Safety and Efficacy of Low-Dose Atropine Eyedrops for the Treatment of Myopia Progression in Chinese Children A Randomized Clinical Trial 低剂量阿托品眼药水治疗中国儿童近视进展的安全性和有效性 随机临床试验
IMPORTANCE Because studies have suggested that atropine might slow the progression of myopia in children, randomized clinical trials are warranted to understand this potential causal relationship. 重要性 因为研究表明阿托品可能会减缓儿童近视的进展，因此有必要进行随机临床试验以了解这种潜在的因果关系。
OBJECTIVE To evaluate the efficacy and safety of atropine, 0.01%, eyedrops on slowing myopia progression and axial elongation in Chinese children. 目的 评估 0.01%阿托品眼药水在减缓中国儿童近视进展和轴向延长方面的疗效和安全性。
DESIGN, SETTING, AND PARTICIPANTS This was a randomized, placebo-controlled, double-masked study. A total of 220 children aged 6 to 12 years with myopia of -1.00 D to -6.00 D in both eyes were enrolled between April 2018 and July 2018 at Beijing Tongren Hospital, Beijing, China. Cycloplegic refraction and axial length were measured at baseline, 6 months, and 12 months. Adverse events were also recorded. 设计、设置和参与者 这是一项随机、安慰剂对照、双盲研究。共有 220 名年龄在 6 至 12 岁之间、双眼近视度数在-1.00 D 至-6.00 D 的儿童于 2018 年 4 月至 2018 年 7 月在中国北京同仁医院入组。基线、6 个月和 12 个月时测量了睫状麻痹屈光度和轴长。同时也记录了不良事件。
INTERVENTIONS Patients were randomly assigned in a 1:1 ratio to atropine, 0.01%0.01 \%, or placebo groups to be administered once nightly to both eyes for 1 year. 干预 患者以 1:1 的比例随机分配到阿托品、 0.01%0.01 \% 或安慰剂组，每晚在双眼中使用一次，持续 1 年。
MAIN OUTCOMES AND MEASURES Mean changes and percentage differences in myopia progression and axial elongation between atropine, 0.01%, or placebo groups. 主要结果和测量：阿托品 0.01%组或安慰剂组之间近视进展和轴向延长的平均变化和百分比差异。
RESULTS Of 220 participants, 103 were girls (46.8%), and the mean (SD) age was 9.64 (1.68) years. The mean (SD) baseline refractive error and axial length were -2.58 (1.39) D and 24.59 ( 0.87 ) mm. Follow-up at 1 year included 76 children ( 69%69 \% ) and 83 children ( 75%75 \% ) allocated into the atropine, 0.01%0.01 \%, and placebo groups, respectively, when mean myopia progression was - 0.49 (0.42) D and -0.76 (0.50) D in the atropine, 0.01%, and placebo groups (mean difference, 0.26D;95%Cl,0.12-0.41D;P < .0010.26 \mathrm{D} ; 95 \% \mathrm{Cl}, 0.12-0.41 \mathrm{D} ; \mathrm{P}<.001 ), with a relative reduction of 34.2%34.2 \% in myopia progression. The mean (SD) axial elongation in the atropine, 0.01%0.01 \%, group was 0.32 (0.19) mm compared with 0.41 (0.19) mm in the placebo group (mean difference, 0.09 mm ; 95%Cl,0.03-0.15mm;P=.004)95 \% \mathrm{Cl}, 0.03-0.15 \mathrm{~mm} ; P=.004), with relative reduction of 22.0%22.0 \% in axial elongation. Fifty-one percent and 13.2%13.2 \% of children progressed by at least 0.50 D and 1.00 D in the atropine, 0.01%0.01 \%, group, compared with 69.9%69.9 \% and 34.9%34.9 \% in the placebo group. No serious adverse events related to atropine were reported. 结果 在 220 名参与者中，103 名为女孩（46.8%），平均年龄（标准差）为 9.64（1.68）岁。基线屈光不正和轴长的平均值（标准差）分别为-2.58（1.39）D 和 24.59（0.87）mm。1 年的随访包括 76 名儿童（ 69%69 \% ）和 83 名儿童（ 75%75 \% ），分别分配到阿托品、 0.01%0.01 \% 和安慰剂组，当时阿托品、0.01%和安慰剂组的平均近视进展为-0.49（0.42）D 和-0.76（0.50）D（平均差异， 0.26D;95%Cl,0.12-0.41D;P < .0010.26 \mathrm{D} ; 95 \% \mathrm{Cl}, 0.12-0.41 \mathrm{D} ; \mathrm{P}<.001 ），近视进展的相对减少为 34.2%34.2 \% 。阿托品、 0.01%0.01 \% 组的平均（标准差）轴向延长为 0.32（0.19）mm，而安慰剂组为 0.41（0.19）mm（平均差异，0.09 mm； 95%Cl,0.03-0.15mm;P=.004)95 \% \mathrm{Cl}, 0.03-0.15 \mathrm{~mm} ; P=.004) ，轴向延长的相对减少为 22.0%22.0 \% 。51%和 13.2%13.2 \% 的儿童在阿托品、 0.01%0.01 \% 组中至少进展了 0.50 D 和 1.00 D，而安慰剂组中分别为 69.9%69.9 \% 和 34.9%34.9 \% 。没有报告与阿托品相关的严重不良事件。
CONCLUSIONS AND RELEVANCE While the clinical relevance of the results cannot be determined from this trial, these 1-year results, limited by approximately 70% follow-up, suggest that atropine, 0.01%0.01 \%, eyedrops can slow myopia progression and axial elongation in children and warrant future studies to determine longer-term results and potential effects on slowing sight-threatening pathologic changes later in life. 结论与相关性 虽然无法从本试验中确定结果的临床相关性，但这些为期 1 年的结果（约 70%的随访限制）表明，阿托品 0.01%0.01 \% 眼药水可以减缓儿童近视进展和轴向延长，值得未来研究以确定长期结果及其对减缓日后可能威胁视力的病理变化的潜在影响。
Author Affiliations: Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Ophthalmology and Visual Science Key Lab, Beijing Institute of Ophthalmology, Capital Medical University, Beijing, China (Wei, Li, An, Du, Liang, Sun, Tian, Wang); Peking Union Medical College, Beijing, China (Zhang). 作者单位：北京同仁眼科中心，北京同仁医院，北京眼科与视觉科学重点实验室，北京眼科研究所，首都医科大学，中国北京（魏，李，安，杜，梁，孙，田，王）；北京协和医学院，中国北京（张）。
Corresponding Author: Ningli Wang, MD, PhD, Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Ophthalmology and Visual Science Key Lab, Beijing Institute of Ophthalmology, Capital Medical University, No. 1 Dongjiaominxiang St, Dongcheng District, Beijing, China, 100730 (wningli@vip.163.com). 通讯作者：王宁丽，医学博士，北京同仁眼科中心，北京同仁医院，北京市眼科与视觉科学重点实验室，北京眼科研究所，首都医科大学，东城区东交民巷街 1 号，中国，北京，100730（wningli@vip.163.com）。
Myopia has become a critical public health problem among both children and adults, especially in some East and Southeast Asian countries such as China and Singapore. ^(1,2){ }^{1,2} A 2016 review ^(3){ }^{3} predicted that approximately half of the world’s population will have myopia by 2050, with 10%10 \% being high myopia. ^(3){ }^{3} In China, the prevalence of myopia reaches 5.2%5.2 \% in children aged 6 years, nearly 70%70 \% in seventh-grade students, and exceeds 80%80 \% in university students. ^(4-6){ }^{4-6} Myopia is not only the most common cause of avoidable visual impairment and blindness, but high or pathologic myopia is also associated with increased risk of irreversible blinding conditions, including myopic retinopathy, retinal detachment, choroidal neovascularization, and glaucoma, ^(7-10){ }^{7-10} leading to a heavy cost burden on individuals and communities. ^(11){ }^{11} 近视已成为儿童和成人中一个严重的公共卫生问题，尤其是在中国和新加坡等一些东亚和东南亚国家。2016 年的一项回顾预测，到 2050 年，全球约一半的人口将患有近视，其中高近视的比例较高。在中国，6 岁儿童的近视患病率达到近 70%，七年级学生接近 80%，大学生超过 90%。近视不仅是可避免的视觉障碍和失明的最常见原因，高度或病理性近视还与不可逆失明病症的风险增加相关，包括近视性视网膜病、视网膜脱落、脉络膜新生血管和青光眼，这给个人和社区带来了沉重的经济负担。
Several randomized clinical trials have been investigated to halt or slow myopic progression including undercorrection, progressive addition lenses, contact lenses, pirenzepine gel, and increased outdoor activity. ^(12-16){ }^{12-16} However, the results of their effects are disappointing or positive results of marginal clinical significance. At present, topical atropine has been demonstrated to have the strongest clinical effect on slowing the progression of myopia. ^(17-19){ }^{17-19} In 2006, the Atropine for the Treatment of Myopia 1 (ATOM 1) study found that the mean (SD) rate of myopia progression after 2 years was only -0.28 (0.92) D in the atropine, 1%1 \%, group compared with -1.20 (0.69) D in the placebo group. ^(18){ }^{18} However, ocular adverse effects induced by atropine, 1%1 \%, such as blurred near vision, photophobia cycloplegia, and allergy, have limited its use. Furthermore, there was a greater myopic rebound in eyes that had received atropine, 0.5%0.5 \% and 0.1%0.1 \%, after treatment was discontinued (ATOM 2 study), whereas those receiving a low-dose 0.01%0.01 \% concentration proved sustained and minimal change after treatment cessation. ^(20){ }^{20} Therefore, low concentration of atropine, 0.01%0.01 \%, is increasingly applied to clinical treatment for children with myopia in Asia. 已经进行了几项随机临床试验，以阻止或减缓近视进展，包括不足矫正、渐进多焦点镜片、隐形眼镜、吡仑帕尼凝胶和增加户外活动。 ^(12-16){ }^{12-16} 然而，它们的效果结果令人失望或仅有边际临床意义的积极结果。目前，局部阿托品已被证明对减缓近视进展具有最强的临床效果。 ^(17-19){ }^{17-19} 2006 年，阿托品治疗近视 1（ATOM 1）研究发现，阿托品组在 2 年后近视进展的平均（标准差）速度仅为-0.28（0.92）D，而安慰剂组为-1.20（0.69）D。 ^(18){ }^{18} 然而，阿托品引起的眼部不良反应，如近距离视力模糊、畏光、睫状肌麻痹和过敏，限制了其使用。此外，在停止治疗后，接受阿托品治疗的眼睛出现了更大的近视反弹 0.5%0.5 \% ，而接受低剂量 0.01%0.01 \% 浓度治疗的患者在停止治疗后表现出持续且变化最小的效果。 因此，低浓度的阿托品在亚洲越来越多地应用于儿童近视的临床治疗。
Most studies have been performed to evaluate the efficacy and safety of low concentration of atropine, 0.01%0.01 \%, through nonrandomized controlled trials, ^(21-23){ }^{21-23} but few data are available from randomized clinical trials, with the exception of 2 in Singapore (ATOM 2 study) and Hong Kong, China (LowConcentration Atropine for Myopia Progression [LAMP] study). ^(19,24){ }^{19,24} However, the lack of a placebo control group was an acknowledged weakness of the ATOM 2 study. The LAMP study from Hong Kong, China, first provided placebocompared data of low-concentration atropine eyedrops in slowing myopia progression. ^(24){ }^{24} Thus, the effect of low concentration of atropine, 0.01%0.01 \%, has not been extensively evaluated through placebo-controlled trial. Therefore, we aimed to evaluate the efficacy and safety of low concentrations of atropine, 0.01%0.01 \%, in this randomized, double-masked, placebocontrolled trial in mainland China. 大多数研究都是为了评估低浓度阿托品的疗效和安全性，通过非随机对照试验，但来自随机临床试验的数据很少，除了新加坡的 2 项（ATOM 2 研究）和中国香港的（低浓度阿托品对近视进展的影响[LAMP]研究）。然而，ATOM 2 研究缺乏安慰剂对照组被认为是一个公认的弱点。来自中国香港的 LAMP 研究首次提供了低浓度阿托品眼药水在减缓近视进展方面的安慰剂对照数据。因此，低浓度阿托品的效果尚未通过安慰剂对照试验进行广泛评估。因此，我们旨在在中国大陆进行这项随机、双盲、安慰剂对照试验，以评估低浓度阿托品的疗效和安全性。
Methods 方法
Study Design 研究设计
This is a randomized, double-masked, placebo-controlled trial aimed to investigate the efficacy and safety of low concentra- 这是一个随机、双盲、安慰剂对照试验，旨在研究低浓度的疗效和安全性
Key Points 关键点
Question Do atropine, 0.01%, eyedrops slow the myopia progression and axial elongation when compared with a placebo group in Chinese children? 阿托品 0.01%眼药水在中国儿童中与安慰剂组相比，是否能减缓近视进展和轴向延长？
Findings In this randomized clinical trial, atropine, 0.01%, eyedrops reduced myopia progression and axial elongation compared with placebo treatment after 1 year. 在这项随机临床试验中，0.01%的阿托品眼药水在 1 年后与安慰剂治疗相比，减少了近视进展和轴向延长。
Meaning While the clinical relevance of the results cannot be determined from this trial, these results support the potential that atropine, 0.01%0.01 \%, eyedrops can slow myopia progression in Chinese children and warrant future studies to determine longer-term results and potential effects on slowing sight-threatening pathologic changes later in life. 虽然无法从这项试验中确定结果的临床相关性，但这些结果支持阿托品 0.01%0.01 \% 眼药水在中国儿童中减缓近视进展的潜力，并值得未来的研究以确定长期结果及其对减缓日后可能威胁视力的病理变化的潜在影响。
tions of atropine, 0.01%0.01 \%, in children with low and moderate myopia from April 2018 to July 2020. Two phases were included in this study. All children were recruited and randomized to receive either atropine, 0.01%0.01 \%, or placebo eyedrops in both eyes once daily at an allocation ratio of 1:1 for 1 year in phase 1. At the beginning of the second year, the atropine, 0.01%0.01 \%, group will be crossed over to the placebo group, and the placebo group will be crossed over to the atropine, 0.01%0.01 \%, group for 1 year in phase 2 . All eyedrops in monodose preparation were prepared by Shenyang Xingqi Pharmaceutical Co Ltd. Informed written consent was obtained from at least 1 parent as well as verbal assent from each child. No compensation or incentives were offered to the children and parents. This clinical trial adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board of Beijing Tongren Hospital, Capital Medical University. The trial protocol is available in Supplement 1. 在 2018 年 4 月至 2020 年 7 月期间，对低度和中度近视儿童使用阿托品的研究。该研究包括两个阶段。所有儿童均被招募并随机分配接受阿托品、 0.01%0.01 \% 或安慰剂眼药水，每天在双眼中使用一次，分配比例为 1:1，持续 1 年。在第二年的开始，阿托品 0.01%0.01 \% 组将交叉到安慰剂组，安慰剂组将交叉到阿托品 0.01%0.01 \% 组，持续 1 年，作为第二阶段。所有单剂量眼药水均由沈阳星奇药业有限公司制备。至少 1 名家长签署了知情书面同意书，并且每个儿童均口头同意。未向儿童和家长提供任何补偿或奖励。本临床试验遵循《赫尔辛基宣言》的原则，并获得了首都医科大学北京同仁医院伦理委员会的批准。试验方案可在补充材料 1 中获得。
Study Population 研究人群
We recruited the children with myopia who visited Beijing Tongren Hospital, Beijing, China, between April 2018 and July 2018. All participants met the following inclusion criteria: children aged 6 to 12 years with refractive error of spherical equivalent (SE) range of -1.00 D to -6.00 D in both eyes, astigmatism of -1.50 D or less in both eyes, best-corrected distance visual acuity 0.20 logMAR0.20 \operatorname{logMAR} or better in both eyes, and intraocular pressure (IOP) of less than 21 mm Hg . Exclusion criteria were as follows: children with other combined ocular diseases (eg, amblyopia, strabismus, corneal scar, cataract, glaucoma, or ocular tumor); previous or current treatment with atropine, pirenzepine, contact lenses, bifocals, or progressive addition lenses for myopia; and allergy to atropine, cyclopentolate, or excipients. 我们招募了在 2018 年 4 月至 2018 年 7 月期间访问中国北京同仁医院的近视儿童。所有参与者符合以下纳入标准：年龄在 6 至 12 岁之间，双眼球面等效屈光不正（SE）范围为-1.00 D 至-6.00 D，双眼散光不超过-1.50 D，双眼最佳矫正远视力 0.20 logMAR0.20 \operatorname{logMAR} 或更好，眼内压（IOP）低于 21 mm Hg。排除标准如下：有其他合并眼病的儿童（例如，弱视、斜视、角膜瘢痕、白内障、青光眼或眼肿瘤）；曾经或目前使用阿托品、吡仑帕尼、隐形眼镜、双光眼镜或渐进多焦点眼镜治疗近视；以及对阿托品、环戊酮或辅料过敏。
Sample Size 样本大小
Sample size was calculated based on the results from the previous studies. ^(18,19,23){ }^{18,19,23} We assume that atropine, 0.01%0.01 \%, reduces the myopia progression rate by at least -0.36 D with standard deviation of 0.70 D , assuming a power of 90%90 \% with a 2 -sided test of 5%5 \%. Thus, this study required 80 participants in each group. Considering a dropout rate of 25%25 \%, a total of 220 participants would be adequate. 样本量是根据之前研究的结果计算得出的。 ^(18,19,23){ }^{18,19,23} 我们假设阿托品， 0.01%0.01 \% ，将近视进展率降低至少 -0.36 D，标准差为 0.70 D，假设功效为 90%90 \% ，进行 5%5 \% 的双侧检验。因此，本研究需要每组 80 名参与者。考虑到 25%25 \% 的流失率，总共需要 220 名参与者。
Randomization and Masking 随机化和盲法
With the schedule generated by SAS program (SAS Institute Inc), a statistician operated the randomization independently. Every eligible 4 children were randomly allocated into the intervention group or control group according to the priority order the children visited the hospital for treatment. The atropine, 0.01%0.01 \%, and placebo eyedrops were packaged in identical bottles, and thus, investigators and participants were not able to identify the contents. The data analysts were also blinded to minimize observational bias. 根据 SAS 程序（SAS Institute Inc）生成的时间表，一名统计学家独立地进行了随机分配。每 4 名符合条件的儿童根据他们就医的优先顺序随机分配到干预组或对照组。阿托品、 0.01%0.01 \% 和安慰剂眼药水被包装在相同的瓶子中，因此研究人员和参与者无法识别内容。数据分析师也被盲化以最小化观察偏差。
Study Procedures 研究程序
All children who participated in this study underwent the same, standardized examination procedure at the baseline, 6-month, and 12 -month visits. Patients were given a calendar to mark out the days when the trial medications were used and, with more than 80%80 \% compliance rate, were considered to be included in the results analysis. Children were also provided photochromatic glasses (which darken on exposure to ultraviolet light or sunlight) if they experienced glare or their parents were worried of excessive light exposure or progressive glasses (reading add) if they experienced difficulty with near vision. 所有参与本研究的儿童在基线、6 个月和 12 个月的访视中都进行了相同的标准化检查程序。患者被提供一个日历，以标记试验药物使用的日期，且在合规率超过 80%80 \% 的情况下，才被视为纳入结果分析。儿童还被提供光变眼镜（在紫外线或阳光照射下变暗），如果他们感到眩光，或者如果他们的父母担心过度光照，或者提供渐进眼镜（阅读加）如果他们在近距离视力上遇到困难。
Cycloplegic refraction was measured by an autorefractor (HRK7000 A; Huvitz) 3 times consecutively, with average data used for analysis. All 3 readings should be at most 0.25 D apart in both the spherical and cylinder components. During the examination of each patient, 3 drops of cyclopentolate, 1%1 \% (Alcon), were administered at a 5-minute interval. Thirty min- 通过自动折射仪（HRK7000 A；Huvitz）连续测量了 3 次调节麻痹屈光度，使用平均数据进行分析。所有 3 个读数在球面和柱面分量上相差最多应为 0.25 D。在对每位患者的检查过程中，每 5 分钟滴入 3 滴环戊烯（Alcon）。三十分钟-
utes after the last drop, if pupillary light reflex was still present or the pupil size was less than 6.0 mm , a fourth drop of 1%1 \% cyclopentolate was administered and the examination was repeated 15 minutes later. Axial length (AL) was measured using the Lenstar LS900 (Haag-Streit), with 5 readings taken and averaged. A noncontact tonometer (HNT-7000; Huvitz) was used to measure the intraocular pressure with 3 repeated measurements. 在最后一滴药水后 5 分钟，如果瞳孔光反射仍然存在或瞳孔大小小于 6.0 毫米，则给予第四滴 1%1 \% 环戊烯酮，并在 15 分钟后重复检查。使用 Lenstar LS900（Haag-Streit）测量轴长（AL），进行了 5 次读数并取平均值。使用非接触式眼压计（HNT-7000；Huvitz）测量眼内压，进行了 3 次重复测量。
Additionally, a detailed interviewer-administered questionnaire answered by parents was used to collect the information of their children on the age at myopia onset, number of parents with myopia, and time near work and outdoors activities (hours per day) after school hours.,425,26 此外，使用了一份由访谈者管理的详细问卷，由父母填写，以收集他们孩子的近视发病年龄、近视父母的数量以及课后近距离工作和户外活动的时间（每天小时）。
Outcomes 结果
The SE was calculated as the dioptric powers of the sphere and half of the cylinder (sphere +0.5 xx+0.5 \times cylinder). Myopia progression defined as the mean change in cycloplegic SE over 1 year. Three levels of myopia progression were defined as less than 0.50 D (mild), between 0.50 D and less than 1.00 D (moderate), and 1.00 D or greater (severe). If the myopia progression was less than 0.50 D over 1 year, children were considered as nonprogressors and otherwise as progressors. The secondary outcomes included AL change over 1 year. Adverse events were recorded based on what patients and parents were asked and examined during the treatment. SE 的计算为球镜的屈光度和圆柱镜的一半（球镜 +0.5 xx+0.5 \times 圆柱镜）。近视进展定义为 1 年内循环麻痹 SE 的平均变化。近视进展分为三个级别：小于 0.50 D（轻度）、介于 0.50 D 和小于 1.00 D 之间（中度）以及 1.00 D 或更大（重度）。如果 1 年内近视进展小于 0.50 D，则儿童被视为非进展者，否则视为进展者。次要结果包括 1 年内 AL 的变化。根据患者和家长在治疗期间被询问和检查的内容记录不良事件。
Statistical Analyses 统计分析
For all analyses, SPSS, version 20.0 (SPSS), was used. For continuous variables, the independent tt test and analysis of covariance were used to determine statistical significance between the atropine and control groups. The chi^(2)\chi^{2} tests were used to compare the categorized data. To explore potential risk factors, including age at baseline, sex, initial spherical equivalent, intraocular pressure, age at myopia onset, parental myopia, time outdoors, and near work, associated with progressors in atropine, 0.01%0.01 \%, group, the multiple log-binomial regression analysis was performed using those factors as the dependent variable. Analyses were only performed on the right eye. A 2 -sided PP-value less than .05 was considered statistically significant for the primary outcome. 对于所有分析，使用了 SPSS 20.0 版本（SPSS）。对于连续变量，使用独立 tt 检验和协方差分析来确定阿托品组和对照组之间的统计显著性。使用 chi^(2)\chi^{2} 检验来比较分类数据。为了探索与阿托品 0.01%0.01 \% 组进展者相关的潜在风险因素，包括基线年龄、性别、初始球面等效、眼内压、近视发病年龄、父母近视、户外时间和近距离工作，进行了多重对数二项回归分析，使用这些因素作为因变量。分析仅在右眼进行。对于主要结果，双侧 PP 值小于 0.05 被认为具有统计学显著性。
Results 结果
Between April 2018 and July 2019, a total of 268 children were initially assessed in this study; 21 of them did not meet the inclusion criteria, 12 of them met the exclusion criteria, and 15 of them declined to participate in this study, leaving 220 children were enrolled in the study with equal randomization to the atropine, 0.01%, and the placebo-control groups (Figure 1). At baseline, there were no relevant differences identified in demographics, initial SE, initial AL, IOP, age at myopia onset, parental myopia, time outdoors, and near work between 2 groups (Table 1). Twenty-five participants ( 11.4%11.4 \% ) did not complete the first 6 months of the study ( 16 in the atropine, 0.01%, group and 9 in the placebo group; Figure 1). Finally, a total of 76 children (69%) and 83 children (75%) allocated into 在 2018 年 4 月至 2019 年 7 月期间，本研究最初评估了 268 名儿童；其中 21 名未满足纳入标准，12 名符合排除标准，15 名拒绝参与本研究，最终有 220 名儿童被纳入研究，并随机分配到阿托品 0.01%组和安慰剂对照组（图 1）。在基线时，两个组在人口统计学、初始屈光度、初始眼轴、眼内压、近视发病年龄、父母近视、户外活动时间和近距离工作方面没有发现相关差异（表 1）。25 名参与者（ 11.4%11.4 \% ）未能完成研究的前 6 个月（阿托品 0.01%组 16 名，安慰剂组 9 名；图 1）。最终，共有 76 名儿童（69%）和 83 名儿童（75%）被分配到
the atropine, 0.01%, and placebo groups, respectively, returned for the 1-year primary outcome assessment visit (Figure 1). There was no significant difference in initial SE and AL between completed and discontinued patients in the atropine, 0.01%0.01 \%, group as well as placebo group. Baseline characteristics for those children who completed the 1-year fol-low-up are shown in eTable 1 in Supplement 2. 阿托品、0.01%和安慰剂组分别返回进行 1 年主要结果评估访视（图 1）。在阿托品、 0.01%0.01 \% 组以及安慰剂组中，完成和中断患者的初始 SE 和 AL 之间没有显著差异。完成 1 年随访的儿童的基线特征见补充材料 2 中的 eTable 1。
At the 1-year follow-up, the mean (SD) myopia progression values for the atropine, 0.01%0.01 \%, group and the placebo group were -0.49 (0.42) D and -0.76 (0.50) D (mean difference, 0.26 D ; 95% CI, 0.12-0.41 D; PP < .001), with relative reduction of 34.2%34.2 \% in myopia progression (Table 2). Nonprogressors had a mean myopia progression of -0.14 (0.23) D compared with -0.83 ( 0.24 ) D for progressors ( P < .001P<.001 ). The mean 1-year change in spherical equivalent was -0.49 D ( 95%95 \% CI, -0.59 to -0.39 D ) for the atropine, 0.01%0.01 \%, group and -0.77 D ( 95%CI,-0.8695 \% \mathrm{CI},-0.86 to -0.67 D ) for the placebo group (analysis of covariance, mean difference, 0.28 D ; 95%CI95 \% \mathrm{CI}, 0.14-0.42 D; PP < .001) after adjusting for age at baseline. The mean (SD) axial elongation values for the atropine, 0.01%0.01 \%, group and placebo group were 0.32 (0.19) mm and 0.41 (0.19) mm (mean difference, 0.09 mm ; 95% CI, 0.03-0.15 mm;P=.004\mathrm{mm} ; P=.004 ), with a reduction of 22.0%22.0 \% in axial elongation (Table 2). Nonprogressors had a mean (SD) axial elongation of -0.18(0.14)mm-0.18(0.14) \mathrm{mm}, compared with -0.45 ( 0.14 ) mm for progressors ( PP < .001). The mean 1-year change in axial length was 0.31 mm ( 95%95 \% CI, 0.27-0.35mm0.27-0.35 \mathrm{~mm} ) for the atropine, 0.01%0.01 \%, group and 0.41 mm ( 95%CI,0.37-0.45mm95 \% \mathrm{CI}, 0.37-0.45 \mathrm{~mm} ) for the placebo group (analysis of covariance, mean difference, 0.10 mm ; 95% CI, 0.05-0.16 mm; PP < .001) after adjusting for age at baseline. 在 1 年随访中，阿托品组和安慰剂组的平均（标准差）近视进展值分别为-0.49（0.42）D 和-0.76（0.50）D（均值差，0.26 D；95%置信区间，0.12-0.41 D； PP < .001），近视进展相对减少了 34.2%34.2 \% （表 2）。非进展者的平均近视进展为-0.14（0.23）D，而进展者为-0.83（0.24）D（ P < .001P<.001 ）。阿托品组的球面等效 1 年平均变化为-0.49 D（ 95%95 \% 置信区间，-0.59 到-0.39 D），安慰剂组为-0.77 D（ 95%CI,-0.8695 \% \mathrm{CI},-0.86 到-0.67 D）（协方差分析，均值差，0.28 D； 95%CI95 \% \mathrm{CI} ，0.14-0.42 D； PP < .001），调整基线年龄后。阿托品组和安慰剂组的平均（标准差）轴向延长值分别为 0.32（0.19）mm 和 0.41（0.19）mm（均值差，0.09 mm；95%置信区间，0.03-0.15 mm;P=.004\mathrm{mm} ; P=.004 ），轴向延长减少了 22.0%22.0 \% （表 2）。非进展者的平均（标准差）轴向延长为 -0.18(0.14)mm-0.18(0.14) \mathrm{mm} ，而进展者为-0.45（0.14）mm（ PP < .001）。阿托品组的轴长 1 年平均变化为 0.31 mm（ 95%95 \% 置信区间， 0.27-0.35mm0.27-0.35 \mathrm{~mm} ），安慰剂组为 0。41 毫米 ( 95%CI,0.37-0.45mm95 \% \mathrm{CI}, 0.37-0.45 \mathrm{~mm} ) 对于安慰剂组（协方差分析，平均差异，0.10 毫米；95% CI，0.05-0.16 毫米； PP < .001）在基线年龄调整后。
At 6 months, 81.6%81.6 \% of children progressed by less than 0.5 D in the atropine, 0.01%0.01 \%, group compared with 61.5%61.5 \% in the placebo group, whereas no children progressed by 1.00 D or greater, compared with 3.6% in the placebo group (Figure 2). At 12 months, 48.7%48.7 \% of children progressed by less than 0.50 D and 13.2%13.2 \% at least 1.00 D in the atropine, 0.01%0.01 \%, group, compared with 30.1%30.1 \% and 34.9%34.9 \%, respectively, in the placebo group (Figure 2). 在 6 个月时， 81.6%81.6 \% 的儿童在阿托品组中进展少于 0.5 D，而在安慰剂组中为 61.5%61.5 \% ，而且没有儿童进展达到 1.00 D 或更高，而安慰剂组为 3.6%（图 2）。在 12 个月时， 48.7%48.7 \% 的儿童在阿托品组中进展少于 0.50 D， 13.2%13.2 \% 至少为 1.00 D，而在安慰剂组中分别为 30.1%30.1 \% 和 34.9%34.9 \% （图 2）。
eTable 2 in Supplement 2 presents a comparison of demographics and other characteristics between nonprogressors and progressors in the atropine, 0.01%0.01 \%, group. In multiple logbinomial regression analyses, among the atropine, 0.01%0.01 \%, group, a higher risk of being a progressor was associated with initial SE (relative risk [RR], 1.324; 95% CI, 1.048-1.620; P=.004P=.004; eTable 3 in Supplement 2). The adjusted analysis showed that the risk of progressive myopia increased by 32.4%32.4 \% for every 1.0 D less initial SE. However, among the placebo group, no association was found for risk factors with progressors in multiple log-binomial regression analyses (eTable 4 in Supplement 2). 补充材料 2 中的表 2 展示了在阿托品 0.01%0.01 \% 组中，非进展者与进展者之间的人口统计学和其他特征的比较。在多重对数二项回归分析中，在阿托品 0.01%0.01 \% 组中，初始 SE 与成为进展者的较高风险相关（相对风险[RR]，1.324；95% CI，1.048-1.620； P=.004P=.004 ；补充材料 2 中的表 3）。调整后的分析显示，随着初始 SE 每减少 1.0 D，进展性近视的风险增加了 32.4%32.4 \% 。然而，在安慰剂组中，在多重对数二项回归分析中未发现与进展者的风险因素相关的关联（补充材料 2 中的表 4）。
No serious adverse events associated with atropine were reported. Five children ( 4.5%4.5 \% ) reported photophobia in the atropine, 0.01%0.01 \%, group compared with 1 child ( 0.9%0.9 \% ) in the control group. Allergic reactions were uncommon, with 4 children experiencing allergic conjunctivitis; 1 of them was in control group. None of the children in either group reported near-blurred vision. 与阿托品相关的严重不良事件没有报告。五名儿童（ 4.5%4.5 \% ）在阿托品组（ 0.01%0.01 \% ）中报告了畏光，而对照组中有 1 名儿童（ 0.9%0.9 \% ）报告了畏光。过敏反应不常见，有 4 名儿童出现过敏性结膜炎；其中 1 名在对照组。两个组中的儿童都没有报告近距离模糊视力。
Table 1. Demographics and Baseline Characteristics of Participants 表 1. 参与者的人口统计学和基线特征
