Dietary Supplement Crocetin Has a Suppressive Effect Against Myopia Progression: A Randomized Clinical Trial

Abstract

Background: The natural carotenoid crocetin has been reported to suppress experimental myopia in mice. The purpose of this study is to investigate the minimum effective dosage and the preventive efficacy of crocetin with a murine model and human subjects, respectively. Methods: Three-week-old male mice (C57B6/J) were equipped with a -30 diopter (D) lens. Changes of refractive errors and axial lengths (AL) were evaluated to determine the minimum effective dosage. A multicenter randomized double-blind placebo-controlled clinical trial was performed with 69 participants aged 6 to 12 years, whose cycloplegic spherical equivalent refractions (SER) were between -1.5 and -4.5 D. We evaluated AL elongation and change of SER for 24 weeks. A mixed effect model was used for analysis using both eyes. Findings: As the minimum dose, 0.001% of crocetin containing extract chow showed a significant (P<0.001) suppressive effect against both refractive and AL changes in the murine model. 7.5 mg/day of crocetin, which is the equivalent dosage to the animal experiment, was administered in the clinical trial. Two participants dropped out and 67 children completed this trial. The change of SER (D) in the placebo group, -0.41±0.05 (mean±standard deviation), was significantly greater than that in the crocetin group, -0.33±0.05 (P=0.049). The AL elongation (mm) in the placebo group, 0.21±0.02, was significantly greater than that in the placebo group, 0.18±0.02 (P=0.046). Interpretation: Dietary crocetin showed a suppressive effect of myopia progression in children. Trial Registration Number: This trial was also registered by Japic Clinical Trials Information with the registration number JapicCTI-173777. Funding: This study was supported by ROHTO Pharmaceutical Co., Tsubota Laboratory Inc., and Specified contribution from Keio University. Declaration of Interest: The current study was financially supported from ROHTO Pharmaceutical Co.,Ltd., Tsubota Laboratory, Inc., and the specified contribution from Keio University. Patents have been registered for the therapeutic effects of crocetin (patent application no. 2017-210596 by Tsubota Laboratory, Inc. and Rohto Pharmaceutical Co., Ltd.) and applied for the design of the mouse eyeglass by Tsubota Laboratory, Inc. (patent application no. 2017-41349). Ethical Approval: This trial was approved by the institutional review board of Keio University School of Medicine (approval no. 20180079) and Medical Corporation Heishinkai OPHAC Hospital Ethical Review Committee (approval no. 1011PC). All procedures were performed in accordance with the National Institutes of Health (NIH) guidelines for work with laboratory animals and the Association for Research in Vision and Ophthalmology (ARVO) statement for the Use of Animals in Ophthalmic and Vision Research, and were approved by the Institutional Animal Care and Use Committee at Keio University (registration no.3930).