Conditions: Myopia
Keywords: Myopia atropine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 200
Healthy volunteers: no

Brief summary:
Study Objectives

The objectives for this randomized trial are:

1. To determine the efficacy of daily low-dose atropine (0.01%) for slowing myopia progression over a two-year treatment period in children aged 5 to less than 13 years (Primary Outcome On-Treatment).
2. To determine the efficacy of atropine treatment on myopia progression 6 months following cessation of low-dose atropine treatment (Secondary Outcome Off-Treatment).

Synopsis of Study Design The current study is designed as an efficacy study, making effort to maximize adherence to treatment group assignments. After a run-in phase during which all participants are treated with daily artificial tear eyedrops for 2-4 weeks (and glasses are updated if required) to assess their ability to adhere to daily eye drops, participants are randomly assigned to daily atropine or placebo for 24 months, followed by 6 months off treatment.

Detailed description:
Study Objectives

The objectives for this randomized trial are:

1. To determine the efficacy of daily low-dose atropine (0.01%) for slowing myopia progression over a two-year treatment period in children aged 5 to less than 13 years with myopia -1.00 to -6.00D at the time of enrollment (Primary Outcome On-Treatment).
2. To determine the efficacy of atropine treatment on myopia progression 6 months following cessation of low-dose atropine treatment (Secondary Outcome Off-Treatment).

Synopsis of Study Design The current study is designed as an efficacy study, making effort to maximize adherence to treatment group assignments. After a run-in phase during which all participants are treated with daily artificial tear eyedrops for 2-4 weeks (and glasses are updated if required) to assess their ability to adhere to daily eye drops, participants are randomly assigned to daily atropine or placebo for 24 months, followed by 6 months off treatment.

Arms:
arm 1: 0.01% atropine eyedrops administered 1 drop to each eye daily in each eye for 24 months, followed by 6 months off atropine eyedrops arm 2: Placebo eyedrops administered 1 drop to each eye daily in each eye for 24 months, followed by 6 months off placebo eyedrops

Interventions: intervention 1: Atropine intervention 2: Placebo Eyedrops
Intervention descriptions: intervention 1: Daily 0.01% atropine eyedrops intervention 2: Daily placebo eyedrops

Protocol document:
ICF_000.pdf: 
 
 
 
Low-Dose Atropine for Treatment of 
Myopia (Myopia Treatment Study) 
 
Informed Consent Form 
April 16, 2019 
 
NCT03334253 


 
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CONSENT FOR YOUR CHILD TO TAKE PART IN A RESEARCH STUDY
STUDY TITLE: Low-Dose Atropine for Treatment of Myopia (MTS1)
STUDY DOCTOR’S INFORMATION
Name: __________________________
Contact Number: _______________________
Site Name: ____________________________
Site Address: __________________________
Emergency (24-hour) Number: __________________
Study Coordinator Name/Contact: ___________________
SUMMARY
This consent form will give you important information about this study. It will help you decide if 
would like to allow your child to take part in the study. You do not have to allow your child to be 
in this study. You or your child can decide to stop being in the study at any time. You should 
read and discuss all the information in this consent form with the study doctor and your child.

The study is being done to see if low-dose eye drops of a drug called atropine can help 
prevent myopia (nearsightedness) from getting worse. Atropine is not approved by the 
FDA for treating myopia. It is considered an experimental drug when being used to treat 
myopia.

We are asking that your child be in the study for about two and a half years, and the study 
will involve visits to your study eye doctor’s office about every 6 months. Your child will 
be asked to use eye drops every night for two years.

The most likely risks to your child, which are expected to occur only rarely, are: blurry 
vision, skin irritation around the eyes, redness of the eyes or skin, stinging eyes, light 
sensitivity, an allergic reaction, dry skin and mouth, fast heartbeat, fever, and irritability.

The possible benefits for your child are unknown, but that is what the study is trying to 
find out. Children who take part in this research study will add to new knowledge that 
may help other children with the same problem in the future.

If you do not want your child to participate, there are other treatment options available for 
your child. Talk to your study eye doctor about: no treatment, regular eyeglasses or 
contact lenses, multi-focal contact lenses, rigid-gas permeable lenses at night, or bifocal 
glasses.
 
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LEGALLY AUTHORIZED REPRESENTATIVE (LAR)
Where we say “you” in this form, we mean a natural or adoptive parent, a legal custodian, or a 
legal guardian (collectively known as a “Legally Authorized Representative” or “LAR” for 
short). Where we say “your child” in this form, we mean the child under your direct care as the 
LAR.
WHAT IS INFORMED CONSENT?
We are asking you to allow your child to take part in this research study because your child has 
myopia (also known as nearsightedness).  The goal of this research study is to learn things that 
may help children with myopia.  Research is not the same as treatment.  We want to find out 
what works best for treating your child and other children with this condition. 
Your child’s study doctor and nurse will be talking with you about this study and this form. You 
can take as much time as you need to think about whether or not you want your child to be in this 
study. You can also take a copy of this form with you to review with your child, your friends, 
family, or other doctors to help you decide. Please read this document carefully. Do not allow 
your child to be in this study unless all of your questions and your child’s questions have been 
answered.
You do not have to allow your child to be in this study. If you decide that you do not want your 
child to be in this study, you and your child will not be treated differently. Also, you and your 
child’s regular care will not be impacted. 
WHO IS DOING THE STUDY?
Your child’s eye doctor(s) will carry out this study. Their names are listed on the cover page of 
this form. The study is being done by the Pediatric Eye Disease Investigator Group.  Your child’s 
eye doctor is a member of this group. Funding for the study is being paid for by the National Eye 
Institute, which is part of the federal government.  This funding will be used by the Jaeb Center 
for Health Research to organize the study and to pay your child’s eye doctor for their work on 
the study.  If one of the study doctors gets money or benefits from a company that makes the 
study drug (atropine) in this study, then they have to tell the Jaeb Center. The Jaeb Center has a 
policy to make sure that study doctors cannot work on this study if they get money or benefits 
that would influence how they do the study. 
WHY IS THIS STUDY BEING DONE?
Nearsightedness means that vision is blurry when looking at far-away objects without glasses. 
This condition is also called myopia. Nearsightedness in a child is usually caused by an eye that 
is too long. If the eye continues to grow, children get more nearsighted.  Once a child becomes 
nearsighted, it tends to get worse during childhood and teenage years, and stronger glasses are 
usually needed to correct the vision. 
 
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Some studies have shown that the low-dose atropine study eye drops may slow the progression 
of nearsightedness. The U.S. Food and Drug Administration (FDA) has not approved atropine 
for treating myopia (nearsightedness).  Therefore, it is considered an experimental drug when 
used to treat myopia. The purpose of this study is to see if low-dose atropine eye drops can help 
prevent myopia from getting worse.  The study will also see if any benefit lasts after the eye 
drops are stopped.
We expect about 400 children will take part in this study at about 10 different medical locations 
in the US. 
WHO CAN PARTICIPATE IN THIS STUDY?
To take part in this study, your child must: 

be at least 5 years old, but younger than 13 years old

have nearsightedness (myopia)

have never had atropine eye drops to treat myopia before

have never worn bifocals before

have never worn special types of contact lenses used to slow myopia development

have no known allergy to atropine
There are some other criteria your child must meet to be part of the study. Your study doctor will 
check if your child meets these or not.  If your child meets the criteria but their current glasses do 
not meet the requirements for the study, the study will pay for new glasses or a change in your 
child’s glasses, if you get them at the study doctor’s office, LensCrafters or another study 
contracted optician.
Your child will be in the study for about 2 ½ years.  You should NOT have your child be in 
the study if you are planning to move out of this area in the next 2 ½ years. 
If your child is female, you should not have her take part in the study if she is pregnant or 
intending to become pregnant in the next 2 ½ years, or is nursing an infant.  We will perform a 
pregnancy test at the time of enrollment if she has had a menstrual period.  We will also perform 
pregnancy tests at follow up visits while your child is being treated with study medication (i.e. at 
(6-, 12-, 18- and 24-month visits), if she has had a menstrual period by then. We are required to 
do this testing even if you think there is no possibility that she is pregnant or could get pregnant 
during the study.
WHAT WILL HAPPEN IN THIS STUDY?
At the start of the study, all children will get placebo eye drops (without the atropine drug), also 
called artificial tears.  These placebo eye drops contain no medication. They have no physical 
effect on the patient other than moistening the eye. Children will receive these drops in each eye 
every night for 2 to 4 weeks. Parents can put in the eye drops if the child is not able to.  A 
smartphone app may be offered to parents to remind them to give the drops to their child every 
 
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night. Parents will need to record whether their child gets the eye drop every night. Children will 
need to return to their study eye doctor for another exam after using the eye drops for 2 to 4 
weeks.  
If your child has done well using these eye drops and still meets the criteria, a computer program 
will be used to select whether your child will be given study atropine eye drops or the placebo 
eye drops.  This is like flipping a coin to decide which study group your child will be in, and is 
called randomization.  Two out of three children will be given atropine eye drops. One out of 
three children will use placebo eye drops, which have no medicine.  Neither you nor your doctor 
will know which group your child is in until the end of the study.
Study Atropine 0.01% Eye Drops
Children in the study atropine eye drops group will receive one drop of low-dose atropine in each 
eye every night for 2 years.  Your child will stop having the eye drops after 2 years.  Your child 
will have a visit with the study doctor six months after stopping the drop.  Your child will 
continue to wear glasses or contact lenses throughout the study.
Placebo Eye Drops
Children in the placebo eye drops group will get one drop of placebo (artificial tears with no 
active drug) in each eye every night for 2 years.  Your child will stop having the eye drops after 
2 years.  Your child will have a visit with the study doctor six months after stopping the drop.  
Your child will continue to wear glasses or contact lenses until throughout the study.
In both groups, your child will receive a new pair of glasses at 12 and 24 months and, if 
necessary, a lens change at 6 months and 18 months.  The new glasses and lens changes will be 
provided at no cost to you if you get them at the study doctor’s office, LensCrafters or another 
study contracted optician. The study will not pay for contact lenses or changes in contact lenses.  
Visit Schedule
After starting in a study group, all children in the study will have visits with their study eye 
doctor at:

6 months

12 months

18 months

24 months

30 months
In addition, parents will get a phone call from their study eye doctor’s office at:

2 weeks

3 months

9 months

15 months

21 months

27 months
 
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The phone calls are to see if your child is experiencing any issues with treatment or to see if you 
have any questions about your child’s participation in the study.
In the following table, you will find what will happen at each visit.
Test
Enrollment
Randomization
2-4 weeks
6 
mos
12 
mos
18 
mos
24 
mos
30 
mos
Medical history
X
X
X
X
X
X
X
Pregnancy Test (for females 
who have had a menstrual 
period)
X
X
X
X
X
Questionnaire to evaluate the 
effect of eye drops on your 
child 
X
X
X
X
X
Distance visual acuity to 
measure how well your child 
sees far away 
X
X
Near visual acuity to measure 
how well your child sees at near
X
X
Accommodation (this tests the 
strength of your child’s 
focusing system)
X
X
X
X
X
X
Refraction (your doctor will 
manually measure your child’s 
eyeglasses prescription)
X
X
X
X
X
X**
Autorefraction (an automatic 
way to check your child’s 
eyeglasses prescription; this 
will be done with dilating drops 
in the eyes)
X
X*
X
X
X
X
X
Biometry (to take 
measurements of your child’s 
eyes)
X
X*
X
X
X
X
X
Prescribe artificial tears
X
Prescribe/refill study eye drops
X
X
X
X
Stop study eye drops
X
Prescribe glasses or change in 
spectacle lenses 
X***
X***
X
X***
X
*Repeated at randomization if you child comes back more than 4 weeks from enrollment.
**Standard refraction is not needed at 30 months if your child’s vision has not changed much.
*** New glasses or a change in glasses will be provided at enrollment if needed.  New glasses 
will be provided at 12 and 24 months.  If needed, lenses will be changed at 6 and 18 months.  
The study will not pay for new or a change in contact lenses. 
If you decide not to let your child take part in this study and do not sign this document, your 
child can continue receiving medical care not related to this study.  If you decide to let your child 
 
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participate in the study, you can decide to stop your child’s participation at any time.  No penalty 
or loss of medical care will result from your decision not to let your child take part in this study.  
WHAT ARE THE RISKS OF THIS STUDY?
If you decide to let your child take part in the study, your child will be at risk for the side effects 
listed below.  Risks related to your child’s normal medical care are not listed in this form. We 
encourage you to discuss these with your child’s study doctor, your child’s pediatrician, or 
another health care professional.  
It is always possible that anyone taking a drug for the first time may have an allergic reaction. 
Also, there may be additional risks from the drug or the study procedures that are not known.  If 
we find out that there are any new risks for your child, you will be told about them.  You will be 
able to decide if you want your child to continue in the study based on this new information.
Eye Examinations: 
The risks and discomforts for the examinations will be the same whether or not your child is 
taking part in the study. 
Study Drug(s):
Studies have shown that the risks of using study atropine in both eyes for a long time depend on  
the atropine dose. This study is using a low dose of atropine (0.01%). This low dose of atropine 
has been used in other studies with very few side effects.
Study atropine (0.01%) may cause the following side effects, but these are rare: 

Blurry vision – usually goes away after stopping the drops

Skin irritation around the eyes

Redness of the eyes or skin

Stinging eyes

Some light sensitivity  – children are encouraged to wear a hat with a brim and sunglasses

Allergic reaction

Dry skin and mouth

Fast heart beat

Fever
There are no known risks from taking placebo eye drops.
Risks to Confidentiality:
This study will be capturing some information about your child that includes identifiable, 
personal information, like your child’s date of birth. The study has procedures in place to protect 
that information. There is a chance that a loss of that protection could occur. This would be a loss 
of confidentiality. Please see the “How will my child’s information be protected and kept 
confidential” section below for more information.
 
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Risks for Women:
The risks of the drug used in this study on an unborn baby or a breastfeeding infant are unknown. 
For this reason, if your child is female, she cannot take part in the study if she is pregnant, 
planning to become pregnant within the next 2½ years, or nursing an infant. The study doctor 
will perform pregnancy tests before the study starts and at follow up visits during the two-year 
treatment period, if your child has had a menstrual period. The study doctors are required to do 
this even if you think there is no possibility that your child is pregnant or could get pregnant 
during the study. If the results of your child’s pregnancy test are positive, they will only be told 
to you if your child gives permission.  If your child becomes pregnant during the study, your 
child will stop taking the study drug but would be asked to stay in the study. If you are not 
comfortable with any of the following, then you should not allow your child to participate: 

your child having pregnancy tests

the study doctor informing your child about positive pregnancy test results

how the study doctor must get your child’s permission to tell you pregnancy test results
Washout Period:
This study will involve a washout period without any eye drop treatment. The washout period 
will last 6 months.  The risks associated with the washout period include potential increase in 
myopia or blurry distance vision without glasses.  The washout period will help us understand if 
improvement in myopia is maintained after eye drops are discontinued.   
Eye Drop Questionnaire
At most follow-up visits, your child will be asked to complete a questionnaire assessing 
symptoms and the effect of eye drops on his or her health-related quality of life.  If any questions 
make you or your child uncomfortable, then you or your child can refuse to answer. 
WHAT ARE THE BENEFITS OF MY CHILD TAKING PART IN THIS STUDY?
There may be a possible benefit to your child if you decide to let your child take part in the 
study, but that is what the study is trying to find out.  Your child may receive no direct benefit 
from being in the study.  Children who take part in this research study will add to new 
knowledge that may help other children with the same problem in the future.
ARE THERE OTHER OPTIONS THAN BEING IN THIS STUDY?
If you do not want your child to take part in this study, other options for your child include:

No treatment 

Regular glasses or contact lenses

Multi-focal contact lenses

Rigid-gas permeable lenses at night

Bifocal glasses
We encourage you to discuss these choices with your child’s study doctor, your child’s 
pediatrician, or another health care professional who has knowledge of myopia.  
 
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CAN MY CHILD STOP BEING IN THE STUDY?
You or your child can stop participation in this study at any time. If you or your child decide to 
stop being in this study, you and your child will not be treated differently. Also, you and your 
child’s regular care will not be impacted. Please talk to your child’s study doctor or staff so they 
know why you and your child are stopping the study and can help your child do so safely.
If we find out that there are any new risks, you will be told about them. You will be able to 
decide if you want your child to continue in the study based on this new information.
The study may stop or the study doctor may decide to take your child out of the study at any 
time. You do not have to give permission for the study to stop or for the study doctor to remove 
your child from the study. You and your child will be told if this happens. 
Some reasons why your child may be removed from the study include:

The doctors feel that it is in the best interest of your child

The doctors think that being in the study may cause your child harm

If your child experiences an injury related to the study

If your child needs additional or different medication

If your child does not follow the study instructions
If your child is removed from the study or the study is stopped, your child may continue to 
receive care like your child normally would if your child were not in this study.
ARE THERE COSTS RELATED TO MY CHILD TAKING PART IN THE STUDY?
The costs of routine treatment, office visits, and tests that are part of your child’s regular care 
will be billed to you or your child’s insurance company like they normally would if your child 
were not in a study. The study will pay for the visits, procedures and drugs listed below. Any 
additional tests and procedures for standard care will be billed to you or your child’s insurance 
company like they normally would.  The study will pay for:

Office visits that are part of the study (randomization visit, and visits at 6, 12, 18, 24, and 
30 months).  

All eye drops used during the study (e.g. placebo artificial tears and atropine). At the end 
of the study, or if you decide to remove your child from the study, you must return any 
remaining eye drops to your child’s eye doctor.   

Eyeglasses at enrollment (if needed), 12 months, and 24 months if you get them at the 
study doctor’s office, LensCrafters or another study contracted optician.  The study will 
also pay for lens changes at 6 and 18 months if the study requires it and the lenses come 
from the study doctor’s office, LensCrafters or another study contracted optician.  If your 
child has problems with schoolwork or reading, your child’s eye doctor may prescribe 
bifocals.  The study will pay for these bifocals if needed.  
 
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The study will not pay for:

Eyeglasses obtained from somewhere other than the study doctor’s office, LensCrafters 
or another study contracted optician.  

Contact lenses or a change in contact lenses.
IS THERE PAYMENT FOR TAKING PART IN THIS STUDY?
If you allow your child take part in the study, you will receive up to $350 for participation. These 
payments will be paid as follows: $50 to cover travel expenses for completion of the enrollment 
exam, randomization exam, and each study visit at 6, 12, 18, 24, and 30 months. These payments 
will be made by check or money card. If you have travel expenses that make it difficult for you 
to return for study visits, reimbursement may also be available for additional mileage at the 
Standard Mileage Rates specified by the government (for example, 54 cents per mile). 
If you withdraw your child from the study, or if your child withdraws, you will still be paid for 
the visits that your child has completed. You will not receive extra payments for visits that are 
required as part of your child’s normal care or for visits that are for treating an illness or injury. 
WHAT HAPPENS IF MY CHILD HAS AN ILLNESS OR INJURY FROM BEING IN 
THE STUDY?
If your child has an illness or injury that is related to your child’s participation in the study, then 
you can get care for your child like you normally would. If your child has an emergency, please 
seek emergency care as soon as possible. Please tell the emergency doctor that your child is in a 
research study.  Please also tell the study doctor about the emergency as soon as you can. The 
study will not provide costs for care or other expenses relating to illnesses or injuries. The costs 
of care for illnesses or injuries will be billed to you or your child’s insurance company like they 
normally would. Your child’s study doctor, the doctor’s office, and the Jaeb Center are not 
offering payment for lost wages, direct losses, or indirect losses.
CONTACT INFORMATION FOR QUESTIONS OR PROBLEMS
For questions about this study, a research illness or injury; or have concerns, suggestions or 
questions about the study, then contact the study doctor using the contact information on the first 
page of this form. You may also contact Pediatric Eye Disease Investigator Group (PEDIG) staff 
at 1-888-797-3344.
Contact the Jaeb Center for Health Research Institutional Review Board (IRB) Office at 813-
975-8690 or irb@jaeb.org if you:

Have questions about your rights as a research participant

Wish to talk about your concerns or suggestions about the research

Want additional information about the research, or

Want to provide comments about the research.
 
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HOW WILL MY CHILD’S INFORMATION BE PROTECTED AND KEPT 
CONFIDENTIAL?
As required by law, study related records with identifying information will be kept confidential. 
Safety measures for the access, security, and privacy of your child’s information have been put 
in place by law. Unless the law requires it, your child’s name, address, social security number, 
telephone number, or any other direct identifying information will not be used to identify your 
child. 
Certificate of Confidentiality 
The National Institute of Health (NIH) has given us a Certificate of Confidentiality for this study. 
This adds special protection for study information that identifies your child and allows us, in 
some cases, to refuse to give out information that could identify your child without your consent. 
This could be done when the information is requested by a federal, state, local court or public 
agency. If your child needs medical help, we may still share your child’s identifiable 
information. As described in this form or in other cases, we may share identifiable information. 
For example, if the government inspects us, they may see your child’s identifiable information. 
Your child’s study doctor and research team will follow local laws and will tell the local or state 
authorities:

if certain diseases are present;

if they suspect neglect, abandonment, or abuse of your child; and

if your child’s study doctor or research team learns that your child plans to harm 
self or others  
Purpose of Authorization
We have rules to protect information about your child. Federal and state laws also protect your 
child’s information. By signing this form you are giving your permission, called your 
“authorization,” for the use and sharing of information protected by the law. 
You must sign the Protected Health Information Authorization at the end of this form if you want 
your child to be in the study. When you sign the form, you give permission for the use and 
sharing of your child’s Protected Health Information (PHI) for the study. PHI is health 
information that identifies your child. Your authorization is beneficial and important for the 
study. Without your authorization, your child will not be able to be in this study.
Using and Sharing Your Child’s PHI
Your child’s study doctor will collect information about your child. This information includes 
things learned from study procedures as well as your child’s name, address, date of birth, and 
information from your child’s medical records. These are examples of identifiable information. 
A code number will replace your child’s name, address, telephone number, or social security 
number in the results given to the Jaeb Center for Health Research in Tampa, Florida.   
 
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The study doctor’s office will not share study results that can identify your child except as 
explained in this form or when required by law. The Jaeb Center and your child’s study doctor’s 
office will guard the privacy of your child’s study PHI.
Study results without the identifiable information may be shared in medical journals and at 
scientific meetings. Your child’s records will be confidential. No one will share your child’s 
identity in a medical journal or at a scientific meeting.  
Results from the study will be sent to you in a newsletter upon completion of the research.
Who Can Receive and Use Your Child’s Study Information?
It is possible that people outside of this doctor’s office and the Jaeb Center may need to see or 
receive your child’s information from this study. Some examples include government agencies 
(such as the Food and Drug Administration), committees that monitor safety, other sites in the 
study, and companies that sponsor the study. In most cases the information will have a code 
number with it instead of your child’s name, address, telephone number, or social security 
number. 
There are some situations where the information will not have a code number but may include 
your child’s name, address, telephone number, or social security number (PHI). If so, people 
outside this doctor’s office who assist in your child’s care may see your child’s study PHI.  They 
may not be covered by the law. Everyone who needs to see your child’s information will be told 
it is confidential, but we cannot guarantee full confidentiality once it leaves the doctor’s office. 
Other Considerations
The information collected in the study may be used in future studies without additional 
permission from you. This may include research done by other researchers. The information that 
may be shared will not contain any information that could identify your child. There may still be 
a chance that someone could identify your child, but this is not likely. The study results will also 
be made public. These results will not have any information that could identify your child.
Contact from the Jaeb Center
Separately from your child’s research data, the Jaeb Center for Health Research in Tampa, 
Florida will be provided with information on how to contact you.   

If your doctor’s office is not able to locate you when they try to schedule your child’s 
follow-up visit, the Jaeb Center may try to contact you through the alternative contact 
information you have given us.  If this is not successful, the Jaeb Center may use the 
information you have given us to try to locate you through the use of a third-party 
search service.

You may also receive updates about the study in the mail.
Study Eyeglasses
Your child will receive eyeglasses as part of the study. They will be provided at no cost to you if 
you get them at the study doctor’s office, LensCrafters or another study contracted optician.  
 
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Page 12 of 13
Your child’s study eye doctor may send you to LensCrafters or another contracted optician to get 
the new eyeglasses.  In order to provide your child with new eyeglasses, the optician or 
LensCrafters will receive information on your child.  Your child’s name, birth date, and study 
identification number will be given to the optician who is making the eyeglasses.  If your child is 
to receive study-paid eyeglasses through LensCrafters, this information will be given to 
LensCrafters by the Jaeb Center, via the EyeMed/Eye Care Plan of America website, to help 
process the making of your child’s eyeglasses.
Clinical Trial Reporting
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by law. This website will not include information that can identify your child.  At most, the 
website will include a summary of the results. You can search this website at any time. 
Can You Cancel Your Authorization?
You may cancel your permission for the use and sharing of your child’s study PHI at any time. 
You will need to contact your child’s study doctors and give them a written notice of 
cancellation. When you cancel your permission or when you withdraw your child from the study 
directly, your child will no longer be a part of the study. No new information about your child 
will be gathered for the study except when there is a safety concern related to the study. If there 
is a safety concern, your child’s entire medical record may need to be reviewed.  
The Jaeb Center will receive all the information that was collected for the study up to the time 
that you cancel or withdraw your child from the study. The Jaeb Center will receive any new 
information about any safety concerns that may be related to the study.
When Will the Use and Sharing of Your Child’s PHI Stop? 
Some of your child’s study PHI does not have a code number with it. Your permission for the 
use and sharing of your child’s PHI lasts 50 years from the date that you sign this form or until 
the end of the study, whichever comes first.  
The rest of your child’s study information does have a code number with it. When it is collected, 
it becomes part of a research report. Your permission for the use and sharing of this coded 
information will never end. This coded data does not have your child’s name, address, telephone 
number, or social security number.
Some of your child’s information from this study may be stored separately from or added to your 
child’s medical record.  You will not be able to see this information until the study ends. If your 
child’s regular doctors require it for your child’s care, they will be able to view it. 
 
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Page 13 of 13
Child’s Full Name (printed): _____________________________________________________
Legally Authorized Representatives (LARs) Permission
Investigator’s Certification
I, ______________________________________ (print name of legally authorized representative 
(“LAR”)) attest that I am one of the following individuals authorized to provide consent for the 
child named above as I am one of the following LARs (checkbox):
☐ Natural or Adoptive Parent
☐ Legal Custodian, or
☐ Legal Guardian
By signing below, you agree to allow your child to take part in this study. Your signature means that:

you have read this informed consent form

you have been given the chance to discuss the study and to ask questions to your satisfaction

you authorize the use and sharing of your child’s protected health information that is collected 
as part of the study

you freely choose to allow your child to participate, you and your child can withdraw your 
child at any time, and you will receive a copy of this consent form
LAR Signature
Date
 
I certify that the LAR(s) named above are in fact the person(s) authorized to consent for the 
child. I also certify that to the best of my knowledge the participant or LAR understands 
the nature, demands, risks, and benefits involved in the participation of this study. 
________________________         _______________________                 ______________ 
Investigator’s Printed Name         Investigator’s Signature 
Date
 
JCHR IRB
APPROVED
 
16/Apr/2019
 

SAP_002.pdf: 























Prot_001.pdf: 
 
MTS1 Protocol V5.1 (06Apr2020) 
 
1 
 
1 
 
2 
 
3 
 
4 
MYOPIA TREATMENT STUDY 
5 
(MTS1) 
6 
 
7 
Low-Dose Atropine for Treatment of Myopia 
8 
 
9 
PROTOCOL 
10 
 
11 
Protocol Identifying Number: MTS1 
12 
IND Sponsor: Jaeb Center for Health Research, Inc.  
13 
Version Number: v5.1 
14 
April 6, 2020 
 
15 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
2 
PROTOCOL AMENDMENT IV (24 Mar 2020) 
16 
 
17 
This amendment provides for the following protocol changes:  
18 
 
19 
Protocol Change # 1 
20 
  
21 
Original Protocol 
22 
Office visits are conducted at 6, 12, and 18-months post-randomization.  
23 
 
24 
Protocol Change 
25 
A virtual visit may be completed at 6, 12, or 18-months in the event that an in-person office visit 
26 
cannot be completed by the participant.  Data collected during a virtual visit are a subset of the 
27 
data that are collected at an in-office visit (summarized in section 4.9) that can be collected by 
28 
means of a phone call, or other smartphone or computer based video/audio method of 
29 
communication such as teleconferencing.   
30 
 
31 
Rationale for Change and Impact on Study Design 
32 
Due to the coronavirus (COVID-19) pandemic, participating clinical centers may be unable to 
33 
see research participants for in-office study visits in the coming months.  The protocol is being 
34 
amended to allow for a virtual visit to be completed at 6, 12, or 18-months instead of an office 
35 
visit.  Given that these visits are prior to the 24-month primary outcome visit, the overall 
36 
scientific integrity of the study is maintained.   
37 
 
38 
Effect of Change on Informed Consent Form and Study Participants 
39 
No changes are needed to the current informed consent or assent forms.  The data collected by 
40 
virtual visit are a subset of the data that would be collected at an in-office visit already described 
41 
in the consent form.    
42 
  
43 
Protocol Change # 2 
44 
  
45 
Original Protocol 
46 
Females who have experienced menarche will undergo a urine pregnancy test at each follow up 
47 
visit after randomization. Study medication will be discontinued if the test result is positive. 
48 
 
49 
Protocol Change 
50 
A pregnancy test will be performed at home if an office visit cannot be completed.  Pregnancy 
51 
testing is being omitted at the 30-month visit which occurs 6 months after study medication has 
52 
been discontinued.    
53 
 
54 
Rationale for Change and Impact on Study Design 
55 
Female participants who have experienced menarche must not be pregnant to continue on study 
56 
medication.  The protocol has been revised to require a pregnancy test to be performed at home 
57 
instead of in the office if an in-person office visit cannot be completed by the participant.     
58 
 
59 
Effect of Change on Informed Consent Form and Study Participants 
60 
No changes are needed to the current informed consent form as the form states that pregnancy 
61 
tests are required at 6, 12, and 18-months for females who have experienced menarche.   
62 
 
 
63 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
3 
PROTOCOL AMENDMENT III (25 Feb 2019) 
64 
 
65 
This amendment provides for the following protocol changes:  
66 
 
67 
Protocol Change #1 
68 
   
69 
Original Protocol 
70 
Potential participants with systemic diseases, the specified eye abnormalities, or the inability to 
71 
perform study testing were not explicitly excluded from the study.   
72 
 
73 
Protocol Change 
74 
The following items have been added as exclusion criteria in section 2.2.: 
75 
• Diseases known to affect accommodation, vergence, or ocular motility (e.g., multiple 
76 
sclerosis, Grave’s disease, myasthenia gravis, diabetes mellitus, Parkinson’s disease) 
77 
• Existing ocular conditions (e.g., retinal disease, cataracts, ptosis) or 
78 
systemic/neurodevelopmental conditions (e.g., Down syndrome) which may influence 
79 
refractive development. 
80 
• Any condition that in the judgement of the investigator could potentially influence 
81 
refractive development.   
82 
• Existing conditions that may affect the long-term health of the eye or require regular 
83 
pharmacologic treatment that may adversely interact with study medication (e.g., JIA, 
84 
glaucoma, diabetes mellitus, pre-diabetes). 
85 
• Inability to comprehend and/or perform any study-related clinical tests. 
86 
 
87 
Rationale for Change 
88 
The reasons for excluding certain diseases and/or conditions are specified in the criteria to aid 
89 
investigators in understanding the exclusions.  The inability to comprehend and/or perform any 
90 
study-related clinical tests by a potential participant would prevent the study from collecting 
91 
necessary valid and complete data. 
92 
 
93 
Protocol Change #2 
94 
   
95 
Original Protocol 
96 
Section 4.1 includes the following two statements: 
97 
• A central pharmacy will compound the atropine and placebo eyedrops based on a participant-
98 
specific treatment group and will package them in identical single-use ampules to maintain 
99 
masking.   
100 
• The atropine eyedrops will consist of 0.01% atropine. The placebo eyedrops will consist of 
101 
0.5% hydroxypropol methylcellulose and 1:10,000 benzalkonium chloride.   
102 
 
103 
Protocol Change 
104 
A separate section 4.1 has been added to better describe Study Medication.   
105 
 
106 
Nevakar is manufacturing the study drug (0.01% atropine) and placebo and packaging both in 
107 
identical-appearing single-use ampules.  In addition to 0.01% atropine, the ampules contain a 
108 
buffer similar to artificial tears while the placebo contains just the buffer similar to artificial 
109 
tears.  The atropine and placebo ampules are sent to a central pharmacy, which will label and 
110 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
4 
package multiple atropine or placebo ampules into three month supply packages to maintain 
111 
masking.  The packages of ampules will be shipped to participating sites in insulated shipping 
112 
boxes designed to maintain study drug at 59 to 77 degrees F during shipping.  Participating sites 
113 
will store study drug at room temperature (between 68 and 77 degrees F) prior to dispensing 
114 
study medication packages to study participants.  Additional study medication details are 
115 
summarized within a separate investigational product manual.  
116 
 
117 
Rationale for Change 
118 
The terms “compound” and “1:10,000 benzalkonium chloride” were inadvertent holdovers from 
119 
a previous draft protocol that was written when the study was expected to use a compounding 
120 
pharmacy to produce the atropine eyedrops.  No compounding or preservative is needed for the 
121 
study medication currently manufactured in single-use ampules (monitored by US FDA) which 
122 
are shipped directly from the manufacturer.   
123 
 
124 
Protocol Change #3 
125 
 
126 
Original Protocol 
127 
Section 4.3 on phone calls stated that “Two weeks following randomization (±3 days), the site 
128 
will contact parents to confirm receipt of study medication and question the parent as to whether 
129 
the child is experiencing any issues with treatment.”  
130 
 
131 
Protocol Change 
132 
The phrase “to confirm receipt of study medication” has been omitted.    
133 
 
134 
Rationale for Change 
135 
There is no need to confirm receipt of study medication on the 2-week phone call because study 
136 
medication is handed directly to participants at their office visit at the time of randomization.  
137 
The “to confirm receipt of study medication” wording was an inadvertent holdover from a 
138 
previous draft protocol which was written when the study was expected to mail study medication 
139 
to participants.   
140 
 
141 
Protocol Change #4 
142 
 
143 
Original Protocol 
144 
Although a negative urine pregnancy test is required for enrollment of any female who had 
145 
reached menarche, no pregnancy testing was described during follow up.   
146 
 
147 
Protocol Change 
148 
A pregnancy test is now required at every post-randomization follow up visit for females who 
149 
have experienced menarche. 
150 
 
151 
Rationale for Change 
152 
Pregnancy testing during post-randomization follow up (section 4.9) was felt necessary to 
153 
enforce the existing requirement that study medication be discontinued in the event of pregnancy 
154 
during the study. 
155 
 
156 
Protocol Change #5 
157 
 
158 
Original protocol  
159 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
5 
One inclusion criteria for randomization was interocular difference <= 0.1 logMAR (<= 5 letters 
160 
by E-ETDRS testing). 
161 
 
162 
Protocol change  
163 
This inclusion criteria has been changed to interocular difference <= 0.2 logMAR (<= 10 letters 
164 
by E-ETDRS testing) in sections 1.11, 1.12, and 3.4. 
165 
 
166 
Rationale for Change  
167 
The intent of the exclusion criteria for interocular difference was to exclude children with 
168 
amblyopia; however, the previous interocular difference of 0.1 (5 letters) is within test-retest 
169 
variability for E-ETDRS visual acuity testing. The criteria was expanded to allow enrollment of 
170 
children with interocular differences up to 0.2 logMAR (10 letters), the threshold that is used to 
171 
define amblyopia in several other PEDIG studies of intermittent exotropia.      
172 
 
173 
 
174 
 
 
175 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
6 
PROTOCOL AMENDMENT II (12 Jun 2018) 
176 
 
177 
This amendment provides for the following protocol changes:  
178 
 
179 
Protocol Change #1 
180 
   
181 
Original Protocol 
182 
It was not an inclusion criterion that participants were required to have excellent compliance 
183 
with spectacle correction either to be enrolled into the run-in phase or to be eligible for 
184 
randomization. Participants who were not currently wearing refractive correction were eligible 
185 
for the study and could have spectacle correction initiated during the run-in phase.      
186 
 
187 
Protocol Change 
188 
Excellent compliance with refractive correction (76% to 100% of waking hours) for at least one 
189 
month will be an eligibility criterion for enrollment into the run-in phase (sections 1.11, 1.12, 
190 
and 2.2). Similarly, excellent compliance with refractive correction during the run-in phase will 
191 
be encouraged and will be required to be eligible for randomization (sections 1.11, 1.12, 2.5, 2.6, 
192 
3.2, 3.3, and 3.4).    
193 
 
194 
Rationale for Change 
195 
It is not known whether spectacle compliance could interact with the effect of atropine eyedrops, 
196 
but limiting the study to children who are compliant with refractive correction will guard against 
197 
the possibility of having lowered statistical power for analysis should such an interaction exist.  
198 
It was also felt that children who are compliant with refractive spectacle correction might also be 
199 
more likely to be compliant with nightly eyedrops for two years than children who are not 
200 
compliant with refractive correction.  It is acknowledged that the study results will be 
201 
generalizable only to children who are compliant with refractive correction.    
202 
 
203 
Protocol Change #2 
204 
   
205 
Original Protocol 
206 
The original protocol indicated that “It is the investigators’ opinion that the protocol’s level of 
207 
risk falls under DHHS 46.404, which is research not involving greater than minimal risk.” 
208 
(section 6.4.3) 
209 
 
210 
Protocol Change 
211 
The revised protocol states that “The Jaeb Center Institutional Review Board has classified the 
212 
protocol as research involving greater than minimal risk using the federal definition under 45 
213 
CFR 46.102i.”   
214 
 
215 
Rationale for Change 
216 
The protocol was assigned the risk level of “research involving greater than minimal risk” by the 
217 
Jaeb Center for Health Research Institutional Review Board when it approved the protocol.   
218 
 
219 
Protocol Change #3 
220 
Original Protocol 
221 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
7 
Mean corneal radius was one of the biometric parameters to be measured. Three summary 
222 
measurements of axial length, mean corneal radius, anterior chamber depth and lens thickness 
223 
were to be taken using an optical biometer (e.g. IOLMaster, LENSTAR).      
224 
 
225 
Protocol Change 
226 
Flat corneal radius will be measured instead of mean corneal radius because that is what both optical 
227 
biometers can measure.  The first summary measurement of axial length, flat corneal radius, anterior 
228 
chamber depth and lens thickness will be collected, with each value based on the individual 
229 
instrument’s method of taking and then averaging multiple measures.   
230 
   
231 
Rationale for Change 
232 
For corneal curvature, the only common measurement and unit of measure for the two optical 
233 
biometers being used is flat corneal radius and diopter.  To avoid increasing the testing burden 
234 
for participants, a single measurement was deemed sufficient for these four biometric 
235 
parameters.     
236 
 
237 
In addition, the following minor corrections/clarifications have been made.  
238 
 
239 
• Typos were corrected in protocol change #1 in protocol amendment I and in section 7.4.2 to 
240 
reflect that near visual acuity is measured binocularly, not in each eye.      
241 
 
242 
• Clarification that the average spherical equivalent between eyes is used for the primary 
243 
analysis of myopia progression (section 1.1) 
244 
 
245 
• In section 3.4 concerning eligibility for randomization, clarified that participants who do not 
246 
meet eligibility criteria will be withdrawn from the study without being randomized.   
247 
 
248 
• Clarified in section 6.4.2 that it refers to the 24-month primary outcome in the section 
249 
pertaining to participants develops adverse effects serious enough to discontinue study 
250 
medication.  
251 
 
252 
• The enrollment visit has been added to the list of visits that are paid for by the study (section 
253 
5.4); it was originally omitted in error.   
254 
 
255 
• In section 7.1.1 regarding the 24-month on-treatment primary analysis 
256 
o Clarified that adjustment covariates are included to improve power for the treatment 
257 
group comparison, as well as to account for potential residual confounding 
258 
Clarified that baseline spherical equivalent refractive error (SER) will be included in the 
259 
analysis model as an adjustment factor, while the change in SER at all follow-up visits 
260 
up to and including the 24-month visit will be included in the longitudinal outcome 
261 
vector.  Further details, including handling of missing data, will be included in the 
262 
separate Statistical Analysis Plan. 
263 
 
264 
• Section 7.6 has been updated based on recent decision from the Data Safety and Monitoring 
265 
Committee that evaluation of whether an interim monitoring is needed would be made after 6 
266 
months of recruitment and before any outcome data are reviewed.    
267 
 
268 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
8 
• In Section 6.4.2, clarified that the reason for trying progressive lenses is to address adverse 
269 
events related to near focusing problems.  
270 
 
271 
• In the statistical analysis chapter, a few minor corrections have been made to the data for two 
272 
previous studies (CLEERE and ATOM2) that are cited as background data for estimating 
273 
sample size (sections 7.8.2. 7.8.3). Note that none of these minor changes affected the sample 
274 
size calculation.  
275 
 
276 
• In section 7.8.5, a few minor corrections have been made to the numbers in Table 2 on the 
277 
expected width of confidence intervals on the treatment group comparisons of myopia 
278 
progression in racial subgroups. None of these minor changes were substantive.     
279 
 
280 
• In section 7.8.1, the purpose of the general considerations for sample size section was 
281 
clarified.  In addition, two sentences were omitted here as they were already covered 
282 
elsewhere in section 7.8. 
283 
 
284 
• In section 2.4, some details of the cycloplegic autorefraction and other biometry 
285 
measurements have been omitted and moved to a separate manual of procedures.     
286 
 
 
287 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
9 
 
288 
PROTOCOL AMENDMENT I (11 Dec 2017) 
289 
 
290 
This amendment provides for the following protocol change:  
291 
 
292 
Protocol Change #1 
293 
 
294 
Original Protocol 
295 
Binocular near visual acuity will be assessed at the 6-month visit only.  The analysis plan 
296 
consisted of tabulating 6-month binocular near visual acuity by treatment group.    
297 
 
298 
Protocol Change 
299 
Binocular near visual acuity will be assessed at both the Randomization visit and the 6-month visit 
300 
(section 3.2).  The analysis plan was changed to calculate the proportion of participants with loss of 
301 
best corrected near vision >1 logMAR line at 6 months (sections 1.1, 1.12, and 7.4.2).    
302 
  
303 
Rationale for Change 
304 
Binocular near visual acuity is an important outcome to assess the safety of low-dose atropine.  
305 
In order to interpret any change in binocular near visual acuity between randomization to six 
306 
months, a baseline measure is needed at the time of randomization.   
307 
 
308 
Protocol Change #2 
309 
 
310 
Original Protocol 
311 
The eye drop questionnaire will be completed at each follow up visit.   
312 
 
313 
Protocol Change 
314 
The eye drop questionnaire will be completed at each follow up visit except the 30-month visit 
315 
(sections 1.1.1, 1.12, 4.8, and 7.4.1).   
316 
 
317 
Rationale for Change 
318 
The eye drop questionnaire is not relevant to the 30-month visit as eye drops are to be 
319 
discontinued at the 24-month visit.    
320 
 
321 
Protocol Change #3 
322 
 
323 
Original Protocol 
324 
The criterion for a serious adverse event did not include a congenital anomaly/birth defect.   
325 
 
326 
Protocol Change 
327 
The criterion for a serious adverse event now includes a congenital anomaly/birth defect (section 
328 
6.2).   
329 
 
330 
Rationale for Change 
331 
Congenital anomalies and birth defects are part of the Food and Drug Administration definition 
332 
of a serious adverse event.   
333 
 
 
334 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
10 
KEY ROLES 
335 
JCHR Coordinating Center Director 
 
Name, degree 
Raymond Kraker, M.S.P.H. 
Title 
Director, PEDIG Coordinating Center 
Institution Name 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
Phone: 1-888-797-3344 
Fax: 1-888-697-3344 
Email: rkraker@jaeb.org 
http://www.pedig.net 
JCHR Principal Investigator 
 
Name, degree 
Danielle Chandler, M.S.P.H. 
Title 
Principal Investigator 
Institution Name 
Jaeb Center for Health Research  
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
Phone: 1-888-797-3344 
Fax: 1-888-697-3344 
Email: dchandler@jaeb.org 
http://www.pedig.net 
Protocol Co-Chair 
 
Name, degree 
Michael X. Repka, M.D. 
Title 
Protocol Co-Chair  
Institution Name 
Wilmer Eye Institute 
233 Wilmer Institute, 600 N Wolfe St 
Baltimore, MD 21287 
Phone: (410) 955-8314 
Fax: (410) 955-0809 
Email: mrepka@jhmi.edu 
Protocol Co-Chair  
 
Name, degree 
Katherine K. Weise, O.D.  
Title 
Protocol Co-Chair  
Institution Name 
University of Alabama at Birmingham School of Optometry  
1720 2nd Ave South 
Birmingham, AL 35294 
Phone: (205) 934-2933 
Fax: (205) 934-6758 
Email: kweise@uab.edu 
Medical Monitor 
 
Name, degree 
Roy W. Beck, M.D., Ph.D. 
Title 
Director, Jaeb Center for Health Research 
Institution Name 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
Phone: 1-888-797-3344 
Fax: 1-888-697-3344 
 
 
336 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
11 
TABLE OF CONTENTS 
337 
 
338 
KEY ROLES....................................................................................................................................................................... 10 
339 
LIST OF ABBREVIATIONS ............................................................................................................................................ 13 
340 
CHAPTER 1: BACKGROUND AND SUMMARY ....................................................................................................... 1-1 
341 
1.1 
Epidemiology and Clinical Characteristics: ........................................................................................... 1-1 
342 
1.2 
Retardation of Myopia Progression: ....................................................................................................... 1-1 
343 
1.3 
Atropine Treatment: ............................................................................................................................... 1-1 
344 
1.4 
Previous Randomized Trials of Atropine Treatment to Reduce Myopia Progression: ........................... 1-2 
345 
1.5 
Persistence of Atropine Effect: ............................................................................................................... 1-6 
346 
1.6 
Atropine and Race: ................................................................................................................................. 1-6 
347 
1.7 
Safety of Atropine Treatment: ................................................................................................................ 1-6 
348 
1.8 
Why is Another RCT Needed? ............................................................................................................... 1-9 
349 
1.9 
Public Health Importance ....................................................................................................................... 1-9 
350 
1.10 
Study Objectives ................................................................................................................................... 1-10 
351 
1.11 
Synopsis of Study Design ..................................................................................................................... 1-10 
352 
1.12 
Study Flow Chart .................................................................................................................................. 1-13 
353 
CHAPTER 2: ENROLLMENT ....................................................................................................................................... 2-1 
354 
2.1 
Eligibility Assessment and Informed Consent/Assent ............................................................................ 2-1 
355 
2.2 
Eligibility Criteria for Enrollment into Run-in Phase ............................................................................. 2-1 
356 
2.3 
Historical Information ............................................................................................................................ 2-2 
357 
2.4 
Testing at the Enrollment/Run-in Visit ................................................................................................... 2-2 
358 
2.5 
Refractive Correction ............................................................................................................................. 2-3 
359 
2.6 
Treatment in Run-In Phase ..................................................................................................................... 2-4 
360 
CHAPTER 3: RANDOMIZATION................................................................................................................................. 3-1 
361 
3.1 
Assessment of Compliance with Artificial Tears ................................................................................... 3-1 
362 
3.2 
Assessment of Compliance with Refractive Correction ......................................................................... 3-1 
363 
3.3 
Testing at the Randomization Visit ........................................................................................................ 3-1 
364 
3.4 
Confirmation of Eligibility for Randomization ...................................................................................... 3-2 
365 
3.5 
Randomization ........................................................................................................................................ 3-3 
366 
CHAPTER 4: TREATMENT AND FOLLOW-UP IN RANDOMIZED TRIAL........................................................ 4-1 
367 
4.1 
Study Medication .................................................................................................................................... 4-1 
368 
4.2 
Treatment 0 to 24 Months ...................................................................................................................... 4-1 
369 
4.3 
Telephone Calls ..................................................................................................................................... 4-1 
370 
4.4 
Masking of Treatment Group ................................................................................................................. 4-1 
371 
4.5 
Compliance with Study Treatment ......................................................................................................... 4-1 
372 
4.6 
Off-Treatment Phase >24 to 30 Months ................................................................................................. 4-2 
373 
4.7 
Side Effects of Treatment ....................................................................................................................... 4-2 
374 
4.8 
Follow-up Visit Schedule in Randomized Trial ..................................................................................... 4-2 
375 
4.9 
Follow-up Visit Testing Procedures ....................................................................................................... 4-2 
376 
4.10 
Management of Refractive Error ............................................................................................................ 4-3 
377 
4.11 
Non-Randomized Treatment Other than Refractive Correction ............................................................. 4-4 
378 
4.12 
General Considerations........................................................................................................................... 4-4 
379 
CHAPTER 5: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP ............................................................. 5-1 
380 
5.1 
Participant Withdrawals ......................................................................................................................... 5-1 
381 
5.2 
Discontinuation of Study ........................................................................................................................ 5-1 
382 
5.3 
Travel Reimbursement ........................................................................................................................... 5-1 
383 
5.4 
Costs Covered by the Study .................................................................................................................... 5-1 
384 
5.5 
Costs Not Covered by the Study ............................................................................................................. 5-1 
385 
CHAPTER 6: ADVERSE EVENTS AND RISKS .......................................................................................................... 6-1 
386 
6.1 
Recording of Adverse Events ................................................................................................................. 6-1 
387 
6.2 
Reporting Serious or Unexpected Adverse Events ................................................................................. 6-2 
388 
6.3 
Data and Safety Monitoring Committee Review of Adverse Events ..................................................... 6-2 
389 
6.4 
Risks ....................................................................................................................................................... 6-2 
390 
6.4.1 
Risks of Examination Procedures ...................................................................................................... 6-2 
391 
6.4.2 
Risk of Atropine Therapy .................................................................................................................. 6-3 
392 
6.4.3 
Risk Assessment ................................................................................................................................ 6-4 
393 
CHAPTER 7: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS .................................................... 7-1 
394 


 
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12 
7.1 
Primary Objective:  Efficacy on Atropine Treatment (24 Months) ........................................................ 7-1 
395 
7.1.1 
Primary Analysis – Refractive Error at 24 Months (On-Treatment) .................................................. 7-1 
396 
7.1.1.1 
Sensitivity Analyses ...................................................................................................................... 7-1 
397 
7.1.2 
Secondary Outcomes at 24 Months (On-Treatment) ......................................................................... 7-1 
398 
7.1.2.1 
Proportion of Participants with Progression >=2D at 24 Months ................................................. 7-1 
399 
7.1.2.2 
Change in Axial Length at 12 and 24 Months............................................................................... 7-2 
400 
7.1.2.3 
Compliance ................................................................................................................................... 7-2 
401 
7.1.3 
Secondary Outcomes at 12 Months (On-Treatment) ......................................................................... 7-2 
402 
7.1.3.1 
Refractive Error at 12 Months ....................................................................................................... 7-2 
403 
7.1.3.2 
Proportion of Participants with Progression >=1D at 12 Months ................................................. 7-2 
404 
7.2 
Secondary Objective:  Efficacy off Atropine Treatment (30 Months) ................................................... 7-2 
405 
7.3 
Additional Analyses ............................................................................................................................... 7-3 
406 
7.3.1 
Treatment Effect in Subgroups .......................................................................................................... 7-3 
407 
7.3.2 
Treatment Effect over Time ............................................................................................................... 7-3 
408 
7.3.3 
Exploratory Analyses of Additional Ocular Biometric Parameters ................................................... 7-3 
409 
7.4 
Safety Analyses ...................................................................................................................................... 7-3 
410 
7.4.1 
Adverse Effects of Eye Drops............................................................................................................ 7-3 
411 
7.4.2 
Visual Acuity ..................................................................................................................................... 7-3 
412 
7.5 
Need for Bifocals .................................................................................................................................... 7-4 
413 
7.6 
Interim Analysis ..................................................................................................................................... 7-4 
414 
7.7 
Data Tabulations and Other Analyses .................................................................................................... 7-4 
415 
7.8 
Sample Size ............................................................................................................................................ 7-4 
416 
7.8.1 
General Considerations ...................................................................................................................... 7-4 
417 
7.8.2 
Sample Size for Primary Objective: Efficacy on Atropine Treatment ............................................... 7-4 
418 
7.8.3 
Sample Size for Secondary Objective: Efficacy off Atropine Treatment .......................................... 7-5 
419 
7.8.4 
Summary of Sample Size Estimation................................................................................................. 7-6 
420 
7.8.5 
Precision within Racial Subgroups .................................................................................................... 7-6 
421 
CHAPTER 8: DATA COLLECTION AND MONITORING ....................................................................................... 8-1 
422 
8.1 
Case Report Forms and Device Data ...................................................................................................... 8-1 
423 
8.2 
Study Records Retention ........................................................................................................................ 8-1 
424 
8.3 
Quality Assurance and Monitoring ......................................................................................................... 8-1 
425 
8.4 
Protocol Deviations ................................................................................................................................ 8-2 
426 
CHAPTER 9: ETHICS/PROTECTION OF HUMAN PARTICIPANTS .................................................................... 9-1 
427 
9.1 
Ethical Standard ...................................................................................................................................... 9-1 
428 
9.2 
Institutional Review Boards ................................................................................................................... 9-1 
429 
9.3 
Informed Consent Process ...................................................................................................................... 9-1 
430 
9.3.1 
Consent Procedures and Documentation ........................................................................................... 9-1 
431 
9.3.2 
Participant and Data Confidentiality .................................................................................................. 9-1 
432 
CHAPTER 10: REFERENCES ..................................................................................................................................... 10-1 
433 
 
 
434 


 
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13 
LIST OF ABBREVIATIONS 
435 
 
436 
ABBREVIATION 
DEFINITION 
ANCOVA 
Analysis of Covariance 
ATOM 
Atropine for the Treatment of Childhood Myopia Study  
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLEERE 
Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error 
CRF 
Case Report Form 
DSMC 
Data Safety and Monitoring Committee 
FDA 
Food and Drug Administration 
GCP  
Good Clinical Practice 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
MCMC 
Monte Carlo Markov Chain 
PI 
Principle Investigator 
PEDIG 
Pediatric Eye Disease Investigator Group 
QA 
Quality Assurance 
QC 
Quality Control 
RBM 
Risk Based Monitoring 
SE  
Spherical equivalent 
SER 
Spherical equivalent refractive error 
SVL  
Single vision lenses 
437 


 
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1-1 
Chapter 1: BACKGROUND AND SUMMARY 
438 
 
439 
This study is being conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and 
440 
funded through a cooperative agreement from the National Eye Institute of the National 
441 
Institutes of Health.   
442 
 
443 
1.1 
Epidemiology and Clinical Characteristics: 
444 
Myopia is one of the most commonly occurring ocular disorders, with an estimated prevalence of 
445 
13% to 49% in adult population-based studies.1, 2  In children, the prevalence of myopia in 
446 
population-based studies worldwide ranges from 1.2% to 59.1%,1, 3, 4 with variations due to age 
447 
and race and definition used to classify myopia.  In the US, in children 6-72 months of age, 
448 
prevalence has been reported at 0.7 -1.2% in Non-Hispanic white children,5, 6 3.98% in Asian 
449 
children,6 5.5-6.6% in African American children5, 7 and 3.7% in Hispanic children.7  Not only is 
450 
the prevalence of myopia in adults relatively high, but it is increasing in the US8 
451 
(http://www.nei.nih.gov/eyedata/myopia.asp#4) and around the world.9 
452 
 
453 
Progression of myopia primarily occurs due to elongation of the axial length of the eye.  The 
454 
average increase in myopia has been estimated at 0.5 diopters per year (personal communication 
455 
with the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) 
456 
study group between November 2015 and April 2016).10-12  Retarding progression of myopia has 
457 
been the focus of much research, since high levels of myopia (>-6.00D) are associated with 
458 
retinal and vitreous detachment, myopic macular degeneration, and increased risk of glaucoma 
459 
and cataract.13, 14 A recent report for the US Population estimated the prevalence of high myopia 
460 
and myopic choroidal neovascularization to be 3.92% (95% confidence interval [CI], 2.82-5.60) 
461 
and 0.017% (95% CI, 0.010-0.030), respectively, among adults in the United States aged 18 
462 
years and older in 2014.15 This translated into a population burden of approximately 9 614 719 
463 
adults with high myopia, and 41 111 adults with myopic choroidal neovascularization. 
464 
 
465 
1.2 
Retardation of Myopia Progression: 
466 
Treatment to retard myopia progression is important for preventing the development of high 
467 
myopia and associated sequelae.  Various management approaches have been reported, with 
468 
varying success, including the use of anti-muscarinic pharmacological agents (atropine, 
469 
pirenzepine, cyclopentolate), bifocals, progressive additional lenses, contact lenses, contact 
470 
lenses with peripheral myopic defocus, under-correction or part-time optical correction, and 
471 
orthokeratology.16,17  Some studies have found that an increase in the amount of time spent 
472 
outdoors may have a protective effect on the progression of myopia.18-20  In a recent Cochrane 
473 
Systematic Review entitled Interventions to Slow Progression of Myopia in Children,16 anti-
474 
muscarinic pharmacological treatments were found to be more effective than other treatments. 
475 
Nevertheless, side-effects from mydriasis and cycloplegia with atropine 1% were significant.  
476 
More conclusive evidence is needed regarding optimal dose (i.e., dose with meaningful treatment 
477 
effect with minimal side-effects), lasting effects of treatment, and efficacy of anti-muscarinic 
478 
pharmacological treatments combined with other treatment modalities, such as bifocals.16  
479 
 
480 
1.3 
Atropine Treatment: 
481 
Use of topical atropine for treatment of myopia has been advocated since the 1800s.21 
482 
Summarizing a wealth of knowledge on atropine treatment for reduction of myopia progression, 
483 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-2 
1% atropine daily with or without multi-focal spectacles is most commonly used, resulting in an 
484 
average reduction of myopia progression of 90%.22  The mechanism by which atropine slows 
485 
myopia progression is largely unknown, but has been hypothesized to occur via elimination of 
486 
accommodation, local retinal effects that slow progression, or potential biochemical changes 
487 
brought about through binding of atropine with the muscarinic receptors.16 Another possible 
488 
mechanism of slowing myopic progression with atropine may be via increased UVA exposure23 
489 
as a result of a dilated pupil, which exposure has been shown to strengthen the sclera via 
490 
crosslinking of scleral collagen,24 potentially limiting axial lengthening.  Although this last 
491 
mechanism is somewhat speculative, the general impression from the literature is that, regardless 
492 
of mechanism, 1% atropine appears to be very effective. 
493 
 
494 
1.4 
Previous Randomized Trials of Atropine Treatment to Reduce Myopia Progression: 
495 
Several randomized trials of prevention of myopia progression using atropine have been 
496 
conducted in recent years.   
497 
• Yen and colleagues25 in 1989 compared one year of 1% atropine every other night, 1% 
498 
cyclopentolate every night, and normal saline every night in 96 children aged 6 to 14 
499 
years with myopia ranging from -0.50D to -4.00D.  Children in the atropine group had a 
500 
mean myopia progression over 1 year of -0.219D, whereas children receiving 
501 
cyclopentolate progressed -0.578D and children receiving normal saline progressed -
502 
0.914D.  
503 
• In 1999, Shih and colleagues26 reported a study of 200 children aged 6 to 13 years with 
504 
myopia ranging from -0.50D to -6.75D that compared 0.5%, 0.25%, and 0.1% atropine to 
505 
5% tropicamide. Children received atropine or tropicamide eyedrops nightly for up to 2 
506 
years.  At the end of 2 years, all atropine-treatment groups had less myopia progression (-
507 
0.04±0.63 D/year, -0.45±0.55D/year, and -0.47± 0.91D/year, respectively) than the 
508 
tropicamide group (-1.06±0.61D/year).   
509 
• Subsequently, Shih and colleagues27 studied the effect of multi-focal glasses with and 
510 
without atropine to control progression of myopia.  The study randomized 227 children to 
511 
18 months of 0.5% atropine + multifocal lenses, multi-focal lenses alone, or single vision 
512 
glasses.  Myopia progressed only -0.42D±0.07D with atropine + multi-focal lenses 
513 
compared with -1.19D±0.07D with multi-focal lenses and -1.40D±0.09D with single 
514 
vision lenses, leading the authors to conclude that atropine treatment is effective for 
515 
slowing the progression of myopia and may act via a mechanism of accommodation 
516 
inhibition.  
517 
• More recently, the Atropine for the Treatment of Childhood Myopia (ATOM) study was 
518 
a RCT comparing nightly administration of 1% atropine to vehicle (0.5% hydroxypropyl 
519 
methylcellulose and 1:10,000 benzalkonium chloride) over 2 years in 400 children ages 6 
520 
to 12 years with myopia ranging from -1.00D to -6.00D.28 Only one eye of each child 
521 
was chosen for treatment.  After 2 years, myopia in children receiving 1% atropine had 
522 
progressed -0.28D±0.92D versus -1.20D±0.69D in the placebo-treated eye (Figure 1).  
523 
Axial length was also reduced in atropine-treated eyes compared with placebo-treated 
524 
eyes (-0.02±0.35mm vs 0.38±0.38mm).   
525 
• The ATOM2 study29 compared 3 doses of atropine (0.5%, 0.1% and 0.01%) in 400 
526 
children with myopia of at least -2.00D and found 2-year myopia progression of -
527 
0.30±0.60D, -0.38±60D, and -0.49±0.63D respectively (Figure 1). Although there was no 
528 
control group, myopia progression was significantly lower than that observed in controls 
529 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-3 
in ATOM1 (-1.20D±0.69D), but was not different from the 1% atropine-treated cohort (-
530 
0.28D±0.92D).  Axial length growth was lower in both 0.5% and 0.1% groups compared 
531 
with the 0.01% group (0.27 ± 0.25mm, 0.28 ±0.27mm, and 0.41±0.32mm respectively, 
532 
P<0.001).  
533 
 
534 
The effect of treatment on myopia progression and axial length in these randomized trials is 
535 
compiled in Table 1. Although there were good overall results with atropine treatment, a logistic 
536 
regression analysis of ATOM1 data suggested that there is a subgroup of participants (younger 
537 
participants with higher levels of myopia and trending towards progression) whose myopia 
538 
progressed significantly despite atropine treatment.30 
539 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-4 
Table 1: Summary of Randomized Trials Evaluating Effect of Atropine on Myopia Progression 
540 
Study 
Ethni-
city  
Treatment 
Group ** 
N 
Time 
point 
Change in Myopia 
(D) 
Change in 
Axial  
Length (mm) 
Comments 
Yen25 
Asian 
Control (saline) 
32 
1 yr 
-0.914 ± 0.581 
not reported 
Only about 40% (96/247) of randomized participants included in 
analysis. Excluded participants with less than 100% compliance. 
Atropine 1%*** 
32 
1 yr 
-0.219 ± 0.538 
not reported 
Cyclopentolate 1% 
32 
1 yr 
-0.578  ± 0.490 
not reported 
Shih26 
Asian 
Atropine 0.5% 
41 
≤2 yr 
-0.04 ± 0.63 
not reported 
Likely confounded by refractive correction as “suggested” bifocals in 
atropine 0.5%, under-correction in atropine 0.25, and full correction 
in atropine 0.1%. Outcomes by cycloplegic autorefraction.  Length of 
treatment/follow-up not well defined.     
Atropine 0.25% 
47 
≤2 yr 
-0.45 ±  0.55 
not reported 
Atropine 0.1% 
49 
≤2 yr 
-0.47 ± 0.91 
not reported 
Tropicamide 
49 
≤2 yr 
-1.06 ± 0.61 
not reported 
Shih27 
Asian 
Control (SVL)**** 
61 
1.5 yr 
-1.40 ± 0.09 
0.59 ± 0.04 
Double blind randomization.  
Multifocal lenses 
66 
1.5 yr 
-1.19 ± 0.07 
0.49 ± 0.03 
Atropine 0.5% + 
multifocal lenses 
61 
1.5 yr 
-0.42 ± 0.07 
 
0.22 ± 0.03 
 
ATOM28 
Asian 
Control 
NR 
1 yr 
-0.76 ± 0.44 
0.20 ± 0.30 
Outcomes by masked cycloplegic autorefraction. 
 
Number of participants analyzed at 1yr not specified but suspect 
similar to number analyzed at 2yrs.    
190 
2 yr 
-1.20 ± 0.69 
0.38 ± 0.38 
Atropine 1% 
NR 
1 yr 
0.03 ± 0.50 
-0.14 ± 0.28 
166 
2 yr 
-0.28 ± 0.92 
-0.02 ±0.35 
ATOM229  
Asian 
Atropine 0.5% 
NR 
1 yr 
-0.17 ± 0.47 
0.11 ± 0.17 
Outcomes by cycloplegic autorefraction, but no control group.    
 
Number of participants analyzed at 1yr not specified but suspect 
similar to number analyzed at 2yrs.    
 
 
139 
2 yr 
-0.30 ± 0.60 
0.27 ± 0.25 
Atropine 0.1% 
NR 
1 yr 
-0.31± 0.50 
0.13 ± 0.18 
141 
2 yr 
-0.38 ± 0.60 
0.28 ± 0.27 
Atropine 0.01% 
NR 
1 yr 
-0.43 ± 0.52 
0.24 ± 0.19 
75 
2 yr 
-0.49 ± 0.60 
0.41 ± 0.32 
ATOM231 
Asian 
Atropine 0.01% 
17 
5 yr 
-2.25 ±  1.11 
1.21 ±  0.54 
Children progressing more than 0.50 D during washout year three 
were started back on atropine 0.01% for two additional years.  
Atropine 0.1% 
82 
5 yr 
-2.34 ± 1.07 
1.08 ± 0.53 
Atropine 0.5% 
93 
5 yr  
-2.32 ± 1.04 
1.03 ± 0.47 
*N = number with outcome data.  NR = not reported. **Daily treatment unless otherwise noted ***Treatment every other day.   ****SVL = single vision lenses 
541 
 
 
542 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-5 
Figure 1: Summary of Findings from ATOM28 and ATOM229 Studies* 
543 
 
544 
 
545 
 
546 
 
547 
 
548 
*Figure reproduced from Chia et al, 2016.31
549 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-6 
 
550 
1.5 
Persistence of Atropine Effect: 
551 
Following cessation of atropine treatment, there appears to be a rebound of myopia progression, 
552 
although the rate of myopia progression differs between studies and depending on which dose of 
553 
atropine was used.  In a prospective long-term study, Brodstein and colleagues32 followed 253 
554 
children treated with atropine for up to 9 years.  They found a rebound in myopia progression, 
555 
but the rate was no higher than observed in control participants.  In a retrospective population-
556 
based study of atropine treatment for myopia, 214 children in Olmsted County, MN were 
557 
followed for a mean of 11.7 years, along with age-matched controls.  Final refraction data at age 
558 
20 years indicated that benefits of atropine treatment remain after atropine treatment was 
559 
discontinued.  Nevertheless, length of treatment and follow-up was not standardized in this 
560 
retrospective study.  In the ATOM1 study, children were followed off atropine treatment, and 
561 
myopia progression was reported after 1 year.33 A higher rate of myopia progression in atropine-
562 
treated eyes following cessation of atropine compared with control fellow eyes was reported (-
563 
1.14±0.80D vs -0.38±0.39D in 1 year) (Figure 1). However, overall myopia remained less severe 
564 
in atropine-treated eyes at the end of 3 years.  In the subsequent ATOM2 study,34 356 of the 400 
565 
children enrolled in ATOM2 were followed for an additional year after stopping atropine. 
566 
Myopia progression off atropine was greatest following treatment with 0.5% atropine (-
567 
0.87±0.52D), with less progression off treatment with 0.1% (-0.68±0.45D) and 0.01% (-
568 
0.28±0.33D), leading to the conclusion that the effect of 0.01% atropine is more sustained 
569 
following treatment than with higher doses (Figure 1). The 0.01% atropine was restarted in a 
570 
subgroup that progressed more than 0.5 D in the washout year (year 3) for two additional years. 
571 
The resumption of atropine 0.01% treatment showed a lower progression in the subgroup treated 
572 
initially with atropine 0.01%, compared with higher doses in the first phase of the study (years 
573 
one and two).31 
574 
  
575 
1.6 
Atropine and Race: 
576 
Early in the 1900’s, differences in dilation response to mydriatic drugs (although not specifically 
577 
atropine) were reported between different races, with African American and Asian participants 
578 
requiring a longer time for mydriasis than White participants.35  This phenomenon has become a 
579 
common clinical experience and has been reproduced by the works of others.36  Work by Salazar 
580 
et al explored the mechanism by which this racial difference may occur, reporting that atropine is 
581 
rapidly taken up by melanocytes and released over time, leading to a longer time required to 
582 
achieve mydriasis and a prolonged mydriatic effect in heavily-pigmented eyes as atropine is 
583 
released over an extended period of time.37  In a meta-analysis of atropine for slowing 
584 
progression of myopia, Li et al38 report that atropine slows the progression of myopia more in 
585 
Asian populations of children than it does for populations of white children, but note that 
586 
comparisons are limited by the lack of studies in non-Asian populations. They conclude that 
587 
further studies to determine ethnic differences in the effect of atropine for slowing the 
588 
progression of myopia are needed. 
589 
 
590 
1.7 
Safety of Atropine Treatment: 
591 
Atropine use is associated with photophobia, mydriasis, accommodative paralysis, and allergic or 
592 
hypersensitivity reactions.  In an effort to reduce these side effects, Shih et al26 used 3 lower 
593 
doses of atropine than the commonly used 1% concentration (i.e., 0.5%, 0.25%, 0.1%), reporting 
594 
that 0.25% and 0.1% atropine were well-tolerated throughout their 2-year study (no systemic or 
595 
ocular complications identified).  The ATOM2 study also tested lower concentrations of atropine 
596 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-7 
(0.5%, 0.1%, and 0.01%), reporting that allergic conjunctivitis and dermatitis occurred in the 
597 
0.5% and 0.1% groups, but were absent in the 0.01% group, which only reported 1 case of near 
598 
blur and 1 case of irritation.29 The authors reported that 7% of children receiving atropine 0.01% 
599 
requested glasses for blur or for photosensitivity in years one and two.  In the further extension 
600 
study to 5 years, no child required glasses for blur at near or for photosensitivity.31 Cooper at al39 
601 
conducted a study to determine the maximal dose of atropine that is not associated with clinical 
602 
symptoms associated with higher doses, reporting that a dose of 0.02% atropine is the maximum 
603 
effective dose without clinical signs or symptoms.  A recent study in 14 white university students 
604 
found atropine 0.01% to be well tolerated.40 
605 
 
606 
Below (Table 2) is a summary of side effects reported with various doses of atropine for the 
607 
treatment of myopia progression in children. 
608 
 
609 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-8 
Table 2. Side Effects/Safety of Atropine Treatment of Myopia 
610 
Study 
Ethnicity / 
Eye Color  
Study 
Type* 
N** 
Dose*** 
 
Side effects 
Yen 198925 
Asian  
Pro 
32 
  1% 
**** 
All experienced photophobia. No systemic or ocular complications reported. 
Kennedy 200041 
Minnesota  
--mainly 
white  
Retro 
214 
1% 
Photophobia (40.2%), Blurred vision (10.7%), Ocular allergic reaction (3.7%), Ocular discomfort (3.7%), Headache 
(2.3%), Bad taste in mouth (2.3%), Dry mouth (1.9%), Dry eyes (1.4%), Psychological problems (0.5%), Dizziness 
(0.5%) 
ATOM1 (Chua 
2006) 28  
Asian 
Pro 
200 
1% 
No serious adverse events. Study withdrawals due to allergic or hypersensitivity reaction (4.5%), glare (1.5%), and 
blurred vision (1%) 
ATOM1 
recovery (Tong 
2009)33 
Asian  
Pro 
158 
1% 
Small decrease in best-corrected visual acuity from baseline, but ≤3 letters in all participants (occurred in controls as 
well). No reduction in near visual acuity compared with controls. No lens opacities. 
Shih 199926 
Asian 
Pro 
41 
 
47 
49 
0.5% 
 
0.25% 
0.1% 
0.5%: light sensitivity persisting >3 months in 22%, 2 children with intolerable photophobia, 2 children with fear of 
long-term effects, 1 child with recurrent blepharitis.  
0.25%: light sensitivity >4 weeks in 7%. No systemic or ocular complications. 
0.1%: No light sensitivity beyond 4 weeks. No systemic or ocular complications. 
ATOM2 (Chia 
2012)29 
Asian 
Pro 
139 
 
141 
 
75 
0.5% 
 
0.1% 
 
0.01% 
0.5%: Reduced accommodation, impaired near visual acuity, and pupil size increased >3mm. Allergic conjunctivitis 
(6.2%). Serious adverse reactions (2%) 
0.1%: Reduced accommodation, impaired near visual acuity, and pupil size increased >3mm. Allergic conjunctivitis 
(4.5%). Serious adverse reactions (2%) 
0.01%: Serious adverse reactions (1%). Minimally reduced accommodation. No allergic conjunctivitis or dermatitis. 
ATOM2 
recovery (Chia 
2014)34 
Asian 
Pro 
138 
 
139 
71 
0.5% 
 
0.1% 
0.01% 
0.5%: Accommodation reduced for 1 year after stopping (2 years administration). Near acuity reduced for an 
additional month. 
0.1%: No effects after stopping 
0.01%: No effects after stopping. 7% were given glasses for blur or photosensitivity31 
Wu 201142 
Asian 
Retro 
97 
0.05% for 6 
months, 
then 0.1% 
No reports of cataract or retinopathy noted during study period. Complaints of near blurring were “uncommon” 
Cooper 201339 
Brown iris 
U.S. 
race not 
specified 
Pro 
3 
 
6 
 
3 
0.05% 
 
0.025% 
 
0.012% 
0.05%: Accommodation deficits- no accommodation in 1 participant, 6D accommodation in 2 participants.  
0.025%: borderline accommodation in 2 of 6 participants, clinically significant pupil dilation in 4 of 6 participants 
and minimal in 2 of 6. 
0.0125%: 2 of 3 with subnormal accommodation (but no blurred vision). 
Lee 200643 
Asian 
Retro 
21 
0.05% 
33% had morning photophobia (1 into afternoon). 10% had hampered near vision. No irritation or allergic effects. 
Fang 201044 
Asian 
Retro 
24 
0.025% 
16% complained of photophobia with atropine vs 8% in control (p=0.4). No complaints of blurred vision. No 
systemic side effects. 
Ekdawi 2015 
(AAPOS Poster 
2015) 
Mostly 
Caucasian 
Retro 
7 
0.01% 
1(14%) participant had headaches and discontinued treatment after 7 months.  Participants (number not specified) had 
difficulty with reading in the first weeks that did not persist past 4-6 weeks with continued use. 
*Study type:  Pro = prospective study Retro = retrospective study  
611 
**N = number with outcome data.   
612 
***Treatment is daily unless otherwise noted 
613 
****Treatment is every other day.  
614 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-9 
1.8 
Why is Another RCT Needed? 
615 
To date, randomized trials of atropine for slowing the progression of myopia in children have 
616 
been primarily conducted on Asian populations.  A meta-analysis comparing the effect of 
617 
atropine on myopia progression in Asian and White children using data from both RCTs and 
618 
prospective cohort studies concluded that atropine may have a greater effect in Asian 
619 
populations.38 A potential explanation of the observed differences of myopia progression 
620 
between Asian and White children may be the mydriatic differences observed between highly 
621 
pigmented and lowly pigmented eyes in response to atropine.35-37  Although results of current 
622 
RCTs are promising, additional studies in non-Asian populations are needed38 to test the efficacy 
623 
of atropine in counteracting myopia progression, including dose studies.  
624 
 
625 
1.9 
Public Health Importance 
626 
The increasing prevalence of myopia and the unresolved problem of myopia progression pose 
627 
significant healthcare concerns.  Increasing axial length and especially high levels of myopia (>-
628 
6.00D) are associated with serious ocular co-morbidities, often resulting in visual impairment or 
629 
even blindness.45  These include retinal detachment, myopic maculopathy, glaucoma and 
630 
cataract.  While much research has considered the impact of preventing high myopia 
631 
development, there are relatively few participants who progress to those levels that would benefit 
632 
from reduction in progression. What is omitted from that discussion is the impact on reducing the 
633 
proportion of participants who progress even to moderate myopia. Many individuals would 
634 
retain the ability to function without correction for some activities of daily living and not be 
635 
constantly dependent on vision correction.  But far more important to this research is the 
636 
recognition that there is a large number of individuals who progress to moderate myopia and 
637 
who by doing so are at increased risk for the same myopic complications compared with 
638 
emmetropic individuals. While the risk of each adverse impact from myopia is lower at lesser 
639 
amounts of myopia on an individual basis, the risk affects many more participants and thus 
640 
slowing progression could protect more participants than from just preventing high myopia.  
641 
 
642 
Flitcroft has opined that it is important to slow progression even in the moderate range of -1.00 
643 
to -6.00 D as those levels of myopia are also significantly associated with an increased risk of a 
644 
range of ocular pathologies from glaucoma to retinal detachment46  compared with emmetropia. 
645 
Similarly, in the Blue Mountains Eye Study, the odds ratio for myopic maculopathy was 9.7 
646 
when comparing myopia -3.00 to -4.99D with emmetropia.47   Tideman et al found that the risk 
647 
of visual impairment went up with increasing spherical myopia. They noted that the lifetime risk 
648 
at 75 years of age of was 3.0%.45 
649 
 
650 
Many existing treatments to slow the progression of myopia have proven either ineffective or 
651 
unacceptable to the participant when administered for many years.  Low-dose atropine treatment 
652 
has the potential to reduce the prevalence of high myopia, reduce myopic progression among 
653 
children with moderate myopia, and thereby reduce the incidence of undesirable sequelae 
654 
associated with myopia. 
655 
 
656 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-10 
1.10 
 Study Objectives 
657 
The objectives for this randomized trial are: 
658 
1. To determine the efficacy of daily low-dose atropine (0.01%) for slowing myopia 
659 
progression over a two-year treatment period in children aged 5 to less than 13 years with 
660 
myopia -1.00 to -6.00D at the time of enrollment (Primary Outcome On-Treatment).  
661 
2. To determine the efficacy of atropine treatment on myopia progression 6 months 
662 
following cessation of low-dose atropine treatment (Secondary Outcome Off-Treatment).  
663 
 
664 
1.11 
Synopsis of Study Design 
665 
The current study is designed as an efficacy study, making effort to maximize adherence to 
666 
treatment group assignments.  After a run-in phase during which all participants are treated with 
667 
daily artificial tear eyedrops for 2-4 weeks (and glasses are updated if required) to assess their 
668 
ability to adhere to daily eye drops, participants are randomly assigned to daily atropine or 
669 
placebo for 24 months, followed by 6 months off treatment.  
670 
 
671 
Major Eligibility Criteria for Run-in Phase (see section 2.2 for a complete listing) 
672 
• Age 5 years to <13 years at time of enrollment.  Children within 4 weeks of their 13th 
673 
birthday are not eligible.  
674 
• Refractive error meeting the following by cycloplegic autorefraction:   
675 
o Myopia -1.00D to -6.00D spherical equivalent (SE) in both eyes 
676 
o Astigmatism <=1.50D in both eyes 
677 
o Anisometropia <1.00D SE 
678 
• Currently wearing refractive correction (single vision eyeglasses or contact lenses) 
679 
• Excellent compliance with refractive correction (more than 75% of all waking hours) for 
680 
at least one month, based on investigator judgment after discussion with parent. 
681 
• No current or previous myopia treatment with atropine, pirenzepine or other anti-
682 
muscarinic agent. 
683 
• No current or previous use of bifocals, progressive-addition lenses, or multi-focal contact 
684 
lenses. 
685 
• No current or previous use of orthoK, rigid gas permeable, or other contact lenses being 
686 
used to reduce myopia progression. 
687 
• No known atropine allergy. 
688 
 
689 
Additional Eligibility Criteria for Randomization  
690 
• Compliance with artificial tears at least 90% (days compliant/total days since receiving 
691 
study medication as evident by review of the compliance calendar and count of unused 
692 
ampules) during the run-in phase. 
693 
• Excellent compliance with refractive correction (more than 75% of all waking hours) 
694 
during run-in phase, based on investigator judgment after review of compliance calendars 
695 
and discussion with parent. 
696 
• Refractive correction in each eye (single vision eyeglasses or contact lenses with any 
697 
necessary adjustment for contact lens rotation and vertex distance) that meets the 
698 
following criteria:  
699 
o 
Myopia (by spherical equivalent) in both eyes must be corrected to within ±0.50 D of 
700 
the investigator’s cycloplegic measurement of refractive error. 
701 
o 
Cylinder power in both eyes must be within ±0.50 D of the investigator’s standard 
702 
refraction technique, which can be based on a cycloplegic or non-cycloplegic 
703 
refraction. 
704 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-11 
o 
Cylinder axis for both eyes must be within ±5 degrees of the axis found on the 
705 
investigator’s refraction when cylinder power is >= 1.00 D or within ±15 degrees 
706 
when the cylinder power is <1.00 D. 
707 
Measurement of refractive error for assessing the above criteria may be performed as an 
708 
over-refraction or without refractive correction.   
709 
• Best-corrected distance visual acuity in current correction meeting the following criteria:  
710 
o 20/32 or better in each eye (>=76 letters by E-ETDRS testing) 
711 
o Interocular difference <= 0.2 logMAR (<= 10 letters by E-ETDRS testing) 
712 
 
713 
Treatment Groups 
714 
Participants are randomly assigned 2:1 to the following two treatment groups: 
715 
• Atropine Group: 0.01% atropine eyedrops administered 1 drop to each eye daily in each 
716 
eye for 24 months, followed by 6 months off atropine eyedrops 
717 
• Placebo Group: Placebo eyedrops administered 1 drop to each eye daily in each eye for 
718 
24 months, followed by 6 months off placebo eyedrops 
719 
 
720 
Sample Size 
721 
Approximately 186 participants will be randomized in a 2:1 ratio to the two treatment groups 
722 
(~124 in the atropine group and ~62 in the placebo group).  
723 
 
724 
Visit / Contact Schedule (timed from randomization unless otherwise specified) 
725 
• Enrollment into run-in phase using daily artificial tear eyedrops for 2-4 weeks (and 
726 
glasses updated if required) 
727 
• Randomization Visit (2-4 weeks after enrollment) 
728 
• Phone Calls from site:  after 2 weeks (± 3 days), and after 3, 9, 15, 21, and 27 months (+ 
729 
1 month) 
730 
• Office Visits:  
731 
o 6 months ± 2 weeks* 
732 
o 12 months ± 2 weeks*  
733 
o 18 months ± 2 weeks*  
734 
o 24 months ± 4 weeks: Primary Outcome On-Treatment – discontinue treatment 
735 
after visit  
736 
o 30 months ± 4 weeks: Secondary Outcome Off-Treatment– six months following 
737 
discontinuation of treatment  
738 
 
739 
*A virtual visit may be completed at 6, 12, or 18-months if an in-person office visit cannot be completed 
740 
by the participant. If any safety events are identified during a virtual visit, participants will have 
741 
additional follow up as applicable.   
742 
 
743 
Testing Procedures 
744 
Cycloplegic autorefraction, axial length and additional biometry will be measured by a study 
745 
certified examiner at the enrollment visit and by a masked examiner at all follow up visits using 
746 
the same instrumentation on the participant throughout the study.  Masking will be accomplished 
747 
by having site personnel administer cyclopentolate to both eyes of each participant before he/she 
748 
sees the masked examiner.    
749 
 
750 
At randomization and each follow-up exam except the 30-month visit, the effect of eyedrops will 
751 
be assessed with a questionnaire.  Distance visual acuity will be assessed at randomization and 
752 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-12 
the 30-month visit. Binocular near visual acuity will be assessed at randomization and the 6-
753 
month visit.     
754 
 
755 
Primary Analysis  
756 
• Treatment group comparison of change from baseline to 24 months in spherical 
757 
equivalent (average of both eyes) as measured by a masked examiner using cycloplegic 
758 
autorefraction (on-treatment comparison). 
759 
 
760 
Secondary Analysis 
761 
• Treatment group comparison of change from baseline to 30 months in spherical 
762 
equivalent (average of both eyes) as measured by a masked examiner using cycloplegic 
763 
autorefraction (off-treatment comparison).    
764 
 
 
765 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-13 
1.12 
Study Flow Chart 
766 
 
767 
 
768 
 
769 
 
770 
 
771 
 
 
772 
 
Daily 0.01% Atropine eye drops 
 
Daily Placebo eye drops 
 
IF ELIGIBLE  
RANDOMIZE 2:1 
 
IF NOT ELIGIBLE 
withdraw 
participant from 
study  
RANDOMIZATION VISIT (2-4 WEEKS AFTER ENROLLMENT) 
 
Additional Eligibility Criteria for Randomization 
• 
Compliance with artificial tear eyedrops at least 90% during the run-in phase 
• 
Excellent compliance with refractive correction (more than 75% of all waking hours) during the run-in phase 
• 
Refractive correction in each eye (single vision eyeglasses or contact lenses with any necessary adjustment for 
contact lens rotation and vertex distance) that meets the following criteria: 
➢ 
Myopia (by spherical equivalent) in both eyes must be corrected to within ±0.50 D of the investigator’s 
cycloplegic measurement of refractive error. 
➢ 
Cylinder power in both eyes must be within ±0.50 D of the investigator’s standard refraction technique, 
which can be based on a cycloplegic or non-cycloplegic refraction. 
➢ 
Cylinder axis for both eyes must be within ±5 degrees of the axis found on the investigator’s refraction 
when cylinder power is >= 1.00 D or within ±15 degrees when the cylinder power is <1.00 D. 
• 
Best-corrected distance visual acuity in current correction meeting the following criteria:  
➢ 
20/32 or better in each eye (>=76 letters by E-ETDRS testing) 
➢ 
Interocular difference <= 0.2 logMAR (<= 10 letters by E-ETDRS testing) 
Testing Procedures  
• 
Eye Drop Questionnaire  
• 
Distance Visual Acuity Testing  
• 
Binocular Near Visual Acuity 
• 
Binocular Amplitude of Accommodation 
• 
If > 4 weeks since enrollment into run-in phase, repeat cycloplegic autorefraction, axial length measurement and 
additional biometry 
ENROLLMENT INTO RUN-IN PHASE 
 
Major Eligibility Criteria at Enrollment for Run-in Phase (see section 2.2 for a complete listing) 
• 
Age 5 to <13 years of age at time of enrollment.  Participants within 4-weeks of their 13th birthday are not eligible. 
• 
Refractive error meeting the following by cycloplegic autorefraction:   
➢ 
Myopia -1.00D to -6.00D spherical equivalent (SE) in both eyes 
➢ 
Astigmatism <=1.50D in both eyes 
➢ 
Anisometropia <1.00D SE 
• 
Currently wearing refractive correction  
• 
Excellent compliance with refractive correction (>75% of waking hours) for ≥1 month prior to enrollment  
• 
No current or previous myopia treatment with atropine, pirenzepine or other anti-muscarinic agent 
• 
No current or previous use of bifocals, progressive-addition lenses, or multi-focal contact lenses 
• 
No current or previous use of orthoK, rigid gas permeable, or other contact lenses to reduce myopia progression 
• 
No known atropine allergy   
 
Enrollment Exam Procedures  
• 
Standard Refraction (with or without cycloplegia) 
• 
Cycloplegic Autorefraction  
• 
Cycloplegic Axial Length Measurement and Additional Biometry 
• 
Prescribe refractive correction or change in refractive correction (if needed)  
• 
Prescribe artificial tear eyedrops to be used one drop to each eye nightly for 2-4 weeks  
RUN-IN PHASE (2-4 WEEKS) 
• 
All participants are treated with daily artificial tear eyedrops 
• 
Glasses are updated, if needed 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
1-14 
 
773 
 
774 
 
775 
 
776 
 
777 
 
778 
 
 
779 
  
2-Week Phone Call  
To ensure received study medication 
 
WHILE ON TREATMENT  
FOLLOW-UP VISITS AT 6, 12, 18, AND 24 MONTHS* 
PHONE CALLS FROM SITE AT 3, 9, 15, AND 21 MONTHS 
Tests & Assessments: 
• 
Medical History 
• 
Eye Drop Questionnaire  
• 
Binocular Near Visual Acuity (6-months only) 
• 
Binocular Amplitude of Accommodation 
• 
Standard refraction (with or without cycloplegia)  
• 
Cycloplegic Autorefraction (masked)   
• 
Cycloplegic Axial Length Measurement (masked) and Additional Biometry  
 
* A virtual visit may be done at  6, 12, and 18-months if an office visit is not possible 
AFTER 24 MONTH VISIT 
DISCONTINUE TREATMENT 
 
• 
At the 24-month visit, study eye drops will be discontinued for both treatment groups 
• 
No myopia treatment other than optical correction should be prescribed prior to the 30-month visit.     
 
27-MONTH PHONE CALL FROM SITE  
30-MONTH FOLLOW-UP VISIT (OFF TREATMENT) 
 
• 
Medical History 
• 
Distance Visual Acuity Testing 
• 
Binocular Amplitude of Accommodation 
• 
Standard Refraction (with or without cycloplegia) (only if visual acuity ≥5 or more letters 
worse than baseline) 
• 
Cycloplegic Autorefraction (masked)  
• 
Cycloplegic Axial Length Measurement (masked) and Additional Biometry 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
2-1 
Chapter 2: ENROLLMENT 
780 
 
781 
2.1 
Eligibility Assessment and Informed Consent/Assent 
782 
The study plans to enroll a maximum of 400 participants into the Run-In Phase for whom 
783 
informed consent is provided, such that approximately 186 participants will enter the 
784 
Randomized Trial Phase.  The number of participants randomized who self-report as East Asian 
785 
ethnicity will be limited to no more than 25% of the overall sample (n=47 participants).   
786 
 
787 
As the enrollment goal into the Randomized Trial Phase approaches 186 participants, sites will 
788 
be notified of the end date for recruitment into the Run-In Phase. Participants whose parents have 
789 
signed an informed consent form may be entered into the Run-in Phase until the end date, which 
790 
means the expected number for the Randomized Trial Phase might be exceeded during the Run-
791 
in Phase.  Enrollment into the Run-In Phase may be temporarily halted if necessary until it is 
792 
determined how many participants in the Run-in Phase will enter the Randomized Trial Phase.  
793 
The anticipated randomized total of 186 participants could be exceeded as participants already 
794 
enrolled into the Run-In Phase become eligible for the Randomized Trial Phase.    
795 
 
796 
The study will be discussed with the child’s parent(s) or guardian(s) (referred to subsequently as 
797 
parent(s)).  Parents who express an interest in the study will be given a copy of the informed 
798 
consent form to read.  Written informed consent / assent must be obtained from the parent and 
799 
child prior to performing any study-specific procedures that are not part of routine care.  
800 
 
801 
2.2 
Eligibility Criteria for Enrollment into Run-in Phase 
802 
The following criteria must be met for the child to be enrolled into the study: 
803 
 
804 
Inclusion Criteria 
805 
• Age 5 years to <13 years at time of enrollment.  Children within 4 weeks of their 13th 
806 
birthday are not eligible. 
807 
• Refractive error meeting the following by cycloplegic autorefraction:   
808 
o Myopia -1.00D to -6.00D spherical equivalent (SE) in both eyes 
809 
o Astigmatism <=1.50D in both eyes 
810 
o Anisometropia <1.00D SE 
811 
• Currently wearing refractive correction (single vision eyeglasses or contact lenses) 
812 
• Excellent compliance with refractive correction (more than 75% of all waking hours) for 
813 
at least one month, based on investigator judgment after discussion with parent. 
814 
• Gestational age ≥ 32 weeks. 
815 
• Birth weight >1500g. 
816 
• Parent understands the protocol and is willing to accept randomization to atropine or 
817 
placebo. 
818 
• Is willing to participate in a 2 to 4 week run-in phase using daily artificial tear eyedrops. 
819 
• Able to return in 2 to 4 weeks for possible randomization.  
820 
• Parent has a phone (or access to phone) and is willing to be contacted by Investigator’s 
821 
site staff. 
822 
• Relocation outside of the area of an active PEDIG site within next 32 months is not 
823 
anticipated. 
824 
 
825 
Exclusion Criteria 
826 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
2-2 
• Current or previous myopia treatment with atropine, pirenzepine or other anti-muscarinic 
827 
agent. 
828 
• Current or previous use of bifocals, progressive-addition lenses, or multi-focal contact 
829 
lenses.  
830 
• Current or previous use of orthoK, rigid gas permeable, or other contact lenses being used 
831 
to reduce myopia progression. 
832 
• Known atropine allergy. 
833 
• Abnormality of the cornea, lens, central retina, iris or ciliary body. 
834 
• Current or prior history of manifest strabismus, amblyopia, or nystagmus. 
835 
• Prior eyelid, strabismus, intraocular, or refractive surgery. 
836 
• Down syndrome or cerebral palsy. 
837 
• Diseases known to affect accommodation, vergence, or ocular motility (e.g., multiple 
838 
sclerosis, Grave’s disease, myasthenia gravis, diabetes mellitus, Parkinson’s disease) 
839 
• Existing ocular conditions (e.g., retinal disease, cataracts, ptosis) or 
840 
systemic/neurodevelopmental conditions (e.g., Down syndrome) which may influence 
841 
refractive development. 
842 
• Any condition that in the judgement of the investigator could potentially influence 
843 
refractive development.   
844 
• Existing conditions that may affect the long-term health of the eye or require regular 
845 
pharmacologic treatment that may adversely interact with study medication (e.g., JIA, 
846 
glaucoma, diabetes mellitus, pre-diabetes) 
847 
• Inability to comprehend and/or perform any study-related clinical tests 
848 
• Females who are pregnant, lactating, or intending to become pregnant within the next 30 
849 
months. 
850 
➢ A negative urine pregnancy test will be required for all females who have 
851 
experienced menarche.   
852 
 
853 
2.3 
Historical Information 
854 
Historical information elicited will include the following: date of birth, sex, race, ethnicity, 
855 
current refractive correction, iris color (brown or not brown), parental history of myopia (0, 1, or 
856 
2 parents), current medication use, history of and current medical conditions, and myopia 
857 
treatment history.      
858 
 
859 
2.4 
Testing at the Enrollment/Run-in Visit 
860 
Testing at the enrollment visit/run-in visit will include the following:  
861 
 
862 
1. Standard Refraction 
863 
• The investigator may use his/her standard refraction technique (with or without 
864 
cycloplegia) at any time during the visit to ensure that the participant meets eligibility 
865 
criteria with respect to refractive correction as described in section 2.5.   
866 
2. Cycloplegic Autorefraction  
867 
• 1% cyclopentolate – one drop twice to each eye with 5 minutes between drops. The 
868 
use of proparacaine prior to the cycloplegic drops is at investigator discretion.  
869 
• Three measurements of sphere, cylinder, and axis will be obtained for each eye using 
870 
autorefraction (see manual of procedures).  Each measurement will be converted to a 
871 
spherical equivalent refractive error (SER) and the mean of the 3 SER values for each 
872 
eye will be used for confirming eligibility. 
873 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
2-3 
• A specific autorefractor model is not required for the study; however, each participant 
874 
should have their autorefraction assessed using the same instrument during the entire 
875 
study.  
876 
• The cycloplegic autorefraction should occur at 30 minutes ± 5 minutes from the time 
877 
the second drop of 1% cyclopentolate was instilled. 
878 
• If eyes are not sufficiently dilated/cyclopleged and/or if the dilation/cycloplegia has 
879 
worn off before all cycloplegic procedures have been performed, another drop of 1% 
880 
cyclopentolate may be administered, followed by an additional 30-minute wait before 
881 
testing. The use of proparacaine prior to this cycloplegic drop is at investigator 
882 
discretion.   
883 
3. Axial Length Measurement and Additional Biometry 
884 
• One summary reading based on multiple measures with cycloplegia using optical 
885 
biometry will be documented for the following (see procedures manual):  
886 
• 
Axial length 
887 
• 
Flat corneal radius 
888 
• Anterior Chamber depth 
889 
• Lens thickness, if available 
890 
• A specific instrument is not required for the study; however, each participant should 
891 
have axial length and additional biometry assessments made using the same 
892 
instrument during the entire study.  
893 
• If eyes are not sufficiently dilated and/or if the dilation has worn off before all 
894 
cycloplegic procedures have been performed, see procedure for re-dilation in step #2.   
895 
 
896 
2.5 
Refractive Correction  
897 
To be eligible for randomization, the participant must be wearing refractive correction in each 
898 
eye (single vision eyeglasses or soft, daily wear single vision contact lenses with any necessary 
899 
adjustment for contact lens rotation and vertex distance) that meets the following criteria:  
900 
• Myopia (by spherical equivalent) in both eyes must be corrected to within ±0.50 D the 
901 
investigator’s cycloplegic measurement of refractive error. 
902 
• Cylinder power in both eyes must be within ±0.50 D of the investigator’s standard refraction 
903 
technique, which can be based on a cycloplegic or non-cycloplegic refraction. 
904 
• Cylinder axis for both eyes must be within ±5 degrees of the axis found on the investigator’s 
905 
standard refraction when cylinder power is >= 1.00 D or within ±15 degrees when the 
906 
cylinder power is <1.00 D. 
907 
Measurement of refractive error for assessing the above criteria may be performed as an over-
908 
refraction or without refractive correction.   
909 
 
910 
If the participant meets all eligibility criteria for the run-in phase (see section 2.2) but their 
911 
current correction does not meet the requirements for randomization, then a change in refractive 
912 
correction can be prescribed in order to meet the requirements when the participant returns for 
913 
potential randomization.  A change in refractive correction can also be prescribed if the 
914 
investigator elects to change a smaller amount of refractive error, but the resulting prescription 
915 
must meet the criteria above.  The prescribed correction can be single vision eyeglasses or 
916 
contact lenses.  Single vision lenses will be paid for by the study; contact lenses will be at the 
917 
participants’ own expense. A pair of eyeglasses is recommended for all participants.   
918 
 
919 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
2-4 
2.6 
Treatment in Run-In Phase 
920 
Artificial tears will be dispensed in single-use ampules to be used 1 drop to each eye nightly in 
921 
each eye for 2-4 weeks.  Study personnel will demonstrate for the parent and participant how to 
922 
instill a drop in each eye prior to the participant leaving the office.  
923 
 
924 
The following will be done to promote compliance with artificial tears during the run-in phase:  
925 
• A calendar log will be provided to the parent on which the participant or parent will 
926 
record whether or not the installation was done each night.   
927 
• The parent and participant will be instructed to bring all unused ampules of artificial 
928 
tears with them when they return in 2-4 weeks.   
929 
• A smart phone application may be offered to participants and/or parents who provide 
930 
consent to be contacted with a nightly prompt asking if the eyedrops were given.   
931 
 
932 
Participants will be encouraged to wear refractive correction for all waking hours. The calendar 
933 
log used to record artificial tears treatment will also be used to indicate whether refractive 
934 
correction was worn each day. 
935 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
3-1 
936 
Chapter 3: RANDOMIZATION 
937 
 
938 
The participant should return to assess eligibility for randomization within 2-4 weeks after using 
939 
nightly artificial tears wearing the optical correction prescribed at the enrollment visit.  If the 
940 
participant is unable to return for possible randomization within 6 weeks of enrollment into the 
941 
run-in, the participant will be withdrawn from the study.  
942 
 
943 
3.1 
Assessment of Compliance with Artificial Tears 
944 
Calendar logs will be reviewed to assess the level of compliance with artificial tears eyedrops 
945 
during the run-in phase.  The number of unused artificial tears eyedrop ampules will be counted.    
946 
 
947 
To be eligible for randomization, participants must have used artificial tear eyedrops in both eyes 
948 
for at least 2 weeks and must have been at least 90% compliant with instilling the drops in both 
949 
eyes (days compliant/total days since receiving study medication as evident by review of the 
950 
compliance calendar and count of unused ampules) in the run-in phase.  Participants not able to 
951 
return both the unused ampules of artificial tears eyedrops and the calendar log, and participants 
952 
returning the log who are not compliant at least 90% will be withdrawn from the study.  
953 
 
954 
In addition, the parent (or participant) must demonstrate the ability to instill an eyedrop in both 
955 
eyes on their own prior to being considered for randomization.  Participants who can’t 
956 
demonstrate successful instillation of eyedrops (either by themselves or by their parent) will be 
957 
withdrawn from the study.    
958 
 
959 
3.2 
Assessment of Compliance with Refractive Correction  
960 
Calendar logs will be reviewed to assess the level of compliance with refractive correction 
961 
during the run-in phase.  Compliance with refractive correction will be classified as excellent 
962 
(76% to 100% waking hours), good (51% to 75%), fair (26% to 50%), or poor (0 to 25%) based 
963 
on investigator judgment after review of the compliance calendar and discussion with parent.  
964 
Participants with excellent (greater than 75% compliance) will be eligible for randomization. 
965 
Participants 75% compliant or less will be withdrawn from the study.    
966 
 
967 
3.3 
Testing at the Randomization Visit 
968 
Participants judged to be compliant with eyedrops and refractive correction will have the 
969 
following assessed:  
970 
 
971 
1. Eye Drop Questionnaire  
972 
• To be completed by the child prior to any other testing to evaluate effect of eye drops 
973 
on the child 
974 
2. Distance Visual Acuity Testing: Monocular distance visual acuity testing tested at the 
975 
start of the exam without cycloplegia in current correction meeting the requirements in 
976 
section 2.5. 
977 
• Measurement of best corrected visual acuity in each eye by a study certified visual 
978 
acuity tester using the E-ETDRS testing protocol. 
979 
3. Binocular Near Visual Acuity Testing: Binocular near visual acuity is measured using the 
980 
ATS4 Near Acuity Test with the participant wearing current refractive correction and 
981 
prior to administration of cycloplegia. 
982 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
3-2 
4. Binocular Amplitude of Accommodation: Measured with a study-specified and provided 
983 
accommodation near-point rule (e.g. Gulden’s near-point rule) and the participant in their 
984 
current spectacle or contact lens correction.  
985 
 
986 
Cycloplegic autorefraction, axial length and additional biometric assessments (following the 
987 
same procedure as described for enrollment in section 2.4) must be repeated if the enrollment 
988 
visit was completed more than 4 weeks (>28 days) prior to randomization.  If repeated, these will 
989 
be considered the participant’s “baseline” measurements; otherwise the measurements from the 
990 
enrollment/run-in phase visit will be considered the “baseline” measurements.  
991 
 
992 
3.4 
Confirmation of Eligibility for Randomization 
993 
Visual acuity testing to assess eligibility for randomization must be performed in the 
994 
participant’s current refractive correction.   
995 
 
996 
Randomization will occur at the conclusion of the randomization exam after confirming that the 
997 
participant meets the following eligibility criteria: 
998 
 
999 
• Best-corrected distance visual acuity in current correction meeting the following criteria:  
1000 
o 20/32 or better in each eye (>=76 letters by E-ETDRS testing) 
1001 
o Interocular difference <= 0.2 logMAR (<= 10 letters by E-ETDRS testing) 
1002 
 
1003 
• Refractive error meeting the following by cycloplegic autorefraction (only if repeated on 
1004 
day of randomization):   
1005 
o Myopia -1.00D to -6.00D spherical equivalent (SE) in both eyes 
1006 
o Astigmatism <=1.50D in both eyes 
1007 
o Anisometropia <1.00D SE 
1008 
 
1009 
• Refractive correction that is being worn for each eye (single vision eyeglasses or contact 
1010 
lenses with any necessary adjustment for contact lens rotation and vertex distance) must 
1011 
meet the following criteria: 
1012 
o Myopia (by spherical equivalent) in both eyes must be corrected to within ±0.50 
1013 
D of the investigator’s cycloplegic measurement of refractive error. 
1014 
o Cylinder power in both eyes must be within ±0.50 D of the investigator’s standard 
1015 
refraction technique, which can be based on a cycloplegic or non-cycloplegic 
1016 
refraction. 
1017 
o Cylinder axis for both eyes must be within ±5 degrees of the axis found on the 
1018 
investigator’s refraction when cylinder power is >= 1.00 D or within ±15 degrees 
1019 
when the cylinder power is <1.00 D. 
1020 
Measurement of refractive error for assessing the above criteria may be performed as an 
1021 
over-refraction or without refractive correction.   
1022 
• Compliant with artificial tears eyedrops during run-in phase (see definition in section 3.1) 
1023 
• Compliant with refractive correction during run-in phase (see definition in section 3.2).    
1024 
 
1025 
Participants who do not meet eligibility criteria will be withdrawn from the study without being 
1026 
randomized.   
1027 
 
1028 
Prior to randomization, the study requirements should again be discussed with the parent so that 
1029 
site staff have reasonable assurance that the participant will be adherent to the protocol. 
1030 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
3-3 
 
1031 
3.5 
Randomization 
1032 
Eligible participants will be randomly assigned 2:1 to the atropine (0.01%) or placebo group 
1033 
(administering one drop nightly for 24 months), respectively, using a permuted block design 
1034 
stratified by iris color (brown vs non-brown) and by site.  The number of participants 
1035 
randomized who self-report as East Asian ethnicity will be limited to no more than 25% of the 
1036 
overall sample (n=47 participants).   
1037 
 
1038 
A participant is officially enrolled in the randomized trial when the website randomization 
1039 
process is completed. 
1040 
 
1041 
Once a participant is randomized, that participant will be included in the analysis regardless of 
1042 
whether the assigned treatment is received or not.  Participants will remain in the study for 30 
1043 
months of follow-up.  Thus, the investigator must not randomize a participant until he/she is 
1044 
convinced that the parent/participant remains willing to participate and will accept either of the 
1045 
treatment regimens and complete follow-up as previously discussed at enrollment.   
1046 
 
1047 
Treatment must commence within 1 week following randomization; therefore, a participant 
1048 
should not be randomized until both the investigator and parent are ready to start treatment. 
1049 
 
1050 
The participant, parents, coordinators, testers and investigators will be masked to treatment 
1051 
group.  If the need arises, the investigator may become unmasked after discussion of a specific 
1052 
case with the protocol chair in response to any adverse events.  
1053 
 
1054 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
4-1 
Chapter 4:  TREATMENT AND FOLLOW-UP IN RANDOMIZED TRIAL 
1055 
 
1056 
4.1 
Study Medication  
1057 
Nevakar is manufacturing the study drug (0.01% atropine) and placebo and packaging both in 
1058 
identical-appearing single-use ampules.  In addition to 0.01% atropine, the ampules contain a 
1059 
buffer similar to artificial tears while the placebo contains just the buffer similar to artificial 
1060 
tears.  The atropine and placebo ampules are sent to a central pharmacy, which will label and 
1061 
package multiple atropine or placebo ampules into three month supply packages to maintain 
1062 
masking.  The packages of ampules will be shipped to participating sites in insulated shipping 
1063 
boxes designed to maintain study drug at 59 to 77 degrees F during shipping.  Participating sites 
1064 
will store study drug at room temperature (between 68 and 77 degrees F) prior to dispensing 
1065 
study medication packages to study participants.  Additional study medication details are 
1066 
summarized within a separate investigational product manual.  
1067 
 
1068 
4.2 
Treatment 0 to 24 Months  
1069 
Treatment with study medication will be one drop in both eyes each night, including the night 
1070 
before study visits. Participants who are wearing contact lenses will be instructed to remove 
1071 
contact lenses before administering eyedrops and wait at least 30 minutes after eyedrop 
1072 
administration before reinserting contact lenses.     
1073 
 
1074 
During the first 24 months of the study, no myopia progression prevention treatment other than 
1075 
the study eyedrops is permitted.        
1076 
 
1077 
4.3 
Telephone Calls 
1078 
Two weeks following randomization (±3 days), the site will contact parents to question the 
1079 
parent as to whether the child is experiencing any issues with treatment.  
1080 
 
1081 
At three months following randomization (±1 month), the site will contact parents to encourage 
1082 
compliance and question the parent as to whether the child is experiencing any issues with 
1083 
treatment.  
1084 
 
1085 
The site coordinator will make phone calls in between office visits at 9, 15, 21, and 27 months 
1086 
following randomization (±1 month). These calls will be conducted to maintain direct contact 
1087 
with the parents of each participant, to develop and maintain rapport with the participant and/or 
1088 
family, and to assist with the scheduling of study visits if needed.   
1089 
 
1090 
4.4 
Masking of Treatment Group  
1091 
Cycloplegic autorefraction, axial length, and additional biometry will be measured by a masked 
1092 
examiner at all follow-up visits using the same instrumentation on the participant throughout the 
1093 
study. Masking will be accomplished by having site personnel administer cyclopentolate to both 
1094 
eyes of each participant and wait 30 minutes before he/she sees the masked examiner.  The 
1095 
masked examiner may be a technician or an investigator and must be certified to complete these 
1096 
measurements. 
1097 
 
1098 
4.5 
Compliance with Study Treatment  
1099 
Unused study medication ampules will be brought to all visits while on randomized treatment 
1100 
and will be counted as a measure of treatment compliance.  
1101 
 
1102 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
4-2 
To promote compliance with eyedrops, a calendar will be provided on which the child/parent 
1103 
will record the treatment received each day.  At each visit, an assessment of compliance will be 
1104 
recorded on the Follow-up Examination Form after review of the calendars and an interview with 
1105 
the parent and child. 
1106 
 
1107 
If a participant is noncompliant with study eyedrops, the parents and participants should be 
1108 
encouraged to persist with their efforts to treat to the best of their ability.   
1109 
 
1110 
4.6 
Off-Treatment Phase >24 to 30 Months  
1111 
At the 24-month visit, study eyedrops will be discontinued and no myopia treatment other than 
1112 
optical correction should be prescribed prior to the 30-month visit.     
1113 
 
1114 
4.7 
Side Effects of Treatment  
1115 
Reporting of adverse events is described in Chapter 6.  In cases of vision-related adverse events, 
1116 
distance visual acuity should be measured using the E-ETDRS testing protocol (see section 4.8).  
1117 
Prior to deviating from the treatment protocol or prescribing non-protocol treatment, the situation 
1118 
should be discussed with the Protocol Chair.  
1119 
 
1120 
4.8 
Follow-up Visit Schedule in Randomized Trial 
1121 
The follow-up visit schedule consists of the following office visits timed from randomization:  
1122 
• 6 months ± 2 weeks* 
1123 
• 12 months ± 2 weeks*  
1124 
• 18 months ± 2 weeks*  
1125 
• 24 months ± 4 weeks: On-Treatment Primary Outcome – discontinue treatment after visit  
1126 
• 30 months ± 4 weeks: Off-Treatment Secondary Outcome – six months following 
1127 
discontinuation of treatment  
1128 
 
1129 
*A virtual visit may be completed at 6, 12, or 18-months if an in-person office visit cannot be 
1130 
completed by the participant.  If any safety events are identified during a virtual visit, participants will 
1131 
have additional follow up as applicable.   
1132 
 
1133 
Additional visits may be scheduled at investigator discretion. Adverse event data may be reported 
1134 
and collected at any time during the study.  
1135 
 
1136 
4.9 
Follow-up Visit Testing Procedures 
1137 
At each office visit the following tests and assessments will be done with the participant wearing 
1138 
their current refractive correction: 
1139 
 
1140 
1. Medical History - including questioning about the occurrence of adverse effects of treatment.  
1141 
Concomitant medications will be recorded, as well as current eyeglasses or contact lenses 
1142 
correction. 
1143 
2. Compliance Assessment 
1144 
• All unused study medication ampules since the last visit (if brought to the visit) will 
1145 
be counted as a measure of compliance.  
1146 
• Home calendar logs (if brought to the visit) will be reviewed and assessments of 
1147 
compliance with eyedrops and with refractive correction will be recorded on the 
1148 
Follow-up Examination Form 
1149 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
4-3 
3. Eye Drop Questionnaire (all follow up visits except the 30-month visit) 
1150 
• To be completed by the child prior to any other testing to evaluate the effect of eye 
1151 
drops on the child. 
1152 
4. Distance Visual Acuity Testing (30-month visit only): Monocular distance visual acuity 
1153 
tested at the start of the exam without cycloplegia in current correction. 
1154 
• Measurement of best corrected visual acuity in each eye by a study certified visual 
1155 
acuity tester using the E-ETDRS testing protocol. 
1156 
• If the vision is more than one line (>=5 letters) worse than baseline, retest using trial 
1157 
frames or phoropter with the most recent subjective refraction. 
1158 
5. Binocular Near Visual Acuity Testing (6-month visit only): Binocular near visual acuity is 
1159 
measured using the ATS4 Near Acuity Test with participant wearing current refractive 
1160 
correction prior to administration of cycloplegia. 
1161 
6. Binocular Amplitude of Accommodation: Measured in their current correction without 
1162 
cycloplegia with a study-specified and provided accommodation near-point rule (e.g. 
1163 
Gulden’s near-point rule).    
1164 
7. Standard Refraction  
1165 
• The investigator may use their standard refraction technique (with or without 
1166 
cycloplegia) at any time during the visit to ensure that refractive correction meets 
1167 
study criteria at each visit (see section 4.9 below).  
1168 
• At 30-month visit, only required if the vision is more than one line (>=5 letters) 
1169 
worse than baseline.  
1170 
8. Following cycloplegia, at all visits an examiner masked to treatment group will perform:  
1171 
• Cycloplegic Autorefraction – (see section 2.4) 
1172 
• Cycloplegic Axial Length Measurement and Additional Biometry (see section 2.4)  
1173 
 
1174 
If a virtual visit is completed, only items 1 through 3 above will be completed. If any safety events 
1175 
are identified during a virtual visit, participants will have additional follow up as applicable.  
1176 
 
1177 
In addition, females who have experienced menarche will undergo a urine pregnancy test at each 
1178 
follow up visit except the 30-month visit (or at home if a virtual visit is completed).  
1179 
 
1180 
• In the case of pregnancy during the study, study eyedrops will be discontinued although 
1181 
the subject will be retained in the study.   
1182 
 
1183 
4.10 
Management of Refractive Error 
1184 
Spectacle or contact lenses correction must be updated whenever the investigator’s standard 
1185 
refraction technique reveals a change in refractive error.  A change in refractive error is defined 
1186 
as any of the following amounts:  
1187 
 
1188 
• A difference of >0.75 D sphere 
1189 
• A difference of >0.75D cylinder 
1190 
• A difference of >0.50D in SE anisometropia 
1191 
• A difference in axis of 6 degrees or more when the cylinder is ≥1.00D.  
1192 
 
1193 
Whether to update the correction for smaller differences in refraction is at investigator discretion. 
1194 
Glasses required by a contact lens user should be updated when their contact lenses are updated, 
1195 
and these glasses will be paid for by the study.  
1196 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
4-4 
 
1197 
If updated, the refractive correction must meet the requirements described in section 2.5.  
1198 
 
1199 
Daily wear single vision contact lenses may be used for correction of refractive error full time or 
1200 
alternating with spectacle correction. Contact lenses should not differ from a cycloplegic over-
1201 
refraction by more than +/- 0.50D SE. Uncorrected astigmatism should not exceed 1.00D. 
1202 
OrthoK, rigid gas permeable, and other contact lenses being used to affect myopia progression 
1203 
are not allowed. Contacts must be removed from the eyes prior to study medication 
1204 
administration and not reinserted for at least 30 minutes. 
1205 
 
1206 
4.11 
Non-Randomized Treatment Other than Refractive Correction  
1207 
Non-randomized treatment for myopia other than changes in refractive error as described above 
1208 
is not permitted during the study.  The investigator must call the protocol chair to discuss the 
1209 
case and obtain approval for an exception prior to initiating non-randomized treatment (including 
1210 
OrthoK, rigid gas permeable, and other contact lenses being prescribed to affect myopia 
1211 
progression).  
1212 
 
1213 
4.12 
General Considerations 
1214 
The study is being conducted in compliance with the policies described in the study policies 
1215 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
1216 
the protocol described herein, and with the standards of Good Clinical Practice. 
1217 
 
1218 
There is no restriction on the number of participants to be enrolled by each site towards the 
1219 
overall recruitment goal. 
1220 
 
1221 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
5-1 
 
1222 
Chapter 5: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 
1223 
 
1224 
5.1 
Participant Withdrawals 
1225 
Parents may withdraw their child from the study at any time.  If the parents indicate that they 
1226 
want to withdraw their child from the study, the investigator should attempt to speak with the 
1227 
parents personally to determine the reason.  If their interest is in transferring the child’s care to 
1228 
another eye care provider, every effort should be made to comply with this and at the same time 
1229 
try to keep the participant in the study under the new provider’s care. 
1230 
 
1231 
5.2 
Discontinuation of Study 
1232 
The study may be discontinued by the Steering Committee (with approval of the Data and Safety 
1233 
Monitoring Committee) prior to the pre-planned completion of enrollment and follow-up for all 
1234 
participants. 
1235 
 
1236 
5.3 
Travel Reimbursement 
1237 
The parent of each participant will be compensated $50 (by merchandise/money card or check) 
1238 
upon completion of the enrollment exam, the randomization exam, and each study visit at 6, 12, 
1239 
18, 24, and 30 months following randomization, for a maximum of $350.  If there are 
1240 
extenuating circumstances and/or the participant is unable to complete study visits without 
1241 
additional funds due to travel costs, additional funds may be provided. 
1242 
 
1243 
5.4 
Costs Covered by the Study 
1244 
The study will pay for the office visits that are part of the study (enrollment, randomization visit, 
1245 
and visits at 6, 12, 18, 24, and 30 months).  The study will pay for virtual visits.  Any other visits 
1246 
that are part of routine care will be the parent(s) or their insurance company’s responsibility.   
1247 
 
1248 
The study will pay for the following:  
1249 
• Study eyedrops (artificial tears, atropine and placebo) will be provided to the participants 
1250 
at no cost.   
1251 
• Eyeglasses will be provided at enrollment (if needed), and at 12 and 24-month visits if 
1252 
obtained from a study optician.   
1253 
• Lens changes will be provided at 6 and 18-month visits if a change is required (see 
1254 
Section 4.10) and the lenses are obtained from a study optician.   
1255 
• The study will pay for bifocals (progressive-addition lenses) if prescribed by the 
1256 
investigator because of difficulties seeing up close when doing schoolwork or reading. 
1257 
 
1258 
5.5 
Costs Not Covered by the Study 
1259 
The study will not pay for eyeglasses obtained from a non-study optician.  The study will not pay 
1260 
for contact lenses. 
1261 
 
 
1262 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
6-1 
Chapter 6: ADVERSE EVENTS AND RISKS 
1263 
 
1264 
The study will be performed under an Investigation New Drug Application to the FDA of the 
1265 
US.  Specific reporting requirements for adverse events are summarized below.  
1266 
 
1267 
6.1 
Recording of Adverse Events 
1268 
The participant and parent will be queried as to whether or not they have experienced ocular side 
1269 
effects of treatment including lid/conjunctival irritation, light sensitivity, or near blur and/or 
1270 
reading difficulty; as well as any systemic side effects of treatment presenting within one hour 
1271 
following administration of atropine, including dry skin/mouth, tachycardia, fever, flushing, 
1272 
irritability, mental confusion, constipation, aggravation of asthma, or seizures.  In addition, all 
1273 
serious adverse events will be recorded. 
1274 
 
1275 
The study investigator will assess the relationship of each adverse event to be related or 
1276 
unrelated by deciding if there is a reasonable possibility that the adverse event may have been 
1277 
caused by the treatment. 
1278 
 
1279 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1280 
following general guideline when determining whether an adverse event is related: 
1281 
 
1282 
Yes 
1283 
There is a plausible temporal relationship between the onset of the adverse event and 
1284 
administration of the study treatment and the adverse event cannot be readily explained 
1285 
by the participant’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
1286 
adverse event follows a known pattern of response to the study treatment. 
1287 
 
1288 
No 
1289 
Evidence exists that the adverse event has an etiology other than the study treatment (e.g., 
1290 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
1291 
medication); and/or the adverse event has no plausible temporal relationship to study 
1292 
treatment administration.    
1293 
 
1294 
The maximum intensity that occurred since the onset of an adverse event will be rated on a three-
1295 
point scale: (1) mild, (2) moderate, or (3) severe, categorized as follows:  
1296 
 
1297 
Mild - Symptom(s) barely noticeable to participant or does not make participant 
1298 
uncomfortable; does not influence performance or functioning; prescription drug not 
1299 
ordinarily needed for relief of symptom(s). 
1300 
 
1301 
Moderate - Symptom(s) of sufficient severity to make participant uncomfortable; 
1302 
performance of daily activity is influenced; participant is able to continue in study; treatment 
1303 
for symptom(s) may be needed. 
1304 
 1305 
Severe - Symptom(s) cause severe discomfort; severity may cause cessation of treatment 
1306 
with study medication or device; treatment for symptom(s) may be given and/or participant 
1307 
hospitalized. 
1308 
 
1309 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
6-2 
It is emphasized that the term severe is a measure of intensity: thus, a severe adverse event is not 
1310 
necessarily serious. For example, itching for several days may be rated as severe, but may not be 
1311 
clinically serious. 
1312 
 
1313 
Adverse events that continue after the study participant’s discontinuation or completion of the 
1314 
study will be followed until their medical outcome is determined or until no further change in the 
1315 
condition is expected.   
1316 
 
1317 
6.2 
Reporting Serious or Unexpected Adverse Events 
1318 
A serious adverse event is any untoward occurrence that: 
1319 
• Results in death. 
1320 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might 
1321 
have become life-threatening, is not necessarily considered a serious adverse event). 
1322 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
1323 
• Results in persistent or significant disability/incapacity or substantial disruption of the 
1324 
ability to conduct normal life functions (sight-threatening). 
1325 
• Is a congenital anomaly/birth defect. 
1326 
• Is considered a significant medical event by the investigator based on medical judgment 
1327 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
1328 
prevent one of the outcomes listed above). 
1329 
 
1330 
Unexpected adverse events are those that are not identified in the current Clinical Investigator’s 
1331 
Brochure.   
1332 
 
1333 
Serious or unexpected adverse events must be reported to the Coordinating Center immediately 
1334 
via completion of the online serious adverse event form.   
1335 
 
1336 
The Coordinating Center will notify all participating investigators of any adverse event that is 
1337 
both serious and unexpected.  Notification will be made within 10 days after the Coordinating 
1338 
Center becomes aware of the event.   
1339 
 
 
1340 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1341 
abiding by any other reporting requirements specific to their Institutional Review Board.  
1342 
 
1343 
6.3 
Data and Safety Monitoring Committee Review of Adverse Events 
1344 
A Data and Safety Monitoring Committee will approve the protocol, template informed consent 
1345 
form, and substantive amendments, and provide independent monitoring of adverse events.  
1346 
Cumulative adverse event data will be tabulated for review by the DSMC at intervals determined 
1347 
by the coordinating center and the DSMC.  Following each DSMC data review, a summary will 
1348 
be made available for submission to Institutional Review Boards.     
1349 
 
1350 
6.4 
Risks 
1351 
6.4.1 
Risks of Examination Procedures 
1352 
The procedures in this study are part of daily eye care practice in the United States and pose no 
1353 
additional risks. 
1354 
 
1355 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
6-3 
6.4.2 
Risk of Atropine Therapy  
1356 
The effects of long-term use of bilateral atropine eye drops when used as treatment for myopia 
1357 
progression depend on the strength of atropine used. Side effects are uncommon with the 0.01% 
1358 
dosage to be used in this protocol, based on a series of 84 participants treated with 0.01% 
1359 
atropine for 2 years (ATOM2).  In most cases the events were deemed not related to the 
1360 
treatment.  Six children had eye symptoms felt related to the therapy, 1 case of irritation and 1 
1361 
case of blurred vision in the 0.01% group. Further treatment for two additional years was not 
1362 
associated with side-effects. 
1363 
 
1364 
A common side effect of atropine 1% is blurry vision, particularly at near, which may cause 
1365 
problems with reading at school and near work. The 0.01% dosage used in this study is not 
1366 
expected to be frequently associated with reading problems or blur at near. 
1367 
 
1368 
Following atropine administration, local side effects of minimal severity include allergic lid 
1369 
reactions, local irritation, conjunctival hyperemia, and follicular conjunctivitis.  In the ATOM2 
1370 
series, 1% of participants had irritation sufficient to warrant discontinuation of treatment; no 
1371 
cases of allergic conjunctivitis or allergic dermatitis were reported.      
1372 
 
1373 
Potential systemic side effects include dry skin and mouth, tachycardia, fever, flushing and 
1374 
irritability.  These effects were not reported (ATOM2), but rather some more minor complaints 
1375 
such as blurring and some light sensitivity with atropine 0.1% and 0.5% in the first two years of 
1376 
treatment.  The only severe adverse event with 0.01% was 1 participant (1%) with acute gastric 
1377 
pain which was not felt to be related to the atropine (ATOM2).   
1378 
 
1379 
Atropine 1% produces dilation of the pupil, which increases the light that enters the eye.  
1380 
Although it has not been demonstrated that atropine used for 2 years could have harmful ocular 
1381 
effects, excessive exposure to light theoretically could be toxic to the retina.  The strength used 
1382 
in this study is expected to have minimal effect on pupil dilation.39 If there is light sensitivity, 
1383 
clip-on or flip-up sunglasses or photochromic lenses will be provided.  The use of hats with 
1384 
brims or visors will be encouraged along with sunglasses. 
1385 
 
1386 
Participants who experience problems with schoolwork or significant symptoms when reading 
1387 
may be prescribed progressive bifocals paid for by the study.  These will be provided irrespective 
1388 
of treatment assignment after consultation with the protocol chair. 
1389 
  
1390 
Atropine in various dosages from 0.01% to 1% has been used long-term to prevent the 
1391 
progression of myopia without any lasting adverse effect on visual acuity.32, 41, 49, 50  In the 
1392 
ATOM2 trial, the most common side effect in the 0.01% atropine group was loss of one or more 
1393 
lines of distance visual acuity (13%) but this was reversible upon discontinuing medication.  
1394 
 
1395 
If a participant develops adverse effects serious enough to discontinue study medication prior to 
1396 
the 24-month on-treatment primary outcome exam, the Investigator should call the Protocol 
1397 
Chair to discuss the case.  Progressive lenses should be tried for near focusing problems before 
1398 
stopping therapy. Reading glasses may be prescribed for participants using contact lenses.  If 
1399 
study medication is discontinued, the participant will continue in follow-up.  
1400 
 
1401 
In the case of pregnancy during the study, study eyedrops will be discontinued although the 
1402 
subject will be retained in the study.   
1403 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
6-4 
6.4.3 
Risk Assessment  
1404 
 The Jaeb Center Institutional Review Board has classified the protocol as research involving 
1405 
greater than minimal risk using the federal definition under 45 CFR 46.102i.   
1406 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
7-1 
Chapter 7: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS 
1407 
 
1408 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
1409 
analysis plan will be written and finalized without knowledge of study data.  The analysis plan 
1410 
synopsis in this chapter contains the framework of the anticipated final analysis plan. 
1411 
 
1412 
7.1 
Primary Objective:  Efficacy on Atropine Treatment (24 Months) 
1413 
The primary objective is to determine the efficacy of atropine for slowing progression of myopia 
1414 
after 24 months of treatment.    
1415 
 
1416 
7.1.1 
Primary Analysis – Refractive Error at 24 Months (On-Treatment)  
1417 
The primary analysis will be a treatment group comparison of change from baseline to 24-
1418 
months in spherical equivalent refractive error (SER), as measured by a masked examiner using 
1419 
cycloplegic autorefraction, using a longitudinal discrete time mixed model, which allows for 
1420 
interaction between time and treatment group, and adjusts for baseline SER, age, iris color 
1421 
(brown vs. non-brown) and East Asian vs. non-East Asian race, to account for potential residual 
1422 
confounding and improve power for the treatment comparison. At baseline and all follow-up 
1423 
visits, including the 24-month visit, the mean of the three readings from autorefraction in each 
1424 
eye will be calculated and then the mean of both eyes for each participant will be used for the 
1425 
analysis.  If fewer than 3 readings are available in each eye, the mean of available readings will 
1426 
be used for each eye to obtain the mean of both eyes for each participant.  The baseline SER will 
1427 
be included in the analysis model as an adjustment factor, while the change in SER at all follow-
1428 
up visits up to and including the 24-month visit will be included in the longitudinal outcome 
1429 
vector.  Further details, including handling of missing data, will be included in the Statistical 
1430 
Analysis Plan. 
1431 
 
1432 
The treatment group difference (atropine – placebo) and a 95% confidence interval will be 
1433 
calculated based on the model estimates at 24 months.   
1434 
   
1435 
The primary analysis will follow the intention-to-treat principle. All randomized participants will 
1436 
be analyzed according to their randomized treatment group regardless of whether/what treatment 
1437 
was received, including non-randomized treatment for myopia (section 4.109).   
1438 
 
1439 
7.1.1.1 Sensitivity Analyses  
1440 
As a sensitivity analysis, the primary analysis will be repeated using an analysis of covariance 
1441 
model (ANCOVA) model in which SER at 24 months is adjusted for SER at baseline.  Multiple 
1442 
imputation with the Monte Carlo Markov Chain (MCMC) method will be used to impute missing 
1443 
change in SER for participants who missed the 24-month visit or did not complete cycloplegic 
1444 
autorefraction testing at the 24-month visit.  In addition, change in SER will also be imputed for 
1445 
participants who start non-randomized treatment.    
1446 
 
1447 
7.1.2 
Secondary Outcomes at 24 Months (On-Treatment)  
1448 
Each secondary analysis below will be conducted using the same approaches as defined above 
1449 
for the primary analysis unless otherwise specified.    
1450 
 
1451 
7.1.2.1 Proportion of Participants with Progression >=2D at 24 Months 
1452 
The relative risk of progression of myopia SER >= 2D from baseline between participants in the 
1453 
atropine group and the placebo group will be estimated using a Cox proportional hazards model, 
1454 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
7-2 
which adjusts for baseline SER, age, iris color (brown vs. non-brown) and East Asian vs. non-
1455 
East Asian race.  An alternative analysis method will be used if the proportional hazards 
1456 
assumption is not met.    
1457 
 
1458 
7.1.2.2 Change in Axial Length at 12 and 24 Months   
1459 
Axial length will be reported as the distributions of baseline length, 12-month length, 24-month 
1460 
length, and change in axial length from baseline to 12 and 24 months.  A treatment group 
1461 
comparison of the change from baseline to 12 months and 24 months in axial length will be 
1462 
performed using a longitudinal discrete time mixed model, which allows for interaction between 
1463 
time and treatment group, and adjusts for baseline axial length, age, iris color (brown vs. non-
1464 
brown) and East Asian vs. non-East Asian race. At baseline and all follow-up visits, including 
1465 
the 12 and 24-month visits, the mean of the axial length readings in both eyes for each 
1466 
participant will be used for the analysis.  The treatment group difference (atropine – placebo) and 
1467 
a 95% confidence interval will be calculated based on the model estimates at 12 months and 24 
1468 
months.   
1469 
 
1470 
7.1.2.3 Compliance 
1471 
Compliance with study medication will be assessed at the 6-month, 12-month, 18-month, and 24- 
1472 
outcome exams.  For each of these exams, the distribution of number of calendar days that study 
1473 
medication was reported used and the distribution of the number of unused study medication 
1474 
ampules will be compared between treatment groups.    
1475 
 
1476 
Compliance with refractive correction will be assessed at every follow up visit.  After discussion 
1477 
with the parent and child, study personnel will classify the proportion of time refractive error was 
1478 
worn will be described as excellent (76% to 100%), good (51% to 75%), fair (26% to 50%), or 
1479 
poor (≤ 25%). The distribution of refractive correction compliance will be compared between 
1480 
treatment groups.  
1481 
 
1482 
7.1.3 
Secondary Outcomes at 12 Months (On-Treatment)  
1483 
Each secondary analysis below will be conducted using the same approaches as defined above 
1484 
for the primary analysis unless otherwise specified.    
1485 
 
1486 
7.1.3.1 Refractive Error at 12 Months  
1487 
The model used for the primary analysis at 24 months will also be used to perform a treatment 
1488 
group comparison of change from baseline to 12-months in spherical equivalent refractive error 
1489 
(SER), as measured by a masked examiner using cycloplegic autorefraction.    
1490 
 
1491 
7.1.3.2 Proportion of Participants with Progression >=1D at 12 Months 
1492 
The relative risk of progression of myopia SER >= 1D from baseline between participants in the 
1493 
atropine group and the placebo group will be estimated using a Cox proportional hazards model, 
1494 
adjusting for baseline SER, age, iris color (brown vs. non-brown) and East Asian vs. non-East 
1495 
Asian race. An alternative analysis method will be used if the proportional hazards assumption is 
1496 
not met.    
1497 
 
1498 
7.2 
Secondary Objective:  Efficacy off Atropine Treatment (30 Months) 
1499 
The secondary objective of the study is to determine the efficacy of atropine treatment for 
1500 
slowing progression of myopia after a period of 6 months off treatment.  All analyses as 
1501 
described in section 7.1 above will be repeated using data from the 30-month off-treatment visit.  
1502 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
7-3 
 
1503 
7.3 
Additional Analyses 
1504 
7.3.1 
Treatment Effect in Subgroups 
1505 
The treatment difference for spherical equivalent refractive error (SER) change from baseline to 
1506 
24 and 30 months within the following subgroups will be explored:   
1507 
• Baseline SER 
1508 
• Brown iris versus non-brown iris 
1509 
• Race/ethnicity 
1510 
• Baseline age  
1511 
• Baseline age and baseline SER 
1512 
 
1513 
These planned subgroup analyses will repeat the primary analysis, including the baseline factor 
1514 
and the baseline factor by treatment interaction.  In general, statistical power will be low for 
1515 
detection of interactions unless the interaction is very large.  
1516 
 
1517 
Subgroup analyses will be interpreted with caution, particularly if the corresponding overall 
1518 
analysis does not demonstrate a significant treatment group difference.   
1519 
 
1520 
7.3.2 
Treatment Effect over Time 
1521 
The treatment effect on change in spherical equivalent refractive error (SER) from baseline 
1522 
through the first year will be compared with the treatment effect on change in SER from end of 
1523 
first year through the second year, by constructing the appropriate contrasts in the primary 
1524 
analysis model. 
1525 
      
1526 
7.3.3 
Exploratory Analyses of Additional Ocular Biometric Parameters 
1527 
As exploratory analyses at 24 and 30 months, change in flat corneal radius, anterior chamber 
1528 
depth, and lens thickness will each be compared between treatment groups at 24 and 30 months 
1529 
using a longitudinal discrete time mixed model which allows for interaction between time and 
1530 
treatment group, and adjusts for the baseline value of the parameter, age, iris color (brown vs. 
1531 
non-brown), and East Asian vs. non-East Asian race.    
1532 
 
1533 
7.4 
Safety Analyses  
1534 
 
1535 
7.4.1 
Adverse Effects of Eye Drops 
1536 
An eyedrops questionnaire will be administered at randomization and at each follow-up visit 
1537 
except the 30-month visit.  The distribution of scores on each survey item will be summarized by 
1538 
treatment group at the time of randomization and at each follow-up exam up until and including 
1539 
the 24-month visit.  The average of the item responses at the 24-month visit will be calculated 
1540 
and compared with a t-test for difference in means between treatment groups.   
1541 
 
1542 
7.4.2 
 Visual Acuity 
1543 
The proportion of participants with loss of best corrected distance vision >1 logMAR line at 30 
1544 
months in either eye will be compared between treatment groups using Barnard’s test. The 
1545 
proportion of participants with loss of best corrected near binocular vision >1 logMAR line at 6 
1546 
months will be compared between treatment groups using Barnard’s test.  
1547 
 
1548 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
7-4 
7.5 
Need for Bifocals 
1549 
The proportion of participants needing bifocals in both groups will be evaluated. 
1550 
 
1551 
7.6 
Interim Analysis  
1552 
As specified by the DSMC, the decision of whether an interim analysis will be conducted will be 
1553 
evaluated after 6 months of recruitment and before any outcome data is reviewed. An interim 
1554 
monitoring plan will be developed at that point if circumstances warrant. 
1555 
 
1556 
7.7 
Data Tabulations and Other Analyses 
1557 
The following tabulations will be performed according to treatment group: 
1558 
• Baseline demographics and clinical characteristics 
1559 
• A flow chart accounting for all participants for all visits and phone calls 
1560 
• Visit and phone contact completion rates for each follow-up visit  
1561 
• Protocol deviations  
1562 
 
1563 
7.8 
Sample Size 
1564 
7.8.1 
General Considerations 
1565 
The goal of this section is to summarize data from prior studies of myopia progression, use these 
1566 
data to formulate assumptions about the expected treatment effect and its standard deviation, and 
1567 
to calculate the sample size needed to provide at least 90% power for each of the 2 hypothesis 
1568 
tests corresponding to the 24-month on treatment (primary) and 30-month off-treatment 
1569 
secondary objectives.   
1570 
 
1571 
To collect more safety data from participants using atropine, sample size was based on a 2:1 
1572 
allocation (2 participants will be randomized to the atropine group for every 1 participant 
1573 
randomized to the placebo group).   
1574 
 
1575 
7.8.2 
Sample Size for Primary Objective: Efficacy on Atropine Treatment 
1576 
 
1577 
Comparison of SER at 24 months  
1578 
Sample size calculations for the on-treatment comparison of refractive error at 24 months were 
1579 
based upon data from the CLEERE group and ATOM1 for untreated participants meeting similar 
1580 
eligibility criteria, and data from participants treated with atropine 0.01% in the ATOM2 study.28, 
1581 
31, 51  The participants in these studies were 6 to <13 years old with refractive error of -1.00D to -
1582 
6.00D spherical equivalent and astigmatism of -1.50D or less. The ATOM1 and ATOM2 studies 
1583 
were conducted in Asian populations whereas the race/ethnicity of participants in the CLEERE 
1584 
study was more reflective of the US population.  
1585 
 
1586 
• In 404 untreated participants from CLEERE (N=214) and ATOM1 (N=190), the mean 
1587 
progression after 24 months was 1.12D (95% CI = 1.05 to 1.18D) with standard deviation 
1588 
(SD) of 0.69D (95% CI = 0.65 to 0.75D). 
1589 
 
1590 
• In 75 participants treated with 0.01% atropine from ATOM2, the mean progression after 
1591 
24 months was 0.49D (95% CI = 0.35 to 0.63D) with SD of 0.60D (95% CI = 0.52 to 
1592 
0.72).  
1593 
 
1594 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
7-5 
The on-treatment effect after 24 months in our study is estimated to be 0.50D based on a 
1595 
conservative estimate of 1.00D 24-month progression in untreated participants and an estimated 
1596 
0.50D 24-month progression in participants treated with 0.01% atropine.  
1597 
 
1598 
Assuming a conservative standard deviation of 0.80D (based on CLEERE), and using a 2-sided 
1599 
t-test with alpha = 0.05, a sample size of 123 participants (82 in the atropine group and 41 in the 
1600 
placebo group) is needed to detect a difference in mean change in SER (atropine – placebo) at 24 
1601 
months with 90% power, assuming the true mean difference is 0.50D or larger (Table 1).     
1602 
Since the correlation between baseline refractive error and change in refractive error at 24 
1603 
months in the CLEERE data was low (r=0.05), no reduction in sample size was taken to account 
1604 
for the correlation between baseline and the outcome at 24 or 30 months. Accounting for up to 
1605 
10% loss to follow-up over 24 months, the sample size for this objective is 138 participants 
1606 
overall (92 in the atropine group and 46 in the placebo group).   
1607 
  
1608 
Table 1:  Total Sample Size Estimates for Various Treatment Group Differences in Mean 
1609 
SER Score at 24 Months or 30 Months* 
1610 
 Standard Deviation 
Mean SER Change 
from Baseline to  
24 Months or 30 
Months(D) 
True Treatment Group Difference (D)  
in Mean SER Change between Baseline and 24 Months or 30 Months 
0.40 
0.50 
0.60 
0.625 
0.60 
111 (74:37)   
72 (144:72) 
51 (34:17) 
48 (32:16) 
0.70 
147 (98:49) 
96 (64:32) 
69 (46:23) 
63 (42:21) 
0.80 
192 (128:64) 
123 (82:41) 
87 (58:29) 
81 (54:27) 
0.90 
243 (162:81) 
156 (104:52) 
111 (74:37) 
102 (68:34) 
1.00 
300 (200:100) 
192 (128:64) 
135 (90:45) 
123 (82:41) 
Cells indicate total sample size needed assuming a 2:1 randomization.  (Numbers in parenthesis reflect number 
1611 
needed in each group atropine:placebo). 
1612 
*Sample sizes based on a t-test to evaluate a difference between treatment groups in mean change from baseline at 
1613 
24-months, with a 2-sided alpha=0.05, and power=90%.    
1614 
    
1615 
7.8.3 
Sample Size for Secondary Objective: Efficacy off Atropine Treatment    
1616 
 
1617 
Comparison of SER at 30 months  
1618 
In CLEERE, the mean progression after 36 months was 1.50D in 127 untreated participants 
1619 
(95% CI = 1.34 to 1.66 D) with a SD of 0.89D (95% CI = 0.79 to 1.02 D).  If the rate of 
1620 
progression in our study is similar (approximately 0.25D every 6 months), then the progression 
1621 
rate between baseline and 30-months in placebo participants is estimated to be 1.25D.  
1622 
 
1623 
In ATOM2, the 71 participants who stopped atropine at 24 months progressed a mean of 0.28D 
1624 
(SD = 0.33D) after 12 months off treatment (95% CI for mean change = 0.20 to 0.36 D); and 
1625 
their mean progression from baseline to 36 months was 0.72D (95% CI = 0.55 to 0.89 D) with 
1626 
SD of 0.72D (95% CI = 0.62 to 0.86 D).  
1627 
 
1628 
If atropine group participants progress at the same rate as ATOM2 participants between 24 and 
1629 
30 months 
1630 
If atropine participants progress at the same rate as ATOM2 participants between 24 and 30 
1631 
months (estimated to be about 0.125 D over six months), then the estimated progression rate 
1632 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
7-6 
between baseline and 30-months in the atropine group is 0.625D (0.50D at 24 months plus 
1633 
0.125D between 24 and 30 months).  Compared with the estimated 1.25D progression rate in the 
1634 
placebo group between baseline and 30-months (based on CLEERE data), the treatment group 
1635 
difference would be expected to be 0.625D in favor of the atropine group. 
1636 
 
1637 
Assuming a slightly larger standard deviation of 0.90D at 30-months, and using a 2-sided t-test 
1638 
with alpha = 0.05, a sample size of 102 participants (68 in the atropine group and 34 in the 
1639 
placebo group) is needed to detect a mean difference in SER (atropine – placebo) at 30 months 
1640 
with 90% power, if the magnitude of the true mean difference is 0.625D or larger (Table 1).  
1641 
Accounting for up to 15% loss to follow-up over 30 months, the sample size for this objective is 
1642 
120 participants overall (80 in the atropine group and 40 in the placebo group) under this 
1643 
scenario.  
1644 
 
1645 
If atropine group participants progress at the same rate as placebo participants in CLEERE 
1646 
between 24 and 30 months 
1647 
If atropine participants progress at the same rate as placebo participants in CLEERE (i.e. no 
1648 
treatment effect) between 24 and 30 months (0.25D), then the estimated progression rate 
1649 
between baseline and 30-months in the atropine group is 0.75D (0.50D at 24 months plus 0.25D 
1650 
between 24 and 30 months).  Compared with the estimated 1.25D progression rate in the placebo 
1651 
group between baseline and 30-months (based on CLEERE data), the treatment group difference 
1652 
would be expected to be 0.50D in favor of the atropine group. 
1653 
 
1654 
Assuming a slightly larger standard deviation of 0.90D at 30-months, and using a 2-sided t-test 
1655 
with alpha = 0.05, a sample size of 156 participants (104 in the atropine group and 52 in the 
1656 
placebo group) is needed to detect a mean difference in SER (atropine – placebo) at 30 months 
1657 
with 90% power, if the magnitude of the true mean difference is 0.50D or larger (Table 1).  
1658 
Accounting for up to 15% loss to follow-up over 30 months, the sample size for this objective is 
1659 
186 participants overall (124 in the atropine group and 62 in the placebo group) under this 
1660 
scenario.  
1661 
 
1662 
7.8.4 
Summary of Sample Size Estimation     
1663 
To be conservative, sample size for the study was chosen based upon the comparison of SER at 
1664 
30 months (secondary objective) assuming that atropine group participants will progress at the 
1665 
same rate as placebo between 24 and 30 months and that expected treatment group difference 
1666 
between baseline and 30 months will be 0.50D, the scenario which has the largest sample size 
1667 
requirement.   
1668 
 
1669 
The total sample size for the study will be 186 participants (124 in the atropine group and 62 in 
1670 
the placebo group).   
1671 
 
1672 
7.8.5 
Precision within Racial Subgroups     
1673 
Table 2 below summarizes the expected ½-width of a 2-sided 95% confidence interval on the 
1674 
treatment group difference of myopia progression for the exploratory analysis within subgroups 
1675 
defined by race/ethnicity with an overall sample size of 156 participants completing the 30-
1676 
month primary outcome exam.    
1677 
 
1678 
For example: if participants of East Asian race/ethnicity make up 25% of the total sample (26 in 
1679 
atropine group and 13 in placebo group) and the standard deviation of progression in this group 
1680 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
7-7 
is 0.80D, then the expected width of 2-sided 95% confidence interval for the treatment group 
1681 
difference in East Asians is  ±0.55D. 
1682 
 
1683 
Table 2.  Expected width of 2-sided 95% confidence interval on the treatment group 
1684 
comparison of myopia progression as a function of the standard deviation of progression 
1685 
and sample size per race/ethnicity subgroup* 
1686 
Race/Ethnicity 
Subgroup as 
Proportion of 
Total Sample 
Size 
 Standard Deviation of 
Mean SER Change from Baseline** (D) 
0.8 
0.9 
1.0 
1.1 
1.2 
1.3 
1.4 
10% n=15 
±0.95 
±1.06 
±1.18 
±1.30 
±1.42 
±1.54 
±1.66 
20% n=30 
±0.63 
±0.71 
±0.79 
±0.87 
±0.95 
±1.03 
±1.11 
25% n=39 
±0.55 
±0.62 
±0.69 
±0.76 
±0.83 
±0.89 
±0.96 
30% n=48 
±0.49 
±0.55 
±0.62 
±0.68 
±0.74 
±0.80 
±0.86 
40% n=63 
±0.43 
±0.48 
±0.53 
±0.59 
±0.64 
±0.69 
±0.75 
50% n=78 
±0.38 
±0.43 
±0.48 
±0.53 
±0.57 
±0.62 
±0.67 
60% n=93 
±0.35 
±0.39 
±0.44 
±0.48 
±0.52 
±0.57 
±0.61 
70% n=108 
±0.32 
±0.36 
±0.40 
±0.45 
±0.49 
±0.53 
±0.57 
80% n=126 
±0.30 
±0.34 
±0.37 
±0.41 
±0.45 
±0.49 
±0.52 
90% n=141 
±0.28 
±0.32 
±0.35 
±0.39 
±0.42 
±0.46 
±0.49 
 
1687 
*Cells show the expected ½-width of 2-sided 95% confidence interval on the treatment group comparison of myopia 
1688 
progression as a function of the standard deviation of progression and sample size per race/ethnicity subgroup.   
1689 
 
1690 
**The range of standard deviation was based on the standard deviation of progression in CLEERE group data at 36-
1691 
months, stratified by race/ethnicity group. At 36 months, the standard deviations of progression in Asian, Black, 
1692 
Hispanic, and White populations were 1.02D (95% CI =0.82 to 1.36D), 0.61D (95% CI =0.47 to 0.88D), 0.82D 
1693 
(95% CI =0.67 to 1.05D), and 0.92D (95% CI =0.70 to 1.36D) respectively.  
1694 
 
1695 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
8-1 
Chapter 8: DATA COLLECTION AND MONITORING 
1696 
 
1697 
8.1 
Case Report Forms and Device Data 
1698 
The main study data are collected through electronic case report forms (CRFs).  These electronic 
1699 
CRFs from the study website are considered the primary source documentation. 
1700 
When data are directly collected in electronic case report forms, this will be considered the 
1701 
source data.  Each participating site will maintain appropriate medical and research records for 
1702 
this trial, in compliance with ICH E6 and regulatory and institutional requirements for the 
1703 
protection of confidentiality of participants. 
1704 
 
1705 
8.2 
Study Records Retention 
1706 
Study documents will be retained for a minimum of 3 years following the submission of the final 
1707 
financial report for the last grant cycle for which the study is conducted or 2 years following the 
1708 
date a marketing application is approved for the drug for the indication for which it is being 
1709 
investigated; or if not approved, 2 years after the IND is withdrawn, whichever is later.  No 
1710 
records will be destroyed without the written consent of the sponsor.  It is the responsibility of 
1711 
the sponsor to inform the investigators when study documents no longer need to be retained. 
1712 
 
1713 
8.3 
Quality Assurance and Monitoring 
1714 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1715 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1716 
conducted and data are generated, documented and reported in compliance with the protocol, 
1717 
Good Clinical Practice (GCP) and the applicable regulatory requirements.  Adverse events will 
1718 
be prioritized for monitoring. 
1719 
 
1720 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1721 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
1722 
Investigations — A Risk-Based Approach to Monitoring” (August 2013).  Study conduct and 
1723 
monitoring will conform with 21 Code of Federal Regulations (CFR) 812. 
1724 
 
1725 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1726 
events.  Therefore, the RBM plan will focus on these areas.  As much as possible, remote 
1727 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1728 
verity and completeness of the key site data.  Elements of the RBM may include: 
1729 
• Qualification assessment, training, and certification for sites and site personnel 
1730 
• Oversight of Institutional Review Board (IRB) coverage and informed consent 
1731 
procedures 
1732 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1733 
review of entered data and edits, statistical monitoring, study closeout 
1734 
• On-site monitoring (site visits): source data verification, site visit report 
1735 
• Communications with site staff 
1736 
• Patient retention and visit completion 
1737 
• Quality control reports 
1738 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
8-2 
• Management of noncompliance 
1739 
• Documenting monitoring activities 
1740 
• Adverse event reporting and monitoring 
1741 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
1742 
order to maintain current and personal knowledge of the study through review of the records, 
1743 
comparison with source documents, observation and discussion of the conduct and progress of 
1744 
the study. 
1745 
 
1746 
8.4 
Protocol Deviations 
1747 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1748 
requirements.  The noncompliance may be either on the part of the participant, the investigator, 
1749 
or the study site staff.  As a result of deviations, corrective actions are to be developed by the site 
1750 
and implemented promptly. 
1751 
 
1752 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements.  
1753 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
1754 
 
1755 
 
 
1756 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
9-1 
Chapter 9: ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
1757 
 
1758 
9.1 
Ethical Standard 
1759 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1760 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1761 
21 CFR Part 56, and/or the ICH E6. 
1762 
 
1763 
9.2 
Institutional Review Boards 
1764 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1765 
be submitted to the IRB for review and approval.  Approval of both the protocol and the 
1766 
consent/assent forms must be obtained before any participant is enrolled.  Any amendment to the 
1767 
protocol will require review and approval by the IRB before the changes are implemented to the 
1768 
study.  All changes to the consent and/or assent form will be IRB approved; a determination will 
1769 
be made regarding whether previously consented participants need to be re-consented. 
1770 
 
1771 
9.3 
Informed Consent Process 
1772 
9.3.1 
Consent Procedures and Documentation 
1773 
Informed consent (and assent if required) is a process that is initiated prior to the parent and child 
1774 
agreeing to participate in the study and continues throughout the individual’s study participation.  
1775 
Extensive discussion of risks and possible benefits of participation will be provided to the 
1776 
participants and their families.  Consent forms and assent forms if required will be IRB-approved 
1777 
and the parent and child if required will be asked to read and review the document.  The 
1778 
investigator will explain the research study to the parent and child and answer any questions that 
1779 
may arise.  All parent(s) will receive a verbal explanation in terms suited to their comprehension 
1780 
of the purposes, procedures, and potential risks of the study and of their child’s rights as research 
1781 
participants.  Parent(s) will have the opportunity to carefully review the written consent form and 
1782 
ask questions prior to signing. 
1783 
 
1784 
The parent(s) and child should have the opportunity to discuss the study with their surrogates or 
1785 
think about it prior to agreeing to participate.  The parent will sign the informed consent 
1786 
document prior to any procedures being done specifically for the study.  The participants may 
1787 
withdraw consent at any time throughout the course of the trial.  A copy of the informed consent 
1788 
document will be given to the participants for their records.  The rights and welfare of the 
1789 
participants will be protected by emphasizing to them that the quality of their medical care will 
1790 
not be adversely affected if they decline to participate in this study. 
1791 
 
1792 
9.3.2 
Participant and Data Confidentiality 
1793 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1794 
and the sponsor(s) and their agents.  Therefore, the study protocol, documentation, data, and all 
1795 
other information generated will be held in strict confidence.  No information concerning the 
1796 
study or the data will be released to any unauthorized third party without prior written approval 
1797 
of the sponsor. 
1798 
 
1799 
The study monitor, other authorized representatives of the Jaeb Center for Health Research, or 
1800 
representatives of the IRB may inspect all documents and records required to be maintained by 
1801 
the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
1802 
pharmacy records for the participants in this study.  The clinical study site will permit access to 
1803 
such records. 
1804 


 
MTS1 Protocol V5.1 (06Apr2020) 
 
9-2 
The study participant’s contact information will be securely stored at each clinical site for 
1805 
internal use during the study.  At the end of the study, all records will continue to be kept in a 
1806 
secure location for as long a period as dictated by local IRB and Institutional regulations. 
1807 
Study participant research data, which is for purposes of statistical analysis and scientific 
1808 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research.  Individual 
1809 
participants and their research data will be identified by a unique study identification number.   
1810 
 
1811 
The study data entry and study management systems used by clinical sites and by the Jaeb Center 
1812 
for Health Research Coordinating Center research staff will be secured and password protected.  
1813 
At the end of the study, all study databases will be de-identified and archived at the Jaeb Center 
1814 
for Health Research and made available to the public.   
1815 
 
 
1816 


 
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10-1 
Chapter 10: REFERENCES 
1817 
 
1818 
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Ophthalmic & Physiological Optics 2012;32(1):3-16. 
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2. 
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adults in the United States, Western Europe, and Australia. Archives of Ophthalmology 
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2004;122(4):495-505. 
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3. 
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4. 
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astigmatism in non-Hispanic white and Asian children: multi-ethnic pediatric eye disease 
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study. Ophthalmology 2013;120(10):2109-16. 
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Vitale S, Sperduto RD, Ferris FL, 3rd. Increased prevalence of myopia in the United 
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Fan DS, Lam DS, Lam RF, et al. Prevalence, incidence, and progression of myopia of 
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Walline JJ, Lindsley K, Vedula SS, et al. Interventions to slow progression of myopia in 
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Sherwin JC, Reacher MH, Keogh RH, et al. The association between time spent outdoors 
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Guo Y, Liu LJ, Xu L, et al. Outdoor activity and myopia among primary students in rural 
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Prepas SB. Light, literacy and the absence of ultraviolet radiation in the development of 
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using riboflavin and UVA. Acta Ophthalmologica Scandinavica 2005;83(4):477-82. 
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Shih YF, Chen CH, Chou AC, et al. Effects of different concentrations of atropine on 
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Tong L, Huang XL, Koh AL, et al. Atropine for the treatment of childhood myopia: 
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changes after stopping atropine 0.01%, 0.1% and 0.5%. Am J Ophthalmol 
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Pharmacology and Experimental Therapeutics 1976;197(1):79-88. 
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38. 
Li SM, Wu SS, Kang MT, et al. Atropine slows myopia progression more in Asian than 
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Loughman J, Flitcroft DI. The acceptability and visual impact of 0.01% atropine in a 
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Kennedy RH, Dyer JA, Kennedy MA, et al. Reducing the progression of myopia with 
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atropine: a long term cohort study of Olmsted County students. Binocular Vision & 
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Tideman JW, Snabel MC, Tedja MS, et al. Association of Axial Length With Risk of 
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1941