refraction [10]: (1) Starting with autorefraction and refine subjectively; (2) Occlude the left eye; (3) Determine best sphere first; (4) Determine cylindrical error; (5) Refine sphere using +1.00D blur back test monocularly and finish by offering a binocular +0.25D add; (6) Binocular balance (prism dissociation). Stop when no difference between the upper and lower line.
Secondary outcome: To determine whether DIMS lenses are noninferior to PALs for the prevention of axial elongation (mm) determined by noncontact interferometry measurements [10] in the two groups of subjects at baseline and the last follow-up visit.
Exploratory outcomes: Several innate and environmental factors are useful in understanding the control of myopia progression [6, 8, 15], including age and refractive error at onset, family history (e.g., parental myopic status), visual and environmental habits (e.g., near work time, outdoor time, spectacle wear time, brightness of light exposure, etc.), binocular vision (e.g., accommodative lag, elevated accommodative convergence to accommodation [AC/A] ratio, etc.), peripheral refraction, pupil size, and treatment compliance. Thus, we plan to evaluate these factors as secondary and exploratory outcome measure items in the present study, as shown in Tables 1, 2, 3, and 4.
Cycloplegia protocol: All of the refraction and AL measurements will be obtained by a standard cycloplegia protocol. The recommended dosage for cycloplegic refraction is 2 drops of 1% tropicamide given 5 minutes separately. Cycloplegic refraction outcome measures will be obtained 30-45 minutes after the first drop of tropicamide is instilled, which ensures the maximal cycloplegic effect. Refraction will be measured with an open-field autorefractor (Shin-Nippon NVision-K 5001 autorefractor). The AL will be measured by an IOL Master system (Carl Zeiss). For SER and AL, 5 measurements will be obtained at each visit and then averaged for each eye for statistical analysis.
Follow-up examination and measurement schedule: All of the ophthalmic exanimation measures will be assessed at baseline, 1 month, 3 months, 6 months, and then every 6 months until 3 years after randomization. The differences in all of the mean values at each follow-up visit from baseline will be analyzed. Additionally, to avoid binocular interaction bias, only one eye will be randomly chosen for analysis of the study outcomes.
Training of the study staff: All staff from each site will be trained under the control of PKUPH, including in taking the standard measurements related to the primary, secondary, and exploratory outcomes, implementing the clinical trial protocol, managing data and addressing key issues raised by participants. The training process is necessary for consistency, reproducibility, and repeatability. The standard training program will include but not be limited to obtaining BCVA, refraction, AL, binocular vision, corneal curvature, and peripheral refraction measurements, administering the questionnaire, and recording data.
During the whole study, the SMO from PKUPH will play an internal quality control role to ensure the study is performed in a uniform manner at all study centers.
Sample size calculation
Estimation of the sample size is based on the two following methods: statistical analysis and recommendations from review articles.
Statistical analysis: The two-sample t-test for non-inferiority statistical analysis was used for the sample size calculation. The non-inferiority null hypothesis is that the refractive error, measured by SER, will be worse with DIMS lenses than PALs for the treatment of myopia, and the rejection of this null hypothesis is powered to detect a noninferiority margin (Δ) of less than 10% [15]. According to previously published articles, the 2-year difference in myopia progression with DIMS is 0.44±0.09, while the difference in myopia progression with PALs is 0.20±0.08 [10, 15, 20]. Thus, the mean difference between DIMS lenses and PALs is 0.22. Because the detected variation in myopia is approximately 0.25-0.5, we chose 0.5 as the standard deviation factor. Other parameters used include a significance level of 0.05, 95% confidence interval (CI) (two-sided), 80% power and 1:1 allocation. Based on these parameters, the estimated sample size for each group is 201 subjects. Based on our previous experience with clinical trials for treating myopia and other published data, we estimated the rate of subject loss to follow-up over 3 years to be approximately 40%. Considering these factors together, the estimated sample size for each group is 282.
IMI recommendation: The International Myopia Institute (IMI) summarized key issues in view of more than 170 peer-reviewed published articles on myopia control, and more than 85 multidisciplinary experts contributed to reports on clinical practice, basic research and future directions [6, 7, 8, 15]. According to these IMI reports, key information about the sample size calculation is missing in published articles, and a reasonable number of subjects per group ranges from ~70 to 333 children over 2 to 3 years of follow up [15]. In particular, the sample size per group for spectacles ranges from 125 to 333 [15].
Based on the expert consensus of the reviewed articles and the statistical calculation, a sample of 300 eligible children will be required in each arm of the trial. We do not plan to stratify any subgroups.
Randomization and masking
The research coordinator will guide the participants to perform and finish all of the examinations, go through the results, and mask the groups to which the subjects belong. In addition, the coordinator will contact individuals before their follow-up visits.
The unmasked investigator (UMI) will be responsible for group allocation, i.e., allocating all of the children into either the DIMS lens group or PALs group through the sequence generation method (a random number table) at a 1:1 allocation ratio. In addition, the UMI will also be in charge of spectacle lens fitting, after care, performance assessments, data recording, and answering questions from participants and their parents/gradients.
The masked investigator (MI) will be responsible for ophthalmic assessment and data measurements, blinded to the allocation, and not allowed to handle spectacle lenses throughout the study.
In addition, to avoid accidental unmasking, the spectacles will be kept by the UMI until the subjects finish the examination by the MI. Additionally, to avoid selection bias, allocation concealment will be ensured until the participants and their parents/guardians have been recruited into the clinical trial after the individuals finish all of the baseline examinations.
During the clinical trials, neither the participants (together with their parents/guardians) nor the MI will be aware of the groups allocation.
Data management and data analyses
Data from the two groups will be presented as the mean ± SD, except for the gender and patient number in each group will be presented as proportion. Data from a random eye will be used for data analysis according to a random table considering the high correlation between the two eyes of the same participant. Baseline group data will be analyzed by unpaired t-tests. Repeated measures ANOVA will be used to determine changes from baseline over time and between the two study groups. Bonferroni corrections will be used for post hoc comparisons. Correlations between changes will be calculated using Pearson’s correlation coefficient.
In the present study, all randomized participants will be included in the data analysis, regardless of protocol adherence. Missing data will not be included in the following analysis and will not be imputed from the timepoint of dropout. An interim analysis of the primary endpoint will be performed by an independent statistician when 50% of the participants have been allocated and completed a 6-moth follow-up examination.
Once the subjects are enrolled, retention efforts will be addressed to participants and parents/guardians. Coordinators, study investigators and examination staff will (1) provide periodic communications about the clinical trial and myopia control strategies for the subjects; (2) provide feedback regarding the eye care data of the subjects; and (3) provide reminders of the follow-up visit and final visit.
An internal data monitoring committee (DMC) will be established and will consist of ophthalmologists who are not involved in the running trial, statistical experts, and members of the ethics committee. The chair of DMC will be Dr. Mu Shuang, the PKUPH ethics committee director. Data monitoring will be performed quarterly by the DMC, including monitoring for data completeness, safety information, and adverse events, etc. No auditing will be performed through a professional organization. The integrity of the trial for each subject will be cross checked between sites to ensure the appropriate allocation and completeness, accuracy, and timeliness of data collection, etc.
In the present study, the main adverse event will likely be decreased visual clarity and discomfort after wearing glasses. Adverse events occurring after the dispensing of spectacle lenses will be recorded, and investigators will address the signs and symptoms of the subjects in a timely manner.
Participants may withdraw from the study for any reason at any time. In addition, the investigators may also withdraw participants from the study to protect their safety. All study-related information will be stored securely in locked file cabinets in the research laboratory at each study site. All of the records containing personal identifiers, such as names and informed consent, will be stored separately from data records identified by code number.
Ethical approval and conduct
Ethical approval has been proven by Peking University People’s Hospital, and all amendments will be re-submitted to the ethics committee. Patient recruitment has not yet started at the time of manuscript submission.