A Randomized Placebo-controlled Trial of Spectacles With Highly Aspherical Lenslet Target (H.A.L.T.) MAX Technology or 0.05% Atropine to Slow Progression of Myopia in Children
Phase: PHASE3
Conditions: Myopia
Sponsor: Jaeb Center for Health Research

JAEB CENTER FOR HEALTH RESEARCH 
 
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A Randomized Placebo-Controlled Trial of Spectacles 
with Highly Aspherical Lenslet Target (H.A.L.T.) 
MAX Technology or 0.05% Atropine to Slow 
Progression of Myopia in Children 
 
 
Protocol Identifying Number: MTS2 
IND Sponsor: Jaeb Center for Health Research 
IND #: 137441 
 
 
Funded by: National Eye Institute, National Institutes of Health 
EssilorLuxottica provided partial support 
 
 
Version Number: 2.0 
January 24th, 2026 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT07095894

JAEB CENTER FOR HEALTH RESEARCH 
 
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KEY ROLES 
JCHR Principal Investigator 
Name, degree 
Danielle Chandler, MSPH 
Title 
Epidemiologist  
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 
 
Signature/date 
 
Protocol Co-Chair 
Name, degree 
Lori Ann F. Kehler, OD 
Title 
Associate Professor of Ophthalmology 
Institution Name 
 
 
 
 
Vanderbilt University Medical Center 
Vanderbilt Eye Institute 
2311 Pierce Avenue 
Nashville, TN 37232 
Phone: 615-936-2020 
Email: lori.ann.kehler@vumc.org 
 
Signature/date 
 
Protocol Co-Chair 
Name, degree 
Katherine A. Lee, MD, PhD 
Title 
Clinical Instructor 
Institution Name 
 
 
 
 
Faculty of Medicine 
Department of Ophthalmology and Visual Sciences 
University of British Columbia 
Administrative Office 
Vancouver Eye Care Center 
2550 Willow Street 
Vancouver, BC V5Z 3N9 
Phone: 1-888-797-3344 
Fax: 1-888-697-3344 
Phone: 1-888-797-3344 
Email: kathlee058@gmail.com 
 
Signature/date 
 
Medical Monitor 
Name, degree 
Michael X. Repka, MD, MBA 
Title 
Medical Monitor 
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 
 
Signature/date 
 
 

JAEB CENTER FOR HEALTH RESEARCH 
 
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VERSION HISTORY 
VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
 
1.0  
Katherine Lee 
Lori Ann Kehler 
KatherineWeise  
Danielle Chandler  
 
Katherine Lee 
Lori Ann Kehler 
KatherineWeise  
Danielle Chandler 
Michael Repka  
 
29Apr2025 
Original document submitted to IRB 
2.0* 
Danielle Chandler 
Ray Kraker  
Wesley Beaulieu  
Katherine Lee 
Lori Ann Kehler 
KatherineWeise  
Danielle Chandler 
Michael Repka  
 
24Jan2026 
PROTOCOL AMENDMENT I 
 
The following major changes were made to the protocol 
prior to starting the study:  
• Updated background section to reflect recent 
literature with respect to lenses with Highly 
Aspherical Lenslet Target (H.A.L.T.) MAX 
technology, and the receipt of market authorization 
from the FDA of spectacle lenses with HAL in 
September 2025. 
• Updated protocol to evaluate spectacle lenses with 
H.A.L.T. MAX technology rather than spectacle 
lenses with HAL technology.   
• Updated statistical chapter to estimate the effect of 
spectacle lenses with H.A.L.T. MAX technology and 
to include a powered comparison of combined therapy 
versus placebo as a primary comparison of interest 
(instead of exploratory).  
 
 
In addition, the following minor changes were made to 
the protocol prior to study start: 
• Deleted eligibility exclusion criteria for allergy to 
benzalkonium chloride (eyedrop preservative) 
because the study drug is preservative free, as it is 
packaged in a multidose eyedropper bottle. 
• Added exclusion criteria for known shellfish allergy.  
• Specifies the following limitations on randomization:  
o Proportion of participants who are 10–<12 years 
old be limited to ≤40% 
o Proportion of participants who self report aa 
“East Asian or Southeast Asian” ethnicity be 
limited to ≤20%  
• Updated protocol clinical testing to:  
o 
Add flat corneal radius measurement.   
 
Updated Statistical Chapter to: 
o 
Remove anterior chamber depth, and lens 
thickness as exploratory objectives as the 
measures are not collected in MTS2.  
o 
Expand analysis of change in monocular 
accommodation to be performed at the 18- 
and 30-month timepoints. 
o 
Change the method for comparison for safety 
outcomes from Fisher’s Exact test to 
Barnard’s Unconditional test. 
o 
Added analysis of flat corneal radius data   
• Minor editorial changes/clarifications throughout.   
* Approved protocol at time of study initiation (first participant enrolled).  
 

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TABLE OF CONTENTS 
 
CHAPTER 1: 
BACKGROUND INFORMATION .......................................................................................... 16 
1.1 
Epidemiology and Clinical Characteristics ................................................................................. 16 
1.2 
Treatments to Slow Myopia Progression .................................................................................... 16 
1.2.1 
Atropine Treatment ................................................................................................................. 16 
1.2.1.1 
Low-Concentration Atropine Eye Drops in Non-Asian Populations .............................. 17 
1.2.1.2 
Low-Concentration Atropine Eye Drops in Asian Populations ....................................... 18 
1.2.1.3 
Higher Atropine Concentrations (>0.05%) ...................................................................... 19 
1.2.2 
Spectacles Lenses with Highly Aspherical Lenslets (HAL) ................................................... 19 
1.2.2.1 
Spectacle Lenses with HAL: Mechanism of Action ........................................................ 19 
1.2.2.2 
Spectacle Lenses with HAL Clinical Trial Data .............................................................. 21 
1.2.3 
Spectacle Lenses with Highly Aspherical Lenslet Target (H.A.L.T.) MAX Technology ...... 22 
1.2.3.1 
Spectacle Lenses with H.A.L.T. MAX Technology: Clinical Trial Data ........................ 23 
1.2.4 
Combined Atropine and Spectacle Lenses with HAL ............................................................ 24 
1.3 
Rationale for the Present Study ................................................................................................... 24 
1.4 
Public Health Importance ............................................................................................................ 25 
1.5 
Potential Risks and Benefits of Study Treatment ....................................................................... 25 
1.5.1 
Known Potential Risks of Atropine Eye Drops ...................................................................... 25 
1.5.2 
Known Potential Risks of HAL Lens Wear ............................................................................ 28 
1.5.3 
Known Potential Risks of H.A.L.T MAX Lens Wear ............................................................ 28 
1.5.4 
Known Potential Risks of Spectacle Lenses with H.A.L.T. MAX Technology plus Atropine28 
1.6 
Known Potential Benefits ........................................................................................................... 28 
1.7 
Risk Assessment ......................................................................................................................... 28 
1.8 
General Considerations ............................................................................................................... 29 
CHAPTER 2: 
STUDY ENROLLMENT AND SCREENING ........................................................................... 30 
2.1 
Participant Recruitment and Enrollment ..................................................................................... 30 
2.2 
Informed Consent and Authorization Procedures ....................................................................... 30 
2.3 
Participant Inclusion Criteria ...................................................................................................... 30 
2.4 
Participant Exclusion Criteria ..................................................................................................... 31 
2.5 
Screening/Enrollment Procedures ............................................................................................... 32 
2.5.1 
Demographic & Historical Information .................................................................................. 32 
2.6 
Testing at the Enrollment Visit ................................................................................................... 32 
2.7 
Run-In Phase Refractive Correction ........................................................................................... 33 
2.8 
Run-in Phase ............................................................................................................................... 33 
2.9 
Treatment in the Run-In Phase .................................................................................................... 33 
CHAPTER 3: 
RANDOMIZATION .............................................................................................................. 35 
3.1 
Assessment of Adherence with Artificial Tears .......................................................................... 35 
3.2 
Assessment of Adherence with Refractive Correction Wear ...................................................... 35 

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3.3 
Testing at the Randomization Visit ............................................................................................. 35 
3.4 
Confirmation of Eligibility for Randomization ........................................................................... 36 
3.5 
Randomization ............................................................................................................................ 37 
CHAPTER 4: 
TREATMENT AND FOLLOW-UP IN RANDOMIZED TRIAL ................................................ 38 
4.1 
Treatment from 0 to 24 months ................................................................................................... 38 
4.1.1 
Study Medication .................................................................................................................... 38 
4.1.2 
Study Spectacles ..................................................................................................................... 38 
4.2 
Treatment from 24 to 30 months ................................................................................................. 39 
4.3 
Telephone Calls........................................................................................................................... 39 
4.4 
Adherence with Study Treatment ............................................................................................... 39 
4.5 
Side Effects of Treatment ........................................................................................................... 40 
4.6 
Study Visits and Phone Calls in the Randomized Trial .............................................................. 40 
4.7 
Procedures at 4-Week Treatment Initiation Visit ........................................................................ 41 
4.8 
Procedures at Follow-Up Visits Between 6 and 30 Months ....................................................... 42 
4.8.1 
Lensometry ............................................................................................................................. 42 
4.8.2 
Procedures at Clinical Follow Up Visits ................................................................................. 42 
4.9 
Procedures at Study Spectacle Fittings ....................................................................................... 43 
4.10 
Management of Refractive Error ................................................................................................ 44 
4.11 
Non-Randomized Treatment ....................................................................................................... 44 
4.12 
Text Message Contacts ............................................................................................................... 44 
CHAPTER 5: 
TESTING PROCEDURES AND QUESTIONNAIRES .............................................................. 45 
5.1 
Questionnaires ............................................................................................................................. 45 
5.1.1 
PEDIG Myopia Treatment Impact Questionnaire (Child and Parent) .................................... 45 
5.2 
Clinical Testing Procedures and Assessments ............................................................................ 45 
5.2.1 
Lensometry ............................................................................................................................. 45 
5.2.2 
Medical History....................................................................................................................... 45 
5.2.3 
Adherence Assessment (all follow-up visits except 30 months) ............................................. 46 
5.2.4 
Urine Pregnancy Test .............................................................................................................. 46 
5.2.5 
Automated Pupillometry ......................................................................................................... 46 
5.2.6 
Distance Visual Acuity Testing .............................................................................................. 46 
5.2.7 
Binocular Near Visual Acuity Testing .................................................................................... 47 
5.2.8 
Monocular Amplitude of Accommodation (right eye only) ................................................... 47 
5.2.9 
Drop Instillation for Testing Under Cycloplegia .................................................................... 47 
5.2.10 Cycloplegic Autorefraction ..................................................................................................... 47 
5.2.11 Axial Length and Flat Corneal Radius Measurements with Cycloplegia ............................... 47 
5.2.12 Spectacle Prescription Determination with Cycloplegia ......................................................... 48 
CHAPTER 6: 
UNANTICIPATED PROBLEM / ADVERSE EVENT, AND DEVICE ISSUE REPORTING ........ 49 

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6.1 
Unanticipated Problems .............................................................................................................. 49 
6.2 
Adverse Events ........................................................................................................................... 49 
6.2.1 
Definitions ............................................................................................................................... 49 
6.3 
Reportable Adverse Events ......................................................................................................... 50 
6.4 
Relationship of Adverse Event to Study Drug, Device or Procedure ......................................... 51 
6.5 
Severity (Intensity) of Adverse Event ......................................................................................... 51 
6.6 
Expectedness ............................................................................................................................... 52 
6.7 
Coding of Adverse Events .......................................................................................................... 52 
6.8 
Outcome of Adverse Event ......................................................................................................... 52 
6.9 
Reportable Device (Spectacles) Issues ........................................................................................ 53 
6.10 
Timing of Event Reporting ......................................................................................................... 53 
6.11 
Safety Oversight .......................................................................................................................... 53 
6.12 
Criteria for Suspending or Stopping Study ................................................................................. 54 
6.13 
Participant Discontinuation of Study Treatment ......................................................................... 54 
CHAPTER 7: 
MISCELLANEOUS CONSIDERATIONS ............................................................................... 55 
7.1 
Contacts by the Jaeb Center for Health Research and Sites ........................................................ 55 
7.2 
Pregnancy Reporting ................................................................................................................... 55 
7.3 
Prohibited Medications, Treatments, and Procedures ................................................................. 55 
7.4 
Precautionary Medications, Treatments, and Procedures ........................................................... 55 
7.5 
Participant Compensation ........................................................................................................... 55 
7.6 
Participant Withdrawal ............................................................................................................... 55 
7.7 
Confidentiality ............................................................................................................................ 55 
CHAPTER 8: 
STATISTICAL CONSIDERATIONS ...................................................................................... 56 
8.1 
Statistical and Analytical Plans ................................................................................................... 56 
8.2 
Statistical Hypotheses ................................................................................................................. 56 
8.3 
Sample Size ................................................................................................................................. 56 
8.3.1 
Estimate of Effect with PLACEBO ........................................................................................ 56 
8.3.2 
Estimate of Effect with Spectacle Lenses with H.A.L.T. MAX Technology ......................... 57 
8.3.3 
Estimate of Effect with ATROPINE and with Spectacle Lenses with HAL .......................... 57 
8.3.4 
Required Sample Size for Current Study ................................................................................ 58 
8.4 
Outcome Measures ...................................................................................................................... 58 
8.4.1 
Primary Efficacy Outcome ...................................................................................................... 58 
8.4.2 
Secondary Efficacy Outcomes ................................................................................................ 58 
8.4.3 
Exploratory Outcomes ............................................................................................................ 58 
8.5 
Analysis Cohorts ......................................................................................................................... 59 
8.6 
Analysis of the Primary Efficacy Outcome ................................................................................ 59 
8.7 
Analysis of the Secondary Outcomes ......................................................................................... 60 
8.7.1 
Change in Spherical Equivalent Refractive Error from Baseline to 24 Months ..................... 60 
8.7.2 
Change in Axial Length from Baseline to 30 Months ............................................................ 60 

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8.7.3 
Change in Spherical Equivalent Refractive Error from Baseline to 30 Months ..................... 60 
8.7.4 
Changes in Axial Length and SER at 6, 12, and 18 Months ................................................... 60 
8.8 
Analyses of Exploratory Outcomes ............................................................................................ 60 
8.8.1 
Change in Monocular Amplitude of Accommodation at 6, 12, 18, 24, and 30 Months ......... 60 
8.8.2 
Change in Pupil Size at 6, 12, 18, 24, and 30 Months ............................................................ 60 
8.8.3 
Change in Flat Corneal Radius at 6, 12, 18, 24, and 30 Months ............................................. 60 
8.8.4 
Change in Axial Length Over 24 Months (Area Under the Curve) ........................................ 60 
8.8.5 
Change in Axial Length from 12 to 24 Months ...................................................................... 61 
8.8.6 
Change in Axial Length from 24 to 30 Months ...................................................................... 61 
8.8.7 
Change in Spherical Equivalent Refractive Error from 12 to 24 Months ............................... 61 
8.8.8 
Change in Spherical Equivalent Refractive Error from 24 to 30 Months ............................... 61 
8.8.9 
Change in Spherical Equivalent Refractive Error Over 24 Months ........................................ 61 
8.8.10 Treatment Impact Questionnaire ............................................................................................. 61 
8.9 
Safety Analyses ........................................................................................................................... 62 
8.10 
Intervention Adherence ............................................................................................................... 62 
8.11 
Protocol Adherence and Retention ............................................................................................. 62 
8.12 
Baseline Descriptive Statistics .................................................................................................... 62 
8.13 
Planned Interim Analyses ........................................................................................................... 62 
8.14 
Subgroup Analyses ..................................................................................................................... 62 
8.15 
Multiple Comparison/Multiplicity .............................................................................................. 63 
8.16 
Additional Tabulations and Analyses ......................................................................................... 63 
8.17 
Exploratory Analyses in COMBINED Atropine + H.A.L.T. MAX Group ................................ 64 
CHAPTER 9: 
DATA COLLECTION AND MONITORING .......................................................................... 65 
9.1 
Case Report Forms and Other Data Collection ........................................................................... 65 
9.2 
Study Records Retention ............................................................................................................. 65 
9.3 
Quality Assurance and Monitoring ............................................................................................. 65 
9.4 
Protocol Deviations ..................................................................................................................... 66 
CHAPTER 10: 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS ........................................................ 67 
10.1 
Ethical Standard .......................................................................................................................... 67 
10.2 
Institutional Review Boards ........................................................................................................ 67 
10.3 
Informed Consent, Assent, and HIPAA Authorization Process .................................................. 67 
10.3.1 Procedures and Documentation .............................................................................................. 67 
10.3.2 Participant and Data Confidentiality ....................................................................................... 67 
10.3.3 Future Use of Data .................................................................................................................. 68 
CHAPTER 11: 
REFERENCES ................................................................................................................... 69 

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LIST OF ABBREVIATIONS 
 
ABBREVIATION 
DEFINITION 
ANCOVA 
Analysis of covariance 
ATS 
Amblyopia Treatment Study  
BCVA 
Best-corrected visual acuity 
CI 
Confidence interval 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
D 
Diopter 
DHHS 
Department of Health and Human Services 
DSMC 
Data safety and monitoring committee 
eCRF 
Electronic case report form  
FDA 
Food and Drug Administration 
GCP  
Good clinical practice 
HAL 
Spectacles with Highly Aspherical Lenslets  
H.A.L.T. MAX 
Spectacles with Highly Aspherical Lenslet Target MAX technology 
HRQOL 
Health-related quality of life 
ICH 
International Council for Harmonisation 
IOD 
Interocular difference 
IRB 
Institutional Review Board 
JCHR 
Jaeb Center for Health Research 
logMAR 
Logarithm of the minimal angle of resolution 
NIH 
National Institutes of Health 
ODM 
Occlusion dose monitor 
PACT 
Prism and alternate cover test 
PEDIG 
Pediatric Eye Disease Investigator Group  
QA 
Quality assurance 
QC 
Quality control 
RBM 
Risk-based monitoring 
RCT 
Randomized clinical trial 
SER 
Spherical equivalent refractive error 
SAL 
Slightly aspherical lenslet spectacles 
VoNFL 
Volume of non-focused light 

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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
 
Protocol Title: A Randomized Placebo-controlled Trial of Spectacles with Highly 
Aspherical Lenslet Target MAX Technology or 0.05% Atropine to Slow Progression of 
Myopia in Children 
 
Protocol Version / Date: 2.0 / January 24th, 2026 
 
I have read the protocol specified above. In my formal capacity as a Site Principal Investigator, 
my duties include ensuring the safety of the study participants enrolled under my supervision and 
providing the Jaeb Center for Health Research, which serves as the coordinating center for the 
protocol, with complete and timely information, as outlined in the protocol. It is understood that 
all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. 
 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as 
required by the following: United States (US) Code of Federal Regulations (CFR) applicable to 
clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 
CFR Part 812).  
 
As the Principal Investigator, I will assure that no deviation from or changes to the protocol will 
take place without prior agreement from the sponsor and documented approval from the 
Institutional Review Board (IRB), or other approved Ethics Committee, except where necessary 
to eliminate an immediate hazard(s) to the trial participants. 
 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Participants Protection Training and Good Clinical Practice Training. Further, 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
 
Investigator’s Signature __________________________________ Date: _____ / _____ / _____ 
 
dd 
mmm 
yyyy 
 
Investigator’s Name: ____________________________________ 
 
 
Site Name/Number: ____________________________________ 

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PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
A Randomized Placebo-controlled Trial of Spectacles with Highly Aspherical Lenslets MAX or 0.05% 
Atropine to Slow Progression of Myopia in Children 
Précis 
Although results of recent randomized clinical trials outside the US are promising, additional studies in 
children are needed to test the safety and efficacy of low-concentration atropine and specially designed 
spectacle lenses as treatments to slow the progression of myopia during the peak years for eye growth.  
 
After a run-in phase to demonstrate adherence with nightly eyedrops (artificial tears) and spectacle 
correction, children 5 to <12 years old with myopia of 0.75D to 6.00D cycloplegic spherical equivalent 
refractive error (SER) and at least 0.75D myopia in both principal meridians of each eye will be 
randomized in a 2x2 factorial design to treatment with 1) nightly 0.05% atropine or placebo eyedrops, 
and 2) spectacle lenses with Highly Aspherical Lenslet Target (H.A.L.T.) MAX technology or single 
vision spectacles, and followed every six months for 24 months. Change in axial length over 24 
months and change in SER over 24 months are the primary and secondary outcomes, respectively.  
 
All children will return for a visit at 30 months (after 6 months of no treatment other than single-vision 
spectacles alone between 24 and 30 months). 
Investigational Drug 
Atropine 0.05% eyedrops 
Investigational Device 
Spectacle lenses with Highly Aspherical Lenslet Target (H.A.L.T.) MAX technology  
Treatment Groups 
Eligible participants will be randomly assigned 1:1:1:1 to four treatment groups for 24 months: 
 
• 
Daily low-concentration atropine (0.05%) eyedrops plus spectacles with single vision lenses 
(SVL) (hereafter ATROPINE group) 
• 
Daily placebo eyedrops plus spectacle lenses with Highly Aspherical Lenslet Target MAX 
technology (hereafter (H.A.L.T. MAX group) 
• 
Daily low-concentration atropine (0.05%) eyedrops plus spectacle lenses with H.A.L.T. MAX 
technology (hereafter COMBINED group)  
• 
Daily placebo eyedrops plus spectacles with single-vision lenses (SVL) (hereafter PLACEBO 
group) 
Objectives 
Primary 24-Month Timepoint Objectives (On Treatment) 
• 
To compare the effectiveness of ATROPINE versus PLACEBO and of H.A.L.T. MAX 
versus PLACEBO and of COMBINED versus PLACEBO for slowing myopia 
progression in axial length (AL) over a two-year treatment period in children aged 5 to less 
than 12 years with SER myopia of 0.75D to 6.00D and at least 0.75D myopia in both 
principal meridians of each eye at the time of enrollment.  
 
Secondary 24-Month Timepoint Objectives (On Treatment) 
• 
To compare the effectiveness of ATROPINE versus PLACEBO and of H.A.L.T. MAX  
versus PLACEBO and of COMBINED versus PLACEBO for slowing myopia 
progression in SER over a two-year treatment period in children aged 5 to less than 12 
years with SER myopia of 0.75D to 6.00D and at least 0.75D myopia in both principal 
meridians of each eye at the time of enrollment.  
 
Exploratory 24-Month Timepoint Objectives (On Treatment) 
• 
To compare the effectiveness of ATROPINE versus H.A.L.T. MAX and of ATROPINE 
versus COMBINED and of H.A.L.T. MAX versus COMBINED for slowing myopia 
progression in axial length (AL) over a two-year treatment period in children aged 5 to less 
than 12 years with SER myopia of 0.75D to 6.00D and at least 0.75D myopia in both 
principal meridians of each eye at the time of enrollment.  
• 
To compare the effectiveness of ATROPINE versus H.A.L.T. MAX and of ATROPINE 
versus COMBINED and of H.A.L.T. MAX versus COMBINED for slowing myopia 
progression in SER over a two-year treatment period in children aged 5 to less than 12 
years with SER myopia of 0.75D to 6.00D and at least 0.75D myopia in both principal 
meridians of each eye at the time of enrollment.  
 
Exploratory 30-Month Timepoint (Off-Treatment) Objectives  
• 
All analyses described for the 24-month primary timepoint above will be repeated as 
exploratory analyses at 30 months to evaluate the progression of myopia over 30 months 
(after 6 months of no treatment other than single-vision spectacles alone between 24 and 30 
months).   
 

JAEB CENTER FOR HEALTH RESEARCH 
 
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PARTICIPANT AREA 
DESCRIPTION 
Study Design 
Multicenter Phase III Randomized Clinical Trial 
Number of Sites 
18 to 40 
Endpoints 
Primary Efficacy Outcome (On-Treatment): 
Change in axial length from baseline to 24 months (on-treatment) as measured by a masked examiner 
using cycloplegic biometry.  
 
Key Secondary Efficacy Outcome (On-Treatment):  
Change in spherical equivalent refractive error (SER) from baseline to 24 months (on-treatment), as 
measured by a masked examiner using cycloplegic autorefraction. 
 
Exploratory Efficacy Outcomes (Off-Treatment): 
Change in axial length and SER from baseline to 30 months.  
 
Key Safety Outcomes: 
• 
Proportion of adverse events reported in each group. 
• 
Proportion of participants with loss of >2 logMAR lines in best-corrected distance visual 
acuity in either eye at any follow visit. 
Population 
Key Eligibility Criteria for Enrollment Into Run-in Phase:  
• 
Age 5 to <12 years at time of enrollment. Children within 4 weeks of their 12th birthday are not 
eligible. 
• 
Refractive error meeting the following by cycloplegic autorefraction: 
o 
Myopia of at least 0.75D in both principal meridians of each eye  
o 
Myopia 0.75D to 6.00D SER in both eyes 
o 
Astigmatism <2.50D in both eyes 
o 
SE Anisometropia <1.50D  
• 
Investigator has confirmed the following regarding best-corrected distance visual acuity (VA) in 
habitual spectacles or trial frames using the investigator’s preferred optotype VA testing method: 
o 
VA is age normal in both eyes 
o 
5-6 years: approximately 20/32 or better, ≤ 0.24 logMAR, ≥ 73 letters 
o 
7-<12 years: approximately 20/25 or better, ≤ 0.14 logMAR, ≥ 78 letters 
o 
Interocular difference ≤2 logMAR lines (0.2 logMAR) or ≤ 10 letters 
• 
Wearing single-vision spectacles ≥90% of waking hours ≥30 days before enrollment 
• 
Agree to refrain from wearing contact lenses for duration of the study 
• 
Willing to wear study spectacles full time (i.e., at least 10 hours per day) 
• 
No current or past pharmacologic agents or light therapy used for myopia treatment  
• 
No current or previous use of bifocals, progressive-addition lenses, multi-focal contact lenses, or 
focus- or contrast-modifying spectacle lenses including spectacle lenses with HAL or H.A.L.T. 
MAX technology  
• 
No current or previous use of orthokeratology, rigid gas permeable, or other contact lenses used 
to slow myopia progression 
• 
No known allergy to atropine  
• 
No known allergy to shellfish  
Sample Size 
87 participants per group (348 total).  
The maximum proportion of 10–<12-year-olds will be capped at 40% (140 children) and the maximum 
proportion of  participants who self-report as “East Asian or Southeast Asian” ethnicity will be capped 
at 20%. 
 
Phase 
Phase III Randomized Clinical Trial 
Participant Duration 
31 months 
Study Duration Planned 
(1st participant in to last out) 
46 months 

JAEB CENTER FOR HEALTH RESEARCH 
 
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PARTICIPANT AREA 
DESCRIPTION 
Protocol Overview/Synopsis 
Upon signing informed consent and assent (if needed), eligible children are considered enrolled into a 
2- to 4-week run-in phase designed to determine adherence with nightly eyedrops (artificial tears) and 
spectacle correction. If adherence criteria are met (≥90% of expected days with eyedrops 
administered), and the participant still meets eligibility criteria, they will be randomized to 1 of 4 
treatments described above (ATROPINE, H.A.L.T. MAX, PLACEBO, or COMBINED groups) for 24 
months.  
 
Four weeks after randomization, each participant will return for a Treatment Initiation Visit to be fitted 
with a new pair of spectacles and receive study eyedrops. Four weeks after initiating randomized 
treatment, sites will contact the parent to check for treatment problems and to encourage adherence 
with the prescribed treatment. Study visits will occur at 6, 12, 18, and 24 months (on-treatment primary 
outcome), and 30 months (off-treatment outcome) from randomization. Study glasses will be changed 
every 6 months and dispensed at glasses fitting visits occurring four weeks after every follow up visit 
except the 30-month final study visit. After the Treatment Initiation Visit, Eyedrops will be dispensed 
at each 6-, 12-, and 18-month office visits. 
 
 

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STUDY SUMMARY FLOW CHART 
 
ENROLLMENT INTO RUN-IN PHASE 
Major Eligibility Criteria at Enrollment for Run-in Phase  
• Age 5 to <12 years of age at enrollment. Children within 4 weeks of their 12th birthday are not eligible. 
• Refractive error meeting the following by cycloplegic autorefraction:  
•
Myopia of 0.75D to 6.00D SER and at least 0.75D in both principal meridians of each eye 
•
Astigmatism <2.50D in both eyes  
•
Anisometropia <1.50D SE  
•
Wearing single-vision spectacles ≥90% of waking hours ≥30 days duration before enrollment. (Exception exists for subjects with 
broken or lost spectacles. Details in section 2.3.) 
• Investigator has confirmed the following regarding best-corrected distance visual acuity (VA) in habitual spectacles or trial frames using 
the investigator’s preferred optotype VA testing method: 
o
VA is age normal in both eyes (ref)  
o
5-6 years: approximately 20/32 or better, ≤ 0.24 logMAR, ≥ 73 letters 
o
7-<12 years: approximately 20/25 or better, ≤ 0.14 logMAR, ≥ 78 letters 
o
Interocular difference ≤2 logMAR lines (0.2 logMAR) or ≤ 10 letters 
• Willing to wear study spectacles for at least 10 hours per day,6 days per week 
• No current or past pharmacologic agents or light therapy used for myopia treatment 
• No current or previous use of bifocal spectacles, progressive-addition lenses, defocus or contrast modifying spectacle lenses, or multi-
focal contact lenses including HAL or spectacle lenses with H.A.L.T. MAX technology  
• No current or previous use of orthokeratology, rigid gas permeable, or other contact lenses being used to slow myopia progression  
• Agree to refrain from wearing contact lenses for duration of the study 
• No known atropine allergy 
• No known allergy to shellfish  
• No strabismus other than a phoria  
 
Enrollment Exam Procedures  
• Cycloplegic Autorefraction  
• Cycloplegic Axial Length Measurement 
• Spectacle Prescription Determination with Cycloplegia (using investigators usual method) to prescribe new spectacles if necessary 
(broken, lost, or not meeting tolerances) 
• Prescribe artificial tear eyedrops to be used one drop to each eye until run-in follow up/randomization visit in 2-4 weeks 
RUN-IN PHASE (2-4 WEEKS) 
• Run in phase starts the day after enrollment for all participants.  
• All participants are treated with nightly artificial tear eyedrops  
• Habitual spectacles are continued until the Randomization Visit or until new spectacles are obtained, if prescribed  
RANDOMIZATION VISIT (2-4 WEEKS AFTER ENROLLMENT) 
 
Assessed in new spectacles if prescribed at enrollment; otherwise, habitual spectacles. Trial frames if spectacles out of tolerances. 
 
Additional Eligibility Criteria for Randomization  
Best-corrected distance visual acuity (VA) meeting the following: 
o
VA is age normal in both eyes  
o
5-6 years: approximately 20/32 or better by ATS-HOTV  
o
7-12 years: approximately 20/25 or better, ≤ 0.14 logMAR, ≥ 78 letters using E-ETDRS 
o Interocular difference ≤2 logMAR lines (0.2 logMAR) or ≤ 10 letters 
•
Current spectacles meet refractive error tolerances 
•
At least 90% adherent with artificial tear eyedrop installation  
 
Testing Procedures  
•
Distance Visual Acuity Testing (ATS-HOTV for children <7 years old; E-ETDRS for children ≥7 years old) 
•
Binocular Near Visual Acuity  
•
Monocular Amplitude of Accommodation (Right Eye Only) 
•
Automated pupillometry (for sites with equipment deemed study qualified) 
•
Urine Pregnancy Test (for participants who have experienced menarche (i.e., at least one menstrual cycle) 
 

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STUDY SPECTACLES FITTING VISIT 
4 Weeks After Randomization and Clinical Follow Up Exams  
If 4 weeks after 6 or 12 months 
WHILE ON TREATMENT, CLINICAL FOLLOW-UP VISITS AT 6, 12, 18, AND 24 
MONTHS AFTER RANDOMIZATION); PHONE CONTACTS FROM SITE AT 8 WEEKS 
AND, 3, 9, 15, AND 21 MONTHS AFTER RANDOMIZATION 
(assessed in study spectacles) 
 
•
Medical History  
•
Adherence assessment 
•
Urine pregnancy test (if participant has experienced menarche (at least one menstrual cycle) 
•
Treatment Impact Questionnaire (child and parent 6 and 24 month only) 
•
Automated pupillometry  
•
Distance Visual Acuity Testing in study spectacles 
•
Binocular Near Visual Acuity in study spectacles 
•
Monocular Amplitude of Accommodation (Right Eye Only) 
•
Cycloplegic Autorefraction 
•
Spectacle Prescription Determination with cycloplegia (using investigators usual method)  
•
Axial Length with cycloplegia 
•
Spectacle Prescription Determination  
H.A.L.T. MAX Group 
H.A.L.T. MAX spectacles 
+ nightly placebo eyedrop 
ATROPINE Group 
SVL spectacles + nightly 
atropine 0.05% eye drops 
COMBINED Group 
H.A.L.T. MAX spectacles + nightly 
atropine 0.05% eyedrops  
PLACEBO Group 
SVL spectacles + nightly 
placebo eyedrops 
IF NOT ELIGIBLE: 
withdraw participant 
from study 
IF ELIGIBLE: 
RANDOMIZE 1:1:1:1 
4-Week Treatment Initiation Visit  
•
To fit/dispense study spectacles and study medication 
If 4 weeks after 18 months 
27-Month Phone Contact 
24-MONTH VISIT (AFTER RANDOMIZATION)- DISCONTINUE TREATMENT 
• At the 24-month visit, study eyedrops and H.A.L.T. MAX study lenses will be discontinued for all treatment groups. All 
participants will be prescribed single vision lenses (SVLs only until the 30-month visit.  
• No myopia treatment other than optical correction with SVLs should be prescribed prior to the 30-month visit.  
30-MONTH VISIT AFTER RANDOMIZATION (OFF TREATMENT) 
 
• Medical History  
• Distance Visual Acuity Testing in habitual correction 
• Binocular Near Visual Acuity in habitual correction 
• Monocular Amplitude of Accommodation Right Eye Only 
• Cycloplegic Autorefraction  
• Axial Length Measurement with cycloplegia 
Study Spectacles 
Fitting Visit 
4 Weeks After 
 24-month Visit  

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SCHEDULE OF STUDY CALLS, VISITS, AND PROCEDURES 
Enrollment 
Visit 
Random- 
ization 
Visit 
4-Week 
Treatment 
Initiation  
Visit 
6- 
Month 
Clinical 
Visit 
12- 
Month 
Clinical 
Visit 
18- 
Month 
Clinical 
Visit 
24- 
Month 
Clinical 
Visit 
30- 
Month 
Clinical 
Visit 
Spectacle 
Fittings 
After Each 
Clinical Visit1 
 
 
Phone  
Calls2 
Consent/assent (Enrollment) 
I 
  
 
  
  
  
  
  
 
 
Medical history  
I 
 
I 
I 
I 
I 
I 
 
 
Adverse events 
 
 
 
I3 
I3 
I3 
I3 
I 
 
CT or CO 
Demographics  
CO, CT or I 
 
 
 
Urine pregnancy test4 
CO, CT or I 
 
CO, CT or I3 
CO, CT or I3 
CO, CT or I3 
CO, CT or I3 
 
 
Treatment Impact Questionnaire (parent and child 
versions) 
 
 
 
CO, CT or I 
 
 
CO, CT or I 
 
 
 
Lensometry  
CO, CT or I 
SF 
CT 
CT 
CT 
CT 
CT or I 
SF 
 
Automated pupillometry 
CT or I 
 
CT 
CT 
CT 
CT 
CT or I 
 
 
Monocular distance visual acuity 
CT or I 
 
CT 
CT 
CT 
CT 
CT or I 
 
 
Binocular near visual acuity 
CT or I 
 
CT 
CT 
CT 
CT 
CT or I 
 
 
Monocular amplitude of accommodation  
CT or I 
 
CT 
CT 
CT 
CT 
CT or I 
 
 
Dilating eye drop instillation5  
CO, CT or I 
 
CO or CT 
CO or CT 
CO or CT 
CO or CT 
CO, CT or I 
 
 
Cycloplegic autorefraction5  
CT, BT or I 
 
BT or I 
BT or I 
BT or I 
BT or I 
CT, BT or I 
 
 
Axial length and additional biometry with 
cycloplegia5  
CT, BT or I 
 
BT or I 
BT or I 
BT or I 
BT or I 
CT, BT or I 
 
 
Refractive error determination with cycloplegia 
I 
  
 
I 
I 
I 
I 
I 
 
 
Initiate run-in phase6  
I 
 
 
 
 
 
 
 
 
 
Assess eligibility / randomize participant  
 
I 
 
 
 
 
 
 
 
 
Dispense study spectacles 
 
 
SF 
 
 
 
 
 
SF 
 
Dispense study medication  
 
 
CT or CO 
CT or CO 
CT or CO 
CT or CO 
 
 
 
 
Collect unused study medication and empty bottles 
 
 
 
CT or CO 
CT or CO 
CT or CO 
CT or CO 
 
 
 
Collect study spectacles (when new spectacles fitted)7 
 
 
 
 
 
 
 
 
CT, CO, or SF 
 
Review treatment and encourage adherence  
 
 
 
 
 
 
 
 
 
CT or CO 
There is a minimum of two study personnel required to conduct this study; roles may also be split into additional personnel. Backup personnel are encouraged.  
1) Investigator/Biometry Tester  
2) Coordinator/Certified Tester/Spectacles Fitter 
I = Investigator (MD, DO, or OD). For all post-randomization visits, the Investigator may not see the participant before dilating eyedrops are administered, unless the participant is wearing stereo spectacles (to 
prevent observation of pupils before dilating eyedrops are administered). After dilating eyedrops have been administered, the Investigator may see the participant without the participant wearing stereo 
spectacles. The Investigator may also serve as Biometry Tester, but may not serve as Coordinator, Certified Tester, or Spectacles Fitter. CT = Certified Tester. The CT may be the Coordinator, Spectacles 
Fitter, or other person also trained and certified in study procedures. The Certified Tester may not be the Biometry Tester or the Investigator. BT = Biometry Tester. The BT is trained and certified in 
autorefraction and biometry. For all post-randomization visits, autorefraction and biometry must be performed by either the Investigator or a Biometry Tester. The BT will only see the participant after dilating 
eyedrops have been administered. The Investigator may serve as BT, but the BT may not be the Coordinator, Certified Tester, or Spectacles Fitter. CO = Coordinator. The Coordinator may also serve as 
Certified Tester and/or Spectacles Fitter, but not as Biometry Tester or Investigator. SF = Spectacles Fitter. The study Spectacles Fitter will be trained and certified to fit, dispense, and repair study spectacles. 
The Spectacles Fitter may be the Coordinator, Certified Tester, or another person trained to handle study spectacles. The Spectacles Fitter is unmasked to type of spectacles and may not be the Biometry Tester 
or the Investigator.  
1There will be a spectacle dispensing visit 4 ±2 weeks after each semi-annual clinical research visit conducted by the Coordinator or Certified Tester and Spectacles Fitter.  
2Phone calls will occur at 8 weeks and at, 3, 9, 15, 21, and 27 months to review treatment, manage any problems encountered and encourage compliance.  
3Participant should wear stereo spectacles to prevent Investigator from observing pupils.  
4For all participants who have experienced menarche.  
5Testing is repeated at randomization only if >28 days since enrollment (consent/assent).  
6At the end of the Enrollment Visit, the participant will begin nightly artificial tears for 2 to 4 weeks.  
7The SVL spectacles prescribed at 24 months may be kept by participants after the study ends. 
 

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Chapter 1: 
Background Information 
1 
 
2 
1.1 
Epidemiology and Clinical Characteristics 
3 
Myopia is one of the most commonly occurring ocular disorders, with an estimated prevalence in 
4 
children of 1.2% to 59.1%,1-3 in population-based studies conducted worldwide with variation 
5 
attributed to age, race, and definition of myopia. In children 6-72 months of age in the US, 
6 
population-based prevalence has been reported at 0.7-1.2% in non-Hispanic white children,4, 5 
7 
3.98% in Asian children,5 5.5-6.6% in African American children,4, 6 and 3.7% in Hispanic 
8 
children.6 50% of children aged 11 to 13 years enrolled in a large health plan in California who had 
9 
eye examinations with refraction were found to have myopia7 Longitudinal studies demonstrate a 
10 
relatively high and increasing prevalence of myopia in adults.8-10 In a study of white children and 
11 
black children between 12 and 17 years of age, the US prevalence of myopia increased from 24% in 
12 
1971-1972 to 34% in 1999-2004.6  
13 
 
14 
Progression of myopia primarily occurs due to axial elongation of the eye. In a 2023 Cochrane 
15 
review11 of interventions for myopia control in children living mainly in China or other Asian 
16 
countries (61% of studies) and North America (20% of studies), the meta-analyses of control 
17 
populations estimated the median progression of myopia to be -0.65D over 1 year (36 studies; 2846 
18 
participants analyzed) and −1.02D over 2 years (24 studies; 2282 participants). Retarding 
19 
progression of myopia has been the focus of much research,11 given high levels of myopia are 
20 
associated with retinal and vitreous detachment, myopic macular degeneration, and increased risk of 
21 
glaucoma and cataract.12, 13  
22 
 
23 
A report for the US population in 2014 estimated the prevalence of high myopia and myopic 
24 
choroidal neovascularization to be 3.92% (95% confidence interval [CI], 2.82-5.60) and 0.017% 
25 
(95% CI, 0.010-0.030), respectively, among adults in the United States aged 18 years and older.14 
26 
This translated into a population burden of approximately 9.6 million adults with high myopia and 
27 
approximately 41,000 adults with myopic choroidal neovascularization. 
28 
 
29 
1.2 
Treatments to Slow Myopia Progression 
30 
Treatments to slow myopia progression could be important for preventing the development of high 
31 
myopia and associated sequelae although not yet demonstrated to be effective in long-term studies. 
32 
Various management approaches have been reported to decrease the rate of myopic progression in 
33 
children, with varying success, including the use of anti-muscarinic pharmacological agents (e.g., 
34 
atropine, pirenzepine, cyclopentolate), bifocals, progressive additional lenses, specially designed 
35 
spectacle lenses such as spectacle lenses with highly aspherical lenses and Highly Aspherical 
36 
Lenslet Target (H.A.L.T.) MAX technology, contact lenses, contact lenses with peripheral myopic 
37 
defocus, under-correction or part-time optical correction, and orthokeratology.11, 15  
38 
 
39 
The Cochrane review11 primarily compared pharmacological and optical treatments, finding that 
40 
these interventions may slow myopia and reduce axial elongation over one year. However, results 
41 
were heterogeneous, with some treatments seeming to be less effective in year two compared to 
42 
year one.  
43 
 
44 
1.2.1 Atropine Treatment 
45 
The mechanism by which atropine slows myopia progression is believed to be unrelated to 
46 
accommodation but is otherwise largely unknown. Atropine has been hypothesized to modify eye 
47 
growth regulatory pathways and reduce axial elongation through several mechanisms including 
48 
locally at the retinal level (potentially through dopamine channels), at the choroidal level 
49 
(potentially through increasing its thickness), or through other mechanisms including nitric oxide 
50 

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and gamma-aminobutyric acid (GABA); however, such conclusions on causal relationships between 
51 
these effects and atropine are mixed.11, 16 
52 
 
53 
1.2.1.1 Low-Concentration Atropine Eye Drops in Non-Asian Populations 
54 
Four studies of 0.01% and 0.02% atropine eye drops have been conducted in largely non-Asian 
55 
populations in North America, Europe and Australia: 
56 
 
 
57 
• The Pediatric Eye Disease Investigator Group (PEDIG) randomized trial in the U.S. 
58 
compared 0.01% atropine to placebo17 and found no difference in mean (SD) change in SER 
59 
over 24 months. At the 24-month primary outcome visit, the adjusted mean (95% CI) 
60 
change in SER from baseline was −0.82D (−0.96 to −0.68) and −0.80D (−0.98 to −0.62) in 
61 
the atropine and placebo groups, respectively (adjusted difference = −0.02D; 95% CI, −0.19 
62 
to +0.15D; P = 0.83). 
63 
• The Western Australian Atropine for the Treatment of Myopia (WA-ATOM) 2-year 
64 
randomized trial 18 found myopia progression of -0.64D with 0.01% atropine compared with 
65 
-0.78D with placebo (adjusted mean difference over 2 years = 0.14D; 95% CI: -0.03 to 
66 
+0.29D). 
67 
• The Childhood Atropine for Myopia Progression (CHAMP) randomized clinical trial19 
68 
conducted at sites across North America and Europe found 0.02% atropine (primary 
69 
outcome comparison) was not effective for slowing mean SER progression compared with 
70 
placebo (least squares mean difference, 0.10D; 95% CI, −0.02 to 0.22 D; P = .10) at 36 
71 
months , whereas efficacy was suggested for 0.01% (secondary outcome comparison) 
72 
compared with placebo (least squares mean difference, 0.24D; 95% CI, 0.11 to 0.37D; P < 
73 
.001). 
74 
• The Myopia Outcome Study of Atropine in Children (MOSAIC)20 conducted in Ireland 
75 
found SER change over 24 months was not significantly different between 0.01% atropine 
76 
and placebo groups (-0.53D in the 0.01% atropine and -0.63D in the placebo group; adjusted 
77 
difference in SER effect = 0.12 D, p = 0.07).  
78 
 
79 
Given the lack of evidence supporting efficacy of the 0.01% and 0.02% atropine eyedrops in 
80 
slowing myopia progression in the United States, there is a need to evaluate stronger atropine 
81 
concentrations to determine whether a meaningful treatment effect can be found without 
82 
unreasonable side effects.  
83 
 
84 
Loughman et al21 (MOSAIC2) evaluated the effectiveness of 0.05% atropine in a mostly non-Asian 
85 
population, in a 1-year extension of their original two-year randomized trial22: participants 
86 
originally randomized to two years of placebo eyedrops were given 0.05% atropine eyedrops  for 
87 
the third year (n=61) and participants initially randomized to 0.01% atropine for two years were re-
88 
randomized to placebo or tapering of 0.01% for the third year. Over the third year, those using 
89 
0.05% atropine showed 0.13D less myopia progression and 0.06mm less axial elongation, compared 
90 
with the placebo/tapering group, suggesting a possible effect of 0.05% atropine in this group. 
91 
 
92 
There are currently no published randomized trials using 0.05% in largely non-Asian populations. 
93 
However, as of August 2024, there are two such randomized trials registered on ClinicalTrials.gov 
94 
indicating active recruitment, one based in the Netherlands comparing 0.05% and 0.50% atropine 
95 
concentrations (NCT05667454) and the other in France, comparing defocus incorporated multiple 
96 
segments (DIMS) lenses, 0.05% atropine and single vision lenses (NCT05062031).  
97 
 
98 

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1.2.1.2 Low-Concentration Atropine Eye Drops in Asian Populations  
99 
The earliest randomized trials of low-concentration atropine for slowing myopia progression were 
100 
conducted in Asian populations.  
101 
 
102 
• In 1999, Shih and colleagues22 reported outcomes on 186 children (of 200 randomized) aged 
103 
6 to 13 years with myopia ranging from -0.50D to -6.75D that compared 0.5%, 0.25%, and 
104 
0.1% atropine to 0.5% tropicamide. Children received atropine or tropicamide eyedrops 
105 
nightly for up to 2 years. All three atropine-treatment groups had less 2-year myopia 
106 
progression (-0.04±0.63 D/year, -0.45±0.55D/year, and -0.47± 0.91D/year, respectively) 
107 
than the tropicamide group (-1.06±0.61D/year).  
108 
• Subsequently, Shih and colleagues23 studied the effect of multi-focal spectacles with and 
109 
without atropine to control progression of myopia. The study randomized 227 children to 18 
110 
months of 0.5% atropine + multifocal lenses, multi-focal lenses alone, or single vision 
111 
spectacles. Myopia progressed only -0.42D±0.07D with atropine + multi-focal lenses 
112 
compared with -1.19D±0.07D with multi-focal lenses alone and -1.40D±0.09D with single 
113 
vision lenses, leading the authors to conclude that atropine treatment is effective for slowing 
114 
the progression of myopia and may act via a mechanism of accommodation inhibition.  
115 
• The ATOM2 study24 randomized 400 children (2:2:1) with myopia of at least -2.00D to 3 
116 
different concentrations of atropine (0.5%, 0.1% and 0.01%) and found 2-year myopia 
117 
progression of -0.30±0.60D, -0.38±60D, and -0.49±0.63D respectively. Although there was 
118 
no control group, myopia progression was significantly lower than that observed in controls 
119 
in ATOM125 (-1.20D±0.69D). Axial length growth was lower in both 0.5% and 0.1% groups 
120 
compared with the 0.01% group (0.27 ± 0.25mm, 0.28 ±0.27mm, and 0.41±0.32mm 
121 
respectively, P<0.001).  
122 
 
123 
Two recent randomized trials26-28 provide data on 0.05% atropine eye drops for slowing myopia 
124 
progression in Asian populations.  
125 
 
126 
The LAMP study27, 29 randomized 438 children aged 4-12 years with at least -1.00D of myopia to 
127 
0.05%, 0.025%, 0.01% atropine, or placebo eye drops For the 383 (87%) children completing the 
128 
12-month outcome,26 the mean change in spherical equivalent refractive error from baseline was -
129 
0.27D, -0.46D, -0.59D in the 0.05%, 0.025%, and 0.01% atropine groups respectively compared 
130 
with 0.81D in the placebo group (p <0.001); the mean change in axial length from baseline was 
131 
0.20mm, 0.29mm, 0.36mm in the 0.05%, 0.025%, and 0.01% atropine groups compared with 
132 
0.41mm in the placebo group (<0.001). 
133 
 
134 
For the 93 children completing 24 months (85% of 109 randomized) of treatment and follow up,27 
135 
the mean change in spherical equivalent refractive error from baseline was -0.55D, -0.85D, -1.12D 
136 
and in the 0.05%, 0.025%, and 0.01% atropine groups, respectively. (There were no placebo 
137 
controls after 12 months). The mean change in axial length from baseline was 0.39 mm, 0.50 mm, 
138 
0.59mm and in the 0.05%, 0.025%, and 0.01% atropine groups, respectively. 
139 
 
 
140 
Zhu et al28 enrolled 142 children aged 7-12 years with -1.00 D to -6.00 D of myopia and 
141 
randomized to 0.05% atropine or placebo eye drops. For the 72 children using 0.05% for 24 months, 
142 
the mean change in spherical equivalent refractive error was  
143 
-0.46±0.30D vs -1.72±1.12D in children using placebo (n=70), for a mean difference of 1.26±0.08D 
144 
(95% CI 1.10 to 1.42 D calculated using reported standard error of ±0.08; P<0.001); mean change 
145 
in axial length was 0.26±0.30 mm in the 0.05% atropine group vs 0.76±0.62 mm with placebo, for a 
146 
mean difference of 0.05±0.04 mm (95% CI 0.42 to 0.58 D calculated using reported standard error 
147 
of ±0.04; P=0.002).  
148 

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149 
Four additional ongoing randomized trials of 0.05% atropine (versus either spectacle lenses with 
150 
HAL, Defocus Incorporated Multiple Segments (DIMS) spectacle lenses, 0.01% atropine or 0.025% 
151 
atropine) in Asian populations are on ClinicalTrials.gov (NCT06344429, NCT06282848, 
152 
NCT02130167, NCT05597163).  
153 
 
 
154 
1.2.1.3 Higher Atropine Concentrations (>0.05%) 
155 
Higher concentrations of atropine (>0.05%) have been studied and appear to be more effective at 
156 
reducing myopia progression,11 but are associated with significant side effects11 and, therefore, were 
157 
not further considered for this study.  
158 
 
159 
1.2.2 Spectacles Lenses with Highly Aspherical Lenslets (HAL) 
160 
The utilization of optical defocus technology for slowing myopia progression has gained 
161 
momentum in recent years.  
162 
 
163 
One example utilizing defocus technology is spectacle lenses with Highly Aspherical Lenslets 
164 
(HAL), which comprise a single vision zone and a Highly Aspherical Lenslet Target (H.A.L.T.) 
165 
technology zone to slow myopia progression. The single vision zone is the area of the lens without 
166 
lenslets and provides correction of any refractive error in all gaze directions. H.A.L.T. technology 
167 
consists of 1021 contiguous highly aspherical lenslets spread over 11 rings. The light rays passing 
168 
through the lenslets create a volume of myopic defocus in front of the retina, which follows the 
169 
shape of a child’s theoretical myopic retina.30 The prescription (Rx) surfacing is made on the back 
170 
surface of the lens to obtain the appropriate prescription (to correct myopia and astigmatism). The 
171 
lenslets are placed on the front surface of the lens and are nearly invisible. A schematic of the uncut 
172 
lens is outlined below in Figure 1. 
173 
 
174 
Figure 1 - Schematic describing a spectacle lens with Highly Aspherical Lenslets (HAL) 
175 
   
176 
 
177 
 
178 
 
179 
1.2.2.1 Spectacle Lenses with HAL: Mechanism of Action  
180 
Studies in various animal species have shown that hyperopic defocus in the central part of the retina 
181 
stimulates eye elongation.31-33 Additionally, research indicates that relative peripheral hyperopia can 
182 
promote the development of central axial myopia in primates, even when clear central retinal 
183 

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images are present.32, 33 These findings highlight the critical role of the peripheral retina in 
184 
regulating eye growth. 
185 
 
186 
Further animal studies have demonstrated that when exposed to competing defocus (simultaneous 
187 
myopic and hyperopic defocus), the emmetropization process is more influenced by myopic defocus 
188 
than hyperopic defocus, protecting the eye against elongation.32, 34 Two other studies investigated in 
189 
animals the effects of aspherical lenses with a power gradient on emmetropization.35, 36 Unlike 
190 
competing defocus lenses, which focus light on two distinct surfaces, these aspherical lenses 
191 
redirect light rays continuously in a nonlinear manner, creating a three-dimensional quantity of light 
192 
in front of the retina known as the volume of myopic defocus. Greater asphericity, corresponding to 
193 
a larger volume of myopic defocus, has been shown to reduce lens-induced myopia in chicks.35, 36 
194 
 
195 
Based on these findings: 
196 
• 
The light rays passing through the single vision zone of the lens focuses light on the 
197 
retina to ensure the correction of refractive error in all gaze directions 
198 
• 
The light rays passing through the highly aspherical lenslets create a volume of myopic 
199 
defocus in front of the retina. Within a single ring lenslets are of the same geometry, but 
200 
lenslets from each ring have different geometries. The aspherical geometry of the lenslets 
201 
does not focus light at a single point but instead distributes it across a range in front of 
202 
the retina (volume of myopic defocus). As the geometry of the lenslets from each ring 
203 
has been computed so that the created volume is equidistant from a theoretical myopic 
204 
retina at any eccentricity.30 The volume of myopic defocus created by the lenslets 
205 
provides the slowing of myopia progression signal.  
206 
 
207 
The following schematic (Figure 2) describes how light rays penetrating through a spectacle lens 
208 
with HAL split into two different signals. Light rays passing through the single vision zone (blue) 
209 
are focused on the retina to provide sharp vision and corresponds to the correction signal. Light rays 
210 
passing through all the highly aspherical lenslets create a volume of myopic defocus in front of the 
211 
retina and following its shape (white), which corresponds to the myopia progression control signal. 
212 
 
213 
Figure 2 – Optical design of spectacle lenses with highly aspherical lenslets showing (i) light 
214 
rays passing through the single-vision zone focused on the retina; and (ii) light rays passing 
215 
through the aspherical lenslets creating a volume of myopic defocus in front of the retina. 
216 
 
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1.2.2.2 Spectacle Lenses with HAL Clinical Trial Data 
218 
Several randomized clinical trials conducted across multiple countries have demonstrated that 
219 
spectacle lenses with HAL slow myopia progression compared with single-vision lenses.37-39 
220 
 
221 
Two of these randomized trials are discussed in more detail below.  
222 
a) Spectacle lenses with HAL were initially evaluated in a double-masked, three-group, 
223 
parallel, randomized, single-center clinical trial initiated in 2018 in Wenzhou, China.37, 40 
224 
170 children aged 8-13 years with a cycloplegic spherical equivalent refraction of -0.75 D to 
225 
-4.75 D and astigmatism with less than -1.50 D were recruited and randomly assigned to one 
226 
of three groups: spectacle lenses with HAL, spectacle lenses with slightly aspherical lenslets 
227 
(SAL), or single vision lenses (SVL). Follow-up visits occurred every six months to assess 
228 
outcomes. Of 157 participants who completed each visit, 54 were analyzed in the HAL 
229 
group, 53 in the SAL group, and 50 in the SVL group. Results demonstrated that higher 
230 
lenslet asphericity led to higher myopia control efficacy, with spectacle lenses with HAL 
231 
proving more effective at slowing myopia progression than spectacle lenses with SAL.37, 40 
232 
After two years spectacle lenses with HAL slowed myopia progression by 0.80D (55%) and 
233 
axial elongation by 0.35mm (51%), on average, compared to single-vision spectacle lenses 
234 
(SVL).37 
235 
 
236 
Furthermore, when worn 12 hours per day every day, spectacle lenses with HAL slowed 
237 
myopia progression by 67% (0.99D), on average, and axial elongation by 60% (0.41mm), on 
238 
average, compared to single vision lenses over 2 years.37 After the first and second year, the 
239 
eye growth of 9 out of 10 children wearing spectacle lenses with HAL full time was found to 
240 
be similar or slower than non-myopic children.41 
241 
Following year two, participants were invited to continue wearing spectacle lenses with HAL 
242 
to assess the long-term impact on myopia progression, with data collected at years four, five, 
243 
and six. From the six-year follow-up, efficacy in controlling myopia progression with Essilor® 
244 
Stellest® lenses was sustained in participants aged up to 19 years of age (unpublished data on 
245 
file, Essilor Luxottica, 2025). 
246 
b) Spectacle lenses with HAL were more recently evaluated in a randomized, controlled clinical 
247 
trial conducted at nine clinical sites in the United States. The clinical trial enrolled 175 children 
248 
aged 6–12 years with a manifest spherical equivalent refraction ranging from −0.75 D to −4.50 
249 
D and astigmatism of no more than 1.50 D at baseline. Of those enrolled, 149 participants 
250 
(64% White; 20% Asian) were dispensed the trial lenses and included in the analysis 
251 
population, with 91% (135 participants) completing the full 2-year follow-up. Participants 
252 
were randomly assigned to wear either spectacle lenses with HAL or single vision spectacle 
253 
lenses. 
254 
After two years, children wearing spectacle lenses with HAL exhibited a mean change in cycloplegic 
255 
spherical equivalent refraction of −0.25 D compared with −0.90 D in the single-vision lens group, 
256 
corresponding to a 71% reduction in myopia progression. Mean axial elongation was 0.21 mm in the 
257 
HAL spectacle lens group compared with 0.45 mm in the single-vision group, representing a 53% 
258 
reduction in axial length growth over the 2-year period (unpublished data on file, Essilor Luxottica, 
259 
2025). 
260 
The U.S. Food and Drug Administration (FDA) evaluated the 2-year data from this clinical trial and 
261 
on September 25, 2025, the FDA authorized the marketing of spectacle lenses with HAL to both 
262 
correct myopia and slow myopia progression in children with non-diseased eyes, who, at the 
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initiation of treatment, are aged 6-12 years and have a spherical equivalent refraction of -0.75 D to - 
264 
4.50 D, and astigmatism up to 1.50 D.42 
265 
1.2.3 Spectacle Lenses with Highly Aspherical Lenslet Target (H.A.L.T.) MAX Technology  
266 
The development of spectacle lenses with H.A.L.T. MAX technology builds on key learnings from 
267 
the 2-year, double-masked randomized clinical trial in China,37, 40 described above, and the broader 
268 
scientific literature.32, 33  
269 
From the clinical trial: Children were randomly assigned to wear spectacle lenses with HAL, 
270 
spectacle lenses with SAL, or single vision lenses.37, 40 The primary differences between the 
271 
aspherical lens designs used in the clinical trial lie in the depth of volume of myopic defocus and 
272 
it’s position relative to the retina. Spectacle lenses with SAL produces a thinner volume of myopic 
273 
defocus located closer to the retina, whereas spectacle lenses with HAL generates a larger volume 
274 
of myopic defocus positioned further away from the retina. The clinical trial found that a dose 
275 
dependent relationship exists, with higher asphericity leading to greater efficacy in controlling 
276 
myopia progression.37, 40 
277 
 
278 
From the literature: The eye is expected to adjust its axial growth in response to optical defocus 
279 
created by positive lenses.32, 43 Based on this principle, the optical characteristics of spectacle lenses 
280 
with SAL and HAL lenses were analyzed and an opportunity to enhance lenslet design identified. By 
281 
increasing both the mean power and asphericity in H.A.L.T. MAX, the lenslets were optimized to 
282 
aim to improve the eye’s full adaptive response to optical defocus. 
283 
Therefore, the mean power and asphericity of each individual lenslet in spectacle lenses with 
284 
H.A.L.T. MAX technology has been increased compared to spectacle lenses with HAL.  
285 
Figure 3 – A single light beam passing through a lenslet with H.A.L.T. MAX technology 
286 
(right) produces a micro-element of myopic defocus with increased depth of volume, 
287 
positioned farther from the retina compared to the element formed by a HAL lens (left). 
288 
As a result, in spectacle lenses with H.A.L.T. MAX technology provide twice the depth volume of 
289 
non-focused light, positioned further from the retina compared to spectacle lenses with HAL. 
290 
 
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Figure 4: The depth of volume of myopic defocus is a) doubled and b) further from the retina 
292 
in spectacle lenses with H.A.L.T. MAX technology compared to spectacle lenses with HAL  
293 
 
294 
1.2.3.1 Spectacle Lenses with H.A.L.T. MAX Technology: Clinical Trial Data  
295 
A recent clinical trial involving 50 Singaporean children 6 to 10 years of age with myopia -0.50D to 
296 
-4.75D SER, evaluated whether the myopia control efficacy of spectacle lenses with H.A.L.T. MAX 
297 
technology was better in slowing down axial elongation over spectacle lenses with HAL.44  
298 
Participants were randomized to wear a spectacle lens with H.A.L.T. MAX technology in one eye 
299 
and a spectacle lens with HAL in the other and after six months, the lenses were switched for the 
300 
following six months.44  Results demonstrated spectacle lenses with H.A.L.T. MAX technology 
301 
significantly reduced axial elongation compared to spectacle lenses with HAL in both phases of the 
302 
clinical trial. 
303 
 
304 
In Phase 1, which was the first 6 months, the mean (standard error) change in axial length was 0.11 
305 
(0.02) mm in eyes wearing spectacle lenses with HAL and 0.04 (0.02) mm in eyes wearing 
306 
spectacle lenses with H.A.L.T. MAX technology (difference = -0.06 mm, 95% CI: -0.09 to -0.04 
307 
mm, P < 0.001).44  
308 
  
309 
In Phase 2, after 6 months, the mean (standard error) change in axial length was 0.12 (0.01) mm in 
310 
eyes wearing spectacle lenses with HAL and 0.08 (0.01) mm in eyes wearing spectacle lenses with 
311 
H.A.L.T. MAX technology (difference = -0.05, 95% CI: -0.07 to -0.03, P < 0.001).44   
312 
Combining results for each treatment from both phases across eyes, the difference in axial 
313 
elongation between eyes wearing spectacle lenses HAL and H.A.L.T. MAX technology was -0.05 
314 
mm (95% CI: -0.07 to -0.04, P < 0.001).44 
315 
 
316 
Results indicated that younger children (aged ≤8.5 years) and those with faster axial elongation may 
317 
particularly benefit in terms of slowing axial elongation.44   
318 
 
319 
Changes in SER suggested less myopic progression in eyes wearing spectacle lenses H.A.L.T. 
320 
MAX technology than with HAL but did not reach statistical significance. Of note, the study was 
321 
powered to detect a difference in axial length, but not in SER.  
322 
 
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1.2.4 Combined Atropine and Spectacle Lenses with HAL 
324 
Emerging data suggest an additive effect of low-concentration atropine and spectacle lenses with 
325 
HAL.45,46, 47  
326 
 
327 
A one-year non-randomized prospective study of combined spectacle lenses with HAL and atropine  
328 
included 50 Singaporean children (86% ethnic Chinese) 6-11 years old, with myopia of -1.50D to -
329 
6.00D and astigmatism <2.00D, who were being treated with atropine 0.01% or 0.025% for an 
330 
unspecified duration, and had ≥0.50 progression in at least one eye in the previous 6 months.46 
331 
Treatment with HAL lenses was initiated, and participants continued treatment with atropine 0.01% 
332 
or 0.025%. Mean change in SER and AL over one year was -0.15D (0.28) and 0.14mm (0.14) 
333 
compared with -0.60D (0.38) and 0.24mm (0.12) in the 6 months prior to the study. The conclusion 
334 
that combination therapy is more effective than atropine alone was not based upon a comparison 
335 
with children staying on the original treatment and thus should not be considered adequate evidence 
336 
of efficacy.    
337 
 
338 
An abstract by Vagge et al.45 reported outcomes from a retrospective study of Italian children aged 
339 
6 to 13 years (mean 9.2 years) with myopia (range not specified). Children were grouped according 
340 
to the treatment(s) used: HAL only (N=41), 0.01% atropine only (N=34), combined HAL and 
341 
0.01% atropine (N=33), and SVL “controls” (N=35). The three treatment groups each significantly 
342 
slowed SER myopia progression and AL elongation at 12 months compared with the SVL group 
343 
(p< 0.001). At 12 months, the combined HAL and atropine group significantly reduced SER 
344 
progression compared with the HAL-only group and the atropine group (p values < 0.03). The 
345 
combined HAL and atropine group showed reduced AL elongation compared with the 0.01% 
346 
atropine group (p value < 0.05) at 12 months, but showed no difference compared with the HAL 
347 
group (p=0.52). 
348 
 
349 
A recent retrospective study of 366 myopic children (366 eyes) conducted at the Eye Hospital of 
350 
Wenzhou Medical University stratified participants into six treatment groups: orthokeratology (n = 
351 
52), orthokeratology + atropine (n = 50), spectacle lenses with HAL (n = 83), spectacle lenses with 
352 
HAL + atropine (n = 69), single-vision spectacles (n = 65), and single-vision spectacles + atropine 
353 
(n = 47). After one year, all active treatment groups showed significantly less axial elongation 
354 
compared with the single-vision spectacle group. The spectacle lenses with HAL + atropine 
355 
combination demonstrated the greatest reduction in axial elongation, with a statistically significant 
356 
difference compared with all other groups (P < 0.01).47 
357 
 
358 
To date, we are unaware of any studies evaluating the combined effect of any concentration of 
359 
topical atropine and spectacle lenses with H.A.L.T. MAX technology.  
360 
 
361 
1.3 
Rationale for the Present Study 
362 
Spectacle lenses with HAL recently received marketing authorization from the U.S. Food and Drug 
363 
Administration for slowing myopia progression in children. Shortly thereafter, information emerged 
364 
that spectacle lenses with H.A.L.T. MAX technology were developed and had shown compelling 
365 
initial data compared with spectacle lenses with HAL in an Asian population.44  Because further 
366 
study of spectacle lenses with H.A.L.T. MAX technology is needed, particularly in non-Asian 
367 
populations, spectacle lenses with H.A.L.T. MAX technology were chosen for the present study 
368 
rather than spectacle lenses with HAL.   
369 
  
370 
Randomized trials of 0.01% atropine have shown little to no clinically meaningful effect in the 
371 
US.17, 19 Thus, there is a need to evaluate stronger atropine concentrations, balancing the anticipated 
372 
increase in effectiveness due to greater potency with the possibility of increased side effects. For 
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this reason, a 0.05% concentration was chosen for the present study rather than a stronger 
374 
concentration.  
375 
 
376 
In addition, because there may be a greater benefit when using 0.05% atropine and spectacle lenses 
377 
with H.A.L.T. MAX technology simultaneously than either alone,45,46 the study includes a 
378 
combined treatment group of atropine 0.05% and spectacle lenses with H.A.L.T. MAX technology 
379 
to provide efficacy, safety, and tolerability data.    
380 
 
381 
1.4 
Public Health Importance 
382 
The increasing prevalence of myopia and the unresolved problem of myopia progression pose 
383 
significant healthcare concerns. Increasing axial length and high levels of myopia (>6.00D) are 
384 
associated with serious ocular co-morbidities, (including retinal detachment, myopic maculopathy, 
385 
glaucoma, and cataract), often resulting in visual impairment or even blindness.48 While children 
386 
with high myopia are at the greatest risk for these complications, both moderate and low myopes are 
387 
at increased risk relative to persons with emmetropia.49 Reduced myopic progression would allow 
388 
many individuals to retain the ability to function without correction for some activities of daily 
389 
living and not be constantly dependent on vision correction. But far more important to this research 
390 
is the recognition that many individuals progress to moderate myopia and, by doing so, are at 
391 
increased risk for myopic co-morbidities compared with emmetropic individuals. The objective of 
392 
slowing the progression of myopia is that the associated risks that come with higher myopia may be 
393 
reduced for a large population.  
394 
 
395 
Flitcroft has opined that it is important to slow progression even in the moderate range of -1.00 to -
396 
6.00D as those levels of myopia are also significantly associated with an increased risk of a range of 
397 
ocular pathologies from glaucoma to retinal detachment50 compared with emmetropia. Similarly, in 
398 
the Blue Mountains Eye Study, there was a greater prevalence of myopic maculopathy in 
399 
individuals with myopia -3.00 to -4.99D compared with those with emmetropia.51 Tideman et al.48 
400 
analyzed several population-based studies and found that visual impairment was increased in adults 
401 
with higher axial lengths and higher spherical myopia, for example myopia -6.00 or less had a 
402 
cumulative risk of vision impairment of 39% (SE 4.9%) at 75 years of age.      
403 
 
404 
Treatment for myopia progression has proven effective; however, no treatment prevents myopia 
405 
onset.11 Low-concentration atropine treatment and/or HAL MAX spectacle lenses may potentially 
406 
reduce the prevalence of high myopia and myopic progression among children with moderate 
407 
myopia, thereby possibly reducing the incidence of undesirable sequelae associated with myopia. 
408 
Additionally, Bullimore et al has suggested that slowing myopia by 1 diopter would reduce the 
409 
likelihood of a patient developing myopic maculopathy by 40%.52  
410 
 
411 
1.5 
Potential Risks and Benefits of Study Treatment 
412 
 
413 
1.5.1 Known Potential Risks of Atropine Eye Drops 
414 
Atropine use can be associated with photophobia, mydriasis, accommodative paralysis, allergic or 
415 
hypersensitivity reactions, superficial keratitis and reduced lacrimation. As summarized in the 
416 
Living Cochrane review,11 adverse events related to atropine are concentration dependent and 
417 
occurred with greater frequency in studies using high (≥0.5%) compared to moderate or low 
418 
(<0.1%) concentrations of atropine.  
419 
 
420 
In the Yam et al randomized trial27 (Asian population), photochromic spectacles for light sensitivity 
421 
were needed in 29 (31%) of 93 treated with 0.05% atropine over 1 year and 31 (33%) over 2 years. 
422 
Progressive lenses for near blur were needed in only 1 (1%) over 2 years. In the same study, allergic 
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conjunctivitis occurred in 2 (2%) of 93 over 1 year and 9 (10%) over 2 years. These rates were 
424 
comparable to those in children treated with 0.01% and 0.025% concentrations.  
425 
 
426 
In the MOSAIC2 extension study of a randomized trial21 of 66 (mostly non-Asian) participants 
427 
using one year of atropine 0.05% following two years of placebo treatment, blurred near vision was 
428 
reported in 10 (15%; 3 of 10 opted to use varifocal lenses) and photophobia was reported in 5 
429 
(7.6%; none opted to use photochromic lenses). Overall, the rate of adverse events was higher in 
430 
participants using 0.05% in the third year than in those using 0.01% atropine or placebo during that 
431 
time. 
432 
 
433 
Potential systemic side effects include dry skin and mouth, tachycardia, fever, flushing and 
434 
irritability. Of these specific systemic effects, none have been reported in studies of 0.05% and 
435 
lower atropine eyedrop concentrations17-21, 24, 27 other than one occurrence of tachycardia with 
436 
atropine 0.02% eyedrops.19   
437 
A rebound effect following cessation of atropine may occur, defined as the rate of progression of 
438 
myopia being faster than natural history would suggest following treatment cessation (the myopia 
439 
progression is simply delayed, not slowed). Per a recent review by Bullimore and Brennan,53 the 
440 
rebound effect was highest (≥0.14 mm) in red light therapy and atropine studies.  
441 
 
442 
The table below summarizes potential side effects of low dose use of atropine for myopia 
443 
progression.  
 
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Table 1: Summary of Side Effects Reported in Randomized Trials Evaluating Low Dose Atropine for Myopia Progression 
445 
Study 
Ethnicity 
Treatment 
Group 
N 
Blur/ 
Progressive  
lenses 
Skin 
 irritation 
Allergy 
Decreased  
VA 
Photophobia/ 
glare 
Photochromic 
lenses 
Other 
Repka17 
(PEDIG) 
Non-
Asian 
Atropine 0.01% 
125 
17 
NA 
10* 
6 
32 
 
0 
Eye irritation (90) 
Ocular discomfort (8) 
Visual impairment (6) 
Eye pain (5) 
Blepharitis (6) 
Meibomian gland dysfunction (3) 
Any systemic adverse event (28) 
Lee18 
(WA-ATOM) 
Non-
Asian 
Atropine 0.01% 
104 
1 
0 
2* 
0 
0 
 
0 
Sore/heavy feeling eye (2) 
Visual floaters (1) 
Adnexal foreign body (1) 
Migraine (1) 
Asthma attack (1) 
Zadnik19 
(CHAMP) 
Non-
Asian 
Atropine 0.01% 
164 
2 
0 
3* 
NA 
4 
 
NA 
Eye irritation (1) 
Mydriasis (2) 
Eyelid swelling (3) 
Elevated heart rate (0) 
Atropine 0.02% 
247 
4 
2 
11* 
NA 
11 
 
NA 
Eye irritation (2) 
Mydriasis (4) 
Eyelid swelling (1) 
Elevated heart rate (2) 
Loughman20 
(MOSAIC) 
Non-
Asian 
Atropine 0.01% 
167 
1 
2 
NA 
NA 
0 
NA 
Eye discomfort (3) 
Temporary mydriasis (1) 
Loughman21 
(MOSAIC2) 
(Non-randomized 
extension) 
Non-
Asian 
Atropine 0.05% 
66 
10 
0 
NA 
NA 
5 
0 
Mydriasis (1) 
Discomfort with drops (1) 
Yam27 
(LAMP) 
2-year outcome 
Asian 
Atropine 0.05% 
93 
1 
NA 
9* 
NA 
4 
31 
4 hospitalizations (reasons not 
specified) 
Atropine 0.025% 
86 
1 
NA 
10* 
NA 
3 
28 
6 hospitalizations 
(reasons not specified) 
Atropine 0.01% 
91 
2 
NA 
11* 
NA 
5 
31 
5 hospitalizations 
(reasons not specified) 
Chia24 
(ATOM2) 
Asian 
 
Atropine 0.01% 
71 
1 
0 
0 
11 
0 
NA 
Ocular irritation (1) 
Acute gastric pain (1) 
NA = not assessed or reported  
446 
*allergic conjunctivitis 
447 
 
448 
 
 
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1.5.2 Known Potential Risks of HAL Lens Wear 
450 
Review of available literature suggests there are little to no adverse events related to spectacle 
451 
lenses with HAL. Bao et al.37 reported no adverse events in a 2-year study of HAL lens wear  
452 
• A recent randomized trial of peripheral defocus spectacles conducted in India reported no 
453 
adverse events associated with spectacle lenses with HAL over 1 year.39  
454 
• In the manufacturer-sponsored multicenter randomized trial of spectacle lenses with HAL 
455 
(versus “control”) conducted in the USA,42 no adverse events were reported. Specific 
456 
symptoms noted were: blurred vision (9%; 7/74), headache (3%; 2/74), double vision (1%; 
457 
1/74) and halos (1%; 1/74), but all occurred at a similar frequency in the control group.42  
458 
• A retrospective study in European children54 reported minor visual difficulties (further 
459 
described as “non-specific visual disturbances”) in 8% (6 of 73), with most resolving within 
460 
a few days. 
461 
 
462 
Per a recent review by Bullimore and Brennan,53 mean annualized rebound with optical correction 
463 
was -0.01 ± 0.03 mm; however, data on rebound effect are not yet available in U.S. patients.   
464 
          
465 
Adaptation to the HAL lenses may take up to 1 week.42  During this time, study participants should 
466 
use caution doing things that could potentially injure them, like riding a bike or skateboard, 
467 
climbing walls, or playing sports.   
468 
 
469 
1.5.3 Known Potential Risks of H.A.L.T MAX Lens Wear 
470 
The potential risks related to spectacle lenses with H.A.L.T. MAX technology wear are expected to 
471 
be minimal. Nallour Raveendran et al reported no spectacle related adverse events in a 12-month 
472 
study of spectacle lenses with HAL and H.A.L.T. MAX technology wear with only 5 non-spectacle-
473 
related adverse events (such as the common cold) reported in both groups.44 
474 
     
475 
1.5.4 Known Potential Risks of Spectacle Lenses with H.A.L.T. MAX Technology plus 
476 
Atropine 
477 
Although more than one study has evaluated the combination of atropine with spectacle lenses with 
478 
HAL,45-47 only one prospective cohort study has reported adverse events and tolerability outcomes. 
479 
In that study, no child reported glare, near blur, or peripheral blur after initiation of combination 
480 
treatment.46 
481 
 
482 
1.6 
Known Potential Benefits 
483 
The potential benefit of 0.05% atropine, spectacle lenses with H.A.L.T. MAX technology or the two 
484 
combined is to slow myopia progression.  
485 
 
486 
1.7 
Risk Assessment 
487 
The Sponsor (Jaeb Center for Health Research) has determined that the protocol’s level of risk is 
488 
consistent with 45 CFR 46.405 and 21 CFR 50.52 ISO 14971:2016, which indicates research 
489 
involving greater than minimal risk but presenting the prospect of direct benefit to the individual 
490 
child participating in the research; the risk is justified by the anticipated benefits; the relation of the 
491 
anticipated benefit to the risk is at least as favorable to the participants as that presented by available 
492 
alternative approaches; and adequate provisions will be made for soliciting the assent of the 
493 
children and permission of their parents or guardians as instructed by the IRB.   
494 
 
495 
The use of atropine in this study will require an IND submission to the FDA. The use of spectacle 
496 
lenses with H.A.L.T. MAX technology in this study will follow the abbreviated requirements of 21 
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CFR 812.2(b) as a non-significant risk device as it is not (1) intended as an implant and presents a 
498 
potential for serious risk to the health, safety, or welfare of a subject; (2) purported or represented to 
499 
be for a use in supporting or sustaining human life and presents a potential for serious risk to the 
500 
health, safety, or welfare of a subject; (3) for a use of substantial importance in diagnosing, curing, 
501 
mitigating, or treating disease, or otherwise preventing impairment of human health and presents a 
502 
potential for serious risk to the health, safety, or welfare of a subject; or (4) otherwise presenting a 
503 
potential for serious risk to the health, safety, or welfare of a subject. 
504 
 
505 
1.8 
General Considerations 
506 
The study is being conducted in compliance with the policies described in the PEDIG network 
507 
policies document, the ethical principles in the Declaration of Helsinki,55 the protocol described 
508 
herein, and the standards of Good Clinical Practice (GCP).56 
509 
 
510 
When feasible, data will be directly entered in real-time in electronic case report forms that will be 
511 
considered the source data. 
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Chapter 2: 
Study Enrollment and Screening 
513 
 
514 
2.1 
Participant Recruitment and Enrollment 
515 
The study plans to enroll up to 500 participants into the Run-In Phase for whom informed consent 
516 
and assent will be obtained, such that approximately 348 participants will enter the Randomized 
517 
Trial Phase. The maximum proportion of 10–<12-year-olds randomized will be capped at 40% (140 
518 
children). This will ensure at least 60% of the cohort is aged 5–9 years. The maximum proportion of 
519 
participants randomized who self-report as “East Asian or Southeast Asian” ethnicity will be capped 
520 
at 20%.    
521 
 
522 
Study participants will be recruited from PEDIG clinical centers in the United States. All eligible 
523 
participants will be included regardless of gender, race, or ethnicity. There is no restriction on the 
524 
number of participants to be enrolled by each site. 
525 
 
526 
As the enrollment goal into the Randomized Trial Phase approaches 348 participants, sites will be 
527 
notified of the end date for recruitment into the Run-In Phase. Participants whose parents have 
528 
signed an informed consent form may be entered into the Run-in Phase until the end date, which 
529 
means the expected number of participants for the Randomized Trial Phase might be exceeded. 
530 
Enrollment into the Run-In Phase may be temporarily halted until it is determined how many 
531 
participants will enter the Randomized Trial Phase.  
532 
 
533 
2.2 
Informed Consent and Authorization Procedures 
534 
A child is considered for the study after undergoing a routine eye examination (i.e., as part of 
535 
standard of care) that identifies myopic refractive error appearing to meet the eligibility criteria. The 
536 
study will be discussed with the child’s parent(s) or guardian(s) (referred to subsequently as 
537 
parent(s)). Parent(s) who express an interest in the study will be given a copy of the informed 
538 
consent form to read. Written or electronic informed consent/assent must be obtained from a parent 
539 
and child (the JCHR IRB requires assent for children 7 years of age and older) prior to performing 
540 
any study-specific procedures that are not part of the child’s routine care. 
541 
 
542 
If a child turns 7 years of age after enrollment, then assent must be obtained before performing 
543 
additional study-specific procedures, including data collection for the study. If assent cannot be 
544 
obtained, then study procedures, including data collection, cannot continue and no data from the 
545 
turning of age date can be used for the study. 
546 
 
547 
If the participant and/or parent(s) are not fluent in written and spoken English, then the consent 
548 
and/or assent forms, as well as all other participant/parent-facing materials (e.g., dosing instructions, 
549 
questionnaires), must be translated into the language of fluency for the participant/parent(s). 
550 
Further, a qualified interpreter must be available for the consent process and for all subsequent 
551 
study-related interactions.  
552 
 
553 
A child is considered enrolled when the informed consent form and assent form (as applicable) have 
554 
been signed.  
555 
 
556 
2.3 
Participant Inclusion Criteria 
557 
Individuals must meet all the following inclusion criteria to be eligible: 
558 
 
559 

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1. Age 5 years to <12 years at time of enrollment. Children within 4 weeks of their 12th 
560 
birthday are not eligible. 
561 
2. Refractive error meeting the following by cycloplegic autorefraction: 
562 
o  Myopia of 0.75D to 6.00D SER and at least 0.75D in both principal meridians of 
563 
each eye 
564 
o Astigmatism <2.50D both eyes 
565 
o Anisometropia <1.50D SER 
566 
3. Investigator has confirmed the following regarding best-corrected distance visual acuity 
567 
(VA) in habitual spectacles or trial frames using the investigator’s preferred VA testing 
568 
method: 
569 
o VA is age normal in both eyes57, 58  
570 
o 5-6 years: approximately 20/32 or better, ≤ 0.24 logMAR, ≥ 73 letters 
571 
o 7-<12 years: approximately 20/25 or better, ≤ 0.14 logMAR, ≥ 78 letters 
572 
o Interocular difference ≤2 logMAR lines (0.2 logMAR) or ≤ 10 letters 
573 
4. Wearing spectacles by parent report ≥90% of waking hours ≥30 days duration before 
574 
enrollment. For children who meet all other inclusion criteria but whose single-vision 
575 
spectacles are broken or lost within the last 90 days, enrollment can proceed as long as the 
576 
child was wearing their single-vision spectacles ≥90% of waking hours ≥30 days before the 
577 
spectacles were broken or lost. 
578 
5. Gestational age ≥ 32 weeks. 
579 
6. Birth weight >1500 g. 
580 
7. Parent(s) and assenting child understand the study procedures and are willing to accept 
581 
randomization to atropine 0.05%, spectacle lenses with H.A.L.T. MAX technology, atropine 
582 
combined with spectacle lenses with H.A.L.T. MAX technology, or placebo (i.e., neither 
583 
active treatment). 
584 
8. Parent is willing to participate in a 2- to 4-week run-in phase using nightly artificial tear 
585 
eyedrops in both eyes. 
586 
9. Family can return in 2 to 4 weeks for possible randomization. 
587 
10. Child is willing to refrain from contact lenses for the duration of the study. 
588 
11. Parent has a phone (or access to a phone) and is willing to be contacted by the clinical site 
589 
staff. 
590 
12. Relocation outside of the area of an active PEDIG site within the next 32 months is not 
591 
anticipated. 
592 
 
593 
2.4 
Participant Exclusion Criteria 
594 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from study 
595 
participation: 
596 
 
597 
1. Current or previous pharmacologic or light therapy used for myopia treatment. 
598 
2. Current or prior contact lens wear more than 7 days in the past 12 months 
599 
3. Current or previous use of bifocals, progressive-addition lenses, multi-focal contact lenses, 
600 
or focus- or contrast-modifying spectacle lenses, including spectacle lenses with HAL or 
601 
H.A.L.T. MAX technology. 
602 
4. Current or previous use of orthokeratology, rigid gas permeable, or other contact lenses used 
603 
to slow myopia progression. 
604 
5. Current or previous myopia control treatment or other uses of atropine, pirenzepine or other 
605 
anti-muscarinic agents. 
606 
6. Known atropine allergy 
607 
7. Known allergy to shellfish  
608 

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8. Abnormality of the cornea, lens, central retina, iris, or ciliary body 
609 
9. Current constant or intermittent strabismus (phorias are acceptable) 
610 
10. Verified history of amblyopia or nystagmus. 
611 
11. Prior strabismus, intraocular, or refractive surgery 
612 
12. Down syndrome or cerebral palsy 
613 
13. Diseases known to affect accommodation, vergence, or ocular motility (e.g., multiple 
614 
sclerosis, Graves’ disease, myasthenia gravis, diabetes mellitus) 
615 
14. Any condition that, in the judgment of the investigator, could influence refractive error 
616 
development.  
617 
15. Existing conditions in the opinion of the investigator that may affect the long-term health of 
618 
the eye or require regular pharmacologic treatment that may adversely interact with study 
619 
medication (e.g., JIA, glaucoma, pre-diabetes). 
620 
16. Inability to comprehend and/or perform any study-related procedures. 
621 
17. Participants who are pregnant, lactating, or intending to become pregnant within the next 30 
622 
months. 
623 
a. A negative urine pregnancy test at randomization and the 6-, 12-, 18-, and 24-month 
624 
follow-up visits will be required for participants who have experienced menarche (at 
625 
least one menstrual cycle). 
626 
18. Immediate family member (spouse, biological or legal guardian, child, sibling, parent) who 
627 
is investigative site personnel directly affiliated with this study or who is an employee of the 
628 
Jaeb Center for Health Research. 
629 
19. Sibling of, or living in the same household as, another child who is concurrently enrolled in 
630 
the study. 
631 
 
632 
2.5 
Screening/Enrollment Procedures 
633 
After informed consent is obtained (and written or verbal assent, if applicable), a potential 
634 
participant will be evaluated for study eligibility by reviewing their medical history, along with data 
635 
collection and testing as specified below.  
636 
 
637 
2.5.1 Demographic & Historical Information 
638 
The following demographic and historical information will be collected: date of birth, sex, race, 
639 
ethnicity, current refractive correction, iris color (brown or not brown), parental history of myopia 
640 
(0, 1, or 2 parents), current medication use, history of and current medical conditions, and myopia 
641 
treatment history.  
642 
 
643 
2.6 
Testing at the Enrollment Visit 
644 
Refer to Chapter 5 herein and the MTS2 Site Manual of Procedures for a complete description of 
645 
testing procedures, performed in the following order. 
646 
 
647 
1. Drop Instillation for Testing Under Cycloplegia  
648 
• 2 drops of cyclopentolate 1% 5 minutes apart 
649 
2. Cycloplegic Autorefraction 
650 
• Taken 30 minutes ± 5 minutes after the second drop of 1% cyclopentolate is instilled 
651 
• Sphere and cylinder will be recorded in 0.125D increments. 
652 
3. Axial Length Measurement and Additional Biometry with Cycloplegia 
653 
• Axial length 
654 
• Flat corneal radius 
655 
4. Spectacle Prescription Determination with Cycloplegia (section 5.2.12) 
656 

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• A new spectacle prescription will be determined by cycloplegic refraction according to the 
657 
investigator’s usual method for all study participants. This may include retinoscopy, 
658 
autorefraction, and/or subjective refinement.  
659 
 
660 
2.7 
Run-In Phase Refractive Correction  
661 
To complete the run-in phase without a change in spectacles, the participant must be currently 
662 
wearing single vision spectacles that meet the following criteria:  
663 
 
664 
• Myopia (by spherical equivalent) in both spectacle lenses corrected to within ±1.00D of the 
665 
investigator’s cycloplegic measurement of refractive error. 
666 
• Cylinder power in both spectacle lenses within ±1.00D of the investigator’s cycloplegic 
667 
measurement of refractive error. 
668 
• Cylinder axis for both spectacle lenses within ±20 degrees of the axis found on the 
669 
investigator’s cycloplegic measurement of refractive error when cylinder power is ≥ 1.00D 
670 
or within ±30 degrees when the cylinder power is <1.00D. 
671 
 
672 
If the participant’s current refractive correction is within these tolerances, the participant will 
673 
continue wearing their current spectacles during the run-in phase until new study spectacles are 
674 
received after randomization. 
675 
 
676 
If the participant meets all eligibility criteria for the run-in phase (see sections 2.3 and 2.4) but their 
677 
current spectacle correction 1) is broken or lost or 2) does not meet the tolerances for refractive 
678 
correction above, then new spectacles will be prescribed (paid for by the study) using the method 
679 
described in section 2.7. These patients will start the run-in phase wearing their habitual correction 
680 
or no spectacles (if spectacles are lost or broken) but will wear the study run-in phase spectacles 
681 
once they are obtained prior to randomization. Participants who do not meet refractive error 
682 
eligibility criteria at enrollment may be brought back later for a subsequent chance to be enrolled. 
683 
 
684 
2.8 
Run-in Phase 
685 
All potential participants meeting study inclusion and exclusion criteria (sections 2.3 and 2.4) will 
686 
be enrolled in the run-in phase to further determine eligibility for the RCT by assessing adherence 
687 
with eyedrops.  
688 
 
689 
2.9 
Treatment in the Run-In Phase  
690 
Artificial tears will be dispensed, and families will be instructed to instill 1 drop in each eye nightly 
691 
for 2-4 weeks. Study personnel will demonstrate to the parent and participant how to instill a drop 
692 
in each eye before the participant leaves the office. Parents and participants will be told that 90% 
693 
adherence with artificial tears is required to be eligible for study randomization.  
694 
Participants will be instructed to wear their refractive correction full time (i.e., at least 10 hours per 
695 
day). Families will be asked to complete an adherence calendar indicating Yes/No for spectacle 
696 
wear and Yes/No for drop instillation each day. (The same calendar will be used to monitor 
697 
adherence during the study.) 
698 
 
699 
To promote and monitor adherence with artificial tears and with spectacles during the run-in phase: 
700 
 
701 
• A calendar log will be provided to the parent, and the participant or parent will record 
702 
whether the drop instillation was done each night in both eyes (yes/no) and whether the 
703 
spectacles were worn at least 10 hours per day (yes/no). 
704 

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• The parent and participant will be instructed to bring the calendar logs to the study 
705 
randomization visit when they return in 2-4 weeks. 
706 
• The coordinator or investigator will assess adherence with drop instillation based on the 
707 
calendar logs at the Randomization Visit. 
708 
• Note: If 90% eyedrop adherence is not verified, then the participant shall be withdrawn from 
709 
the study. 
710 
• Participants who do not meet these criteria for randomization (e.g., for adherence) cannot be 
711 
brought back later for a subsequent chance at randomization or enrollment.   
712 
 
713 
Participants will be scheduled for a return visit for potential randomization in 2-4 weeks.  
714 

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Chapter 3: 
Randomization 
715 
 
716 
The participant should return to reassess study eligibility for randomization within 2-4 weeks of the 
717 
Enrollment Visit and initiation of the run-in phase. If the participant cannot return for possible 
718 
randomization within 6 weeks of enrollment (consent/assent) into the run-in phase, the participant 
719 
will be withdrawn from the study.  
720 
 
721 
3.1 
Assessment of Adherence with Artificial Tears 
722 
Calendar logs will be reviewed to assess the level of adherence with the instillation of the artificial 
723 
tear eyedrops during the run-in phase.  
724 
 
725 
To be eligible for randomization, participants must have been at least 90% adherent with instilling 
726 
the drops in both eyes, defined as the number of days the drops were instilled in both eyes divided 
727 
by the total number of days since receiving the artificial tears determined by reviewing the 
728 
adherence calendar log for the run-in phase.  
729 
 
730 
Participants who are not able to 1) return the calendar log and 2) be at least 90% adherent with 
731 
eyedrop instillation will be withdrawn from the study. Extension of the run-in phase or re-
732 
enrollment in the run-in phase to potentially meet the eyedrop adherence criteria is not allowed.  
733 
 
734 
In addition, the parent (or participant) must demonstrate, to the investigator or study coordinator, 
735 
the ability to instill an eyedrop in both eyes before being considered for randomization. Participants 
736 
who cannot demonstrate successful eyedrop instillation (either by themselves or their parents) will 
737 
be withdrawn from the study before randomization.  
738 
 
739 
3.2 
Assessment of Adherence with Refractive Correction Wear 
740 
Adherence with refractive correction will be collected during the run-in phase (using the same 
741 
calendars that will be used throughout the study). However, adherence with glasses will not be used 
742 
to determine eligibility for randomization because 1) adherence with glasses wear is an inclusion 
743 
criterion that must be for at least 30 days in the 90 days prior to enrollment visit and 2) participants 
744 
enrolling who have lost or broken glasses should not be penalized for apparent nonadherence while 
745 
obtaining new pre-randomization glasses.  
746 
  
747 
3.3 
Testing at the Randomization Visit  
748 
Participants judged to be adherent with eyedrops will undergo the assessments outlined for the 
749 
randomization visit, further described below.  
750 
 
751 
Prior to any clinical testing, the participants' current spectacles (i.e., new prescribed at enrollment or 
752 
pre-study spectacles that met tolerance criteria at enrollment/did not require updating) will need to 
753 
meet the following criteria compared with the prescribed refractive correction at enrollment 
754 
(Section 2.7) OR the participants are tested in trial frames with prescribed refractive correction at 
755 
enrollment (Section 2.7): 
756 
 
757 
• Myopia (by spherical equivalent) in both eyes corrected to within ±0.50D of the 
758 
investigator’s cycloplegic measurement of refractive error. 
759 
• Cylinder power in both eyes within ±0.50D of the investigator’s cycloplegic measurement of 
760 
refractive error. 
761 
• Cylinder axis for both eyes must be within ±5 degrees of the axis found on the investigator’s 
762 

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cycloplegic measurement of refractive error when the cylinder power is ≥ 1.00D or within 
763 
±15 degrees when the cylinder power is <1.00D 
764 
 
765 
Refer to Chapter 5 herein and the MTS2 Site Manual of Procedures for a complete description of 
766 
testing procedures, performed in the following order. 
767 
 
768 
1. Automated Pupillometry 
769 
2. Monocular Distance Visual Acuity Testing  
770 
• Method: ATS-HOTV protocol if <7 years and E-ETDRS protocol if age 7 or older 
771 
• Refractive correction: habitual spectacles (which may be new spectacles prescribed 
772 
at enrollment) in refractive correction determined at enrollment (spectacles or trial 
773 
frame)  
774 
3. Binocular Near Visual Acuity Testing 
775 
4. Monocular Amplitude of Accommodation Right Eye Only 
776 
5. Urine Pregnancy Test – for participants who have experienced menarche (at least one 
777 
menstrual cycle) 
778 
• This test can be performed at any time during the visit. 
779 
 
780 
The following must be performed (i.e., repeated) only if the cycloplegic autorefraction, axial length, 
781 
and flat corneal radius measurements at the enrollment visit(s) were completed more than 4 weeks 
782 
(>28 days) prior to the randomization visit (following the same instillation of cycloplegic eyedrop 
783 
procedure as described for enrollment in section 2.6).  If repeated, these will be considered the 
784 
participant’s “baseline” measurements and must meet the same eligibility criteria for enrollment 
785 
(sections 2.3 and 2.4). 
786 
 
787 
5. Cycloplegic Autorefraction (only if >28 days since enrollment visit)   
788 
6. Axial Length and Flat Corneal Radius Measurements with Cycloplegia (only if >28 days 
789 
since enrollment visit) 
790 
 
791 
If a participant is unable to complete the testing listed above in a single visit or does not meet visual 
792 
acuity eligibility criteria, testing may be completed within 7 days. 
793 
 
794 
3.4 
Confirmation of Eligibility for Randomization  
795 
Randomization will occur at the end of the randomization visit after confirming the participant 
796 
meets the following eligibility criteria: 
797 
 
798 
1. Best-corrected distance visual acuity in habitual spectacles (which may be new spectacles 
799 
prescribed at enrollment) meeting tolerances (section 3.3) or trial frames meeting the following 
800 
criteria using the ATS-HOTV protocol if <7 and E-ETDRS protocol if age 7 or older:  
801 
o If age 5-6 years: 20/32 or better by ATS-HOTV 
802 
o If age 7-<12 years: ≥ 78 letters by E-ETDRS 
803 
o Interocular difference ≤2 logMAR lines (0.2 logMAR) or ≤ 10 letters 
804 
2. Refractive error meeting the following by cycloplegic autorefraction (performed at enrollment 
805 
or the day of randomization, if repeat autorefraction required): 
806 
o Myopia of 0.75D to 6.00D SER and at least 0.75 D in both principal meridians of each eye  
807 
o Astigmatism <2.50D both eyes 
808 
o Anisometropia <1.50D SER 
809 
3. At least 90% adherence with artificial tear eyedrops during the run-in phase 
810 

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811 
Participants who do not meet the adherence or refractive error eligibility criteria for randomization 
812 
will be withdrawn from the study. If >28 days have elapsed since the enrollment visit, cycloplegic 
813 
autorefraction, axial length, and flat corneal radius measurements will need to be repeated (section 
814 
3.3).   
815 
 
816 
Prior to randomization, the study requirements should be discussed again with the parent and child 
817 
so there is reasonable assurance that the participant will adhere to the study requirements. 
818 
  
819 
3.5 
Randomization 
820 
Eligible participants will be randomly assigned 1:1:1:1 to the following groups: 
821 
 
822 
• ATROPINE GROUP:  atropine (0.05%) eyedrops + single vision lenses 
823 
• H.A.L.T. MAX GROUP: placebo eyedrops + spectacle lenses with H.A.L.T. MAX 
824 
technology 
825 
• COMBINED GROUP: atropine (0.05%) eyedrops + spectacle lenses with H.A.L.T. MAX 
826 
technology 
827 
• PLACEBO GROUP: placebo eyedrops + single vision lenses 
828 
 
829 
A Master Randomization List using a permuted block design stratified by baseline age (5 to <9, 9 to 
830 
<12), specifying the order of treatment group assignments, will be used for randomization.  
831 
 
832 
Once the website randomization process is complete, a study participant is randomized. The 
833 
participant will be included in that group for analysis regardless of whether the assigned treatment is 
834 
received. Thus, the investigator must not randomize the participant unless convinced that the child 
835 
is eligible, and the family will accept whichever treatment group is assigned through randomization. 
836 
 
837 
Study spectacles and study medication will be dispensed at the 4-week Treatment Initiation Visit. 
838 
 
839 
The participant, parents, coordinators, testers, and investigators will be masked to treatment group. 
840 
If the need arises, the investigator may become unmasked after discussion of a specific case with 
841 
the protocol chair in response to any adverse events.  
842 
 
 
843 

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Chapter 4: 
Treatment and Follow-Up in Randomized Trial 
844 
 
845 
4.1 Treatment from 0 to 24 months 
846 
All participants will use study eyedrops and study spectacles as follows: 
847 
 
848 
• Treatment with study eyedrops will be one drop in both eyes each night of either atropine 
849 
0.05% or placebo (based on randomized treatment group), including the night before study 
850 
visits. 
851 
 
852 
• Study spectacles with either single-vision lenses or H.A.L.T. MAX technology should be 
853 
worn full time (i.e., at least 10 hours per day). 
854 
 
855 
No myopia control treatments other than the randomized assignments to study eyedrops and study 
856 
spectacles can be used for the duration of the study. Only study spectacles are allowed.  
857 
 
858 
4.1.1 Study Medication 
859 
A compounding pharmacy will package the study drug (0.05% atropine and placebo) in identical-
860 
appearing preservative free, multi-dose bottles (Novelia®). In addition to 0.05% atropine, the 
861 
atropine eyedrops contain 99.95% buffered solution with inactive ingredients, while the placebo 
862 
eyedrops contain 100% buffered solution with inactive ingredients. The study drug will be shipped 
863 
to a central pharmacy for labelling, to maintain masking. The central pharmacy will supply labelled 
864 
medication to clinical sites, who will dispense it to participants. Additional study medication details 
865 
are summarized within a separate investigator brochure.   
866 
  
867 
Eyedrops will be dispensed to participants concurrently with study spectacles at the Treatment 
868 
Initiation Visit 4 weeks after randomization. Eyedrops will then be dispensed at each 6, 12, and 18-
869 
month office visit. At each semi-annual clinical visit and any other time the parent picks up 
870 
eyedrops at the site, the previously dispensed eyedrop bottles (used or unused) will be retrieved and 
871 
destroyed by the site. This is to avoid use of expired eyedrops or use of eyedrops when not 
872 
prescribed later in the study.    
873 
 
874 
4.1.2 Study Spectacles 
875 
Study spectacles with either single-vision lenses or H.A.L.T. MAX technology will be prescribed at 
876 
randomization, 6, 12, and 18, month visits; single vision spectacles will be prescribed to all 
877 
participants at 24 months. New spectacles are prescribed regardless of any change in refractive 
878 
correction every 6 months to ensure that the benefits of wear are not compromised by scratched 
879 
lenses or bent frames.  
880 
 
881 
The spectacle prescription is determined by cycloplegic refraction according to the investigator’s 
882 
usual method. This may include retinoscopy, autorefraction, and subjective refinement. Once the 
883 
refractive error is determined under cycloplegic conditions, the spectacle prescription should match 
884 
the cycloplegic refraction (i.e., “cutting” minus, cyl, etc. is not allowed).   
885 
 
886 
Spectacles prescribed at randomization should be based on the cycloplegic refraction performed at 
887 
the enrollment visit, unless the cycloplegic refraction had to be repeated at randomization (i.e., 
888 
because it had been more than 4 weeks (>28 days) since the enrollment visit), in which case 
889 
spectacles should be prescribed based on the cycloplegic refraction at randomization. Spectacles 
890 
prescribed at follow up visits should be based on the cycloplegic refraction that occurs at the visit.          
891 

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892 
Once manufactured, two identical pairs of study spectacles will be sent to the study site where the 
893 
Spectacles Fitter will verify each pair (primary and backup) using lensometry (section 4.8.1) and 
894 
dispense one pair to the study participant (see sections 4.7 and 4.9) at the 4-Week Study Spectacle 
895 
Fitting visit.  
896 
 
897 
Staff responsible for receiving, verifying and dispensing the study spectacles will be informed about 
898 
the study and instructed on the importance of not disclosing the type of lenses to the child or their 
899 
family. Treatment with study spectacles will commence as soon as study spectacles are fit and 
900 
dispensed. Eyedrops will be dispensed concurrently with study spectacles at the 4-Week Treatment 
901 
Initiation Visit. 
902 
 
903 
Participants will be instructed to wear their study spectacles full-time (i.e., at least 10 hours per 
904 
day). 
905 
 
906 
At each semi-annual visit, the previously dispensed spectacles will be retrieved and maintained at 
907 
the site once new spectacles are given to the participant. This is to avoid wearing outdated 
908 
spectacles, and because they are for investigational use only.  
909 
 
910 
4.2 
Treatment from 24 to 30 months 
911 
At the 24-month visit, study interventions will be discontinued. All participants will be prescribed 
912 
single-vision-lens spectacles. The eyedrops will be returned to the site at the visit and the study 
913 
spectacles will be exchanged at the spectacle fitting visit for the single vision spectacles prescribed. 
914 
No myopia treatment should be prescribed from the 24-month visit until completion of the 30-
915 
month visit.  
916 
 
917 
4.3 
Telephone Calls 
918 
Eight (8) weeks following randomization (± 2 weeks), the site will contact parents to question the 
919 
parent as to whether the child is experiencing any issues with treatment or has had any changes in 
920 
medications.  
921 
 
922 
At three months (±2 weeks) following randomization, the site will contact the participant’s parents 
923 
to encourage adherence to the randomized treatment and ask the parent if the participant is 
924 
experiencing any issues with treatment  
925 
 
926 
The site will make phone calls at 9, 15, 21, and 27 months (±2 weeks) after randomization, 
927 
timepoints which are equidistant between the scheduled study visits). These calls will be conducted 
928 
to maintain direct contact with participants’ parents, develop and maintain rapport with participants 
929 
and/or families, and assist with scheduling study visits if needed.  
930 
 
931 
4.4 
Adherence with Study Treatment 
932 
A calendar will be provided to promote adherence with eyedrops and study spectacles, on which the 
933 
child/parent will record daily both whether an eyedrop was instilled into both eyes in the evening 
934 
and whether the participant wore their study spectacles at least 10 hours.  
935 
 
936 
At each office visit, an assessment of adherence will be recorded on the Follow-up Examination 
937 
Form after a review of the calendars and an interview with the parent and child. Separately for 
938 
eyedrops (whether received daily) and for spectacles (whether worn at least 10 hours per day), study 
939 

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personnel will describe the proportion of time that treatment that was used per protocol as excellent 
940 
(76% to 100%), good (51% to 75%), fair (26% to 50%), or poor (≤ 25%).  
941 
 
942 
Adherence will be encouraged at each visit and each phone call. If a participant does not adhere to 
943 
the study treatment, parents and participants should be encouraged to continue trying their best to 
944 
follow the study treatment plan.  
945 
 
946 
4.5 
Side Effects of Treatment  
947 
Reporting of adverse events is described in Chapter 6. Prior to deviating from the treatment protocol 
948 
or prescribing non-protocol treatment, the situation should be discussed with and approved by a 
949 
Protocol Co-chair.  
950 
 
951 
If a participant is experiencing photophobia, the investigator may prescribe clip-on sunglasses.  
952 
 
953 
If a participant reports blurry vision or difficulty seeing up close when doing schoolwork, reading, 
954 
or other near activities, the investigator must call a Protocol Co-chair to discuss management.    
955 
 
956 
If a participant has a confirmed allergic reaction to eye drops, the investigator must call a Protocol 
957 
Co-chair to discuss management, and the child would need to stop the study eye drops and continue 
958 
in the study. 
959 
 
960 
If a participant’s eyes feel dry after using study medication, artificial tears may be used 10 minutes 
961 
after the study eye drops to moisturize the eyes. 
962 
 
963 
4.6 
Study Visits and Phone Calls in the Randomized Trial 
964 
Study visits and interactions will be timed from randomization unless otherwise specified and will 
965 
occur at: 
966 
 
967 
• 
A Treatment Initiation Visit (Spectacles Fitting and Eyedrop Dispensing) at: 4 ± 2 weeks  
968 
• 
A phone call at 8 weeks ± 2 weeks 
969 
• 
A phone call at 3 months ± 2 weeks 
970 
• 
A follow-up clinical visit at 6 months ± 2 weeks 
971 
• 
A spectacle fitting visit at 7 months ± 2 weeks 
972 
• 
A phone call at 9 months ± 2 weeks 
973 
• 
A follow-up clinical visit at 12 months ± 2 weeks 
974 
• 
A spectacle fitting visit at 13 months ± 2 weeks 
975 
• 
A phone call at 15 months ± 2 weeks 
976 
• 
A follow-up clinical visit at 18 months ± 2 weeks 
977 
• 
A spectacle fitting visit at 19 months ± 2 weeks 
978 
• 
A phone call at 21 months ± 2 weeks 
979 
• 
A follow-up clinical visit at 24 months ± 2 weeks  
980 
o On-Treatment Primary Outcome – after which all eyedrops and study spectacles will be 
981 
discontinued and SVLs will be prescribed for all.  
982 
• 
A spectacle fitting visit at 25 months ± 2 weeks 
983 
• 
A phone call at 27 months ± 2 weeks 
984 
• 
A follow-up clinical visit at 30 months ± 2 weeks 
985 
o Off-Treatment Secondary Outcome – six months following treatment discontinuation.  
986 
 
987 
 
988 
 
989 

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990 
Visit 
Target Day 
Target Window 
(around Target Day) 
Allowable Window 
(around Target Day) 
4-week treatment 
initiation visit 
(spectacle fitting 
and eyedrop 
dispensing) 
Randomization + 28 days 
± 2 weeks 
26 to 42 days 
± 2 weeks 
26 to 42 days 
 
8-week call 
 
Randomization + 56 days 
± 2 weeks 
42 to 70 days 
± 2 weeks 
42 to 70 days 
3-month call   
Randomization + 91 days 
±2 weeks 
77 to 105 days 
±2 weeks 
77 to 105 days 
6-month clinical 
visit 
Randomization + 183 days 
± 2 weeks 
169 to 197 days 
± 3 months 
91 to 273 days 
9-month call 
Randomization + 273 days 
± 2 weeks 
259 to 287 days 
± 2 weeks 
259 to 287 days 
12-month clinical 
visit* 
Randomization + 365 days 
± 2 weeks 
335 to 379 days 
± 3 months 
273 to 454 days 
15-month call 
 
Randomization + 454 days 
± 2 weeks 
440 to 468 days 
± 2 weeks 
440 to 468 days 
18-month clinical 
visit 
Randomization + 548 days 
± 2 weeks 
534 to 562 days 
± 3 months 
454 to 838 days 
21-month call 
 
Randomization + 638 days 
± 2 weeks 
624 to 652 days 
± 2 weeks 
624 to 652 days 
24-month clinical 
visit* 
Randomization + 731 days 
± 2 weeks 
717 to 745 days 
± 3 months 
638 to N/A days 
27-month call 
Randomization + 821 days 
± 2 weeks 
807 to 835 days 
± 2 weeks 
624 to 652 days 
30-month clinical 
visit* 
Randomization + 913 days 
± 2 weeks 
899 to 927 days 
± 3 months 
821 to N/A 
Additional study 
spectacle fittings 
after each clinical 
visit 
Clinical follow up visits  
(6, 12, 18, and 24- months) + 28 
days 
± 2 weeks 
± 2 weeks 
*Denotes key study visits.  
991 
 
992 
The goal is for all participants to complete all scheduled visits. However, participants unable or 
993 
unwilling to return for all follow-up visits will be permitted to return for key visits only as an 
994 
alternative to withdrawal from the study. In such instances, a missed visit form will be entered for 
995 
each missed visit with the reason specified as “Other” with comment that the parent/participant is 
996 
unwilling to return except for key visits; these missed visits will not be recorded as protocol 
997 
deviations.   
998 
 
999 
4.7 
Procedures at 4-Week Treatment Initiation Visit 
1000 
At the 4-week Treatment Initiation Visit, participants will be seen by the Spectacles Fitter for fitting 
1001 
of the study spectacles (section 4.9) and by the site coordinator for dispensing of study medication; 
1002 
no clinical assessments will be performed.   
1003 
 
1004 
The following procedures should be performed:     
1005 
 
1006 
1. Lensometry (section 0) of primary spectacles and backup spectacles (if available) 
1007 
2. Fit both primary and back up spectacles 
1008 
3. Dispense primary spectacles to the participant (Spectacles Fitter) 
1009 
4. Retain backup spectacles at the site  
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5. Dispense study medication (Coordinator)   
1011 
6. Provide treatment instructions sheets and compliance calendars (4-week visit only) 
1012 
(Coordinator)   
1013 
 
1014 
4.8 
Procedures at Follow-Up Visits Between 6 and 30 Months  
1015 
 
1016 
4.8.1 Lensometry 
1017 
Prior to any clinical testing, the participants' current spectacles (primary or backup pair) will need to 
1018 
meet the following criteria compared with the last prescribed refractive correction OR the 
1019 
participants are tested in trial frames with the last prescribed refractive correction: 
1020 
 
1021 
• Myopia (by spherical equivalent) in both eyes corrected to within ±0.50D of the 
1022 
investigator’s cycloplegic measurement of refractive error. 
1023 
• Cylinder power in both eyes within ±0.50D of the investigator’s cycloplegic measurement of 
1024 
refractive error. 
1025 
• Cylinder axis for both eyes must be within ±5 degrees of the axis found on the investigator’s 
1026 
cycloplegic measurement of refractive error when the cylinder power is ≥ 1.00D or within 
1027 
±15 degrees when the cylinder power is <1.00D. 
1028 
 
1029 
If these criteria are not met, or the child did not bring their spectacles to the visit, testing must be 
1030 
done with the participant wearing their backup study spectacles; otherwise, in prescribed correction 
1031 
in trial frames. 
1032 
 
1033 
4.8.2 Procedures at Clinical Follow Up Visits 
1034 
Unless otherwise specified, the following procedures will be performed in the specified order at 
1035 
each visit with the participant wearing their study spectacles (primary or backup pair) or trial frames 
1036 
(see section 0), according to the description of procedures and assessments outlined in Chapter 5 
1037 
and the MTS2 Site Manual of Procedures.  
1038 
 
1039 
1. Lensometry (section 0) 
1040 
 
1041 
2. Medical History 
1042 
o Including questioning about adverse events and concomitant medications.  
1043 
 
1044 
3. Adherence to Eyedrop and Spectacles Treatment Assessment (all visits except 30-month) 
1045 
 
1046 
4. Urine Pregnancy Test – for participants who have experienced at least one menstrual cycle 
1047 
at all visits except 30-month) 
1048 
 
1049 
5. Treatment Impact Questionnaire (parent and child at 6 and 24-month visit only; must be 
1050 
administered prior to clinical testing)  
1051 
 
1052 
6. Automated Pupillometry (for sites with equipment)  
1053 
 
1054 
7. Monocular Distance Visual Acuity Testing  
1055 
a. Method: investigator discretion 
1056 
b. Refractive correction: habitual spectacles  
1057 
 
1058 
8. Binocular Near Visual Acuity Testing  
1059 

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1060 
9. Monocular Amplitude of Accommodation in Right Eye Only  
1061 
o Measured once using the 20/30 Bernell line with the participant in their study 
1062 
spectacles or trial frames (see section 4.8.1).  
1063 
 
1064 
10. Drop instillation for Testing Under Cycloplegia 
1065 
 
1066 
11. Cycloplegic Autorefraction  
1067 
 
1068 
12. Axial Length and Flat Corneal Radius Measurements with Cycloplegia 
1069 
 
1070 
13. Refractive Error Determination with Cycloplegia  
1071 
o Refine refractive error (section 4.9) 
1072 
 
1073 
14. If pre-cycloplegic monocular distance visual acuity in either eye was worse than 20/32 for 
1074 
children 5-6 years old at time of randomization or worse than 20/25 for children 7-<12 years 
1075 
old at time of randomization, retest monocular distance VA using phoropter or trial frames 
1076 
by same method used at randomization (ATS-HOTV or E-ETDRS).  
1077 
 
1078 
15. Order Study Spectacles (all visits except 30 months, will be SVL for all at 24 months) 
1079 
o Participant selects frame from sample frame collection at site. 
1080 
o Site orders two identical pairs of study spectacles.  
1081 
▪ One pair will be dispensed to the participant at the Study Spectacles Visit.  
1082 
▪ The second pair will be sent to the site to serve as a backup in case the 
1083 
participant breaks or loses their spectacles, or to use for clinical testing if 
1084 
spectacles are not brought to the Clinical Follow Up Visit. 
1085 
 
1086 
16. Manage study medication  
1087 
o Collect unused study medication (6, 12, 18, and 24 months)   
1088 
o Dispense supply of study medication (6, 12, and 18 months)  
1089 
o Provide treatment instructions sheets and compliance calendars    
1090 
 
1091 
4.9 
Procedures at Study Spectacle Fittings 
1092 
At Spectacles Fitting Visits, participants will be seen by the Spectacles Fitter for fitting of both pair 
1093 
of study spectacles (primary and backup); no clinical assessments will be performed. 
1094 
 
1095 
• One pair of spectacles will be dispensed to the participant.  
1096 
• The second pair will serve as a backup in case the participant breaks or loses their 
1097 
spectacles, or to use for clinical testing if spectacles are not brought to the Clinical Follow 
1098 
Up Visit. 
1099 
 
1100 
The following procedures should be performed:   
1101 
 
1102 
1. Lensometry (section 0) of primary spectacles and backup spectacles  
1103 
2. Collect study spectacles being replaced  
1104 
3. Fit both primary and backup spectacles 
1105 
4. Dispense primary spectacles to participant (Spectacles Fitter) 
1106 
5. Retain backup spectacles at the site  
1107 
 
1108 

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4.10 Management of Refractive Error 
1109 
A new spectacle prescription will be determined by cycloplegic refraction according to the 
1110 
investigator’s usual method of refinement for all study participants. This may include retinoscopy, 
1111 
autorefraction, and subjective refinement. Once the refractive error is determined under cycloplegic 
1112 
conditions, the spectacle prescription should match the cycloplegic refraction (i.e., “cutting” minus, 
1113 
cyl, etc., is not allowed).  
1114 
 
1115 
The study spectacles will be updated even if there is no change in the refraction.  
1116 
 
1117 
4.11 Non-Randomized Treatment  
1118 
Non-randomized treatment for myopia other than study-specified eyedrops and spectacles is not 
1119 
permitted during the study. The investigator must call the Protocol Co-chair to discuss the case and 
1120 
obtain approval for an exception before starting any non-randomized treatment. If sports spectacles are 
1121 
approved, they will be paid for by the study.  
1122 
 
1123 
4.12 Text Message Contacts 
1124 
Families may be offered the choice to opt-in to text messages to receive appointment reminders.  
1125 

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Chapter 5: 
Testing Procedures and Questionnaires 
1126 
 
1127 
All reasonable efforts will be made to maintain masking for all study personnel and families 
1128 
throughout the study. After randomization, the investigator will not view a participant’s pupils 
1129 
before dilation or any study spectacles. Participants and their families will be instructed not to 
1130 
discuss the appearance of the study spectacle lenses with the investigator. For the randomized trial, 
1131 
a certified tester who is not the investigator must perform lensometry and any procedures where the 
1132 
participant’s study spectacles and/or pupils could be observed (and for which it is not reasonable for 
1133 
the participant to wear stereo spectacles to prevent pupil observation). Measurement of cycloplegic 
1134 
autorefraction and biometry (primary outcome measures) must be performed by either the 
1135 
investigator or a separate biometry tester (BT), who is not also the certified tester (CT), coordinator 
1136 
(CO), or Spectacles Fitter (SF) for all visits after randomization. 
1137 
 
1138 
Refer to the MTS2 Site Manual of Procedures for additional details on Testing Procedures and 
1139 
Questionnaires described below.  
1140 
 
1141 
5.1 
Questionnaires 
1142 
 
1143 
5.1.1 PEDIG Myopia Treatment Impact Questionnaire (Child and Parent)  
1144 
At 6- and 24-month outcome exams, participants will complete a novel 24-item questionnaire 
1145 
assessing the impact of the child’s eyedrop and spectacles treatment on the child. For participants 
1146 
requiring assistance, the questions should be read verbatim by study personnel (not the parent) and 
1147 
the participant’s answers recorded.  
1148 
 
1149 
A similar novel 21-item questionnaire will be completed by the parent to assess the impact of the 
1150 
child’s treatment on the parent and family. Testing is expected to take 5-7 minutes for the child and 
1151 
5-7 minutes for the parent. 
1152 
 
 
1153 
5.2 
Clinical Testing Procedures and Assessments  
1154 
The following procedures will be performed at each visit.  
1155 
 
1156 
5.2.1 Lensometry 
1157 
The current refractive correction (sphere, cylinder, and axis in each eye) will be verified using a 
1158 
lensometer at all visits. Lensometry must be performed by a certified tester who is not the 
1159 
investigator at 6-, 12-, 18-, and 24-month visits. 
1160 
 
1161 
Testing time is approximately 3 minutes. 
1162 
 
1163 
5.2.2 Medical History  
1164 
The participant’s medical history must be taken while they are wearing stereo spectacles (with or 
1165 
without their study spectacles) to prevent the investigator from observing the participant’s pupils 
1166 
before dilation. The investigator will determine whether any adverse events occurred since the last 
1167 
study visit and update previously recorded adverse events. If an adverse event has occurred, any 
1168 
initiation, discontinuation, or dosage change in non-study medications concomitant to the adverse 
1169 
event will be recorded.  
1170 
 
1171 
Completion time is approximately 5-15 minutes.  
1172 
 
1173 

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5.2.3 Adherence Assessment (all follow-up visits except 30 months) 
1174 
Calendar logs (if brought to the visit) will be reviewed, and the level of nightly adherence with 
1175 
eyedrop administration and all-day study spectacle wear will be documented on the Follow-up 
1176 
Examination Form. If calendar logs are reviewed by the investigator, the participant must wear 
1177 
stereo spectacles to prevent the investigator from seeing the participant’s pupils before dilation. If 
1178 
the calendars are not brought to the study visit, they should be mailed to the local site.  
1179 
 
1180 
Completion time is approximately 5 minutes.  
1181 
 
1182 
5.2.4 Urine Pregnancy Test 
1183 
For participants who have experienced menarche (at least one menstrual cycle), a dipstick-type 
1184 
urine pregnancy test will be required at enrollment and 6-, 12-, 18- and 24-month follow-up visits. 
1185 
If pregnancy testing is reviewed by the investigator, the participant must wear stereo spectacles to 
1186 
prevent the investigator from seeing the participant’s pupils before dilation. 
1187 
 
1188 
Testing time is approximately 7 minutes. 
1189 
 
1190 
5.2.5 Automated Pupillometry  
1191 
Pupil diameter will be measured using an automated method at sites with automated pupillometry 
1192 
equipment. The same method and lighting conditions are to be used throughout the study. This test 
1193 
must be performed by a certified tester who is not the investigator at the 6-, 12-, 18-, and 24-month 
1194 
visits. 
1195 
 
1196 
Testing time is approximately 3 minutes. 
1197 
 
1198 
5.2.6 Distance Visual Acuity Testing  
1199 
Monocular distance visual acuity should be measured with the participant wearing most recent 
1200 
refractive correction in study spectacles (primary or backup) or trial frames; however, the testing 
1201 
method to be used varies by visit and purpose as follows:  
1202 
 
1203 
• At the Enrollment Visit, monocular distance visual acuity should be tested in habitual 
1204 
refractive correction. The pre-cycloplegia method of visual acuity is at investigator 
1205 
discretion. 
1206 
 
1207 
• At the Randomization Visit, children aged <7 years at the time of randomization will use the 
1208 
ATS-HOTV protocol on a study-certified VA device, and children 7 years and older will use 
1209 
E-ETDRS protocol on a study-certified VA device.  
1210 
 
1211 
• At all visits after randomization, monocular distance visual acuity should be tested in 
1212 
habitual refractive correction. The pre-cycloplegia method of visual acuity is at investigator 
1213 
discretion. This test must be performed by a certified tester who is not the investigator at the 
1214 
6-, 12-, 18-, 24-, and 30-month visits. If pre-cycloplegia visual acuity is less than age 
1215 
appropriate, monocular distance visual acuity should be repeated following cycloplegic 
1216 
refractive error determination using the EVA method that was conducted at Randomization.  
1217 
 
1218 
Testing time is approximately 5 to 10 minutes. 
1219 
 
1220 

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5.2.7 Binocular Near Visual Acuity Testing  
1221 
Binocular near visual acuity is measured using the ATS4 Near Acuity Test with the participant 
1222 
wearing optimal refractive correction (section 2.7) in study spectacles (primary or backup) or trial 
1223 
frames and without cycloplegia. This test must be performed by a certified tester who is not the 
1224 
investigator at the 6-, 12-, 18-, and 24-month visits. 
1225 
 
1226 
Testing time is approximately 3 minutes. 
1227 
 
1228 
5.2.8 Monocular Amplitude of Accommodation (right eye only)  
1229 
Only the right eye is measured, and it is measured once using the 20/30 Bernell line with the 
1230 
participant wearing optimal refractive correction (section 2.7) in study spectacles (primary or 
1231 
backup) or trial frames without cycloplegia. This test must be performed by a certified tester who is 
1232 
not the investigator at the 6-, 12-, 18-, 24-month, and 30-month visits. 
1233 
 
1234 
Testing time is approximately 3 minutes. 
1235 
 
1236 
5.2.9 Drop Instillation for Testing Under Cycloplegia  
1237 
Two drops of 1% cyclopentolate, separated by 5 minutes, will be administered to both eyes. The use 
1238 
of proparacaine prior to the cycloplegic drops is at investigator discretion. The cycloplegic 
1239 
autorefractions must be taken 30 minutes ± 5 minutes from the time the second drop of 1% 
1240 
cyclopentolate was instilled in the second eye. Biometry and refraction measurements should follow 
1241 
autorefraction. If eyes are not sufficiently dilated and cyclopleged or if the dilation/cycloplegia has 
1242 
worn off before all procedures requiring cycloplegia have been performed, a third drop of 1% 
1243 
cyclopentolate may be administered, followed by an additional 30-minute wait before testing. The 
1244 
drop installation cannot be performed by the investigator at the 6-, 12-, 18-, and 24-month visits. 
1245 
 
1246 
Testing time is approximately 35 minutes. 
1247 
 
1248 
5.2.10 Cycloplegic Autorefraction 
1249 
For each eye, 3 autorefraction measurements are taken. For each measurement, the autorefractor 
1250 
will yield a final reading (either an individual reading or the mean/median of several readings, 
1251 
depending on the autorefractor) consisting of sphere, cylinder, and axis (see MTS2 Manual of 
1252 
Procedures). The mean of 3 measurements is used for analysis.   
1253 
 
1254 
Each participant must have their autorefraction measurements made using the same instrument (or 
1255 
same make and model of instrument) for all study visits. 
1256 
 
1257 
Testing time is approximately 2-4 minutes (after drop instillation and cycloplegia). 
1258 
 
1259 
5.2.11 Axial Length and Flat Corneal Radius Measurements with Cycloplegia 
1260 
Axial length will be measured (with pupillary dilation with cycloplegia) 3 times in each eye using 
1261 
optical biometry. The mean of 3 values is used for analysis.   
1262 
 
1263 
Each participant must have their axial length measurements made using the same instrument for all 
1264 
study visits.  Flat corneal radius/flag meridian (K1) will be measured during the axial length (AL) 
1265 
measurement. The mean of 3 values is used for analysis.   
1266 
 
1267 
Testing time is approximately 5-10 minutes. 
1268 
 
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5.2.12 Spectacle Prescription Determination with Cycloplegia 
1270 
Spectacle prescription is determined by cycloplegic refraction according to the investigator’s usual 
1271 
method of refinement. This may include retinoscopy, autorefraction, and subjective refinement. 
1272 
Once the refractive error is determined under cycloplegic conditions, the spectacle prescription 
1273 
should match the cycloplegic refraction (i.e., “cutting” minus, cyl, etc., is not allowed). 
1274 
 
1275 
Testing time is approximately 5-10 minutes.  
1276 

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Chapter 6: 
Unanticipated Problem / Adverse Event, and Device 
1277 
Issue Reporting 
1278 
 
1279 
6.1 
Unanticipated Problems 
1280 
Site investigators will promptly report to the JCHR on an eCRF all unanticipated problems meeting 
1281 
the criteria below. Sites must report Unanticipated Problems to the IRB within seven (7) calendar 
1282 
days of recognition. For this protocol, an unanticipated problem is an incident, experience, or 
1283 
outcome that meets all the following criteria: 
1284 
 
1285 
• Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
1286 
that are described in the protocol-related documents, such as the IRB-approved research 
1287 
protocol and informed consent document; and (b) the characteristics of the subject 
1288 
population being studied 
1289 
• Related or possibly related to participation in the research (possibly related means there is a 
1290 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
1291 
procedures involved in the research) 
1292 
• Suggests that the research places participants or others at a greater risk of harm than was 
1293 
previously known or recognized (including physical, psychological, economic, or social 
1294 
harm)  
1295 
 
1296 
The JCHR also will report to the JCHR IRB all unanticipated problems not directly involving a 
1297 
specific site, such as unanticipated problems that occur at the JCHR or another participating entity, 
1298 
such as a pharmacy or laboratory. These instances must be reported to the JCHR IRB within seven 
1299 
(7) calendar days of recognition. The Director of the Human Research Protection Program will 
1300 
report to the appropriate regulatory authorities if the JCHR IRB determines that the event indeed 
1301 
meets the criteria of an Unanticipated Problem that requires further reporting.  
1302 
 
1303 
6.2 
Adverse Events 
1304 
 
1305 
6.2.1 Definitions 
1306 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
1307 
relationship between the adverse event and the drug(s) and device under investigation.  
1308 
To further clarify, an adverse event is any unintended disease or injury, or untoward clinically 
1309 
significant symptom or clinical sign (including abnormal laboratory findings) in a research 
1310 
participant that manifests while in the study if it was not present before enrolling in the study, or if 
1311 
it was present before enrolling, it has increased in severity, frequency or type since enrolling in the 
1312 
study. For this purpose, a participant is considered enrolled once the participant has signed the 
1313 
consent form. For clarity, abnormalities identified as part of study screening (e.g., laboratory 
1314 
abnormality, physical exam abnormality) are not considered AEs even though they may have been 
1315 
identified after consent was signed. 
1316 
 
1317 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
1318 
• Results in death. 
1319 
• Is life-threatening (a non-life-threatening event which, had it been more severe, might have 
1320 
become life-threatening, is not necessarily considered a serious adverse event). 
1321 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
1322 
• Results in persistent or significant disability/incapacity or substantial disruption of the 
1323 
ability to conduct normal life functions (e.g., sight threatening). 
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• Is a congenital anomaly or birth defect in the offspring of a participant. 
1325 
• Is considered a significant medical event by the investigator based on medical judgment 
1326 
(e.g., may jeopardize the participant or may require medical/surgical intervention to prevent 
1327 
one of the outcomes listed above). 
1328 
 
1329 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
1330 
any life-threatening problem or death caused by, or associated with a study device, if that effect, 
1331 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
1332 
investigational plan or application (including a supplementary plan or application), or any other 
1333 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
1334 
participants (21 CFR 812.3(s)). 
1335 
 
1336 
Adverse Device Effect (ADE): An adverse event related to the use of a study investigational 
1337 
medical device. This definition includes adverse events resulting from insufficient or inadequate 
1338 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of the 
1339 
investigational medical device. This definition includes any event resulting from use error or from 
1340 
intentional misuse of the investigational medical device. This includes comparator if the comparator 
1341 
is a comparable medical device to the investigational device. (Note that (1) ADE refers specifically 
1342 
to the study investigational device and not to any device used in the study and (2) an Adverse Event 
1343 
CRF is to be completed in addition to a Device Deficiency or Issue CRF for all ADEs. 
1344 
 
1345 
Comparator: Medical device, therapy (e.g., active treatment, normal clinical practice), placebo or no 
1346 
treatment, used in the control group in a clinical investigation. (ISO 14155:2020) 
1347 
 
1348 
Device Complaints and Malfunctions: A device complication or complaint is something that 
1349 
happens to a study device or related to study device performance, whereas an adverse event happens 
1350 
to a participant. A device complaint may occur independently from an AE, or along with an AE. An 
1351 
AE may occur without a device complaint or there may be an AE related to a device complaint. A 
1352 
device malfunction is any failure of a device to meet its performance specifications or otherwise 
1353 
perform as intended. Performance specifications include all claims made in the labeling for the 
1354 
device. For cleared devices, the intended performance of a device refers to the intended use for 
1355 
which the device is labeled or marketed (21 CFR 803.3). Note: for reporting purposes, sites will not 
1356 
be asked to distinguish between device complaints and malfunctions. 
1357 
 
1358 
Use Error: User action or lack of user action while using the medical device that leads to a different 
1359 
result than that intended by the manufacturer or expected by the user. Includes the inability of the 
1360 
user to complete a task. Use errors can result from a mismatch between the characteristics of the 
1361 
user, user interface, task or use environment. Users might be aware or unaware that a use error has 
1362 
occurred. An unexpected physiological response of the patient is not by itself considered a use error. 
1363 
A malfunction of a medical device that causes an unexpected result is not considered a use error 
1364 
(ISO 14155:2020). 
1365 
 
1366 
6.3 
Reportable Adverse Events 
1367 
For this protocol, any events between enrollment and randomization will be entered as prior medical 
1368 
conditions.  
1369 
 
1370 
During the randomized trial, the following are reportable adverse events:  
1371 
• Ocular symptoms and signs meeting the definition of an adverse event (section 0) 
1372 
• Systemic symptoms and signs meeting the definition of an adverse event (section 0) and 
1373 

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occurring within one hour of drop administration. 
1374 
• Events meeting the definition of serious adverse events (section 0).  
1375 
• Events meeting the definition of adverse device effects (section 0) 
1376 
 
1377 
All reportable Adverse Events and Adverse Device Effects, whether volunteered by the 
1378 
participant’s parents, discovered by study personnel during questioning, or detected through 
1379 
physical examination, laboratory testing, or other means, will be reported online on an adverse 
1380 
event form. The Medical Monitor will review each adverse event form to verify the coding. 
1381 
 
1382 
6.4 
Relationship of Adverse Event to Study Drug, Device or Procedure 
1383 
The study investigator will assess the relationship of each adverse event to be related or unrelated 
1384 
to the study treatment or procedure by deciding if there is a reasonable possibility that the adverse 
1385 
event may have been caused by the treatment or study procedure. The Medical Monitor also will 
1386 
make this assessment, which may or may not agree with that of the site investigator. Reporting 
1387 
requirements will be based on the Medical Monitor’s assessment. The investigator brochure that 
1388 
will be developed will list potential adverse events that may be expected.  
1389 
 
1390 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1391 
following general guideline when determining whether an adverse event is related: 
1392 
 
1393 
Yes 
1394 
There is a plausible temporal relationship between the onset of the adverse event and 
1395 
administration of the study treatment, and the adverse event cannot be readily explained by 
1396 
the participant’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
1397 
adverse event follows a known pattern of response to the study treatment. 
1398 
 
1399 
No 
1400 
Evidence exists that the adverse event has an etiology other than the study treatment (e.g., 
1401 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
1402 
medication), and/or the adverse event has no plausible temporal relationship to study 
1403 
treatment administration.  
1404 
 
1405 
6.5 
Severity (Intensity) of Adverse Event 
1406 
The severity (intensity) of an adverse event will be rated by the site investigator and Medical 
1407 
Monitor. A severity assessment is a clinical determination of the maximum intensity of the adverse 
1408 
event. Thus, a severe adverse event is not necessarily serious. For example, itching for several days 
1409 
may be rated as severe, but may not be clinically serious. 
1410 
 
1411 
• MILD: Usually transient, requires no special treatment, and does not interfere with the 
1412 
participant’s daily activities. 
1413 
 
1414 
• MODERATE: Usually causes a low level of inconvenience, discomfort, or concern to 
1415 
the participant and may interfere with daily activities, but is usually ameliorated by 
1416 
simple therapeutic measures, and the participant is able to continue in the study. 
1417 
 
1418 
• SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may 
1419 
cause discontinuation of study drug, and generally requires systemic drug therapy or 
1420 
other treatment. 
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1422 
6.6 
Expectedness 
1423 
For a serious adverse event that is considered possibly related to the study treatment, the Medical 
1424 
Monitor will classify the event as unexpected if the nature, severity, or frequency is inconsistent 
1425 
with the risk information previously described in the background section.  
1426 
 
1427 
6.7 
Coding of Adverse Events 
1428 
Adverse events will be coded using the MedDRA dictionary. To facilitate coding, the site will enter 
1429 
a preliminary event descriptor code, which the Medical Monitor may accept or change (the Medical 
1430 
Monitor’s coding will be used for all reporting and the site’s preliminary coding will not be updated 
1431 
or used in reporting).  
1432 
 
1433 
The Medical Monitor will review the investigator’s assessments of causality and severity and may 
1434 
agree or disagree. For causality, the Medical Monitor will only attempt to reconcile differences for 
1435 
causality when one party’s coding is no/unlikely and the other party’s coding is possible/probable/ 
1436 
definite. For severity, the Medical Monitor will only attempt to reconcile differences when one 
1437 
party codes as severe and the other party as mild/moderate. The investigator’s and Medical 
1438 
Monitor’s assessments do not need to agree. For reporting purposes, the Medical Monitor will make 
1439 
the final determination with respect to causality as well as whether an event is classified as a serious 
1440 
adverse event and/or an unanticipated adverse device effect. However, both the investigator’s and 
1441 
the Medical Monitor’s coding will be recorded. 
1442 
 
1443 
6.8 
Outcome of Adverse Event 
1444 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1445 
 
1446 
 
RECOVERED/RESOLVED: The participant recovered from the AE/SAE without sequelae. 
1447 
Record the AE/SAE stop date. 
1448 
 
RECOVERED/RESOLVED WITH SEQUELAE: The event persisted and stabilized without 
1449 
change in the event anticipated. Record the AE/SAE stop date. 
1450 
 
FATAL: A fatal outcome is defined as an SAE that results in death. Only the event that was 
1451 
the cause of death should be reported as fatal. AEs/SAEs that were ongoing at the time of 
1452 
death, but were not the cause of death, will be recorded as “resolved” at the time of death. 
1453 
Primary and secondary (if applicable) causes of death will be recorded. 
1454 
 
NOT RECOVERED/NOT RESOLVED (ONGOING): An ongoing AE/SAE is defined as a 
1455 
still ongoing event with an undetermined outcome. 
1456 
 
An unresolved outcome will require follow up by the site to determine the final outcome 
1457 
of the AE/SAE. 
1458 
The outcome of an ongoing event at the time of death that was not the cause of death 
1459 
will be updated and recorded as “resolved,” with the date of death recorded as the stop 
1460 
date.  
1461 
• UNKNOWN: An unknown outcome is defined as an inability to contact the participant or 
1462 
access the participant’s records to determine the outcome (for example, a participant lost to 
1463 
follow-up). 
1464 
 
1465 
If any reported adverse events are ongoing when a participant completes the study (or withdraws), 
1466 
adverse events classified as suspected, unexpected serious adverse reactions (SUSARs) will be 
1467 
followed until they are either resolved or have no prospect of improvement or change, even after the 
1468 
participant has completed all study visits/contacts. For all other adverse events, data collection will 
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end when the participant completes the study. Note: participants should continue to receive 
1470 
appropriate medical care for an unresolved adverse event after their participation in the study ends. 
1471 
 
1472 
6.9 
Reportable Device (Spectacles) Issues  
1473 
All UADEs and ADEs as defined in section 0 will be reported on both a Device Issue CRF and AE 
1474 
CRF. 
1475 
 
1476 
Study device complaints and device malfunctions will be reported except in the following 
1477 
circumstances. These occurrences are expected and will not be reported on a Device Issue CRF 
1478 
assuming criteria for a UADE or ADE have not been met. 
1479 
 
1480 
6.10 Timing of Event Reporting 
1481 
Serious or unexpected adverse events must be reported to the JCHR within 24 hours by completing 
1482 
the online adverse event form. 
1483 
 
1484 
Other reportable adverse events will be reported within three (3) days of the site staff becoming 
1485 
aware of the event by completion of an electronic case report form.  
1486 
 
1487 
Each principal investigator is responsible for reporting study-related events and abiding by any 
1488 
other reporting requirements specific to his/her local Institutional Review Board or Ethics 
1489 
Committee. As the JCHR IRB is the overseeing IRB, sites must also report all serious adverse 
1490 
events that they have determined to be unexpected and are probably, possibly, or definitely related 
1491 
to the study to the JCHR IRB within seven (7) calendar days.  
1492 
 
1493 
The JCHR will be responsible for notifying the FDA and all participating investigators of any 
1494 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case 
1495 
later than seven (7) calendar days after initial receipt of the information. In addition, the JCHR will 
1496 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
1497 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case 
1498 
later than fifteen (15) calendar days after the sponsor determines that the information qualifies for 
1499 
reporting.  
1500 
 
1501 
6.11 Safety Oversight 
1502 
The Medical Monitor will review all adverse events that are reported during the study. SAEs 
1503 
typically will be reviewed within twenty-four (24) hours of reporting. Other AEs typically will be 
1504 
reviewed on a weekly basis.  
1505 
 
1506 
A Data and Safety Monitoring Committee (DSMC) will review compiled safety data at periodic 
1507 
intervals, with a frequency of no less than twice a year. The DSMC can request modifications to the 
1508 
study protocol, suspension, or outright stoppage of the study if deemed necessary based on the 
1509 
safety data available. Details regarding the DSMC review will be documented in a separate DSMC 
1510 
charter.  
1511 
 
1512 
The objective of the DSMC review is to determine whether the study (or the treatment for an 
1513 
individual or study cohort) should continue as planned, proceed with caution, undergo further 
1514 
investigation, be discontinued, or be modified before continuing. Suspension of enrollment (for a 
1515 
particular group, a particular study site, or for the entire study) is a potential outcome of a DSMC 
1516 
safety review. 
1517 
 
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6.12 Criteria for Suspending or Stopping Study  
1519 
The study may be discontinued by the Steering Committee (with approval of the Data and Safety 
1520 
Monitoring Committee) prior to the preplanned completion of follow-up for all study participants. 
1521 
 
1522 
The study may also be suspended or discontinued if the Medical Monitor deems it necessary based 
1523 
on the totality of safety data available or if the manufacturer of any constituent study medication or 
1524 
device requires stoppage of use for safety reasons (e.g., drug or product recall). 
1525 
 
1526 
6.13 Participant Discontinuation of Study Treatment 
1527 
Rules for discontinuing study treatment (spectacles and/or eyedrops) use are:  
1528 
 
1529 
1. The investigator believes it is unsafe for the participant to continue to receive the treatment.  
1530 
2. The participant requests that the treatment be stopped. 
1531 
3. Eyedrop discontinuation in case of participant pregnancy 
1532 
 
1533 
Even if the study treatment is discontinued, the participant will be encouraged to remain in the study 
1534 
and complete all remaining study visits. For each specific treatment discontinued, the CRF 
1535 
treatment prescribed form at each subsequent visit will record that the specified treatment was 
1536 
discontinued (spectacles, medication) and the reason.  
1537 
 
1538 
Participants who discontinue the study will be included in the primary analysis of all randomized 
1539 
patients who complete the 24-month visit. 
 
1540 

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Chapter 7: 
Miscellaneous Considerations 
1541 
 
1542 
7.1 
Contacts by the Jaeb Center for Health Research and Sites 
1543 
The Jaeb Center is the Sponsor and also serves as the PEDIG Coordinating Center. The Jaeb Center 
1544 
will be provided with the parent’s contact information. The Jaeb Center may contact the parents of 
1545 
the participants. Permission for such contacts will be included in the Informed Consent Form. The 
1546 
principal purpose of the contacts will be to develop and maintain rapport with the participant and 
1547 
family and to help coordinate the scheduling of the outcome examinations.  
1548 
 
1549 
7.2 
Pregnancy Reporting 
1550 
If pregnancy occurs, eyedrops will be discontinued, but the participant will continue wearing the 
1551 
randomized spectacle lenses and remain in the study.  The occurrence of pregnancy will be reported 
1552 
to the JCHR via the study database, and to the JCHR IRB via the Unanticipated Problem xForm in 
1553 
IRBManager, within seven (7) days of the site learning of the pregnancy.  
1554 
 
1555 
7.3 
Prohibited Medications, Treatments, and Procedures 
1556 
As previously described, participants are prohibited from using other myopia-control treatments and 
1557 
contact lens wear during the study.  
1558 
 
1559 
7.4 
Precautionary Medications, Treatments, and Procedures 
1560 
There are no precautionary medications, treatments, or procedures. 
1561 
 
1562 
7.5 
Participant Compensation 
1563 
Participant compensation will be specified in the informed consent form. 
1564 
 
1565 
7.6 
Participant Withdrawal 
1566 
Participation in the study is voluntary, and a participant may withdraw at any time. For participants 
1567 
who withdraw, their data will be used up until the time of withdrawal. 
1568 
 
1569 
7.7 
Confidentiality 
1570 
For security and confidentiality purposes, participants will be assigned an identifier that will be used 
1571 
instead of their name. Protected health information gathered for this study will be shared with the 
1572 
Jaeb Center for Health Research in Tampa, FL as specified in the consent forms. De-identified 
1573 
participant information may also be provided to research sites involved in the study, also as 
1574 
specified in the consent forms.
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Chapter 8: 
Statistical Considerations 
1576 
 
1577 
8.1 
Statistical and Analytical Plans  
1578 
The approaches to sample size and statistical analyses are summarized below.  
1579 
 
1580 
8.2 
Statistical Hypotheses 
1581 
A test of superiority will be used to evaluate three treatment-group comparisons for the change in 
1582 
axial length from baseline to the 24-month visit (primary outcome): 
1583 
 
1584 
• Between spectacles with single vision lenses + nightly placebo eye drops (hereafter 
1585 
PLACEBO group) and spectacle lenses with H.A.L.T. MAX technology lenses + nightly 
1586 
placebo eye drop (hereafter H.A.L.T. MAX group)  
1587 
 
1588 
AND 
1589 
 
1590 
• Between PLACEBO group and spectacles with single vision lenses + nightly atropine 
1591 
0.05% eye drop (hereafter ATROPINE group) 
1592 
 
1593 
AND 
1594 
 
1595 
• Between PLACEBO group and spectacle lenses with H.A.L.T. MAX technology + nightly 
1596 
atropine 0.05% eye drop (hereafter COMBINED group) 
1597 
 
1598 
The familywise error rate will be controlled for multiplicity arising from multiple treatment group 
1599 
comparisons with a common control using the Dunnett procedure (see Section 8.15). 
1600 
 
1601 
For each comparison, the following hypotheses will be evaluated: 
1602 
 
1603 
• Null Hypothesis (H0): There is no difference in the primary outcome between the 
1604 
PLACEBO group and the treatment group. 
1605 
 
1606 
• Alternative Hypothesis (Ha): There is a nonzero difference in the primary outcome between 
1607 
the PLACEBO group and the treatment group. 
1608 
 
1609 
8.3 
Sample Size 
1610 
 
1611 
8.3.1 Estimate of Effect with PLACEBO 
1612 
Data from the MTS1 randomized trial of 0.01% atropine eyedrops vs. placebo eyedrops were used 
1613 
to estimate the effect of PLACEBO in the current study.17 Among participants in MTS1 who were 
1614 
aged 5 to <12 years at enrollment and randomized to spectacles with single vision lenses and daily 
1615 
placebo eye drop, 53 completed 24 months of follow-up. The mean change in axial length from 
1616 
baseline after 24 months was 0.43 mm (95% CI: 0.35 to 0.51 mm), and the standard deviation was 
1617 
0.28 mm (95% CI: 0.23 to 0.32 mm). The standard deviation adjusted for baseline axial length and 
1618 
age was 0.24 mm (95% CI: 0.17 to 0.29 mm).  
1619 
 
1620 
The mean change in spherical equivalent refractive error (SER) after 24 months was -0.77 D (95% 
1621 
CI: -0.94 to -0.60 D), and the standard deviation was 0.60 D (95% CI: 0.47 to 0.71 D). The standard 
1622 
deviation adjusted for baseline SER and age was 0.56 D (95% CI: 0.42 to 0.66 D).  
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1624 
8.3.2 Estimate of Effect with Spectacle Lenses with H.A.L.T. MAX Technology 
1625 
Because only one study has evaluated spectacle lenses with H.A.L.T. MAX technology, using a 
1626 
contralateral crossover design over a 12-month study period in a cohort of 50 children in Singapore, 
1627 
44 sample size estimates for the present study are informed by data from prior studies of spectacle 
1628 
lenses with HAL. A previous study of spectacle lenses with HAL vs spectacle lenses with SAL vs 
1629 
SVL lenses demonstrated a clear dose-response relationship in treatment effect (see Bao et al. in 
1630 
Table 1 below).Based on these findings, we hypothesize that, in a U.S. population, the treatment 
1631 
effect of spectacle lenses with H.A.L.T. MAX technology will be at least as large as, and potentially 
1632 
greater than, that observed with the previous generation spectacle lenses with HAL. In other words, 
1633 
we hypothesize that the treatment effect with spectacle lenses with H.A.L.T. MAX technology≥ 
1634 
spectacle lenses with HAL > spectacle lenses with SAL > SVL. 
1635 
 
1636 
8.3.3 Estimate of Effect with ATROPINE and with Spectacle Lenses with HAL 
1637 
Prior studies in Asian populations evaluating either nightly 0.05% atropine eye drops or spectacle 
1638 
lenses with HAL 28, 37, 38, 40 and one study evaluating spectacle lenses with HAL in the U.S. have 
1639 
demonstrated a reduction in SER and axial length greater than 50% (Table 1).42    
1640 
 
1641 
This study will be powered to detect a treatment effect (ATROPINE, H.A.L.T. MAX, OR 
1642 
COMBINED) versus PLACEBO equal to a 40% reduction in myopia progression and axial length 
1643 
change after 24 months. Because studies conducted in Asian populations and in the U.S. saw a 
1644 
larger effect (>50% reduction), this choice of 40% is a conservative estimate.28, 37 
1645 
 
1646 
Table 1. Prior Studies of Daily Atropine 0.05% and of Spectacles with HAL Lenses for 
1647 
Myopia Treatment  
1648 
Study 
& 
Populati
on 
Treatment 
Studied 
Treatment Effect (Follow-up – Baseline) 
Percentage 
Reduction in 
Myopia 
Progression over 
24 Months 
(Active 
Treatment vs. 
Placebo) 
Mean change in axial 
length (mm) at 24 
months (Standard 
Deviation) 
Mean change in SER (D) at 
24 months (Standard 
Deviation) 
Axial  
Length 
SER 
Placebo  
Active 
Treatment  Placebo  
Active 
Treatment  
Zhu et 
al28 
Asian 
Atropine 
0.05% 
N=70 
0.76 (0.62) 
N=72 
0.26 (0.30) 
N=70 
-1.72 (1.12) 
N=72 
-0.46 (0.30) 
66% 
73% 
Bao et 
al40* 
Asian 
Spectacle 
lenses with 
HAL  
N=50 
0.69 (0.28) 
N=54 
0.34 (0.22) 
N=50 
-1.46 (0.64) 
N=54 
-0.66 (0.66) 
51% 
55% 
Spectacle 
lenses with 
SAL  
N=50 
0.69 (0.28) 
N=53 
0.51 (0.29) 
N=50 
-1.46 (0.64) 
N=53 
-1.04 (0.44) 
26% 
29% 
FIN-
3101 
Study**4
2 
US 
Spectacle 
lenses with 
HAL  
N=132 
0.44 (0.24) 
N=136 
0.20 (0.23) 
N=130 
-0.85 (0.70) 
N=136 
-0.22 (0.53) 
55% 
74% 
*Standard deviations calculated from reported standard errors multiplied by the square root of the sample size.  
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**The U.S. FDA evaluated two years of data from a clinical trial of 149 children across 9 clinical sites in the U.S. that 
1650 
demonstrated that spectacle lenses with HAL slowed myopia progression compared to single vision control lenses. 42 
1651 
 
1652 
8.3.4 Required Sample Size for Current Study 
1653 
Sample size has been calculated for 90% power and 5% familywise type 1 error rate (two-sided 
1654 
1.87% comparison-wise type 1 error rate [critical value of t∞ = 2.35] based on the Dunnett 
1655 
procedure, see Section 8.15). 
1656 
 
1657 
If the true mean difference in change in AL is 0.17 mm (i.e., a 40% reduction in progression relative 
1658 
to similarly aged MTS1 control group participants) and the adjusted standard deviation for change 
1659 
in AL is 0.29 mm, then the sample size required per group is 78 participants for a total of 312 across 
1660 
4 groups (PLACEBO, H.A.L.T. MAX, ATROPINE, and COMBINED). Adjusting for 10% loss to 
1661 
follow-up results in a sample size of 87 participants per group, 348 total. If the true mean difference 
1662 
were 0.215 mm (i.e., a 50% reduction), then this sample size would provide 99% power.  
1663 
 
1664 
Assuming a 40% reduction in SER with treatment (mean difference of 0.31 D) and an adjusted 
1665 
standard deviation of 0.56 D, this sample size will provide 86% power for evaluating the difference 
1666 
in SER. If the true mean difference in SER were 0.385 D (i.e., a 50% reduction), then the power for 
1667 
SER would be 97%.  
1668 
 
1669 
Because age is associated with axial elongation (younger children experience greater changes) and 
1670 
relative treatment may be greater in younger children,44, 59 the maximum proportion of 10–<12-
1671 
year-olds will be capped at 40% (140 children). This will ensure at least 60% of the cohort is aged 
1672 
5–9 years.  
1673 
 
1674 
8.4 
Outcome Measures 
1675 
 
1676 
8.4.1 Primary Efficacy Outcome 
1677 
• Change in axial length from baseline to 24 months 
1678 
 
1679 
8.4.2 Secondary Efficacy Outcomes 
1680 
• Change in spherical equivalent refractive error (SER) from baseline to 24 months 
1681 
• Change in axial length from baseline to 30 months 
1682 
• Change in SER from baseline to 30 months 
1683 
• Change in axial length from baseline to 18 months 
1684 
• Change in SER from baseline to 18 months 
1685 
• Change in axial length from baseline to 12 months 
1686 
• Change in SER from baseline to 12 months 
1687 
• Change in axial length from baseline to 6 months 
1688 
• Change in SER from baseline to 6 months 
1689 
 
1690 
8.4.3 Exploratory Outcomes 
1691 
• Change in monocular amplitude of accommodation from baseline to 6, 12, 18, 24, and 30 
1692 
months 
1693 
• Change in pupil size from baseline to 6, 12, 18, 24, and 30 months 
1694 
• Change in flat corneal radius from baseline to 6, 12, 18, 24, and 30 months 
1695 
• Change in axial length from baseline over 24 months (area under the curve) 
1696 
• Change in axial length from 12 to 24 months 
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• Change in axial length from 24 to 30 months 
1698 
• Change in SER from baseline over 24 months (area under the curve) 
1699 
• Change in SER from 12 to 24 months 
1700 
• Change in SER from 24 to 30 months 
1701 
• Child and Parent Treatment Impact Questionnaire scores at 6 months and 24 months. 
1702 
 
1703 
8.5 
Analysis Cohorts 
1704 
• Intention-To-Treat (ITT) Analysis Cohort: all randomized participants, irrespective of 
1705 
treatment received, will be analyzed according to treatment assignment. 
1706 
• Safety Analysis Cohort: participants who receive at least one dose of the randomly assigned 
1707 
study medication (placebo or 0.05% atropine) or wear the randomly assigned spectacles 
1708 
(spectacle lenses with H.A.L.T. MAX technology or SVL) for any amount of time. 
1709 
 
1710 
The primary analysis will follow the ITT principle. It will include all randomized participants. The 
1711 
data from the ITT cohort will be analyzed according to the group to which the participants were 
1712 
assigned through randomization, regardless of treatment received. 
1713 
 
1714 
8.6 
Analysis of the Primary Efficacy Outcome 
1715 
The average of three separate axial length measurements will be calculated for each eye at baseline 
1716 
and all follow-up visits. If fewer than three measurements are available for an eye at a timepoint, the 
1717 
mean of the available measurements will be used to calculate the mean axial length for each eye. 
1718 
The mean of the right and left eyes will be used for analysis. The change in mean axial length from 
1719 
baseline to the 24-month visit will be used as the primary outcome.  
1720 
 
1721 
The primary analysis will be a treatment group comparison of change in axial length from baseline 
1722 
to 24-month visit, using a longitudinal discrete time mixed effects model using axial length at 
1723 
randomization, 6, 12, 18, and 24 months as dependent variable and adjusting for age to account for 
1724 
confounding due to potential imbalances between groups and to increase statistical power. The 
1725 
treatment group difference (active treatment – placebo) for change in mean axial length from 
1726 
baseline to 24 months, confidence interval, and P value for the null hypothesis of no difference will 
1727 
be calculated based on the model estimates at 24 months. 
1728 
 
1729 
The model assumption for the mixed model will be assessed, including the linearity of the 
1730 
adjustment covariates (baseline axial length and age), and normality and homoscedasticity of the 
1731 
residuals.  
1732 
 
1733 
Only data from visits completed within the analysis windows (±3 months from the expected visit 
1734 
date) will be included in the analysis. There will be no explicit imputation of outcome data for 
1735 
exams not completed or completed outside of the analysis window, as the mixed model will 
1736 
produce an unbiased estimate of treatment effect via direct maximum likelihood as long as the 
1737 
missing outcome data are missing at random (MAR).  
1738 
 
1739 
Sensitivity analyses evaluating the robustness of the primary analysis will be outlined in the 
1740 
statistical analysis plan. 
1741 
 
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8.7 
Analysis of the Secondary Outcomes 
1743 
 
1744 
8.7.1 Change in Spherical Equivalent Refractive Error from Baseline to 24 Months 
1745 
The mean SER of each eye at baseline and all follow-up visits, measured by the masked examiner 
1746 
using cycloplegic autorefraction, will be calculated as the average of the three separate readings 
1747 
from autorefraction. If fewer than three readings are available, the average of available readings will 
1748 
be used. The mean of the right and left eyes will be used for analysis. A longitudinal discrete time 
1749 
mixed effects model will be used for treatment group comparison of change in SER from baseline 
1750 
to the 24-month visit using SER at randomization, 6, 12, 18, and 24 months as dependent variables 
1751 
and adjusting for age. The other aspects of the analysis are the same as outlined in the primary 
1752 
analyses (Section 8.4.1). 
1753 
 
1754 
8.7.2 Change in Axial Length from Baseline to 30 Months 
1755 
The same method described for the primary outcome (Section 8.4.1) will be used, but data from 6, 
1756 
12, 18, 24, and 30 months will be included in the model. 
1757 
 
1758 
8.7.3 Change in Spherical Equivalent Refractive Error from Baseline to 30 Months 
1759 
The same method as described in Section 0 will be used but with data from 6, 12, 18, 24, and 30 
1760 
months included in the model. 
1761 
 
1762 
8.7.4 Changes in Axial Length and SER at 6, 12, and 18 Months 
1763 
The same methods described in Sections 8.4.1 and 0 will be used. 
1764 
  
1765 
8.8 
Analyses of Exploratory Outcomes 
1766 
 
1767 
8.8.1 Change in Monocular Amplitude of Accommodation at 6, 12, 18, 24, and 30 Months 
1768 
Change in the monocular amplitude of accommodation will be analyzed using a discrete time 
1769 
longitudinal mixed effects model adjusted for age similar to the primary outcome (Section 8.4.1). 
1770 
 
1771 
8.8.2 Change in Pupil Size at 6, 12, 18, 24, and 30 Months 
1772 
Change in pupil will be analyzed using a discrete-time longitudinal mixed effects model adjusted 
1773 
for age similar to the primary outcome (Section 8.4.1). 
1774 
 
1775 
8.8.3 Change in Flat Corneal Radius at 6, 12, 18, 24, and 30 Months 
1776 
Change in flat corneal radius will be analyzed using a discrete-time longitudinal mixed effects 
1777 
model adjusted for age similar to the primary outcome (Section 8.4.1). 
1778 
 
1779 
8.8.4 Change in Axial Length Over 24 Months (Area Under the Curve) 
1780 
The change in axial length over 24 months (area under the curve) will be calculated and compared 
1781 
between treatment groups using the same discrete-time longitudinal mixed effects model used for 
1782 
the analyses of the primary outcome (Section 8.4.1). The area under the curve can be interpreted as 
1783 
a weighted average of the change in axial length at each visit with weights proportional to the time 
1784 
between visits.  
1785 
 
1786 
AUC will be calculated by linear combination of model estimates using the trapezoidal rule and the 
1787 
following formula: 
1788 
𝐴𝑈𝐶= ∑(𝑋𝑖+ 𝑋𝑖+1
2
× 𝑚)
𝑛
𝑖=1
  
1789 

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1790 
Where Xi is the axial length measured at the ith visit, m is the number of months between visits i and 
1791 
i+1, and n is the number of outcome visits included in the analysis. In this analysis there are n = 5 
1792 
visits total: 0, 6, 12, 18, and 24 months. For presentation, AUC will be divided by the number of 
1793 
months between baseline and the nth visit (i.e., 24) so that the value calculated will have units of 
1794 
millimeters rather than millimetermonths.  
1795 
 
1796 
8.8.5 Change in Axial Length from 12 to 24 Months  
1797 
The change in axial length from 12 to 24 months will be calculated and compared between 
1798 
treatment groups using the same discrete-time longitudinal mixed effects model used for the 
1799 
analyses of the primary outcome (Section 8.4.1). 
1800 
 
1801 
8.8.6 Change in Axial Length from 24 to 30 Months  
1802 
The change in axial length from 24 to 30 months will be calculated and compared between 
1803 
treatment groups using the same discrete-time longitudinal mixed effects model used for the 
1804 
analyses of the secondary outcome of change in axial length from baseline to 30 months (Section 
1805 
8.7.2).  
1806 
 
1807 
8.8.7 Change in Spherical Equivalent Refractive Error from 12 to 24 Months  
1808 
The change in SER from 12 to 24 months will be calculated and compared between treatment 
1809 
groups using the same discrete-time longitudinal mixed effects model used for the analyses of the 
1810 
secondary outcome of change in SER from baseline to 24 months (Section 8.7.1). 
1811 
 
1812 
8.8.8 Change in Spherical Equivalent Refractive Error from 24 to 30 Months  
1813 
The change in SER from 24 to 30 months will be calculated and compared between treatment 
1814 
groups using the same discrete-time longitudinal mixed effects model used for the analyses of the 
1815 
secondary outcome of change in SER from baseline to 30 months (Section 8.7.3).  
1816 
 
1817 
8.8.9 Change in Spherical Equivalent Refractive Error Over 24 Months  
1818 
The change in SER over 24 months (area under the curve) will be calculated and compared between 
1819 
treatment groups using the same discrete-time longitudinal mixed effects model used for the 
1820 
analyses of the primary outcome (Section 8.4.1). The area under the curve can be interpreted as a 
1821 
weighted average of the change in SER at each visit with weights proportional to the time between 
1822 
visits. AUC will be calculated as described in Section 8.8.4. 
1823 
 
1824 
8.8.10 Treatment Impact Questionnaire 
1825 
The Treatment Impact Questionnaire (TIQ) will be used as a quantitative measure to evaluate 
1826 
opinions regarding the burdens and impact of the randomized treatment at 6 months and 24 months 
1827 
(as questions for the child – the Child TIQ and the parent themselves – the Parent TIQ).   
1828 
 
1829 
The Child-TIQ and Parent-TIQ will undergo separate factor analysis to determine the number of 
1830 
domains for each TIQ. Each domain will be refined through the evaluation of misfitting items and 
1831 
will then be Rasch scored.  
1832 
 
1833 
Note that because the TIQ is not administered at baseline (because treatment has not been started), 
1834 
there will be no adjustment for baseline score in any analysis.  
1835 
 
1836 
Additional methods to score and analyze the Treatment Impact Questionnaire will be detailed in a 
1837 
separate SAP. 
1838 

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1839 
8.9 
Safety Analyses 
1840 
Safety analyses will be performed in the safety analysis cohort (section 8.5Error! Reference 
1841 
source not found.). Adverse events will be coded and tabulated based on the Medical Dictionary of 
1842 
Regulatory Activities (MedDRA) by treatment group. The severity, frequency, and relationship to 
1843 
study treatment will also be tabulated. There will be no formal statistical comparison of adverse 
1844 
events.  
1845 
 
1846 
The proportion of participants with loss of ≥ 2 logMAR lines of binocular near visual acuity at any 
1847 
visit after randomization will be tabulated for each group and compared using the Barnard 
1848 
Unconditional Exact Test; risk differences and 95% CIs will be estimated using the exact Mid-P 
1849 
method of Agresti and Min.60  
1850 
 
1851 
The proportion of participants with loss of ≥ 2 logMAR lines of monocular distance visual acuity in 
1852 
best correction at any visit after randomization will be tabulated for each group and compared using 
1853 
the Barnard Unconditional Exact Test; risk differences and 95% CIs will be estimated using the 
1854 
exact Mid-P method of Agresti and Min.  
1855 
 
1856 
8.10 Intervention Adherence 
1857 
Adherence to study eyedrops (atropine and placebo eyedrop) and spectacles (SVL and spectacle 
1858 
lenses with H.A.L.T. MAX technology) based on calendars brought to each follow-up visit will be 
1859 
tabulated in each treatment group. 
1860 
 
1861 
8.11 Protocol Adherence and Retention 
1862 
Protocol deviations and visit completion rates (excluding participant deaths) will be tabulated for 
1863 
each treatment group. 
1864 
 
1865 
8.12 Baseline Descriptive Statistics 
1866 
The following baseline characteristics will be tabulated according to treatment group: 
1867 
• Age 
1868 
• Sex 
1869 
• Race 
1870 
• Ethnicity 
1871 
• Iris color 
1872 
• Number of biological parents with myopia 
1873 
• Distance visual acuity in habitual refractive correction 
1874 
 
1875 
8.13 Planned Interim Analyses 
1876 
There are no formal planned interim analyses for this study. The Data and Safety Monitoring 
1877 
Committee will review safety and efficacy data approximately every 6 months; they have the 
1878 
authority to recommend stopping the trial if deemed necessary.  
1879 
 
1880 
8.14 Subgroup Analyses 
1881 
Subgroup analyses will be considered exploratory. The treatment group difference for change in 
1882 
axial length and change in SER from baseline to 24 within the following subgroups will be 
1883 
evaluated: 
1884 
• Sex 
1885 
• ”East Asian or Southeast Asian” vs. “Not East Asian or Southeast Asian”  
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• Brown iris vs. non-brown iris 
1887 
• Age (continuous) 
1888 
• Axial Length (continuous) 
1889 
• SER (continuous) 
1890 
 
1891 
These planned subgroup analyses will modify the primary and secondary analyses by including the 
1892 
baseline factor and the baseline factor by treatment interaction. In general, statistical power will be 
1893 
low for detecting interactions unless the interaction is very large.  
1894 
 
1895 
Subgroup analyses will be interpreted with caution, particularly if the corresponding overall 
1896 
analysis does not demonstrate a significant treatment group difference. 
1897 
 
1898 
8.15 Multiple Comparison/Multiplicity 
1899 
To control for multiplicity arising from multiple treatment group comparisons (3 treatment groups 
1900 
each compared with a common control group), the Dunnett procedure with k equal to 3 will be 
1901 
used.61  
1902 
 
1903 
For the secondary outcomes (Section 8.4.2), multiplicity arising from evaluating multiple outcomes 
1904 
will be controlled with a hierarchical (i.e., fixed sequence) approach.62 If the null hypothesis for the 
1905 
primary outcome (axial length) is rejected, then the comparison of the first secondary outcome 
1906 
(change in SER at 24 months) will be considered confirmatory. If the primary outcome null 
1907 
hypothesis is not rejected, then the comparison of change in SER at 24 months will be considered 
1908 
exploratory; a 95% confidence interval (adjusted for multiple treatment group comparisons using 
1909 
the Dunnett procedure) will be presented, but a p-value will not be presented. Subsequent secondary 
1910 
outcomes will be tested in the order listed in Section 8.4.2.  
1911 
 
1912 
For exploratory outcomes, the adaptive two-stage step-up procedure63 will be used to control the 
1913 
false discovery rate at 5% by adjusting both the confidence intervals and P values for the analysis of 
1914 
multiple outcomes. The families for FDR adjustment will be as follows: 
1915 
 
1916 
• Pupil size, accommodation, and flat corneal radius 
1917 
• SER and axial length 
1918 
• Treatment Impact Questionnaire 
1919 
 
1920 
There will be no formal adjustment for safety analyses because type 2 errors (false negatives) are of 
1921 
greater concern than type 1 errors (false positives).  
1922 
 
1923 
The adaptive two-stage step-up procedure63 will be used to control the false discovery rate at 5% to 
1924 
for multiple subgroup analyses. Both interaction P values and within-group confidence intervals 
1925 
will be adjusted. P values for interactions will only be presented if the overall analysis indicates a 
1926 
significant effect.  
1927 
 
1928 
8.16 Additional Tabulations and Analyses 
1929 
• A flow chart accounting for all participants for all visits and phone calls will be developed.  
1930 
• Visit and phone contact completion rates for each follow-up visit will be tabulated. 
1931 
• Proportion of participants with a change in myopia of ≥ 0.50 D, ≥ 0.75 D, and ≥ 1.0 D from 
1932 
baseline to 12, 24, and 30 months. 
1933 
• Proportion of participants with a change in axial length ≥ 0.25 mm, ≥ 0.375 mm, and ≥ 0.50 
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mm from baseline to 12, 24, and 30 months. 
1935 
 
1936 
8.17 Exploratory Analyses in COMBINED Atropine + H.A.L.T. MAX Group 
1937 
Exploratory comparisons between the ATROPINE, H.A.L.T.  MAX, and COMBINED groups will 
1938 
parallel the analyses conducted for the ATROPINE vs PLACEBO, H.A.L.T.  MAX vs PLACEBO, 
1939 
and COMBINED vs PLACEBO comparisons.  
1940 
 
1941 
An exploratory analysis pooling across cells in the factorial design will be conducted if prespecified 
1942 
criteria suggesting absence of an interaction are met. Details will be provided in the SAP. 
1943 

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Chapter 9: 
Data Collection and Monitoring 
1944 
 
1945 
9.1 
Case Report Forms and Other Data Collection 
1946 
The main study data are collected on electronic case report forms (eCRFs). When data are directly 
1947 
collected in real-time in electronic case report forms, this will be considered the source data. For 
1948 
any data points for which the eCRF is not considered source (e.g., lab results that are transcribed 
1949 
from a printed report into the eCRF; other data that are not directly entered in real-time), the 
1950 
original source documentation must be maintained in the participant’s study chart or medical 
1951 
record. This source must be readily verifiable against the values entered into eCRF. Even where all 
1952 
study data are directly entered into the eCRFs at office visits, evidence of interaction with a live 
1953 
participant must be recorded (e.g., office note, visit record, etc.).  
1954 
 
1955 
Electronic device data files are obtained from the study software and individual hardware 
1956 
components. These electronic device files are considered the primary source documentation. 
1957 
Each participating site will maintain appropriate medical and research records for this trial, in 
1958 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1959 
confidentiality of participants. 
1960 
 
1961 
9.2 
Study Records Retention 
1962 
Study documents should be retained for a minimum of three (3) years after completion of the final 
1963 
grant reporting, or for two (2) years after a marketing application is approved for the investigational 
1964 
product(s); or, if an application is not approved, until two (2) years after shipment and delivery of 
1965 
the product for investigational use is discontinued and the FDA has been so notified. These 
1966 
documents should be retained for a longer period, however, if required by local regulations or 
1967 
institutional requirements. No records will be destroyed without the written consent of the sponsor. 
1968 
It is the responsibility of the sponsor to inform the investigator when these documents no longer 
1969 
need to be retained. 
1970 
 
1971 
9.3 
Quality Assurance and Monitoring 
1972 
Designated personnel from the JCHR will be responsible for maintaining quality assurance (QA) 
1973 
and quality control (QC) systems to ensure that the clinical portion of the trial is conducted and data 
1974 
are generated, documented, and reported in compliance with the protocol adhering to Good Clinical 
1975 
Practice (GCP) and the applicable regulatory requirements, as well as to ensure that the rights and 
1976 
wellbeing of trial participants are protected and that the reported trial data are accurate, complete, 
1977 
and verifiable. Adverse events will be prioritized for monitoring. 
1978 
 
1979 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the study, 
1980 
consistent with the FDA’s “Guidance for Industry Oversight of Clinical Investigations — A Risk-
1981 
Based Approach to Monitoring” (August 2013). This plan describes in detail who will conduct the 
1982 
monitoring, at what frequency monitoring will be done, at what level of detail monitoring will be 
1983 
performed, and the distribution of monitoring reports. 
1984 
 
1985 
The data of most importance for monitoring at the site are informed consent/assent, participant 
1986 
eligibility, and adverse events. Therefore, the RBM plan will focus on these areas. Whenever 
1987 
possible, remote monitoring will be conducted in real-time supplemented by on-site monitoring to 
1988 
evaluate the accuracy and completeness of the key study data.  
1989 
 
1990 
Elements of the RBM may include: 
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• Qualification assessment, training, and certification for sites and site personnel 
1992 
• Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
1993 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1994 
review of entered data and edits, statistical monitoring, study closeout 
1995 
• On-site monitoring (site visits): source data verification, site visit report 
1996 
• Agent/Device accountability 
1997 
• Communications with site staff 
1998 
• Patient retention and visit completion 
1999 
• Quality control reports 
2000 
• Management of noncompliance 
2001 
• Documenting monitoring activities 
2002 
• Adverse event reporting and monitoring 
2003 
 
2004 
JCHR representatives or their designees may visit the study facilities at any time to maintain current 
2005 
and personal knowledge of the study through review of the records, comparison with source 
2006 
documents, observation, and discussion of the conduct and progress of the study. The 
2007 
investigational site will provide direct access to all trial related sites, source data/documents, and 
2008 
reports for monitoring and auditing by the sponsor and inspection by local and regulatory 
2009 
authorities. 
2010 
 
2011 
9.4 
Protocol Deviations 
2012 
A protocol deviation is noncompliance with the clinical trial protocol, GCP, or clinical procedure 
2013 
requirements. Noncompliance may be on the part of the participant, the investigator, or the study 
2014 
site staff. As a result of deviations, the site must develop and implement corrective actions 
2015 
promptly. 
2016 
 
2017 
The site PI and study staff are responsible for knowing and adhering to their local requirements. 
2018 
Further details about the handling of protocol deviations will be included in the Monitoring Plan. 
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Chapter 10: 
Ethics/Protection of Human Participants 
2020 
 
2021 
10.1 Ethical Standard 
2022 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
2023 
Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR 
2024 
Part 56, and/or the ICH E6. 
2025 
 
2026 
10.2 Institutional Review Boards 
2027 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
2028 
submitted to the JCHR IRB for review and approval. Approval of both the protocol and the consent 
2029 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
2030 
require review and approval by the JCHR IRB before the changes are implemented to the study. All 
2031 
changes to the consent form will be JCHR IRB approved; a determination will be made regarding 
2032 
whether previously consented participants need to be re-consented. 
2033 
 
2034 
10.3 Informed Consent, Assent, and HIPAA Authorization Process 
2035 
 
2036 
10.3.1 Procedures and Documentation 
2037 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate, or 
2038 
allowing their child to participate, in the study and continues throughout study participation. Assent 
2039 
is the process by which a child is informed of the study and has the right and requirement to provide 
2040 
affirmative agreement to participate (verbally or in writing as required by the overseeing IRB). 
2041 
HIPAA Authorization is the process by which the parent/participant provides their approval to 
2042 
allow their protection health information to be collected and shared as specified in a similarly 
2043 
named document, or within the applicable section of the consent form. Extensive discussion of risks 
2044 
and possible benefits of participation will be provided to the participants and their parent(s). 
2045 
Consent, assent and HIPAA forms will be IRB-approved and the parent(s)/participant will be asked 
2046 
to read and review the document(s) as applicable. The investigator will explain the research study to 
2047 
the parent(s)/participant and answer any questions that may arise. All parents/participants will 
2048 
receive a verbal explanation in terms suited to their comprehension of the purposes, procedures, and 
2049 
potential risks of the study and of their rights as research participants. Parents/participants will have 
2050 
the opportunity to carefully review the written form(s) and ask questions prior to signing. 
2051 
 
2052 
The parents/participants should have the opportunity to discuss the study with their surrogates or 
2053 
think about it prior to agreeing to participate. The parent(s)/participant will sign the applicable 
2054 
forms prior to any procedures being done or data being collected for the study. The 
2055 
parents/participants may withdraw consent, assent or HIPAA Authorization at any time throughout 
2056 
the course of the study. A copy of the forms will be given to the parents/participants for their 
2057 
records. The rights and welfare of the participants will be protected by emphasizing that the quality 
2058 
of their medical care and benefits to which they are otherwise entitled will not be adversely affected 
2059 
if they decline to participate in this study or withdraw at a later date. 
2060 
 
2061 
10.3.2 Participant and Data Confidentiality 
2062 
Parent/participant confidentiality is strictly held in trust by the participating investigators, their staff, 
2063 
and the sponsor(s) and their agents. This confidentiality is extended to include testing of biological 
2064 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
2065 
the study protocol, documentation, data, and all other information generated will be held in strict 
2066 

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confidence. No information concerning the study or the data from the study will be released to any 
2067 
unauthorized third party without prior written approval of the sponsor. 
2068 
 
2069 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
2070 
regulatory agencies, or company supplying the study product may inspect all documents and 
2071 
records required to be maintained by the investigator, including, but not limited to, medical records 
2072 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study 
2073 
site will permit access to such records. 
2074 
 
2075 
The study participant’s contact information will be securely stored at each clinical site for internal 
2076 
use during the study. At the end of the study, all records will remain in a secure location for as long 
2077 
as dictated by the reviewing IRB, institutional policies, or sponsor requirements. 
2078 
 
2079 
Study participant research data for statistical analysis and scientific reporting will be transmitted to 
2080 
and stored at the Jaeb Center for Health Research. This will not include the participant’s contact or 
2081 
identifying information. Instead, individual participants and their research data will be identified by 
2082 
a unique study identification number. The study data entry and management systems used by 
2083 
clinical sites and Jaeb Center for Health Research staff will be secured and password protected.  
2084 
 
2085 
At the end of the study, all study databases will be de-identified and archived at the Jaeb Center for 
2086 
Health Research. 
2087 
 
2088 
To further protect the privacy of study participants, a Certificate of Confidentiality is provided from 
2089 
the NIH. This certificate protects identifiable research information from forced disclosure. It allows 
2090 
the investigator and others who have access to research records to refuse to disclose identifying 
2091 
information on research participation in any civil, criminal, administrative, legislative, or other 
2092 
proceeding, whether at the federal, state, or local level. By protecting researchers and institutions 
2093 
from being compelled to disclose information that would identify research participants, Certificates 
2094 
of Confidentiality help achieve the research objectives and promote participation in studies by 
2095 
helping assure confidentiality and privacy to participants. 
2096 
 
2097 
10.3.3 Future Use of Data 
2098 
Data collected for this study will be analyzed and stored at the Jaeb Center for Health Research. 
2099 
After the study is completed, the de-identified, archived data will be made available to the public as 
2100 
specified in the consent form(s). 
2101 

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Chapter 11: 
References 
2102 
 
2103 
1. 
Pan CW, Ramamurthy D, Saw SM. Worldwide prevalence and risk factors for myopia. 
2104 
Ophthalmic Physiol Opt 2012;32:3-16. 
2105 
2. 
Foster PJ, Jiang Y. Epidemiology of myopia. Eye (Lond) 2014;28:202-208. 
2106 
3. 
French AN, Morgan IG, Burlutsky G, Mitchell P, Rose KA. Prevalence and 5- to 6-year 
2107 
incidence and progression of myopia and hyperopia in Australian schoolchildren. Ophthalmology 
2108 
2013;120:1482-1491. 
2109 
4. 
Giordano L, Friedman DS, Repka MX, et al. Prevalence of refractive error among preschool 
2110 
children in an urban population: the Baltimore Pediatric Eye Disease Study. Ophthalmology 
2111 
2009;116:739-746. 
2112 
5. 
Multi-Ethnic Pediatric Eye Disease Study Group. Prevalence of myopia, hyperopia, and 
2113 
astigmatism in non-Hispanic white and Asian children: multi-ethnic pediatric eye disease study. 
2114 
Ophthalmology 2013;120:2109-2116. 
2115 
6. 
Multi-Ethnic Pediatric Eye Disease Study Group. Prevalence of myopia and hyperopia in 6- 
2116 
to 72-month-old African American and Hispanic children: the Multi-Ethnic Pediatric Eye Disease 
2117 
Study. Ophthalmology 2010;117:140-147. 
2118 
7. 
Theophanous C, Modjtahedi BS, Batech M, Marlin DS, Luong TQ, Fong DS. Myopia 
2119 
prevalence and risk factors in children. Clin Ophthalmol 2018;12::1581-1587. 
2120 
8. 
Vitale S, Sperduto RD, Ferris FL, 3rd. Increased prevalence of myopia in the United States 
2121 
between 1971-1972 and 1999-2004. Arch Ophthalmol 2009;127:1632-1639. 
2122 
9. 
Holden BA, Fricke TR, Wilson DA, et al. Global prevalence of myopia and high myopia 
2123 
and temporal trends from 2000 through 2050. Ophthalmology 2016;123:1036-1042. 
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