A Multicenter, Randomized, Double-masked, Vehicle-controlled Study to Assess the Safety and Efficacy of SYD-101 Ophthalmic Solution for the Treatment of Myopia in Children
Phase: PHASE3
Conditions: Nearsightedness, Near Sightedness, Near-sightedness
Sponsor: Sydnexis, Inc.

 
CLINICAL STUDY PROTOCOL 
IND 128,081 
A Multicenter, Randomized, Double-Masked, Vehicle-Controlled Study to 
Assess the Safety and Efficacy of SYD-101 Ophthalmic Solution for the 
Treatment of Myopia in Children 
PROTOCOL NO. SYD-101-001 
NCT03918915 
Sponsor Sydnexis, Inc. 
445 Marine View Avenue, Suite 295 
Del Mar, CA 92014 USA 
Protocol Version and Date Version 3.0, 16 February 2023 
Version History Final Original Protocol (Version 1.0), 12 November 2018 
Amended Protocol Version 1.1, 01 February 2019 
Amended Protocol Version 1.2, 20 February 2019 
Amended Protocol Version 2.0, 13 November 2020 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Sydnexis, Inc.  The 
concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Sydnexis. 
The study will be conducted according to the International Council for Harmonisation harmonised 
tripartite guideline E6(R2): Good Clinical Practice.  
 

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PROTOCOL APPROVAL – SPONSOR SIGNATORY 
Study Title 
A Multicenter, Randomized, Double-Masked, Vehicle-Controlled 
Study to Assess the Safety and Efficacy of SYD-101 Ophthalmic 
Solution for the Treatment of Myopia in Children 
Protocol Number 
SYD-101-001 
Protocol Version 
and Date 
Version 3.0 
16 February 2023 
Protocol accepted and approved by:  
President 
Patrick Johnson, PhD 
Sydnexis, Inc. 
445 Marine View Avenue, Suite 295 
Del Mar, CA 92014 USA 
 
 
 
 
Signature 
 
Date 
 

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DECLARATION OF INVESTIGATOR 
I have read and understood all sections of the protocol entitled “A Multicenter, Randomized, 
Double-Masked, Vehicle-Controlled Study to Assess the Safety and Efficacy of SYD-101 Ophthalmic 
Solution for the Treatment of Myopia in Children” and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the current protocol, the International Council for Harmonisation harmonised 
tripartite guideline E6(R2): Good Clinical Practice, and all applicable government regulations.  I will 
not make changes to the protocol before consulting with Sydnexis, Inc. or implement protocol 
changes without independent ethics committee/institutional review board approval except to 
eliminate an immediate risk to participants.  I agree to administer study treatment only to 
participants under my personal supervision or the supervision of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it.  Confidentiality 
will be protected.  Participant identity will not be disclosed to third parties or appear in any study 
reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Sydnexis, Inc.  
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL APPROVAL – SPONSOR SIGNATORY ................................................................... 2 
DECLARATION OF INVESTIGATOR ............................................................................................... 3 
TABLE OF CONTENTS ...................................................................................................................... 4 
LIST OF TABLES .............................................................................................................................. 6 
1 
PROTOCOL SUMMARY ......................................................................................................... 7 
1.1 
Synopsis ........................................................................................................................... 7 
1.2 
Study Schema................................................................................................................ 10 
1.3 
Schedule of Activities (SOA) ....................................................................................... 11 
2 
INTRODUCTION ..................................................................................................................... 13 
2.1 
Background and Rationale .......................................................................................... 13 
2.1.1 
Epidemiology of Myopia ............................................................................. 13 
2.1.2 
Treatment of Myopia and Atropine ........................................................... 13 
2.1.3 
Rationale for Study...................................................................................... 15 
2.2 
Nonclinical Information ................................................................................................. 16 
2.3 
Risk/Benefit Assessment ............................................................................................. 16 
2.3.1 
Known Potential Risks ................................................................................ 16 
2.3.2 
Known Potential Benefits ........................................................................... 17 
2.3.3 
Assessment of Potential Risks and Benefits .......................................... 17 
3 
OBJECTIVES AND ENDPOINTS ........................................................................................ 18 
4 
STUDY DESIGN ..................................................................................................................... 21 
4.1 
Overall Design ............................................................................................................... 21 
4.2 
Scientific Rationale for Study Design ......................................................................... 22 
4.3 
Justification for Selected Doses .................................................................................. 23 
4.4 
End of Study Definition ................................................................................................. 23 
5 
STUDY POPULATION ........................................................................................................... 24 
5.1 
Inclusion Criteria ............................................................................................................ 24 
5.2 
Exclusion Criteria .......................................................................................................... 25 
5.3 
Lifestyle Considerations ............................................................................................... 26 
5.4 
Screen Failures.............................................................................................................. 26 
5.5 
Strategies for Recruitment and Retention ................................................................. 26 
6 
STUDY INTERVENTION ....................................................................................................... 27 
6.1 
Study Drug Administration ........................................................................................... 27 
6.1.1 
Description of Study Drug .......................................................................... 27 
6.1.2 
Dosing and Administration ......................................................................... 27 
6.2 
Study Drug Preparation/Handling/Storage/Accountability ...................................... 27 
6.2.1 
Acquisition and Accountability ................................................................... 27 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................. 27 
6.2.3 
Product Storage and Stability .................................................................... 28 
6.2.4 
Preparation ................................................................................................... 28 
6.3 
Measures to Minimize Bias: Randomization and Masking ..................................... 28 

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6.4 
Study Intervention Compliance ................................................................................... 29 
6.5 
Concomitant Therapy ................................................................................................... 29 
6.5.1 
Prohibited Therapy ...................................................................................... 30 
6.5.2 
Escape Medication ...................................................................................... 30 
7 
STUDY DRUG DISCONTINUATION AND PARTICIPANT DISCONTINUATION OR 
WITHDRAWAL FROM STUDY ............................................................................................ 31 
7.1 
Discontinuation of Study Drug ..................................................................................... 31 
7.2 
Participant Discontinuation/Withdrawal From the Study ......................................... 31 
7.3 
Lost to Follow-Up .......................................................................................................... 32 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 33 
8.1 
Efficacy Assessments ................................................................................................... 33 
8.2 
Safety and Other Assessments .................................................................................. 33 
8.3 
Adverse Events and Serious Adverse Events .......................................................... 35 
8.3.1 
Definition of Adverse Events (AE) ............................................................ 35 
8.3.2 
Definition of Serious Adverse Events (SAE) ........................................... 35 
8.3.3 
Classification of an Adverse Event ........................................................... 36 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ... 37 
8.3.5 
Adverse Event Reporting ........................................................................... 37 
8.3.6 
Serious Adverse Event Reporting ............................................................ 39 
8.3.7 
Reporting Events to Participants .............................................................. 39 
8.3.8 
Events of Special Interest .......................................................................... 39 
8.4 
Reporting of Pregnancy................................................................................................ 40 
8.5 
Procedures During COVID-19 Pandemic .................................................................. 40 
9 
STATISTICAL CONSIDERATIONS ..................................................................................... 41 
9.1 
Statistical Hypotheses .................................................................................................. 41 
9.1.1 
Primary Efficacy Estimands ....................................................................... 41 
9.1.2 
Secondary Efficacy Endpoints .................................................................. 49 
9.2 
Sample Size Determination ......................................................................................... 55 
9.3 
Populations for Analyses.............................................................................................. 57 
9.4 
Statistical Analyses ....................................................................................................... 58 
9.4.1 
General Approach ....................................................................................... 58 
9.4.2 
Analysis of the Primary Efficacy Endpoint ............................................... 58 
9.4.3 
Analysis of the Secondary Endpoints ...................................................... 61 
9.4.4 
Safety Analyses ........................................................................................... 62 
9.4.5 
Baseline Descriptive Statistics .................................................................. 63 
9.4.6 
Planned Interim Analyses .......................................................................... 63 
9.4.7 
SubGroup Analyses .................................................................................... 64 
9.4.8 
Tabulation of Individual Participant Data ................................................. 64 
9.4.9 
Exploratory Analyses .................................................................................. 64 
10 
REFERENCES ........................................................................................................................ 66 
11 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........ 69 
11.1 
Regulatory, Ethical, and Study Oversight Considerations ...................................... 69 

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11.1.1 
Ethical Conduct of the Study ..................................................................... 69 
11.1.2 
Study Discontinuation and Closure .......................................................... 71 
11.1.3 
Confidentiality and Privacy ........................................................................ 72 
11.1.4 
Future Use of Stored Specimens and Data ............................................ 73 
11.1.5 
Safety Oversight .......................................................................................... 73 
11.1.6 
Study Monitoring and Auditing .................................................................. 73 
11.1.7 
Quality Assurance and Quality Control .................................................... 74 
11.1.8 
Data Handling and Record Keeping ......................................................... 74 
11.1.9 
Protocol Deviations ..................................................................................... 76 
11.1.10 
Publication and Data Sharing Policy ........................................................ 76 
11.1.11 
Conflict of Interest Policy............................................................................ 76 
11.2 
Additional Considerations ............................................................................................ 76 
11.3 
Abbreviations ................................................................................................................. 77 
11.4 
Protocol Amendment History ....................................................................................... 78 
 
LIST OF TABLES 
Table 6-1: 
Summary of Study Drug Components ..................................................................... 27 
Table 8-1:  
PPD Pharmacovigilance Contact Information ........................................................ 39 
Table 9-1:  
Summary of Estimands for EMA and FDA ............................................................. 41 
Table 9-2:  
Summary of Intercurrent Event Handling for Primary Estimands ....................... 42 
Table 9-3:  
Summary of Additional Sensitivity Analyses........................................................... 45 
Table 9-4:  
Order of Testing Efficacy Endpoint for EMA and FDA Analyses......................... 50 
Table 9-5:  
Summary of Intercurrent Event Handling for Key Secondary Estimands .......... 52 
Table 9-6: 
Intercurrent Event Approaches for Secondary Estimands ................................... 54 
 

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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
A Multicenter, Randomized, Double-Masked, Vehicle-Controlled Study to 
Assess the Safety and Efficacy of SYD-101 Ophthalmic Solution for the 
Treatment of Myopia in Children 
Study Description: 
This multinational Phase 3 study has been designed to evaluate the 
following clinical hypotheses: 
• 
SYD-101 is safe as assessed by the incidence and severity of 
adverse events (AEs) compared with Vehicle 
• 
SYD-101 is superior to Vehicle in slowing the progression of 
myopia 
Objectives: 
Efficacy 
• 
To evaluate the efficacy of SYD-101 for slowing the progression of 
myopia in children 
Safety 
• 
To evaluate the safety and tolerability of SYD-101  
Endpoints and 
Scheduled Analyses: 
Analysis of safety and efficacy data will be performed at Month 24, 
Month 36, and Month 48.  For regulatory submission in the European 
Union (EU) and United States (US), endpoints will be analyzed as 
requested by the respective regulatory authorities.  Refer to 
Sections 3 and 9 of this protocol for details. 
Efficacy 
• 
Proportion of participants with confirmed myopic progression 
>0.75 diopters (D) 
• 
Mean annual progression rate of myopia 
• 
Proportion of participants with annual myopia progression rate 
≤0.50 D/year 
• 
Proportion of participants with annual myopia progression rate 
≤0.25 D/year 
• 
Proportion of participants with an increase of myopia >0.50 D 
• 
Time to progression of myopia >0.75 D  
• 
Mean annual progression rate using Month 24 data on Subgroup 
of participants with refractive history of progression ≥ 0.5D  
• 
Mean annual progression rate using Month 24 data on Subgroup 
of participants with refractive history of progression ≥ 0.75D  
• 
Mean change from baseline in axial length (at sites with the 
requisite equipment; at least 50% of study participants) 

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Safety  
• 
Evaluation of AEs and serious AEs 
• 
Changes from baseline in vital sign measurements 
• 
Mean change from baseline in pupil diameter 
Endpoints and 
Scheduled Analyses 
(continued): 
• 
Changes from baseline in eye examination findings (including 
best-corrected visual acuity (BCVA), biomicroscopy, intraocular 
pressure, and ophthalmoscopy) 
• 
Changes from baseline in corneal endothelial cell count (selected 
sites only; approximately 25% of study participants) 
• 
Tolerability questionnaire responses 
In addition, pregnancy tests will be administered to female participants of 
childbearing potential.  Pregnancy outcomes will be assessed. 
Study Population: 
A total of approximately 840 male and female pediatric participants with 
myopia, who are in good general health, and between 3 and 14 years of 
age (inclusive) will be enrolled in this study. 
Phase: 
3 
Description of Sites 
Enrolling Participants: 
Up to 41 study sites located in the United States (US) and up to 6 study 
sites located in Europe. 
Description of Study 
Intervention: 
There are 3 study drugs in this study, SYD-101 0.01%, SYD-101 0.03%, and 
Vehicle.  Study drug will be administered as eyedrops.  Each night at 
bedtime, 1 drop of assigned study drug will be instilled in each eye. 
SYD-101 0.01% is a sterile topical ophthalmic solution of atropine sulfate. 
SYD-101 0.03% is a sterile topical ophthalmic solution of atropine sulfate. 
Vehicle (control) is identical to SYD-101, except that it does not contain 
active drug and uses H2O instead of deuterium oxide (D2O). 
Escape Medication: If a participant has measured myopia progression 
≥2.00 D from baseline in spherical equivalent (SE) at a visit occurring 
between Month 18 and Month 36 (inclusive), and myopia progression is 
confirmed 6 months later at the next scheduled visit (ie, visit between 
Month 24 and Month 42 [inclusive]), then treatment with escape 
medication (active SYD-101 0.03%) may be initiated at the confirmatory 
visit and continued until Month 48. 
Study Duration: 
The anticipated duration of clinical study conduct is 70 months, including 
recruitment/enrollment and 48 months of treatment with study drug. 

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Participant Duration: 
The duration of participation for each study participant will be up to 
48 months, plus a Screening visit (screening procedures will be performed 
up to 21 days prior to study enrollment on Day 1).   
 

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1.2 STUDY SCHEMA 
 
Abbreviation: BL, baseline.  
 

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1.3 SCHEDULE OF ACTIVITIES (SOA) 
Study Period 
Screening 
Part 1: Primary Treatment Period 
Part 2: Randomized Withdrawal 
Visit 
SCR 
BL 
Week 2 Mo 3 
Mo 6 
Mo 9 
Mo 12 Mo 15 Mo 18 Mo 21 Mo 24 Mo 27 Mo 30 Mo 33 Mo 36 Mo 39 Mo 42 
Mo 48/EOS 
Visit Window 
Within 21 
days prior 
to Day 1 a 
Day 
1 a 
Day 
14 ± 3 
Week 
13 ± 1 
Week 
26 ± 2 
Week 
40 ± 2 
Week 
52 ± 2 
Week 
65 ± 2 
Week 
78 ± 2 
Week 
91 ± 2 
Week 
104 ± 2 
Week 
117 ± 2 
Week 
130 ± 2 
Week 
143 ± 2 
Week 
156 ± 2 
Week 
169 ± 2 
Week 
182 ± 2 
Week  
208 ± 2 (or ET) 
Informed Consent/Assent b 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Inclusion/Exclusion Review 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Med Hx c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds/Procedures d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs e 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Urine Pregnancy Test f 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Tolerability Questionnaire g 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
QOL Questionnaire h 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
BCVA by ETDRS i 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Binocular Near-BCVA 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Pupil Diameter 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Accommodative Amplitude 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Specular Microscopy j 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
Biomicroscopy 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
IOP k 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Cycloplegic Autorefraction l 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Cycloplegic Biometry m 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Dilated Ophthalmoscopy 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Supply Study Drug 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Study Coordinator Call n 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Activities/Compliance 
Questionnaire o 
X 
eCRF Completion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE, adverse event; BCVA, best-corrected visual acuity; BL, baseline; Con Meds/Procedures, concomitant medications and concurrent procedures; eCRF, electronic case report form; 
EOS, end of study; ET, early termination; ETDRS, Early Treatment of Diabetic Retinopathy Study; IOP, intraocular pressure; Med Hx, medical history; Mo, month; QOL, Quality of Life; 
SCR, Screening. 
Note: Eye assessments will be performed in both eyes at all timepoints. 
a. 
Screening and Day 1 procedures may be performed on the same calendar day.  Ophthalmic exams performed during the screening period (within 21 days of Baseline/Day 1) do not need to be 
repeated on Day 1. 

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b. 
Informed consent is an ongoing process.  Participant capacity to assent will be evaluated annually; confirmation of continued affirmative assent will be sought and documented as appropriate. 
c. 
Demographic data will include age, sex, ethnicity/race, and eye color.  Participant medical history will include parental myopia history. 
d. 
AEs, concomitant medications, and concurrent procedures will be monitored throughout the study, with scheduled inquiries at visits.  If any issues are reported by a participant or 
parent/guardian, an unscheduled visit will be performed promptly to assess for AEs. 
e. 
Vital sign measurements will include blood pressure, heart rate, height, and body weight. 
f. 
Females of childbearing potential only; additional pregnancy tests may be performed at any time/day during the study.  Females will be queried annually regarding childbearing potential 
status. 
g. 
The investigator’s designee will administer a tolerability questionnaire to participant (or parents/guardians) to assess potential side effects of study drug (blurred vision, burning/stinging, eye 
pain, grittiness in eye, sensitivity to light, headache).  
h. 
The investigator’s designee will administer a QOL questionnaire to participant (or parents/guardians) 
i. 
BCVA will be measured in each eye prior to cycloplegia with the participant wearing current correction and will be qualified by study-certified visual acuity testing using the ETDRS charts.  If the 
vision is more than 1 line (≥5 letters) worse than baseline, the testing will be redone using trial frames or phoropter. Standard manual refraction may also be performed, if needed, to confirm 
loss of BCVA using the standard refraction technique. 
j. 
Corneal endothelial cell count data will be obtained using specular microscopy (selected sites only; approximately 25% of participants). 
k. 
IOP measurements will be taken prior to pupil dilation. 
l. 
For cycloplegic autorefraction, 1 drop of 1% cyclopentolate will be applied 2 times to each eye, with 5 minutes between drops.  The autorefraction will occur at least 40 minutes (but no more 
than 60 minutes) after the second drop of 1% cyclopentolate has been instilled.  If a participant has progression of myopia >0.75 D, the participant will need to return to the clinic within 
3 to 28 days for an unscheduled visit to confirm the progression.  Standard manual refraction should be performed at screening for initial BCVA and if Spherical Equivalent is ≥0.75 D (to verify 
components of inclusion #9) and may be performed as needed throughout the study. 
m. 
Axial length will be measured by cycloplegic biometry (at sites with the requisite equipment; at least 50% of participants). 
n. 
At Week 2, and between clinic visits, the study coordinator will phone the participant or parent/guardian to encourage compliance and ask about any complaints (potential AEs).  
o. 
Time spent on various activities (near-vision activities, daylight outdoor leisure, exercise, wearing a wide-brimmed hat or dark glasses while outdoors) and adherence to the dosing regimen will 
be collected via a questionnaire on a phone or web-based application.  The questionnaires will be completed weekly for the first 6 months and then monthly until Month 48/End of Study. 
 

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2 
 
INTRODUCTION 
2.1 
BACKGROUND AND RATIONALE 
2.1.1 EPIDEMIOLOGY OF MYOPIA 
Myopia, or nearsightedness, is defined as having a refractive error of worse than 0.50 diopters (D).  
Myopia is the most common ocular disorder with an estimated prevalence of 13% to 49% in adult 
population-based studies (Pan 2012, Eye Diseases Prevalence Research Group 2004).  In Europe, the 
prevalence of myopia is increasing (Williams 2015); in the United States, 41.6% of the population 
had a diagnosis of myopia as of 2004 – up from 25% in 1971 (Vitale 2009); and in Asia, myopia has 
been classified as an epidemic with estimates of greater that 50% of the population having myopia 
in 2020 (Holden 2016).  Not only is the prevalence increasing across the globe, the severity of 
myopia is increasing as well (Matsumura 1999, Vitale 2009, Leo 2011, Morgan 2012). 
Myopia progression in children is the result of elongation of the axial length of the eye.  Retarding 
progression of myopia has been the topic of significant research since high myopia (>6.00 D) is 
associated with significant risk of pathologic changes including glaucoma, cataract, retinal 
detachment, choroidal degeneration, choroidal neovascularization, and retinoschisis, all of which 
can cause irreversible vision loss (Wong 2014).  Myopia is among the 5 conditions that have been 
identified as immediate priorities by the World Health Organization in its Global Initiative for the 
Elimination of Avoidable Blindness (WHO 2015).  The recent increase in the awareness of myopia 
has been fueled by research suggesting that an increase in near activities (such as electronic screen 
time; Huang 2015, Leo, 2017, Aldrich 2018) and lack of outdoor activity (Xiong 2017) may increase 
one’s risk for developing myopia.  In fact, schools in Taiwan have implemented new guidance 
referred to as ROC711, which requires mandatory outdoor time for children while at school, 
increased outdoor activity during school hours, and even homework outside of classroom 
recommendations to specifically reduce the incidence of myopia in their population (Wu 2018). 
2.1.2 TREATMENT OF MYOPIA AND ATROPINE 
The recent increase in the awareness of myopia has created the need for a treatment to decrease 
myopic progression.  Historically, the majority of clinical trials have investigated nonpharmacologic 
interventions for treatment of the progression of myopia, including progressive lenses and rigid 
gas-permeable contact lenses, but these have yielded disappointing results. 
Atropine is a nonselective muscarinic antagonist approved in both the European Union and the 
United States as a 1% ophthalmic solution for cycloplegia during refraction and for treatment of 
uveitis and iritis in both adults and children (>3 months of age).  Topical atropine 1% has been used 
chronically in young children for many years for a number of approved therapeutic ophthalmic 
indications including amblyopia therapy, iritis treatment, and uveitis treatment, and off-label for 
arresting or slowing myopia progression. 

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The mechanism of atropine’s reduction of myopia progression has been hypothesized to be a 
consequence of the elimination of the ability to accommodate, local retinal effects that slow 
progression, or potential biochemical changes from binding atropine with muscarinic acetylcholine 
receptors within the eye.  Another mechanism may be via increased ultraviolet A exposure (Prepas 
2008).  While the mechanism is not specifically known, many clinical trials have been conducted 
concluding that atropine 1% administered nightly effectively slows myopia progression in children. 
Early studies of topical 1.0% atropine were small, poorly designed, and lacked appropriate controls.  
Chua and colleagues launched the Atropine for the Treatment of Myopia (ATOM)1 study, which was 
the first randomized, double-masked, placebo-controlled trial designed primarily to test whether 
topically administered atropine 1.0% could slow the progression of mild and moderate myopia in 
children between 8 and 12 years of age (Chua 2006).  This study was conducted in Singapore in 
400 children who received atropine 1% drops or placebo daily over 2 years.  Myopia progression was 
reduced 77% (progression of 0.28 D vs 1.20 D).  However, despite the reduced myopic progression, 
the study reported cycloplegia and mydriasis, which in some cases led to discontinuation of its use in 
children receiving atropine.  More importantly, there was a rebound effect after discontinuing the 
medication where myopia was noted to increase at a faster than normal pace.  These data 
prompted additional studies to evaluate lower doses of atropine to try to minimize the side effects 
while maintaining efficacy.  Lee and colleagues conducted a retrospective, case-controlled study 
enrolling myopic school-aged children from Taiwan, who received 0.05% atropine eye drops every 
evening, compared with a control group of 36 untreated children (Lee 2006).  Mean myopia 
progression for the treated group was 0.28 ± 0.26 D annually, whereas that of the control group was 
significantly higher at 0.75 ± 0.35 D per year.  In another study (Shih 1999), concentrations of 0.5%, 
0.25%, and 0.1% atropine were evaluated and found that all 3 concentrations were effective in 
delaying myopia progression in a controlled study with 2 years of follow-up. 
It wasn’t until 2012 when another double-masked, randomized study (ATOM2) tested the safety and 
efficacy of lower dose atropine solutions in Singapore (Chia 2012).  Four-hundred children aged 
6 to 12 years with myopia of at least 2.00 D and astigmatism of 1.50 D or less were enrolled in the 
study with 0.5%, 0.1%, and 0.01% atropine administered once a day at bedtime to both eyes for 
2 years.  No control group was included in this study; instead, the control group from ATOM1 was 
used for comparison.  Although the reduction of mean myopic progression and axial length was less 
in the 0.01% group than the higher doses, the differences between groups were clinically 
insignificant and, importantly, the rebound effect was negligible in the atropine 0.01% group as 
compared to the higher doses.  Atropine 0.01% had minimal effects on accommodation and pupil 
size and no effect on visual acuity.  The authors concluded atropine 0.01% had minimal side effects 
and similar efficacy in controlling myopia progression when compared with other dilutions. 
In a recent follow-up of the ATOM2 study, 356 children (89%) were reviewed at 26, 32, and 
36 months after drug administration was discontinued, and spherical equivalent (SE), axial length, 
visual acuity, pupil size, and accommodation were measured (Chia 2014).  Those findings indicated 
that there was a myopic rebound in patients who had received either atropine 0.5% or atropine 

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0.1%.  In the patients who had received atropine 0.01%, the atropine effect on progression was 
sustained, with no rebound effect. 
A clinical study of 200 children between 9 and 12 years of age with baseline bilateral myopia of 
0.50 D to 2.00 D and less than 1.50 D astigmatism were included in a prospective study conducted in 
multiple centers in Spain (Diaz-Llopis 2018).  Subjects received either atropine 0.01% solution 
(applied nightly to both eyes) or no treatment and were followed for 5 years.  The annual 
progression rate was 0.14 ± 0.35 D in the atropine group compared to 0.65 ± 0.54 D in the untreated 
control.  The authors concluded that atropine 0.01% eye drops applied once daily before bedtime 
slowed down the progression of myopia, further recommending it as a therapeutic option.  The 
0.01% atropine solutions used for this study were prepared and renewed monthly. 
A few well-controlled studies are now ongoing that have similar designs in that they are masked and 
vehicle-controlled.  In the United States, the Myopia Treatment Study (MTS1), funded by the 
National Institutes of Health, will evaluate 186 children receiving 0.01% atropine or artificial tears 
for 2 years (National Clinical Trial [NCT] 0333425).  In Ireland, the MOSAIC study will evaluate 250 
children receiving 0.01% atropine or placebo for 2 years (ISRCTN36732601).  Studies with similar 
designs are also ongoing in Australia and Japan.  For further details, see the investigator’s brochure 
(IB). 
2.1.3 RATIONALE FOR STUDY 
While clinical trial results with dilute atropine are a marked improvement over those seen with 1% 
atropine, there are no approved, commercially available formulations of atropine 0.01%.  In some 
countries in Europe and in the United States, patients can obtain atropine 0.01% from a 
compounding pharmacy with a prescription.  However, there are several issues with compounded 
0.01% atropine that have created the need for the rapid approval of a pharmaceutical quality 0.01% 
atropine product.  First and foremost, compounded topical atropine 0.01% products are currently 
prescribed to control myopia in young children and recent data demonstrate that once the 
concentration of atropine is reduced below 1.0% the formulation becomes unstable.  An unstable 
product with very limited shelf-life (that goes untested by compounding pharmacies) may lack the 
efficacy that doctors rely upon when they prescribe such a product, especially to children, and may 
also contain untested degradation products with unknown safety concerns.  Coupled with the lack 
of guaranteed sterility and frequent shut-downs of the compounding pharmacies, young patients 
are being subject to unnecessary risks when they use compounded low-dose atropine.  This 
situation has been exacerbated because the World Society of Paediatric Ophthalmology and 
Strabismus (WSPOS 2017) and American Academy of Ophthalmology (Pineles 2017) have both 
endorsed use of 0.01% atropine drops as the preferred treatment for pediatric myopia; as a result, 
downsides associated with use of off-label compounded low-dose atropine will only be magnified in 
the years to come. 

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Sydnexis has developed low-dose formulations of atropine using deuterium oxide (D2O) as an 
excipient; D2O significantly extends the shelf life at 25°C at near physiologic pH, creating a room 
temperature stable formulation.  This Phase 3 study is being conducted to establish the safety and 
efficacy of atropine 0.01% and 0.03% in a topical ophthalmic solution [SYD-101] in children to slow 
progression of myopia. 
2.2 
NONCLINICAL INFORMATION 
To address the safety of SYD-101 and to support the safety of this SYD-101 clinical trial, a 26-week 
ocular toxicity study has been conducted in male pigmented (Dutch Belted) rabbits.  Six animals in 
each of the following 5 groups were dosed 1 drop bilaterally for 26 weeks: negative control (three 
times daily [TID]); vehicle control (TID); SYD-101 0.01% (TID); SYD-101 0.01% (once daily [QD]); and 
atropine 1% (QD).  Clinical observations were unremarkable and dosing was well tolerated.  For 
further details on nonclinical studies, see the IB. 
2.3 
RISK/BENEFIT ASSESSMENT 
2.3.1 KNOWN POTENTIAL RISKS  
There have been many long-term studies using atropine 1% chronically in children as young as 
3 years old with no significant adverse events (AEs) (Paediatric Eye Disease Investigator Group 2002, 
Chua 2006, Li 2009, Scheiman 2008, Tong 2009).  Common side effects with atropine 1% include 
photophobia and blurred vision due to cycloplegia (SmPC, Minims Atropine Sulfate 1% Eye Drops, 
solution, Pan 2012), dry eye, burning stinging, tearing, and increased heart rate and blood pressure.  
More dilute concentrations have been well tolerated (Shih 1999) with allergic conjunctivitis reported 
only in the 0.5% and 0.1% treatment groups (Chia 2012).  Upon cessation of atropine 1% after 
2 years of treatment in the ATOM1 study, there was a marked rebound on the myopia progression 
(Tong 2009), but even at 3 years of follow-up, the treated group had significantly less myopia than 
the control group. 
More dilute concentrations have been well tolerated (Shih 1999) with allergic conjunctivitis reported 
only in the 0.5% and 0.1% treatment groups (Chia 2012).  In the ATOM2 study, the low-dose 
atropine (0.01%) had a minimal loss of accommodation (2-3 D), minimal pupil dilation (0.8 mm), and 
no effect on near visual acuity (Chia 2012).  Clark (2015) reported 2 cases of intermittent light 
sensitivity to bright sunlight and 1 case with a history of migraine headaches with intermittent 
blurred vision; no case was symptomatic enough to warrant discontinuation of atropine 0.01%.  In a 
study conducted in Spain (Diaz-Llopis 2018), 2% of the atropine 0.01%-treated patients discontinued 
medication due to AEs, including photophobia, reading difficulty, mydriasis, and headaches; up to 
5% of patients reported slight photophobia, difficulties in very near reading, and excessive mydriasis 
that did not require treatment withdrawal.  Gong and colleagues conducted a meta-analysis of 
19 peer-reviewed studies on the efficacy and AEs of atropine in childhood myopia; no corneal AEs 
were identified with any strength and there were no differences in the incidence of AEs between 
Asians and Caucasians (Gong 2017). 

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To demonstrate the safety of atropine on visual function, retinal sensitivity was measured over time 
in atropine-treated myopic children.  Thirty-five of 50 children enrolled in the ATOM2 study 
consented to have full-field electroretinogram (ffERG) recordings at baseline, 24 months (end of 
treatment [EOT]), and 32 months (8 months after cessation of atropine).  Twenty-nine children had 
good quality ffERG on all 3 visits; their mean age was 9.5 ± 0.8 years and mean SE was 5.0 ± 1.6 D.  
There was no significant correlation of axial length with any ffERG measures (saturated amplitude, 
scotopic and photopic ffERG amplitude, implicit time).  Multivariate analysis showed that a change 
in 30 Hz flicker response amplitude was associated with increased axial length, but there was no 
evidence that changes in other responses were associated with age, axial length, or atropine doses.  
The conclusion was that the atropine treatment did not have an impact on scotopic or photopic 
visual responses (Fang 2013).  
The Sydnexis topical ophthalmic formulations of atropine 0.01% and 0.03%, SYD-101 0.01% and 
SYD-101 0.03%, have not been tested in humans.  See the IB for additional details. 
2.3.2 KNOWN POTENTIAL BENEFITS 
Recognition of the myopia rebound effect with atropine 1% led to testing lower solutions (0.5%, 
0.1%, 0.05%, and 0.01%) (Wu 2011, Chia 2012, Chia 2014, Chia 2015, Clark 2015, Polling 2016).  It 
was noted in all of these studies that there was significantly less rebound effect after cessation of 
the more dilute atropine and that patients using atropine 0.01% do not require bifocal wear as 
accommodation is preserved.  A 5-year study conducted in Spain found that atropine 0.01% reduced 
the myopia progression from 0.65 D/year to 0.15 D/year or 77% (Diaz-Llopis 2018). 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
The risks associated with atropine 0.01% and anticipated with atropine 0.03% eyedrops are minimal 
and reversible upon treatment withdrawal (Chia 2012).  Transient dilation and nominal changes in 
accommodative amplitude resulting from 0.01% and 0.03% atropine will be mitigated by the 
implementation of a once-nightly (QHS) dosing regimen, as the pharmacological effects of the 
formulation should be minimized within 8 to 12 hours. 
The American Academy of Ophthalmology produced a technology assessment concluding that 
level 1 evidence supports the use of atropine to prevent myopic progression and that the 0.01% 
minimizes the myopic rebound (Pineles 2017).  The World Society of Paediatric Ophthalmology and 
Strabismus produced a consensus statement on myopia (2017), “Atropine 0.01% dose appears to 
offer an appropriate risk-benefit ratio, with no clinically significant visual side effects balanced 
against a reasonable and clinically significant 50% reduction in myopia progression.”   
 

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3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVE 
ENDPOINT 
JUSTIFICATION FOR ENDPOINT 
Efficacy 
 
 
To evaluate the 
efficacy of SYD-101 
for slowing the 
progression of 
myopia in children 
• Proportion of participants with confirmed 
myopic progression >0.75 D at Month 36 
(and Month 24 for EU), based on SE as 
measured by cycloplegic autorefraction 
Measuring SE by cycloplegic autorefraction has become the standard in myopia trials.  
For each participant, the autorefraction will be done 3 times for the right eye and 
3 times for the left eye.  The SE for each measurement will be calculated for each eye 
and then averaged by eye; the participant’s averaged right eye SE and averaged left eye 
SE will then be averaged (ie, a single averaged SE value for a given visit will be obtained 
for each participant by taking the “average of the averages”).  A single averaged SE value 
will be used for analyses to reduce bias at the study site level as well as to reduce 
variability in the measure. 
To qualify for reaching the primary endpoint of progression of myopia of >0.75 D, the 
study participant will need to return to the clinic within 3 to 28 days for an unscheduled 
visit to confirm the progression.  This confirmatory step will further reduce variability in 
the measure. 
A change of 0.75 D represents a meaningful change in visual performance (3 lines of 
vision) and warrants a new prescription. 
Analysis of data will be performed at Month 24, Month 36, and Month 48. 
The primary efficacy analysis for EU regulatory submission will be performed at 
Month 24; this is the most frequent duration published and is supported by major 
ophthalmology societies to demonstrate safety and efficacy of atropine in myopia.  A 
duration of 24 months is also supported by European Medicines Agency/International 
Council for Harmonisation (ICH) Guidance, which states ethical and practical concerns 
are raised when using a placebo control for long-term outcome measures. 
As requested by the FDA, the primary efficacy analysis for US regulatory submission will 
be performed at Month 36. 
 
• Mean annual progression rate of myopia 
based on 36 months of follow-up for the 
US (24 months for EU) 
The annual rate of myopic progression frequently appears in the literature as a key 
endpoint and therefore will serve as a reference to other clinical trials.  Medical Products 
Agency (Sweden) requested a continuous variable as it provides for more information. 

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OBJECTIVE 
ENDPOINT 
JUSTIFICATION FOR ENDPOINT 
Efficacy (continued)  
 
To evaluate the 
efficacy of SYD-101 
for slowing the 
progression of 
myopia in children 
• Proportion of participants with annual 
myopia progression rate ≤0.50 D/year 
A rate of progression of ≤0.50 D/year is considered very low and will add further 
characterization to the effects of SYD-101. 
• Proportion of participants with annual 
myopia progression rate ≤0.25 D/year 
A change of ≤0.25 D is within testing error of autorefraction and is therefore considered 
to be negligible. 
• Proportion of participants with an 
increase of myopia of >0.50 D at 
Month 36 (Month 24 for EU) 
Results of the ATOM2 study showed that 0.01% atropine reduced myopic progression by 
0.49 D over 2 years (<0.25 D/year).  As an endpoint, the proportion of patients with an 
increase of myopia of >0.50 D at Month 36 (Month 24 for EU) would enable comparison 
of this study’s results with those of other clinical trials in addition to further 
characterizing the effects of SYD-101. 
• Time to progression of myopia >0.75 D 
This measures the time to failure. 
 
• Mean annual progression rate on Subgroup 
of participants with refractive history of 
progression ≥ 0.5D (month 24 for EU) 
Patients with previous myopia progression are more likely to have worse subsequent 
progression. 
• Mean annual progression rate on Subgroup 
of participants with refractive history of 
progression ≥ 0.75D (month 24 for EU) 
Patients with previous myopia progression are more likely to have worse subsequent 
progression. 
 
• Mean change from baseline in axial length 
(at sites with the requisite equipment; at 
least 50% of study participants)  
While myopia is primarily due to elongation of axial length, most pediatric clinics lack the 
biometry equipment to measure this.  Therefore, axial length will be measured for 
participants enrolled at sites with the requisite equipment. 
Exploratory 
 
 
 
• Mean change from baseline in SE at 
Month 48 (ie, 12 months after 
randomized withdrawal) 
This analysis will be conducted to evaluate the persistence of effect of SYD-101.  
High-dose atropine (eg, 1%) is associated with a significant rebound effect upon 
cessation of therapy. 
• Mean time spent on various activities will 
be solicited via questionnaire  
Activities such as time spent outdoors during daylight and working on near-vision tasks 
are associated with decreases and increases in myopia progression, respectively. 
 

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OBJECTIVE 
ENDPOINT 
JUSTIFICATION FOR ENDPOINT 
 
• Proportion of agreement to QOL 
statements 
Use of SYD-101 eyedrops may affect the QOL of the participant.  Selected questions are 
taken from a questionnaire used in an amblyopia pediatric population (Holmes 2008). 
Safety 
 
 
To evaluate the 
safety and 
tolerability of 
SYD-101 
• Evaluation of AEs and SAEs 
Severity and causality of AEs are standard endpoints. 
To evaluate the 
safety and 
tolerability of 
SYD-101 
• Changes from baseline in vital sign 
measurements 
Vital signs are standard non-invasive investigations of systemic health suitable for a 
pediatric population. 
• Mean change from baseline in pupil 
diameter 
Atropine has mydriatic properties.  This analysis will be conducted to investigate the 
extent of dilation to determine if it is significant with SYD-101. 
• Mean change from baseline in binocular 
accommodative amplitude 
Atropine has cycloplegic properties.  This analysis will be conducted to investigate the 
extent of change in near-accommodation to determine if it is significant with SYD-101. 
• Changes from baseline in findings 
detected by best-corrected visual acuity 
(BCVA), biomicroscopy, intraocular 
pressure (IOP), and ophthalmoscopy 
Clinically significant findings from the complete eye examination will be recorded as 
adverse events. 
• Changes from baseline in corneal 
endothelial cell count (selected sites only; 
approximately 25% of study participants)  
Effect on endothelial cell counts will be assessed in a subset of participants enrolled at 
sites with the requisite specular microscopy equipment. 
• Tolerability to the masked study drug will 
be solicited via questionnaire 
Symptoms such as blurred vision, burning/stinging, eye pain, grittiness in eye, sensitivity 
to light, and headache are potential side effects to the study drug. 
 
• Pregnancy test results (female 
participants of childbearing potential only) 
This population is at risk for becoming pregnant and outcomes of pregnancy will be 
assessed. 
 

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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
The clinical hypotheses for this study are as follows: 
• 
SYD-101 is safe as assessed by the incidence and severity of AEs compared with Vehicle 
• 
SYD-101 is superior to Vehicle in slowing the progression of myopia  
o For European Medicines Agency (EMA) submission, the primary assessment of 
myopia progression will be assessed by the mean annual progression rate of myopia 
o For US Food and Drug Administration (FDA) submission, the primary assessment of 
progression will be assessed by the proportion of participants with an increase in 
myopia >0.75 D 
This is a Phase 3, multicentered, randomized, double-masked, vehicle-controlled study to assess the 
safety and efficacy of SYD-101 eyedrops in male and female children between 3 and 14 years of age 
(inclusive) with myopia of 0.50 D to 6.00 D (inclusive). 
The study will have 3 treatment groups: SYD-101 0.01%, SYD-101 0.03%, and the Vehicle of SYD-101.  
Each night at bedtime, 1 drop of masked study drug will be instilled in each eye.  See Section 1.2 for 
the figure describing the treatment assignments. 
• 
Baseline Randomization.  At Baseline, participants will be randomly assigned into 1 of 3 
treatment arms, with participants allocated in a 1:1:1 ratio to receive either SYD-101 0.01%, 
SYD-101 0.03%, or Vehicle during Part 1 (Primary Treatment Period).  Allocation to the 
treatment groups will be stratified according to the following 2 factors: baseline SE and age 
(see Section 6.3 for stratification details). Enrollment thresholds may be utilized to limit the 
number of participants in each level of demographic characteristic such as age group, 
baseline SE group, race, etc. These thresholds will be defined within the interactive voice 
response system (IVRS)/interactive web response system (IWRS) and may be modified 
during the course of the study. 
• 
Re-randomization.  At Month 36, participants will be randomly assigned to receive study 
treatment during Part 2 (Randomized Withdrawal Period) as follows:  
o Those initially assigned to the SYD-101 0.01% arm will be re-randomized in a 1:1 
ratio to receive either masked SYD-101 0.01% or Vehicle 
o Those initially assigned to the SYD-101 0.03% arm will be re-randomized in a 1:1 
ratio to receive either masked SYD-101 0.03% or Vehicle 

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o Those initially assigned to the Vehicle arm (not on escape medication) will be 
re-randomized to receive masked SYD-101 0.03% 
For participants with measured myopia progression ≥2.00 D from baseline in SE at a visit occurring 
between Month 18 and Month 36 (inclusive), and measurements obtained 6 months later at the 
next scheduled visit confirm myopia progression (ie, confirmation at a visit between Month 24 and 
Month 42 [inclusive]), then treatment with escape medication (active SYD-101 0.03%) may be 
initiated at the confirmatory visit and continued until Month 48.  Participants on escape medication 
will adhere to the same visit schedule.  No medications will be dispensed during or after the 
Month 48/End of Study (EOS) visit. 
Clinic visits (with an investigator) will be at Screening, Baseline (Day 1), Month 3, Month 6, and every 
6 months thereafter until Month 48 or Early Termination (ET).  A telephone visit with the study 
coordinator will occur at Week 2 and between clinic visits, from Months 9 through 39. 
Specular microscopy will be done so that approximately 25% of participants will have an assessment 
for endothelial cell counts at sites with the requisite equipment.  Axial length will be measured at 
sites with the requisite equipment (at least 50% of study participants). 
There are 3 planned database locks for this study.  The first will occur after all participants have 
completed the Month 24 visit for the purpose of submitting data for regulatory submission to the 
EU (ie, Month 24 analysis).  The second database lock will occur after all participants have complete 
the Month 36 visit for regulatory submission to the US (ie, Month 36 analysis).  The final database 
lock will occur after all participants have completed the last study visit (Month 48 or ET) to allow 
assessment of the persistence of effect of SYD-101 after 12 months of randomized withdrawal (ie, 
Month 48/Final analysis).  Details regarding efficacy analyses are provided in Section 9.4.2. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
A placebo control is the gold standard clinical trial design appropriate for conditions without any 
approved treatments so that superiority of the treatment can be established.  In the case of 
pediatric myopia, low-dose atropine has been investigated in many trials, many of which used a 
placebo control and found atropine to be effective.  Parents/guardians of the participants may not 
understand the scientific and regulatory need for a placebo control or a randomized withdrawal.  
Therefore, this study utilizes the following strategies to encourage recruitment and adherence to 
the study procedures:  uneven randomization (allocation to treatment with active SYD-101: Vehicle 
in a 2:1 ratio at Baseline), re-randomization to treatment with active SYD-101 0.03% at Month 36 for 
all participants initially assigned to receive Vehicle, and allowance for treatment with active 
SYD-101 0.03% as escape medication (per Section 6.5.2) for participants with measured myopia 
progression once confirmed. 

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4.3 
JUSTIFICATION FOR SELECTED DOSES 
The 0.01% dose of atropine was selected for this study based on published dose-response data 
concluding this dose provided the optimal benefit with the least amount of adverse effects.   
Although several studies have demonstrated the beneficial effects of 0.01% atropine, the literature 
has also reported that patient responses to 0.01% atropine can vary.  Investigators have noted the 
potential for factors such as dark iris color and rapid progression of myopia to lessen a child’s 
response to low-dose atropine.  Therefore, the slightly stronger dose of 0.03% atropine has also 
been selected for this study as it may mitigate inter-patient variability reported in the literature (ie, 
offer additional benefit to participants with dark irises and/or those who may experience more rapid 
myopia progression). 
Both selected doses, 0.01% and 0.03% atropine, offer potential benefit while remaining below the 
dose threshold of 0.05% atropine, as results reported in literature have shown doses at or above 
0.05% to be associated with increased risk of AEs.   
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if s/he has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities 
(SOA), Section 1.3. 

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5 
STUDY POPULATION 
Participants will be assigned to study drug only if they meet all of the inclusion criteria and none of 
the exclusion criteria.   
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or participant safety.  
Therefore, adherence to the criteria as specified in the protocol is essential. 
5.1 
INCLUSION CRITERIA 
Participants must meet all of the inclusion criteria to be included in the study: 
1. Parent/guardian has the ability to understand the study informed consent form (ICF) and 
agrees to sign the ICF prior to initiation of any protocol-related procedures; participant has 
the ability to give assent, as applicable, at the time of parental/guardian consent 
2. Participant is male or female between 3 and 14 years of age (inclusive) at the time of 
Screening 
3. Participant and parent/guardian are willing and able to comply with study instructions, 
study visits, and procedures 
4. Participant (or parent/guardian) has demonstrated ability to administer artificial eyedrops at 
the Screening or Baseline visit 
5. Participant is in good general health, with no clinically significant findings based on medical 
history and vital signs, as determined by the investigator at the time of Screening 
6. Postmenarchal female participants must have negative urine pregnancy test results 
The following inclusion criteria (#7 through #11) are required of both eyes: 
7. Refractive error by cycloplegic autorefraction at the baseline visit: 
a) Myopia of 0.50 D to 6.00 D (inclusive) 
b) Astigmatism ≤1.50 D 
c) Anisometropia ≤1.00 D 
8. If the baseline myopia (SE) is <0.75 D, participant must have a history of myopia progression 
of 0.50 D in the previous 6 to 12 months 
9. If baseline myopia (SE) is ≥0.75 D, participant must be wearing refractive correction (single 
vision eyeglasses or soft, daily-wear, single-vision contact lenses) that meets the following 
criteria: 
a) Myopia (SE) corrected to within ±0.50 D of the investigator’s cycloplegic 
measurement of refractive error 

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b) Cylinder power must be within ±0.50 D of the investigator’s standard refraction 
technique, which can be based on a cycloplegic or non-cycloplegic refraction 
c) Cylinder axis must be within ±5 degrees of the axis found on the investigator’s 
standard refraction when cylinder power is ≥1.00 D or within ±15 degrees when the 
cylinder power is <1.00 D 
10. BCVA of 75 letters (Snellen equivalent 20/32) or better 
11. Normal IOP <21 mmHg 
5.2 
EXCLUSION CRITERIA 
Participants who meet any of the exclusion criteria will be excluded from the study: 
1. Participant is a female who is pregnant, lactating, or intending to become pregnant within 
next 4 years 
2. Participant has a known allergy or hypersensitivity to atropine or any of the components of 
SYD-101 
3. Participant has history or current evidence of a medical condition predisposing the 
participant to degenerative myopia (eg, Marfan syndrome, Stickler syndrome) or a condition 
that may affect visual function or development (eg, diabetes mellitus, chromosome 
anomaly) 
4. One or more biological parents with a history of myopia ≥9.00 D 
5. Current use of a monoamine oxidase inhibitor 
6. History of, or currently receiving treatment for, any systemic infection or autoimmune 
disease considered serious by the investigator 
7. Participation in an investigational drug or device study within 30 days prior to Screening 
8. Evidence of any ocular inflammation or infection in either eye, including blepharitis, 
conjunctivitis, keratitis, and scleritis 
9. History or evidence of the following in either eye: 
a) Retinopathy of prematurity 
b) Abnormal refractive anatomy (eg, keratoconus, lenticonus, spherophakia) 
c) Amblyopia, manifest strabismus, or nystagmus 
10. Use of any of the following (previously, currently, or plans to do so in the future): 
a) Orthokeratology (orthoK), rigid gas-permeable, bifocal, progressive-addition, 
multi-focal, or other lenses to reduce myopia progression 

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b) Use of atropine, pirenzepine, or other anti-muscarinic agent for myopia 
11. History or evidence of any ocular surgery or planned future ocular surgery in either eye 
12. History or current evidence of ocular disease in the either eye that, in the opinion of the 
investigator, may confound assessment of visual acuity and/or refraction 
13. Unwillingness or inability to comply with study requirements and restrictions, including but 
not limited to those specified in Section 5.3 (eg, required conversion from extended wear 
lenses to daily wear lenses, full-time use of contact lenses or spectacles) 
5.3 
LIFESTYLE CONSIDERATIONS 
During this study, participants are asked to continue with usual indoor and outdoor activities. 
Study participants will be required to remove contact lenses at night throughout the duration of 
study treatment.  Participants are required to wear corrective lenses (contact lenses or spectacles) 
on a full-time basis. 
Use of continuous extended-wear contact lenses is not permitted during the study.  Participants 
who have been using extended-wear contact lenses will be required to change to daily wear lenses 
at least 14 days prior to Baseline. 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study.  A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, 
to meet the Consolidated Standards of Reporting Trials publishing requirements, and to respond to 
queries from regulatory authorities.  Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse event (SAE). 
Individuals with concurrent infection or inadequate corrective lenses may be rescreened.  
Rescreened participants should be assigned the same participant number as for the initial screening.  
A given participant may only be rescreened once. 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Sites will recruit participants from their database as well as locally.  Group enrollment shortly after 
the study opens will be encouraged.  Any advertisement must be approved by the institutional 
review board (IRB)/ethics committee (EC).  Participants will be encouraged to remain in the study by 
offering escape medication and eye examinations at no cost, as well as required glasses or contacts 
necessary to adhere to the spectacle correction requirement.   
Refer to the Manual of Procedures (MOP) for additional information. 

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6 
STUDY INTERVENTION 
6.1 
STUDY DRUG ADMINISTRATION 
6.1.1 DESCRIPTION OF STUDY DRUG 
The active study treatment, SYD-101, is a sterile topical ophthalmic solution of atropine sulfate.  The 
Vehicle (control) treatment formulation is identical to SYD-101, except that it does not contain 
active drug (atropine sulfate) and H2O is used instead of D2O.  Components of each study drug are 
listed in Table 6-1. 
Table 6-1: 
Summary of Study Drug Components 
Component 
SYD-101 0.01% 
SYD-101 0.03% 
Vehicle 
Atropine sulfate monohydrate 
0.01% 
0.03% 
0% 
Excipients 
HCl/NaOH, D2O, 
citric acid 
HCl/NaOH, D2O, 
citric acid 
HCl/NaOH, H2O, 
citric acid 
Benzalkonium chloride 
(preservative) 
0.01% 
0.01% 
0.01% 
Abbreviations: D2O, deuterium oxide; H2O, water; NaOH, sodium hydroxide. 
 
6.1.2 DOSING AND ADMINISTRATION 
Prior to randomization, the participant or parent/guardian will administer 1 drop of an artificial tear 
to each eye to demonstrate cooperation and performance with eyedrop instillation.  Once study 
entry procedures have been completed, the investigator’s designee will obtain the randomization 
assignment and drug kit number from the IVRS/IWRS and provide training to the participant or 
parent/guardian in the correct administration.  One drop will be administered to each eye nightly.  
Detailed instructions are described in the MOP including resupply procedures. 
6.2 
STUDY DRUG PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
The investigator designee must keep an accurate accounting of the number of investigational units 
received from Sydnexis and the number of units returned to Sydnexis or the sponsor’s designee 
during and at the completion of the study.  A detailed inventory must be completed for the study 
drug. 
All clinical study drug and/or supplies will be returned to Sydnexis or its designee for destruction. 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
SYD-101 and Vehicle are clear ophthalmic solutions packaged in identical white, 5-mL low-density 
polyethylene (LDPE) ophthalmic bottles and supplied by Sydnexis or its designee.  All study drugs will 

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be labeled with the protocol number and medication kit numbers.  The label will also specify the 
storage conditions (room temperature) and state that the study drug is limited to investigational 
use. 
6.2.3 PRODUCT STORAGE AND STABILITY 
The study drug must be stored between 5°C (41°F) and 25°C (77°F) and protected from excessive 
heat.  Do not freeze.  Temperature will be monitored while stored at sites.  Refer to the Pharmacy 
Manual for further information.  
6.2.4 PREPARATION 
Not applicable. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND MASKING 
Allocation to study treatment will occur in a double-masked manner on 2 occasions: initial 
randomization at Baseline (for Primary Treatment Period [Part 1]) and re-randomization at 
Month 36 (for Randomized Withdrawal Period [Part 2]). 
For Part 1, prior to initiation of study treatment, randomization will occur by site staff via the 
IVRS/IWRS once it is confirmed that the participant meets the final study entry criteria (see 
Sections 5.1 and 5.2).  The IVRS/IWRS will provide the participant identification number used on all 
study documents and will be used to manage the randomization and treatment assignment based 
on a stratified randomization scheme prepared by Sydnexis’ designee.  Initial randomization will be 
in a 1:1:1 ratio of SYD-101 0.01%: SYD-101 0.03%: Vehicle and stratified by baseline SE (0.50 D to 
3.0 D and >3.0 D to 6.0 D) and age (3 years to <6 years, 6 years to <9 years, 9 years to <12 years, and 
12 years to 14 years). 
To maintain treatment masking for Part 2, sites will contact the IVRS/IWRS at Month 36 for all 
participants.  At Month 36, participants who were initially assigned (at Baseline) to SYD-101 0.01% 
will be re-randomized in a 1:1 ratio to masked SYD-101 0.01% or Vehicle; participants initially 
assigned (at Baseline) to SYD-101 0.03% will be re-randomized in a 1:1 ratio to masked 
SYD-101 0.03% or Vehicle.  The Re-randomization of SYD-101 participants will not be stratified.  All 
participants who were initially assigned (at Baseline) to Vehicle will be re-randomized to masked 
SYD-101 0.03% at Month 36.  
Sites will also contact the IVRS/IWRS at the time a participant qualifies to initiate treatment with 
escape medication (ie, at confirmatory visit when measurements confirm progression of myopia 
≥2.00 D in SE from baseline) for ANY participant who has qualified for and desires to use escape 
medication.  
Study drug will be labeled with medication kit numbers, and the IVRS/IWRS will provide each site 
with the specific medication kit number(s) for each randomized participant at the time of 

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randomization and any required drug resupply visit.  Additionally, to maintain study masking, the 
IVRS/IWRS will assign a new medication kit for all participants at any timepoints study treatments 
might switch based on study design (ie, the re-randomization at Month 36, at escape for confirmed 
≥2.00 D progression), even if the new medication kit will be of the same treatment type of the 
medication kit currently assigned.  Sites will dispense study drug according to the IVRS/IWRS 
instructions.  Sites will receive the IVRS/IWRS confirmation notifications for each transaction.  All 
notifications are to be maintained with the study source documents. 
Masking of individual participant treatment assignments will be maintained throughout the study 
for all participants and required site staff until the database is locked for the EOS analysis at 
Month 48.  If it is necessary for the safety and appropriate treatment of a participant, the treatment 
assignment can be unmasked by the site via the IVRS/IWRS.  When possible, the medical monitor 
should be notified prior to the unmasking, and the reason for breaking the mask will be documented 
in the source documentation.  The investigator should inform the medical monitor of the unmasking 
if there is no notification prior to the unmasking.  The treatment assignment for the participant can 
be determined by designated site staff calling into the IVRS/IWRS via password-protected access.  
The reason for breaking the code must be recorded in the participant’s source documents and 
electronic case report form (eCRF). 
To minimize bias, results of the Month 24 analyses for EU submission will neither be made public, 
nor shared with study sites nor study monitors until after completion of the Month 36 analysis. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Participants will be queried on adherence to the dosing regimen on the Activities/Compliance 
Questionnaire.  Refer to the MOP for further information.   
6.5 
CONCOMITANT THERAPY 
The decision to administer a prohibited medication/treatment is done with the safety of the study 
participant as the primary consideration.  Whenever possible, the medical monitor should be 
notified before the prohibited medication/treatment is administered. 
Medication considered necessary for the participant's welfare may be given at the discretion of the 
investigator.  Participants should be instructed to maintain a stable dose of chronic medications 
during the study whenever possible.  All concurrent medications (prescription, over-the-counter, 
and supplements), adjunct therapies, and concurrent procedures will be recorded on the 
appropriate eCRF page. 

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Topical drops for examination procedures, such as anesthetics, dilating agents, and fluorescein are 
permitted.  Acute use of eye drops for allergies or anti-infective eye drops for treatment of bacterial 
or viral conjunctivitis is permitted; however, administration of any such treatment must precede 
that of the study drug by 15 minutes. 
1% Cyclopentolate will be used for cycloplegic autorefraction measurements in this study. 
6.5.1 PROHIBITED THERAPY 
Due to the potential for drug-drug interactions, monoamine oxidase inhibitors are prohibited.  Refer 
to the MOP for further information. 
During the study, participants must not use the following: 
• 
Any lenses to reduce myopia progression is prohibited, including but not limited to 
orthokeratology, rigid gas-permeable, bifocal, progressive-addition, and multi-focal lenses 
• 
Any anti-muscarinic agent for myopia, including but not limited to atropine and pirenzepine 
6.5.2 ESCAPE MEDICATION 
For participants with measured myopia progression ≥2.00 D from baseline in SE at a visit occurring 
between Month 18 and Month 36 (inclusive), and myopia progression is confirmed 6 months later at 
the next scheduled visit (ie, visit between Month 24 and Month 42 [inclusive]), treatment with 
escape medication (active SYD-101 0.03% on an open-labeled basis) may be initiated at the 
confirmatory visit and continued until Month 48. 
As with masked study treatment, open-label SYD-101 0.03% (escape medication) will be provided by 
the sponsor, managed and tracked using IVRS/IWRS, and dispensed to participants by the study 
coordinator.   

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7 
STUDY DRUG DISCONTINUATION AND PARTICIPANT DISCONTINUATION OR 
WITHDRAWAL FROM STUDY 
7.1 
DISCONTINUATION OF STUDY DRUG 
Discontinuation from study drug does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol.  If a clinically significant 
finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is 
needed.  Any new clinically relevant finding will be reported as an AE. 
The data to be collected at the time of study intervention discontinuation will include the 
procedures as listed in the schedule of activities. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to discontinue the study at any time, for any reason, and without prejudice to 
further treatment.  The investigator may remove a participant if, in the investigator’s judgment, 
continued participation would pose unacceptable risk to the participant or to the integrity of the 
study data.  Reasons for removal or withdrawal might include the following: 
• 
Withdrawal of consent 
• 
Administrative decision by the investigator or sponsor 
• 
Significant protocol deviation 
• 
Participant noncompliance or other significant protocol deviation 
• 
Pregnancy 
• 
Safety concern by the investigator or sponsor 
• 
Lost to follow-up 
With the exception of withdrawal of consent, participant withdrawal should be discussed with the 
sponsor, when possible, prior to withdrawing.  Notification of early participant discontinuation from 
the study and the reason for discontinuation will be made to Sydnexis and will be clearly 
documented on the appropriate eCRF.  If a participant discontinues prior to completing the study, 
the procedures outlined for the Month 48 visit should be performed at the ET visit (ie, last visit the 
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Participants who sign the ICF and are randomized but do not receive study drug may be replaced by 
randomization of an additional participant (ie, the replacement participant will not necessarily 
receive the same treatment assignment as the original participant being replaced).  Participants who 
sign the ICF, are randomized and receive the study intervention, and subsequently withdraw, or are 
withdrawn or discontinued from the study, will not be replaced. 
7.3 
LOST TO FOLLOW-UP 
At any point during the trial, if a participant fails to return for a scheduled visit and is unable to be 
contacted by the site staff, he or she will be considered lost to follow-up.  This does not include a 
single missed visit of which the site was notified or a missed visit with subsequent contact from the 
participants indicating an intention to continue on the study.  The following actions must be taken if 
a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within the 
visit window and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.  If 
this make-up visit is outside the allowable window, a protocol deviation will be recorded. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the participant’s 
medical record or study file. 
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up, and a protocol 
deviation will be recorded. 

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8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
EFFICACY ASSESSMENTS  
Refer to the MOP for details on the efficacy measures and procedures. 
• 
Spherical Equivalent (SE) as measured by cycloplegic autorefraction; 3 SE readings will be 
obtained for each eye and the average calculated for both eyes (average of averages).  One 
drop of 1% cyclopentolate will be applied 2 times to each eye, with 5 minutes between 
drops.  The cycloplegic autorefraction will occur within the window of maximum cycloplegic 
effects, ie, at least 40 minutes (but no more than 60 minutes) after the second drop of 1% 
cyclopentolate has been instilled.  A third drop of 1% cyclopentolate may be applied to each 
eye if there is a delay before performing refraction.  The cycloplegic autorefraction will 
occur at least 40 minutes (but no more than 60 minutes) after the last drop.  Refer to the 
MOP for further details.  If a participant has progression of myopia >0.75 D, the participant 
will need to return to the clinic within 3 to 28 days for an unscheduled visit to confirm the 
progression. 
• 
Axial Length will be measured by cycloplegic biometry at sites with the requisite equipment, 
either IOLMaster, LENSTAR, or Pentacam (at least 50% of participants).  Axial length 
measurements will be obtained 3 times in each eye. 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Findings that are of clinical significance will be recorded as AEs on the eCRF.  Refer to the MOP for 
details on the assessments. 
• 
Demographics and Medical History, including the following information, will be recorded at 
Baseline:  age, sex, ethnicity/race, eye color, participant medical history, and parental 
myopia history. 
• 
Concomitant Medications and Concurrent Procedures will be recorded on the eCRF. 
• 
Vital Sign Measurements will include heart rate, blood pressure, height, and body weight. 
• 
Pregnancy Testing will be performed using a human chorionic gonadotropin pregnancy 
urine dipstick test (female participants of childbearing potential only).  Female participants 
will be queried annually regarding childbearing potential status. 
• 
Standard Manual Refraction will be performed for initial BCVA and to verify inclusion #9.  
Manual refraction may be performed, if needed, to ensure proper corrective lenses during 
the course of the study.  The refraction correction being worn for each eye will be assessed 
to determine if adjustment is needed to meet the following:  

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o Myopia (by SE) in both eyes must be corrected to ±0.50 D of the investigator’s 
cycloplegic measurement of refractive error 
o Cylinder power in both eyes must be within ±0.50 D of the investigator’s standard 
refraction technique, which can be based on cycloplegic or non-cycloplegic refraction 
o Cylinder axis for both eyes must be within ±5 degrees of the axis found on the 
investigator’s refraction when cylinder power is ≥1.00 D or within ±15 degrees when 
the cylinder power is <1.00 D 
Measurement of refractive error may be performed as an over-refraction or without 
refractive correction. 
• 
Best-Corrected Visual Acuity (BCVA) will be measured in each eye prior to cycloplegia with 
the participant wearing current correction.  Best-corrected visual acuity will be qualified by 
study-certified visual acuity testing using the Early Treatment of Diabetic Retinopathy Study 
(ETDRS) charts.  If the vision is more than 1 line (≥5 letters) worse than baseline, the testing 
will be redone using trial frames or phoropter. Standard manual refraction may also be 
performed, if needed, to confirm loss of BCVA using the standard refraction technique. 
• 
Binocular Near-BCVA will be measured using the ATS4 Near Acuity Test with participant 
wearing current refractive correction prior to administration of cycloplegia. 
• 
Pupil Diameter will be measured prior to any cycloplegia using a hand-held pupil card 
provided to the sites. 
• 
Binocular Accommodative Amplitude will be measured with the participant wearing 
current refractive correction prior to cycloplegia with a study-specified accommodation 
near-point rule. 
• 
Corneal Endothelial Cell Count data will be obtained using specular microscopy at selected 
sites with the required equipment (approximately 25% of study participants). 
• 
Biomicroscopy (with fluorescein) will be performed by slit-lamp examination of lids, 
conjunctiva, cornea, iris and lens with findings reported as normal, abnormal clinically 
significant, or abnormal not clinically significant.  Corneal staining will be graded on the 
following scale: 0 = none, 0.5 = trace, 1 = mild, 2 = moderate, and 3 = severe. 
• 
Intraocular Pressure will be measured with a tonometer per study site’s standard operating 
procedures. 
• 
Ophthalmoscopy.  A dilated fundus examination will be performed to evaluate any 
posterior segment abnormalities. 
• 
Tolerability Questionnaire.  The investigator’s designee will administer a questionnaire to 
participants (or parents/guardians) to assess potential side effects of study drug (blurred 

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vision, burning/stinging, eye pain, grittiness in eye, sensitivity to light, headache); severity 
(scored on a 0 to 3 scale [none, mild, moderate, severe]) and frequency will be recorded. 
• 
QOL Questionnaire.  The investigator’s designee will administer a questionnaire to 
participants (or parents/guardians) to assess potential impact of treatment on the 
participant’s quality of life.  Responses will be marked as strongly agree, agree, neither 
agree or disagree, disagree, strongly disagree.  See the MOP for further details. 
• 
Activities/Compliance Questionnaire: Time spent on various activities (near-vision 
activities, daylight outdoor leisure, exercise, wearing a wide-brimmed hat or dark glasses 
while outdoors) and adherence to the dosing regimen will be collected via a questionnaire. 
Unscheduled visits can be included if safety concerns arise.  Additional examinations may be 
performed as necessary to ensure the safety and wellbeing of participants during the study.  An 
eCRF must be completed for each unscheduled visit. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
The investigator is responsible for reporting all AEs that are observed or reported during the study, 
regardless of their relationship to study drug.   
An AE is defined as any untoward medical occurrence in a participant enrolled into this study 
regardless of its causal relationship to study drug.  Participants will be instructed to contact the 
investigator at any time after randomization if any symptoms develop. 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to study drug 
or any event already present that worsens in either intensity or frequency after exposure to study 
drug. 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An SAE is defined as any event that, in the view of either the investigator or sponsor:  
• 
Results in death 
• 
Is immediately life-threatening 
• 
Results in inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
Is a congenital anomaly/birth defect 

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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For AEs not included in the protocol-defined grading system, the following guidelines will be used to 
describe severity.  
• 
Mild:  Event requires minimal or no treatment and does not interfere with the participant’s 
daily activities. 
• 
Moderate:  Event results in a low level of inconvenience or concern with the therapeutic 
measure(s).  Moderate events may cause some interference with functioning. 
• 
Severe:  Event interrupts a participant’s usual daily activity and may require systemic drug 
therapy or other treatment.  Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious.” 
8.3.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
A determination will be made of the relationship (if any) between an AE and the study drug.  A 
causal relationship is present if a determination is made that there is a reasonable possibility that 
the AE may have been caused by the drug. 
• 
Not Related:  A causal relationship can be excluded, and another documented cause of the 
AE is most plausible 
• 
Unlikely Related:  A causal relationship is improbable, and another documented cause of 
the AE is most plausible 
• 
Possibly Related:  A causal relationship is clinically/biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of the study drug 
• 
Related:  A causal relationship is clinically/biologically highly plausible, there is a plausible 
time sequence between onset of the AE and administration of the study drug, and there is a 
reasonable response on withdrawal 
8.3.3.3 EXPECTEDNESS 

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The investigator will be responsible for determining whether an AE is expected or unexpected based 
on the information provided in the IB.  An AE will be considered unexpected if the nature, severity, 
or frequency of the event is not consistent with the risk information previously described for the 
study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Any medical condition that is present at the time that the participant is screened will be considered 
as medical history and not reported as an AE.  However, if the study participant’s condition 
deteriorates at any time after the time of informed consent, it will be recorded as an AE. 
Changes in the severity of an AE will be documented in the source and eCRF to allow an assessment 
of the duration of the event at each level of severity to be performed.  Adverse events characterized 
as intermittent require documentation of onset and duration of each episode. 
The collection of AEs and SAEs will commence from the time the ICF is signed and continue until the 
last day of study participation.  Events will be followed for outcome information until resolution or 
stabilization during the study or continue until 7 days (for non-serious AEs) or 30 days (for SAEs) 
after the last day of study participation. 
Adverse events will be monitored throughout the study beginning at the time of informed consent.  
At each post-Screening visit, the investigator will begin by querying for AEs by asking each 
participant a general, non-directed question, such as “How have you been feeling since the last 
visit?”  Directed questioning and examination will then be done as appropriate.  If the participant 
presents a potential AE during a telephone visit, the participant will come to the clinic for an 
unscheduled visit to assess the potential AE.  All reported AEs will be documented on the 
appropriate page of the eCRF, including seriousness, severity, relationship to study drug, action 
taken, and outcome (including date of resolution or stabilization, if AE is not ongoing).  If AEs occur, 
the first concern will be the safety of the study participants.  
8.3.5 ADVERSE EVENT REPORTING 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF.  
Information to be collected includes the following: 
• 
Drug treatment 
• 
Dose 
• 
Event term 
• 
Time of onset 
• 
Investigator-specified assessment of severity and relationship to study drug 
• 
Time of resolution of the event 
• 
Seriousness 
• 
Any required treatment or evaluations 
• 
Outcome 

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Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported.  All AEs will be 
followed to adequate resolution.  The Medical Dictionary for Regulatory Activities (MedDRA) will be 
used to code all AEs. 
Any medical condition that is present at the time that the participant is screened but does not 
deteriorate should not be reported as an AE.  However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
The following are special considerations when determining and reporting AEs: 
• 
Whenever possible, the investigator should group signs or symptoms that constitute a single 
diagnosis under a single AE term (eg, “cough, rhinitis, and sneezing” might be grouped 
together as “upper respiratory tract infection”) 
• 
Any item from the Tolerability Questionnaire with a severity of moderate or severe is to be 
recorded as an AE 
• 
Corneal staining with a severity of 2 or 3+ is to be recorded as an AE; if other signs or 
symptoms are present, a diagnosis, such as keratitis, should be recorded 
• 
Progression of myopia, which is collected as a clinical efficacy variable and assessed as 
unequivocally associated with the disease progression and/or lack of efficacy, should not be 
reported as an AE unless progression is greater than anticipated in the natural course of the 
disease 
• 
Any item from the Tolerability Questionnaire with a mild severity is not considered as an AE 
• 
Corneal staining with a severity of 0.5 or 1+ is not considered as an AE 
• 
Small changes in pupil diameter should not be reported as an AE, however, the pursuant 
symptoms such as photophobia may be an AE 
• 
A pre-existing condition is not considered an AE unless the condition worsens (increases in 
frequency, severity, or specificity) during or following study drug administration.  
Fluctuations in a pre-existing condition should be assessed by the investigator, and those 
that fall within the limits of expected fluctuations for the disease state (and are not assessed 
as worsening of the disease) should not be considered AEs.  Any change assessed as 
clinically significant worsening of the disease from baseline must be documented as an AE 
• 
Elective surgery or routine diagnostic procedures are not considered AEs.  However, an 
untoward medical event occurring during the prescheduled elective surgery or diagnostic 
procedure should be recorded as an AE 
• 
Death itself is not considered an AE; it is instead the outcome of an AE 

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• 
A TEAE is an AE with an onset anytime from when the participant has received study drug 
through 30 days after the last dose of study drug, whether or not it is considered causally 
related to the study drug 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
Any AE that meets SAE criteria (Section 8.3.2) must be reported to the PPD Pharmacovigilance (PVG) 
Department immediately (ie, within 24 hours) after the time site staff first learn about the event.  
The study site will record all SAE information on the appropriate eCRF page and submit an SAE 
report via the electronic data capture (EDC) system. 
If, for any reason, reporting an SAE in the EDC system is not possible (eg, the EDC system is 
unavailable), the study site will record the SAE on the paper SAE Reporting Form and fax it to PPD 
PVG (Table 8-1).  Any SAE reported via fax must be entered into the EDC system as soon as possible.  
The safety hotline should only be used if the EDC system is unavailable and the paper SAE Reporting 
Form cannot be sent via fax (ie, the safety hotline will not be used routinely for SAE reporting). 
Table 8-1:  PPD Pharmacovigilance Contact Information 
Region 
Contact Information 
Europe 
Safety fax line: +44 1223 374 102 
Safety hotline: +44 1223 374 240 
United States 
Safety fax line: +1 888 529 3580 
Safety hotline: +1 888 483 7729 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to 
be chronic or the participant is stable.  Other supporting documentation of the event may be 
requested by the study sponsor and should be provided as soon as possible. 
The study sponsor will be responsible for notifying the FDA and other regulatory authorities of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case 
later than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the 
sponsor must notify FDA and all participating investigators in an Investigational New Drug safety 
report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no 
case later than 15 calendar days after the sponsor determines that the information qualifies for 
reporting. 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
Not applicable. 
8.3.8 EVENTS OF SPECIAL INTEREST  

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Not applicable. 
8.4 
REPORTING OF PREGNANCY  
If a female participant becomes pregnant during the study, the investigator will notify the sponsor’s 
designee and the medical monitor immediately after the pregnancy is confirmed, and the 
participant will be permanently discontinued from study drug but remain in the study for monitoring 
of safety and outcome of pregnancy.  The investigator will (1) notify the participant’s physician that 
the participant was being treated with the study drug, and (2) follow the progress of the pregnancy 
to term on the participant providing written informed consent for release of these data.  The 
investigator should document the outcome of the pregnancy and provide a copy of the 
documentation to the sponsor’s designee. 
8.5 
PROCEDURES DURING COVID-19 PANDEMIC 
If a participant visit cannot be performed as a direct result of COVID-19 (eg, the site is closed, social 
distancing rules), the investigator’s designee will complete a phone/video call in lieu of a clinic visit 
to: 
• 
Query the parent for any healthy changes since the last visit for potential AEs.  The 
investigator will speak directly with the parent/participant for additional details regarding 
any AEs; if medically warranted, the participant will return to the clinic as soon as is feasible 
• 
Inquire about changes in concomitant medications 
• 
Complete the Tolerability Questionnaire and the Quality of Life Questionnaire 
• 
IP will be dispensed from IRT and shipped to the participant via courier as per local 
regulation or parent/participant may collect from the site when a phone visit is complete 
These will be considered as non-substantial protocol deviations.  The Investigator will attempt to 
have participants return to the clinic for safety exams as operation permit at the study site for out-
of-window visits. 
 

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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
9.1.1 PRIMARY EFFICACY ESTIMANDS 
The primary efficacy endpoint will differ for the EMA and US FDA submissions based on guidance 
received from the different regulatory authorities (endpoints are defined and justified in Section 3).  
The primary estimand for each regulatory agency is summarized in the table below. 
Table 9-1:  Summary of Estimands for EMA and FDA 
Objective: 
To evaluate the efficacy of SYD-101 for slowing the progression of myopia in 
children 
 
Estimand Label 
EMA Primary  
 
FDA Primary 
Estimand Description 
Difference in the mean annual 
progression rate of myopia based on 
24 months of follow-up assuming no 
use of prohibited or escape 
medication or dosing 
interruptions/discontinuations due to 
logistical issues.  For discontinuations 
due to tolerability issues (ie, due to a 
related AE), it is assumed that the 
effect in those participants is similar to 
that in participants receiving vehicle 
without escape medication or 
prohibited treatments  
 
Difference in the proportion of 
participants with confirmed myopic 
progression >0.75 D at or before 
Month 36 allowing for use of 
prohibited treatment or escape 
medication and assuming no dosing 
interruptions/discontinuations due to 
logistical issues.  For discontinuations 
due to tolerability reasons (ie, due to a 
related AE), participants will be 
considered to have progressed 
Target Population 
Pediatric population of myopic 
children between 3 and 14 years of 
age at the time of screening that meet 
study criteria with parental/guardian 
consent 
 
Pediatric population of myopic 
children between 3 and 14 years of 
age at the time of screening that meet 
study criteria with parental/guardian 
consent 
Endpoint 
The annual progression rate of myopia 
through Month 24 
Proportion of participants with 
confirmed myopic progression >0.75 D 
at or before Month 36 
 
Treatment Condition 
Test: SYD-101 0.01% 
Test: SYD-101 0.03% 
Reference: Vehicle 
All without use of escape therapy for 
myopia control 
 
Test: SYD-101 0.01% 
Test: SYD-101 0.03% 
Reference: Vehicle 
Escape medication for myopia control 
allowed 
Population-Level 
Summaries 
Difference in mean annual progression 
rate of myopia through Month 24 
between SYD-101 0.01% and Vehicle  
 
Difference in proportion of 
participants with confirmed myopic 
progression >0.75 D at or before 

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Difference in mean annual progression 
rate of myopia through Month 24 
between SYD-101 0.03% and Vehicle  
 
Month 36 between SYD-101 0.01% 
and Vehicle  
Difference in proportion of 
participants with confirmed myopic 
progression >0.75 D at or before 
Month 36 between SYD-101 0.03% 
and Vehicle  
Intercurrent events will be handled in the same manner for both the FDA and EMA primary 
estimands as presented in the table below.   
Table 9-2:  Summary of Intercurrent Event Handling for Primary Estimands 
Intercurrent Event  
Strategy for Primary Estimands 
Justification 
Intermittent Missing Data 
Hypothetical 
• 
Intermittent missing data will 
be multiply imputed assuming 
data is missing at random 
(MAR) 
 
Intermittent missing data are expected 
to be missing at random/due to 
logistical issues 
Prohibited Treatment 
EMA Endpoint: While on Treatment 
• 
MMRM using observed data 
until receipt of prohibited 
treatment (no multiple 
imputation) 
 
FDA Endpoint: Composite 
• 
Participants who receive 
prohibited treatment will be 
considered non-responders (eg, 
have progressed)  
 
Prohibited treatments include therapies 
that have known efficacy for slowing 
myopia progression (e.g., MiSight 
multifocal contact lenses, Ortho-K 
lenses, compounded atropine, etc.) and  
use may be uneven between the 
groups, and this could distort the 
treatment effect of SYD to Vehicle 
Escape Therapy 
EMA Endpoint: While on Treatment 
• 
MMRM using observed data 
until receipt of prohibited 
treatment (no multiple 
imputation) 
 
FDA Endpoint: Composite 
• 
Participants who receive 
escape medication will be 
considered non-responders (eg, 
have progressed)  
 
The American Academy of 
Ophthalmology recommends low dose 
atropine to reduce myopia progression.  
As escape medication use may be 
uneven between the groups, this could 
distort the treatment effect of SYD to 
Vehicle 
 
If escape medication is initiated per 
protocol, it is not to be given until after 
the 2-year EMA endpoint. Additionally, 
escape criterion of 2.0 D progression is 
larger than the FDA endpoint defined 
progression > 0.75 D. However, if sites 
should choose to treat participants prior 
to the defined escape criteria being 
met, that would indicate a belief that 
participants have progressed 

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Treatment 
Discontinuation 
EMA Endpoint: Hypothetical 
• 
Observations after DC due to a 
related AE will be multiply 
imputed assuming missing not 
at random (MNAR) using a 
sequential vehicle-based 
pattern regression 
• 
Observations after Treatment 
DC for other reasons will be 
multiply imputed assuming 
MAR 
FDA Endpoint: Composite 
• 
Participants with 
discontinuation (DC) due to a 
related AE are non-responders 
• 
Observations after DC for other 
reasons will be multiply 
imputed assuming MAR 
 
Discontinuation due to related AE are 
labelled non-responders is a 
conservative strategy as the 
discontinuation is related to treatment.  
Other reasons for discontinuation will 
be considered to occur at random 
 
Treatment policy will be used as a 
sensitivity analysis as this will reflect 
real world use including potential 
rebound effect when participants 
discontinue treatment 
Study Discontinuation 
EMA Endpoint: Hypothetical 
• 
Observations after DC due to a 
related AE will be multiply 
imputed assuming MNAR using 
a sequential vehicle-based 
pattern regression 
• 
Observations after Treatment 
DC for other reasons will be 
multiply imputed assuming 
MAR 
FDA Endpoint: Composite 
• 
Participants with DC due to a 
related AE are non-responders 
• 
Observations after DC for other 
reasons will be multiply 
imputed assuming MAR 
 
This study was enrolling, and a large 
portion of participant follow-up was 
during the ongoing COVID-19 pandemic.  
The majority of study discontinuations 
are logistical due to withdrawal of 
consent. 
 
Discontinuation due to related AE are 
labelled non-responders and is a 
conservative strategy as the 
discontinuation is related to treatment.  
Other reasons for discontinuation will 
be considered to occur at random. 
 
Invalid SE Values 
Treatment Policy 
• 
Invalid SE values will be used 
 
Given the age of children in 
participants, in clinical practice it would 
be expected to have non-ideal auto-
refraction assessments. 
Due to technical issues or non-compliant participants (eg, wiggly child), not all SE assessments 
performed may be valid.  For sensitivity analysis based on valid SE values, the final average SE (over 
both eyes) will be calculated only if there is a valid per eye average SE for each eye.  A per eye 
average SE value will be considered valid if there are three non-missing assessments performed for 
that eye.  However, if there are three non-missing SE assessments for a given eye, but one of the SE 
values differs from the other two SE values for that eye by at least 1 D, only the two SE values that 

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are within 1 D of each other will be considered valid and used to calculate the valid average SE for 
that eye.  Otherwise, all three SE values will be used to calculate the per aye average SE. If there are 
only two non-missing assessments available for a given eye and the two SE values for that eye are 
within 0.25 D of each other (i.e., -0.25 D ≤ SE Measurement 1 – SE Measurement 2 ≤ 0.25 D) then 
the per eye average SE of those two assessments will be considered valid.  Otherwise, the per eye SE 
value will be considered invalid for that eye at that visit. 
Additional sensitivity analyses utilizing different approaches for missing data an intercurrent events 
will be performed.  These analyses are summarized in the following table and full details will be 
provided in the statistical analysis plan. 
 

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Table 9-3:  Summary of Additional Sensitivity Analyses 
Analysis 
Intercurrent Events 
Intermittent Missing 
Data 
Receipt of Prohibited 
Treatment 
Receipt of Escape 
Therapy 
Treatment 
Discontinuation  
Study Discontinuation  
Invalid SE Values 
Sensitivity Analysis 1   
PPS MAR Multiple 
Imputation 
Hypothetical  
Multiple imputation 
assuming MAR 
 
EMA Endpoint: While 
on Treatment  
 
MMRM using 
observed data until 
receipt of prohibited 
treatment (no 
multiple imputation) 
 
FDA Endpoint: 
Composite 
Observations after 
receipt of prohibited 
treatment will be 
considered non-
responders (e.g., have 
progressed) 
 
EMA Endpoint: 
While on Treatment 
 
MMRM using 
observed data until 
receipt of escape 
medication (no 
multiple imputation) 
 
FDA Endpoint: 
Composite 
Observations after 
receipt of escape 
medication will be 
considered non-
responders (e.g., have 
progressed) 
FDA Endpoint: 
Composite 
Participants with 
discontinuation (DC) 
due to a related AE 
are non-responders 
Observations after DC 
for other reasons will 
be multiply imputed 
assuming MAR 
EMA Endpoint: 
Hypothetical 
Observations after 
discontinuation (DC) 
due to a related AE 
will be multiply 
imputed assuming 
MNAR using a 
sequential vehicle-
based pattern 
regression 
Observations after 
Treatment DC for 
other reasons will be 
multiply imputed 
assuming MAR 
FDA Endpoint: 
Composite 
Participants with 
discontinuation (DC) 
due to a related AE 
are non-responders 
Observations after DC 
for other reasons will 
be multiply imputed 
assuming MAR 
EMA Endpoint: 
Hypothetical 
Observations after 
discontinuation (DC) 
due to a related AE 
will be multiply 
imputed assuming 
MNAR using a 
sequential vehicle-
based pattern 
regression 
Observations after 
Treatment DC for 
other reasons will be 
multiply imputed 
assuming MAR 
Hypothetical  
 
Multiple imputation 
assuming MAR 

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Analysis 
Intercurrent Events 
Intermittent Missing 
Data 
Receipt of Prohibited 
Treatment 
Receipt of Escape 
Therapy 
Treatment 
Discontinuation  
Study Discontinuation  
Invalid SE Values 
Sensitivity Analysis 2  
FAS Treatment Policy 
for Prohibited and 
Rescue Treatments 
Hypothetical  
Multiple imputation 
assuming MAR 
Treatment Policy  
Use observed data 
Treatment Policy  
Use observed data 
Treatment Policy  
Use observed data 
FDA Endpoint: 
Composite 
Participants with 
discontinuation (DC) 
due to a related AE 
are non-responders 
Observations after DC 
for other reasons will 
be multiply imputed 
assuming MAR 
EMA Endpoint: 
Hypothetical 
Observations after 
discontinuation (DC) 
due to a related AE 
will be multiply 
imputed assuming 
MNAR using a 
sequential vehicle-
based pattern 
regression 
Observations after 
Treatment DC for 
other reasons will be 
multiply imputed 
assuming MAR 
Treatment Policy  
Use observed data 

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Analysis 
Intercurrent Events 
Intermittent Missing 
Data 
Receipt of Prohibited 
Treatment 
Receipt of Escape 
Therapy 
Treatment 
Discontinuation  
Study Discontinuation  
Invalid SE Values 
Sensitivity Analysis 3 
FAS MAR Tipping 
Point   
Add fixed values of c 
to SYD imputed values  
Hypothetical  
Multiple imputation 
assuming MAR 
Hypothetical 
Observations after 
receipt of prohibited 
medication will be 
multiply imputed 
assuming MAR 
Hypothetical   
Observations after 
receipt of escape 
medication will be 
multiply imputed 
assuming MAR 
Treatment Policy  
Use observed data 
Hypothetical  
Multiple imputation 
assuming MAR 
Treatment Policy  
Use observed data 
Sensitivity Analysis 4 
FAS MNAR – exclude 
prohibited and escape 
observations before 
MNAR 
Hypothetical  
Multiple imputation 
assuming MAR 
Hypothetical  
Observations after 
receipt of prohibited 
medication will be 
multiply imputed 
assuming MNAR using 
a sequential vehicle-
based pattern 
regression 
Hypothetical  
Observations after 
receipt of escape 
medication will be 
multiply imputed 
assuming MNAR using 
a sequential vehicle-
based pattern 
regression  
Treatment Policy 
Use observed data 
Hypothetical  
Observations after 
receipt study 
discontinuation will 
be multiply imputed 
assuming MNAR using 
a sequential vehicle-
based pattern 
regression 
Treatment Policy 
Use observed data 
Sensitivity Analysis 5 
FAS MNAR – include 
vehicle post 
prohibited and escape 
observations 
Hypothetical  
Multiple imputation 
assuming MAR 
Treatment policy for 
vehicle 
Use observed data 
Hypothetical for SYD 
Observations after 
receipt of prohibited 
medication will be 
multiply imputed 
assuming MNAR using 
a sequential vehicle-
based pattern 
regression 
Treatment policy for 
vehicle 
Use observed data 
Hypothetical for SYD 
Observations after 
receipt of prohibited 
medication will be 
multiply imputed 
assuming MNAR using 
a sequential vehicle-
based pattern 
regression 
Treatment Policy  
Use observed data 
Hypothetical   
Observations after 
study discontinuation 
will be multiply 
imputed assuming 
MNAR using a 
sequential vehicle-
based pattern 
regression  
Treatment Policy  
Use observed data 

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Analysis 
Intercurrent Events 
Intermittent Missing 
Data 
Receipt of Prohibited 
Treatment 
Receipt of Escape 
Therapy 
Treatment 
Discontinuation  
Study Discontinuation  
Invalid SE Values 
Sensitivity Analysis 6 
FAS for FDA only – 
missing = progression 
Hypothetical  
Multiple imputation 
assuming MAR 
Hypothetical   
Observations after 
receipt of prohibited 
medication will be 
multiply imputed 
assuming MAR 
Hypothetical   
Observations after 
receipt of prohibited 
medication will be 
multiply imputed 
assuming MAR 
Treatment Policy 
Use observed data 
Composite 
If participant has 
missing assessment at 
Month X and 
participant 
discontinued study 
prior to Month x, a 
progression will be 
imputed for Month X 
Treatment Policy  
Use observed data 
Sensitivity Analysis 7  
FAS for EMA only – 
MMRM no imputation 
Hypothetical  
MMRM assumes MAR 
Hypothetical  
Observations after 
receipt of prohibited 
medication will be 
censored.   
MMRM assumes MAR 
Hypothetical  
Observations after 
receipt of escape 
medications will be 
censored.   
MMRM assumes MAR 
Treatment Policy  
Use observed data 
Hypothetical  
MMRM assumes MAR 
Treatment Policy  
Use observed data 
 

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EMA Submission: 
The primary efficacy analysis for the EMA submission will test the following hypothesis: 
• H0:  The mean annual progression rate through Month 24 is equal between Vehicle and 
SYD-101. 
• H1:  The mean annual progression rate through Month 24 is different between Vehicle and 
SYD-101. 
US FDA Submission: 
The primary efficacy analysis for the FDA submission will test the following hypothesis: 
• H0:  The proportion of participants with myopic progression > 0.75 D at or before 
Month 36 is equal between Vehicle and SYD-101. 
• H1:  The proportion of participants with myopic progression > 0.75 D at or before 
Month 36 is different between Vehicle and SYD-101. 
For submission to both the EMA and FDA, the primary efficacy analysis (EMA and FDA) will be tested 
at alpha=0.05 (2-sided) level of significance.  Each dose of SYD-101, 0.01% and 0.03%, will be 
independently compared to Vehicle.  A truncated Hochberg adjustment (γ=0.80) will be performed 
to establish significance for comparisons of each of the active doses to Vehicle whilst controlling the 
overall type I error.  With truncation parameter γ=0.80, if both comparisons result in a P-value 
<0.045, then both comparisons will be statistically significant.  If one comparison results in a P-value 
≥0.045, then the second comparison will be statistically significant if the resulting P-value is <0.025. 
Note there is no correction for multiplicity for the primary efficacy analysis for EMA and for FDA.  
This is in accordance with ICH Guidance E17-General Principles for Planning & Design of MRCT 
where it is stated “because regulatory approvals are based on different primary endpoints by 
different authorities, no multiplicity adjustment is needed for regulatory decision-making.” 
9.1.2 SECONDARY EFFICACY ENDPOINTS 
Refer to Section 3 for definition and justification of endpoints. 
The hypothesis testing of secondary endpoints will be conducted using a gatekeeping procedure 
based on a closed fixed-sequence test, provided the primary endpoint comparison is statistically 
significant.  Additionally, the truncated Hochberg adjustment (γ=0.80) will be utilized to control for 
potential multiple dose comparisons for each endpoint.  This procedure controls the study-wise 
type I error at the 0.05 significance level as described below.    
In order to evaluate a dose comparison at each step, all preceding comparisons are to be statistically 
significant in favor of SYD-101 for that dose, ie, for a given endpoint, comparisons will only be 

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performed for the SYD-101 dose(s) that are statistically significant for the prior endpoint assessed.  If 
both SYD-101 dose comparisons are statistically significant for the prior endpoint, the truncated 
Hochberg adjustment (γ=0.80) will be used to control type I error between the two doses for the 
given endpoint.  Based on the truncated Hochberg adjustment with truncation parameter γ=0.80, if 
both dose comparisons were significant in the prior step, alpha of 0.05 is retained to the next step.  
In that step the truncated Hochberg adjustment will again be applied if there are two dose 
comparisons for the given step.  However, if in the prior comparison, only one dose comparison of 
two comparisons was significant, then alpha of 0.005 is retained and the one dose comparison must 
yield a P value < 0.005 to be significant.     
For the EMA submission, the SYD treatment arms will be combined and compared to vehicle for 
endpoints assessed on subset of fast progressors.  For those endpoints, the one comparison will be 
assessed at the alpha level retained from the prior comparison (either 0.05 if both dose comparisons 
were significant for both doses for all prior endpoints assessed or 0.005 if only one dose comparison 
was significant for the prior endpoint assessed.)   
Again, no correction for multiplicity for the different efficacy analysis for EMA and for FDA is 
required. 
Table 9-4 summarizes all efficacy endpoints in order of testing for the EMA and FDA analyses. 
Table 9-4:  Order of Testing Efficacy Endpoint for EMA and FDA Analyses 
Endpoint 
EMA 
FDA 
1. Primary 
Efficacy 
Endpoint 
Mean annual progression rate of myopia 
through month 24 
 
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
Proportion of participants with myopic 
progression >0.75 D at or before Month 
36 
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
2. Key Secondary 
Efficacy 
Endpoint 
Proportion of participants with myopic 
progression >0.75 D at or before Month 
24 
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
Mean annual progression rate of myopia 
through month 36 
 
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
Other Secondary Efficacy Endpoints 
3.  
Proportion of participants with annual 
myopia progression rate through Month 
24 ≤0.50 D/year  
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
Proportion of participants with annual 
myopia progression rate through Month 
36 ≤0.50 D/year  
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 

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Endpoint 
EMA 
FDA 
4.  
Proportion of participants with annual 
myopia progression rate through Month 
24 ≤0.25 D/year 
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
Proportion of participants with annual 
myopia progression rate through Month 
36 ≤0.25 D/year 
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
5.  
Proportion of participants with increase 
of myopia of >0.50 D at or before Month 
24 
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
Proportion of participants with increase 
of myopia of >0.50 D at or before Month 
36 
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
6.  
Time to progression of myopia of >0.75 D 
through Month 24 
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
Time to progression of myopia of >0.75 D 
through Month 36 
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
7.  
Mean annual progression rate using 
Month 24 data on Subgroup of 
participants with refractive history of 
progression ≥ 0.5D 
 
If both dose comparisons are significant 
for prior endpoint, the SYD-101 0.01% 
and 0.03% arms will be combined for 
single comparison to vehicle at alpha 
retained from prior step.  Otherwise, if 
only one treatment comparison is 
significant, then only that dose will be 
compared to vehicle using alpha retained 
from prior comparison 
Mean change from baseline in axial 
length at Month 36 (at sites with the 
requisite equipment; at least 50% of 
participants) 
 
Truncated Hochberg to control alpha for 
the two pairwise SYD to Vehicle 
comparisons 
8.  
Mean annual progression rate using 
Month 24 data on Subgroup of 
participants with refractive history of 
progression ≥ 0.75D 
 
If both dose comparisons are significant 
for time to progression endpoint and the 
pooled dose comparison for prior 
endpoint was significant, the SYD-101 
0.01% and 0.03% arms will be combined 
for single comparison to vehicle at alpha 
retained from prior step 
 
9.  
Mean change from baseline in axial 
length at Month 24 (at sites with the 
requisite equipment; at least 50% of 
participants) 
 

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Endpoint 
EMA 
FDA 
 
Hochberg to control alpha for the two 
pairwise SYD to Vehicle comparisons 
If the comparison is not statistically significant at any step, then remaining comparisons in the stated 
hierarchy will be considered nominal, descriptive, and exploratory.  The study-wise type I error will 
be maintained with the above closed procedure.  No type I error adjustment is required for the 
different primary endpoints between regulatory agencies as efficacy will be assessed independently 
in each submission. 
Intercurrent events will be handled in the for the FDA and EMA key secondary estimands as 
presented in the table below.   
Table 9-5:  Summary of Intercurrent Event Handling for Key Secondary Estimands 
Intercurrent Event  
Strategy for Key Secondary 
Estimands 
Justification 
Intermittent Missing Data 
Hypothetical 
• 
Intermittent missing data will be 
multiply imputed assuming data 
is missing at random (MAR) 
Intermittent missing data are 
expected to be missing at 
random/due to logistical issues 
Prohibited Treatment 
EMA Composite 
• 
Participants who receive 
prohibited treatment will be 
considered non-responders 
 
FDA Hypothetical 
• 
Observations after receipt of 
prohibited treatment will be 
multiple imputed assuming 
MNAR using a sequential 
vehicle-based pattern 
regression. Observations after 
receipt of prohibited treatment 
will be removed for all 
treatment arms prior to 
imputation 
Prohibited treatment includes 
therapies that have known efficacy 
for slowing myopia progression (eg, 
MiSight multifocal contact lenses, 
Ortho-K lenses, compounded 
atropine, etc.) and use may be 
uneven between the groups, and this 
could distort the treatment effect of 
SYD-101 to Vehicle 

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Intercurrent Event  
Strategy for Key Secondary 
Estimands 
Justification 
Escape Medication 
EMA Composite 
• Participants who receive escape 
medication will be considered 
non-responders 
 
FDA Hypothetical 
• 
Observations after receipt of 
escape medication will be 
multiple imputed assuming 
MNAR using a sequential 
vehicle-based pattern 
regression. Observations after 
receipt of escape medications 
will be removed for all 
treatment arms prior to 
imputation 
The American Academy of 
Ophthalmology, among others, 
currently recommends low dose 
atropine for treatment of myopia 
progression.  As escape medication 
use may be uneven between the 
groups, this could distort the 
medication effect of SYD-101 to 
Vehicle  
 
If escape medication is initiated per 
protocol, it is not to be given until 
after the 2-year EMA endpoint. 
Additionally, escape criterion of 2.0 
D progression is larger than the FDA 
endpoint defined progression > 0.75 
D. However, if sites should choose to 
treat participants prior to the 
defined escape criteria being met, 
that would indicate a belief that 
participants have progressed 
 
Treatment Discontinuation 
Hypothetical 
• 
Observations after DC due to a 
related AE will be multiply 
imputed assuming missing not 
at random (MNAR) using a 
sequential vehicle-based pattern 
regression 
• 
Observations after Treatment 
DC for other reasons will be 
multiply imputed assuming MAR 
Discontinuation due to related AE 
are labelled non-responders is a 
conservative strategy as the 
discontinuation is related to 
treatment.  Other reasons for 
discontinuation will be considered to 
occur at random 
 
Treatment policy will be used as a 
sensitivity analysis as this will reflect 
real world use including potential 
rebound effect when participants 
discontinue treatment 

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Intercurrent Event  
Strategy for Key Secondary 
Estimands 
Justification 
Study Discontinuation 
Hypothetical 
• 
Observations after DC due to a 
related AE will be multiply 
imputed assuming MNAR using 
a sequential vehicle-based 
pattern regression  
• 
Observations after DC for other 
reasons will be multiply imputed 
assuming MAR 
 
This study was enrolling, and a large 
portion of participant follow-up was 
during the ongoing COVID-19 
pandemic.  The majority of study 
discontinuations are logistical due to 
withdrawal of consent 
 
Discontinuation due to related AE 
are labelled non-responders and is a 
conservative strategy as the 
discontinuation is related to 
treatment.  Other reasons for 
discontinuation will be considered to 
occur at random 
 
Invalid SE Values 
Treatment Policy 
• 
Invalid SE values will be used 
Given the age of children as 
participants, in clinical practice it 
would be expected to have non-ideal 
auto-refraction assessments 
For all other secondary endpoints secondary endpoints excepting axial length, time to progression, 
and the Fast Progression subgroups, intercurrent events will be handled as specified in the table 
below. 
Table 9-6: 
Intercurrent Event Approaches for Secondary Estimands 
Intercurrent Event  
Strategy for Secondary Estimands 
Justification 
Intermittent Missing Data 
Hypothetical 
• 
Intermittent missing data will 
be multiply imputed assuming 
data is missing at random 
(MAR) 
Intermittent missing data are expected to 
be missing at random/due to logistical 
issues 
Prohibited Treatment 
Hypothetical 
• 
Observations after receipt of 
prohibited treatment will be 
multiply imputed assuming 
MAR 
Prohibited treatments include therapies 
that have known efficacy for slowing 
myopia progression (eg, MiSight 
multifocal contact lenses, Ortho-K 
lenses, compounded atropine, etc.) and 
use may be uneven between the groups 
and this could distort the treatment effect 
of SYD-101 to Vehicle 
Escape Medication 
Hypothetical 
• 
Observations after receipt of 
escape medication will be 
multiply imputed assuming 
MAR 
The American Academy of 
Ophthalmology, among others, currently 
recommends low dose atropine for 
treatment of myopia progression.  As 
escape medication use may be uneven 
between the groups, this could distort 

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the treatment effect of SYD-101 to 
Vehicle  
Treatment 
Discontinuation 
Hypothetical 
• 
Observations after DC due to a 
related AE will be multiply 
imputed assuming missing not 
at random (MNAR) using a 
sequential vehicle-based pattern 
regression 
• 
Observations after DC for other 
reasons will be multiply 
imputed assuming MAR 
 
Discontinuation due to related AE are 
labelled non-responders is a 
conservative strategy as the 
discontinuation is related to treatment.  
Other reasons for discontinuation will be 
considered to occur at random 
 
Treatment policy will be used as a 
sensitivity analysis as this will reflect 
real world use including potential 
rebound effect when participants 
discontinue treatment 
 
Study Discontinuation 
Hypothetical 
• 
Observations after DC due to a 
related AE will be multiply 
imputed assuming MNAR using 
a sequential vehicle-based 
pattern regression 
• 
Observations after DC for other 
reasons will be multiply 
imputed assuming MAR 
 
 
This study was enrolling, and a large 
portion of participant follow-up was 
during the ongoing COVID-19 
pandemic.  The majority of study 
discontinuations are logistical due to 
withdrawal of consent 
 
Discontinuation due to related AE are 
labelled non-responders and is a 
conservative strategy as the 
discontinuation is related to treatment.  
Other reasons for discontinuation will be 
considered to occur at random 
 
Invalid SE Values 
Treatment Policy 
• 
Invalid SE values will be used 
Given the age of children as participants, 
in clinical practice it would be expected 
to have non-ideal auto-refraction 
assessments 
 
9.2 
SAMPLE SIZE DETERMINATION 
Group sample sizes of 280 in each treatment arm will achieve at least 90% power to detect a 
difference in the percentage of participants with myopic progression (>0.75 D) of at least 15% 
between a SYD-101 arm and Vehicle.  Power calculations presented in Figure 9-1 are based on the 
Chi-squared test at a 2-sided significance level of 0.025. 

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Figure 9-1:  Power for 2-Sided Chi-Square Test Evaluated at Alpha=0.025 for Proportion 
Responders When 280 Participants Per Arm 
 
Additionally, group sample sizes of 280 per treatment arm achieves >90% power to detect a 
reduction of 0.18 D or more in the annual progression rate between SYD-101 and Vehicle, assuming 
a common SD of 0.60 D.  Power calculations presented in Figure 9-2 are based on a 2-sample t-test 
evaluated at the 0.025 significance level. 

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Figure 9-2:  Power for 2-Sided T-Test Evaluated at Alpha=0.025 for Annual Progression Rate 
When 280 Participants Per Arm 
 
Calculations were performed using SAS® 9.3 Software (SAS Institute, Inc, Cary, North Carolina). 
This study plans to continue follow-up for all enrolled participants through Month 48, regardless of 
early discontinuation of study treatment or receipt of escape medication/prohibited therapy.  All 
participants will be included in analyses based on their observed data.  Because the effect size 
estimates have already taken into consideration the impact of no therapy/escape medication, 
enrollment of additional participants beyond 280 participants per treatment arm has not been 
planned. 
9.3 
POPULATIONS FOR ANALYSES 
The Full Analysis Set (FAS) will include all randomized participants who receive at least 1 drop of 
study drug.  The FAS will be the primary population used for the efficacy analyses.  Treatment 
assignment will be based on the randomized treatment. 

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The Safety Analysis Set will include all participants who receive any amount of study drug 
(SYD-101 0.01%, SYD-101 0.03%, or Vehicle).  The Safety Analysis Set will be the primary population 
used for safety analyses.  Treatment assignment will be based on the treatment actually received. 
The Per-Protocol Analysis Set will include all participants in the FAS who do not have any important 
protocol deviations and have at least 1 post-baseline measurement for SE.  Important protocol 
deviations are to be defined and assigned prior to database lock and breaking the study mask.  
Efficacy endpoints analyzed for the Per-Protocol Analysis Set are to be treated as a sensitivity 
analysis.  Treatment assignment will be based on the treatment actually received.   
Additionally, for the EMA Submission special subsets are defined to identify participants with a 
history of fast progression based historical refraction data.   
Subgroup 1: FAS Participants with progression ≥ 0.50 D/year based on historical refraction 
Subgroup 2: FAS Participants with progression ≥ 0.75 D/year based on historical refraction 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
Statistical analyses will be reported with tables, figures, and listings.  Tables and figures will be 
summarized by treatment group.  Tables summarizing demographics and other baseline 
characteristics will also include a column for all participants combined.  
In general, continuous variables will be summarized to indicate the population sample size (N), 
number of participants with available data (n), mean, SD, median, minimum, and maximum values.  
Categorical variables will be summarized by the N, n, number of participants in each category, and 
the percentage of participants in each category.  Unless otherwise noted, the denominator to 
determine the percentage of participants in each category will be based on the number of 
participants with available data.  Select ordinal data may be summarized using both descriptive 
statistics and counts and percentages of participants in each category, as appropriate. 
Statistical significance testing will be 2-sided and performed using alpha=0.05.  
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
SE values will be calculated as per Section 3.   Per protocol, the autorefraction procedure is to be 
performed 3 times in each eye.  SE values will be calculated for each autorefraction for each eye as 
the sum of the sphere power with half of the cylinder power (SE = sphere + ½ cylinder).  If there are 
less than three measurements for a given eye, the available SE values will be averaged for that eye 
prior to averaging the right and left per eye SE averages for the average SE value for analysis.  The 
final average SE (over both eyes) will be missing if the per eye SE average SE is missing for either 
eye. 

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A combination of hypothetical, composite, and treatment policy strategies for intercurrent events 
will be used for the primary estimands.  For FDA and EMA, intermittent missing data or observations 
post study or treatment discontinuation not due to a related AE will be multiply imputed using via 
Markov Chain Monte Carlo (MCMC) methods assuming the missing data is MAR (Missing at 
Random).      
For the EMA, observations after specified prohibited or escape treatment will be observed until day 
of prohibited or escape treatment; observations following prohibited or escape treatment will be 
censored and not imputed.  For the FDA primary estimand, observations post prohibited or escape 
treatment will be considered non-responders.   
For the EMA primary estimand, observations post study or treatment discontinuation due to a 
related AE will be multiply imputed assuming missing data is MNAR (Missing Not at Random).  For 
the FDA primary estimand, observations post study or treatment discontinuation due to a related AE 
will be considered non-responders.   
For the EMA and FDA, observations with invalid SE values will be analyzed as observed. 
For any imputations, the value to be imputed is the average SE value (average of both eyes).  This 
same set of imputed SE values will be used to calculate the primary efficacy endpoints for EMA and 
FDA, as well as the key secondary and applicable secondary efficacy endpoints derived from SE.  All 
imputations will be based on set SEEDS.  It is planned to perform k=50 imputations, however the 
number of imputations may be increased depending on the amount of missing data. 
MAR imputations will be performed separately for each treatment arm and the imputation model 
will include terms for age at baseline, baseline SE (average of both eyes), and SE values (average of 
both eyes) for each post baseline scheduled visit through the specified analysis timepoint, Month 24 
or Month 36 as applicable.   
Imputations for data assumed to be MNAR will be first imputed via MCMC multichain methods to 
obtain monotone data as above for MAR imputations.   The remaining missing SE values will be 
imputed via a sequential vehicle-based pattern imputation using regression methods (Ratitch, 2011) 
for the scheduled SE visits through the analysis timepoint, Month 24 or Month 36, using a model 
including age at baseline and baseline SE (average of both eyes) followed by sequential visits 
through M24 or M36, imputed values for those on SYD-101 treatment will be based on the Vehicle 
group.   
EMA Submission: 
The annual progression rate of myopia for a given timepoint will be calculated as the negative 
change in SE (average of both eyes) from baseline, divided by the number of days to the timepoint 
(visit date − date of first dose of study drug + 1), and multiplied by 365.25 days/year.  The average of 
SE for the right and left eyes will be used for analysis.   

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SYD-101 0.01% and SYD-101 0.03% will be compared to Vehicle for the annual progression rate of 
myopia after 24 months of treatment using a REML-based MMRM model including fixed effects for 
treatment group, baseline age category, categorical visit, and the treatment group by visit 
interaction, with baseline SE value (average of both eyes) as a covariate.  An appropriate covariance 
structure will be selected, and the Kenward-Roger Method will be used to calculate the 
denominator degrees of freedom for the test of fixed effects.  All visits through Month 24 will be 
included in the model, with the primary comparison at the Month 24 visit.   
The MMRM model will be repeated for each imputation and the results combined via SAS PROC 
MIANALYZE for final treatment estimates.  The mean annual progression rate of myopia for each 
treatment and the estimated mean difference between each SYD-101 treatment group and Vehicle 
will be presented along with their corresponding 95% CIs. 
The analysis of the primary endpoint will be based on the FAS.  As a sensitivity analysis, an analysis 
will be repeated for the Per-Protocol Analysis Set and using other imputation approaches for the 
FAS. 
US FDA Submission:  
Progression is defined as an increased negative change where change is calculated as visit SE 
value − baseline SE value.  As described in Section 3, a single averaged SE value (average of both 
eyes) will be used for analysis.  Progression must be confirmed at the next assessment. 
The proportion of participants with confirmed myopia progression (>0.75 D) at Month 36 (see 
Section 3) in the 3 treatment groups will be compared between each dose of SYD-101 and Vehicle 
using pairwise CMH tests to account for randomization factors (ie, baseline SE and age categories).  
The CMH tests will be repeated for each imputation and the results combined via SAS PROC 
MIANALYZE for final treatment estimates.    
Rubin’s pooling methodology utilized in SAS PROC MIANALYZE is based on assumption that the 
estimates are asymptotically normally distributed.  The CMH test follows a Chi-Square distribution 
which is highly skewed for smaller degrees of freedom and can violate Rubin’s assumptions.  Prior to 
combination of data in the MIANALYZE procedure, the individual CMH test statistics will be 
transformed to an approximate Normal (0,1) variables using the Wilson-Hilferty transformation 
(Wilson & Hilferty, 1931; Goria, 1992). 
The number and percentage of participants in each treatment group who meet the definition of 
myopic progression will be presented, as will estimates of the differences between each SYD-101 
treatment group and Vehicle with 95% confidence intervals (CI) for the treatment differences.   
The analysis of the primary endpoint will be based on the FAS.  As a sensitivity analysis, analysis of 
the primary endpoint will be repeated for the Per-Protocol Analysis Set and using other imputation 
approaches for the FAS. 

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9.4.3 ANALYSIS OF THE SECONDARY ENDPOINTS 
All secondary endpoints will be primarily analyzed for the FAS and repeated for the Per-Protocol 
Analysis Set as sensitivity analyses.  Additional sensitivity analyses using other imputation/tipping 
point approaches for the FAS will be performed for the key secondary endpoints only.  For the EMA 
submission, the key secondary endpoint will be the proportion of participants with myopic 
progression >0.75 D at or before Month 24.  The analysis will use the same methodology as stated in 
Section 9.4.2 as for the FDA primary efficacy endpoint.  
For the US FDA submission, the key secondary endpoint will be the mean annual progression rate of 
myopia using data through Month 36.  The analysis will use the same methodology as specified for 
this endpoint in Section 9.4.2 as for the EMA primary efficacy endpoint. 
Proportionate progression rate endpoints using different cutoffs to define myopic progression at 
Month 36 (eg, ≤0.25 D/year, ≤0.50 D/year, and an increase of myopia of 0.50 D) will be analyzed 
similar to the primary FDA endpoint using pairwise CMH tests.  
Time to progression of myopia will be calculated in days as the date of first confirmed SE 
measurement that represents a progression of >0.75 D or greater minus the date of first dose of 
study drug, plus one.  Participants who do not experience myopic progression through 24 months 
(EMA) or 36 months (FDA) or who have an early discontinuation without a progression will be 
censored at the date of their last SE assessment at or before Month 24 (EMA) or Month 36 (FDA).  
Participants who receive a prohibited treatment or escape therapy prior to myopic progression will 
be censored as of the date they received the prohibited or escape therapy.  Each dose of SYD-101 
will be compared to Vehicle for time to progression of myopia using the log-rank test stratified by 
the randomization stratification factors.  Kaplan-Meier estimates of the distribution of time-to-event 
will be tabulated and plotted by treatment group.  The tabulation will include the Kaplan-Meier 
estimate of the medians, 25th and 75th quartiles, and 95% CIs (if estimable).  The number and 
percent of participants censored and with events will be presented. 
For the EMA submission, the fast progressors subset analyses of the mean annual progression rate 
of myopia using data through Month 24.  The analysis will use the same methodology as specified 
for this endpoint in Section 9.4.2 as for the EMA primary efficacy endpoint, however data after 
receipt of prohibited treatment or escape medication will be censored and multiple imputation will 
not be performed for this endpoint. 
The mean change from baseline in axial length will be analyzed similarly to the annual progression 
rate of myopia as detailed in Section 9.4.2 for the primary EMA analysis, however multiple 
imputation will not be performed and analysis of axial length will be performed on observed data 
only. 
The testing procedure for multiple secondary endpoints is described in Section 9.1. 

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9.4.4 SAFETY ANALYSES 
Safety will be assessed through summaries of AEs and changes in vital signs, BCVA, biomicroscopy, 
IOP, and ophthalmoscopy abnormalities.  Safety data will be summarized by treatment group using 
the Safety Analysis Set. 
Treatment-emergent AEs are defined as those AEs or SAEs that occur after the start of study drug 
dosing.  All TEAEs will be summarized by treatment group (SYD-101 0.01%, SYD-101 0.03%, or 
Vehicle).  In addition, all SAEs, including deaths, will be listed and summarized separately.  Adverse 
events with onset date that is more than 30 days after study treatment discontinuation will be 
summarized separately.   
Summaries that are displayed by system organ class (SOC) and preferred terms will be ordered by 
descending incidence of SOC and preferred term within each SOC.  Summaries displayed by 
preferred term only will be ordered by descending incidence of preferred term.  Summaries of the 
following types will be presented: 
• 
Overall summary of number of unique TEAEs and treatment-emergent SAEs and participant 
incidence of TEAEs meeting various criteria 
• 
Participant incidence of TEAEs by MedDRA SOC and preferred term 
• 
Participant incidence of TEAEs by severity grade, MedDRA SOC, and preferred term 
• 
Participant incidence of TEAEs by relationship to study drug, MedDRA SOC, and preferred 
term 
• 
Participant incidence of severe TEAEs related to study drug by MedDRA SOC and preferred 
term 
• 
Participant incidence of SAEs by MedDRA SOC and preferred term 
At each level of summarization (eg, any AE, SOC, and preferred term), participants experiencing 
more than one TEAE will be counted only once.  In the summary of TEAEs by severity grade, 
participants will be counted once at the highest severity reported at each level of summarization; in 
the summary of TEAEs by relationship, participants will be counted once at the closest relationship 
to study drug.  Related events include those reported as “Possibly Related” or “Related” to study 
drug; events considered not related are those reported as “Unlikely” or “Not Related” to study drug.  
Adverse event data will be presented in data listings by participant, treatment group, and event.  
Serious AEs and AEs leading to discontinuation of the study drug will be presented in separate data 
listings. 
Descriptive statistics of the quantitative vital sign, BCVA, and IOP results will be presented by 
treatment group and study visit, as well as for the change from baseline at each visit.  The baseline 
value is defined as the last non-missing value prior to the first dose of study drug.  Categorical 
variables for biomicroscopy collection, ophthalmoscopy abnormalities, and responses to the 
tolerability questionnaire will be summarized by treatment group with counts and percentages of 

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participants in each category.  Percentages will be based on the number of participants with 
relevant non-missing data at the visit of interest. 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Demographic variables, including age, sex, ethnicity, and race, will be summarized by treatment 
group and over all participants combined for the Safety, FAS, and Per-Protocol Analysis Sets.  Age 
will be summarized using descriptive statistics.  Sex, ethnicity, and race will be summarized with the 
number and percentage of participants in each parameter category. 
Baseline characteristics include medical history, eye color, height, weight, and body mass index 
(BMI).  Body mass index will be calculated as: weight (kg) / [height (cm) / 100]2.  Baseline 
characteristics will be summarized for the Safety Analysis Set by treatment group and over all 
participants combined.  Height, weight, and BMI at baseline will be summarized using descriptive 
statistics.  Frequency counts and percentages to summarize participants reporting abnormal medical 
history by body system will be presented. 
9.4.6 PLANNED INTERIM ANALYSES  
There are no interim analyses planned for this study.   

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9.4.7 SUBGROUP ANALYSES 
Subgroups will be defined based on the following: 
• 
Baseline Age category (same as randomization stratification) 
• 
Baseline Age category (ages 6 to 14 only) 
• 
Baseline SE (same as randomization stratification) 
• 
Baseline SE (≥ 1.0 D only) 
• 
Ocular medical history (progression of SE vs. no progression of SE) 
• 
Iris Color (dark vs light)  
• 
Region (Europe vs United States)  
• 
Race (Caucasian vs Indian vs Asian (Non-Indian) vs Non-Asian) 
• 
Sex (Male vs Female) 
• 
Average Time Outdoors (<= Median Average Time Outdoors, >Median Average Time 
Outdoors) 
• 
Average Time Near Work (<= Median Average Time Near Work, >Median Average Time New 
Work) 
The primary and key secondary efficacy endpoints will be analyzed separately for these subgroups 
using the FAS.  The above subgroup analyses will be descriptive only.  Additional subgroup analyses 
may be considered and will be documented in the statistical analysis plan. 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
In general, all data collected and any derived data will be presented in participant data listings for all 
enrolled participants.  Listings will be ordered by site, participant number, treatment group, and 
assessment or event date.  The treatment group presented in listings will be based on the planned 
assignment, unless otherwise noted. 
9.4.9 EXPLORATORY ANALYSES 
Data collected after Month 36 will be considered exploratory analysis and summarized separately 
using descriptive statistics.  Participants will be grouped by treatment pathway from the start of 
study through the re-randomization (original SYD-101 0.01% and SYD-101 0.03% participants) and 
transition to active treatment (original Vehicle participants) at Month 36: 
• 
Participants initially randomized to SYD-101 0.01% at Baseline and re-randomized to 
SYD-101 0.01% at Month 36 
• 
Participants initially randomized to SYD-101 0.01% at Baseline and re-randomized to Vehicle 
at Month 36 
• 
Participants initially randomized to SYD-101 0.03% at Baseline and re-randomized to 
SYD-101 0.03% at Month 36 

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• 
Participants initially randomized to SYD-101 0.03% at Baseline and re-randomized to Vehicle 
at Month 36 
• 
Participants initially randomized to Vehicle at Baseline and re-randomized to SYD-101 0.03% 
at Month 36 
In general, data collected after Month 36 will be summarized according to the above groupings.  As 
applicable, the groupings above may be further refined based on receipt of escape medication 
between Month 24 and Month 42 (inclusive).  Changes in continuous measures will be relative to 
the data collection at the Month 36 visit, unless otherwise specified.  Adverse events will be 
summarized separately for those events with onset after Month 36. 
To evaluate the potential rebound effect once participants discontinue SYD-101 therapy, 
exploratory analyses will be conducted on the set of participants initially randomized to SYD-101 
(0.01% or 0.03%) at Baseline who are re-randomized to Vehicle at Month 36.  The mean annual 
progression rate from baseline to Month 36 will be numerically compared to the mean annual 
progression rate from Month 36 to Month 48 within this set of participants.   
Select summaries will be provided for the group of participants initially randomized to SYD-101 
(0.01% or 0.03%) at Day 1 (Baseline) and re-randomized to SYD-101 at Month 36 and who remain on 
SYD-101 for the entire duration of the study.  This will be done to characterize the safety and 
efficacy profile of those participants receiving up to 48 months of SYD-101 treatment. 
To evaluate the impact of a second course of SYD-101 therapy, participants initially randomized to 
SYD-101 (0.01% or 0.03%), who are re-randomized to Vehicle at Month 36 and who then initiate 
active escape therapy after receipt of Vehicle therapy will have their mean annual progression rate 
while on Vehicle therapy numerically compared to their mean annual progression rate from the date 
participants switch from Vehicle to SYD-101 therapy until Month 48. 
Additional exploratory analyses may be performed. 

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Pan CW, Ramamurthy D, Saw SM.  Worldwide prevalence and risk factors for myopia.  Ophthalmic 
Physiol Opt. 2012;32(1):3-16. 
Pediatric Eye Disease Investigator Group.  A randomized trial of atropine vs. patching for treatment 
of moderate amblyopia in children.  Arch Ophthalmol.  2002;120(3):268-278. 
Pineles SL, Kraker RT, VanderVeen DK, et al. Atropine for the prevention of myopia progression in 
children: A Report by the American Academy of Ophthalmology.  Ophthalmology.  
2017;124(12):1857-1866. 
Polling JR, Kok RGW, Tideman JW, et al. Effectiveness study of atropine for progressive myopia in 
Europeans.  Eye (Lond).  2016;30(7):998-1004. 
Prepas SB. Light, literacy and the absence of ultraviolet radiation in the development of myopia.  
Med Hypotheses.  2008;70(3):635-637.   
Ratitch B, O’Kelly M (2011). “Implementation of Pattern-Mixture Models Using Standard SAS/STAT 
Procedures.” In Proceedings of PharmaSUG 2011 (Pharmaceutical Industry SAS Users Group). Paper 
SP04. Nashville. 

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Scheiman MM, Hertle RW, Kraker RT, et al; Pediatric Eye Disease Investigator Group.  Patching vs 
atropine to treat amblyopia in children aged 7 to 12 years: a randomized trial.  Arch Ophthalmol.  
2008;126(12):1634-1642. 
Shih YF, Chen CH, Chou AC, et al. Effects of different concentrations of atropine on controlling 
myopia in myopic children.  J Ocul Pharmacol Ther.  1999;15(1):85-90. 
Tong L, Huang XL, Koh AL, et al. Atropine for the treatment of childhood myopia: effect on myopia 
progression after cessation of atropine.  Ophthalmology.  2009;116(3):572-579. 
Vitale S, Sperduto RD, Ferris FL III. Increased prevalence of myopia in the United States between 
1971-1972 and 1999-2004.  Arch Ophthalmol.  2009;127(12):1632-1639. 
Williams KM, Bertelsen G, Cumberland P, et al.; European Eye Epidemiology (E(3)) Consortium.  
Increasing prevalence of myopia in Europe and the impact of education.  Ophthalmology.  
2015;122(7):1489-1497.  
Wilson EB, Hilfert MM. 1931. The distribution of chi-squared. Proceedings of the National Academy 
of Sciences, Washington, 17, 684–688. 
Wong TY, Ferreira A, Hughes R, Carter G, Mitchell P. Epidemiology and disease burden of pathologic 
myopia and myopic choroidal neovascularization: an evidence-based systematic review.  Am J 
Ophthalmol.  2014 Jan;157(1):9-25. 
World Health Organization.  Fact Sheet on Blindness: Vision 2020 – The global initiative for the 
elimination of avoidable blindness.  http://www.who.int/mediacentre/factsheets/fs213/en/.  
Accessed 18 May 2018. 
World Health Organization.  The impact of myopia and high myopia: report of the Joint World 
Health Organization-Brien Holden Vision Institute Global Scientific Meeting on Myopia, University of 
New South Wales, Sydney, Australia, 16-18 March 2015.  Geneva: World Health Organization; 2017.   
World Society of Pediatric Ophthalmology and Strabismus (2017) www.WSPOS.org/wp-
content/uploads/2017/01/WSPOS_Consensus-Statement_Myopia.pdf. 
Wu PC, Chen CT, Lin KK, et al. Myopia prevention and outdoor light intensity in a school-based 
cluster randomized trial.  Ophthalmology.  2018 (in press);125(8):1239-1250; 2017 (epub ahead of 
print doi: 10.1016/j.ophtha.2017.12.011). 
Wu PC, Yang YH, Fang PC.  The long-term results of using low-concentration atropine eye drops for 
controlling myopia progression in schoolchildren.  J Ocul Pharmacol Ther.  2011;27(5):461-466. 
Xiong S, Sankaridurg P, Naduvilath T, et al. Time spent in outdoor activities in relation to myopia 
prevention and control: a meta-analysis and systematic review.  Acta Ophthalmol.  
2017;95(6):551-566. 

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11 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
11.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS  
11.1.1 ETHICAL CONDUCT OF THE STUDY 
This protocol was designed and will be conducted, recorded, and reported in compliance with the 
principles of Good Clinical Practice (GCP) as defined in the ICH E6(R2) Guideline for GCP.  The 
principal investigator (PI) and the site staff are responsible for conducting this study in accordance 
with US Code of Federal Regulations (CFR), GCP, ethical principles that have their origin in the 
Declaration of Helsinki, and all other applicable laws and regulations. 
11.1.1.1 PARTICIPANT INFORMATION, INFORMED CONSENT, AND CHILD ASSENT 
An initial informed consent (for parent/guardian) and assent form (for participants, as applicable) 
will be provided to the investigator to prepare the ICF and assent documents to be used at the 
investigator’s site.  Updates to the informed consent template must be communicated to the 
sponsor or designee prior to IRB/EC approval.  Written informed consent and assent, in accordance 
with local clinical investigation regulations and approved by the IRB/EC, must be obtained prior to 
participation in the study.  The investigator will not undertake any measures specifically required for 
the clinical study unless and until valid consent and assent have been obtained. 
Information must be given both in oral and written form.  Written informed consent and assent 
documents that provide information about the study will be prepared and given to the 
parent/guardian and each applicable participant, respectively.  Informed consent documents will 
contain all the elements required by the ICH E6(R2) Guideline for GCP and any additional elements 
required by local regulations.  The information provided in the informed consent will be in a 
language understandable to the parent/guardian and may not include any language that appears to 
waive any of the parent/guardian’s or participant’s legal rights or appears to release the 
investigator, the sponsor, or the institution from liability or negligence. 
The investigator will provide the parent/guardian and prospective participant sufficient time to 
consider whether to participate.  The investigator will explain to the parent/guardian and participant 
that withdrawal from the study is possible at any time without detriment to care.  The ICF and 
assent must include acknowledgement that medical records and medical data derived from the 
study may be forwarded to the sponsor or to the responsible authorities or federal authorities.  At 
the first visit, and prior to initiation of any study-related procedures, the parent/guardian (or the 
participant’s legally authorized representative) and the participant will be asked to give written 
informed consent and assent, respectively, after having been informed about the nature and 
purpose of the study, participation/discontinuation conditions, and risks and benefits.  If the 
parent/guardian is unable to provide written informed consent, the participant’s legally authorized 
representative may provide written consent as allowed by institution-specific guidelines.  The 
informed consent and assent documents must be signed and dated by the parent/guardian (or the 
participant’s legally authorized representative) and the participant, respectively, prior to study 

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participation.  Copies of the signed informed consent and assent documents must be provided to 
the parent/guardian (or the participant’s legally authorized representative) and the participant. 
If the parent/guardian and/or the participant is unable to read, oral presentation and explanation of 
the ICF and/or assent must be provided to the parent/guardian and/or participant in the presence of 
an impartial witness or legally authorized representative.  After the parent/guardian and participant 
provide oral and if capable written/dated informed consent and assent, respectively, the witness 
should sign and date the ICF and/or assent in accordance with the instructions of the relevant 
IRB/EC.  By signing the ICF (assent), the witness attests that the written information was accurately 
explained to, and apparently understood by, the parent/guardian (participant), and that informed 
consent (assent) was freely given by the parent/guardian (participant). 
Original signed/dated consent and assent forms must remain in the participant’s study file and be 
available for verification by the sponsor or their designees at any time. 
Informed consent is an ongoing process.  Participant capacity to assent will be evaluated annually, 
and confirmation of continued affirmative assent will be sought and documented as appropriate. 
11.1.1.2 CHILD ASSENT CONSIDERATIONS 
The IRB/EC approval letter must clearly document the IRB/EC’s assessment of risk in accordance 
with 21 CFR 50.51–50.54, Subpart D.  The ICF should reflect the correct number of signature lines for 
the parent(s)/guardian(s) in accordance with the IRB/EC’s risk assessment of the proposed research 
(see 21 CFR 50.55). 
The IRBs/ECs are required to determine if child assents are appropriate for all studies that include 
pediatric participants.  The IRB/ECs may opt to waive assent if the participants are not capable of 
understanding (ie, based on level of intellectual development or maturity) or if the study is in the 
best interest of the participant (ie, strong possibility of benefit and no other alternatives are 
available).  If an IRB/EC chooses to waive assent, this must be documented in the IRB/EC approval 
letter or be documented in the meeting minutes. 
The contents of an assent are not mandated by the US FDA; however, assents must be factually 
correct, written at an age appropriate level, and not include any coercive language.  The assent must 
have a date and signature line for the child.  State laws differ in their requirements for participants 
who have not reached the legal age of majority and IRB/ECs are responsible for following their local 
regulations.  Use of an assent is not a substitute for parental/guardian permission.  
Parents/guardians must receive a full informed consent to review and sign.  
11.1.1.3 IRB/EC APPROVAL 
This protocol, ICF, and assent documents, and all relevant supporting data, including any 
advertisement used to recruit study participants, must be submitted to the IRB/EC for approval, 
which must be obtained before the study may be initiated.  At least once a year, the investigator is 

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responsible for informing the IRB/EC of the progress of the study and of any changes made to the 
protocol.  The investigator is also responsible for notifying the IRB/EC of any significant AEs that 
occur during the study and of the completion of the study. 
11.1.1.4 PARTICIPANT CONFIDENTIALITY 
The investigator must ensure that each participant’s anonymity will be maintained and that their 
identities are protected from unauthorized parties.  In eCRFs or other documents that are submitted 
to the sponsor, each participant should be identified by an identification code and not by their 
names.  Study findings stored on a computer will be stored in accordance with local data protection 
laws.  Each participant will be informed that representatives of the sponsor, independent IRB/EC, or 
regulatory authorities may inspect their medical records to verify the information collected, and that 
all personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
The investigator should keep a participant enrollment log showing codes, names, and addresses.  All 
data obtained during the course of this study will be transferred, stored, managed, and analyzed in 
compliance with applicable privacy policy. 
If the investigative site is located in the United States, the sponsor or designee will ensure that the 
use and disclosure of protected health information obtained during a research study complies with 
the Health Insurance Portability and Accountability Act Privacy Rule, if applicable.  The Privacy Rule 
provides federal protection for the privacy of protected health information by implementing 
standards to protect and guard against the misuse of individually identifiable health information of 
participants participating in the clinical studies.  Authorization is required from each research 
participant, ie, specific permission granted by an individual to a covered entity for the use or 
disclosure of an individual’s protected health information.  A valid authorization must meet the 
implementation specifications under the Health Insurance Portability and Accountability Act Privacy 
Rule.  Authorization may be combined in the informed consent document (approved by the IRB/EC) 
or it may be a separate document (approved by the IRB/EC) or provided by the investigator or 
sponsor (without IRB/EC).  It is the responsibility of the investigator and institution to obtain such 
waiver/authorization in writing from the appropriate individual. 
11.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to investigators, the Investigational New Drug, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the PI will promptly 
inform study participants, the IRB, and sponsor and will provide the reason(s) for the termination or 
suspension.  Study participants will be contacted, as applicable, and be informed of changes to the 
study visit schedule. 

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Circumstances that may warrant termination or suspension include, but are not limited to the 
following: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed and satisfy the sponsor, IRB, and/or FDA. 
11.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions.  This confidentiality is extended to cover testing of 
clinical information relating to participants.  Therefore, the study protocol, documentation, data, 
and all other information generated will be held in strict confidence.  No information concerning the 
study or the data will be released to any unauthorized third party without prior written approval of 
the sponsor. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study.  The 
clinical study site will permit access to such records. 
The study participant’s/parent’s contact information will be securely stored at each clinical site for 
internal use during the study.  At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
requirements. 
Study participant research data, which are for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the sponsor’s designee.  This will not include the 
participant’s contact or identifying information.  Rather, individual participants and their research 
data will be identified by a unique study identification number.  The study data entry and study 
management systems used by clinical sites and by the sponsor’s designee research staff will be 
secured and password protected.  At the end of the study, all study databases will be deidentified 
and archived. 

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11.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
Not applicable. 
11.1.5 SAFETY OVERSIGHT 
No internal data review committee will be used during this study. 
11.1.6 STUDY MONITORING AND AUDITING 
Details of clinical site monitoring are documented in a clinical monitoring plan.  The clinical 
monitoring plan describes in detail who will conduct the monitoring, at what frequency monitoring 
will be done, at what level of detail monitoring will be performed, and the distribution of monitoring 
reports. 
All aspects of the study will be carefully monitored by the sponsor or authorized representatives of 
the sponsor at regular intervals and with respect to current GCP and standard operating procedures 
for compliance with applicable government regulations.  These individuals will have access, both 
during the study and after study completion, to review and audit all records necessary to ensure 
integrity of the data and verify the entries in the eCRF.  They will periodically review progress of the 
study with the PI. 
Training sessions, regular monitoring of PI and designee by designated personnel, data verification, 
cross-checking, and data audits will be performed, and instruction manuals provided to ensure 
quality of all study data. 
The sponsor’s monitor or designee is responsible for inspecting the eCRF as defined in the 
monitoring plan throughout the study to verify adherence to the protocol; completeness, accuracy, 
and consistency of data; and, adherence to local regulations on the conduct of clinical research.  It 
will be the responsibility of the PI to ensure that participants’ medical records and other 
study-related records needed to verify entries in the eCRF are available at the PI’s site during 
monitoring visits.  In addition to the monitoring visits, communications (email, letter, telephone, and 
fax), by the study monitor will also be utilized to monitor that the investigation is conducted 
according to protocol design and regulatory requirements. 
The PI agrees to cooperate with the monitor to ensure that any problems detected in the course of 
these monitoring visits are resolved. 
In accordance with ICH guidelines and GCP, this study may be selected for audit by the sponsor or 
designees.  Inspection of the site facilities (ie, participant areas, drug storage areas, record storage 
areas) and review of study-related records will occur to evaluate the study conduct and compliance 
with the protocol, ICH, GCP, and applicable regulatory requirements. 
Study close-out visits will be performed by the study monitor upon closure of the study. 

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11.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management. 
Quality control procedures will be implemented beginning with the data entry system, and data 
quality control checks that will be run on the database will be generated.  Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written standard operating procedures, the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), 
and reported in compliance with the protocol, ICH GCP, and applicable regulatory requirements (eg, 
Good Laboratory Practices, Good Manufacturing Practices). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
11.1.8 DATA HANDLING AND RECORD KEEPING  
11.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator.  The investigator is responsible for ensuring that data are properly recorded on 
each participant's eCRFs and related documents in a timely manner.  An investigator who has signed 
the protocol signature page should electronically sign the eCRFs to ensure that the observations and 
findings are recorded on the eCRFs correctly and completely.  All source documents should be 
completed in a neat, legible manner to ensure accurate interpretation of data. 
• 
Clinical data will be entered into eCRFs.  Data entered into the eCRF will correspond with 
and be supported by source documentation maintained at the site(s).  A final report of all 
participant data will be provided to each site at the end of the study to serve as eCRF 
documentation 
• 
IVRS/IWRS will be used for randomizing the participant population 
Source documents may include a participant's medical records, diaries, hospital charts, clinic charts, 
the investigator's participant study files, as well as the results of diagnostic tests, such as x-rays, 
laboratory tests, and ECGs.  The investigator's copy of the eCRFs serves as part of the investigator's 
record of a participant's study-related data.   

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The following information should be entered into the participant's medical record: 
• 
Participant’s name 
• 
Participant’s contact information 
• 
Date that the participant entered the study, participant number, and participant medication 
kit number 
• 
Study title and/or the protocol number of the study and the name of Sydnexis 
• 
Statement that informed consent was obtained (including the date) prior to any study 
procedures being performed and that the participant was provided a copy of the signed 
informed consent.  A statement that country and local participant privacy-required 
documentation for this study has been obtained (including the date) 
• 
Dates of all participant visits 
• 
All concurrent medications (List all prescription and non-prescription medications being 
taken at the time of enrollment.  At each subsequent visit, changes to the list of medications 
should be recorded) 
• 
Occurrence and status of any AEs (including any procedure-related AEs) 
• 
Date the participant exited the study, and a notation as to whether the participant 
completed the study or reason for discontinuation 
• 
Results of laboratory tests performed by the site (eg, urine pregnancy test) 
• 
Results, if applicable, of any procedures performed to confirm eligibility criteria  
• 
Concurrent procedures performed during the study 
• 
Documentation of the participant’s medical history 
• 
Vital signs and physical characteristics (height and weight) 
• 
Printout from autorefractor 
• 
Results of biomicroscopy/ophthalmoscopy examinations 
• 
Documentation of whether any procedure, including study drug administration, was 
performed according to the protocol, noting any deviations (if applicable) 
• 
Study drug accountability (stored separately with the accountability logs in order to 
maintain masking status for site staff with direct contact with participant and/or data) 
11.1.8.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the study intervention.  These documents should be retained for a longer period, 
however, if required by local regulations.  No records will be destroyed without the written consent 
of the sponsor, if applicable.  It is the responsibility of the sponsor to inform the investigator when 
these documents no longer need to be retained. 

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11.1.9 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or MOP 
requirements.  The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff.  As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
The following practices are consistent with ICH GCP:  
• 
Quality Assurance and Quality Control, Section 11.1.7 
It is the responsibility of the site investigator to use continuous vigilance to identify and promptly 
report deviations.  All deviations must be addressed in study source documents, reported to the 
sponsor’s designee.  Protocol deviations must be sent to the reviewing IRB per their policies.  The 
site investigator is responsible for knowing and adhering to the reviewing IRB requirements.  Further 
details about the handling of protocol deviations will be included in the MOP. 
11.1.10 
PUBLICATION AND DATA SHARING POLICY 
Sydnexis, as the sponsor, has proprietary interest in this study.  Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and Sydnexis 
personnel.  Authorship will be established prior to the writing of the manuscript.  As this study 
involves multiple centers, no individual publications will be allowed prior to completion of the final 
report of the multicenter study except as agreed with Sydnexis. 
This study will be registered on the ClinicalTrials.gov registry. 
11.1.11 
CONFLICT OF INTEREST POLICY 
Due to potential conflict of interest, participants or members of the participant’s household who are 
employees of the investigative site are not eligible for enrollment in the study. 
11.2 ADDITIONAL CONSIDERATIONS 
Not applicable. 

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11.3 ABBREVIATIONS 
Abbreviation 
Definition 
µL 
microliter 
AE 
adverse event 
ATOM 
Atropine for the Treatment of Myopia 
BCVA 
best-corrected visual acuity  
BMI 
body mass index 
CFR 
Code of Federal Regulations 
D 
diopters 
D2O 
deuterium oxide 
EC 
ethics committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eg 
exempli gratia (for example) 
EMA 
European Medicines Agency 
EOS 
End of Study 
ET 
Early Termination 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
ffERG 
full-field electroretinogram 
GCP 
Good Clinical Practice 
IB 
investigator’s brochure 
ICF 
informed consent form  
ICH 
International Council for Harmonisation  
ie 
id est (in other words) 
IOP 
intraocular pressure 
IRB 
institutional review board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
MNAR 
missing not at random 
MOP 
Manual of Procedures 
N 
number of participants or Sample size 
n 
number of participants with available data 
NCT 
National Clinical Trial 
PI 
principal investigator 
PVG 
pharmacovigilance  
QA 
quality assurance 
QC 
quality control 

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Abbreviation 
Definition 
QD 
quaque die (once a day) 
QHS 
quaque hora somni (every bedtime) 
QOL 
Quality of Life 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
spherical equivalent 
SOA 
Schedule of Activities 
SOC 
system organ class 
SYD-101 
Sydnexis’ formulation of atropine sulfate (0.01% or 0.03%) topical ophthalmic 
solution 
TEAE 
treatment-emergent adverse event 
TID 
ter in die (3 times a day) 
WSPOS 
World Society of Paediatric Ophthalmology and Strabismus 
 
11.4 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Section 
affected 
Description of Change  
Brief Rationale 
1.2 
20 
Feb 
2019 
 
Original Document 
 
2.0 
13 
Nov 
2020 
Description of 
Sites (Synopsis) 
Up to 41 US sites and 6 
EU sites 
Update of actual sites 
 
 
Study Duration 
(Synopsis) 
Anticipated duration of the 
study is 70 months 
Delayed recruitment due to COVID-
19 
 
 
Specular 
microscopy 
Will be completed at early 
exit visit 
Correction 
 
 
Escape 
Medication 
Replaced ‘will be initiated” 
with “may be initiated” 
For flexibility 
 
 
Study 
Procedures 
Standard manual refraction 
should be performed at 
screening visit for initial 
BCVA and if SE is >0.75 
D.   
Lens will be assessed with 
findings as normal, 
abnormal clinically 
significant or abnormal not 
clinically significant 
 
To verify components of inclusion #9 
 
 
 
 
Correction.  AREDs scale was not 
implemented 
 
 
Entry Criteria 
Criterion #10 BCVA of 75 
letters (Snellen equivalent 
20/32) or better 
Correct typographical error of 85 
letters 
 
 
Participant 
Withdrawal 
Should be discussed with 
the sponsor 
Correction 
 
 
Efficacy 
Assessments 
3 SE readings will be 
obtained for each eye and 
Clarification 

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the average calculated for 
both eyes 
Axial length can also be 
measured by Pentacam  
 
 
Activities and 
Compliance 
Questionnaire 
Deleted on a phone or 
web-based application 
Data were collected via paper diary 
for about 6 months until the 
phone/web-based application could be 
launched 
 
 
Adverse Event 
Revised definition to 
require that corneal 
staining > 2+ and 
Tolerability items > 
moderate must be recorded 
as an AE.  These items 
with less severity are not 
AEs, nor are small changes 
in pupil diameter. 
 
Deleted ‘The AE will be 
recorded on the eCRF 
under the highest level of 
severity achieved” 
Clarification of procedures for 
consistency 
 
 
 
 
 
 
 
Conflicted with previous sentence 
 
 
Study 
Assessments 
and Procedures 
Follow-up visits may be 
done by phone or video 
call in lieu of a clinic visit 
in the event the site is 
closed or social distancing 
cannot be maintained.  
Questionnaires will be 
completed by phone.  
Investigational product will 
be dispensed via courier or 
curbside pick-up 
Due to COVID-19 lockdown 
requirements, alternative measures 
were put into place to continue 
monitoring of participants and to 
maintain dosing compliance 
3.0 
17 
Feb 
2023 
Secondary 
Endpoints 
(Synopsis, 
Section 3 and 
Section 9.1.2 
Addition of two secondary 
endpoints for EMA 
submission for subgroup 
analysis of participants 
with a refractive history of 
myopia progression of  
> 0.5D and > 0.75D 
Requested by Sponsor partner for 
EMA submission since EMA is 
interested in this population.  Patients 
with previous myopia progression are 
more likely to have worse subsequent 
progression 
 
 
Primary 
Efficacy 
Estimands, 
Section 9.1.1  
Replaced endpoint with 
estimands.  Added a table 
to summarize the 
estimands for EMA and 
FDA. Added a table to 
describe the handling of 
intercurrent events and 
their justification. Added a 
table of sensitivity 
analyses.  Added text for 
truncation parameter and 
multiplicity 
To update and clarify statistical 
methods for EMA and FDA 
 
 
Secondary 
Efficacy 
Added text for truncated 
Hochberg adjustment.  
Added a table to 
To update and clarify statistical 
methods for EMA and FDA 

Sydnexis, Inc. 
SYD-101 
Protocol SYD-101-001 
Version 3.0 
Confidential 
Page 80 of 80 
16 February 2023 
Endpoints, 
Section 9.1.2 
summarize the order of 
testing for EMA and FDA 
analyses of secondary 
endpoints.  Added a table 
to describe the handling of 
intercurrent events and 
their justification for key 
secondary estimands and 
also for secondary 
estimands 
 
 
Populations for 
analysis, 
Section 9.3 
Added text for the 
subgroups of fast 
progressors 
To support new secondary endpoints 
for EMA 
 
 
Analysis of the 
primary 
endpoint, 
Section 9.4.2 
and secondary 
endpoints, 
Section 9.4.3, 
subgroup 
analyses, 
Section 9.4.7 
Added text for the 
calculation of SE, 
imputations, modeling, and 
sensitivity analyses 
Additional detail provided 
on subgroup analyses 
Clarification 
 
 
Justification for 
endpoints, 
Section 3 
Added text that the SE for 
each measurement will be 
calculated for each eye and 
then averaged by eye. 
Clarification 
 
 
Product Storage 
(Section 6.2.3) 
Reference to Pharmacy 
Manual instead of MOP 
Correction 
 
 
Protocol 
Deviations 
(Section 11.1.9) 
Updated cross reference to 
Quality Assurance and 
Quality Control 
Correction 
 
 
Abbreviations, 
Section 11.3 
Added MAR, MNAR, 
MCMC 
Updated to include new statistical 
terms 
 
 
References, 
Section 11.4 
Added new references 
Updated to include new statistical 
references