Clinical trial NCT03374306
Conditions: Myopia
Keywords: Myopia Myopia control Atropine Electroretinogram Multifocal Electroretinogram
Sponsor: The Hong Kong Polytechnic University
Start date: 2018-02-01; Completion date: 2020-08-31
Enrollment: 71 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Our project is a 24-month longitudinal randomized controlled trial that aims to investigate the myopia development after topical application of 0.01% atropine in children with either fast or slow myopia progression classified according to their initial electro-retinal responses. This will help elucidate the effectiveness of using low concentration atropine for myopia control in children with different myopia progression rates.

Detailed description:

Arms: arm 1: Group receiving atropine treatment for 18 months arm 2: Group receiving placebo for 18 months
Interventions: intervention 1: Atropine (0.01%) intervention 2: Artificial tear
Intervention descriptions: intervention 1: tropical application intervention 2: tropical application

Protocol documents:
ICF_002.pdf: 
                                  Patient Information Sheet (English)_Version 3_2_2_2018 
 
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Information sheet 
 
Title of project: 
Treatment effect of topical application of low-concentration (0.01%) atropine on 
the human eye with fast and slow myopia progression rate as classified by 
electro-retinal responses 
 
Project Team: 
 
Dr. Henry Chan (Associate Professor) 
School of Optometry, The Hong Kong Polytechnic University (Tel: 2766 7937) 
Dr. Alex Ng (Clinical Assistant Professor) 
Department of Ophthalmology, The University of Hong Kong (Tel: 2255 5632) 
Dr. Lydia Yu (Clinical Optometrist) 
School of Optometry, The Hong Kong Polytechnic University (Tel: 3400 2911) 
 
Why is the study being performed? 
Short-sightedness (myopia) has been an epidemic worldwide. In Hong Kong, the 
prevalence of myopia is approximately 80% at the end of childhood, and the rate of 
myopia progression among children varies. Use of 0.01% atropine is a newly 
recommended drug treatment for myopia control. Recent studies reported that it is 
effective to slow down myopia progression. From our recent study, we can use a 
special measurement to predict the risk of fast myopia progression for each child 
according to the electrical signal from the retina. In this study, we will study the effect 
of 0.01% atropine on the children who have been identified with the risk of fast or 
slow myopia progression. This project helps us better understand the effectiveness of 
this drug treatment in myopia control for the children with different predisposed risks. 
It also helps us to develop an optimal protocol to maximize the effect of myopia 
control treatment. We aim to include 80 subjects in this study with a 1:1 group 
allocation ratio. 
 
Inclusion criteria: 
The subject must: 
1. 
be aged between 7 and 10 years 
2. 
have no reported ocular disorder and no family history of ocular disease 
3. 
be able to participate in this study for 18 months 
4. 
not have any current or history of epilepsy 
5. 
not have any current or history of asthma  
6. 
have refractive error between -0.50D and -4.00D and less than 1.50D of 
astigmatism with best corrected visual acuity of LogMAR 0.0 or better 


                                  Patient Information Sheet (English)_Version 3_2_2_2018 
 
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7. 
have no detected ocular diseases or disorders after eye examination, except 
myopia 
 
What do volunteers have to do for this study? 
If you agree to have your child volunteered to participate in this study, you will be 
asked to: 
1.  sign an informed consent form for your child that states you on behalf of your 
child understand the study information. In addition, your child will also be asked to 
sign an accent form to state that he/she agrees to participate in this study. 
2.  provide your child’s personal information including name, date of birth and 
contact number. 
 
If, and only if, your child meets the subject inclusion criteria (item 1-5) of this study, 
your child will be asked to: 
1. 
attend a comprehensive eye examination including cycloplegic refraction and 
ocular health assessment. Optometrist will administrate 2 drops of 1% Cyclopentolate 
to dilate the pupil and paralyze the ciliary muscle for the relaxation of accommodation, 
in order to obtain more accurate refractive status and exam the eye. It takes about 45 
minutes for the drug to exert its effect and approximately 18 hours to recover. Then 
different ocular parameters including length of eyeball and eye pressure will be 
measured and fundus photos of the eyes will be taken. This eye examination lasts for 
about 2 hours; 
2. 
if your child meets the subject inclusion criterion (item 6-7) of this study, your 
child will be asked to attend an electrophysiological assessment (multifocal 
electroretinogram (mfERG)) at the Polytechnic University. It will take about 30 
minutes to complete the electrophysiological assessment and both eyes will be 
recorded simultaneously; 
3. 
another visit will be arranged to have the consultation by an ophthalmologist at 
the eye clinic of Grantham Hospital. In this visit, your child will be randomly 
allocated into treatment or placebo groups. You will receive the packs of eye drops 
vials (treatment drug or placebo) for daily instillation over 3-month period. You and 
your child should fill the logbook given for the record of compliance; 
4. 
A follow-up consultation will be conducted by the ophthalmologist in every 
3-month to review the condition and to deliver another 3-month supply of eye drops; 
5. 
A follow-up eye examination will be conducted by the optometrist in every 
6-month to review refraction (including cycloplegic refraction), different ocular 
parameters, eye health and electrophysiological assessment. Each visit lasts for about 
2.5 hours; 
6. 
your child has to attend total 7 consultations by ophthalmologist and total 4 eye 


                                  Patient Information Sheet (English)_Version 3_2_2_2018 
 
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examinations by optometrist over 18 months. 
 
Schedule of visits 
1st visit 
Comprehensive eye check and electrophysiological measurement 
2nd visit 
Consultation by Ophthalmologist and receiving 1st 3-month eye drops 
3rd visit 
Consultation by Ophthalmologist and receiving 2nd 3-month eye drops 
4th visit 
Follow up eye check and electrophysiological measurement 
5th visit 
Consultation by Ophthalmologist and receiving 3rd 6-month eye drops 
6th visit 
Follow up eye check and electrophysiological measurement 
7th visit 
Consultation by Ophthalmologist and receiving 4th 6-month eye drops 
8th visit 
Last follow up eye check and electrophysiological measurement 
9th visit 
Last consultation by Ophthalmologist  
 
* Ophthalmologist assessment: Eye clinic, Grantham Hospital 
 Electrophysiological measurement: Optometry clinic, Polytechnic University 
 
Procedure for electrophysiological examination 
1. 
Sensors placement 
A thread-like sensor will be placed on the lower lid of the eye, and the cup-like 
sensors will be placed 10 mm next to the eyes, the central forehead, posterior skull 
and earlobe. The refractive error of the tested eye will be fully corrected for the 
viewing distance. 
2. 
Your child sits in front of the screen. 
3. 
Your child will be asked to fixate on a red cross at the center of the monitor 
during the recording process without blinking, and will be given a rest between test 
intervals. 
 
Is there any benefit or risk for the volunteer who participates in the study? 
Risks: 
The risks are minimal. Your child will be instilled with 2 drops of 1.0% 
Cyclopentolate, which are common diagnostic eye drops in general ophthalmic 
practice for accurate assessment of refractive status and ocular health for children. 
These eye drops may have mild stinging sensation for a few seconds but do no harm 
your child’s eyes. Some people may develop transient adverse effects such as blur 
vision, red eye, glare sensation, weakening the near vision ability and swollen eye 
after the instillation of the eye drops. The possible risks include narrowing the anterior 
angle resulting in acute angle-closure glaucoma but the chance is very low. Our 
optometrist will assess the suitability of the eye to use the diagnostic eye drops before 
instillation in order to keep the risk minimal. Only the suitable subjects will be 


                                  Patient Information Sheet (English)_Version 3_2_2_2018 
 
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allowed to join the study. The effect of the diagnostic agent will last for about 18 
hours in which your child may experience blur at near and photophobia during this 
period. Your child is recommended to avoid near works until the effect of eye drop 
disappears. Wearing sunglasses is suggested during this period.  
 
Traditionally, high concentration of atropine (i.e. 1%) is also a common diagnostic 
eye drop in general ophthalmic practice for accurate assessment of refractive status 
for children. Its adverse effects are very similar to Cyclopentolate. After instillation of 
atropine, your child may have mild stinging sensation for a few seconds but do no 
harm your child’s eyes. Some people may develop transient adverse effects such as 
blur vision, red eye, glare sensation, weakening the near vision ability and swollen 
eye after the instillation of the eye drops. The effect of the diagnostic agent will last 
for about 18 hours in which your child may experience blur at near and photophobia 
during this period. 
 
In this study, a very low concentration of atropine (0.01%) will be used as myopia 
control treatment and be given to the subjects in the treatment group. Since the 
concentration is much lower than the high concentration atropine used for diagnostic 
purpose, the above mentioned adverse effects will be less. According to previous 
reports, the long term use of 0.01% atropine for myopia control may have the 
following additional adverse effects. For example, allergic conjunctivitis (4.1%), 
allergy-related dermatitis of the eyelids (1.3%), ocular irritation (1.2%), blur vision 
(1.2%), and glare intolerance (0.6%). In addition, there were some reported very rare 
cases requiring hospitalization, including acute gastric pain (0.3%), appendicitis 
(0.3%), respiratory infection (0.3%), Ewing’s sarcoma (0.3%), tachycardia (0.3%), 
dengue fever (0.3%) and gastroenteritis (0.3%). However, none of these events had 
direct association with the use of atropine. 
 
You will be educated to differentiate minor discomfort from complications, eg. 
allergic conjunctivitis, acute glaucoma attack, etc., that require immediate medical 
treatment. You may contact Dr. Alex Ng (Ophthalmologist) during office hours or Dr. 
Lydia Yu (Optometrist) both office and non-office hours if you have any problems of 
your child after instilling the eye drops. 
 
Benefit: 
Your child who fit for the inclusion criteria can receive a series of eye examinations 
over 18 months performed by a registered optometrist in which the required fee will 
be covered by this project. Also, children may have chance to receive this drug 
treatment for myopia control. 


                                  Patient Information Sheet (English)_Version 3_2_2_2018 
 
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Can a volunteer withdraw from the study? 
Yes, your child can withdraw from the study at any time without any penalty or 
affecting your child’s future eye care. 
 
Alternatives 
Your participation is voluntary. Your refusal to participate will not change any of your 
medical care, and you will not lose any benefits you have now. You may stop 
participation at any time without any changes or loss of your medical care. Your 
investigator can withdraw you from the study without your consent if he or she 
believes it is necessary for your safety or if you do not follow the study requirements. 
 
Can I get more information on the study? 
Yes, you can contact Dr. Henry Chan (Tel: 2766 7937) for any questions you have. He 
will try to answer all questions you have. 
 
Confidentiality 
Any information that is obtained in this study concerning your child will be 
confidential. Publication or other public distribution of the experimental results will 
not mention your child by name. Research records will be stored securely and only 
members of this project will have access to the records. Raw data will be destroyed 7 
years upon the completion of this project.  
 
Thank you for participation of your child. 
 
This study has been approved by the Departmental Research Committee (DRC) of the 
School of Optometry of The Hong Kong Polytechnic University. If you have any 
complaints about the conduct of this research study, please do not hesitate to contact 
the Chairman of DRC (School of Optometry) of The Hong Kong Polytechnic 
University, in person or in writing. 
 
This study has also been reviewed and approved by the Institutional Review Board of 
the University of Hong Kong / Hospital Authority Hong Kong West Cluster. For 
enquiry on the ethical rights of a research subject, please contact the Institutional 
Review Board (IRB) office at 2255 4086. 

Prot_000.pdf: 
Summary 
Myopia (short-sightedness) has been an epidemic worldwide. In Hong Kong, the prevalence of 
myopia is approximately 80% at the end of childhood, and the rate of myopia progression among 
children varies. Tropical application of 0.01% atropine is a newly recommended 
pharmacological myopia control treatment. Recent studies reported that it is effective to slow 
down myopia progression. The findings from my GRF 2013 study showed that young children 
with an initial weakened central electrical signal from the inner retina had faster myopia 
progression. This indicates that the central retinal electro-activity is an important indicator to 
find out the predisposed risk of fast myopia progression. Since the electro-retinal activities 
measured by my new protocol can classify the children into fast or slow myopia progression 
group, we speculate that studying the effect of atropine on these two groups will help us better 
understand the effectiveness of the drug in myopia control for the children with different 
predisposed risks.  
There has been no study investigating the treatment effect of atropine on the children with 
either fast or slow myopia progression rate, neither has there been clinical finding to 
demonstrate whether the children with either fast or slow myopia progression will show the 
same treatment effect of atropine. Hence, longitudinally studying the underlying retinal 
activities that regulate the control of myopia progression using atropine in these two group of 
children will help evaluate the clinical effectiveness and improve the clinical judgement in 
prescribing this treatment.    
Our project is a 24-month longitudinal randomized controlled trial that aims to investigate the 
myopia development after topical application of 0.01% atropine in children with either fast or 
slow myopia progression classified according to their initial electro-retinal responses. This will 
help elucidate the effectiveness of using low concentration atropine for myopia control in 
children with different myopia progression rates. All of the participated children will be 
allocated into fast or slow myopia progression group in accordance with the electro-retinal 
activities as measured by our established protocol from my GRF 2013 study. This protocol also 
enables us to find out how the retinal electrophysiological changes under the atropine treatment 
over a 24-month period. The characteristics of these retinal activities will help us to understand 
the retinal contribution to myopia development in human eye. Furthermore, it will advance our 
clinical decision to prescribe an appropriate myopia control treatment and be beneficial for the 
design of a highly effective treatment protocol for myopia control.  
Title of project:
Tropical application of low-concentration (0.01%) atropine on the human eye with fast and slow myopia progression rate 
NCT03374306           Date:1 Jan 2018


Subjects 
Based on the study of ATOM2 (Chia et al., 2012), the mean myopia progression rate under 0.01% 
atropine was -0.49±0.63D and the mean myopia progression rate in control was -1.20±0.69D). 
Hence, 9 subjects should be required for this project to demonstrate the effect of atropine on 
myopia control (type I error of 5% and the power of 80%; effect size = 1.07, two-tailed; paired 
group; GPower 3.1). However, based on the mfERG data of our pilot study (Figure 1), the mean 
inner retinal responses from fast and slow myopia progression group are 67.04±30.54 uV/deg2 
and 80.61±27.24 uV/deg2, therefore the proposed study requires 38 subjects (type I error of 5% 
and the power of 80%; effect size = 0.47, two-tailed; paired group; GPower 3.1). Assume that the 
dropout rate of this study throughout the 2-year period is around 5% (according to our 
preliminary result from my GRF 2013 study) and after consolidation of both analyses, at least 40 
subjects aged from 8 to 9 years will be recruited. Children at this age range are believed to be the 
group with the highest chance of myopia progression. As this study is a randomized controlled 
trial with two arms, one is the treatment arm and the other one is placebo arm. We will recruit 
80 subjects in this study. All of them will receive an ophthalmic assessment including history 
taking, preliminary tests, objective and subjective refraction, external and internal ocular health 
assessments. The subjects who meet the following criteria will be recruited to participate in this 
study. The subjects must have the refractive error between -0.5D and -1D in both eyes and with 
the best-corrected visual acuity of logMAR 0.00 or better, normal color vision and ocular health. 
Subjects with any ocular disease, systemic disease and current or history of epilepsy will be 
excluded from the study. 
 

SAP_001.pdf: 
Title of Project: Tropical application of low-concentration (0.01%) atropine on the human 
eye with fast and slow myopia progression rate 
 
NCT03374306 
 
 
 
 
 
 
 
Date: 1 Jan 2018 
 
Statistical analysis  
Due to COVID-19-dependent closure of the university campus, the eye examinations were 
not always performed within the study-defined time window and were in-part delayed. To 
minimize the effect of delayed visits, change from baseline in SER and AL were normalized 
for time and expressed as annualized change for each participant. All participants included in 
the analysis had completed the baseline eye examination and at least 2 visits of follow-up eye 
examinations during the study period.  
The data distribution was approximately normal (Shapiro-Wilk test – SER: p = 0.16; AL: p = 
0.27). A univariate general linear model (GLM) was used to compare annualized change in 
SER and AL between the treatment groups (atropine vs. placebo), controlling for the baseline 
SER and age as covariates. Since a weakened central inner retinal response was reported as a 
risk factor for myopia development, the relationship between Ring 1 IC and annualized 
change in SER and AL were evaluated using GLM, and compared between the atropine and 
the placebo groups using moderator analysis. The correlation coefficients (Rp vs. Ra) were 
also compared between treatment types using Fisher’s R-to-Z test in the Ring 1 IC, as well as 
other regions and MOFO mfERG parameters. All statistical procedures were performed with 
SPSS22.0 (IBM, Armonk, NY). Hochberg’s adjustment was applied for multiple 
comparisons, with significance level set at p ≤0.05. A receiver operating characteristics 
analysis was also performed to evaluate the predictive value of baseline Ring 1 IC on fast 
progressor (annualized progression ≥1.0 D) in each of the atropine and control group.