A randomized clinical trial of photobiomodulation therapy combined with continuous microlens radial array lenses for myopia control in children

A randomized clinical trial of photobiomodulation therapy combined with continuous microlens radial array lenses for myopia control in children | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A randomized clinical trial of photobiomodulation therapy combined with continuous microlens radial array lenses for myopia control in children Ying Li, Kaikai Qiu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7023715/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Purpose To assess the clinical efficacy and safety of photobiomodulation therapy (PBMT) combined with continuous microlens radial array (CMRA) lenses in controlling myopia progression. Methods This study was designed as a prospective, randomized, double-blind, controlled clinical trial. We enrolled a total of 220 myopia aged 6–13 years. Participants were randomly assigned in a 1:1:1:1 ratio to one of four groups: Group PBMT + CMRA, Group PBMT + single vision spectacles (SVS), Group CMRA, and a control group with SVS. The primary outcomes were cycloplegic refraction and axial length (AL), measured at baseline and 6-month follow-up, using a PBMT device with a 650 nm low-intensity laser diode (0.20 mW irradiance). Results A total of 159 myopic children completed the 6-month study and were included in the final analysis. The mean axial length (AL) changes were − 0.02 ± 0.13 mm, -0.06 ± 0.38 mm, + 0.18 ± 0.07 mm, and + 0.26 ± 0.19 mm across the four groups, respectively, with a statistically significant intergroup difference (P < 0.001). No treatment-related adverse events were observed. Conclusions PBMT + CMRA demonstrated superior efficacy in controlling axial elongation compared to PBMT + SVS, CMRA, or SVS alone (P < 0.001). This combination therapy represents a promising non-pharmacological strategy for mitigating myopia progression in pediatric populations. Trial Registration NCT05756959, registered on 09/03/2023. Photobiomodulation Myopia Children Randomized clinical trial Figures Figure 1 Figure 2 Introduction Laser technology, particularly Class III lasers, is known to pose risks to the eyes if gazed at directly for an extended period. 1 Traditionally, AL in children is believed to either elongate or stabilize during growth, 2 with any shortening being attributed to measurement errors or daily fluctuations. However, research on photobiomodulation therapy (PBMT) has contradicted this belief, demonstrating its potential to manage myopia by slightly shortening axial length (AL) over time. 3 – 5 This has gained traction in clinical studies in China over the last five years. PBMT employs low-intensity laser (0.20–2.5 mW) therapy, which has been shown to effectively control myopia, resulting in 0.01–2% shortening of AL after one month to a year of treatment for 20–50% of myopic eyes. 3 – 6 The treatment involves using red light with a wavelength of 650 nm, applied to the central retina for three minutes, twice daily. The efficacy of photobiomodulation therapy (PBMT) may depend on illuminating the central retina, particularly the macular fovea, rather than the peripheral retina. However, this could pose risks of thermal and photochemical damage to the fovea. 7 – 8 Maximum permissible exposure (MPE) calculations from two PBMT devices have addressed these safety concerns. 9 Current myopia control interventions like peripheral defocus lenses and orthokeratology have limitations. A study found that combining PBMT with orthokeratology can enhance myopia control when orthokeratology alone is insufficient. 10 Therefore, we have conducted this clinical trial to access whether combining PBMT with continuous microlens radial array (CMRA) lenses offers superior myopia control outcomes compared to either intervention alone. CMRA lenses consist of 500 micro-lenses with + 2.00D to + 4.00D focus, designed to redirect part light from the central to peripheral retina, potentially slowing myopia progression. To our limited knowledge, it was the first prospective, randomized controlled clinical trial, to evaluate the efficacy of lighting the peripheral retina with PBMT + CMRA against lighting the central retina with PBMT + single vision spectacles (SVS), CMRA alone, or SVS alone. Our hypothesis was that it would be significant better or not worse with combing therapy (PBMT + CMRA). Methods Study design and setting This prospective, randomized, parallel, controlled clinical trial of children with myopia was conducted from December 2022 to August 2024 at one hospital in Xuzhou, China. All eligible subjects in this study were randomized at an allocation ratio of 1:1:1:1 into the PBMT + CMRA group, PBMT + SVS group, CMRA group and SVS group, following the treatment schedule of 3-min exposures,≥4-h spacing between twice-daily treatments, 5 days per week. This randomized clinical trial was carried out in accordance with the ethical principles stipulated in the Declaration of Helsinki. The study protocol and informed consent were reviewed and approved by the Institutional Review Board (IRB) of Xuzhou Medical University Affiliated Xuzhou Municipal Hospital prior to its initiation (IRB #xyyll [2023] 002) on January 13, 2023. Subjects were recruited at Xuzhou Medical University Affiliated Xuzhou Municipal Hospital in line with the IRB standard for recruitment practice. Written informed consent and verbal consent were provided by a parent/legal guardian and the subject. before the start of the study. This trial with protocol is registered with ClinicalTrials.gov, number NCT05756959. Eligibility criteria Eligible patients were diagnosed as myopia through cycloplegic refraction and met the following inclusion and exclusion criteria: Inclusion criteria included that written informed consent was obtained from the child and the legal guardian; Children aged 6 to 13 years old; The spherical equivalence diopter (SED) after cycloplegia was between − 5.50D to -0.50D; Astigmatism was of 1.50D or less; The best corrected visual acuity (BCVA) was 0.8 (decimal record) or better; Anisometropia was of 1.50D or less; No other myopia interventions during the study period. Exclusion criteria included ocular lesions affecting vision or diseases (such as cataract, glaucoma, macular pathology, cornea lesions, uveitis, retina detachment, congenital optic abnormalities, etc.); Halo, glare, attention deficit and hyperactive disorder, psoriasis. Systemic diseases such as immune diseases, central nerve system disorders, Down syndrome, asthma, severe cardiopulmonary abnormalities, severe liver and renal dysfunctions; Squint, ocular lesions or acute inflammation; Other myopia control interventions within the recent 3 months, including atropine, devices, orthokeratology, soft lenses, and multi-focus spectacles. Randomization and masking After verifying eligibility and obtaining consent, eligible subjects were randomly allocated in a 1:1:1:1 ratio to either the intervention group (PBMT + CMRA, PBMT + SVS, CMRA) or the control group (SVS). Treatment allocation was completed by the investigators and the statistical expert (unmasked) using closed sealed envelopes which had randomized numbers printed on them by the investigators. Randomization was facilitated by a computer-generated sequence using simple randomization, with Software R (version 4.3.1; The R Foundation for Statistical Computing, Vienna, Austria)by a statistician who was not involved in subject recruitment or data collection. Only one investigator, aware of the study allocation, was responsible for group allocation and device-dispensing. Intervention Subjects in the intervention groups received PMBT + CMRA, PBMT + SVS, CMRA only, respectively while the control group received the SVS only. Both PBMT groups follow the PBMT with 3-min exposures and ≥ 4-h spacing between twice-daily, 5 days weekly treatments. The PBMT device was a desktop light therapy device, BSJ-B3 (Eye power illuminator, Changchun, China), which has obtained approved by national medical product administration as Class II medical device with the approved code of JiXieZhuZhun 20212160371. The light power entering a 7 mm pupil (the standard pupil size according to ISO GB 7247.1–2012, not the actual pupil size during therapy) is 0.20 mW/m 2 for PBMT device. The irradiance is the lowest among all the approved lists. Subjects were asked to look directly at the red light binocularly for each session of PBMT, which was under the supervision of their parent/legal guardians. At enrollment, randomized assignments were recorded in an electronic data entry system, ensuring blinding for both subjects and investigators post-assignment. Outcome The primary endpoint was the change in AL at Month 6, analyzed using the last observation carried forward (LOCF) method. Secondary endpoints included change in spherical equivalence diopter (SED), best-corrected visual acuity (BCVA), and the incidence of adverse events (AEs). All parameters were assessed at baseline, Month 3, and Month 6. A protocol amendment implemented post-trial initiation led to the exclusion of accommodation and binocular function measurements from endpoint analyses to reduce screening-related costs. Refraction was performed three times using an antorefractor (KR-800, Topcon, Tokyo, Japan) after cycloplegia, which was achieved using 3 drops of 1% tropicamide Compound eyedrop (Shiqi, Shenyang, China) to each eye at 0, 5, 20 minutes, respectively. Refraction measurements were taken 10 minutes after the third drop of compound tropicamide eyedrop if full cycloplegia was obtained. Spherical equivalent refraction (SER) was calculated as spherical power plus half of the cylinder power according to the final subjective trial lenses during the cycloplegia. AL was measured using partial coherence interferometry AL-SCAN (NIDEK Co., Ltd, Japan). Three readings were taken and averaged. Distance BCVA in logarithm of the minimum angle of resolution (logMAR) was assessed by trained optometrists using the most common Chinese standard logMAR visual acuity chart according to GB11533-2011 (Danyang Hualong Medical Devices Co., Ltd, Danyang, China). Adverse events Children who conducted any mentioned therapy for at least once were analyzed for safety. At each follow-up visit and any unplanned visits if needed, children and their parents were asked about any AE and checked their fovea by optical coherence topography(OCT)to detect any lesion. They were also specifically asked about dazzling, short-term glare, flash blindness, and afterimages following treatment, and whether children had been ill or hospitalized since the last visit. All AEs and OCT examinations were documented and a final determination of the AE related to above mentioned treatment was analyzed by the investigators and associated researchers. Sample size Sample size calculations were based on a Type 1 error rate of 0.05 and 80% power, with an effect size of 1.0. The anticipated change in AL at the primary endpoint from PBMT + CMRA was 0.00 mm for the intervention group and 0.20 mm for the SVS group, with a standard deviation of 0.20 of both groups. Adjusting for 20% loss to follow-up yielded at least 20 subjects in either group, respectively, or a total sample size of 80 participants. Statistical analyses All data were analyzed based on intention-to-treat principles. Data from subjects who participated in at least one follow-up visit were included in the present analysis. Missing data on the primary outcome (change of AL at Month 6) were imputed based on the last observation carried forward. Mean ocular parameter values were calculated from the right eye of each subject. The one-way ANOVA test and independent t-test were both used to test group differences in continuous data; For parameters among 4 groups, ANOVA was first considered while for only t-test was used between 2 groups. Chi-square tests were used to assess inter group differences in categorical variables. Adjusted for age, gender, and baseline values. We used SPSS (Version 22, IBM Corp. USA) for statistical analyses. All statistical tests were tow-sided and were performed at the 5% significance level. Estimated effect [r] was evaluated with Cohen d. Results A total of 220 participants were recruited into the study between January 14, 2023 and August 5, 2024 and were randomly assigned to receive PBMT + CMRA (n = 55), PBMT + SVS (n = 55), CMRA (n = 55), or SVS (n = 55) intervention. At last 6-month visit, the completed participants of four groups were 55, 27, 22 and 55, respectively (Fig. 1). Baseline characteristics At baseline, no significant difference in AL, spherical equivalent refraction (SER), age, gender or other ocular parameters, including best-corrected visual acuity (BCVA), were observed among the four groups (all P > 0.05), as presented in Table 1. Primary outcome The change in AL at 6 months from baseline were statistically significant among four groups (P = 0.001; Table 2, Fig. 2). The mean change in AL was negative in Group PBMT + CMRA (-0.02 ± 0.12mm) and positive in Group PBMT + SVS (+ 0.08 ± 0.36mm) ; Significantly differed between them (Cohen d: 0.07, estimated effect size[r]: 0.03, P = 0.012). Neither difference was found between Group CMRA (0.15 ± 0.07 mm)and Group SVS (0.25 ± 0.11 mm, 95% confidence interval [CI]:0.07, 0.23mm༉ ༈P = 0.984༉. While Group PBMT + CMRA had both significant less change in AL at 6 months than that of Group CMRA (Cohen d: -2.05, estimated effect size[r]: -0.72, P < 0.001), or Group SVS (Cohen d: -1.41, estimated effect size[r]: -0.57, P < 0.001). Secondary outcome The mean change in SER at 6 months differed significantly among the four groups (P = 0.001, Table 2); Only Group CMRA (-0.64 ± 0.24D)significant minus was found between the PBMT + CMRA group (-0.01 ± 0.41D,, P < 0.001) and the PBMT + SVS group (-0.14 ± 0.30D, P = 0.004); No significant difference was observed among other groups (Table 2). At the 1-month and 3-month follow-up, the change in AL was significantly different among the four groups (P = 0.003, P = 0.001, Table 2, Fig. 2). At the 1-month follow-up, the mean change in AL was significantly different between Group PBMT + CMRA and Group CMRA (-0.04 ± 0.09 mm vs -0.01 ± 0.05 mm, P = 0.002), Group PBMT + CMRA and Group SVS (-0.04 ± 0.09 mm vs 0.02 ± 0.05 mm, P = 0.047), and Group PBMT + SVS and Group CMRA (-0.01 ± 0.05 mm vs 0.05 ± 0.06 mm, P = 0.012). No significant difference was found between Group PBMT + CMRA and Group PBMT + SVS (P = 0.205) or between Group PBMT + SVS and Group SVS (P = 0.200). At the 3-month follow-up, the mean AL change was significantly different between Group PBMT + CMRA and Group SVS (P = 0.020) as well as between Group PBMT + CMRA and Group CMRA (P < 0.001). No significant differences were observed among Group PBMT + SVS, Group CMRA, and Group SVS (P = 0.075, P = 0.200, P = 0.316) or between Group PBMT + CMRA and Group PBMT + SVS (P = 0.068). At the final visit, the mean (SD) distance best-corrected visual acuity (BCVA) (P = 0.712) and uncorrected visual acuity (UCVA) (P = 0.605) were comparable across all four groups. Adverse events No severe or mild adverse events (AEs) were reported across any follow-up assessments for all participants. Notably, only one incident of a CMRA lens being accidentally broken was reported; however, this caused no harm to the participant. Discussion In this randomized, controlled clinical trial, PBMT + CMRA reduced myopia progression by 0.15m、0.18mm and 0.29D、0.16D over 6 months when compared against Group SVS, respectively. And there was no reported AE. This result provided the new evidence for combining therapy of PBMT with CMRA as well as PBMT with SVS as the efficacy and safe options. First PBMT with the least irradiance This study utilized PBMT with the lowest irradiance among all approved light-based therapeutic devices in China. Combining PBMT with CMRA (a myopic defocus lens designed to direct 50% of light defocus to the peripheral retina) was found to be significantly more effective than using CMRA or SVS alone. Even when PBMT was used with SVS, the myopia control efficacy was significantly better than with CMRA alone. The mean change in AL over 6 months in PBMT group was consistent with previous studies. 3 – 6 , 10 – 12 However, some studies reported different irradiance values based on 1600 lux measurements. Calculations through 4 mm pupils indicated an irradiance of 2.0 mW/m² at a 7 mm pupil size according to GB7247.1-2012, which translates to 0.29 mW/m² at a 4 mm pupil size. It should be noted that the exact pupil size during illumination is approximately 2.0 mm.Moreover, combining CMRA—a type of myopic defocus lens—with PBMT yielded significantly better myopia control outcomes than using CMRA alone. Traditional myopia control interventions, such as DIMS, 13 orthokeratology, 14 MiSight, 15 and low-concentration atropine (0.01–0.1%) , 16 primarily aimed to slow axial elongation, yet progression still occurred. Notably, 1% atropine stands out as an exception in this context. 17 Combining therapy had similar efficacy The non-significant differences in AL and SER change between the PBMT + CMRA group and the PBMT + SVS group might be attributed to the limited sample size and the relatively short - term follow - up of 6 months. Similarly, the same might apply to the nonsignificant differences between the CMRA group and the SVS group. However, when illuminating the peripheral retina using CMRA during PBMT with a very low irradiance of 0.20 mW/m², the safety of PBMT could be further enhanced. This approach may lead to a reduction in adverse events (AEs) in long-term studies involving large sample sizes, particularly among younger participants. Safety Profile Importantly, the study reported no deaths or serious adverse events (AEs), indicating a favorable safety profile for the PBMT and CMRA interventions. This finding is consistent with previous findings and highlights the tolerability of these interventions in pediatric populations. Limitations This study has several limitations. Firstly, it was a small sample size study. The sample size was determined based on the primary outcomes and might lack statistical power for the exploratory and secondary outcomes. Therefore, caution is necessary when interpreting the results of these analyses, particularly those of AE analyses. Secondly, we had unmasked participants as PBMT and CMRA have obvious identifiable appearances, respectively. Additionally, the assessment of mild adverse events was not conducted in the study; But we had corrected all follow-up images (including all baseline and follow-up optical coherence topography for all groups) and all the images were normal. Nevertheless, the rates of reported after-images of PBMT, temporary vision disturbances, and dizziness were similar across both PBMT groups since the PBMT irradiance was too low (0.2mW) to alarm children and their parents to pay attention. Thirdly, the study population was homogeneous in that the participants were all Chinese. Thus, the generalizability of the results to other populations would be limited, especially for individuals with different iris pigmentation and education backgrounds. Fourthly, as this was a single-center study, external validation involving multiple centers was necessary. Fifthly, the participant dropout rate was much higher than anticipated, which could potentially hinder the statistical power and lead to bias. However, analyses suggested that the dropout was not related to the treatment groups, and sensitivity analyses indicated that the dropouts did not affect the main results. Conclusions Combination PBMT and CMRA did not lead to a significantly slower progression of myopia compared to PBMT + SVS; PMBT demonstrated better efficacy than CMRA alone, or SVS alone at the 6-month follow-up. Declarations -Ethics approval and consent to participate This randomized clinical trial was carried out in accordance with the ethical principles stipulated in the Declaration of Helsinki. The study protocol and informed consent were reviewed and approved by the Institutional Review Board (IRB) of Xuzhou Medical University Affiliated Xuzhou Municipal Hospital prior to its initiation (IRB #xyyll [2023] 002) on January 13, 2023. Subjects were recruited at Xuzhou Medical University Affiliated Xuzhou Municipal Hospital in line with the IRB standard for recruitment practice. Written informed consent and verbal consent were provided by a parent/legal guardian and the subject. before the start of the study. -Consent for publication Yes, all authors consent for publication. -Availability of data and materials Data and materials are provided within the manuscript. -Competing interests The authors declare that they have no competing interests. -Funding The present work was supported in part by a grand (no. KC22228) of Construction of Xuzhou Myopia Prevention and Control Electronic Archives and Big Data Network Platform v 2.0. -Authors' contributions All authors contributed to the conceptualization and design of the study (Conceptualization, Methodology). Li and Qiu performed and collected the data; Qiu analyzed the data (Investigation, Formal Analysis). QIU drafted the manuscript (Writing – Original Draft), and all authors reviewed and approved the final version (Writing – Review & Editing). -Acknowledgements The authors thank the corporation of Yandongli Co., Ltd. And New Tianhong Optical Co. Ltd. For providing the photobiomodulation therapy devices and the lenses of CMRA and SVS, respectively. In addition, the authors gratefully acknowledge the ophthalmic technicians who helped conduct the testing and corrected the data in conjunction with ophthalmologist at Xuzhou Municipal Hospital. Finally, the authors sincerely thank the families and children who participated in this study. Authors Ying Li, MD, PhD1 Kaikai Qiu*, MD2 Affiliations 1-Xuzhou Medical University affiliated Xuzhou Municipal Hospital, Xuzhou, China 2-Fuzhou Southeast Institute of Visual Ophthalmology, Fuzhou, China Corresponding Authors Dr. Kaikai Qiu Email: [email protected] References Gregori NZ, Cai L, Moshiri Y. Self-Inflicted Laser-Induced Retinopathy. Diagnostics (Basel). 2024 Feb 7;14(4):361. doi: 10.3390/diagnostics14040361.PMID: 38396400 Hou W, Norton TT, Hyman L, Gwiazda J; COMET Group. Axial Elongation in Myopic Children and its Association With Myopia Progression in the Correction of Myopia Evaluation Trial. Eye Contact Lens. 2018 Jul;44(4):248-259. doi: 10.1097/ICL.0000000000000505. PMID: 29923883; PMCID: PMC6013843. Zhou L, Tong L, Li Y, Williams BT, Qiu K. Photobiomodulation therapy retarded axial length growth in children with myopia: evidence from a 12-month randomized controlled trial evidence. Sci Rep. 2023 Feb 27;13(1):3321. doi: 10.1038/s41598-023-30500-7. Cao K, Tian L, Ma DL, Zhao SQ, Li A, Jin ZB, Jie Y. Daily Low-Level Red Light for Spherical Equivalent Error and Axial Length in Children with Myopia: A Randomized Clinical Trial. .JAMA Ophthalmol. 2024 Jun 1;142(6):560-567. doi: 10.1001/jamaophthalmol.2024.0801. Qiu K, David C, Li Y, Lei Z, Tong L, Lin W. A retrospective study of cumulative absolute reduction in axial length after photobiomodulation therapy. BMC Ophthalmol. 2024 Apr 25;24(1):191. doi: 10.1186/s12886-024-03427-4. Zhou L, Xing C, Qiang W, Hua C, Tong L. Low-intensity, long-wavelength red lights slows the progression of myopia in children: an Eastern China-based cohort. Ophthalmic Physiol Opt. 2022 Mar; 42(2): 335-344. doi: 10.1111/opo.12939. Epub 2022 Jan 3. Chen Y, Xiong R, Yang S, Zhu Z, Li H, Xiang K, Congdon N, Wang W, He M. Safety of repeated low-level red-light therapy for myopia: A systematic review. Asia Pac J Ophthalmol (Phila). 2024 Nov-Dec;13(6):100124. doi: 10.1016/j.apjo.2024.100124. Epub 2024 Dec 12. PMID: 39672511. Liu H, Yang Y, Guo J, Peng J, Zhao P. Retinal Damage After Repeated Low-level Red-Light Laser Exposure. JAMA Ophthalmol. 2023 Jul 1;141(7):693-695. doi: 10.1001/jamaophthalmol.2023.1548. PMID: 37227712. Ostrin LA, Schill AW. Red light instruments for myopia exceed safety limits. Ophthalmic Physiol Opt. 2024 Mar;44(2):241-248. doi: 10.1111/opo.13272. Epub 2024 Jan 5. PMID: 38180093; PMCID: PMC10922340. Xiong R，Wang W, Tang X, He M, Hu Y, Zhang J, Du B, Jiang Y, Zhu Z, Chen Y, Zhang S, Kong X, Wei R, Yang X, He M. Myopia Control Effect of Repeated Low-Level Red-Light Therapy Combined with Orthokeratology: A Multicenter Randomized Controlled Trial. Ophthalmology. 2024 Nov;131(11):1304-1313. doi: 10.1016/j.ophtha.2024.05.015. Epub 2024 May 18. PMID: 38763303 Jiang Y, Zhu Z, Tan X, Kong X, Zhong H, Zhang J, Xiong R, Yuan Y, Zeng J, Morgan IG, He M. Effect of Repeated Low-Level Red-Light Therapy for Myopia Control in Children: A Multicenter Randomized Controlled Trial. Ophthalmology. 2022 May;129(5):509-519. doi: 10.1016/j.ophtha.2021.11.023. Epub 2021 Dec 1. PMID: 34863776. Dong J, Zhu Z, Xu H, He M. Myopia Control Effect of Repeated Low-Level Red-Light Therapy in Chinese Children: A Randomized, Double-Blind, Controlled Clinical Trial. Ophthalmology. 2023 Feb;130(2):198-204. doi: 10.1016/j.ophtha.2022.08.024. Epub 2022 Aug 29. PMID: 36049646. Buzzonetti L, Petroni S, Federici M, Valente P, Iarossi G. Effectiveness of Defocus Incorporated Multiple Segments in Slowing Myopia Progression in Pediatric Patients as a Function of Age: Three-Year Follow-Up. Diseases. 2024 Sep 18;12(9):222. doi: 10.3390/diseases12090222.PMID: 39329891 Jakobsen TM, Møller F. Control of myopia using orthokeratology lenses in Scandinavian children aged 6 to 12 years. Eighteen-month data from the Danish Randomized Study: Clinical study Of Near-sightedness; TReatment with Orthokeratology Lenses (CONTROL study). Acta Ophthalmol. 2022 Mar;100(2):175-182. doi: 10.1111/aos.14911. Epub 2021 Jul 7. PMID: 34233094; PMCID: PMC9292027. Chamberlain P, Peixoto-de-Matos SC, Logan NS, Ngo C, Jones D, Young G. A 3-year Randomized Clinical Trial of MiSight Lenses for Myopia Control. Optom Vis Sci. 2019 Aug;96(8):556-567. doi: 10.1097/OPX.0000000000001410. PMID: 31343513. Yam JC, Jiang Y, Tang SM, Law AKP, Chan JJ, Wong E, Ko ST, Young AL, Tham CC, Chen LJ, Pang CP. Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control. Ophthalmology. 2019 Jan;126(1):113-124. doi: 10.1016/j.ophtha.2018.05.029. Epub 2018 Jul 6. PMID: 30514630. Yi S, Huang Y, Yu SZ, Chen XJ, Yi H, Zeng XL. Therapeutic effect of atropine 1% in children with low myopia. J AAPOS. 2015 Oct;19(5):426-9. doi: 10.1016/j.jaapos.2015.04.006. Epub 2015 Jul 27. PMID: 26228967. Table 2 Table 2 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table2.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 15 Sep, 2025 Reviews received at journal 07 Sep, 2025 Reviewers agreed at journal 26 Aug, 2025 Reviews received at journal 26 Aug, 2025 Reviewers agreed at journal 26 Aug, 2025 Reviewers invited by journal 15 Jul, 2025 Editor assigned by journal 07 Jul, 2025 Submission checks completed at journal 05 Jul, 2025 First submitted to journal 05 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7023715","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":486040950,"identity":"b8baafd4-bb23-4a06-98c1-bbc6f9bdd6ab","order_by":0,"name":"Ying Li","email":"","orcid":"","institution":"Xuzhou Medical University affiliated Xuzhou Municipal Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Li","suffix":""},{"id":486040951,"identity":"378e4ba6-8da9-4066-b31a-c4aa49b6ac5d","order_by":1,"name":"Kaikai Qiu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYBACCR4GhgMMBgxybOzNB0jTYszHcyyBeC0gkDhPIkeBOC2SPYcfHnhTcDi9jSGHgeFHxTbCWqR52wwOzjE4nNvGcPYAY8+Z24S1yPEzGBzmAWlh7EtgZmwjSgv7B5CWdDZmHgPitEjz9oBtSWBjI1aLZM+ZAqBf0g3beNgSDhLlF4kz6Zs/vPljLS8///HBBz8qiNACBtC4AcYp0YCHsJJRMApGwSgYyQAAqPY58fBVs/YAAAAASUVORK5CYII=","orcid":"","institution":"Fuzhou Southeast Institute of Visual Ophthalmology","correspondingAuthor":true,"prefix":"","firstName":"Kaikai","middleName":"","lastName":"Qiu","suffix":""}],"badges":[],"createdAt":"2025-07-01 22:53:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7023715/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7023715/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87362319,"identity":"8e9d88f1-3eff-4fef-8f55-1238fc664dde","added_by":"auto","created_at":"2025-07-23 05:55:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":451205,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure101.png","url":"https://assets-eu.researchsquare.com/files/rs-7023715/v1/852dcf7ce26c1343ca1c9bc8.png"},{"id":87362314,"identity":"29752c67-5aaa-46da-b1be-f55d04b4b66b","added_by":"auto","created_at":"2025-07-23 05:55:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":576761,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Figure201.png","url":"https://assets-eu.researchsquare.com/files/rs-7023715/v1/3ea93a681cf766090f83f686.png"},{"id":87363247,"identity":"e819ab38-056f-4ad7-bb37-12e1066a744f","added_by":"auto","created_at":"2025-07-23 06:03:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1441600,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7023715/v1/7928de58-6ed0-4918-92f3-b56550c4c10e.pdf"},{"id":87360460,"identity":"6dc4ee8e-a9b3-4b6a-a5c4-e96040b04b92","added_by":"auto","created_at":"2025-07-23 05:47:36","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":15748,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7023715/v1/9b4fd4a8f7ca623dfcaf2186.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A randomized clinical trial of photobiomodulation therapy combined with continuous microlens radial array lenses for myopia control in children","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLaser technology, particularly Class III lasers, is known to pose risks to the eyes if gazed at directly for an extended period.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Traditionally, AL in children is believed to either elongate or stabilize during growth, \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e with any shortening being attributed to measurement errors or daily fluctuations. However, research on photobiomodulation therapy (PBMT) has contradicted this belief, demonstrating its potential to manage myopia by slightly shortening axial length (AL) over time.\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e–\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e This has gained traction in clinical studies in China over the last five years.\u003c/p\u003e\u003cp\u003ePBMT employs low-intensity laser (0.20–2.5 mW) therapy, which has been shown to effectively control myopia, resulting in 0.01–2% shortening of AL after one month to a year of treatment for 20–50% of myopic eyes.\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e–\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e The treatment involves using red light with a wavelength of 650 nm, applied to the central retina for three minutes, twice daily. The efficacy of photobiomodulation therapy (PBMT) may depend on illuminating the central retina, particularly the macular fovea, rather than the peripheral retina. However, this could pose risks of thermal and photochemical damage to the fovea.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Maximum permissible exposure (MPE) calculations from two PBMT devices have addressed these safety concerns. \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Current myopia control interventions like peripheral defocus lenses and orthokeratology have limitations. A study found that combining PBMT with orthokeratology can enhance myopia control when orthokeratology alone is insufficient.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Therefore, we have conducted this clinical trial to access whether combining PBMT with continuous microlens radial array (CMRA) lenses offers superior myopia control outcomes compared to either intervention alone.\u003c/p\u003e\u003cp\u003eCMRA lenses consist of 500 micro-lenses with + 2.00D to + 4.00D focus, designed to redirect part light from the central to peripheral retina, potentially slowing myopia progression. To our limited knowledge, it was the first prospective, randomized controlled clinical trial, to evaluate the efficacy of lighting the peripheral retina with PBMT + CMRA against lighting the central retina with PBMT + single vision spectacles (SVS), CMRA alone, or SVS alone. Our hypothesis was that it would be significant better or not worse with combing therapy (PBMT + CMRA).\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eStudy design and setting\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis prospective, randomized, parallel, controlled clinical trial of children with myopia was conducted from December 2022 to August 2024 at one hospital in Xuzhou, China. All eligible subjects in this study were randomized at an allocation ratio of 1:1:1:1 into the PBMT + CMRA group, PBMT + SVS group, CMRA group and SVS group, following the treatment schedule of 3-min exposures,≥4-h spacing between twice-daily treatments, 5 days per week.\u003c/p\u003e\u003cp\u003e This randomized clinical trial was carried out in accordance with the ethical principles stipulated in the Declaration of Helsinki. The study protocol and informed consent were reviewed and approved by the Institutional Review Board (IRB) of Xuzhou Medical University Affiliated Xuzhou Municipal Hospital prior to its initiation (IRB #xyyll [2023] 002) on January 13, 2023. Subjects were recruited at Xuzhou Medical University Affiliated Xuzhou Municipal Hospital in line with the IRB standard for recruitment practice. Written informed consent and verbal consent were provided by a parent/legal guardian and the subject. before the start of the study.\u003c/p\u003e\u003cp\u003eThis trial with protocol is registered with ClinicalTrials.gov, number NCT05756959.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEligibility criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003e Eligible patients were diagnosed as myopia through cycloplegic refraction and met the following inclusion and exclusion criteria: Inclusion criteria included that written informed consent was obtained from the child and the legal guardian; Children aged 6 to 13 years old; The spherical equivalence diopter (SED) after cycloplegia was between − 5.50D to -0.50D; Astigmatism was of 1.50D or less; The best corrected visual acuity (BCVA) was 0.8 (decimal record) or better; Anisometropia was of 1.50D or less; No other myopia interventions during the study period. Exclusion criteria included ocular lesions affecting vision or diseases (such as cataract, glaucoma, macular pathology, cornea lesions, uveitis, retina detachment, congenital optic abnormalities, etc.); Halo, glare, attention deficit and hyperactive disorder, psoriasis. Systemic diseases such as immune diseases, central nerve system disorders, Down syndrome, asthma, severe cardiopulmonary abnormalities, severe liver and renal dysfunctions; Squint, ocular lesions or acute inflammation; Other myopia control interventions within the recent 3 months, including atropine, devices, orthokeratology, soft lenses, and multi-focus spectacles.\u003c/p\u003e\u003cp\u003e\u003cb\u003eRandomization and masking\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAfter verifying eligibility and obtaining consent, eligible subjects were randomly allocated in a 1:1:1:1 ratio to either the intervention group (PBMT + CMRA, PBMT + SVS, CMRA) or the control group (SVS). Treatment allocation was completed by the investigators and the statistical expert (unmasked) using closed sealed envelopes which had randomized numbers printed on them by the investigators. Randomization was facilitated by a computer-generated sequence using simple randomization, with Software R (version 4.3.1; The R Foundation for Statistical Computing, Vienna, Austria)by a statistician who was not involved in subject recruitment or data collection. Only one investigator, aware of the study allocation, was responsible for group allocation and device-dispensing.\u003c/p\u003e\u003cp\u003e\u003cb\u003eIntervention\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSubjects in the intervention groups received PMBT + CMRA, PBMT + SVS, CMRA only, respectively while the control group received the SVS only. Both PBMT groups follow the PBMT with 3-min exposures and ≥ 4-h spacing between twice-daily, 5 days weekly treatments. The PBMT device was a desktop light therapy device, BSJ-B3 (Eye power illuminator, Changchun, China), which has obtained approved by national medical product administration as Class II medical device with the approved code of JiXieZhuZhun 20212160371. The light power entering a 7 mm pupil (the standard pupil size according to ISO GB 7247.1–2012, not the actual pupil size during therapy) is 0.20 mW/m\u003csup\u003e2\u003c/sup\u003e for PBMT device. The irradiance is the lowest among all the approved lists. Subjects were asked to look directly at the red light binocularly for each session of PBMT, which was under the supervision of their parent/legal guardians. At enrollment, randomized assignments were recorded in an electronic data entry system, ensuring blinding for both subjects and investigators post-assignment.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcome\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe primary endpoint was the change in AL at Month 6, analyzed using the last observation carried forward (LOCF) method. Secondary endpoints included change in spherical equivalence diopter (SED), best-corrected visual acuity (BCVA), and the incidence of adverse events (AEs). All parameters were assessed at baseline, Month 3, and Month 6. A protocol amendment implemented post-trial initiation led to the exclusion of accommodation and binocular function measurements from endpoint analyses to reduce screening-related costs.\u003c/p\u003e\u003cp\u003eRefraction was performed three times using an antorefractor (KR-800, Topcon, Tokyo, Japan) after cycloplegia, which was achieved using 3 drops of 1% tropicamide Compound eyedrop (Shiqi, Shenyang, China) to each eye at 0, 5, 20 minutes, respectively. Refraction measurements were taken 10 minutes after the third drop of compound tropicamide eyedrop if full cycloplegia was obtained. Spherical equivalent refraction (SER) was calculated as spherical power plus half of the cylinder power according to the final subjective trial lenses during the cycloplegia.\u003c/p\u003e\u003cp\u003eAL was measured using partial coherence interferometry AL-SCAN (NIDEK Co., Ltd, Japan). Three readings were taken and averaged. Distance BCVA in logarithm of the minimum angle of resolution (logMAR) was assessed by trained optometrists using the most common Chinese standard logMAR visual acuity chart according to GB11533-2011 (Danyang Hualong Medical Devices Co., Ltd, Danyang, China).\u003c/p\u003e\u003cp\u003e\u003cb\u003eAdverse events\u003c/b\u003e\u003c/p\u003e\u003cp\u003eChildren who conducted any mentioned therapy for at least once were analyzed for safety. At each follow-up visit and any unplanned visits if needed, children and their parents were asked about any AE and checked their fovea by optical coherence topography(OCT)to detect any lesion. They were also specifically asked about dazzling, short-term glare, flash blindness, and afterimages following treatment, and whether children had been ill or hospitalized since the last visit. All AEs and OCT examinations were documented and a final determination of the AE related to above mentioned treatment was analyzed by the investigators and associated researchers.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSample size\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSample size calculations were based on a Type 1 error rate of 0.05 and 80% power, with an effect size of 1.0. The anticipated change in AL at the primary endpoint from PBMT + CMRA was 0.00 mm for the intervention group and 0.20 mm for the SVS group, with a standard deviation of 0.20 of both groups. Adjusting for 20% loss to follow-up yielded at least 20 subjects in either group, respectively, or a total sample size of 80 participants.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStatistical analyses\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAll data were analyzed based on intention-to-treat principles. Data from subjects who participated in at least one follow-up visit were included in the present analysis. Missing data on the primary outcome (change of AL at Month 6) were imputed based on the last observation carried forward. Mean ocular parameter values were calculated from the right eye of each subject. The one-way ANOVA test and independent t-test were both used to test group differences in continuous data; For parameters among 4 groups, ANOVA was first considered while for only t-test was used between 2 groups. Chi-square tests were used to assess inter group differences in categorical variables. Adjusted for age, gender, and baseline values. We used SPSS (Version 22, IBM Corp. USA) for statistical analyses. All statistical tests were tow-sided and were performed at the 5% significance level. Estimated effect [r] was evaluated with Cohen d.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 220 participants were recruited into the study between January 14, 2023 and August 5, 2024 and were randomly assigned to receive PBMT\u0026thinsp;+\u0026thinsp;CMRA (n\u0026thinsp;=\u0026thinsp;55), PBMT\u0026thinsp;+\u0026thinsp;SVS (n\u0026thinsp;=\u0026thinsp;55), CMRA (n\u0026thinsp;=\u0026thinsp;55), or SVS (n\u0026thinsp;=\u0026thinsp;55) intervention. At last 6-month visit, the completed participants of four groups were 55, 27, 22 and 55, respectively (Fig.\u0026nbsp;1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt baseline, no significant difference in AL, spherical equivalent refraction (SER), age, gender or other ocular parameters, including best-corrected visual acuity (BCVA), were observed among the four groups (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), as presented in Table\u0026nbsp;1.\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n\u003cdiv\u003e\u003cstrong\u003ePrimary outcome\u003c/strong\u003e\u003c/div\u003e\n\u003cp\u003eThe change in AL at 6 months from baseline were statistically significant among four groups (P\u0026thinsp;=\u0026thinsp;0.001; Table 2, Fig.\u0026nbsp;2). The mean change in AL was negative in Group PBMT\u0026thinsp;+\u0026thinsp;CMRA (-0.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12mm) and positive in Group PBMT\u0026thinsp;+\u0026thinsp;SVS (+\u0026thinsp;0.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.36mm) ; Significantly differed between them (Cohen d: 0.07, estimated effect size[r]: 0.03, P\u0026thinsp;=\u0026thinsp;0.012). Neither difference was found between Group CMRA (0.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 mm)and Group SVS (0.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11 mm, 95% confidence interval [CI]:0.07, 0.23mm༉ ༈P\u0026thinsp;=\u0026thinsp;0.984༉. While Group PBMT\u0026thinsp;+\u0026thinsp;CMRA had both significant less change in AL at 6 months than that of Group CMRA (Cohen d: -2.05, estimated effect size[r]: -0.72, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), or Group SVS (Cohen d: -1.41, estimated effect size[r]: -0.57, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003cdiv\u003e\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mean change in SER at 6 months differed significantly among the four groups (P\u0026thinsp;=\u0026thinsp;0.001, Table\u0026nbsp;2); Only Group CMRA (-0.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24D)significant minus was found between the PBMT\u0026thinsp;+\u0026thinsp;CMRA group (-0.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41D,, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and the PBMT\u0026thinsp;+\u0026thinsp;SVS group (-0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30D, P\u0026thinsp;=\u0026thinsp;0.004); No significant difference was observed among other groups (Table\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003eAt the 1-month and 3-month follow-up, the change in AL was significantly different among the four groups (P\u0026thinsp;=\u0026thinsp;0.003, P\u0026thinsp;=\u0026thinsp;0.001, Table\u0026nbsp;2, Fig.\u0026nbsp;2). At the 1-month follow-up, the mean change in AL was significantly different between Group PBMT\u0026thinsp;+\u0026thinsp;CMRA and Group CMRA (-0.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09 mm vs -0.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 mm, P\u0026thinsp;=\u0026thinsp;0.002), Group PBMT\u0026thinsp;+\u0026thinsp;CMRA and Group SVS (-0.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09 mm vs 0.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 mm, P\u0026thinsp;=\u0026thinsp;0.047), and Group PBMT\u0026thinsp;+\u0026thinsp;SVS and Group CMRA (-0.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 mm vs 0.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06 mm, P\u0026thinsp;=\u0026thinsp;0.012). No significant difference was found between Group PBMT\u0026thinsp;+\u0026thinsp;CMRA and Group PBMT\u0026thinsp;+\u0026thinsp;SVS (P\u0026thinsp;=\u0026thinsp;0.205) or between Group PBMT\u0026thinsp;+\u0026thinsp;SVS and Group SVS (P\u0026thinsp;=\u0026thinsp;0.200). At the 3-month follow-up, the mean AL change was significantly different between Group PBMT\u0026thinsp;+\u0026thinsp;CMRA and Group SVS (P\u0026thinsp;=\u0026thinsp;0.020) as well as between Group PBMT\u0026thinsp;+\u0026thinsp;CMRA and Group CMRA (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). No significant differences were observed among Group PBMT\u0026thinsp;+\u0026thinsp;SVS, Group CMRA, and Group SVS (P\u0026thinsp;=\u0026thinsp;0.075, P\u0026thinsp;=\u0026thinsp;0.200, P\u0026thinsp;=\u0026thinsp;0.316) or between Group PBMT\u0026thinsp;+\u0026thinsp;CMRA and Group PBMT\u0026thinsp;+\u0026thinsp;SVS (P\u0026thinsp;=\u0026thinsp;0.068). At the final visit, the mean (SD) distance best-corrected visual acuity (BCVA) (P\u0026thinsp;=\u0026thinsp;0.712) and uncorrected visual acuity (UCVA) (P\u0026thinsp;=\u0026thinsp;0.605) were comparable across all four groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo severe or mild adverse events (AEs) were reported across any follow-up assessments for all participants. Notably, only one incident of a CMRA lens being accidentally broken was reported; however, this caused no harm to the participant.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this randomized, controlled clinical trial, PBMT\u0026thinsp;+\u0026thinsp;CMRA reduced myopia progression by 0.15m、0.18mm and 0.29D、0.16D over 6 months when compared against Group SVS, respectively. And there was no reported AE. This result provided the new evidence for combining therapy of PBMT with CMRA as well as PBMT with SVS as the efficacy and safe options.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFirst PBMT with the least irradiance\u003c/b\u003e\u003c/p\u003e\u003cp\u003e This study utilized PBMT with the lowest irradiance among all approved light-based therapeutic devices in China. Combining PBMT with CMRA (a myopic defocus lens designed to direct 50% of light defocus to the peripheral retina) was found to be significantly more effective than using CMRA or SVS alone. Even when PBMT was used with SVS, the myopia control efficacy was significantly better than with CMRA alone. The mean change in AL over 6 months in PBMT group was consistent with previous studies.\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e However, some studies reported different irradiance values based on 1600 lux measurements. Calculations through 4 mm pupils indicated an irradiance of 2.0 mW/m\u0026sup2; at a 7 mm pupil size according to GB7247.1-2012, which translates to 0.29 mW/m\u0026sup2; at a 4 mm pupil size. It should be noted that the exact pupil size during illumination is approximately 2.0 mm.Moreover, combining CMRA\u0026mdash;a type of myopic defocus lens\u0026mdash;with PBMT yielded significantly better myopia control outcomes than using CMRA alone. Traditional myopia control interventions, such as DIMS,\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e orthokeratology, \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e MiSight,\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e and low-concentration atropine (0.01\u0026ndash;0.1%) ,\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e primarily aimed to slow axial elongation, yet progression still occurred. Notably, 1% atropine stands out as an exception in this context.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eCombining therapy had similar efficacy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe non-significant differences in AL and SER change between the PBMT\u0026thinsp;+\u0026thinsp;CMRA group and the PBMT\u0026thinsp;+\u0026thinsp;SVS group might be attributed to the limited sample size and the relatively short - term follow - up of 6 months. Similarly, the same might apply to the nonsignificant differences between the CMRA group and the SVS group.\u003c/p\u003e\u003cp\u003eHowever, when illuminating the peripheral retina using CMRA during PBMT with a very low irradiance of 0.20 mW/m\u0026sup2;, the safety of PBMT could be further enhanced. This approach may lead to a reduction in adverse events (AEs) in long-term studies involving large sample sizes, particularly among younger participants.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSafety Profile\u003c/b\u003e\u003c/p\u003e\u003cp\u003eImportantly, the study reported no deaths or serious adverse events (AEs), indicating a favorable safety profile for the PBMT and CMRA interventions. This finding is consistent with previous findings and highlights the tolerability of these interventions in pediatric populations.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis study has several limitations. Firstly, it was a small sample size study. The sample size was determined based on the primary outcomes and might lack statistical power for the exploratory and secondary outcomes. Therefore, caution is necessary when interpreting the results of these analyses, particularly those of AE analyses. Secondly, we had unmasked participants as PBMT and CMRA have obvious identifiable appearances, respectively. Additionally, the assessment of mild adverse events was not conducted in the study; But we had corrected all follow-up images (including all baseline and follow-up optical coherence topography for all groups) and all the images were normal. Nevertheless, the rates of reported after-images of PBMT, temporary vision disturbances, and dizziness were similar across both PBMT groups since the PBMT irradiance was too low (0.2mW) to alarm children and their parents to pay attention. Thirdly, the study population was homogeneous in that the participants were all Chinese. Thus, the generalizability of the results to other populations would be limited, especially for individuals with different iris pigmentation and education backgrounds. Fourthly, as this was a single-center study, external validation involving multiple centers was necessary. Fifthly, the participant dropout rate was much higher than anticipated, which could potentially hinder the statistical power and lead to bias. However, analyses suggested that the dropout was not related to the treatment groups, and sensitivity analyses indicated that the dropouts did not affect the main results.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eCombination PBMT and CMRA did not lead to a significantly slower progression of myopia compared to PBMT\u0026thinsp;+\u0026thinsp;SVS; PMBT demonstrated better efficacy than CMRA alone, or SVS alone at the 6-month follow-up.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e-Ethics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis randomized clinical trial was carried out in accordance with the ethical principles stipulated in the Declaration of Helsinki. The study protocol and informed consent were reviewed and approved by the Institutional Review Board (IRB) of Xuzhou Medical University Affiliated Xuzhou Municipal Hospital prior to its initiation (IRB #xyyll [2023] 002) on January 13, 2023. Subjects were recruited at Xuzhou Medical University Affiliated Xuzhou Municipal Hospital in line with the IRB standard for recruitment practice. Written informed consent and verbal consent were provided by a parent/legal guardian and the subject. before the start of the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-Consent for publication\u003c/p\u003e\n\u003cp\u003eYes, all authors consent for publication.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;-Availability of data and materials\u003c/p\u003e\n\u003cp\u003eData and materials are provided within the manuscript.\u003c/p\u003e\n\u003cp\u003e-Competing interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;-Funding\u003c/p\u003e\n\u003cp\u003eThe present work was supported in part by a grand (no. KC22228) of Construction of Xuzhou Myopia Prevention and Control Electronic Archives and Big Data Network Platform v 2.0.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;-Authors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the conceptualization and design of the study (Conceptualization, Methodology). Li and Qiu performed and collected the data; Qiu analyzed the data (Investigation, Formal Analysis). QIU drafted the manuscript (Writing \u0026ndash; Original Draft), and all authors reviewed and approved the final version (Writing \u0026ndash; Review \u0026amp; Editing).\u003cbr\u003e\u0026nbsp;-Acknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors thank the corporation of Yandongli Co., Ltd. And New Tianhong Optical Co. Ltd. For providing the photobiomodulation therapy devices and the lenses of CMRA and SVS, respectively. In addition, the authors gratefully acknowledge the ophthalmic technicians who helped conduct the testing and corrected the data in conjunction with ophthalmologist at Xuzhou Municipal Hospital. Finally, the authors sincerely thank the families and children who participated in this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Authors\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYing Li, MD, PhD1\u003c/p\u003e\n\u003cp\u003eKaikai Qiu*, MD2\u003c/p\u003e\n\u003cp\u003eAffiliations\u003c/p\u003e\n\u003cp\u003e1-Xuzhou Medical University affiliated Xuzhou Municipal Hospital, Xuzhou, China\u003c/p\u003e\n\u003cp\u003e2-Fuzhou Southeast Institute of Visual Ophthalmology, Fuzhou, China\u003c/p\u003e\n\u003cp\u003eCorresponding Authors\u003c/p\u003e\n\u003cp\u003eDr. Kaikai Qiu\u003c/p\u003e\n\u003cp\u003eEmail: [email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGregori NZ, Cai L, Moshiri Y. Self-Inflicted Laser-Induced Retinopathy. Diagnostics (Basel). 2024 Feb 7;14(4):361. doi: 10.3390/diagnostics14040361.PMID: 38396400 \u003c/li\u003e\n\u003cli\u003eHou W, Norton TT, Hyman L, Gwiazda J; COMET Group. Axial Elongation in Myopic Children and its Association With Myopia Progression in the Correction of Myopia Evaluation Trial. Eye Contact Lens. 2018 Jul;44(4):248-259. doi: 10.1097/ICL.0000000000000505. PMID: 29923883; PMCID: PMC6013843.\u003c/li\u003e\n\u003cli\u003eZhou L, Tong L, Li Y, Williams BT, Qiu K. Photobiomodulation therapy retarded axial length growth in children with myopia: evidence from a 12-month randomized controlled trial evidence. Sci Rep. 2023 Feb 27;13(1):3321. doi: 10.1038/s41598-023-30500-7.\u003c/li\u003e\n\u003cli\u003eCao K, Tian L, Ma DL, Zhao SQ, Li A, Jin ZB, Jie Y. Daily Low-Level Red Light for Spherical Equivalent Error and Axial Length in Children with Myopia: A Randomized Clinical Trial. .JAMA Ophthalmol. 2024 Jun 1;142(6):560-567. doi: 10.1001/jamaophthalmol.2024.0801.\u003c/li\u003e\n\u003cli\u003eQiu K, David C, Li Y, Lei Z, Tong L, Lin W. A retrospective study of cumulative absolute reduction in axial length after photobiomodulation therapy. BMC Ophthalmol. 2024 Apr 25;24(1):191. doi: 10.1186/s12886-024-03427-4.\u003c/li\u003e\n\u003cli\u003eZhou L, Xing C, Qiang W, Hua C, Tong L. Low-intensity, long-wavelength red lights slows the progression of myopia in children: an Eastern China-based cohort. Ophthalmic Physiol Opt. 2022 Mar; 42(2): 335-344. doi: 10.1111/opo.12939. Epub 2022 Jan 3.\u003c/li\u003e\n\u003cli\u003eChen Y, Xiong R, Yang S, Zhu Z, Li H, Xiang K, Congdon N, Wang W, He M. Safety of repeated low-level red-light therapy for myopia: A systematic review. Asia Pac J Ophthalmol (Phila). 2024 Nov-Dec;13(6):100124. doi: 10.1016/j.apjo.2024.100124. Epub 2024 Dec 12. PMID: 39672511.\u003c/li\u003e\n\u003cli\u003eLiu H, Yang Y, Guo J, Peng J, Zhao P. Retinal Damage After Repeated Low-level Red-Light Laser Exposure. JAMA Ophthalmol. 2023 Jul 1;141(7):693-695. doi: 10.1001/jamaophthalmol.2023.1548. PMID: 37227712.\u003c/li\u003e\n\u003cli\u003eOstrin LA, Schill AW. Red light instruments for myopia exceed safety limits. Ophthalmic Physiol Opt. 2024 Mar;44(2):241-248. doi: 10.1111/opo.13272. Epub 2024 Jan 5. PMID: 38180093; PMCID: PMC10922340.\u003c/li\u003e\n\u003cli\u003eXiong R，Wang W, Tang X, He M, Hu Y, Zhang J, Du B, Jiang Y, Zhu Z, Chen Y, Zhang S, Kong X, Wei R, Yang X, He M. Myopia Control Effect of Repeated Low-Level Red-Light Therapy Combined with Orthokeratology: A Multicenter Randomized Controlled Trial. Ophthalmology. 2024 Nov;131(11):1304-1313. doi: 10.1016/j.ophtha.2024.05.015. Epub 2024 May 18. PMID: 38763303 \u003c/li\u003e\n\u003cli\u003eJiang Y, Zhu Z, Tan X, Kong X, Zhong H, Zhang J, Xiong R, Yuan Y, Zeng J, Morgan IG, He M. Effect of Repeated Low-Level Red-Light Therapy for Myopia Control in Children: A Multicenter Randomized Controlled Trial. Ophthalmology. 2022 May;129(5):509-519. doi: 10.1016/j.ophtha.2021.11.023. Epub 2021 Dec 1. PMID: 34863776.\u003c/li\u003e\n\u003cli\u003eDong J, Zhu Z, Xu H, He M. Myopia Control Effect of Repeated Low-Level Red-Light Therapy in Chinese Children: A Randomized, Double-Blind, Controlled Clinical Trial. Ophthalmology. 2023 Feb;130(2):198-204. doi: 10.1016/j.ophtha.2022.08.024. Epub 2022 Aug 29. PMID: 36049646.\u003c/li\u003e\n\u003cli\u003eBuzzonetti L, Petroni S, Federici M, Valente P, Iarossi G. Effectiveness of Defocus Incorporated Multiple Segments in Slowing Myopia Progression in Pediatric Patients as a Function of Age: Three-Year Follow-Up. Diseases. 2024 Sep 18;12(9):222. doi: 10.3390/diseases12090222.PMID: 39329891\u003c/li\u003e\n\u003cli\u003eJakobsen TM, M\u0026oslash;ller F. Control of myopia using orthokeratology lenses in Scandinavian children aged 6 to 12 years. Eighteen-month data from the Danish Randomized Study: Clinical study Of Near-sightedness; TReatment with Orthokeratology Lenses (CONTROL study). Acta Ophthalmol. 2022 Mar;100(2):175-182. doi: 10.1111/aos.14911. Epub 2021 Jul 7. PMID: 34233094; PMCID: PMC9292027.\u003c/li\u003e\n\u003cli\u003eChamberlain P, Peixoto-de-Matos SC, Logan NS, Ngo C, Jones D, Young G. A 3-year Randomized Clinical Trial of MiSight Lenses for Myopia Control. Optom Vis Sci. 2019 Aug;96(8):556-567. doi: 10.1097/OPX.0000000000001410. PMID: 31343513.\u003c/li\u003e\n\u003cli\u003eYam JC, Jiang Y, Tang SM, Law AKP, Chan JJ, Wong E, Ko ST, Young AL, Tham CC, Chen LJ, Pang CP. Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control. Ophthalmology. 2019 Jan;126(1):113-124. doi: 10.1016/j.ophtha.2018.05.029. Epub 2018 Jul 6. PMID: 30514630.\u003c/li\u003e\n\u003cli\u003eYi S, Huang Y, Yu SZ, Chen XJ, Yi H, Zeng XL. Therapeutic effect of atropine 1% in children with low myopia. J AAPOS. 2015 Oct;19(5):426-9. doi: 10.1016/j.jaapos.2015.04.006. Epub 2015 Jul 27. PMID: 26228967.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 2","content":"\u003cp\u003eTable 2 is available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Photobiomodulation, Myopia, Children, Randomized clinical trial","lastPublishedDoi":"10.21203/rs.3.rs-7023715/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7023715/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eTo assess the clinical efficacy and safety of photobiomodulation therapy (PBMT) combined with continuous microlens radial array (CMRA) lenses in controlling myopia progression.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis study was designed as a prospective, randomized, double-blind, controlled clinical trial. We enrolled a total of 220 myopia aged 6\u0026ndash;13 years. Participants were randomly assigned in a 1:1:1:1 ratio to one of four groups: Group PBMT\u0026thinsp;+\u0026thinsp;CMRA, Group PBMT\u0026thinsp;+\u0026thinsp;single vision spectacles (SVS), Group CMRA, and a control group with SVS. The primary outcomes were cycloplegic refraction and axial length (AL), measured at baseline and 6-month follow-up, using a PBMT device with a 650 nm low-intensity laser diode (0.20 mW irradiance).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 159 myopic children completed the 6-month study and were included in the final analysis. The mean axial length (AL) changes were \u0026minus;\u0026thinsp;0.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13 mm, -0.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38 mm, +\u0026thinsp;0.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 mm, and +\u0026thinsp;0.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19 mm across the four groups, respectively, with a statistically significant intergroup difference (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). No treatment-related adverse events were observed.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003ePBMT\u0026thinsp;+\u0026thinsp;CMRA demonstrated superior efficacy in controlling axial elongation compared to PBMT\u0026thinsp;+\u0026thinsp;SVS, CMRA, or SVS alone (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This combination therapy represents a promising non-pharmacological strategy for mitigating myopia progression in pediatric populations.\u003c/p\u003e\u003ch2\u003eTrial Registration\u003c/h2\u003e\u003cp\u003eNCT05756959, registered on 09/03/2023.\u003c/p\u003e","manuscriptTitle":"A randomized clinical trial of photobiomodulation therapy combined with continuous microlens radial array lenses for myopia control in children","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 05:47:31","doi":"10.21203/rs.3.rs-7023715/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-15T06:20:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-07T11:24:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"162786036721994085445601783764486648822","date":"2025-08-26T19:37:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-26T15:49:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286297017198782818369879733526637092451","date":"2025-08-26T15:14:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-16T02:35:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-07T06:37:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-05T11:33:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2025-07-05T11:30:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5ba8c26a-738b-4a54-a9dc-b9ef1e6a4dd5","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-01T15:08:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-23 05:47:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7023715","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7023715","identity":"rs-7023715","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}