Study design
This is a prospective, double-masked, cross-over, and randomized clinical trial. The duration of the study is 13 months (see Fig. 1 for more details about the timeline of this study), and it consists of 7 visits.
Eligible subjects were randomized into two groups. Group 1 will wear SAL lenses for 6 months, followed by 6 months of wearing single vision lenses. In Group 2, the order in which the lenses are worn is reversed. In this paper, we refer to the spectacles worn during the first 6 months (regardless of lens type) as study equipment 1 and the spectacles worn during the second 6 months (regardless of lens type) as study equipment 2 (Fig. 1). At each visit, all subjects are instructed to wear the study equipment for more than seven hours every day.
The study is being conducted at the Hangzhou Branch of Zhejiang Eye Hospital Affiliated to Wenzhou Medical University. The study and its protocol follow the tenets of the Declaration of Helsinki and were approved by the institutional review board of the Eye Hospital of Wenzhou Medical University. Written informed consent was obtained from participants and their guardians after a detailed explanation about this study and the possible risks and benefits at the first visit. The study is registered at the Chinese Clinical Trial Registry (ChiCTR1900021002, 24/01/2019).
Study participants
A total of 100 children were recruited from the hospital into this study between January and March 2019. The inclusion criteria were best-corrected visual acuity equal to or better than 1.0, age between 8 and 13 years inclusive, spherical equivalent of cycloplegic autorefraction between -0.75 D to -4.75 D in each eye, astigmatism no more than 1.50 D, anisometropia no more than 1.00 D, and absence of strabismus. Subjects with a history of ocular or systemic disease, history of wearing PALs, or prior myopia control treatment were excluded from participation in the study.
The study was designed to achieve 80% power to detect a minimum difference of 0.27 D with a SD of 0.37 D in 6 months at a 5% level of significance. Using an online sample size calculator by Clinical & Translational Science Institute33, the theoretical sample size was 42 with a 1:1 sample ratio in each group. Allowing a maximum drop-out rate of 15%, the number to be recruited for each group was estimated to be 50.
Randomization and masking
All subjects were assigned into the two groups (described in the Study Design section) at a 1:1 ratio using covariate-adaptive randomization[33]. A scheduled randomization was generated and children were randomly assigned by Study Manager (ESSILOR R&D). The investigators cannot access to the randomization list.
According to the scope of responsibilities, the examiners are either masked or unmasked. The masked examiners are responsible for subjective refraction, cycloplegic autorefraction, axial length, corneal thickness, anterior chamber depth measurements and assessing visual acuity with the study equipment. The unmasked examiners are in charge of dispensing and documenting adverse events.
Test lenses
The treatment lens is a polycarbonate single vision spectacle lens with a spherical front surface with 11 concentric rings formed by contiguous slightly aspherical lenslets.
The control lens is a standard polycarbonate single vision lens.
Main outcome measures
There are two main outcome measures: the axial length (AL) and the spherical equivalent (SER) of cycloplegic autorefraction. The AL is measured using an optical low-coherence reflectometry device (Lenstar LS900; Haag-Streit, Koeniz, Switzerland). Five measurements are taken, and the average value per eye is used for data analysis. The refraction is measured by a closed-field autorefractors (Topcon RM-800 and Topcon 8900). The measurement is taken ten times on each eye and the mode of the sphere, cylinder, and axis per eye is recorded for data analysis. The SER is calculated as sphere + 0.5 x cylinder. The SER is taken only at baseline, the fifth visit and the last visit to minimize cycloplegia during the study.
Secondary outcome measures
Corneal thickness (CT), anterior chamber depth (ACD), and lens thickness (LT) are taken with the Lenstar LS900 (Haag-Streit, Koeniz, Switzerland) together with AL. Five measurements are taken, and the average value per eye is used for further data analysis. Distance-corrected visual acuity (DCVA) is evaluated using a standard 100% contrast English Early Treatment Diabetic Retinopathy Study (ETDRS) logMAR chart at 4 m with usual correction or new distance prescription. DCVA is scored using the standard technique of subtracting 0.02 logMAR units for each correctly identified optotype.
Study equipment questionnaire
The questionnaire contains six questions. The first four questions evaluate adaptation and subjectively evaluate various aspects of vision with the study equipment on a scale of 1 to 10. Question 1 quantifies the clarity of vision (1 = blurred, 10 = clear); question 2 evaluates perception of ghost images (1 = none, 10 = severe); question 3 evaluates satisfaction with the study equipment (1 = not satisfied, 10 = satisfied), and question 4 evaluates the comfort of study equipment (1 = uncomfortable, 10 = comfortable). The remaining questions assess compliance in terms of how long the study equipment is worn (question 5: hours per day, and question 6: days per week).
Study visits and procedures
The procedures performed at each visit are summarized in Table 1.
During the recruitment and baseline visit, we first performed a full ocular examination, including presenting visual acuity, objective and subjective refraction, anterior segment and fundus inspection, and binocular vision status (near and far phoria, near point of convergence (NPC), Worth 4-dot test), followed by acquisition of the primary outcome measures (cycloplegic SER and AL) and all secondary outcome measures (DCVA, AL, CT, ACD, and LT). The subjects chose their frame, and the same frame is used for SAL and control single vision lenses, i.e., before and after cross-over. At the end of the baseline visit, the subjects are dispensed with washout single vision lenses corresponding to the prescription for their first study equipment.
The main follow-up visits include the 6-month cross-over visit and the final 12-month visit with all primary outcome measures, including the questionnaires.
The additional study visits comprise the dispensing visit (approximately one month after the baseline), 3-month, 5-month, and 9-month visits with only non-cycloplegic AL and secondary outcome measures. In addition, at the 5-month visit, we acquire non-cycloplegic subjective refraction as a basis for the prescription for the study equipment worn during the second phase of the study (i.e., after cross-over).
Between one and three days after the dispensing visit and 6-month visit, we administer the compliance and adaptation questionnaire over the phone.
During all study visits, the study equipment is adjusted, and subjects are instructed to wear it at least 7 hours per day.
Cycloplegia is always induced by 1% cyclopentolate hydrochloride (Alcon Laboratories) eyedrops delivered three times, five minutes apart after induction of corneal anaesthesia with proparacaine (0.5% Alcaine, Alcon Laboratories).
Table 1. Visit schedule for the study. V1 to V7 represent visits 1 through 7
AL, axial length; CT, corneal thickness; ACD, anterior chamber depth; LT, lens thickness; DCVA, distance-corrected visual acuity
Visit schedule
|
V1
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V2
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V3
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V4
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V5
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V6
|
V7
|
Informed consent
|
X
|
|
|
|
|
|
|
Eye examination
|
X
|
|
|
|
|
|
|
Inclusion and exclusion criteria
|
X
|
|
|
|
|
|
|
Study frame choice
|
X
|
|
|
|
|
|
|
Monocular pupillary distance and fitting measurements
|
X
|
|
|
X
|
|
|
|
Washout spectacles delivery
|
X
|
|
|
|
|
|
|
Study spectacles delivery
|
|
X
|
|
|
X
|
|
|
AL, CT, ACD and LT measurements
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
Cycloplegic autorefraction
|
X
|
|
|
|
X
|
|
X
|
Non-cycloplegic subjective refraction
|
X
|
|
|
X
|
|
|
|
DCVA
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
Data analyses
Baseline data analyses
For data showing normal distribution, paired-sample t-tests were used for within-subject interocular comparisons and independent-sample t-tests were used for between-group comparisons. For data showing non-normal distribution, equivalent non-parametric tests were used. Bivariate correlations were used to evaluate the relationships between outcome measures. As the inter-eye correlation for ocular parameters is high, only the right eye data were analyzed. Statistical analyses were performed using SPSS 16.0 (SPSS Inc., Chicago, IL, USA).
Prospective data analyses
The changes in spherical equivalent cycloplegic auto-refractive error and AL between the follow-up and baseline data will be used to evaluate myopia progression. Myopia progression and axial elongation will be compared between the SAL lenses and the single vision lenses using independent-sample t-tests. A multivariate regression model will be used to evaluate the relationships between variables such as age, gender, baseline myopia, parental myopia, NPC and phoria level, and myopia progression.