Five-Year Clinical Trial on Atropine
for the Treatment of Myopia2
Myopia Control with Atropine0.01%Eyedrops
Audrey Chia,FRANZCO,PhD,1,2Qing-Shu Lu,PhD,3,4Donald Tan,FRCS,FRCOphth1,2,4,5
Purpo:To compare the safety and efficacy of different concentrations of atropine eyedrops in controlling myopia progression over5years.
Design:Randomized,double-masked clinical trial.
Participants:A total of400children originally randomized to receive atropine0.5%,0.1%,or0.01%once daily in both eyes in a2:2:1ratio.
Methods:Children received atropine for24months(pha1),after which medication was stopped for12 months(pha2).Children who had myopia progression(!À0.50diopters[D]in at least1eye)during pha2 were restarted on atropine0.01%for a further24months(pha3).
视频课堂Main Outcome Measures:Change in spherical equivalent and axial length over5years.
Results:There was a do-related respon in pha1with a greater effect in higher dos,but an inver do-related increa in myopia during pha2(washout),resulting in atropine0.01%being most effective in reducing myopia progression at3years.Some24%,59%,and68%of children originally in the atropine0.01%, 0.1%,and0.5%groups,respectively,who progresd in pha2were restarted on atropine0.01%.Younger children and tho with greater myopic progression in year1were more likely to require re-treatment.The lower myopia progression in the0.01%group persisted during pha3,with overall myopia progression and change in axial elongation at the end of5years being lowest in this group(À1.38Æ0.98D;0.75Æ0.48mm)compared with the0.1%(À1.83Æ1.16D,P¼0.003;0.85Æ0.53mm,P¼0.144)and0.5%(À1.98Æ1.10D,P<0.001;0.87Æ0.49 mm,P¼0.075)groups.Atropine0.01%also caud minimal pupil dilation(0.8mm),minimal loss of accom-modation(2e3D),and no near visual loss compared with higher dos.
Conclusions:Over5years,atropine0.01%eyedrops were more effective in slowing myopia progression with less visual side effects compared with higher dos of atropine.Ophthalmology2016;123:391-399ª2016 by the American Academy of Ophthalmology.
See Editorial on page232.
Several studies have shown that atropine eyedrops are effective in slowing myopia progression in young child-ren.1e19In our past Atropine for the Treatment of Myopia (ATOM)1and2(phas1and2)clinical trials,we demonstrated a do-related respon to atropine,with higher dos inhibiting myopia progression to a slightly greater degree than lower dos,although the myopia pro-gression ofÀ0.49diopters(D),À0.38D,andÀ0.30D in the atropine0.01%,0.1%,and0.5%groups,respectively, were not significantly different at24months.16,19However, when atropine was stopped for12months after24months of treatment(pha2of ATOM2),there was a rapid increa in myopia in children originally treated with higher concen-trations of atropine,whereas tho receiving the lowest concentration of0.01%showed minimal change.18,20This resulted in myopia progression being significantly lower in children previously assigned to the0.01%group(À0.72D) at36months compared with that in the0.1%(À1.04D)and 0.5%(À1.15D)groups.In addition,the lowest do also caud less photopic pupil dilation(0.74mm,compared with2.25and3.11mm in the0.1%and0.5%groups, respectively)and no clinically significant loss in accom-modation or near visual acuity(4.6D,compared with10.1 and11.8D in the0.1%and0.5%groups,respectively).20 Although proven effective and safe in the short-term, there was concern about the long-term effectiveness of atropine,particularly in children who experienced an in-crea in myopia after atropine was stopped.In thefinal pha(pha3),spanning t
he fourth andfifth years of the ATOM2study,children who continued to progress(>0.5 D/year)during pha2(the washout year)were re-treated with atropine0.01%.The aim of this study was to eval-uate the efficacy and safety of atropine over this last pha and the entire5-year study period.
In pha1of the ATOM2study(treatment pha),400Asian children(aged6e12years)with myopia ofÀ2.00D or wor in each eye were randomized to receive atropine0.01%,0.1%,
and
0.5%once nightly in both eyes for2years.Children were assigned to treatment in a1:2:2ratio,stratified by6gender and age strata.In
pha2(washout pha),atropine was stopped and children were monitored for12months.In pha3(re-treatment pha),children who exhibited myopia progression ofÀ0.50D or more in at least1 eye during the washout pha were restarted on atropine0.01%for a further24months.
Written informed connt was obtained from parents and verbal asnt was obtained from children before randomization.The in-vestigators,study team performing the ocular measurements,par-ents,and children were masked to an initial do of atropine throughout the entire5-year study,and the study team was also blinded to whether or not children were restarted on atropine during the last pha of the study.
After asssment at a screening visit,children were reassd again after they had been receiving atropine for2weeks(baline visit).Children were then reviewed every4months during pha1, at26,32,and36months during pha2,and all children,including tho who were not restarted atropine treatment,were reviewed every6months during pha3and then again in2months after all medication had been stopped.
At each visit,cycloplegic autorefraction,axial length(AL),mesopic and photopic pupil size,accommodation and distance,and near loga-rithm of the minimum angle of resolution visual acuity were measured.19,20Cycloplegia was achieved using3drops of cyclo-pentolate1%administered5minutes apart,and cycloplegic autore-fraction was measured,30minutes after the last drop,using a Canon RK-F1autorefractor(Canon Inc.Ltd.,Tochigiken,Japan).Five read-ings,all of which were within0.25D apart,were averaged.Spherical equivalent was calculated as the s
phere plus half cylindrical power. Axial length was obtained using the Zeiss IOL Master(Carl Zeiss Meditec Inc.,Dublin,CA).Five readings,all within0.05mm or less, were averaged.The photopic pupil size was measured using the Neu-roptics pupillometer(Neuroptics Inc.,Irvine,CA)at300lux of lumi-nance.Accommodation was measured using the Royal Air Force rule while the subjects ud their best-corrected distance spectacles.Dis-tance and near vision were measured using logarithm of the minimum angle of resolution Early Treatment Diabetic Retinopathy Study charts.
The primary outcome was progression of myopia,defined as change in spherical equivalent over pha3and the entire5-year study period.The condary outcome was change in AL.Other study variables include changes in photopic pupil size,accom-modation,and distance/near visual acuity.
The study was conducted according to the tenets of the Declaration of Helsinki.Ethics approval was obtained from the Singapore Eye Rearch Institute Review Board,and the study was registered with vwebsite(registration no: NTC00371124).
Statistical Analysis
All analys were bad on an intention-to-treat principle and performed using the statistical software SASv9.3(SAS Inc.,Cary, NC).Data were summarized by initial atropine treatment group in t
he re-treated and untreated children at the pha3stage.For person-level data such as gender,the Fisher exact test was ud to test for the difference in proportion of children between groups, and analysis of variance was ud for the difference in means between groups.Data of ocular parameters from both eyes were pooled in a combined analysis using the Huber e White robust standard errors to allow for correlation between eyes within a person.21Although P values(without adjustment for multiple comparison)were obtained for both the global null hypothesis of no difference among treatment groups and the pairwi comparison,interpretation only began with considering the global null hypothesis to prevent inflation of type I error rate.Among the400children enrolled in the study,44were lost in pha1and11were lost in pha2,with345(86%)continuing to pha3(Fig1).Children still in the study at the start of pha3 were more myopic at baline but had less myopic progression over thefirst year compared with children who were lost to follow-up(Table1).The majority of the children(91%)were of ethnic Chine origin.
天津mba辅导Of the345children,192(56%)were restarted on atropine 0.01%becau they had progresd0.5D or more during the preceding pha2washout year;this included17of70children (24%)in the0.01%group,82of139children(59%)in the0.1% group,and93of136children(68%)in the0.5%group(Fig2). Compared with children who were not restarted on atropine, tho restarted on
treatment were younger,had less myopia and shorter AL at baline,but had greater myopia progression and change in AL during thefirst year of the study(Table1). Multivariate analysis revealed that younger age and assignment to higher initial atropine do predispod children to greater myopic progression in pha2(Table2)and thus more likely to be re-treated with atropine0.01%in pha3.delis
Myopia Progression
Children who required re-treatment had higher rates of myopia progression during thefirst24months(pha1)and in the washout pha(pha2)compared with tho who did not require re-treatment(Table3).In the re-treated children,mean annual myopia progression during pha3(À0.38toÀ0.52D)was lower than in the preceding pha2period(À0.62toÀ1.09D)in all3 atropine groups,but higher than tho who did not require re-treatment(À0.30toÀ0.38D)(Table3).The overall mean myopia progression in pha3wasÀ0.69Æ0.46D,À0.81Æ0.57 D,andÀ0.84Æ0.61D in the atropine0.01%,0.1%,and0.5% groups,respectively(P¼0.09)(Fig3).In contrast,the mean myopia progression over the entire5years was less in the0.01% group(À1.38Æ0.98D)than in the0.1%(À1.83Æ1.16D,P¼0.003)and0.5%(À1.98Æ1.10D,P<0.001)groups.
The rate of myopic progression in children restarted on atropine slowed in pha3.The mean increa in myopia over the fourth andfifth years(À0.86Æ0.56D in0.01%group,À0.87Æ0.59D in 0.1%group,À0.90Æ0.66D in0.5%group)was similar to that in children originally assigned to the0.01%group,who required re-treatment during pha1(À0.77Æ0.49D,P>0.286),suggesting that re-treatment with0.01%was as effective as primary treatment with atropine0.01%(Table3).
Overall,fewer eyes progresd by!2.0D in the original atropine0.01%(27%)group compared with tho in the0.1% (41%)and0.5%(47%)groups at the end of the study(P¼0.006) (Fig4).The percentages of high myopia(myopia!6.0D)in both eyes was44%,49%,and50%in the atropine0.01%,0.1%,and 0.5%groups,respectively(P¼0.70).Very high myopia (myopia of!8.0D in both eyes)was noted in7%,9%,and 17%of children in the0.01%,0.1%,and0.5%groups, respectively(P¼0.07).
Change in Axial Length
There was no significant difference in AL in all3atropine groups at the start of pha3(P¼0.653)(Fig5).However,by the end of pha3,the mean change in AL was smaller in the0.01%group (0.19Æ0.18mm)compared with the0.1%(0.24Æ0.21mm,P¼0.042)and0.5%(0.26Æ0.23mm,P¼0.013)
groups(Table3). The mean overall change in AL over5years was0.75Æ0.48the son
Ophthalmology Volume123,Number2,February2016
mm,0.85Æ0.53mm,and 0.87Æ0.49mm in the 0.01%,0.1%,and 0.5%groups,respectively (P ¼0.185).
In the children who were not restarted on atropine,AL elon-gation gradually slowed during pha 3and there was no difference in AL among groups at 5years (P ¼0.555)(Table 3).In children in whom atropine was restarted,AL elongation slowed in all groups (0.32Æ0.22mm in 0.01%group,0.27Æ0.25mm in 0.1%group,0.29Æ0.25mm in 0.5%group)over pha 3to a rate
lower than that noted during pha 1in the 0.01%group that required re-treatment (0.58Æ0.27mm,P <0.001).
Change in Pupil Size,Accommodation,and Distance/Near Vision
At 36months,before restarting children on atropine,the pupil size,accommodation,and near vision were similar in all 3groups
Table 1.Comparison of Subjects Who Required Re-treatment and Tho Who Did Not,and Tho Still in Study and Tho Lost To
Follow-up at 3Years
Re-treated Children n [192(55.6%)
Untreated Children n [153(44.4%)
P Value Still in Study (at 3Years)n [345(86.2%)
Lost to Follow-up n [55(13.8%)
P Value Age at screening,yrs,
mean (SD)9.1(1.3)10.5(1.2)<0.0019.7(1.5)9.5(1.9)0.329Male,n (%)
104(54.2)75(49.0)0.386179(51.9)32(58.2)0.467Spherical equivalent (D)Baline,mean (SD)À4.34(1.64)À4.70(1.51)0.031À4.50(1.59)À3.89(1.71)0.018Change at 1yr À0.30(0.47)À0.20(0.48)0.033À0.25(0.48)À0.64(0.66)0.003AL (mm)
Baline,mean (SD)25.05(0.91)25.30(0.86)0.00825.16(0.90)25.00(0.92)0.225Change at 1yr
0.17(0.17)
0.10(0.16)
<0.001
0.14(0.17)
mention0.28(0.29)
0.008
AL ¼axial length;SD ¼standard
deviation.
Figure 1.Subject flowchart of Atropine for the Treatment of Myopia (ATOM)2.
Chia et al
Atropine for the Treatment of Childhood Myopia
(Table 4).On restarting atropine 0.01%,there was a mean increa in photopic pupil size of approximately 1mm and a loss of accommodation of 2.00to 3.00D,which were similar to the change noted in eyes treated with atropine 0.01%during pha 1(Table 4).The mild side effects were deemed clinically insigni ficant,becau there was no change or loss in distance or near visual acuity.Children were offered progressive addition or photochromatic (tinted)glass if they encountered near blur or glare.During pha 1,7%of children receiving atropine 0.01%requested glass,19but no child who was restarted on atropine 0.01%requested glass during pha 3.Pupil size and accommodation returned to levels similar to tho in untreated children at the final visit (2months after stopping atropine).
In our first randomized placebo-controlled clinical trial using atropine eyedrops to control myopia pro
gression in children (ATOM1),we established the clinical safety and ef ficacy of atropine 1%at least in the short term.16,18In pha 1of ATOM2,we established that atropine 0.01%was almost as effective in reducing myopia progression as higher concen-trations but with minimal pupil dilation accommodation and
near vision loss.19,20In pha 2,we further established that children receiving lower dos had less myopic progression after atropine was stopped,20resulting in 0.01%being more effective in reducing myopia progression at 3years.
In the last pha of ATOM2(pha 3),all children with myopia progression of À0.50D or more in the washout year were restarted on atropine 0.01%for a further 24months.Fewer children in the 0.01%group (24%)needed re-treatment compared with children in the 0.1%(59%)and 0.5%(68%)groups (Fig 2).By the end of the study,the overall 5-year progression of myopia was less in the 0.01%group (À1.38Æ0.98D)compared with the 0.1%(À1.83Æ1.16,P ¼0.003)and 0.5%(À1.98Æ1.10D,P <0.001)groups (Fig 3).This was largely becau fewer children in the 0.01%group progresd after atropine was stopped,and the rate of progression in the washout year in tho who needed re-treatment was also less in the 0.01%group (À0.63D,À0.94D,and À1.09D in the 0.01%,0.1%,and 0.5%groups,respectively)(Table 3).The subquent myopic progression in children
who required re-treatment was similar between groups over the last 2years (À0.86to À0.91D),which was also similar to that in children in the 0.01%group who required re-treatment over the first 2years (À0.79D).This suggests that re-treatment with atropine 0.01%could be as effective as primary treatment with atropine 0.01%,and that clinicians may be able to titrate treatment by stopping and restarting treatment according to individual progression rates (Table 3).
Findings from the ATOM1and ATOM2studies are summarized in Figure 6.Conducted a few years apart,both studies had similar study designs,with the main differences being that children in the ATOM2study were slightly older (9.7vs.9.2years)and had slightly higher levels of baline myopia (À4.7D vs.À3.5D).16,19,20By combining the 2studies,we found that in the initial 8months,there was a hyperopic shift in the 1.0%group and continued myopic progression in the other groups,which was greater in the lower dos,before growth slowed between the 8-and 24-month periods.By the end of pha 1,there was clustering of mean myopia progression between 0.2and 0.5D in the atropine-treated eyes,compared with 1.2D in the placebo eyes.16,19This plateauing of myopia progression in the cond year suggests that there may be a maximal effect
Table 2.Regression Analysis of Myopic Rebound (Change in Spherical Equivalent)during Pha 2(Washout)Period
Baline Characteristics Unadjusted Analysis
Adjusted Analysis
Coef ficient (95%CI)P Value Coef ficient (95%CI)P Value Age 0.16(0.13e 0.19)<0.0010.16(0.13e 0.18)<0.001Gender Female 0.03(À0.07to 0.14)
0.5290.02(À0.06to 0.10)
0.584Male
-0
成人初学者-Spherical equivalent À0.03(À0.06to À0.003)0.031À0.01(À0.04to 0.01)0.229Treatment group Atropine 0.01%0
-0
-Atropine 0.1%À0.40(À0.50to À0.31)<0.001À0.40(À0.49to À0.31)<0.001Atropine 0.5%À0.60(À0.70to À0.49)
<0.001
À0.60(À0.70to À0.51)
<0.001
CI ¼con fidence
interval.
Figure 2.Percentage of children in each atropine group who required re-treatment at 3years with atropine 0.01%,0.1%,and 0.5%becau they had progresd by more than 0.50diopters (D)during the washout period (pha 2).
Ophthalmology Volume 123,Number 2,February 2016
summervacationafter which higher dos are ineffective.After stopping atropine,there was a significant myopic progression in eyes receiving higher dos with myopia than in eyes previously receiving atropine1.0%,almost approaching that of placebo eyes,with less change noted in lower dos.18,20 Much of the changes noted could be explained by the pharmacologic effect of atropine on the actively growing myopic eye.Although the exact mechanism of atropine is not known,it is believed that atropine acts directly or indirectly on the retina or sclera,inhibiting thinning or stretching of the sclera,and thereby eye growth.20,22This eye growth possibly involves a ries of biochemical steps, and atropine presumably inhibits1or more steps along this pathway,creating changes in the feedback mechanisms and up-or downregulating other receptors both up-and down-stream.When atropine is withdrawn,it is not surprising that there may be a sudden growth spurt as the inhibitory action is relea
d.If the process involved a simple inhibition of growth,then one would expect that after a sudden increa, eyeball growth would then slow to a rate appropriate for age.However,the rate of growth emed to continue at a steady pace over the washout year in children previously receiving the higher0.1%and0.5%dos of atropine,slowing only when atropine0.01%was restarted.This suggests that the effects,particularly of higher dos of atropine,may be more complex than we think,possibly causing change or modification of the mechanism regulating eye growth at different anatomic and biochemical levels.20,22It is uncertain whether the changes could be ,resulting in sustained acceleration of myopia even years after stopping atropine),the system will ret itlf,or we can modulate subquent eye , by tapering atropine more slowly over time).Somewhat reassuring is thefinding that the proportion of children who progresd>0.5D in the washout ,requiring re-treatment)decread with increasing age in all3treatment arms(Fig2).From clinical experience,we also note that by slowly tapering the frequency of atropine,we can dampen the change in myopia and retain the beneficial effect on myopia progression.In contrast,the change in myopia progression after stopping atropine0.01%emed less marked,and it is hoped as AL growth slowed naturally,as it did during pha3,that atropine could be safely ,by the mid to late-teens).
On the basis of the results,we conclude that low-do (0.01%)atropine for periods up to5years is a clinical viable
Table3.Demographics and Changes in Spherical Equivalent and Axial Length in Children within Different Atropine Groups(0.01%,
0.1%,and0.5%)Who Were Re-treated and Who Did Not Require Re-treatment
Re-treated Children
P Value Untreated Children
P Value
Atropine 0.01% N¼17 (24.3%)Atropine
0.1%
light是什么意思
N¼82
(58.9%)
Atropine
0.5%
N¼93
(68.4%)
Atropine小学一年级阅读
0.01%
N¼53
(73.5%)报纸的拼音
Atropine
0.1%
N¼57
(41.1%)
Atropine
0.5%
N¼43
(31.6%)
Age at screening,yrs,mean(SD)8.6(1.1)9.0(1.3)9.2(1.4)0.26110.0(1.3)10.7(1.2)10.9(1.0)<0.001 Male,n(%)9(52.9)43(52.4)52(55.9)0.90827(50.9)31(54.4)17(39.5)0.317 SE,D,mean(SD)
BalineÀ4.07(1.26)À4.31(1.40)À4.41(1.89)0.617À4.80(1.55)À4.76(1.35)À4.49(1.65)0.593 24mosÀ4.84(1.22)À4.84(1.29)À4.74(1.76)0.898À5.12(1.63)À4.88(1.30)À4.63(1.61)0.332 36mosÀ5.47(1.27)À5.78(1.28)À5.83(1.78)0.554À5.27(1.64)À5.18(1.36)À5.05(1.54)0.772 48mosÀ5.76(1.42)À6.16(1.48)À6.28(1.93)0.406À5.58(1.81)À5.54(1.51)À5.46(1.75)0.939 60mosÀ6.20(1.59)À6.63(1.67)À6.77(2.19)0.428À5.86(1.85)À5.91(1.75)À5.80(1.83)0.948 Change in SE,D,mean(SD)
Baline to12mosÀ0.54(0.43)À0.41(0.47)À0.16(0.45)<0.001À0.31(0.45)À0.14(0.51)À0.13(0.44)0.055 12e24mosÀ0.24(0.36)À0.12(0.41)À0.17(0.40)0.419À0.01(0.36)0.02(0.37)À0.05(0.37)0.638 24e36mosÀ0.63(0.31)À0.94(0.33)À1.09(0.43)<0.001À0.16(0.24)À0.30(0.30)À0.38(0.34)<0.001 36e48mosÀ0.42(0.47)À0.38(0.50)À0.42(0.51)0.880À0.30(0.39)À0.36(0.42)À0.38(0.37)0.575 48e60mosÀ0.44(0.48)À0.52(0.44)À0.49(0.56)0.762À0.34(0.38)À0.36(0.42)À0.32(0.34)0.910 Baline to60mosÀ2.25(1.11)À2.34(1.07)À2.32(1.04)0.950À1.12(0.77)À1.13(0.88)À1.27(0.86)0.631 AL,mm,mean(SD)
Baline24.97(0.84)24.97(0.81)25.14(0.99)0.41925.37(0.98)25.32(0.78)25.21(0.81)0.654 24mos25.55(0.89)25.33(0.83)25.45(1.05)0.50625.68(1.06)25.47(0.81)25.38(0.84)0.274 36mos25.89(0.92)25.76(0.85)25.87(1.06)0.65925.82(1.10)25.66(0.85)25.56(0.85)0.385 48mos26.01(0.94)25.92(0.91)26.08(1.10)0.58125.91(1.10)25.79(0.87)25.66(0.86)0.442 60mos26.16(0.98)26.07(0.95)26.20(1.14)0.69225.96(1.11)25.86(0.88)25.74(0.88)0.555 Change in AL,mm,mean(SD)
Baline to12mos0.30(0.15)0.18(0.17)0.13(0.16)<0.0010.18(0.15)0.05(0.16)0.06(0.15)<0.001 12e24mos0.28(0.15)0.19(0.13)0.18(0.11)0.0200.14(0.13)0.10(0.11)0.11(0.10)0.183 24e36mos0.34(
0.13)0.43(0.14)0.42(0.18)0.0070.14(0.09)0.18(0.12)0.17(0.14)0.093 36e48mos0.17(0.15)0.15(0.15)0.17(0.16)0.7420.08(0.09)0.13(0.10)0.10(0.09)0.018 48e60mos0.15(0.11)0.12(0.12)0.12(0.13)0.5720.06(0.08)0.07(0.09)0.08(0.10)0.550 Baline to60mos 1.21(0.54) 1.08(0.53) 1.03(0.47)0.3720.60(0.35)0.54(0.34)0.54(0.34)0.495 AL¼axial length;D¼diopter;SD¼standard deviation;SE¼spherical equivalent.
Chia et al Atropine for the Treatment of Childhood Myopia
