Bibliographic data
`
`Title:
`
`COMPOSITION AND/OR METHOD FOR REDUCING AND/OR
`PREVENTING MYOPIA PROGRESSION COMPRISING
`ATROPINE
`
`Pub/Pat no:
`
`WO2012161655A1
`
`Pub/Issue Date:
`
`2012-11-29
`
`Inventor(s):
`
`Applicant(s):
`
`TAN DONALD |CHUA WEL HAN
`
`SINGAPORE HEALTH SERVPTE LTD[SG]/ TAN DONALD
`[SG]| CHUA WEI HAN[SG]
`
`Classification:
`
`AGIK31/46AL; A61P27/10AL
`
`Application number;9WO2012SG00174 2012-05-18
`
`Priority number:
`
`1$201161489016P 2011-05-23:
`
`Abstract of WO2012161655A1
`
`The invention relates to a composition and/or method for reducing and/or preventing myopia,
`progression. The composition coniprises an ultra-low atropine concentration. The composition
`comprises less than 0.025% atropine. For example, the composition comprises about 0.01%
`atropine. The ultra-low atropine composition reduces and/or prevents myopia progression with
`negligible side effecis, suchas loss of accommodation, mydriasis, near-vision blur, allergic
`conjunctivitis and dermatitis.
`
`

`

`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(19) World Intellectual Property
`Organization
`
`COQ ATACATTAAA
`
`InternationalBureau
`
`Zz
`\
`=<
`(43) International Publication Date
`29 November2012 (29.11.2012) WIPO! PCT
`
`GD)
`
`International Patent Classification:
`A61K 31/46 (2006.01)
`AGIP 27/10 (2006.01)
`
`(81)
`
`(21)
`
`International Application Number:
`
`PCT/SG2012/000174
`
`(22)
`
`International Filing Date:
`
`Filing Language:
`
`Publication Language:
`
`18 May 2012 (18.05.2012)
`
`English
`
`English
`
`Priority Data:
`61/489,016
`
`23 May 2011 (23.05.2011)
`
`us (84)
`
`Applicant (for all designated States except US): SINGA-
`PORE HEALTH SERVICES PTE LTD [SG/SG]; 31
`Third Hospital Avenue, #30-03 Bowyer Block C, Singa-
`pore 168753 (SG).
`
`(10) International Publication Number
`WO 2012/161655 Al
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI NO, NZ,
`OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE,ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SL SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`
`(25)
`
`(26)
`
`(30)
`
`(7)
`
`(72)
`(75)
`
`(74)
`
`
`
`wo2012/161655A1|IMIIMNNINMIIMTANMIMTTYAAAAATA
`
`Inventors; and
`(for US only): TAN, Donald
`Inventors/Applicants
`[SG/SG]; 49 Oei Tiong Ham Park, Singapore 267054
`(SG). CHUA, Wei, Han [SG/SG]; 5 Nathan Road, #01-01, Declarations under Rule 4.17:
`Singapore 248727 (SG).
`
`Agent: CHUNG,Jing, Yeng; Marks & Clerk Singapore
`LLP, Tanjong Pagar, P.O. Box 636, Singapore 910816
`(SG).
`
`of inventorship (Rule 4.17(iv))
`Published:
`
`_
`
`with international search report (Art. 21(3))
`
`(54) Title: COMPOSITION AND/OR METHOD FOR REDUCING AND/OR PREVENTING MYOPIA PROGRESSION COM-
`PRISING ATROPINE
`
`
`
`
`(D) o oOo
`
`SphericalEquivalent
`
`2w
`
`4m
`
`8m
`
`12m
`
`16m
`
`20m
`
`24m
`
`—A- Placebo (ATOM1) -O—- A0.01%
`—@—A0.5%
`—k— A 1.0% (ATOM1)
`
`—~O- A0.1%
`
`(57) Abstract: The invention relates to a composition and/or method for reducing and/or preventing myopia progression. The com-
`position comprises an ultra-low atropine concentration. The composition comprises less than 0.025% atropine. For example, the
`composition comprises about 0.01% atropine. The ultra-low atropine composition reduces and/or prevents myopia progression with
`negligible side effects, such as loss of accommodation, mydriasis, near-vision blur, allergic conjunctivitis and dermatitis.
`
`Figure 5
`
`

`

`WO 2012/161655
`
`PCT/SG2012/000174
`
`COMPOSITION AND/OR METHOD FOR REDUCING AND/OR
`
`PREVENTING MYOPIA PROGRESSION COMPRISING ATROPINE
`
`Field of the invention.
`
`The present invention relates to a composition and/or method for reducing and/or
`
`preventing myopia progression.
`
`In particular,
`
`the invention relates to an ultra-low
`
`concentration atropine solution for reducing and/or preventing myopia progression.
`
`Background of the invention
`
`Myopia (nearsightedness or short sightedness) is a type of refractive error of the eye,
`in which the visual image is focused in front of the retina, typically resulting in blurred
`vision of distant objects. Myopia is especially prevalent among Asians and has been
`reported to be as high as 70-90%in Asian countries. Myopia may be corrected by
`prescription lenses (for example, spectacies or contact lenses) or refractive surgery (for
`
`example, LASIK or phakic intraocular jens implantation).
`
`. After onset of myopia, which typically occurs during early childhood, its progression is
`often difficult to control. Atropine is a non-specific muscarinic antagonist. Atropine at
`
`15
`
`1.0% and 0.5% has been demonstrated through randomised irials to be effective in
`
`slowing myopia progression (Shih ef a/., 1999). The safety profile, and associated side-
`local and systemic effects of atropine(i.e. its effect on pupil size and accommodation),
`however, has often been a source of concern, and has greatly deterred the useof this
`
`medication for myopia control. Every unit
`
`increase in pupil size results in an
`
`20
`
`exponential increase in the amountof light entering the eye, and this may cause giare
`and photophobia. The long term effect of excessive amounts of ultraviolet light entering
`an eye which has been chronically dilated with atropine may potentially increase the
`
`risk of cataract or macular degeneration. Atropine also decreases accommodation
`
`amplitude (ability to focus on near objects), thus reducing near vision so that children
`
`25
`
`may require bifocal or progressive glasses to read or see close objects.
`
`In atropine in the treatment of myopia study 1 (ATOM1), 1% atropine was reported to
`be effective in slowing the progression of myopia (Chuaet al., 2006). Side effects were
`
`recognised with 1 % atropine treated eyes,
`
`including blurring of near vision in the
`
`

`

`WO 2012/161655
`
`PCT/SG2012/000174
`
`atropine-treated eye (likely due to cycloplegia) and anisocoria or uneven pupil size,
`(likely due to mydriasis).
`
`In a retrospective non-randomized study, Leeef a/., (2006) found that myopia in 21
`children aged 6-12 years on 0.05%atropine progressed at a rate of 0.28 + 0.26 D per
`
`year, compared to 0.75 + 0.35 D per year in 36 consecutive untreated clinic patients.
`‘Negative side effects including photophobia and hampered nearvision were reported in
`the subjects.
`
`In another retrospective review of 50 pre-myopic children, 24 of whom werestarted on
`
`0.025% atropine, Fang ef a/., (2010) noted that subsequent myopia shift was less (-
`
`10
`
`0.14 + 0.24 D) in the 0.025% atropine group, compared to controls (-0.58 + 0.34 D).
`Both the control group and the 0.025% atropine group exhibited photophobia although
`the difference was not significant. None of the subjects complained of near-vision blur.
`
`It is desirable to provide an atropine composition for reducing and/or preventing myopia
`' progression with negligible or minimal side effects.
`
`15
`
`Summaryof the invention
`
`The present composition provides an ultra-low concentration atropine composition for
`
`reducing and/or preventing myopia progression.
`
`According toafirst aspect, the present invention provides a composition for reducing
`and/or preventing myopia progression comprising less than 0.025%atropine.
`
`20
`
`the invention relates to the use of atropine in the
`According to another aspect,
`preparation of a composition for reducing and/or preventing myopia progression,
`
`wherein the composition comprises less than 0.025%atropine.
`
`reducing and/or preventing myopia
`The invention also provides a method for
`progression comprising administering to a subject a composition comprising less than
`0.025%atropine.
`.
`
`25
`
`

`

`WO 2012/161655
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`PCT/SG2012/000174
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`Brief description of the figures
`
`Figure 1 is a flow chart illustrating the study design of ATOM1.
`
`Figure 2 is a graph showing mean spherical equivalent change from baseline fram
`
`ATOM1.
`
`Figure 3 is a graph showing meanaxial length change from baseline from ATOM1.
`
`Figure 4 is a flow chart illustrating the study design of ATOM2.
`
`Figure 5 is a graph showing the mean change in spherical equivalent for groups from
`
`baseline 2 to 24 months with 0.01%, 0.1% and 0.5% atropine from ATOM2 and
`1% atropine and placebo from ATOM1.
`
`10
`
`Figure 6 is a graph illustrating progression of myopia according to severity (pooled
`
`eyes) with 0.01%, 0.1% and 0.5% atropine from ATOM2 and 1%atropine and placebo
`
`from ATOM1. Myopia progression from baseline 2 is classified as severe (if > 1 D),
`
`moderate (0.5-0.99 D) and mild (if <0.5 D).
`
`Figure 7 is a graphillustrating the main change in axial lengths from baseline 2 to 24
`months from ATOM2.
`.
`
`15
`
`Figure 8 is a graph illustrating the changes in spherical equivalent in groups from
`ATOM2after stopping atropine for 1 year.
`
`Figure 9 is a graphillustrating the changes in axial iength in groups from ATOM2after
`stopping atropine for 1 year.
`.
`
`20
`
`Definitions
`
`The term “about” when used in conjunction with a value, for example about 0.01%,
`
`for 0.01%, 0.006%,
`means a value reasonably close to the value. For example,
`0.007%, 0.008%, 0.009%, 0.0095%, 0.0099%, 00011%, 0.0115%, 0.012%, 0.013%,
`0.014% would be included. In particular, it would include the value itself.
`
`25
`
`

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`WO 2012/161655
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`PCT/SG2012/000174
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`“Accommodation” refers to .the process by which the eye adjusts to a near focus, to
`maintain a clear image (focus) on an object as its distance changes.
`
`“Amblyopia” (also knownas“lazy eye”) refers to a decreaseof vision, either unilaterally
`or bilaterally, with no apparent structural abnormality in the eye.
`In amblyopia, visual
`5_stimulation eitherfails to transmit or is poorly transmitted through the optic nerve to the
`
`brain.
`
`“Anisocoria” refers to a condition where the pupils of the eyes are unevenin size.
`
`“Cycloplegia” refers to paralysis of the ciliary muscle of the eye, resulting in a loss of
`
`accommodation.
`
`1
`
`“Mydriasis” refers to a condition where the pupil of the eye is dilated due to disease,
`trauma or the use of drugs. Mydriasis may be associated with glare intolerance and
`photophobia.
`
`“Photophobia” refers to a condition of sensitivity to light.
`In ordinary medical terms,
`photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to
`the eyes due to light exposure.
`
`“Strabismus” (also known as “crossed eyes”) refers to a condition in which the two eyes
`
`do not line up in the samedirection, and therefore do not look at the same object at the
`
`same time.
`
`Detailed description of the invention
`
`invention comprises an ultra-low concentration of
`~The composition of the present
`atropine, ie.
`less than 0.025% atropine. The concentration of atropine in the
`composition may be any value less than 0.025%, for exampie, the composition may
`comprise 0.001 to 0.0249%atropine; 0.005% to 0.0249%atropine, 0.01 to 0.0249%
`
`atropine, 0.005 to 0.02%atropine, 0.05 to 0.015% atropine or 008 to 0.012% atropine.
`Accordingly,
`the “composition may comprise 0.001%, 0.002%, 0.003%, 0.004%,
`0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.011%, 0.012%, 0.013%, 0.014%,
`
`0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.02%, 0.021%, 0.022%, 0.023%, 0.024%,
`
`10
`
`15
`
`20
`
`25
`
`—___.--0..0245%-or.0.0249%.-atropine._in_particular,_the-composition.comprises-about_0.01%__
`
`

`

`WO 2012/161655
`
`PCT/SG2012/000174
`
`atropine. More in particular, the composition comprises 0.01%. The composition may
`further comprise at least one pharmaceutically acceptable excipient.
`
`The composition according to any aspect of the invention may be for use in reducing
`and/or preventing myopia progression and/or
`treating myopia. Accordingly,
`the
`invention includes a method of
`reducing and/or preventing myopia progression
`
`comprising administering to a subject a composition according to any aspect of the
`
`invention. The composition is
`
`for administration to the eye.
`
`In particular,
`
`the
`
`composition is for topical administration to the eye. More in particular, the composition
`is an eye-drop composition
`
`10
`
`After onset, myopia typically progresses during childhood and may only stabilise in
`adulthood. Accordingly,
`the composition is suitable for reducing and/or preventing
`myopia progression in subjects where myopia is still progressing and/or has not
`stabilised, even in late adulthood. For exampie, the composition is suitable for reducing
`
`and/or preventing myopia progression in subjects from 3 to 30 years old, where myopia
`
`15
`
`is still progressing and/or has not stabilised.
`
`In particular, the composition is suitable
`
`for reducing and/or preventing myopia in children from 6 to 72 years old.
`
`Accordingly,
`
`the invention also provides a method for reducing and/or preventing
`
`myopia progression comprising administering to a subject a composition according to
`
`any aspect of the invention.
`
`20
`
`In a study (Example 2), 400 children were administered either 0.01%, 0.05% or 0.1%
`atropine nightly to both eyes and myopia progression was monitored over a period of 2
`
`years. The results of this study showed that 0.01% atropine was found to induce
`
`negligible side-effects (for example:
`
`loss of accommodation, mydriasis, allergic
`
`conjunctivitis, dermatitis) compared to. atropine at 0.1% and 0.05% and retains
`
`25
`
`comparable efficacy in controlling myopia progression.
`
`the same will be more readily
`Having now generally described the invention,
`understood through reference to the following examples which are provided by way of
`
`illustration, and are not intended to be limiting of the present invention.
`
`

`

`WO 2012/161655
`
`PCT/SG2012/000174
`
`EXAMPLES
`
`1
`
`Example 1 First atropine in the treatment of myopia study (ATOM1)
`
`In ATOM1, 400 children aged 6-12 years with spherical equivalents of -1.00 D and -
`
`6.00 D were randomly assigned to having 1% atropine or placebo medication in one
`eye (Chua ef al, 2006). The design of
`the study is illustrated in Figure 1 and
`summarised below. The results from ATOM1 are compared and also used in Example
`2.
`
`Summary of ATOM 1
`
`Purpose: To evaluate the efficacy and safety of
`
`topical atropine, a nonselective
`
`10
`
`muscarinic antagonist, in slowing the progression of myopia and ocular axial elongation
`
`in Asian children.
`
`Design: Parallel-group, placebo-controlled, randomized, double-masked study.
`
`Subjects: 400 children aged 6 to 12 years with refractive error of spherical equivalent-
`
`1.00 to -6.00 D and astigmatism of -1.50 D orless.
`
`15
`
`Intervention: Subjects (the children) were assigned with equal probability to receive
`
`either 1 % atropine or vehicle eye-drops once nightly for 2 years. Only 1 eye of each
`
`subject was chosen through randomization for treatment.
`
`‘Main Outcome Measures: The main efficacy outcome measures were change in
`
`spherical equivalent refraction as measured by cycloplegic autorefraction and change
`
`20
`
`in ocular axial length as measured by ultrasonography. The primary safety outcome
`
`measure was the occurrence of adverse events.
`
`Results: 346 (86.5%) subjects completed the 2-year study. After 2 years, the mean
`progression of myopia and of axial elongation in the placebo-treated control eyes was-
`1.20 + 0.69 D (Figure 2) and 0.38 + 0.38 mm (Figure 3), respectively.
`In the atropine-
`treated eyes, myopia progression was -0.28 + 0.92 D (Figure 2), whereas the axial
`length remained essentially unchanged compared with baseline (-0.02 + 0.35 mm,
`Figure 3). The changesin refractive error and axial length in the non-treated eyes of
`
`25
`
`

`

`WO 2012/161655
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`PCT/SG2012/000174
`
`subjects in both the atropine group and placebo-contro! group paralleled that of the
`placebo-treated eyes (Figures 2 and 3). The differences in myopia progression and
`axial elongation between the 2 groups were -0.92 D (95% confidenceinterval, -1.10 to -
`0.77 D; P<0.001) and 0.40 mm (95% confidence interval, 0.35-0.45 mm; P<0.001),
`respectively. No serious adverse events related to atropine were reported.In this study,
`glare and photophobia were minimized with the use of photochromatic lenses.
`54
`
`subjects withdrew from the study. Reasons
`
`for withdrawal were:
`
`allergic or
`
`hypersensitivity reactions or discomfort (4.5%), glare (1.5%), blurred near vision (1%),
`logistical difficulties (3.5%), and others (0.5%).
`
`10
`
`Conctusions: Topical 1% atropine was effective in slowing the progression of low and
`moderate myopia and ocular axial elongation in Asian children.
`|
`
`Example 2: Second atropine in the treatment of myopia study (ATOM2)
`In ATOM2, the effect of lower doses of atropine in preventing myopia progression and
`the visual side effects (pupil dilation, loss of accommodation and near-vision blur) were
`assessed.
`
`15
`
`(i) Summary of ATOM 2
`
`Purpose: To compare efficacy and visual side-effects of 3 lower doses of atropine:
`0.5%, 0.1% and 0.01%.
`
`Design: Single-center, double-masked, randomized study. The design of ATOMZ2is
`
`20
`
`illustrated in Figure 4.
`
`Subjects: 400 children aged 6-12 years with myopia of at least -2.0 D and astigmatism
`of -1.50 D or less.
`
`intervention: Subjects (the children) were randomly assigned in a 2:2:1 ratio to 0.5%,
`0.1% and 0.01% atropine, to be administered once nightly to both eyes for 2 years.
`Cycloplegic refraction, axial
`length, accommodation amplitude, ‘pupil diameter and
`visual acuity were noted at baseline, 2 weeks and then every 4 monthsfor 2 years.
`
`25
`
`

`

`WO 2012/161655
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`PCT/SG2012/000174
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`Main outcome measure: Myopia progression at 2 years. Changes were noted and
`differences between groups were compared using the Huber-White robust standard
`error to allow for data clustering of two eyes per subject.
`
`Results: The mean myopia progression at 2 years was -0.30 + 0.60 D, -0.38 + 0.60 D
`and -0.49 + 0.63 D in the 0.5%, 0.1% and 0.01% atropine groups respectively (p=0.02
`between 0.01 and 0.5%groups; other p>0.05).
`In comparison, myopia progression in
`ATOM1 was -1.20 + 0.69 D in the placebo group and -0.28 + 0.92 in the 1%atropine
`
`group. The mean increase in axial length was 0.27 + 0.25 mm, 0.28 + 0.28 mm and
`
`0.41 + 0.32 mm in the 0.5%, 0.1% and 0.01% groups (p<0.01 between the 0.01%and
`
`10
`
`15
`
`0.1% groups and between the 0.01% and 0.5% groups). Differences in myopia
`progression (0.19 D) and axial length change (0.14 mm) between groups, however,
`were small and may be considered clinically insignificant. 0.01% atropine had
`negligible effect on accommodation and pupil size and no effect on near visual acuity.
`Allergic conjunctivitis and dermatitis were the most common adverse effect noted; with
`16 cases in 0.1% and 0.5% atropine groups, nonein the0.01% group.
`
`Conclusion: 0.01% atropine has negligible side-effects compared to atropine at 0.1&
`and 0.5% andretains comparable efficacy in controlling myopia progression.
`
`(ii) ATOM2 in detail
`
`Methods
`
`20
`
`Children aged between 6-12 years with myopic refraction of at least 2.0 D in both eyes,
`
`astigmatism of less than 1.5 D and a documented myopic progression of at least 0.5 D
`in the past year were enrolled in a double-maskedsingle-centre clinicaltrial. Excluded
`were those with ocular pathology (eg. amblyopia, strabismus), previous use of atropine
`
`or pirenzepine, an allergy to atropine, or systemic ill health (eg. cardiac or respiratory
`
`25
`
`illness). Written informed consent was obtained from parents or guardians and verbal
`
`assent was obtained from children. The study was conducted according to the tenets of
`
`the Declaration of Helsinki, with ethics approval from the Singapore Eye Research
`Institute Review Board.
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`

`

`WO 2012/161655
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`Subjects (the children) were randomized to receive 0.5%, 0.1% or 0.01% atropine once
`nightly in both eyes at an allocation ratio of 2:2:1 in six strata defined by gender and
`age-groups of 6-7, 8-10 and 11-12 years to ensure gender and age balance across the
`three treatment arms. Trial medications were pre-packaged so that bottles were pre-
`iabelled with subject number and of similar appearance. Trial medication consisted of
`
`the appropriate dose of atropine sulfate with 0.02% of 50% benzalkonium chloride as
`
`preservative (Ashwood Laboratories Ltd, Macau).
`
`10
`
`15
`
`After assessmentat the time of enrolment (baseline), the subjects were re-assessed 2
`
`weeksafter starting atropine (baseline 2), and then at 4, 8, 12, 16, 20 and 24 months.
`At each visit, best-corrected distance logMarvisual acuity (BCVA) was assessed by an
`optometrist using the Early Treatment Diabetic Retinopathy study chart. Near visual
`acuity was assessed using best-corrected distance spectacle correction with a reduced
`
`LogMar reading chart placed at 40cm under well-lit conditions. The near point of
`accommodation (NPA) was measured using a RAF rule using best-corrected distance
`spectacle correction. Subjects were instructed to move the target inwardstill the N5
`print became slightly blurred,
`and then outwards
`till
`it
`just became clear.
`Accommodation amplitude was calculated as the inverse of NPA. Mesopic pupil size
`was measured with the Procyon 3000 pupillometer (Lion House, Red Lion Street,
`London, UK), using the Meso-Hi (4 lux) setting. Photopic pupil size was measured
`
`‘20
`
`using the Neuroptics pupillometer (Neuroptics Inc, Irvine, CA, USA) while the subjects
`
`were viewing a target placed at 3m, after at least 10second of exposure to lamps
`
`providing 300 lux of luminance. In both cases, at least 5 pupil size readings (with range
`
`<0.5 mm) were recorded and averaged.
`
`Cycloplegic autorefraction was determined 30 minutes after 3 drops of cyclopentolate
`1% (Cyclogyl, Alcon-Convreur) were administered at 5 minutes apart using a Canon
`RK-Fiautorefractor (Canon Inc. Ltd, Tochigiken, Japan). Five readings, all of which
`
`had to be less than 0.25 D apart, were obtained and averaged. Spherical equivalent
`
`was calculated as sphere plus half cylinder power. The Zeiss IOL Master (Carl Zeiss
`Meditec Inc, CA, USA), a non-contact partial coherence interferometry, was used to
`measure the ocular axial length. Five readings, with a maximum-minimum deviation of
`
`25
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`30
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`0.05 mm or iess, were taken and averaged.
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`Parents or guardians, subjects (the children) and study investigators were kept masked
`to the assigned dosage oftrial medications. Each subject (child) kept a diary of usage
`of the trial medication. Compliance level of each subject was classified according to
`mean numberof frequency of using atropine per week as reported by subjects over the
`first 24 months. Subjects with 75% compliance rate (= 5.25 days/week) were
`
`considered compliant.
`
`The primary end-point was myopia progression over 2 years. Since a hyperopic shift
`may occur after commencing atropine, myopic progression was calculated from the
`second baseline, when the subjects had been on trial medication for 2 weeks. Level of
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`10
`
`myopia progression in each eye was further categorized as being mild (<0.5 D),
`
`moderate (0.5 to 0.99 D) or severe (>1.0 D).
`
`‘Secondary end-points included myopia progression at one year, change in axial length
`at one and two years, and side-effect parameters such as changes in accommodation
`amplitude, mesopic and photopic pupil size and best-corrected distance and near
`visual. acuity. Myopia and axial changes were noted from second baseline, while
`
`15
`
`accommodation, pupil size and visual acuity were monitored from first baseline. Any
`
`adverse events, regardless of whether they appeared relevant to atropine use, were
`docu mented.
`
`Statistical analysis
`
`20
`
`All analyses were based on intention to treat principle and performed in statistical
`
`software Stata (version 10.1, Stata Corp., College Station, TX). For demographic and
`
`other person-level data such as compliance and ever experiencing adverse events,
`
`Fisher’s exact test was used to test for difference in proportion of subjects between
`treatment groups and ANOVAfor difference in means between treatment groups.
`Endpoints from both eyes were pooled in a combined analysis using the Huber-White
`robust standard errors to allow for the correlation between eyes within person 25.
`
`25
`
`Results on left and. right eyes were very similar. For example, mean difference (95%
`
`Cl) in 2-year myopia progression between left and right eyes were -0.01 (-0.06, 0.03).
`
`For brevity and better precision, this report shows analyses pooling both eyes with
`robust standard errors for clustered data. The global null hypothesis of no difference
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`between 3 treatment groups was tested first,
`followed by pair-wise comparisons.
`Nominal
`level of statistical significance (p-value) was reported,
`i.e. no adjustment for
`multiple comparison.
`Interpretation will begin with considering the global
`null
`hypothesis between 3 groupsin order to preventinflated type | error rate. Placebo and
`atropine treated. eyes in ATOM1 were used for reference in secondary analyses.
`
`Results
`
`A total of 400 children were recruited into the study, with 161, 155 and 84 children in
`
`the 0.5%, 0.1% and 0.01% atropine treatment arms respectively (Figure 4). There were
`
`almost equal numbers of males and females and 91% of children were of ethnic
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`10
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`Chinese origin (Table 1). No differences were noted in demographics, baseline
`refractive error, accommodation, pupil diameter or best corrected visual acuity between
`groups (Table 1). Correlation between change in spherical equivalent and axial length
`
`over 2 years was high (correlation coefficient=0.82, p<0.001), and suggests good
`
`measurementvalidity.
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`Table 1: Characteristics at baseline and second baseline(ie. 2 weeksafter starting trial
`medication
`
`[VariablesC‘d(LC“(‘#$NCENW_AAtftEPine@(A)doseCd
`
`n 84
`
`n 155
`
`n 161
`
`p-value ?
`
`Age (yr), mean (sd)
`
`Chinese %
`Spherical equivalent (D)
`'
`-
`baseline
`-
`second baseline
`Axial length (mm)
`0.94
`25.2 (0.9)
`25.2 (0.8)
`25.1 (1.0)
`-
`baseline
`
`-__second baseline 25.2 (1.0 25.1 (0.8 25.1 (0.9 0.93
`
`
`
`Accommodation (D)
`-
`baseline
`-
`second baseline
`
` 48.8 46.5 47.2 0.95
`
`
`
`90.5
`92.3
`90.0
`0.99
`
`-4.5 (1.5)
`-4.5 (1.5)
`
`-4.8 (1.5)
`-4.5 (1.4
`
`-4.7 (1.8)
`-4.3 (1.8
`
`0.40
`0.67
`
`16.2 (3.4)
`11.3 (4.3
`
`16.7 (3.0)
`3.8 (2.5
`
`15.8 (3.4)
`2.2 (1.2
`
`;
`
`0.01
`<0.001
`
`
`
`
`
`Mesopic pupil diameter (mm)
`
`.
`
`3.9 (0.6)
`5.2 (0.8)
`
`3.9 (0.6)
`7.2 (0.7)
`
`4.7 (0.7)
`5.8 (0.8)
`
`.
`
`4.6 (0.7)
`7.4 (0.7)
`
`4.0 (0.7
`)
`7.8 (0.5)
`
`4.6 (0.7)
`7.9 (0.6)
`
`0.01 (0.05)
`0.01 (0.05)
`
`0.01 (0.06)
`0.01 (0.05)
`
`0.02 (0.06)
`01 (0.06)
`
`baseline
`-
`second baseline
`-
`Photopic pupil diameter
`(mm)
`baseline
`-
`second baseline
`-
`BCVAdistant (logMar)
`-
`baseline
`-
`second baseline
`Nearvision (logMar)
`0.04 (0.07)
`0.04 (0.08)
`0.04 (0.09)
`-
`baseline
`.
`0.29 (0.18)
`0.06 (0.08
`-
`second baseline
`a. Fisher’s exact test for binary demographic variables; ANOVA for age; Huber-White robust
`standard error for clustered data (both eyes pooled) on ocular parameters
`
`5
`
`Two-year primary endpoint data were available for 355 of 400 (88.8%) subjects. 44
`
`subjects withdrew participation on their own accord; 9 (10.7%), 14 (9.0%) and 21
`
`1
`(13.0%) from the 0.01%, 0.1% and 0.5%treatment group respectively (p=0.43);
`subject did not turn up for the second year assessment. Compliance, defined as >75%
`expected usage was 98.7%, 96.8% and 98.8% in the 0.5%, 0.1% and 0.01% arms
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`10
`
`(p=0.53) in the 2 year period.
`
`Change in myopic progression and axial length
`
`A clinically small, dose related response on myopic progression was noted between the
`3 treatment arms (Figure 5). An initial hyperopia shift of 0.3 to 0.4 D was noted in the
`
`0.1% and 0.5% groups but not in the 0.01% group (Table 1). At the end of 1 year, there
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`was a significant difference in myopia progression between the 0.5%atropine group
`and the 0.01% (p<0.001) and 0.1% (p=0.01) groups, but no statistical significant
`difference between 0.01% and 0.1% groups. The final myopia progression over 2 years
`
`was -0.49 + 0.60 D, -0.38 + 0.60 D and -0.30 + 0.63 D in the atropine 0.01%, 0.1% and
`
`5
`
`0.5% groups respectively (p=0.07), with significant difference only between the 0.01%
`
`and 0.5% groups (Table 2). There was nosignificant difference in spherical equivaient
`
`levels between groups (p=0.20). Fifty percent of the 0.01% group had progressed by
`
`less than 0.5 D, compared to 58% and 63% in the 0.1 and 0.5% group respectively,
`
`with approximately 18% progressing by >1.0 D in all 3 groups (Figure 6).
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Table 2: Ophthalmology parameters at 2" annualvisit
`
`
`_t—“CsSSCSCSCY
`Atropine (A) dose (mean (SD) TT
`POAIAIMTTA5%p-value|
`
`Spherical equivalent (D)
`
`
`'-4.8 (1.4)
`-4.9 (1.5)
`-at1 year
`-4.9 (1.3)
`-5.1 (1.5)
`at 2 years
`
`
`-0.31 (0.50)
`|
`-0.43 (0.52)
`- mean change over 1 year
`
`
`
`
`mean change over 2 years|-0.49 (0.63) -0.38 (0.60)
`
`
`
`Axial length (mm)
`
`
`25.3 (0.9)
`
`
`25.3 (0.8)
`- at lyear
`25.4 (1.0)
`
`
`25.7 (1.0)
`25.4 (0.8)
`at 2years
`25.4 (1.0)
`
`
`
`
`0.13 .18)
`- mean change over 1 year
`0.11 (0.17)
`
` mean change over2 years
`
`
`
`
`
`
`Accommodation (D)
`
`
`
`- at 1 year
`11.7 (4.3)
`<0.001
`6.0 (3.4)
`3.6 (3.2)
`
`
`6.8 (3.4)
`4.0 (2.6)
`at 2 years
`11.8 (3.2)
`
`
`
`-4.4 (4.9)
`-10.9 (4.0)
`-12.4 (3.3)
`- mean change over 1 year
`
`
`-11.8 (4.4)
`.
`-10.1 (4.3)
`mean change over 2 years
`
`
`
`
`
`
`Mesopic pupil size (mm)
`
`
`
`-at 1 year
`6.7 (1.0)
`7.5 (1.1)
`
`
`
`6.7 (1.1)
`at 2 years
`7.5 (1.2)
`
`
`
`- mean change over 1 year
`.
`
`mean change over2 years
`
`
`
`Photopic pupil size (mm)
`
`
`
`7.0 (1.0)
`-at 1 year
`7.7 (1.0)
`
`
`
`6.9 (1.0}
`at 2 years
`7.8 (1.1)
`
`
`
`- mean change over 1 year
`3.11 (1.08)
`
`
`
` mean change over 2 years
`
`
`BCVAdistant (logMar)
`
`
`
`
`
`- at 1 year -0.005 (0.042)|-0.003 (0.054)|-0.003 (0.054)
`
`at 2 years -0.001 (0.057)|0.005 (0.054)|0.011 (0.057)
`
`
`
`
`
`
`-0.02 (0.06)
`-0.03 (0.05)
`- mean change over 1 year
`-0.02 (0.05)
`
`
`
`
`
`mean change over 2 years|-0.02 (0.06)
`
`
`
`Nearvision (logMar)
`
`
`
`
`-at 1 year
`0.03 (-0.06)
`0.15 (0:15)
`0.35 (0.18)
`<0.001 “8°
`at 2 years
`0.01 (0.07)
`0.10 (0.13)
`0.29 (0.18)
`<0.001 *8°.
`
`
`
`
`
`- mean change over1 year
`-0.01 (0.10)
`0.10 (0.16)
`<0.001 *8°
`
`
`
`
`
`mean changeover 2 years
`<0.001 “8°
`
`
`BCVA: best-corrected visual acuity
`Myopia progression and axial length: change from second baseline; other parameters: change
`from initial baseline
`P-values for test of global null hypotheses of all groups being the same are shown. Pairwise
`comparison P-values are represented by A: significant (P<0.05) difference between 0.01% and
`0.5% atropine, B: significant difference between 0.01% and 0.1% atropine, and C: significant
`difference between 0.1% and 0.5% atropine.
`
`With respect to axial length, change at 1 year waslarger in the 0.01% group (0.24 +
`0.19 mm) than in the 0.1% (0.13 + 0.18 mm) and 0.5% (0.11 +
`0.17 mm) groups
`—-—~--(p<0.004)_(Figure—7)Pair-wise-comparison_-showed-_-statistically_significant.difference.—...
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`between 0.01% and the other two groups (p<0.001). This difference persisted till the
`end of the 24 month period (Table 2).
`-
`
`Changes in accommodation, pupil diameter and visual acuity
`
`There was no difference in accommodation, mesopic and photopic pupil diameter
`
`between groups at baseline (Table 1). However, significant dose-related differences
`quickly became evident by second baseline visit (Table 1). Changes within the 0.01%
`group weresignificantly less than in the 2 other groups. Accommodation amplitude in
`the 0.01% group was only reduced to 11.3 D compared to 3.8 D and 2.2 D in the 0.1%
`“and 0.5% groups (Table 1).
`in functional terms, this meant that near visual acuity was
`not significantly impaired in the 0.01% group, while deficiencies were noted in the 2
`other groups. Mean best-corrected distant visual acuity was not affected by atropine
`use (Table 2), although 10% of subjects did encounter mild distance biur (Table 3).
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`10
`
`Table 3. Adverse event and serious adverse events
`
`Exact
`
`
`
`
`
`
`
`a. Fisher’s exact test for proportion of children with adverse events
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`15
`
`Pupil size, under both photopic and mesapic conditions, in the 0.01% group increased
`
`by only 1 mm, while pupils in the 0.1% and 0.5% groups were about 3 mm larger
`
`(Table 2). While the atropine effect on pupil diameter remained unchanged over time,
`
`
`|—_Atopine(A)dose(A) dos