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Soft Contact Lenses with Positive Spherical Aberration for Myopia Control

Cheng, Xu; Xu, Jing; Chehab, Khaled; Exford, Joan; Brennan, Noel

doi: 10.1097/OPX.0000000000000773
Myopia Control

Purpose To determine whether soft contact lenses with positive spherical aberration (+SA) can slow myopia progression.

Methods Eligible subjects (N = 127, primarily Asian) aged 8 to 11 years were randomized to wear either control (spherical design) or test (with +SA) soft daily disposable contact lenses for a minimum of 1 and up to 2 years (treatment phase). Subjects from the initial cohorts (N = 82) were then followed for an additional 1.5 years while wearing a marketed spherical daily disposable contact lens (withdrawal phase). Axial length and spherical equivalent cycloplegic autorefraction (SECAR) were measured at baseline and every 6 months in both phases.

Results During the first year of treatment, lens type (test vs. control) had a statistically significant impact on axial elongation (p = 0.0409). Eyes wearing test lenses increased in length by 0.11 (65.3%) and 0.14 (38.6%) mm less than eyes wearing control soft lenses at 6 and 12 months, respectively (p < 0.05 at both time points). The principal control of axial elongation occurred during the first 6 months. Spherical equivalent cycloplegic autorefraction change from baseline was significantly less in the test cohort than the control cohort by 0.21D (54.0%) at 6 months (p < 0.05) but not at 12 months (0.14D, p > 0.05). Lens type was not overall a significant factor affecting refractive error change (p = 0.0677). After ceasing treatment, neither the rate of axial elongation nor change in SECAR was significantly different between the initial two cohorts.

Conclusions The soft contact lens with +SA slowed axial growth of the eye, although this did not translate into a sustained statistically significant effect on SECAR. The majority of the treatment effect occurred in the initial 6 months of wear. No evidence of rebound effect was observed after ceasing treatment.

*MD, PhD, FAAO

PhD

MS

§OD, FAAO

MScOptom, PhD, FAAO

Johnson and Johnson Vision Care, Inc., Jacksonville, Florida (XC, JX, KC, NB); and Korb & Associates, Boston, Massachusetts (JE).

Xu Cheng Johnson and Johnson Vision Care, Inc. 7500 Centurion Parkway Ste 100/W-2A, Jacksonville, Florida 32256 e-mail: XCheng6@ITS.JNJ.com

Recent research showed that the prevalence of myopia has increased at an unprecedented rate worldwide in the past few decades.1–9 Ocular pathologies associated with high myopia represent a clear and present public health risk10,11; they are quickly becoming an important cause of blindness worldwide.12–27

According to recent research, visual experience and retinal image quality may affect the eye's normal emmetropization process during postnatal maturation.28,29 Animal experiments indicate that axial length (AL) of the eye can be manipulated through imposing hyperopic and myopic retinal blur, which results in animals developing myopia and hyperopia, respectively.30–36 Clinical investigations show that subjects with myopia tend to have a more negative spherical aberration (SA) during near work (accommodation), resulting in a central hyperopic blur,37 and also tend to have a more hyperopic defocus in their peripheral fields than subjects with emmetropia or hyperopia.38–41

It is therefore hypothesized that hyperopic defocus, either in the central or peripheral retinal fields, might trigger excessive eye growth in humans, which results in myopia development and/or progression. Targeting relative central and peripheral retinal hyperopic defocus in young children with low or moderate myopic correction may help control further myopic progression.29,42–44

At present, there are no products that have been cleared by the U.S. Food and Drug Administration (FDA) for controlling myopia progression, although there is a soft contact lens that has been CE marked for related indications and is in use in limited international markets. Several studies have investigated soft contact lens technologies for their capacity to slow axial elongation and refractive error progression.45–48 Collectively, these studies suggest that soft contact lens technologies do indeed have the potential to slow the progression of myopia in pediatric subjects. If appropriately designed soft contact lenses can reduce the rate of myopia progression in children, then the long-term incidence and prevalence of subjects with high myopia may be reduced, thereby mitigating the current public health concern. To date, only one of the previous publications on soft contact lens technology for myopia control has been a bilateral-wear, controlled, double-masked, randomized, parallel-arm study.46 No previous publication has investigated rebound after removal of soft contact lens treatments.

Based on the above hypotheses and a related patent, we developed a soft contact lens with a positive SA (+SA) in the optical design to shift retinal hyperopic blur to the myopic direction. Inherent in such a design is that it also has the net effect of reducing relative peripheral hyperopia. The goal of our study was to evaluate the efficacy of this novel contact lens design for controlling myopia progression in school-aged children in a randomized, controlled, masked study and to investigate the potential for rebound after cessation of treatment. The two phases of the study are registered on ClinicalTrial.gov with the identifiers NCT01829191 (treatment phase) and NCT01829230 (withdrawal phase).

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METHODS

Declaration of Helsinki and Informed Consent

The study (both the treatment and the withdrawal phases) followed the tenets of the Declaration of Helsinki and was approved by the New England College of Optometry Institutional Review Board. Pediatric subjects and their parent(s) or legal guardian(s) were given ample time to ask questions and to make a decision regarding their participation in the study. Informed consent and assent were obtained from the parents and subjects after explaining the nature and possible consequences of the study.

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Study Design

The treatment phase study was a prospective, randomized, controlled, double-masked, bilateral-wear, parallel-arm study. Subjects were randomized into one of two cohorts. For the control cohort, subjects wore soft contact lenses with a standard optical design. In the test cohort, subjects wore soft contact lenses that were identical to those used by the control cohort except for +SA incorporated into the optical design that was intended to provide control of myopia progression. The impact of the treatment on AL and refractive error was monitored for up to 2 years.

The treatment phase was originally designed to include 2 years of follow-up of all subjects. Approximately 2 years after the first subject was enrolled, the study was terminated because sufficient data had been collected from concurrent internal studies of similar designs.49 There were no safety-related concerns that led to the decision to terminate the study. At the point of termination of the treatment phase, all subjects who were currently enrolled had completed at least 1 year of follow-up. These subjects were then invited to participate in the withdrawal phase, which was an open-label, continuation, observational study. After exiting the treatment phase, the control and test lenses were withdrawn and eligible subjects were evaluated at baseline and fit with marketed daily disposable contact lenses in both eyes. Subjects were then seen and monitored for myopia progression at 6-month intervals for 18 months. Both the subjects and investigators involved in gathering data in the withdrawal phase continued to be masked as to the initial treatment assignment in the earlier double-masked component of this investigation.

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Study Site

Data were collected at Korb and Associates in Boston, Massachusetts, between April 2008 and October 2011. Three investigators were involved in data collection. Two conducted lens fittings and provided ongoing care, and a separate masked investigator was responsible for refraction and AL measurements. The same investigators were responsible for the treatment and withdrawal phases of the study.

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Subjects

Eligible subjects were children aged between 8 and 11 years at the time of enrollment with no ocular or systemic pathology and no history of ocular surgeries or myopia control treatment. Eligibility criteria included a baseline refraction (by cycloplegic autorefraction) between −0.75 and −4.00D (inclusive) in sphere and 1.00D or less in cylinder in each eye, with 1.00D or less difference in spherical equivalent refraction between the two eyes. In addition, visual acuities of at least 20/25+2 and 20/25 in each eye with spherocylindrical refraction and best sphere refraction, respectively, were required.

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Contact Lenses

During the treatment phase, the control and test lenses were identical in material (etafilcon A with LACREON technology), diameter (14.0 mm), and base curve (8.5 mm) and were made using the same manufacturing process. The control lenses were FDA-approved, nonmarketed, daily disposable soft lenses with a conventional spherical optical design without +SA. The test lenses were identical to the control lenses in every aspect except that they were designed with aspheric front surfaces incorporating +SA. The level of +SA introduced to the lens' optical zone was about 0.175 μm (for a 5-mm-diameter aperture) across all lens powers, which was chosen to negate the negative SA that occurred in myopic subjects during accommodation (based on internal unpublished data).

During the withdrawal phase, all enrolled subjects were fit with the same currently marketed 1-DAY ACUVUE MOIST lenses. The 1-DAY ACUVUE MOIST lens did not have +SA and had the same optical design as the control lenses used in the treatment phase. All three types of study lenses were worn binocularly on a daily disposable basis.

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Procedures

In the treatment phase, eligible subjects were randomized with equal probability into one of two parallel cohorts within the specified age strata (8, 9, 10, and 11 years) and refraction-within-age strata (≤−2.00D, >−2.00D). Subjects were dispensed with study lenses after successfully completing the training on contact lens insertion and removal and safe wear practices and followed at 1 week, 1 month, and 6 months, then every 6 months thereafter for up to 2 years.

The primary endpoints of the study included change in AL and spherical equivalent cycloplegic autorefraction (SECAR) from baseline across time. Both AL and refraction were monocularly measured only in the right eye at baseline and at 6-month intervals during both treatment and withdrawal phases. Both measurements were performed at least 30 min after cycloplegia (one drop of 1% tropicamide and 1% cyclopentolate each, 5 min apart). Axial length was measured using the IOLMaster (Carl Zeiss Meditec). The mean of five measures was used in the statistical analyses. The SECAR was computed from cycloplegic autorefraction measured with an open-field auto-refractor (WAM-5500 by Grand Seiko Co., Ltd.). Three repeated measurements, each of which was the mean of three consecutive readings, were obtained at each visit. The median of three computed SECARs was used in the statistical analysis.

The prescription of the subjects was evaluated every 6 months during the course of the study. If there was a significant change in the subject's refraction (spherical equivalent refraction of ±0.50D or more) or decrease in visual acuity (to <20/30+2) in either eye, the prescription was updated. Meanwhile, ocular health of the subjects was monitored throughout the study. Slitlamp examinations were performed at each follow-up visit and were evaluated per the FDA's slitlamp classification scale.

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Statistical Analysis

All data from randomized subjects who had completed at least the 6-month follow-up visit were included in the primary analysis regardless of whether the subjects were later discontinued or considered “noncohort” because of protocol violation. The targeted minimum sample size for analysis was N = 32 per cohort who completed the trial. It was a conservative sample size estimate that was sufficient to detect a small treatment effect of 0.25D difference in refraction with a standard deviation (SD) of 0.35D. This was determined using a Type I error rate of 0.05 and a power of 80%. This sample size estimation assumed balanced recruitment by age over the range of 8 to 11 years (inclusive).

Endpoints for both the treatment and withdrawal phases of the study were change in AL and change in SECAR from baseline. Each phase of the study had its own baseline measures. During the treatment phase, both endpoints were summarized with means and SDs at each 6-month treatment interval up to 24 months. Because sample sizes dropped significantly at 18 and 24 months because of early termination of the treatment phase, inferential statistical analyses (i.e., the comparisons of endpoints between two study cohorts) were limited to the first year of treatment.

The analyses of the AL data and the SECAR data were carried out using a generalized linear mixed model (GLMM) that appropriately specified the covariance structure of the residual errors from the same subject at different time points of measurement and was adjusted for each subject's age, sex, baseline AL, baseline cycloplegic refraction, lens type, and lens type–by–time interaction as fixed factors. The least-squares mean (LSM) of the final model was used for statistical inference. The overall Type I error rate was 0.05 for each endpoint analysis (AL and SECAR). To preserve this rate through testing multiple hypotheses and evaluating the outcome at multiple time points within the group, a simulation-based approach was used to adjust the confidence intervals (CIs).50 For each endpoint in the study, the results were summarized by treatment cohort and period.

In addition to comparing the mean changes of AL and SECAR between the two cohorts, we also conducted a post hoc analysis of the distributions of axial elongation and refraction change in terms of magnitude of progression (i.e., fast or slow myopia progression) after 1 year of treatment. Based on a literature review on the rate of myopia progression in Asians, fast and slow myopia progression was arbitrarily defined as more than 0.75 and less than 0.50D per year, respectively, which was converted to more than 0.28 and less than 0.19 mm of axial elongation per year. This conversion was based on the rule of thumb of 1-mm axial elongation being equivalent to 2.70D of refraction change. Comparisons of progression distributions between the two cohorts were carried out with the χ2 test of independence. The GLMM was fitted with binary response (fast progressor and other) to estimate the odds ratio of being a fast progressor in the control group versus being a fast progressor in the treatment group.

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RESULTS

Study Subjects

Treatment Phase

A total of 174 subjects were screened for the study, 132 were eligible, and 127 subjects were randomized to receive either the control or the test soft contact lenses. Five eligible subjects were discontinued from the study before test lens assignment because of consent withdrawal (N = 4) and loss to follow-up (N = 1). Of the 127 randomized subjects, 59 (46.5%) were male and 68 (53.5%) were female; 115 (90.6%) were Asian (88.2% of all randomized subjects were Chinese) and 11 (8.7%) and 1 (0.8%) were white and Hispanic, respectively. Details of age and age distribution are presented in Table 1. Tests of homogeneity of baseline characteristics of the two cohorts are presented in Table 2 (excluding subjects who did not complete at least the 6-month follow-up). There were no statistically significant differences found in the demographics (i.e., age, sex, or ethnicity) or in the baseline AL or refraction between the two cohorts.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

During the entire course of the treatment phase, a total of 21 (17%) subjects were discontinued from the study, among which 14 (22%) and 7 (11%) were from the test cohort and control cohort, respectively. No subject discontinued because of unsatisfactory vision or physiological responses. A detailed description of reasons for discontinuation is provided in Table 3.

TABLE 3

TABLE 3

A total of 106 subjects were actively enrolled at the time of termination of the treatment phase: 56 in the control cohort and 50 in test cohort. These included those who either completed the 2-year follow-up visit or had been actively participating in the study for at least 12 months but had not yet reached the 24-month follow-up visit at the time the study was terminated. Sample size at each follow-up time point is described in Table 1. See Fig. 1.

FIGURE 1

FIGURE 1

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Withdrawal Phase

A total of 82 subjects were enrolled, and 77 subjects completed the withdrawal phase of the study. Of those who completed the withdrawal phase, 38 and 39 had been in the control and test cohorts, respectively, during the treatment phase (Fig. 1).

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Efficacy

Treatment Phase

Fig. 2 plots the mean and SDs of unadjusted axial elongation (change in AL) from baseline across the treatment period for both control and test cohorts.

FIGURE 2

FIGURE 2

Table 4 summarizes the GLMM for axial elongation during the first year of treatment. Lens type (test vs. control) was a statistically significant factor (p = 0.0409), indicating that the test lens did have an impact in slowing axial elongation. Predictably, time was also a statistically significant covariate (p < 0.0001), with the eyes increasing in length on average across time. The lens type–by–time interaction was not significant (p = 0.1501), suggesting that, although a separation between lens types was evident overall across the study, there was no statistically significant variation in this separation between the 6- and the 12-month time points. Age was also a significant covariate with axial elongation. As expected, increasing age was associated with decreasing axial elongation.

TABLE 4

TABLE 4

The LSM differences in axial elongation from baseline between study cohorts and their 95% CIs at the 6- and 12-month time points are provided in Table 5. The test cohort had significantly less axial elongation than the control cohort at each follow-up visit (p < 0.05 for each visit). Compared with the control cohort, the percentage reduction in axial elongation in the test cohort was 65.3% at 6 months and 38.6% at 12 months. One interpretation of these results is that the effect of the test lens in slowing axial elongation was isolated to the initial period (<6 months) of the study. Thereafter, this initial difference in axial elongation was maintained through month 12 but not significantly modified. Because of a significant decrease in sample size at the 18- and 24-month follow-up, statistical analyses were not performed on the data collected during the second year of the treatment phase.

TABLE 5

TABLE 5

The analysis of distributions of axial elongation indicated that, based on the definition of fast or slow progression stated in the Methods section, about 75% of the subjects in the control cohort were “fast progressors” and 11% were “slow progressors” (Table 6). This distribution was significantly different (p < 0.0001) from the test group, where 37% of subjects were “fast progressors” and 52 % of subjects were “slow progressors.” The analysis of odds ratio of fast progression between the two groups indicated that the odds of being a fast progressor in the control cohort was 7.68 (95% CI, 2.87 to 20.50) times that in the test cohort.

Fig. 3 plots the mean and SDs of unadjusted changes in SECAR across the treatment phase for both test and control cohorts.

FIGURE 3

FIGURE 3

TABLE 6

TABLE 6

The GLMM for change in SECAR during the first year of the treatment phase is summarized in Table 4. Baseline refraction was significantly correlated with progression in refractive error (p = 0.0010). The association of lens type (test vs. control) with SECAR was not statistically significant (p = 0.0677). Predictably, time was also a statistically significant covariate (p < 0.0001), with refractive error increasing on average across time. The lens type–by–time interaction was not significant (p = 0.4550). Age was also a significant covariate for SECAR, with an older age at baseline associated with slower increases in myopia.

The LSM differences in change in SECAR from baseline between study cohorts and their 95% CIs at the individual time points are provided in Table 5. The test cohort showed significantly less refractive error increase than the control cohort at the 6-month visit (p < 0.05) but not at the 12-month time point. Again, because of the early termination of the study, sample sizes of both cohorts dropped to less than what was required (i.e., N = 32) to detect any difference in SECAR between two cohorts during the second year of the treatment phase. Therefore, statistical analyses were not performed for the 18- and 24-month SECAR data.

Despite the lack of statistically significant difference in the means of SECAR change between the two cohorts at 1 year, the analysis of the distributions of fast and slow progressors in the two cohorts indicated that the two distributions were significantly different (p = 0.0338) (Table 6). About 40% of subjects in the control cohort were fast progressors compared with 21% in the test cohort. The odds of being a fast progressor in the control group was 2.83 (95% CI, 1.09 to 7.36) times that in the test cohort.

As part of a series of post hoc analyses, the impact of lens wear time on the test lens' myopia control efficacy was examined. First, it was found that there was no significant difference in lens wear time between the two cohorts. Second, the regression analyses of axial elongation and SECAR change against lens wear time indicated no significant correlation between myopia progression and wear time (p > 0.05 for both AL and SECAR) for both test and control groups. The R2 values were small for both axial elongation (control, R2 = 0; test, R2 = 0.075) and SECAR change (control, R2 = 0.004; test, R2 = 0.03). Finally, lens wear time was introduced to the GLMM models as a covariable for both axial elongation and SECAR change. Lens type–by–wear time interaction was found to be an insignificant factor for predicting either axial elongation or refraction change. Note that the majority of our subjects (95%) had an average daily wear time between 10 and 15 hours, which does not lend a sufficient range to detect the impact of lens wear time on the test lens' treatment efficacy.

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Withdrawal Phase

Baseline demographics of the withdrawal phase are provided in Table 7. Sample sizes at the follow-up visits are also listed in Table 7.

In Table 8, the GLMM indicated that, for axial elongation, lens type was not a significant factor (p = 0.796) and neither was lens type–by–time interaction (p = 0.793), which means that there was no significant difference in overall axial elongation during the withdrawal phase between the two cohorts. Time (p < 0.0001) and age (p < 0.0001) were significant factors for predicting axial elongation. Here again, the older the child was at baseline, the less the axial elongation that he or she experienced during the withdrawal phase of the trial. Axial length at the end of the treatment phase was a significant predictor for axial elongation, and the longer the AL was at the second baseline, the greater the axial elongation at the end of the withdrawal phase.

TABLE 7

TABLE 7

TABLE 8

TABLE 8

The LSM differences in axial elongation from baseline between the two cohorts are shown in Table 9. Consistent with results from the GLMM, the difference in axial elongation between the control and test cohorts was not statistically significant at any of the three follow-up visits.

TABLE 9

TABLE 9

The GLMM model (Table 8) indicated that baseline refraction was not a significant factor and is therefore removed from the final model and not included in the table, whereas baseline AL was a significant factor (p = 0.005) and was included in the statistical model for adjustment. Based on the coefficient estimate, the longer the AL was at the second baseline, the greater the myopia progression. Meanwhile, neither lens type nor lens-by-time interaction was a significant factor in predicting change in refraction.

Least-squares mean analysis of SECAR changes during the withdrawal phase indicated that, at the 6-month visit, there was a small, but statistically significant, difference (test – control) between the two cohorts, favoring the test cohort by 0.124D (Table 9). A slightly smaller difference (0.121D) was identified at the 18-month visit. At 12 months, the difference was even smaller (0.113D) and not significantly different (Table 9). These results suggested that the change in refraction across time was not significantly different between the two study cohorts during the withdrawal phase.

In the withdrawal phase, after cessation of investigational lens wear, there were no significant differences in either axial elongation or SECAR change between the prior control and the prior test cohorts. Although the change in refraction appeared to be smaller in the test cohort during the withdrawal phase, the difference was not more than 0.25D, the prespecified boundary of clinical significance across the 18-month follow-up period of the withdrawal phase.

Because of early termination of the treatment phase, interpretation of data at each follow-up visit in the withdrawal phase is somewhat challenging because the baseline of the withdrawal phase of the study was derived from subjects treated for a variable interval during the treatment phase of the double-masked study. Nonetheless, all eligible subjects wore the test article for at least 12 months before entry into the withdrawal phase, and the average length of wear and the frequency distributions of treatment durations between cohorts were similar (Pearson χ2 test of independence, p = 0.169). To address this limitation, treatment duration was first included in the GLMM efficacy analysis. It was found that lens type–by–treatment duration interaction was not a significant factor for predicting change in AL (p = 0.231) or SECAR (p = 0.054). In addition, statistical analysis was repeated on the 82 subjects who participated in both phases of the study to investigate their rate of myopia progression (defined as the slope of the linear fit of axial elongation and SECAR change) during the treatment and withdrawal phases. The results (Fig. 4) showed that the rate of axial elongation was statistically different between the two cohorts during the treatment phase, whereas it was not statistically different during the withdrawal phase. This is evidenced by a statistically significant lens type–by–time interaction term during the treatment phase (coefficient estimate, −0.001; 95% CI, −0.002 to −0.001; p = 0.001) and a nonstatistically significant lens type–by–time interaction term during the withdrawal phase (coefficient estimate, 0.000; 95% CI, −0.001 to +0.001; p = 0.646). Meanwhile, the difference in the rate of SECAR change was not statistically significant in the 82 subjects during either the treatment phase (p = 0.072) or the withdrawal phase (p = 0.074). The coefficient estimates of the lens type–by–time interaction term were 0.002 (95% CI, −0.000 to 0.004) and 0.002 (95% CI, −0.000 to 0.003) during the treatment and withdrawal phases, respectively.

FIGURE 4

FIGURE 4

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Safety Evaluation

Treatment Phase

Among the 127 randomized subjects, there were a total of four ocular adverse events (AEs) involving two subjects (1.6%) that were reported during the course of the treatment phase. Of these, two were from two eyes of one subject in the control cohort (contact dermatitis) and two were from two eyes of one subject in the test cohort (allergic conjunctivitis). All AEs were classified as nonsignificant and were deemed unlikely to be related to wearing the study contact lenses. All AEs were followed to resolution, and both subjects completed the study per protocol. There were no unanticipated adverse device effects and no loss of best corrected visual acuity reported.

Grade 3 and higher slitlamp findings using the FDA slitlamp classification system were considered clinically significant; there were no grade 3 slitlamp findings throughout the conduct of the study.

One incident of grade 2 corneal neovascularization was observed in one eye in the control cohort at a single (6-month) follow-up visit.

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Withdrawal Phase

Among the 82 enrolled subjects, there were a total of two ocular AEs involving allergic conjunctivitis in both eyes of one subject (1.2%). In addition, there was one nonocular AE, a bone fracture, reported during the course of the study. All three AEs were found in subjects who were in the test cohort during the double-masked study. Both ocular AEs were classified as nonsignificant, and the relationship to the study contact lens was “remote (unlikely).” There were no unanticipated adverse device effects reported in this study.

There were no slitlamp findings of grade 3 or higher throughout the course of this phase of the study.

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DISCUSSION

The intent of the novel soft contact lens design used in this study was to correct retinal hyperopic blur caused by negative SA during accommodation. To examine the success of this goal, lens-on-eye wavefront aberrations or, more specifically, lens-on-eye SAs with and without accommodation were monitored throughout the course of the study. The results (to be published in a subsequent article) indicated that lens-on-eye SA with the test lens closely matched the expected result when adding together the SA of the eye and lens. Optical modeling shows that the introduced +SA also has the net effect of reducing relative peripheral hyperopia. We, therefore, measured off-axis refraction at ±25° along the horizontal meridian of the retina and made comparisons between the two cohorts. The results (to be published in a subsequent article) showed that the test lens introduced a myopic shift in relative off-axis refraction at the temporal 25° field of the subjects' retina, which was significantly more negative than with the control lens. The relative off-axis refraction at the nasal 25° field remained hyperopic and was not significantly different from that of the control lens. We hypothesize that the asymmetric impact on off-axis refraction of the test lens may be caused by lens decentration on the eye. Overall, these findings were consistent with the intended design of the test lens for the control of myopia progression. Further investigation of the data will focus on establishing associations between such lens-on-eye optical performance and myopia control effect.

Another consideration of a soft contact lens with a relatively large amount of +SA is its impact on visual performance. Therefore, logMAR visual acuity (measured at 4 m with the Early Treatment Diabetic Retinopathy Study charts by Precision Vision) was monitored throughout the study. The results indicated that, during initial lens fitting and dispensing, monocular distance visual acuity with the test lens was 0.06 ± 0.062 logMAR (mean ± SD), which was about one-half a line worse than that of the control lens (0.00 ± 0.076). However, during subsequent follow-up visits, there was no significant difference in visual acuity between the two cohorts. It appeared that visual acuity deteriorated in both study cohorts presumably because of undercorrection as a result of myopia progression, and the difference in visual acuity between the two cohorts diminished across time throughout each of the 6-month dispensing interval until the lens prescription was updated. Meanwhile, the study was designed to evaluate each subject's acceptance of vision before lens dispensing so that subjects who deemed their study lenses to be unacceptable were not dispensed with study lenses. During the entire course of the study, no subject discontinued because of unacceptable vision. It appeared that, although visual acuity with the test lens was not optimal compared with conventional single-vision lenses, monocular vision of the subjects on average was about 20/25, which would not be expected to affect activities of daily living. We also hypothesize that, since myopia usually progresses in 8- to 13-year-old children with conventional correction, these children may constantly experience some degree of blurry vision because of undercorrection until the prescription is updated, which was shown in the current study. This may explain why an average of 20/25 monocular vision was “acceptable” to the study subjects and no subject discontinued from the study because of unacceptable vision.

Despite the significant slowing in axial elongation induced by the test lens (e.g., a 65.3% and 38.6% slowing of axial elongation after 6 and 12 months of treatment, respectively), this slowing of axial elongation was not manifest as a clinically significant reduction in progression of myopic error, that is, the change in myopic error was less than 0.25D within the first year of treatment. The difference between the change in axial elongation and the change in refractive error could be attributable to the fact that the overall treatment effect was relatively small within the first year, that is, a 0.14-mm difference in axial elongation after 1 year of treatment. Another possibility is that the signal generated by the IOLMaster was more robust, with a repeatability of 30 to 40 μm compared with the WAM-5500 with reported repeatability of 0.11 to 0.21D under cycloplegic conditions.51,52 Finally, there might be a true “mismatch” of reduction in SECAR change compared with AL change because of some kind of “compensatory” mechanisms from other optical components of the eye. Although, in this study, we measured corneal radius of curvature (K values from the auto-refractor) and corneal topography, there were no significant differences in corneal curvature between the two study cohorts. Future studies may consider including measures of other optical metrics of the eye, including anterior chamber depth and lens curvature and thickness, to investigate the apparent discrepancy in myopia control efficacy between AL and SECAR further.

To the extent that the current design slowed axial elongation of the eye, our results confirm the findings of similar studies that have found that soft contact lens technologies can slow the progression of myopia. Table 10 summarizes the efficacy findings of these studies for both AL and refractive error. Various methodologies have been used in these studies, and they may be of importance in interpreting the findings.

TABLE 10

TABLE 10

Anstice and Phillips45 used a contralateral-eye design in which test and control lenses were worn simultaneously in each subject. Although sympathetic eye effects are generally considered to be minor in terms of refractive development, even a small level of interdependence between eyes could have a significant impact on the apparent treatment effect. Sankaridurg et al.47 used a control group from a separate study with participants who wore spectacle lenses. Although this separate study was also prospective and randomized, it is unclear how the separation of the studies in which test and control devices were worn may impact the outcome. In their 2013 article, Walline et al.48 used a historical control group of contact lens–wearing subjects and matched these to their treatment group by age and sex. It is unclear how the lack of randomization of the subjects and the execution of the study under separate protocols might have impacted the results. The study design most similar to the one we have used was conducted by Lam et al.,46 in that it was randomized, controlled, and double masked and of 2 years' duration.

Data shown in Table 10 also indicate that there appeared to be a reduction in the treatment effect across time. It is not immediately apparent from the data if the trend toward a reduced effect across time is real, a factor of the study designs, or inherent random variation. In the study of Lam et al.,46 there was little evidence of a reduced effect across time, although the general magnitude of the effect is relatively modest compared with the other studies. In the current study, the apparent extent of myopia control varied considerably depending on the parameter considered and the time point. At 6 months, the reduction in axial elongation and refractive progression was at the higher end (65.3 and 54.0%, respectively) compared with results from all studies of soft lens technologies (Table 10). Although the apparent impact on axial elongation remained at what might be considered a clinically important level (38.6%) at the 12-month time point, the reduction in refractive error progression of 20.2% was not statistically significant and is unlikely to be considered clinically significant. This substantial change occurred despite the sample size remaining robust for this time point (N = 57 and N = 52 for the control and test cohorts, respectively). Case analysis showed that this finding could not be attributed to outliers.

Although no statistical analyses were performed during the second year of the treatment phase, because of a significant reduction in sample sizes, based on the unadjusted means of change in AL and SECAR at the 18-month follow-up visit, myopia progression was 34.7% less (change in AL) and 34.3% less (change in SECAR) in the test cohort compared with the control cohort. The lack of effect shown at 24 months does need to be considered against the background of the small sample size at this time point. The apparent swings in effect on refractive progression do not appear to be caused by seasonal effects because subjects were enrolled fairly evenly during a 12-month period.

Another interesting feature observable in Table 10 is that the reduction of axial elongation brought about by the test lenses is of greater magnitude than the reduction in refractive progression for all time points in all studies except Walline et al.48 The size of this effect is 22% on average including the Walline data or 30% excluding the Walline data during 1 year of treatment. Again, it is unclear whether this effect is real, but it is certainly worth tracking in future studies, particularly where myopia control with soft lenses is compared against orthokeratology, where AL is the only viable parameter for tracking refractive development.

Furthermore, the choice of control lens remains a matter of debate. Of the five studies on controlling myopia progression with soft contact lenses, four, including the current study, used conventional soft contact lens as the control, whereas only one used the spectacle lens. A spectacle lens control has the advantage of being the standard of care for correcting myopia in most children in the targeted age range. Reporting of results from a spectacle-wearing control group raises issues as to whether factors other than the optical component of soft lenses for myopia control may impact refractive development.

Although there have been reports that have not found statistically significant differences in progression of myopia between spectacle- and contact lens–wearing groups, such studies have not tested for equivalence per se. Small differences such as those observed by Walline et al.53 may have considerable impact when assessing the relatively small differences between treatment and control cohorts in myopia studies.

In this study, we did not find evidence indicating that there was a rebound effect after subjects ceased wearing the novel soft contact lens for myopia control. Rebound has been observed with studies using atropine for myopia control.54,55 There has been no conclusive evidence in the literature indicating that withdrawal of optical treatments in humans results in accelerated myopia progression; however, the magnitude of effect and the sensitivity of study designs to measure an effect should be kept in mind. Consistent with the finding of this study, Berntsen et al.56 reported no rebound effect after subjects were treated with progressive addition lenses. Most recently, Swarbrick et al.57 reported more rapid growth in eyes after ceasing orthokeratology treatment in a contralateral crossover study (N = 24), although, with a similar study design, no obvious acceleration of eye growth or refraction change were found in eyes treated with “dual-focus” soft contact lenses.45 Possible differences observed between optical and pharmacological might be explained by different modes of action in controlling myopia progression. Continued research is warranted to further the understanding of mechanisms of myopia control through different treatment methods.

There are a number of limitations to this study. Although the control lens used was made of the same material and the same manufacturing process, and with the same diameter and base curve as the investigational lens, because of the +SA in the design of the lens, the visual performance of the test lens was not optimal compared with the control lens, which had the conventional spherical design. Therefore, visual acuity measurement during experimental sessions may have given some clue to the investigator as to the identity of lenses being worn. This was mitigated by using a different masked examiner to measure the primary endpoints and performing a lens prescription update.

In addition, the control contact lens had a conventional spherical optical design. Inherent in spherical soft contact lens optics is a small amount of negative SA, which varies in magnitude with the power of the lens. This negative SA could have introduced a small confounding effect; a lens with zero SA would be the ideal control against which to test the technology used here.

Another limitation of the study is that not all of the patients randomized into the two cohorts at baseline of the treatment phase were followed through to their 24-month completion date per protocol. As stated, the study was terminated early, although not because of any safety-related concerns. This means that the sample size of the two cohorts was largest at the month 6 visit and progressively decreased visit by visit; the sample size of each cohort at month 24 of the treatment phase was about 80% smaller than on the month 6 visit. As a result of the progressively decreasing sample size, statistical analyses were not performed at months 18 and 24. Therefore, data during the second year of the treatment phase presented in this article should only be treated as exploratory and be interpreted as inconclusive.

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CONCLUSIONS

In this study, we found that soft contact lenses with +SA slowed axial elongation of the eye, thereby showing potential in controlling myopia progression. After cessation of test lens wear, subjects showed no signs of a rebound effect. Despite control of axial elongation with the current lens design, the magnitude of this effect did not translate into a sustained statistically significant reduction in refraction change, which we consider requisite for the lens to be clinically viable. Future designs should focus on methods to allow achieving a larger treatment effect, which may include increasing the magnitude of +SA in the lens design while minimizing its visual impact.

Xu Cheng

Johnson and Johnson Vision Care Inc.

7500 Centurion Parkway Ste 100/W-2A

Jacksonville, FL 32256

e-mail: XCheng6@ITS.JNJ.com

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ACKNOWLEDGMENTS

Trial Registration: CR-1561 AD-NCT01829191; CR-1561AF-NCT01829230.

Presented at the 14th International Myopia Conference in 2013 at Asilomar, California.

Xu Cheng, Jing Xu, Khaled Chehab, and Noel Brennan are all paid employees of Johnson and Johnson Vision Care, Inc. Joan Exford of Korb & Associates is a contract principal investigator paid by Johnson and Johnson Vision Care, Inc.

We thank Dr. Jichang He of New England College of Optometry and Dr. Victor Finnemore of Korb & Associates for collecting data for the study and Dr. Myles Jaffe of Innova Medical Communications, LLC, who is a contract medical writer paid by Johnson and Johnson Vision Care, Inc. for preparing this manuscript.

Received April 1, 2015; accepted September 24, 2015.

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Keywords:

axial length; myopia control; myopia progression; positive spherical aberration; soft contact lens

© 2016 American Academy of Optometry