Clinical trial NCT03350620
Conditions: Myopia
Keywords: child, myopia, nearsightedness
Sponsor: Vyluma, Inc.
Start date: 2017-11-20; Completion date: 2023-10-19
Enrollment: 670 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Stage 1: To evaluate the safety and efficacy of 2 concentrations of NVK-002 compared to Vehicle (placebo) for slowing the progression of myopia in children over a 3 year treatment period.

Stage 2: To observe safety and efficacy in subjects re-randomized to one (1) year of treatment with NVK-002 or Vehicle following 3 years of treatment in children with progressive myopia.

Detailed description:
This will be a 3-arm randomized, multicenter, double-masked, placebo-controlled study conducted in 2 stages.

Stage 1 is a safety and efficacy phase of 3 years in duration, during which subjects will be allocated to 1 of 3 study medications.

Stage 2 is a randomized follow-up phase of 1 year in duration, during which subjects will be re-randomized to receive 1 of the 3 study medications, with subjects initially randomized to Vehicle only eligible for randomization to low or high-dose NVK-002.

Treatment arms are:

* NVK-002 low dose concentration
* NVK-002 high dose concentration
* Vehicle (placebo)

Arms: arm 1: Stage 1: Subjects will be randomized to NVK-002 Concentration 1

Stage 2: Subjects will be re-randomized to one of the three treatment arms. arm 2: Stage 1: Subjects will be randomized to NVK-002 Concentration 2

Stage 2: Subjects will be re-randomized to one of the three treatment arms. arm 3: Stage 1: Subjects will be randomized to Vehicle (Placebo)

Stage 2: Subjects will be re-randomized to one of the two experimental NVK-002 treatment arms
Interventions: intervention 1: NVK-002 Concentration 1 intervention 2: NVK-002 Concentration 2 intervention 3: Placebo
Intervention descriptions: intervention 1: Study medication will be administered, once daily (QD) intervention 2: Study medication will be administered, once daily (QD) intervention 3: Vehicle (placebo) will be administered, once daily (QD)

Protocol documents:
Prot_001.pdf: 
Atropine Sulfate Ophthalmic Solution, 0.01% and 0.02%  
Vyluma Inc., an affiliate of Nevakar Inc. 
CP-NVK002-0001(5) 14 Jun 2021 
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CONFIDENTIAL AND PROPRIETARY 
 
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CLINICAL TRIAL PROTOCOL 
CP-NVK002-0001 
 
CHILDHOOD ATROPINE FOR MYOPIA 
PROGRESSION (CHAMP): A 3-ARM RANDOMIZED, 
DOUBLE-MASKED, PLACEBO-CONTROLLED, 
PHASE 3 STUDY OF ATROPINE SULFATE 
OPHTHALMIC SOLUTION 0.01% AND 0.02% 
EudraCT Number: 
2018-001077-24 
Study Phase: 
Phase 3  
Product Name: 
Atropine Sulfate Ophthalmic Solution 
Indication: 
Slowing the progression of myopia in children 
Sponsor: 
Vyluma Inc., an affiliate of Nevakar Inc. 
NJ Center of Excellence 
1019 Route 202/206, Bldg. K 
Bridgewater, NJ 08807 
Original Protocol: 
01 July 2017  
Protocol Amendment (1): 05 September 2017 
Protocol Amendment (2): 10 April 2018 
Protocol Amendment (3): 12 August 2019 
Protocol Amendment (4): 09 October 2020 
Protocol Amendment (5): 14 June 2021 
 
CONFIDENTIAL 
The information contained in this document is confidential and proprietary property of Vyluma 
Inc., an affiliate of Nevakar Inc. Neither this document nor the information contained herein may 
be divulged, transmitted, reproduced, published, or otherwise used by others without the express 
written permission of Vyluma Inc., an affiliate of Nevakar Inc. 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: Vyluma Inc., an affiliate of Nevakar Inc. 
Protocol Number: CP-NVK002-0001 
EudraCT Number: 2018-001077-24 
Name of Investigational Product: Atropine Sulfate Ophthalmic Solution 
Name of Active Ingredient: Atropine sulfate 0.01% and 0.02% 
Title of Study: Childhood Atropine for Myopia Progression (CHAMP): A 3-Arm Randomized, 
Double-Masked, Placebo-Controlled, Phase 3 Study of Atropine Sulfate Ophthalmic Solution 
0.01% and 0.02%. 
Study Center(s): 15 – 30 centers in North America, Europe, and United Kingdom. 
Studied Period (Years):  
Estimated date first subject enrolled: November 2017 
Estimated date completion BLEOS Month 36: August 2022 
Estimated last subject completed Month 36-  EOS Month 48: September 2023 
Phase of 
development:  
3 
Objective:  
Primary: To evaluate the safety and efficacy of 2 concentrations of Atropine Sulfate Ophthalmic 
Solution (0.01% and 0.02%) compared to Vehicle (placebo) for slowing the progression of myopia 
in children over a 3-year treatment period. 
Exploratory: To observe safety and efficacy in subjects re-randomized to 1 year of treatment with 
Atropine Sulfate Ophthalmic Solution, 0.01% or 0.02%, or Vehicle following 3 years of treatment 
in children with progressive myopia. 
Study Rationale:  
Vyluma Inc., an affiliate of Nevakar Inc., hereinafter referred to as the Sponsor, is pursuing the 
development of Atropine Sulfate Ophthalmic Solution for slowing the progression of myopia in 
children.  
Ametropia in children is common, and if left uncorrected causes decreased vision, visual discomfort 
(eye strain), strabismus, and/or amblyopia (AAPOS 2013). The most common form of refractive 
error is myopia (nearsightedness), which has its onset in children 6 to 12 years of age 
(Zadnik 2015). 
Study Population:  
Study subjects will be childreQPDOHRUIHPDOHDJHGWR\HDUVDWWKHWLPHRIHQUROOPHQW
with myopia spherical equivalent refraction (SER) of at least -0.50 D and no greater than -6.00 D in 
each eye, astigmatism of no more than -1.50 D in each eye, and anisometropia (SER) of < 1.50 D as 
measured by cycloplegic autorefraction. 
Methodology:  
This will be a 3-arm randomized, multicenter, double-masked, placebo-controlled study conducted 
in 2 stages. Stage 1 is a safety and efficacy phase of 3 years (36 months) in duration, during which 
subjects will be allocated to 1 of 3 study medications. Stage 2 is a randomized cross-over phase of 
1 year (12 months) in duration, during which subjects will be re-randomized to receive 1 of the 3 
study medications with subjects initially randomized to Vehicle only eligible for randomization to 


Atropine Sulfate Ophthalmic Solution, 0.01% and 0.02%  
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RUDWURSLQH6XEMHFWVDJHGWR\HDUVZLOO enter the study with myopia SER of 
at least -0.50 D and no greater than -6.00 D in each eye as measured by cycloplegic autorefraction. 
At screening/baseline (Day 0), the site will obtain signed informed consent from the parent or legal 
guardian of the subject and assent from the subject (as applicable). The subject will then undergo a 
screening evaluation to determine eligibility for the study as per the inclusion and exclusion criteria 
defined in the protocol. Following confirmation of eligibility, the clinical site will access the 
Interactive Response Technology (IRT), which will assign the subject to 1 of the 3 treatment arms 
and assign the initial study medication kit to be dispensed to the parent/guardian following 
instruction on administration. The allocated study medication will be administered, one drop in each 
eye once daily (QD), at bedtime, for 3 years. 
Treatment arms are: 
x 
Atropine Sulfate Ophthalmic Solution, 0.01% 
x 
Atropine Sulfate Ophthalmic Solution, 0.02% 
x 
Vehicle (placebo) 
Both eyes will be treated; myopia must be bilateral to qualify. If myopia is unilateral at screening or 
the child seems likely to cross the threshold for bilateral myopia of at least -0.50 SER, the subject 
can be asked to return while the enrollment period is still open to determine his or her eligibility. 
Subjects will return to the clinical site at 6-month intervals for 3 years to undergo a series of safety 
and efficacy evaluations and at 3-month intervals throughout the study for update of concomitant 
medications and adverse event (AE) assessment. While it is preferred that the subject attend every 
visit, the parent/guardian may attend a 3-month visit without the subject if necessary; both the 
subject and their parent/guardian must be present for all 6-month visits. At each study visit, 
unopened/unused and used study medication materials will be returned, concomitant medications 
will be updated, AE assessment will be conducted, allocated study medication will be dispensed for 
the next 3-month study period, and treatment adherence assessment will be performed. 
Site staff will also contact subjects or their parents/guardians by telephone at the end of Month 1 
and Month 2 and then midway between office visits during the initial year of the study to collect 
information regarding AEs and treatment adherence. Telephone checks can be continued or 
reinstated at any time during the study to assist with maintaining protocol and treatment adherence. 
After a subject completes all safety and efficacy assessments at Month 36 (the primary efficacy time 
point) the randomized cross-over stage (Stage 2) will commence, and each subject will be re 
randomized to receive 1 of the 3 study medications for the final year of the study. Subjects 
randomized to either 0.01% or 0.02% Atropine Sulfate Ophthalmic Solution during Stage 1 will be 
re randomized to treatment with Atropine Sulfate Ophthalmic Solution, 0.01%, Atropine Sulfate 
Ophthalmic Solution, 0.02%, or Vehicle, and subjects randomized to the Vehicle group in Stage 1 
will be re-randomized to active treatment with Atropine Sulfate Ophthalmic Solution, 0.01% or 
Atropine Sulfate Ophthalmic Solution, 0.02%. In Stage 2, study medication will be administered 
one drop in each eye QD at bedtime, as before, for 1 year. 
During Stage 2, the subject and their parents/guardians will again return at 6-month intervals for 
safety and efficacy evaluations and at 3-month intervals for update of concomitant medications and 
AE assessment. As in Stage 1, both the subject and their parent/guardian must be present for all 6-
month visits, but the parent/guardian may attend a 3-month visit without the subject if necessary. At 
each study visit, unopened/unused and used study medication materials will be returned, 
concomitant medications will be updated, AE assessment will be conducted, study medication will 
be dispensed for the next 3-month study period, and treatment adherence assessment will be 


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performed. At Month 45, subjects will receive their final study medication kit and return at Month 
48 for their final study visit assessments. 
Subject or their parent/guardian will be encouraged to record their dosing on a daily basis, starting 
from the same evening after completing their Month 36 visit till the last visit (Stage 2 of the study) 
in an electronic patient diary (e-diary). The subject or their parent/guardian will be encouraged to 
use their cell phone to upload e-diary responses. At Month 36 visit, if subject or their 
parent/guardian do not have a cell phone or are unwilling to use their cell phone, a device will be 
provisioned by Medidata and provided to the subject. Once the instillation of the eye drops has been 
successfully completed, subject or their parent/guardian will log into the application to record 
dosing of the left eye and the right eye and complete diary submission daily. The diary can be 
completed between 6:00 PM and 11:45 PM. If the subject or their parent/guardian do not complete 
the e-diary within the allotted time, they will not be able to enter the missing data retroactively, as 
the purpose is to collect information on the actual date the study drops were instilled. Once data is 
submitted, this information will be automatically entered into the study’s Medidata Rave database. 
Inclusion of the Modified Amblyopia Treatment Index (ATI), quality of life (QoL) 
questionnaire 
At Month 42 and Month 48, in addition to other assessments, the study staff will encourage 
participation in the Modified Amblyopia Treatment Index (ATI), quality of life (QoL) questionnaire 
which has been added to the study to be completed by the subject and their parent/guardian. 
Participation is voluntary and will be documented. The parent/guardian questionnaire should be 
completed prior to the subject’s questionnaire. The questionnaires should be completed prior to the 
Investigator’s examination of the subject. 
All subjects are to be re-consented/re-assented at their next study visit, including subjects 
completing an End of Study (EOS) Visit (Stage 1 – Month 36, Month 39, Month 42, Month 45, and 
Month 48). 
Number of Subjects (Planned): Subjects will be randomized in a 2:2:3 ratio of vehicle: Atropine 
Sulfate Ophthalmic Solution, 0.01%: Atropine Sulfate Ophthalmic Solution, 0.02% 
The target number of subjects to be randomized into the 6- to 10-year age group (436), the primary 
efficacy population, will be: 
x 
Vehicle (placebo):   
 
 
 
 
 
 
125 
x 
Atropine Sulfate Ophthalmic Solution, 0.01%:  125 
x 
Atropine Sulfate Ophthalmic Solution, 0.02%: 186 
Approximately 483 subjects over all eligible ages will be enrolled, resulting in the following 
numbers of subjects in each arm: 
x 
Vehicle (placebo):   
 
 
 
 
 
 
138 
x 
Atropine Sulfate Ophthalmic Solution, 0.01%:  138 
x 
Atropine Sulfate Ophthalmic Solution, 0.02%:  207 
The Sponsor may conduct a sample size re-estimation based on a masked assessment of the primary 
endpoint response rate and/or the subject discontinuation rate. 
The randomization will be stratified twice: (1) by age at randomization (subjects < 9 years; subjects 
\HDUVDQGE\UHIUDFWLYHHUURUOHVVP\RSLF6(5-0.50 to -3.00 D; more myopic: one or 
more eyes with SER-3.01 to -6.00 D). The stratification is used to balance these characteristics 
across the 3 treatment groups. Enrollment will proceed until 436 subjects aged 6 to 10 years have 
been randomized and at least 483 subjects overall have been randomized. Enrollment may be closed 


Atropine Sulfate Ophthalmic Solution, 0.01% and 0.02%  
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CP-NVK002-0001(5) 14 Jun 2021 
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WRVXEMHFWVDJH\HDUVIROORwing enrollment of 50 subjects into this age group to avoid 
over-enrollment into the study.  
The drop-out rate over the 3 years of the safety and efficacy stage of the study (Stage 1) is estimated 
to be 27% (~10% per year). As long as this drop-out rate is not exceeded, then at least 150 subjects 
(300 eyes) receiving the higher concentration (0.02% atropine) will be available for the evaluation 
of safety. 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
1. Children (male or female) aged 3 to 17.0 years. 
2. Myopia SER of at least -0.50 D and no greater than -6.00 D myopia in each eye as 
measured by cycloplegic autorefraction. 
3. If present, astigmatism of no more than -1.50 D in each eye as measured by cycloplegic 
autorefraction. 
4. Anisometropia SER of < 1.50 D as measured by cycloplegic autorefraction. 
5. Normal intraocular pressure of < 21 mm Hg in each eye. 
6. Distance vision correctable to at least 0.1 logMAR or 20/25 Snellen equivalent in each eye. 
7. Female subjects of childbearing potential (post menarche) must have a negative urine 
pregnancy test at screening.  
8. Subject’s parent or legal guardian must provide informed consent on behalf of the subject, 
and the subject should provide assent when applicable, per Institutional Review Board 
(IRB)/Ethics Committee (EC) guidelines. If a subject becomes an adult (depending on 
country regulations) during the study, they will need to sign an informed consent form to 
continue in the study. 


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Exclusion Criteria 
1. Allergy to atropine or any of the excipients of the eye drops. 
2. Current or history of amblyopia or manifest strabismus including intermittent tropia. 
3. Heart rate is persistently (for more than 10 minutes) > 120 beats per minute at 
screening/baseline. 
4. History of any disease or syndrome that predisposes the subject to severe myopia 
(e.g., Marfan syndrome, Stickler syndrome, retinopathy of prematurity). 
5. History in either eye of abnormal ocular refractive anatomy (e.g., keratoconus, lenticonus, 
spherophakia). 
6. History in either eye of previous intraocular or ocular laser/non-laser surgery. 
7. Current or history of glaucoma; anatomic narrow anterior chamber angles. 
8. Serious systemic illness that, in the Investigator’s opinion, would render the subject 
ineligible. 
9. Chronic use of any topical or systemic antimuscarinic/anticholinergic medications 
(e.g.,atropine, scopolamine, tropicamide) within 21 days prior to screening, and/or 
anticipated need for chronic use during the study period (i.e., more than 7 consecutive days 
in 1 month or more than 30 total days in 1 year). (Use of cycloplegic drops for dilated 
ocular exam are allowable.) 
10. Chronic use (more than 3 days per week) of any topical ophthalmic medications (prescribed 
or over-the-counter) other than the assigned study medication. Use of artificial tears is 
allowed but may not be used within 2 hours of administration of study medication. 
11. The anticipated need to use chronic ophthalmic or systemic oral corticosteroids during the 
study. Intranasal, inhaled, topical dermatologic, intra-articular, perianal steroids, and 
short-term oral steroids (i.e., < 2 weeks) are permitted. 
12. Prior myopia control treatment including orthokeratology, bifocal contact lenses, or 
progressive addition spectacle lenses. The only allowable prior treatments are myopic 
correction in the form of single-vision eyeglasses and/or single-vision or toric soft contact 
lenses.  
13. Preplanned hospitalization during the study period. (Note: The study period begins at the 
time of randomization.) 
14. Unwilling or unable to complete study procedures or to be followed up for the 48-month 
duration of the study. 
15. Participation in any other study of investigational therapy during the study period or within 
the last 30 days. 
16. History of any substance abuse (excessive or habitual use of alcohol and/or drug including 
nicotine) and not willing to abstain from these substance(s) during the 4-year study period.  
17. Female subjects who are pregnant, nursing, or plan to become pregnant at any time during 
the study.  
18. Employees of the study site and their family members are not permitted to participate as 
subjects in the study. Immediate family is defined as a spouse, parent, child, or sibling, 
whether biological or legally adopted.   
19. Current or history of significant or severe damage to the cornea. 
 


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Investigational Product, Dosage and Mode of Administration:  
Atropine Sulfate Ophthalmic Solution, 0.01% or 0.02%, dosed QD by topical ocular administration 
into each eye, at bedtime. 
Reference Therapy, Dosage and Mode of Administration:  
Vehicle (placebo) ophthalmic solution, dosed QD by topical ocular administration into each eye, at 
bedtime. 
Duration of Treatment:  
The study will be conducted in 2 stages. Stage 1 is the primary safety and efficacy stage of the study 
and will be 3 years (36 months) in duration. Subjects will be randomized in a 2:2:3 ratio of Vehicle: 
Atropine Sulfate Ophthalmic Solution, 0.01%: Atropine Sulfate Ophthalmic Solution, 0.02%. On 
completion of 3 years of treatment, Stage 2, a randomized cross-over stage will commence, and all 
subjects will be re-randomized to 1 of the 3 study medications and will receive this treatment for 
1 year (12 months). Subjects who were randomized to 0.01% or 0.02% Atropine Sulfate 
Ophthalmic Solution during Stage 1 will be re-randomized in a 1:1:1 ratio to one of the 3 treatment 
arms (Vehicle: Atropine Sulfate Ophthalmic Solution, 0.01%: Atropine Sulfate Ophthalmic 
Solution, 0.02%), and subjects who were randomized to Vehicle during Stage 1 will be re-
randomized in a 1:1 ratio to active treatment (Atropine Sulfate Ophthalmic Solution, 
0.01%: Atropine Sulfate Ophthalmic Solution, 0.02%). 
Study Procedures: 
Office Visits should occur within ± 2 weeks of the expected visit date.  
Screening/Randomization/Baseline Visit (Day 0): Sites should complete 
screening/randomization/baseline procedures and enroll subjects within 30 days from signing the 
informed consent.  
The clinical site will obtain signed informed consent from the parent or legal guardian of the subject 
and assent from the subject (as applicable). The subject will then undergo screening evaluations to 
determine eligibility for the study which will include review of medical/ocular and prior medication 
history, a urine pregnancy test for female subjects of childbearing potential, heart rate (HR), 
monocular Best-Corrected Visual Acuity (BCVA) measurement at distance and near, photopic pupil 
size measurement, slit-lamp examination (SLE) (check for narrow angles), tonometry, dilated 
fundus examination and cycloplegic autorefraction. Height and weight will also be assessed.  
Following confirmation of eligibility, the clinical site will measure axial length and, if possible, 
crystalline lens thickness. The site will access the IRT, which will assign the subject to 1 of the 
3 treatment arms and assign the initial study medication kit to be dispensed to the parent/guardian 
following instruction on administration. 
One (1) drop of the study medication will be administered into each eye QD, at bedtime. Because 
AEs are to be collected beginning after signing of informed consent/assent, the site will document 
any events that may be volunteered spontaneously by the subject or parent/guardian that occur 
before the end of the visit.  
If the subject requires initial or new spectacles/contact lenses (applicable if the refraction reveals at 
least -0.50 D myopic progression and/or if the eye care practitioner deems it clinically necessary to 
improve vision), the site will provide a refractive prescription and lenses/frames (if needed) or soft 
contact lenses. 
All screening evaluations will serve as baseline measurements. 
 


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Stage 1 Telephone Checks – (Months 1, 2, 4.5, 7.5, and 10.5): Sites will contact the subject or 
their parent/guardian by telephone at the end of Month 1 and Month 2 and then midway between 
office visits during the initial year of the study to collect information regarding AEs and treatment 
adherence. Telephone checks can be continued or reinstated at any time during the study to assist 
with maintaining protocol and treatment adherence. 
 
Stage 1 Three-Month Visits (Months 3, 9, 15, 21, 27, and 33) 
At these visits, the subject and their parent/guardian will return to the study site with their 
randomized study medication for an evaluation of treatment adherence. While it is preferred that the 
subject attend every visit, the parent/guardian may attend a 3-month visit without the subject if 
necessary. Sites will update concomitant medications, conduct AE assessment, dispense study 
medication, and perform treatment adherence assessment (i.e., study medication accountability). 
(Note: Enrolled subjects approved by the sponsor to transfer from one site or a new site, who reside 
greater than 150 miles from the new research site, may not be required to attend 3-month interval 
visits. Alternate accommodations may be provided to the subject and subject’s family in order to 
dispense study medication. Assessments may be obtained remotely via telephone and treatment 
adherence assessments completed at 6-Month interval visits). 
 
Stage 1 Six-Month Visits (Months 6, 12, 18, 24, and 30)  
At these visits, subject and their parent/guardian will return to the study site with their randomized 
study medication for an evaluation of treatment adherence. Subjects will undergo a measurement of 
height (yearly), weight (yearly), HR, BCVA measurement (distance and near), photopic pupil size 
measurement, SLE, tonometry, dilated fundus examination (yearly), cycloplegic autorefraction, 
axial length and, if possible, crystalline lens thickness. Sites will update concomitant medications, 
conduct AE assessment, dispense study medication, and perform treatment adherence assessment. 
 
End of Stage 1/End of Study (EOS) Month 36 Primary Efficacy  (BL-Month 36) and 
Evaluation/Commencement of Stage 2: Randomized Cross-Over (EOS Month 36) 
At the Month 36 visit, End of Study (EOS) visit Stage 1, the subject and their parent/guardian will 
return to the study site for the EOS Month 36 study visit (Stage 1). The subject and their 
parent/guardian will return to the study site with their randomized study medication.  
Subjects will undergo a measurement of height, weight, HR, BCVA measurement (distance and 
near), photopic pupil size measurement, SLE, tonometry, dilated fundus examination, cycloplegic 
autorefraction, axial length and, if possible, crystalline lens thickness. Subjects will then be re-
randomized. Sites will update concomitant medications, conduct AE assessment, dispense 
randomized study medication for the randomized cross-over stage (Stage 2), and perform treatment 
adherence assessment. Additionally, the site staff will install an electronic diary application on 
subject’s or their parent’s/guardian’s phone. Subject or their parent/guardian will be encouraged to 
record their dosing on a daily basis, starting from the same evening after completing their Month 36 
visit. If the subject or their parent/guardian do not have a cell phone or are unwilling to use their cell 
phone, a device will be provisioned by Medidata and provided to the subject. Electronic diary 
training and Medidata patient cloud electronic clinical outcome assessments (eCOA) support will be 
provided. 
 
 
 


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Stage 2 Three-Month Visits (Months 39 and 45) 
The subject and their parent/guardian will return to the study site with their randomized study 
medication for an evaluation of treatment adherence (as in Stage 1, it is preferred that the subject 
attend every visit, but the parent/guardian may attend a 3-month visit without the subject if 
necessary). Sites will update concomitant medications, conduct AE assessment, dispense study 
medication, review e-diary, and perform treatment adherence assessment. (Note: Enrolled subjects 
approved by the sponsor to transfer from one site or a new site, who reside greater than 150 miles 
from the new research site, may not be required to attend 3-month interval visits. Alternate 
accommodations may be provided to the subject and subject’s family in order to dispense study 
medication. Assessments may be obtained remotely via telephone and treatment adherence 
assessments completed at 6-Month interval visits). 
 
Stage 2 Six-Month Visit (Month 42) 
At the Month 42 visit, the subject and their parent/guardian will return to the study site with their 
randomized study medication. 
Information related to QoL (modified ATI) will be reviewed with the subject and their 
parent/guardian and they will be asked to participate in the QoL questionnaire. The site staff will 
confirm and document their willingness to participate in completing the questionnaire. Subjects can 
continue on to Stage 2 even if they elect not to participate in the completion of the QoL 
questionnaire. 
The modified ATI will be completed by the parent/guardian and subject prior to the Investigator’s 
examination of the subject. The parent/guardian QoL questionnaire should be completed prior to the 
subject questionnaire. Study staff will verify completion of the QoL questionnaires by both the 
parent/guardian and the subject.  
Once the modified ATI has been completed, subjects will undergo a measurement of HR, BCVA 
measurement (distance and near), photopic pupil size measurement, SLE, tonometry, cycloplegic 
autorefraction, axial length, and, if possible, crystalline lens thickness. Sites will update 
concomitant medications, conduct AE assessment, dispense study medication, review e-diary, and 
perform treatment adherence assessment. 
 
End of Stage 2/End of Study (Month 48) 
At the Month 48/ end of study (EOS) visit Stage 2, the subject and their parent/guardian will return 
to the study site with their randomized study medication for an evaluation of treatment adherence. 
The modified ATI will be completed by the parent/guardian and subject prior to the Investigator’s 
examination of the subject. The parent/guardian QoL questionnaire should be completed prior to the 
subject’s questionnaire. Study staff will verify completion of the QoL questionnaires by both the 
parent/guardian and the subject. 
Once the modified ATI is completed, subjects will undergo a measurement of height, weight, HR, 
BCVA measurement (distance and near), photopic pupil size measurement, SLE, tonometry, dilated 
fundus examination, cycloplegic autorefraction, axial length, and, if possible, crystalline lens 
thickness. Sites will update concomitant medications, conduct AE assessment, review e-diary, and 
perform treatment adherence assessment. The site staff will uninstall the Medidata eCOA 
application (installed on the cell phone) or retrieve the device provisioned by Medidata and 
provided to the subject.  
 
 


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Early Termination Visits 
Every effort should be made to keep subjects in the study and conduct all study visits as scheduled. 
If a subject is discontinued from study medication before the Month 48 visit, then all Month 48 
(EOS) procedures should be performed at the visit the subject is discontinued. 
If a subject is off study medication and is being followed for safety assessments then an EOS Month 
36 visit should be completed, as these subjects will not continue on to Stage 2.  
 
Unscheduled visits 
Unscheduled visits may occur at the Investigator’s discretion to address any possible issues the 
subject may experience that are of concern to the subject or parent/guardian (e.g., blurry vision, 
pain, redness in one or both eyes). 
 
Efficacy Assessments: 
x 
SER error in each eye measured by cycloplegic autorefraction  
x 
Axial length 
x 
Crystalline lens thickness (exploratory efficacy measurement) 
Treatment Adherence: 
Treatment adherence will be measured by study medication accountability. Throughout treatment 
(efficacy/safety portion and randomized cross-over portion), the amount of unopened medication 
units will be recorded at each study visit. 
 
Documentation of Mode of Administration: 
At the EOS Month 36 and EOS Month 48, site will document mode of administration by asking the 
subject or their parent/guardian: 
x 
Who administered the eyedrops to the subject during the study (i.e., self-administered or 
administered by parent/guardian)?  
x 
Was there a transition in the dosing administrator? 
x 
If yes, at what approximate age did the transition occur? 
Safety Assessments: 
x 
Heart Rate 
x 
Monocular BCVA in each eye at 
distance and near 
x 
Photopic pupil size 
x 
Slit Lamp Exam 
 
x 
Dilated fundus examination 
x 
Adverse Events  
x 
Tonometry 
Data and Safety Monitoring Plan: 
To minimize risk and ensure the immediate safety of study subjects, both local and systemic 
anticholinergic and other potential effects of study medication will be measured at each visit. 
Parameters such as heart rate, mydriasis, photophobia, blurred near vision, ocular and conjunctival 
inflammation and allergic reactions to study medication will be carefully and routinely monitored to 
assess both safety and tolerability.   


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All safety data will be collected and entered in the eCRF allowing for real-time review. Medical 
review will be performed concurrently with Data Management’s review of data and issue of queries 
to sites. The aim of the medical review is to monitor eligibility issues, assess potential protocol 
deviations and identify safety issues.  
In addition, the peer-reviewed and grey literature as well as global databases of AEs from other 
atropine products will be routinely and continually monitored. 
Withdrawal of Subjects: 
All subjects randomized into the study will be encouraged to complete all study assessments 
through the Month 48 Visit (End of Study), including subjects that cannot or do not wish to 
continue study treatment (withdraw consent/assent from study treatment but are willing to continue 
study visits). 
The following are the criteria for considering withdrawal from the study (Study discontinuation 
prior to Visit Month 48): 
x 
Withdrawal of subject consent/assent to continue with study visits. 
x 
If the site and/or the overall study is terminated for any reason. 
x 
The Investigator considers it is in the best interest for the subject to leave the study. 
This may include the development of damage to the cornea (Section 8.5 – 
Discontinuation of Study Medication). 
If a subject withdraws from the study, the reason for the subject’s withdrawal will be recorded in 
the electronic case report form (eCRF).  
If a subject is discontinued from study medication before the Month 48 visit, then all Month 48 
procedures should be performed at the visit the subject discontinues study medication. The subject 
should continue in the study off study medication. Subjects should be encouraged to return for the 6 
Month interval visits; however, returning for the 12 Month interval visits is essential. Subjects 
discontinuing study medication prior to Month 36 would continue to be seen for scheduled visits 
(at 6 Month or 12 Month intervals as noted above) until they reach the Month 36 interval. 
 
Criteria for Evaluation: 
Safety: 
The safety of 0.01% and 0.02% Atropine Sulfate Ophthalmic Solution will be compared to Vehicle 
(placebo) with analysis of safety variables including ophthalmic safety assessments (BCVA, 
photopic pupil size, SLE, dilated fundus examination, and tonometry), HR, and AEs. 
 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.02% versus Vehicle) difference  in the proportion of subjects who show < -0.50 D 
myopia progression (SER) at the Month 36 visit.  
The primary and all secondary endpoints comprise a fixed sequence set of endpoints to be tested in 
order. A 2-sided significance level of 0.05 will be adopted. 
 
 


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Secondary Efficacy Endpoints: 
The secondary efficacy endpoints consist of: 
1. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the mean change from baseline in SER at the Month 36 visit. 
2. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the proportion of subjects who show < -0.50 D myopia progression (SER) 
from baseline at the Month 36 visit. 
3. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in mean change from baseline in SER at the Month 36 visit. 
4. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the mean change from baseline in axial length  at the Month 36 visit. 
5. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the mean change from baseline in axial length at the Month 36 visit. 
 
Statistical Methods: 
Analysis Sets: 
Enrolled Set: All subjects enrolled. 
Safety Set: All subjects who were administered at least one dose of study medication for a given 
stage. 
Intent-to-treat (ITT) Set: All randomized subjects for a given stage. 
Modified intent-to-treat (mITT) Set: All randomized subjects, for a given stage, aged 6 to 10 years 
at the time of randomization in Stage 1. This will be the population for the primary efficacy 
analyses. 
Per Protocol Set (PPS): All subjects who remain in the study through end of stage and have no 
major or critical protocol violations (as defined in the SAP). 
Modified Per Protocol Set (mPPS): All subjects in the PPS in each stage who were aged 6 to 10 
years at the time of randomization in Stage 1. 
 
Statistical Analyses: 
The primary and secondary efficacy analyses will be performed using the mITT Set assuming data 
missing at random. 
The primary analysis and any other analysis of binary response measures will be performed using a 
mixed-effects model based on the binomial distribution using  a logit link function.  The model will 
include subject, treatment group, visit, eye (left or right), and baseline age group (as randomized) 
and SER (as randomized) as independent variables and treatment group-by-visit interaction term 
included.  Random intercepts for subject and eye within subject will be included using variance 
components and compound symmetry covariance structures, respectively.   In addition, sensitivity 
analyses will be performed for the primary efficacy endpoint to assess the impact of missing data.  
These sensitivity analyses will be described in the statistical analysis plan. 
For comparisons of mean change from baseline for continuous measures, the analysis will be 
performed using a mixed-effects model with a random intercept.  The model will include treatment 
group, visit, eye (left or right), baseline age group (as randomized), and baseline SER group (as 
randomized) as independent variables and the treatment group-by-visit interaction. Will be 
included.  The degrees of freedom will be determined using the Kenward-Roger approximation.  


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Random intercepts for subject and eye within subject will be included using unstructured 
covariance structures. 
Statistical Analyses (cont’d): 
Note, there will be 8 groups with different treatment histories tor Year 4: 
Treatment Stage  
Possible Treatment Histories 
Stage 1 (Years 1-3) 
Stage 2 (Year 4) 
Atropine 0.01%  
Atropine 0.01% 
Atropine 0.01% 
Atropine 0.02% 
Atropine 0.01% 
Vehicle 
Stage 1 (Years 1-3) 
Stage 2 (Year 4) 
Atropine 0.02% 
Atropine 0.01% 
Atropine 0.02% 
Atropine 0.02% 
Atropine 0.02% 
Vehicle 
Stage 1 (Years 1-3) 
Stage 2 (Year 4) 
Vehicle 
Atropine 0.01% 
Vehicle 
Atropine 0.02% 
 
For all subjects who respond in the Atropine Sulfate Ophthalmic Solution treatment groups at the 
Month 36 visit, summary statistics for the change in SER from Stage 2 baseline (Month 36 visit) 
will be presented at the Month 42 and Month 48 visits for each treatment history where subjects 
receive the same dose of Atropine Sulfate Ophthalmic Solution, a lower dose of Atropine Sulfate 
Ophthalmic Solution, or Vehicle.  
 
Summary statistics will be presented for compliance collected in diaries, the frequency of switching 
from dosing by parent/guardian to dosing by subject, and the modified Amblyopia Treatment Index 
by visit and treatment group in Year 4. 
  
Significance Level: 
The 0.01% and 0.02% atropine response rates will be compared to the vehicle response rate. The 
primary and secondary efficacy endpoints will be tested at the 5% level of significance using a 
hierarchal testing procedure in the order listed. 
 
Sample Size: 
Atropine Sulfate Ophthalmic Solution, 0.02%: 
A Fisher’s exact test with a 0.05 two-sided significance level will have 95% power to detect the 
difference between an Atropine Sulfate Ophthalmic Solution, 0.02% responder proportion of 0.25 
and a Vehicle responder proportion of 0.07 when the sample sizes are 136 and 91, respectively. 
Atropine Sulfate Ophthalmic Solution, 0.01%: 
A Fisher’s exact test with a 0.05 two-sided significance level will have 90% power to detect the 
difference between an Atropine Sulfate Ophthalmic Solution, 0.01% responder proportion of 0.25 
and a Vehicle responder proportion of 0.07 when the sample size in each group is 91. 


Atropine Sulfate Ophthalmic Solution, 0.01% and 0.02% 
 
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Table 2: 
Schedule of Procedures 
Assessment 
Screening 
Baselinea 
Treatment Stage 1 
(Office Visits Every 3 Months and Telephone Checksa ± 2 Weeks) 
Treatment Stage 2 
(Every 3 Months ± 2 
Weeks) 
Visit Number 
1 
T1 
T2 
2 
T3 
3 
T4 
4 
T5 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Month 
0 
1 
2 
3 
4.5 
6 
7.5 
9 
10.5 
12 
15 
18 
21 
24 
27 
30 
33 
 
 36 
39 
42 
45 
48 
(EOS)b 
(EOS)b 
Informed consent/assentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/medical/ocular 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testd  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re-consent/re-assente 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Modified ATI questionnaires (QoL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xef 
 
Xef 
Height and weight  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Heart rate 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Best-corrected visual acuityfg 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Pupil size measurement (photopic) 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Slit-lamp examination 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Intraocular pressure 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Dilated fundus examination 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Cycloplegic autorefraction 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Inclusion/exclusion criteria 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization/re-randomization 
(M 36) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Axial length 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Crystalline lens thickness (where 
feasible) 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Collect study medication materials 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Atropine Sulfate Ophthalmic Solution, 0.01% and 0.02% 
 
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Assessment 
Screening 
Baselinea 
Treatment Stage 1 
(Office Visits Every 3 Months and Telephone Checksa ± 2 Weeks) 
Treatment Stage 2 
(Every 3 Months ± 2 
Weeks) 
Visit Number 
1 
T1 
T2 
2 
T3 
3 
T4 
4 
T5 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Month 
0 
1 
2 
3 
4.5 
6 
7.5 
9 
10.5 
12 
15 
18 
21 
24 
27 
30 
33 
 
 36 
39 
42 
45 
48 
(EOS)b 
(EOS)b 
Concomitant medication review 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study medication 
(frames/lenses)gh 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Treatment adherence assessmenthi 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electronic patient diary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xij 
Xjk 
Xjk 
Xjk 
Xkl 
Abbreviations: ATI = amblyopia treatment index, eCOA = electronic clinical outcome assessments, EOS = end of study, QoL = quality of life. 
a Assessments may be obtained remotely at the end of Month 1 and Month 2, followed by midway between visits during Year 1. Telephone checks can be continued as necessary 
to assist with protocol and treatment adherence. Note: Enrolled subjects approved by the sponsor to transfer from one site or a new site, who reside greater than 150 miles from 
the new research site, may not be required to attend 3-month interval visits. Alternate accommodations may be provided to the subject and subject’s family in order to dispense 
study medication. Assessments may be obtained remotely via telephone and treatment adherence assessments completed at 6-Month interval visits. 
b If a subject is discontinued from study medication before the Month 36 visit in Stage 1, then all Month 36 EOS procedures should be performed. If a subject is discontinued from 
medication before the Month 48 visit in Stage 2,  , then all Month 48 EOS procedures should be performed at the visit the subject is discontinued.  
c Sites should complete screening/randomization/baseline procedures and enroll subjects within 30 days from signing informed consent.  
d Female subjects of childbearing potential (post menarche) only. 
e All subjects are to be re-consented/re-assented at their next study visit if not done at earlier visits, including subjects completing an End of Study (EOS) Visit (Stage 1 – Month 
36, Month 39, Month 42, Month 45, and Month 48).  
ef At Month 42 and Month 48, the modified ATI will be completed by the parent/guardian and subject prior to the Investigator’s examination of the subject. Prior to the 
examination, the site staff will ensure parent/guardian and subject understand the questions, by reading the questions. After each question, the site staff will proceed to read the 
choices. The parent/guardian and subject will pick the answer which comes closest to describing how they feel. The answer will be entered into the database by the site staff.  
fg Measured at distance and near.  
gh Medication dispensed by site. Dosing to be conducted at home each day at bedtime. Prescription for frames/lenses will be provided if necessary, per criteria defined in 
Section 6.1. 
hi Treatment adherence will be verbally assessed during Telephone Check. Drug accountability and details regarding any incorrect dosing will be assessed every 3 months upon 
return of unused ampules. 
ij Diary application uploaded to subject’s or their parent’s/guardian’s phone or Medidata provisioned device (if required), e-diary training and Medidata eCOA support provided.  
jk The site staff will review the electronic patient diary. 
kl The site staff will uninstall the Medidata eCOA application (installed on the cell phone) or retrieve the device provisioned by Medidata and provided to the subject.

SAP_000.pdf: 
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SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 1 of 76 
 
 
 
Statistical Analysis Plan for Interventional Studies 
Sponsor Name: Vyluma, Inc. 
 
Protocol Number: CP-NVK002-0001 
Protocol Title: CHILDHOOD ATROPINE FOR MYOPIA PROGRESSION (CHAMP): A 3-ARM 
RANDOMIZED, DOUBLE-MASKED, PLACEBO-CONTROLLED, PHASE 3 STUDY OF ATROPINE 
SULFATE OPHTHALMIC SOLUTION 0.01% AND 0.02% 
 
Protocol Version and Date: (DD-Mmm-YYYY): Amendment 5 14-Jun-2021 
Syneos Health Project Code: 1010025 
Authors: Wayne Schuck, Principal Biostatistician 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Vyluma, Inc.. Acceptance of this 
document constitutes agreement by the recipient that no information contained herein will be published or 
disclosed without prior written authorization from an official of Vyluma, Inc.. However, this document may 
be disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized 
representatives of a national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, Syneos Health should be 
notified promptly. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 2 of 76 
 
 
 
Revision History 
 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
0.1 
17-Jan-2020 
W. Schuck 
Initial Release Version 
0.2 
17-Jul-2020 
W. Schuck 
Complete update of efficacy analysis due to pending. 
protocol amendment. Specifically, designation of 
secondary and exploratory analyses and order of 
analysis. 
Clarification on how to treat missing data due to 
COVID-19. 
0.3 
21-Aug-2020 
W. Schuck 
Updated based on Nevakar comments 
0.4 
15-Sep-2020 
W. Schuck 
Updated based on Nevakar comments 
Update of visit windows 
Clarification of multiple imputation for tipping point 
analysis 
0.5 
25-Sep-2020 
W. Schuck 
Updated based on Nevakar comments 
Additional clarification of multiple imputation for tipping 
point analysis 
1.0 
28-Sep-2021 
W. Schuck 
Updated Per Vyluma comments and Amendment 5. 
Added sensitivity analysis for proportion of subjects with 
less than 0.50D myopia progression (SER) at Month 36 
Update Treatment compliance for use with added 
treatment diary 
Added summary of switching dosing from parent to 
subject 
Added section for modified Amblyopia Treatment Index 
Added section for Rebound Assessment Based on the 
Change from Stage 2 Baseline 
1.1 
08-Apr-2022 
W. Schuck 
Apply normalization or SER for analysis, summary, and 
listings 
Updated estimate statements to include all scheduled 
visit measurements 
Changed “Adverse Events of Special Interest” to 
“Adverse Events Associated with Antimuscarinic 
Function” 
Updated list of ophthalmological Adverse Events 
Associated with Antimuscarinic Function 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 3 of 76 
 
 
 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
1.2 
18-May-2022 
W. Schuck 
Updated Per Vyluma comments. 
Added Supportive Analysis using subject composite 
endpoint 
Update TEAE definitions to clarify Stage 1 and Stage 2 
definitions 
Revised the description of the primary and secondary 
responder analysis outputs as “between-treatment group 
difference in the proportion of subjects’ eyes who show 
less than 0.5D myopia progression (SER) from baseline” 
1.3 
19-Jun-2022 
W. Schuck 
Updated Subgroup analyses 
Updated Treatment-Emergent Adverse Event Definition 
Clarification of multiple imputation for tipping point 
analysis 
Misc. updates per Vyluma 
1.4 
28-Jun-2022 
W. Schuck 
Misc. updates per Vyluma 
2.0 
29-Jun-2022 
W. Schuck 
Signed as Stable 
2.1 
17-Aug-2022 
W. Schuck 
Addition of subgroup analyses of primary endpoint 
Addition of Adverse Event tables by sex, age, and race 
Update of table numbering 
3.0 
24-Aug-2022 
W. Schuck 
Finalized 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
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I confirm that I have reviewed this document and agree with the content. 
 
 
 
Approvals 
Syneos Health Approval 
Aug 30, 2022 
Wayne Schuck, Principal Biostatistician 
Electronically signed by: 
Wayne SchuckWayne Schuck 
Reason: I am the author 
Date: Aug 30, 2022 13:40 EDT 
Name, Title 
Lead Biostatistician 
 
Signature 
Date (DD-Mmm- 
YYYY) 
David Dai, Principal Biostatistician 
Electronically signed by: David 
Dai 
Reason: I am the reviewer 
Date: Aug 30, 2022 13:49 EDT Aug 30, 2022 
Name, Title 
Senior Statistical Reviewer 
Signature 
Date (DD-Mmm- 
YYYY) 
Myra Yao, 
Associate Director, Biostatistics 
 
Electronically signed by: Myra 
Yao 
Reason: I am the reviewer 
Date: Aug 30, 2022 13:02 CDT 
Aug 30, 2022 
Name, Title 
Signature 
Date (DD-Mmm- 
Senior Statistical Reviewer 
YYYY) 
Vyluma, Inc. Approval 
Simon Chandler, 
Vice President, Ophthalmology 
Electronically signed by: 
Simon ChandlerSimon Chandler 
Reason: I am the approver 
Date: Aug 30, 2022 15:52 EDT Aug 30, 2022 
Name, Title 
Sponsor Contact 
 
Signature 
Date (DD-Mmm- 
YYYY) 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals .................................................................................................................................. 4 
Glossary of Abbreviations ................................................................................................. 10 
Purpose ............................................................................................................................ 12 
  Study Objectives ................................................................................................................ 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endpoints ......................................................................................................................... 19 
 
 
 
 
Analysis Sets .................................................................................................................... 21 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
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  General Aspects for Statistical Analysis ............................................................................ 23 
 
 
 
 
 
 
Demographic, Other Baseline Characteristics and Medication .......................................... 26 
 
 
 
 
 
 
 
  Efficacy .............................................................................................................................. 29 
 
 
 
 
 
 
 
 
 


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 Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc. 
 
 
8.2.3. 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus 
Vehicle) Difference in the Mean Change from Baseline in SER at the Month 36 
Visit ....................................................................................................................... 33 
8.2.4. 
Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus 
Vehicle) Difference in the Mean Change from Baseline in Axial Length at Month 
36 ......................................................................................................................... 34 
8.2.5. 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% Versus 
Vehicle) Difference in Mean Change from Baseline in Axial Length at the Month 
36 Visit .................................................................................................................. 34 
8.3. 
Tertiary Efficacy Endpoint(s) and Analyses ........................................................... 34 
8.3.1. 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% Versus 
Vehicle) Difference in the Proportion of Subjects' eyes who Show less than 0.5 D 
Myopia Progression (SER) From Baseline at the Month 24 and Month 12 visits 34 
8.3.2. 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% versus 
Vehicle) Difference in the Mean Change from Baseline in SER at the Month 24 
and Month 12 Visits ............................................................................................. 34 
8.3.3. 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus 
Vehicle) Difference in the Proportion of Subjects' Eyes Who Show less than 0.5 
D Myopia Progression (SER) from Baseline at the Month 24 and Month 12 Visits 
. ............................................................................................................................ 35 
8.3.4. 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus 
Vehicle) Difference in the Mean Change from Baseline in SER at the Month 24 
and Month 12 Visits .............................................................................................. 35 
8.3.5. 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% versus 
Vehicle) Difference in the Proportion of Subjects' Eyes who Show less than 0.75 
D Myopia Progression (SER) From Baseline at the Month 36 Visit ..................... 35 
8.3.6. 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus 
Vehicle) Difference in the Proportion of Subjects' Eyes who Show less than0.75 
D Myopia Progression (SER) From Baseline at the Month 36 Visit .................... 35 
8.3.7. 
Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus 
Vehicle) Difference in the Time to Change from Baseline in Myopia Progression 
of -0.75 D SER ..................................................................................................... 36 
8.3.8. 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus 
Vehicle) Difference in Time to Change from Baseline in Myopia progression of - 
0.75 D SER .......................................................................................................... 36 
8.3.9. 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% versus 
Vehicle) Difference in the Number of New Prescriptions Given After the Start of 
Treatment Due to Progression through the Month 36 visit. ................................ 36 
8.3.10. 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus 
Vehicle) Difference in the Number of New Prescriptions Given After the Start of 
Treatment Due to Progression through the Month 36 visit. ................................ 37 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
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  Safety ................................................................................................................................. 41 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
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  Quality of Life ................................................................................................................... 46 
Interim Analyses ............................................................................................................... 47 
Changes from Analysis Planned in Protocol ...................................................................... 48 
  Programming Considerations ............................................................................................ 49 
 
 
 
 
 
 
 
 
Quality Control .................................................................................................................. 54 
  References ........................................................................................................................ 55 
  Index of Tables................................................................................................................. 56 
  Index of Figures ............................................................................................................... 74 
  Index of Listings ............................................................................................................... 76 


Statistical Analysis Plan for Interventional Studies 
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SAP Version: 3.0 
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Glossary of Abbreviations 
 
 
 
Abbreviation 
Description 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
ATI 
Amblyopia Treatment Index 
BCVA 
Monocular Best-Corrected Visual Acuity 
BMI 
Body Mass index 
BDRM 
Blinded Data Review Meeting 
CI 
Confidence Interval 
CRA 
Clinical Research Associate 
D 
Diopter 
eCRF 
Electronic Case Report Form 
EC 
Ethics Committee 
EOS 
End Of Study 
GPP 
Good Pharmacoepidemiology Practice 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
mATI 
Modified Amblyopia Treatment Index 
IRT 
Interactive Response Technology 
IQR 
Inter Quartile Range 
ITT 
Intent-to-Treat 
Max 
Maximum 
MCMC 
e 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
mITT 
Modified Intent-to-Treat 
mPPS 
Modified Per Protocol Set 
N/A 
Not Applicable 
PT 
Preferred Term 


Statistical Analysis Plan for Interventional Studies 
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Abbreviation 
Description 
PPS 
Per Protocol Set 
QC 
Quality Control 
OTC 
Over-The-Counter 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SER 
Spherical Equivalent Refraction 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SLE 
Slit-Lamp Examination 
SS 
Safety Set 
TEAE 
Treatment-emergent Adverse Event 
TFL 
Table, Figure, and Listing 
VD 
Vertex Distance 


Statistical Analysis Plan for Interventional Studies 
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Purpose 
 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
 
Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and quality control 
(QC) of all tables, figures, and listings. 
 
Timings of Analyses 
The primary analysis of Stage 1 safety and efficacy is planned after all subjects complete the final study 
visit of Stage 1 or terminate early from the study (see Sec 3.3 and 3.6 for definition of Stages 1 and 2). 
 
Additional analyses of Stage 2 safety and efficacy is planned after all subjects complete the final study visit 
of Stage 2 or terminate early from the study. 


Statistical Analysis Plan for Interventional Studies 
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Study Objectives 
 
 
Primary Objective 
The primary objective of the study is to evaluate the safety and efficacy of 2 concentrations of Atropine 
Sulfate Ophthalmic Solution (0.01% and 0.02%) compared to Vehicle (placebo) for slowing the progression 
of myopia in children over a 3-year treatment period. 
 
 
Exploratory Objective 
The exploratory objective of the study is to observe the safety and efficacy in subjects re-randomized to 1 
year of treatment with Atropine Sulfate Ophthalmic Solution, 0.01% or 0.02%, or Vehicle following 3 years 
of treatment in children with progressive myopia. 
 
 
Brief Description 
This will be a 3-arm randomized, multicenter, double-masked, placebo-controlled, Phase 3 study 
conducted in 2 stages. Stage 1 is a safety and efficacy phase of 3 years (36 months) in duration, during 
which subjects will be allocated one of three study medications. Stage 2 is a randomized cross-over 
phase of 1 year (12 months) in duration, for the purpose of observing the effects of changing or stopping 
treatment. During Stage 2, subjects will be re-randomized to receive 1 of the 3 study medications with 
subjects initially randomized to Vehicle only eligible for randomization to 0.01% or 0.02% Atropine Sulfate 
Ophthalmic Solution. Subjects (aged 3 to ≤ 17.0 years) will enter the study with myopia spherical 
equivalent refraction (SER) of at least -0.50 D and no greater than -6.00 D myopia in each eye as 
measured by cycloplegic autorefraction and following successful eligibility screening at the 
Screening/Baseline visit will be randomized to one of the 3 treatment groups in a 2:2:3 ratio. The 
randomization will be stratified twice: (1) by age at randomization (subjects < 9 years; subjects ≥ 9 years) 
and by (2) refractive error (less myopic: SER -0.50 to -3.00 D; more myopic: one or more eyes with SER - 
3.01 to -6.00 D). The stratification is used to balance these characteristics across the 3 treatment groups. 
 
The target number of subjects to be randomized into the 6-year to 10-year age group (436), the primary 
efficacy population. Approximately 483 subjects over all eligible ages will be enrolled. Enrollment will 
proceed until 436 subjects aged 6 to 10 years have been randomized and at least 483 subjects overall 
have been randomized. Enrollment may be closed to subjects age ≥ 11 years following enrollment of 50 
subjects in this age group to avoid over-enrollment into the study. 
 
 
Subject Selection 
Study subjects will be children, male or female, aged 3 to ≤ 17.0 years at the time of enrollment, with 
myopia spherical equivalent refraction (SER) of at least -0.50 D and no greater than -6.00 D in each eye, 
astigmatism of no more than -1.50 D in each eye, and anisometropia (SER) of < 1.50 D as measured by 
cycloplegic autorefraction. 
 
 
Inclusion Criteria 
1. Children (female and male) aged 3 to ≤ 17.0 years. 
 
2. Myopia SER of at least -0.50 D and no greater than -6.00 D myopia in each eye as measured by 
cycloplegic autorefraction. 
 
3. If present, astigmatism of no more than -1.50 D in each eye as measured by cycloplegic 
autorefraction. 
 
4. Anisometropia SER of < 1.50 D as measured by cycloplegic autorefraction. 
 
5. Normal intraocular pressure of < 21 mm Hg in each eye. 


Statistical Analysis Plan for Interventional Studies 
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6. Distance vision correctable to at least 0.1 logMAR or 20/25 Snellen equivalent in each eye. 
 
7. Female subjects of childbearing potential (post menarche) must have a negative urine pregnancy 
test at screening. 
 
8. Subject’s parent or legal guardian must provide informed consent on behalf of the subject, and 
the subject should provide assent when applicable, per Institutional Review Board (IRB)/Ethics 
Committee (EC) guidelines. If a subject becomes an adult (depending on country regulations) 
during the study, they will need to sign an informed consent form (ICF) to continue in the study. 
 
 
Exclusion Criteria 
1. Allergy to atropine or any of the excipients of the eye drops. 
 
2. Current or history of amblyopia or manifest strabismus including intermittent tropia. 
 
3. Heart rate is persistently (for more than 10 minutes) > 120 beats per minute at 
screening/baseline. 
 
4. History of any disease or syndrome that predisposes the subject to severe myopia (e.g., Marfan 
syndrome, Stickler syndrome, retinopathy of prematurity). 
 
5. History in either eye of abnormal ocular refractive anatomy (e.g., keratoconus, lenticonus, 
spherophakia). 
 
6. History in either eye of previous intraocular or ocular laser/non-laser surgery. 
 
7. Current or history of glaucoma; anatomic narrow anterior chamber angles. 
 
8. Serious systemic illness that, in the Investigator’s opinion, would render the subject ineligible. 
 
9. Chronic use of any topical or systemic antimuscarinic/anticholinergic medications (e.g., atropine, 
scopolamine, tropicamide) within 21 days prior to screening and/or anticipated need for chronic 
use during the study period (i.e., more than 7 consecutive days in 1 month or more than 30 total 
days in 1 year). Use of cycloplegic drops for dilated ocular exam are allowable. 
 
10. Chronic use (more than 3 days per week) of any topical ophthalmic medications (prescribed or 
over-the-counter [OTC]) other than the assigned study medication. Use of artificial tears is 
allowed but may not be used within 2 hours of administration of study medication. 
 
11. The anticipated need to use chronic ophthalmic or systemic oral corticosteroids during the study. 
Intranasal, inhaled, topical dermatologic, intra-articular, perianal steroids, and short-term oral 
steroids (i.e., < 2 weeks) are permitted. 
 
12. Prior myopia control treatment including orthokeratology, bifocal contact lenses, or progressive 
addition spectacle lenses. The only allowable prior treatments are myopic correction in the form 
of single-vision eyeglasses and/or single-vision or toric soft contact lenses. 
 
13. Preplanned hospitalization during the study period. (Note: The study period begins at the time of 
randomization.) 
 
14. Unwilling or unable to complete study procedures or to be followed up for the 48-month duration 


Statistical Analysis Plan for Interventional Studies 
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of the study. 
 
15. Participation in any other study of investigational therapy during the study period or within the last 
30 days. 
 
16. History of any substance abuse (excessive or habitual use of alcohol and/or drug including 
nicotine) and not willing to abstain from these substance(s) during the 4-year study period. 
 
17. Female subjects who are pregnant, nursing, or plan to become pregnant at any time during the 
study. 
 
18. Employees of the study site and their family members are not permitted to participate as subjects 
in the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological 
or legally adopted. 
 
19. Current or history of significant or severe damage to the cornea. 
 
 
Determination of Sample Size 
For the purposes of the study and identifying sample size, a responder is defined as a subject with a 
> -0.50 D myopia progression (SER) from baseline at a given time point. 
 
 
Atropine Sulfate Ophthalmic Solution, 0.02% 
A Fisher's exact test with a 0.05 two-sided significance level will have 95% power to detect the difference 
between an Atropine Sulfate Ophthalmic Solution, 0.02% responder proportion of 0.25, and a Vehicle 
responder proportion of 0.07 when the sample sizes are 136 and 91, respectively. 
 
 
Atropine Sulfate Ophthalmic Solution, 0.01% 
A Fisher's exact test with a 0.05 two-sided significance level will have 90% power to detect the difference 
between an Atropine Sulfate Ophthalmic Solution, 0.01% responder proportion of 0.25, and a Vehicle 
responder proportion of 0.07 when the sample size in each group is 91. 
 
 
Treatment Assignment & Blinding 
 
Stage 1 
In Stage 1, subjects will be randomized in a 2:2:3 ratio of vehicle: Atropine Sulfate Ophthalmic Solution, 
0.01%: Atropine Sulfate Ophthalmic Solution, 0.02%. The target number of subjects to be randomized 
into the 6- to 10-year age group (436), the primary efficacy population, will be: 
 
• 
Vehicle (placebo): 125 
• 
Atropine Sulfate Ophthalmic Solution, 0.01%: 125 
• 
Atropine Sulfate Ophthalmic Solution, 0.02%: 186 
 
Approximately 483 subjects over all eligible ages will be enrolled, resulting in the following numbers of 
subjects in each arm: 
• 
Vehicle (placebo): 138 
• 
Atropine Sulfate Ophthalmic Solution, 0.01%: 138 
• 
Atropine Sulfate Ophthalmic Solution, 0.02%: 207 


Statistical Analysis Plan for Interventional Studies 
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The randomization will be stratified twice: (1) by age at randomization (subjects < 9 years; subjects ≥ 9 
years) and by (2) refractive error (less myopic: SER -0.50 to -3.00 D; more myopic: one or more eyes with 
SER -3.01 to -6.00 D). The stratification is used to balance these characteristics across the 3 treatment 
groups. Enrollment will proceed until 436 subjects aged 6 to 10 years have been randomized and at least 
483 subjects overall have been randomized. Enrollment may be closed to subjects ≥ 11 years following 
enrollment of 50 subjects in this age group to avoid over-enrollment into the study. 
 
If subjects meet eligibility criteria at the Screening/Baseline visit (Day 0), subjects will be randomly 
assigned to masked study medication. Study sites will utilize the IRT to assign kits to subjects. The 
treatment kit number will be recorded in the subject’s eCRF. Study medication from the Interactive 
Response Technology (IRT)-assigned kit will be dispensed to the subject/subject’s parent or guardian for 
dosing that evening. Subjects will return to the study site at 3-month intervals to return their study 
medication and their next assigned study medication kit will be dispensed. It is preferred that the subject 
attend every visit, but the parent/guardian may attend a 3-month visit without the subject if necessary. 
Both the subject and parent/guardian must be present at all 6-month safety and efficacy visits. 
 
The study will be double masked. The study medication will be provided in identical-appearing laminated 
pouches with no labeling indicating the identity of the study group or the contents of the unit dose 
ampules. The laminated pouches will contain identical-appearing unit dose ampules. Study subjects, 
Investigators and staff, and study management personnel will be masked to the identity of treatment until 
after the final database lock of Stage 1. Subjects, investigators, and study site personnel will remain 
blinded to Stage 1 treatment until Stage 2 is completed and database is locked. 
 
 
Stage 2 
At initiation of Stage 2 of the study, all subjects will be re-randomized to receive 1 of 3 study medications. 
Subjects who were randomized to 0.01% or 0.02% Atropine Sulfate Ophthalmic Solution during Stage 1 
will be re-randomized a in a 1:1:1 ratio to one of the 3 treatment arms (Vehicle: Atropine Sulfate 
Ophthalmic Solution, 0.01%: Atropine Sulfate Ophthalmic Solution, 0.02%), and subjects who were 
randomized to Vehicle during Stage 1 will be re-randomized in a 1:1 ratio to active treatment (Atropine 
Sulfate Ophthalmic Solution, 0.01%: Atropine Sulfate Ophthalmic Solution, 0.02%). The randomization list 
will be created by an independent biostatistician and sites will utilize the IRT to assign subject kits as per 
the procedures delineated for Stage 1. Study medication during Stage 2 will continue to be double 
masked. 
 
 
Administration of Study Medication 
First Dose of Study Medication: The subject (or caregiver if the subject is not able to self-administer the 
medication) will administer 1 full drop of the study medication into each eye from a single unit dose 
ampule at bedtime the evening of the randomization visit. 
 
Each subsequent evening of dosing, the subject or caregiver will administer one full drop into each eye 
from a single new ampule and close the eyes gently for 30 seconds. The used ampule will be placed in 
the provided receptacle for return to the study site. 
 
Subjects and/or their parent/guardian should make every effort not to miss administering doses during the 
study. Should a subject miss a dose, then the subject should wait until the following evening and then 
continue with his/her regular dosing schedule. Subject should not administer more than 1 dose to each 
eye per day. 
 
Subjects or their parent/guardian will return all unopened study medication materials at the next office 


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Page 17 of 76 
 
 
 
visit. Site personnel will conduct treatment adherence assessment procedures for the last study period 
and dispense study medication for the next 3-month study period. At the Month 48 visit, final study drug 
accountability will be conducted. The Month 48 visit will mark the end of study treatment; no further study 
medication will be dispensed at this visit. 
 
 
Study Procedures and Flowchart 
During Stage 1, office visits will occur at Screening/Baseline, Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 
33, and 36. 
 
During the Three-Month Visits (Months 3, 9, 15, 21, 27, 33), subjects and their parent/guardian will return 
to the study site with their randomized study medication for an evaluation of treatment adherence. While it 
is preferred that the subject attend every visit, the parent/guardian may attend a 3-month visit without the 
subject if necessary. Sites will update concomitant medications, conduct AE assessment, dispense study 
medication, and perform treatment adherence assessment (i.e., study medication accountability). 
 
During the Stage 1 Six-Month Visits (Months 6, 12, 18, 24, and 30), subjects and their parent/guardian 
will return to the study site with their randomized study medication for an evaluation of treatment 
adherence. Subjects will undergo a measurement of height (yearly), weight (yearly), HR, BCVA 
measurement (distance and near), photopic pupil size measurement, slit-lamp examination (SLE), 
tonometry, dilated fundus examination (yearly), cycloplegic autorefraction, axial length and, if possible, 
crystalline lens thickness. Sites will update concomitant medications, conduct AE assessment, dispense 
study medication, and perform treatment adherence assessment. 
 
During the Month 36 visit, subjects and their parent/guardian will return to the study site with their 
randomized study medication for an evaluation of treatment adherence. Subjects will undergo a 
measurement of height, weight, HR, BCVA measurement (distance and near), photopic pupil size 
measurement, SLE, tonometry, dilated fundus examination, cycloplegic autorefraction, axial length and, if 
possible, crystalline lens thickness. Subjects will then be re-randomized. Sites will update concomitant 
medications, conduct AE assessment, dispense randomized study medication for the randomized 
crossover stage (Stage 2), and perform treatment adherence assessment. 
 
For the Stage 1 Telephone Checks - (Months 1, 2, 4.5, 7.5, 10.5) sites will contact subjects or their 
parent/guardian by telephone at the end of Month 1 and Month 2 and then midway between office visits 
during the initial year of the study to collect information regarding AEs and treatment adherence. 
Telephone checks can be continued or reinstated at any time during the study to assist with maintaining 
protocol and treatment adherence. 
 
Stage 2 begins during the Stage 1 Month 36 visit. During Stage 2, office visits will occur at Months 36, 39, 
42, 45, and 48. 
 
During Stage 2 Three-Month Visits (Months 39 and 45), subjects and their parent/guardian will return to 
the study site with their randomized study medication for an evaluation of treatment adherence (as in 
Stage 1, it is preferred that the subject attend every visit, but the parent/guardian may attend a 3-month 
visit without the subject if necessary). Sites will update concomitant medications, conduct AE 
assessment, dispense study medication, and perform treatment adherence assessment. 
 
During Stage 2 Six-Month Visit (Month 42), subjects and their parent/guardian will return to the study site 
with their randomized study medication for an evaluation of treatment adherence. Subjects will undergo a 
measurement of HR, BCVA measurement (distance and near), photopic pupil size measurement, SLE, 
tonometry, cycloplegic autorefraction, axial length, and, if possible, crystalline lens thickness. Sites will 
update concomitant medications, conduct AE assessment, dispense study medication, and perform 
treatment adherence assessment. 
 
At the Month 48 end of study (EOS) visit, subjects and their parent/guardian will return to the study site 


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with their randomized study medication for an evaluation of treatment adherence. Subjects will undergo a 
measurement of height, weight, HR, BCVA measurement (distance and near), photopic pupil size 
measurement, SLE, tonometry, dilated fundus examination, cycloplegic autorefraction, axial length, and, if 
possible, crystalline lens thickness. Sites will update concomitant medications, conduct AE assessment, 
and perform treatment adherence assessment. 
 
Every effort should be made to keep subjects in the study and conduct all study visits as scheduled. If a 
subject is discontinued from study medication before the Month 48 visit, then all Month 48 (EOS) 
procedures should be performed at the visit the subject is discontinued. 
 
Full details of each visit can be found in Table 2: Schedule of Procedures in the protocol. 


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Endpoints 
 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the overall between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.02% versus Vehicle) difference in the proportion of subjects’ eyes who show less than 0.5 D 
myopia progression (SER) from baseline at the Month 36 visit. 
 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will consist of: 
 
1. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the mean change from baseline in SER at the Month 36 visit. 
2. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the proportion of subjects’ eyes who show less than 0.5 D myopia progression 
(SER) from baseline at the Month 36 visit. 
 
3. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the mean change from baseline in SER at the Month 36 visit. 
 
4. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the mean change from baseline in axial length at the Month 36 visit. 
 
5. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the mean change from baseline in axial length at the Month 36 visit. 
 
 
Tertiary Endpoints 
Tertiary endpoints will consist of: 
 
1. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the proportion of subjects’ eyes who show less than 0.5 D myopia progression 
(SER) from baseline at the Month 24 and Month 12 visits. 
 
2. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the mean change from baseline in SER at the Month 24 and Month 12 visits. 
 
3. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the proportion of subjects’ eyes who show less than 0.5 D myopia progression 
(SER) from baseline at the Month 24 and Month 12 visits. 
 
4. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the mean change from baseline in SER at the Month 24 and Month 12 visits. 
 
5. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the proportion of subjects’ eyes who show less than 0.75 D myopia progression 
(SER) from baseline at the Month 36 visit. 
 
6. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the proportion of subjects’ eyes who show less than 0.75 D myopia progression 
(SER) from baseline at the Month 36 visit. 


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7. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the time to change from baseline in myopia of -0.75 D SER. 
 
8. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the time to change from baseline in myopia of -0.75 D SER 
 
9.  Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the mean number of new prescriptions given after the start of treatment due to 
progression through the Month 36 visit. 
 
10. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the mean number of new prescriptions given after the start of treatment due to 
progression through the Month 36 visit. 
 
11. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the proportion of subjects who progressed from baseline to high myopia (SER -6.00 
D or more myopic) at the Month 36 visit. 
 
12. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the proportion of subjects who progressed from baseline to high myopia (SER -6.00 
D or more myopic) at the Month 36 visit. 
 
13. Interaction between demographic variables (age 6 – 8 years versus 9 – 10 years; baseline SER - 
0.50 to -3.00 D versus more myopic than -3.00 D SER; Asian versus non-Asian; dark irides 
versus light irides, region (U.S. versus E.U.); female versus male and SER at randomization. 
14. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the change from baseline in crystalline lens thickness at the Month 36 visit. 
 
15. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the change from baseline in crystalline lens thickness at the Month 36 visit. 
 
Exploratory Efficacy Endpoints 
Exploratory endpoints will consist of: 
 
1. Between-treatment group difference in the mean change from study baseline in SER at the Month 
48 visit for all subjects who respond in the Atropine Sulfate Ophthalmic Solution treatment groups 
at the Month 36 visit. 
 
2. Between-treatment group difference in the mean change from Stage 2 baseline (Month 36) in 
SER at the Month 48 visit for all subjects who respond in the Atropine Sulfate Ophthalmic 
Solution treatment groups at the Month 36 visit. 
 
3. Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle and 
Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) Difference in the Proportion of 
Subjects' Eyes with Higher Myopia (SER <= -3.00) who Show less than 0.75 D Myopia 
Progression (SER) From Baseline at the Month 36 Visit 


Statistical Analysis Plan for Interventional Studies 
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Analysis Sets 
 
 
Enrolled Set 
The Enrolled Set will include all subjects enrolled. Unless specified otherwise, this set will be used for 
subject listings and summaries of subject disposition. 
 
 
Safety Set 
The Safety Set (SS) will include all subjects who were administered at least one dose of study medication 
for a given stage. Stage 1 Safety Set is defined by administration of at least one dose of study medication 
in Stage 1. Stage 2 Safety Set is defined by administration of at least one dose of study medication in Stage 
2. Subjects will be analyzed according to first treatment received for each stage. In the case of listings or 
tables that present data from both stages, then treatment sequence will be used. The SS will be used for 
all analyses of safety endpoints and for the presentation of subjects in all subject listings. 
 
 
Intent-to-Treat Set 
The Intent-to-Treat (ITT) Set will include all randomized subjects for a given stage. Stage 1 ITT Set is 
defined by randomization of a subject into a Stage 1 treatment. Stage 2 ITT Set is defined by randomization 
of a subject into a Stage 2 treatment. Subjects will be analyzed according to randomized treatment. The 
ITT Set will be used for all analyses of efficacy endpoints, unless otherwise specified, and for the 
presentation of subjects in all subject listings. 
 
 
Modified Intent-to-Treat 
The Modified Intent-to-Treat (mITT) Set will include all randomized subjects, for a given stage, aged 6 to 
10 years at the time of randomization in Stage 1. Stage 1 mITT Set is defined by randomization of a subject, 
aged 6 to 10 years at the time of randomization in Stage 1, into a Stage 1 treatment. Stage 2 mITT Set is 
defined by randomization of a subject, aged 6 to 10 years at the time of randomization in Stage 1, into a 
Stage 2 treatment. This will be the population for the primary efficacy analyses. Subjects will be analyzed 
according to randomized treatment. 
 
 
Per Protocol Set 
The Per Protocol Set (PPS) will include all subjects who remain in the study through end of stage and have 
no major or critical protocol violations. Stage 1 PPS requires subjects to remain in the study through Month 
36. Stage 2 PPS requires subjects to remain in the study through Month 48. This will be the population for 
selected efficacy analyses. Subjects will be analyzed according to randomized treatment. Criteria for 
inclusion in the PPS includes the following important Protocol deviations for which subjects are to be 
included within each analysis set are determined at a BDRM (see 5.7) before unblinding. 
 
 
Modified Per Protocol Set 
The Modified Per Protocol Set (mPPS) will include all subjects in the PP analysis population in each stage 
who were aged 6 to 10 years at the time of randomization. This will be the population for selected efficacy 
analyses. Subjects will be analyzed according to randomized treatment. 
 
 
Protocol Deviations 
Protocol deviations will be collected throughout the study. All protocol deviations classified as Minor, Major, 
or Critical. Based on these classifications, subjects with Major or Critical deviations will be tentatively 


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identified as not in the PPS and Modified PPS. Listings of proposed analysis set designations and protocol 
deviations will be distributed to the sponsor for review. 
 
Protocol deviations and analysis set assignments will be reviewed during a Masked Data Review Meeting 
(BDRM). Additional details of selection criteria, documentation, and scheduling of the BDRM to be provided 
for review will be described in the BDRM Preparation Plan. 


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General Aspects for Statistical Analysis 
 
 
General Methods 
• SAS® version 9.4 or newer is to be used for all analyses and outputs 
 
• Unless otherwise specified, summaries will be presented for each treatment group by study stage 
 
• Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. Due to the expected strong correlation between 
eyes within a subject, eye-related continuous variables, where the object of measure is subjects’ 
eyes, will be summarized using the number of observations (n), mean, Inter Quartile Range (IQR), 
median, minimum, and maximum. Categorical variables will be summarized using number of 
observations (n), frequency, and percentages of subjects. 
• All relevant subject data will be included in listings. All subjects entered into the database will be 
included in subject data listings. 
 
 
Key Definitions 
Treatment-emergent adverse events (TEAEs) of Stage 1 are defined as any new or worsening of existing 
adverse events that occur or worsen between the first dose date of Stage 1 and the last dose date of 
Stage 1. 
 
TEAEs of Stage 2 are defined as any AE the occurs or worsens between the first dose date of Stage 2 
and the last dose date of Stage 2. 
 
First dose date for Stage 1 is defined as the first dose of study medication received after randomization in 
Stage 1. 
First dose date for Stage 2 is defined as the first dose of study medication received after the Stage 1 last 
dose date and subject is re-randomized. 
 
For subjects who did not receive study medication in a given stage, leave first dose date for that stage as 
missing. If the first dose date is missing and if the subject is randomized, impute the missing first dose 
date using the randomization date in the analysis of Time to Change from Baseline in Myopia Progression 
of -0.75D (see 8.3.7 and 8.3.8). 
 
Baseline for Stage 1 is defined as the last measurement prior to first dose of study medication in Stage 1, 
If an adverse event starts or non-study medication taken on the day of first dose it will be treated as 
occurring after treatment started. All other planned measurements are presumed to occur prior to first 
dose of study medication. 
 
Baseline for Stage 2 will be defined as latest results prior to start of study medication in Stage 2, which 
occurs the day after the Month 36 visit. The results of the Month 36 visit will act as the baseline for Stage 
2. 
 
 
Missing Data 
Partial dates of medications will be imputed solely for the purpose of defining prior/concomitant status for 
medications and treatment emergence for adverse events. Dates will be defined using the hierarchy of 
derivations below. 


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• 
For missing start day where month and year are present, the start day will be set to the 1st of the 
month, unless the month and year are the same as the first dose month and year and the 1st of 
the month is before the first dose date, in which case, the start date will be set to the first dose date. 
 
• 
For missing start day and month where year is present, the start day and month will be set to 
January 1st, unless the year is the same as the first dose year and January 1st is before the first 
dose date, in which case, the start date will be set to the first dose date. 
 
• 
For missing end day where month and year are present, the end day will be set to the last day of 
the month, unless the month and year are the same as the subject study termination month and 
year, in which case, the end date will be set to the trial termination date. 
 
• 
For missing end day and month, where year is present, the end date will be set to the trial 
termination date if the years are the same. If the trial termination year is greater than the end year, 
the end day and month will be set to December 31st. 
 
Missing efficacy data will be addressed in the related subsection of 8 below. 
 
 
Visit Windows 
In order to adapt to changes in subjects going to the investigator’s office due to COVID-19, visit windows 
will be applied to incorporate visits that are reported as unscheduled visits or are out of protocol specified 
visit window once subjects were able to return to the investigator’s office. Visit windowing will be applied 
for all analyses results of eye examinations. Examples of applicable eye exams are cycloplegic 
autorefraction and, tonometry intraocular pressure. 
 
There are two sets of visit windows that will be applied. A narrower set of visit windows to be used in any 
appropriate analyses of the PP Set and a broad set of visit windows for all other appropriate analyses. 
 
The day included for a visit is provided in Table 1 and Table 2 below. 
 
Table 1: Visit Window Schedule (except for analysis of PPS) 
Visit 
Scheduled Visit Day 
Visit Window 
Baseline 
Day 1 
≤ Day 1 
Month 6 
Day 182 
Day 2- Day 273 
Month 12 
Day 365 
Day 274 – Day 456 
Month 18 
Day 548 
Day 457 – Day 639 
Month 24 
Day 731 
Day 640 – Day 822 
Month 30 
Day 913 
Day 823 – Day 1004 
Month 36 
Day 1096 
Day 1005 – Day 1187 
Month 42 
Day 1278 
Day 1188 – Day 1369 
Month 48 
Day 1461 
≥ Day 1370 


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Table 2: Visit Window Schedule (for analysis of PPS) 
Visit 
Scheduled Visit Day 
Visit Window 
(±28day except Month 36 visit, ±42 days for Month 36) 
Baseline 
Day 1 
≤ Day 1 
Month 6 
Day 182 
Day 154 - Day 210 
Month 12 
Day 365 
Day 337 – Day 393 
Month 18 
Day 548 
Day 520 – Day 576 
Month 24 
Day 731 
Day 703 – Day 759 
Month 30 
Day 913 
Day 885 – Day 941 
Month 36 
Day 1096 
Day 1068 – Day 1124 
Month 42 
Day 1278 
Day 1250 – Day 1306 
Month 48 
Day 1461 
Day 1419 – Day 1503 
 
 
In case 2 or more visits occur within a visit window, the closest visit to the scheduled visit will be used for 
summaries and analysis. If 2 visits are equidistant from the scheduled visit, then the later visit will be 
used. 
 
Stage 1 is scheduled to run from Baseline until the Month 36 visit. Stage 1 will end when the subject 
leaves the study or completes their Month 36 visit, whichever is earlier. Stage 2 will begin on the day of 
first dose after re-randomization. 
 
 
Pooling of Centres 
This section is not applicable because centre/country is not included in the statistical model. 
 
 
Subgroups 
Subjects are randomized based on two stratifications. The first stratification is by age (subjects < 9 years; 
subjects ≥ 9 years); the second is by refractive error (less myopic: SER -0.50 to -3.00 D; more myopic: 
one or more eyes with SER-3.01 to -6.00 D). The primary and secondary analyses will be repeated for 
each stratification. 
 
Additional subgroup exploratory analyses will be performed differences between select demographic 
variables (Asian versus non-Asian; dark irides versus light irides; female versus male) and change from 
baseline in SER at Month 12, Month 24, and Month 36. 


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Demographic, Other Baseline Characteristics and Medication 
 
Subject Disposition and Withdrawals 
Subject disposition will be presented for all subjects, which include the following: 
 
• 
Number of subjects enrolled 
 
• 
Number of screened and reason for screen failure 
 
• 
Number (%) of subjects randomized for Stage 1 
 
• 
Number (%) of subjects re-randomized for Stage 2 
Among the randomized subjects, the following will be summarized 
• 
Number (%) of subjects in the Stage 1 Safety Set 
 
• 
Number (%) of subjects in the Stage 1 Intent-to-Treat Set 
 
• 
Number (%) of subjects in the Stage 1 Modified Intent-to-Treat Set 
 
• 
Number (%) of subjects in the Stage 1 Per-Protocol Set 
 
• 
Number (%) of subjects in the Stage 1 Modified Per-Protocol Set 
 
• 
Number (%) of subjects who completed the Stage 1 
 
• 
Number (%) of subjects who discontinued treatment in Stage 1 and their reason 
 
• 
Number (%) of subjects who discontinued study prematurely in Stage 1 and their reason 
 
• 
Number (%) of subjects who continuing the study into Stage 2 
 
• 
Number (%) of subjects in the Stage 2 Safety Set 
 
• 
Number (%) of subjects in the Stage 2 Intent-to-Treat Set 
 
• 
Number (%) of subjects in the Stage 2 Modified Intent-to-Treat Set 
 
• 
Number (%) of subjects in the Stage 2 Per-Protocol Set 
 
• 
Number (%) of subjects in the Stage 2 Modified Per-Protocol Set 
 
• 
Number (%) of subjects who completed the study (Stage 2) 
 
• 
Number (%) of subjects who discontinued treatment in Stage 2 and their reason 
 
• 
Number (%) of subjects who discontinued study prematurely in Stage 2 and their reason 
 
A separate by-subject listing of subject disposition and withdrawal will also be provided. Subjects who 
screen failed will be listed along with the date and reason for the screen failure. 


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Randomized subjects not included in an analysis set and their reason for exclusion will be summarized 
and listed. 
 
 
Demographic and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized for the Safety Set by actual 
treatment and overall and for the ITT Set, the mITT Set, the PPS, and the mPPS by randomized 
treatment group and overall. Summary statistics and by-subject listings will be provided. The summary will 
be repeated for all subjects who enter Stage 2. 
 
Demographics and baseline characteristics will include age, sex, ethnicity, race, weight, height, body 
mass index (BMI), age strata (< 9; >= 9 years), and refractive error (less myopic: SER -0.50 to -3.00 D; 
more myopic: one or more eyes with SER-3.01 to -6.00 D). 
Age at Study day 1 = ((Study day 1) visit date - date of birth + 1) / 365.25 and truncated to complete 
years. 
 
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs.) * 0.4536 
BMI (kg/m2) = Weight(kg)/[Height(m)2] 
 
Baseline Disease Characteristics 
Baseline values for spherical equivalent refraction (SER), astigmatism, anisometropia, axial length, and 
crystalline lens thickness will be summarized using descriptive statistics for Safety Set by actual 
treatment, and for the ITT Set, the mITT Set, the PPS, and the mPPS by randomized treatment group 
and overall. Summary statistics and by-subject listings will be provided. The summary will be repeated for 
all subjects who enter Stage 2. 
 
Medical History 
A summary table of the number and percentage of subjects of ocular and other medical history by system 
organ class (SOC) and preferred term (PT) will be produced from the Safety Set. Medical history will be 
sorted alphabetically by SOC and in descending order of subjects per preferred term within each SOC. 
 
All Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
20.1 or higher. 
 
A separate by-subject listing of medical history will also be provided. 
 
 
Medication 
All prior and concomitant medications will be summarized based on classification using the Anatomical 
Therapeutic Chemical (ATC) classification and preferred drug name from the World Health Organization 
Drug Dictionary, version Sep2017, or later. Concomitant medications will be summarized for each stage 
separately. 
 
A separate by-subject listing of medications will also be provided. 


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Prior Medication 
Prior medications are defined as medications entered in the eCRF that either start, or end before the first 
dose of study medication. Prior medications will be summarized by ATC level 2 and preferred drug name 
for the Safety Population. 
 
Prior medications which continue after first dose of study medication will also be classified as a 
concomitant medication 
 
 
Concomitant Medication 
Concomitant medications are defined as medication on the eCRF that are taken on or after or are 
ongoing at the start date of dosing for each stage. Concomitant medications will be summarized by ATC 
level 2 and preferred drug name for the Safety Set for each stage. 


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Efficacy 
 
The primary and all secondary endpoints comprise a fixed sequence set of endpoints to be tested in the 
order given below. All statistical testing will be performed using a two-sided testing procedure with 
α=0.05. Summaries of change for Stage 2 will include change from baseline and change from Stage 2 
baseline (Month 36). 
 
The order for the fixed sequence of endpoints to be tested are: 
 
1. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the proportion of subjects’ eyes who show less than 0.5 D myopia progression 
(SER) from baseline at the Month 36 visit. (Primary Endpoint) 
 
2. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
difference in the mean change from baseline in SER at the Month 36 visit. 
 
3. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the proportion of subjects’ eyes who show less than 0.5 D myopia progression 
(SER) from baseline at the Month 36 visits. 
 
4. Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
difference in the mean change from baseline in SER at the Month 36 visit. 
 
5. Between-treatment group (Atropine Sulfate Ophthalmic Solution 0.02% versus Vehicle) difference 
in the mean change from baseline in axial length at the Month 36) visit, 
 
6. Between-treatment group (Atropine Sulfate Ophthalmic Solution 0.01% versus Vehicle) difference 
in the mean change from baseline in axial length at the Month 36 visit. 
 
Not all sites used the same Vertex distance (VD) in mm when measuring refraction with autorefractor. All 
averaged SER measurements for each participant used in tables and analyses will be normalized to a VD 
of 0 mm to the corneal plane. The normalization (Fannin 1987) will be applied using 
 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 = 
100 
100 
𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 
 
 
where SER is the original SER from CRF. 
೦𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆೦ − ೦ 10 ೦ 
 
The normalized SER will be used in all efficacy analyses for SER. SER values for randomization and 
stratification will not be normalized. Baseline SER will be normalized for use in the statistical analyses of 
efficacy. Both the original SER (from CRF) and normalized SER will be presented in listings. The 
astigmatism value for eligibility purpose will not be normalized because normalization to the corneal plane 
from a spectacle plane will always lead to a less minus power and hence will not change astigmatism 
eligibility for enrolled participants 


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Primary Efficacy Endpoint and Analysis 
 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the between-treatment group (Atropine Sulfate Ophthalmic Solution, 
0.02% versus Vehicle) difference in the proportion of subjects’ eyes who show less than 0.5 D myopia 
progression (SER) from baseline at the Month 36 visit. 
 
Spherical equivalent refraction will be measured using cycloplegic autorefraction at Months 6, 12, 18, 24, 
30, and 36. Subjects’ eyes will be determined at each visit if they have a less than 0.5 D myopia 
progression (SER). All data collected through Month 36 will be used, regardless of when treatment is 
stopped. There will be no imputation for missing data; analysis will be conducted as observed. 
 
The primary analysis will be performed using a Mixed Model based on the binomial distribution using a 
logit link function. Progression as the dependent variable, subject, treatment, visit, eye (left or right) and 
baseline age group (as randomized) and SER (as randomized) as independent variables and treatment 
by visit interaction term included. Random intercepts for subject and eye within subject will be included 
using variance components and compound symmetry covariance structures, respectively. The primary 
analysis will be performed using the mITT analysis set assuming data is missing at random. 
 
proc glimmix data=master empirical method=quad; 
class subjid trtpn(ref='0') avisitn eye agegr1 sergr1; 
model eff(event='1') = trtpn avsitn eye agegrp1 sergrp1 trtpn*avisitn / dist=bin link=logit solution or; 
nloptions tech=nrridg maxiter=25; 
random intercept / subject=subjid type=vc; 
random intercept / subject=eye(subjid) type=cs; 
estimate ‘0.02% vs. Pbo Month 36’ trtpn 0 1 -1 trtpn*avisitn 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1; 
 
The absolute risk difference and associated Wald 95% CI will also be presented at Month 36 using the 
following frequency procedure. 
proc freq data=dat order=data; 
tables trtpn*eff / riskdiff(equal cl=wald); 
 
Counts and percentage of subject’ eyes progressing at each visit for each stage will be summarized. For 
the primary endpoint and associated secondary endpoints, Odds Ratios, 95% confidence interval (CI), 
and p-value will be provided along with an accompanying figure. 
 
 
Supportive Analysis of Primary Endpoint 
8.1.2.1. 
Subject Composite Result 
The supportive efficacy endpoint is the between-treatment group (Atropine Sulfate Ophthalmic Solution, 
0.02% versus Vehicle) difference in the proportion of subjects who show less than 0.5 D myopia 
progression (SER) from baseline at the Month 36 visit without factoring in both eyes within a subject. 
Subjects with at least one eye that shows less than 0.5 D myopia progression (SER) from baseline will be 
considered as responders. The supportive analysis will be performed using a Mixed Model based on the 
binomial distribution using a logit link function. Progression as the dependent variable, subject, treatment, 
visit, and baseline age group (as randomized) and SER (as randomized) as independent variables and 
treatment by visit interaction term included. Random intercept for subject will be included using variance 
components. The supportive analysis will be performed using the mITT analysis set assuming data is 


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missing at random. The supportive analysis is designed to reenforce the expectation of a strong 
correlation between eyes within a subject. 
 
proc glimmix data=master empirical method=quad; for each visit 
class subjid trtpn(ref='0') avisitn agegr1 sergr1; 
model eff(event='1') = trtpn avsitn agegrp1 sergrp1 trtpn*avisitn / dist=bin link=logit solution or; 
nloptions tech=nrridg maxiter=25; 
random intercept / subject=subjid type=vc; 
estimate ‘0.02% vs. Pbo Month 36’ trtpn 0 1 -1 trtpn*avisitn 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1; 
 
 
Sensitivity Analysis of the Primary Endpoint 
Unless otherwise noted, all sensitivity analyses will be performed using the same method and model as 
the primary analysis. 
 
8.1.3.1. 
Subgroup Analyses 
For subgroup analyses, the analysis method will be the same as the primary efficacy analysis as 
described in 8.1.1 above, including sensitivity analyses using the statement: 
 
estimate '0.02% vs. Pbo Month 12 Subgroup_Value1 trt01pn*avisitn1*Subgroup_Var 
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 -1 0 0 0 0 0 0 0 0 0 0 0 / cl; 
 
estimate '0.02% vs. Pbo Month 12 Subgroup Value2 trt01pn*avisitn1*Subgroup_Var 
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0/ cl 
 
8.1.3.2. 
On-Treatment Analysis 
The primary analysis uses all data from the study through Month 36. During that time if a subject stops 
treatment they are encouraged to remain in the study to the scheduled completion of the study at Month 
48. The on-treatment analysis will exclude all data collected more than 4 weeks after last day of 
treatment. 
The analysis method will be the same as the primary efficacy analysis as described in 8.1.1 above. There 
will be no imputation for missing data, analysis will be conducted as observed and data assumed to be 
missing at random. 
 
8.1.3.3. 
Modified Per Protocol Analysis 
A sensitivity analysis will be performed on the modified per protocol population (mPPS). There will be no 
imputation for missing data, analysis will be conducted as observed and data assumed to be missing at 
random. The analysis will be conducted using the same model as the primary efficacy analysis (as 
described in 8.1.1 above). 
 
8.1.3.4. 
Tipping Point Analysis 
A sensitivity analysis of the primary endpoint will be conducted by tipping point analysis: In the event, that 
statistical significance in favor of Atropine Sulfate Ophthalmic Solution, 0.02% is determined on the 
primary analysis. In this scenario, imputations will occur on the continuous value of spherical equivalent 
refraction (SER) which will then be used to determine treatment response. The imputation will be using 
Markov chain Monte Carlo (MCMC) methodology for non-monotone (intermittent) missing data (any 
missing data point with a non-missing data point following) followed by Monotone Regression 


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methodology for the remaining monotone missing data. The regression model for imputation will include, 
at a minimum, treatment, visit, eye (left or right) and baseline age group (as randomized) and SER (as 
randomized), race (Asian vs, non-Asian, see 8.3.13 below), eye color (dark irides versus light irides), and 
region (U.S. vs. E.U.). This set of imputations will be performed 10 times per evolution for a total of 100 
imputations. Missing data from the placebo arm will be imputed according to the normalized placebo SER 
values, and treatment-related missing data on active arm imputation at each visit will adjusted from the 
normalized active SER values, up until the normalized placebo SER values at the respective visit in a 
minimum of 5 steps to assess if a tipping point exists between a statistically significant and a non- 
significant difference. The imputed datasets will be analyzed using the same model as the primary 
analysis. The results of these analyses will be combined into a single result using PROC MIANALYZE for 
each value of the shift. The objective is to determine whether a tipping point exists where the statistical 
significance between the Atropine Sulfate Ophthalmic Solution, 0.02% and placebo arm will no longer 
exist. 
 
Treatment-related missing data are data missing because a subject terminates the study prior to the 
Month 36 visit for the following termination reasons: 
 
- 
Subject withdrew consent 
- 
Medical reason (AE) 
- 
Physician decision to discontinue treatment 
- 
Death 
- 
Lack of efficacy 
 
Non-treatment related missing data are data missing because a subject terminates the study prior to the 
Month 36 visit for the following termination reasons: 
 
- 
Visit missed or telemedicine visit due to COVID-19 
- 
Sponsor terminated study 
- 
Lost to follow-up 
- 
Pregnancy 
- 
Other 
 
 
COVID-19 Analyses 
Data that is missing due to subject unable to go to the investigator’s office due to COVID-19 are 
considered missing at random. The Mixed Model analysis being used in the primary analysis is known to 
be robust in dealing with data that is missing at random. Therefore, no additional sensitivity analyses will 
be performed involving data missing due to COVID-19. 
 
 
Other Analysis of the Primary Endpoint 
The primary analysis will be repeated for the ITT and PPS analysis sets and for each stratification level. 
Sensitivity analyses will be repeated for the ITT population only. There will be no imputation for missing 
data; analysis will be conducted as observed. The analysis will be conducted using the same model as 
the primary efficacy analysis (as described in 8.1.1 above). 
 
As part of the sensitivity analyses for the primary efficacy analysis, the point estimate and 95% Wald 
confidence interval, for the absolute difference in the proportions of subjects with less than 0.50D myopia 
progression (SER) at Month 36 between the treatment groups without any models should be presented. 


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Secondary Efficacy Endpoint(s) and Analyses 
Unless otherwise stated, all secondary analyses will use the mITT Set. The ITT Set will also be analyzed 
in the same manner as supportive analyses. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
Difference in the Mean Change from Baseline in SER at the Month 36 Visit 
A secondary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.02% versus Vehicle) difference in the mean change from baseline in SER at the Month 36 
visit. 
 
The analysis will be performed using a mixed-effect model with a random intercept. Change from baseline 
as the dependent variable, treatment group, visit, eye (left or right) and baseline age group (as 
randomized) and baseline SER group (as randomized) as independent variables and treatment group by 
visit interaction term included. Degrees of freedom will be determined using the Kenward-Roger 
approximation. Random intercepts for subject and eye within subject will be included using unstructured 
covariance structures. 
 
proc mixed data=xxxx noitprint method=REML order=internal; 
class subjid trtpn(ref='0') avisit eye agegr1 sergr1; 
model VA= trtpn avisit eye agegrp1 sergrp1 trtpn*avisit /solution DDFM=KR; 
random int/type=un sub=subjid; 
random int/type=un subject=subjid(eye); 
estimate ‘0.02% vs. Pbo Month 36’ trtpn 0 1 -1 trtpn*avisitn 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1/ cl; 
 
Summary statistics and figure will be presented along with a full data listing by treatment group. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
Difference in the Proportion of Subjects’ Eyes who Show less than 0.5 D Myopia 
Progression (SER) From Baseline at the Month 36 visit 
A secondary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.01% versus Vehicle) difference in the proportion of subjects’ eyes who show less than 0.5 D 
myopia progression (SER) from baseline at the Month 36 visit. The analysis method will be the same as 
the primary efficacy analysis as described in 8.1.1 above, including sensitivity analyses using the updated 
statement: 
 
estimate ‘0.01% vs. Pbo Month 36’ trtpn 1 0 -1 trt01pn*avisitn 10 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 / cl ; 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
Difference in the Mean Change from Baseline in SER at the Month 36 Visit 
A secondary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.01% versus Vehicle) difference in the mean change from baseline in SER at the Month 36 
visits. The analysis method will be the same as the secondary efficacy analysis as described in 8.2.1 
above using the updated statement: 
 
estimate ‘0.01% vs. Pbo Month 36’ trtpn 1 0 -1 trt01pn*avisitn 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0/ cl; 
 
Summary statistics and figure will be presented along with a full data listing by treatment group. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 34 of 76 
 
 
 
 
Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
Difference in the Mean Change from Baseline in Axial Length at Month 36 
A secondary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.02% versus vehicle) difference in the mean change from baseline in axial length at the Month 
36 visit. The analysis method will be the same as the secondary efficacy analysis as described in 8.2.1 
above. 
 
Summary statistics will be presented along with a full data listing by treatment group. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% Versus Vehicle) 
Difference in Mean Change from Baseline in Axial Length at the Month 36 Visit 
A secondary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.1% versus vehicle) change from baseline in axial length at the Month 36 visit. The analysis 
method will be the same as the secondary efficacy analysis as described in 8.2.1 above using the 
updated statement: 
 
estimate ‘0.01% vs. Pbo Month 36’ trtpn 1 0 -1 trt01pn*avisitn 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0/ cl ; 
 
Summary statistics will be presented along with a full data listing by treatment group. 
 
 
Tertiary Efficacy Endpoint(s) and Analyses 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% Versus Vehicle) 
Difference in the Proportion of Subjects’ eyes who Show less than 0.5 D Myopia Progression 
(SER) From Baseline at the Month 24 and Month 12 visits 
A tertiary analysis will be performed on between-treatment group (Atropine Sulfate Ophthalmic Solution, 
0.02% Versus Vehicle) difference in the proportion of subjects’ eyes who show less than 0.5 D myopia 
progression (SER) from baseline at the Month 24 and Month 12 visits. The analysis method will be the 
same as the primary efficacy analysis as described in 8.1.1 above using the updated statements: 
 
estimate ‘0.02% vs. Pbo Month 12’ trtpn 0 1 -1 trtpn*avisitn 0 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0 0 0 
 
trt01pn*agegr1 0 0 0 1 0 -1; 
estimate ‘0.02% vs. Pbo Month 24’ trtpn 0 1 -1 trtpn*avisitn 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0; 
 
Summary statistics and figure will be presented along with a full data listing by treatment group. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
Difference in the Mean Change from Baseline in SER at the Month 24 and Month 12 Visits 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.02% versus vehicle) difference in the mean change from baseline in SER at the Month 24 and 
Month 12 visits. The analysis method will be the same as the secondary efficacy analysis as described in 
8.2.1 above using the updated statements: 
 
estimate ‘0.02% vs. Pbo Month 12’ trtpn 0 1 -1 trtpn*avisitn 0 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0 0 0; 
estimate ‘0.02% vs. Pbo Month 24’ trtpn 0 1 -1 trtpn*avisitn 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0; 
 
Summary statistics and figure will be presented along with a full data listing by treatment group. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 35 of 76 
 
 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
Difference in the Proportion of Subjects’ Eyes Who Show less than 0.5 D Myopia 
Progression (SER) from Baseline at the Month 24 and Month 12 Visits 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.01% versus vehicle) difference in the proportion of subjects’ eyes who show less than 0.5 D 
myopia progression (SER) from baseline at the 24 and Month 12 visits. The analysis method will be the 
same as the primary efficacy analysis as described in 8.1.1 above using the updated statements: 
 
estimate ‘0.01% vs. Pbo Month 12’ trtpn 1 0 -1 trtpn*avisitn 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0 0 ; 
estimate ‘0.01% vs. Pbo Month 24’ trtpn 1 0 -1 trtpn*avisitn 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 ; 
Summary statistics and figure will be presented along with a full data listing by treatment group. 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
Difference in the Mean Change from Baseline in SER at the Month 24 and Month 12 Visits 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.01%) difference in the mean change from baseline in SER at the Month 24 and Month 12 
visits. The analysis method will be the same as the secondary efficacy analysis as described in 8.2.1 
above using the updated statements: 
 
estimate ‘0.01% vs. Pbo Month 12’ trtpn 1 0 -1 trtpn*avisitn 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0 0; 
estimate ‘0.01% vs. Pbo Month 24’ trtpn 1 0 -1 trtpn*avisitn 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0; 
 
Summary statistics and figure will be presented along with a full data listing by treatment group. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
Difference in the Proportion of Subjects’ Eyes who Show less than 0.75 D Myopia 
Progression (SER) From Baseline at the Month 36 Visit 
A tertiary analysis will be performed on difference in the proportion of subjects’ eyes who show less than 
0.75 D myopia progression (SER) from baseline at the Month 36 visit. The analysis method will be the 
same as the primary efficacy analysis as described in 8.1.1 above. 
 
Summary statistics and figure will be presented along with a full data listing by treatment group. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
Difference in the Proportion of Subjects’ Eyes who Show less than0.75 D Myopia 
Progression (SER) From Baseline at the Month 36 Visit 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.01% versus vehicle) difference in the proportion of subjects’ eyes who show less than 0.75 D 
myopia progression (SER) from baseline at the Month 36 visit. The analysis method will be the same as 
the primary efficacy analysis as described in 8.1.1 above using the updated statement: 
 
estimate ‘0.01% vs. Pbo Month 36’ trtpn 1 0 -1 trtpn*avisitn 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0; 
 
Summary statistics will be presented along with a full data listing by treatment group. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 36 of 76 
 
 
 
 
Between-treatment group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
Difference in the Time to Change from Baseline in Myopia Progression of -0.75 D SER 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.02% versus vehicle) difference in the time to change from baseline in myopia progression of - 
0.75 D SER. 
 
The time to change in myopia progression of -0.75 D SER (days) = (first date with a change in myopia 
progression of -0.75 D or more – first date of treatment) +1. For subjects that were not observed to have a 
change in myopia progression of -0.75 D or more = Time to change in myopia progression of -0.75 D 
SER (days) [censored] = (Date of last known visit of Stage 1 – (first date of treatment) + 1. 
 
The point estimate of the hazard ratios and the associated 95% confidence intervals will be obtained 
using the Cox proportional hazards regression model with fixed effects for treatment group, age at 
baseline, and baseline SER as covariates. An approximate Chi-square test based on Wald statistic will be 
used to compare treatment groups. 
 
Summary statistics and associated survival curves (Kaplan-Meier estimates) will be presented along with 
a full data listing by treatment group. 
 
Summary statistics will be presented along with a full data listing by treatment group. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
Difference in Time to Change from Baseline in Myopia progression of -0.75 D SER 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.01% versus vehicle) difference in the time to change from baseline in myopia progression of - 
0.75 D SER. The analysis method will be the same as the tertiary efficacy analysis as described in 8.3.7 
above. 
 
Summary statistics will be presented along with a full data listing by treatment group. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle) 
Difference in the Number of New Prescriptions Given After the Start of Treatment Due to 
Progression through the Month 36 visit 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.02% versus vehicle) difference in the number of new prescriptions given after the start of 
treatment due to progression through the Month 36 visit. The analysis method will be performed using the 
Cochran-Mantel-Haenszel row mean scores (ANOVA) statistic using the statement. 
 
proc freq data=xxxx; 
tables Treatment*Prescriptions /cmh noprint; 
run; 
 
Summary statistics will be presented along with a full data listing by treatment group. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 37 of 76 
 
 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
Difference in the Number of New Prescriptions Given After the Start of Treatment Due to 
Progression through the Month 36 visit 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.01% versus vehicle) difference in number of new prescriptions given after the start of 
treatment due to progression through the Month 36 visit. The analysis method will be performed using the 
Cochran-Mantel-Haenszel row mean scores (ANOVA) statistic using the statement. 
 
proc freq data=xxxx; 
tables Treatment*Prescriptions /cmh noprint; 
run; 
 
Summary statistics will be presented along with a full data listing by treatment group. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% Versus Vehicle) 
Difference in the Proportion of Subjects who Progressed to High Myopia (SER -6.00 D or 
more myopic) at the Month 36 Visit 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.2% versus vehicle) difference in the proportion of subjects who progressed to high myopia 
(SER -6.00 D or more myopic) at the Month 36 visit. Progression to high myopia is defined as either of a 
subject’s eyes progressed to high myopia at any time during a visit window. The analysis method will be 
the same as the analysis as described in 8.3.12 below. Results will be presented as overall results and by 
baseline myopia stratification. 
 
Summary statistics will be presented along with a full data listing by treatment group. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) 
Difference in the Proportion of Subjects who Progressed to High Myopia (SER -6.00 D or 
more myopic) at the Month 36 Visit 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.1% versus vehicle) difference in the proportion of subjects who progressed to high myopia 
(SER -6.00 D or more myopic) at the Month 36 visit. Progression to high myopia is defined as either of a 
subject’s eyes progressed to high myopia at any time during a visit window. 
 
Results will be presented as results and by baseline myopia stratification. The overall analysis will be 
performed using a Mixed Model based on the binomial distribution using a logit link function. Progression 
as the dependent variable, subject, treatment, visit, and baseline age group (as randomized) and SER (as 
randomized) as independent variables, treatment by visit, treatment by SER (as randomized) and 
treatment by visit by SER (as randomized) interaction terms included. Random intercepts for subject will 
be included using variance components. The analysis will be performed using the mITT analysis set 
assuming data is missing at random. 
proc glimmix data=master empirical method=quad; 
class subjid trtpn(ref='0') avisitn agegr1 sergr1; 
model eff(event='1') = trtpn avsitn agegrp1 sergrp1 trtpn*avisitn trtpn*sergr1 trtpn*avisitn*sergr1 / 
dist=bin link=logit solution or; 
random intercept / subject=subjid type=vc; 
estimate ‘0.02% vs. Pbo Month 36’ trtpn 0 1 -1 trtpn*avisitn 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1; 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 38 of 76 
 
 
 
estimate ‘0.02% vs. Pbo Month 36 Low ’ trtpn 0 1 -1 trtpn*avisitn 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 
trtpn*avisitn*blmymop 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 -1 0; 
 
estimate ‘0.02% vs. Pbo Month 36 High ’ trtpn 0 1 -1 trtpn*avisitn 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 
trtpn*avisitn*blmymop 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 -1; 
 
 
 
Summary statistics will be presented along with a full data listing by treatment group. 
 
 
Interaction between Demographic Variables and SER 
Tertiary analyses will be performed on differences between select demographic variables (age 6 – 8 
years versus 9 – 10 years; baseline SER -0.50 to -3.00 D versus -3.01 to 6.00 D SER; Asian versus non- 
Asian; dark irides versus light irides, region (U.S. versus E.U.); female versus male) and change from 
baseline in SER at Month 12, Month 24, and Month 36. The analysis method will be the same as the 
primary or secondary efficacy analysis as described in 8.1.1 and 8.2.1 respectively above , except for the 
addition of the particular demographic variable being analyzed and an associated treatment interaction 
term. Testing of the difference in demographic variable and the demographic variable by treatment 
interaction term will be provided. The tertiary analysis will be performed using the mITT set only. 
 
For the purpose of analysis of irides, light irides will consist of Grade 1 – Grade 3 iris colors while dark 
irides consist of Grade 4 and Grade 5 iris colors. Similarly, for the analysis of race, Asian will be defined 
as Japanese, East Asian, and South Asian. Non-Asian races will consist of all other non-missing races. 
 
Summary statistics will be presented along with a full data listing by treatment group. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% Versus Vehicle) 
Difference in the Mean Change from Baseline in Crystalline Lens Thickness at the Month 36 
visit 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.02% versus vehicle) difference in the mean change from baseline in crystalline lens thickness 
at the Month 36 visit. The analysis method will be the same as the secondary efficacy analysis as 
described in 8.2.1 above. The tertiary analysis will be performed using the mITT and ITT sets. 
 
Summary statistics will be presented along with a full data listing by treatment group. 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.01% Versus Vehicle) 
Difference in the Mean Change from Baseline in Crystalline Lens Thickness at the Month 36 
visit 
A tertiary analysis will be performed on the between-treatment group (Atropine Sulfate Ophthalmic 
Solution, 0.01% versus vehicle) difference in the mean change from baseline in crystalline lens thickness 
at the Month 36 visit. The analysis method will be the same as the secondary efficacy analysis as 
described in 8.2.1 above. The tertiary analysis will be performed using the mITT and ITT sets. 
 
Summary statistics will be presented along with a full data listing by treatment group. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 39 of 76 
 
 
 
 
Rebound Assessment Based on the Change from Stage 2 Baseline (Month 36) at Months 42 
and 48 
The change from baseline from Stage 2 baseline (Month 36) to the Moth 42 and Month 48 visits will be 
summarized using descriptive statistics. Summaries will be provided for active treatment Stage 1 subjects 
who received the same or lower dose, including placebo, Summaries will be provided for Stage 1 and 
Stage 2 treatment combinations listed: 
 
• 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Atropine Sulfate Ophthalmic Solution, 0.02% 
• 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Atropine Sulfate Ophthalmic Solution, 0.01% 
• 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Vehicle 
• 
Atropine Sulfate Ophthalmic Solution, 0.01% -> Atropine Sulfate Ophthalmic Solution, 0.01% 
• 
Atropine Sulfate Ophthalmic Solution, 0.01% -> Vehicle 
 
 
Rebound Assessment Based on the Responders at Months 42 and 48 
For subject on active treatment who were responders (subjects’ eyes who show less than 0.5 D myopia 
progression (SER) from baseline at the Month 36 visit) in Stage 1, their progression from Stage 1 
baseline at Month 42 and Month 48 will by summarize using count and percentage. 
 
Summaries will be provided for Stage 1 and Stage 2 treatment combinations listed: 
 
• 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Atropine Sulfate Ophthalmic Solution, 0.02% 
• 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Atropine Sulfate Ophthalmic Solution, 0.01% 
• 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Vehicle 
• 
Atropine Sulfate Ophthalmic Solution, 0.01% -> Atropine Sulfate Ophthalmic Solution, 0.01% 
• 
Atropine Sulfate Ophthalmic Solution, 0.01% -> Vehicle 
 
 
 
 
Exploratory Efficacy Analyses 
For all Stage 2 exploratory analyses, summary statistics will be provided based on the Stage 1 to Stage 2 
treatment description. Analyses table will only include the groups presented in the analyses. The eight 
treatment groups for these tables will include: 
 
• 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Atropine Sulfate Ophthalmic Solution, 0.02% 
• 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Atropine Sulfate Ophthalmic Solution, 0.01% 
• 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Vehicle 
• 
Atropine Sulfate Ophthalmic Solution, 0.01% -> Atropine Sulfate Ophthalmic Solution, 0.02% 
• 
Atropine Sulfate Ophthalmic Solution, 0.01% -> Atropine Sulfate Ophthalmic Solution, 0.01% 
• 
Atropine Sulfate Ophthalmic Solution, 0.01% -> Vehicle 
• 
Vehicle -> Atropine Sulfate Ophthalmic Solution, 0.02% 
• 
Vehicle -> Atropine Sulfate Ophthalmic Solution, 0.01% 
 
 
Between-treatment Group (Atropine Sulfate Ophthalmic Solution, 0.02% versus Vehicle and 
Atropine Sulfate Ophthalmic Solution, 0.01% versus Vehicle) Difference in the Proportion of 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 40 of 76 
 
 
 
Subjects’ Eyes with Higher Myopia (SER <= -3.00) who Show less than 0.75 D Myopia 
Progression (SER) From Baseline at the Month 36 Visit 
An exploratory analysis will be performed on difference in the proportion of subjects’ eyes who show 
less than 0.75 D myopia progression (SER) from baseline at the Month 36 visit. The analysis method will 
be the same as the primary efficacy analysis as described in 8.1.1 above. 
 
Summary statistics will be presented by treatment group. 
 
 
Between-treatment Group Difference in the Mean Change from Study Baseline in SER at the 
Month 48 Visit. 
The analysis will be performed using the same methods as in 8.2.1 above. Only the four indicated arms 
being test will be included in the analysis model. The analysis will be performed using the mITT analysis 
set. The following treatment comparisons will be made: 
 
• 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Atropine Sulfate Ophthalmic Solution, 0.02% vs. 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Vehicle 
• 
Atropine Sulfate Ophthalmic Solution, 0.01% -> Atropine Sulfate Ophthalmic Solution, 0.01% vs. 
Atropine Sulfate Ophthalmic Solution, 0.01% -> Vehicle 
 
Summary statistics and figure will be presented along with a full data listing for all treatment groups. 
 
 
Between-treatment Group Difference in the Mean Change from Stage 2 Baseline (Month 36) 
in SER at the Month 48 Visit. 
The analysis will be performed using the same methods as in 8.2.1 above. 
 
Only the four indicated arms being test will be included in the analysis model. The analysis will be 
performed using the mITT analysis set. The following treatment comparisons will be made: 
 
• 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Atropine Sulfate Ophthalmic Solution, 0.02% vs. 
Atropine Sulfate Ophthalmic Solution, 0.02% -> Vehicle 
• 
Atropine Sulfate Ophthalmic Solution, 0.01% -> Atropine Sulfate Ophthalmic Solution, 0.01% vs. 
Atropine Sulfate Ophthalmic Solution, 0.01% -> Vehicle 
 
Summary statistics and figure will be presented along with a full data listing for all treatment groups. 
 
 
Other Stage 2 Exploratory Endpoints 
For endpoints described in Sections 8.3.1 through 8.3.15, Summary statistics and listings will be provided 
for Stage 2 using the treatment groups described in 8.4 above. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
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Filing requirements: TMF 
Page 41 of 76 
 
 
 
Safety 
 
The population used for safety analyses will be the Safety Set (SS). Safety will be assessed on the basis 
of ophthalmic safety assessments (BCVA, photopic pupil size, slit-lamp examination (SLE), dilated fundus 
examination, and tonometry), HR, and adverse events (AE). Safety Tables will be provided separately for 
each stage of the study. 
 
 
Extent of Exposure 
Duration of exposure will be summarized using descriptive statistics by treatment group for each stage. 
The duration of exposure will also be categorized (<6, 6-<12, 12-<18, 18-<24, 24-<30, 30-<36, ≥36 
months for Stage 1; <3, 3-<6, 6-<9, 9-<12, ≥12 months for Stage 2), and tabulated by treatment group. 
Duration of exposure (months) will be calculated as ((Date of Last Dose – Date of First Dose) 
+1)/30.4375). If date of last dose is unknown, then the date of last clinical visit will be used. 
 
 
Treatment Compliance 
Subjects are expected to take 1 drop of study medication per eye, once per day. 
 
Treatment compliance for Stage 1, as a percentage, will be calculated as compliance (%) = (number of 
ampules used as determined in Interactive Response Technology) / ((Date of Last Dose of Stage 1 – 
Date of First Dose of Stage 1) +1)) x 100. The number of actual doses withheld will be recorded in the 
eCRF. 
 
Starting on the day of the Month 36 visit, subjects were switch to an electronic dosing diary. Each eye’s 
dosing is collected independently, based on whether eye drops were applied or not for each eye. Any 
missing dosing information between Month 36 visit and last reported dose will be considered as missed 
dose(s). Treatment compliance for Stage 2, as a percentage, will be calculated as compliance (%) = (sum 
of number of reported doses / ((Date of Last Dose of Stage 2 – Date of First Dose of Stage 2) + 1) ) x 
100. 
 
Subjects will be considered compliant overall for study medication if the compliance is ≥80%. Descriptive 
statistics (number of subjects, mean, SD, minimum, median, and maximum) for number of ampules used 
(Stage 1), number of doses received (Stage 2) and treatment compliance will be summarized by 
treatment group for Safety Set by actual treatment and stage and for the ITT Set, the mITT Set, the PPS, 
and the mPPS by randomized treatment for each stage. 
 
Given the duration a subject is enrolled in the study, it is possible for the subject to begin self-dosing 
instead of parental dosing. All subjects will be asked if this occurred and when the change occurred. The 
number and percentage of subject switching to self-dosing during the course of the study will be 
summarized by Stage 1 treatment group and overall. 
 
 
Adverse Events 
The analysis of AEs will be based on the concept of treatment-emergent AEs (TEAEs). An adverse event 
is any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug-related. 
 
Treatment-emergent adverse events (TEAEs) of Stage 1 are defined as any new or worsening of existing 
adverse events that occur or worsen between start (or increase in intensity on or after the first dose date 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
SAP Version: 3.0 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 42 of 76 
 
 
 
of Stage 1 treatment on day 1) and the last dose date of Stage 1. TEAEs of Stage 2 are defined as any 
AE that occurs or worsens between the first dose date of Stage 2 and the last dose date of Stage 2. 
 
The first dose date for Stage 1 is defined as the first dose of study medication received after 
randomization in Stage 1. The first dose date for Stage 2 is defined as the first dose of study medication 
received after the Stage 1 last dose date and subject is re-randomized. All adverse events (AEs) will be 
coded using the MedDRA version 20.1 or higher. The following listings of AEs will be provided by Stage 
and subjects: 
 
• 
All AEs, 
• 
Serious adverse events (SAEs) Serious ocular and non-ocular AEs, respectively 
• 
All deaths 
• 
TEAEs (overall, ocular, non-ocular, respectively) leading to study withdrawal 
• 
TEAEs (overall, ocular, non-ocular, respectively) leading to study drug discontinuation 
• 
Severe AEs 
• 
Study drug related AEs 
• 
Study drug related SAEs 
 
Treatment-emergent adverse events will be included in summary tables by treatment received for each 
stage. Ocular TEAEs will be summarized separately from all other TEAEs. An overall summary table of 
TEAEs for each stage will be produced for the following categories: 
 
• 
Any Ocular TEAE 
• 
Severe Ocular TEAEs 
• 
Study drug-related Ocular TEAEs 
• 
Serious Ocular TEAEs 
• 
Study drug-related Serious Ocular TEAEs 
• 
Ocular TEAEs leading to study discontinuation 
• 
Ocular TEAEs leading to death 
• 
Any Non-Ocular TEAE 
• 
Severe Non-Ocular TEAEs 
• 
Study drug-related Non-Ocular TEAEs 
• 
Serious Non-Ocular TEAEs 
• 
Study drug-related Serious Non-Ocular TEAEs 
• 
Non-Ocular TEAEs leading to study discontinuation 
• 
Non-Ocular TEAEs leading to death 
 
All TEAEs will be classified by System Organ Class (SOC) and Preferred Term (PT). Frequency count of 
TEAEs, the number of unique subjects experiencing a TEAE, percentage of unique subjects experiencing 
a TEAE, and total number of events will be tabulated by treatment and Stage for ocular and other TEAEs 
separately. For the number of unique subjects reporting, if a subject reported more than one TEAE that 
was coded to the same SOC or PT, the subject will be counted only once for that specific SOC or PT. 
 
The following summaries of TEAEs will also be provided: 
 
• 
TEAEs by SOC and PT 
• 
Ocular TEAEs by SOC and PT 
• 
Non-Ocular TEAEs by SOC and PT 


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• 
TEAEs by SOC, PT, and maximum severity 
• 
Ocular TEAEs by SOC, PT, and maximum severity 
• 
Non-Ocular TEAEs by SOC, PT, and maximum severity 
• 
TEAEs by SOC, PT, and maximum relationship 
• 
Ocular TEAEs by SOC, PT, and maximum relationship 
• 
Non-Ocular TEAEs by SOC, PT, and maximum relationship 
• 
Treatment-related TEAEs by SOC and PT 
• 
Ocular Treatment-related TEAEs by SOC and PT 
• 
Non-Ocular Treatment-related TEAEs by SOC and PT 
• 
Serious TEAEs by SOC and PT 
• 
Serious Ocular TEAEs by SOC and PT 
• 
Serious Non-Ocular TEAEs by SOC and PT 
• 
Serious treatment-related TEAEs by SOC and PT 
• 
Serious Ocular treatment-related TEAEs by SOC and PT 
• 
Serious Non-Ocular treatment-related TEAEs by SOC and PT 
• 
TEAEs leading to study withdrawal by SOC and PT 
• 
Ocular TEAEs leading to study withdrawal by SOC and PT 
• 
Non-Ocular TEAEs leading to study withdrawal by SOC and PT 
• 
TEAEs leading to study drug discontinuation by SOC and PT 
• 
Ocular TEAEs leading to study drug discontinuation by SOC and PT 
• 
Non-Ocular TEAEs leading to study drug discontinuation by SOC and PT 
• 
TEAEs leading to death by SOC and PT 
• 
Ocular TEAEs leading to death by SOC and PT 
• 
Non-Ocular TEAEs leading to death by SOC and PT 
• 
TEAEs associated with antimuscarinic function 
• 
Ocular TEAEs associated with antimuscarinic function 
• 
Non-Ocular TEAEs associated with antimuscarinic function 
• 
TEAEs by SOC, PT and Sex 
• 
Ocular TEAEs by SOC, PT and Sex 
• 
Non-Ocular TEAEs by SOC, PT and Sex 
• 
TEAEs by SOC, PT and Race 
• 
Ocular TEAEs by SOC, PT and Race 
• 
Non-Ocular TEAEs by SOC, PT and Race 
• 
TEAEs by SOC, PT and Age 
• 
Ocular TEAEs by SOC, PT and Age 
• 
Non-Ocular TEAEs by SOC, PT and Age 
 
For TEAEs presented by relationship to study treatment, the strongest relationship to study treatment(s) 
during the clinical trial will be presented for each subject if coded to the same SOC or PT. For TEAEs 
presented by severity, the worst severity during the clinical trial will be presented for each subject if coded 
to the same SOC or PT. If either relationship or severity is missing, then the strongest relationship 
(related) or worst severity (life-threatening) will be assigned. Adverse Events associated with 
antimuscarinic function are defined in Table 3. 


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Table 3: Adverse Events Associated with Antimuscarinic Function 
Classification 
Preferred Term 
Ophthalmic 
Photophobia 
Dyschromatopsia 
Night blindness 
Angle closure glaucoma 
Lacrimation decreased 
Non-Ophthalmic 
Blood pressure increased 
Heart rate increased 
Dry skin 
Dry mouth 
Dry throat 
Restlessness 
Irritability 
Delirium 
Flushing 
Seizure 
Epilepsy 
Urinary retention 
Obstruction gastric 
Bronchial secretion retention 
Arrhythmia 
 
 
 
Heart Rate, Weight, and Height 
Heart rate is collected at Baseline and the Month 6, 12, 18, 24, 30, 36, 42, and 48 visits. Weight and 
height are collected at Baseline and the Month 12, 24, 36, and 48 visits. 
Observed values at each visit and changes from study Baseline to each post-baseline visit will be 
summarized by stage, visit and treatment group using descriptive statistics. 
 
Heart rate will be provided in subject data listings. 
 
 
Monocular Best-Corrected Visual Acuity (BCVA) 
Monocular Best-Corrected Visual Acuity (BCVA) is performed at Baseline and the Month 6, 12, 18, 24, 
30, 36, 42, and 48 visits. BCVA will be provided as LogMar BCVA for both distance and near for each 
eye. 
Observed values at each visit and changes from Baseline to each post-baseline visit will be summarized 
by stage, visit and treatment group using descriptive statistics. For Stage 2, the Stage 2 baseline (Month 
36) will be used for the change from baseline calculation. Changes that warranted a new prescription will 
also be identified. 
 
Monocular Best-Corrected Visual Acuity will be provided in subject data listings. 
 
 
Photopic Pupil Size 
Photopic pupil size (mm) is collected at Baseline and the Month 6, 12, 18, 24, 30, 36, 42, and 48 visits. 
Photopic pupil size will be provided for each eye individually. 


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Observed values at each visit and changes from Baseline to each post-baseline visit will be summarized 
by stage, visit and treatment group using descriptive statistics. For Stage 2, the Stage 2 baseline (Month 
36) will be used for the change from baseline calculation. 
 
Photopic pupil size will be provided in subject data listings. 
 
 
Slit Lamp Examination 
A slit lamp exam is performed at Baseline and the Month 6, 12, 18, 24, 30, 36, 42, and 48 visits. 
Assessments of conjunctiva, cornea, anterior chamber, iris, lens, and lids will be provided for each eye 
individually. 
 
Findings at each visit will be summarized by stage, visit and treatment group using descriptive statistics. 
Slit lamp exam results will be provided in subject data listings. 
 
Dilated Fundus Examination 
A dilated fundus examination is performed at Baseline and the Month 12, 24, 36, and 48 visits. 
Assessments of optic nerve head, macula, peripheral retina, iris, and vitreous will be provided for each 
eye individually. 
 
Findings at each visit will be summarized by stage, visit and treatment group using descriptive statistics. 
Dilated fundus examination results will be provided in subject data listings. 
 
Intraocular Pressure 
Intraocular pressure (mmHg) is measured at Baseline and the Month 6, 12, 18, 24, 30, 36, 42, and 48 
visits. Measurement of intraocular pressure will be provided for each eye individually. 
 
Observed values at each visit and changes from Baseline to each post-baseline visit will be summarized 
by stage, visit and treatment group using descriptive statistics. For Stage 2, the Stage 2 baseline (Month 
36) will be used for the change from baseline calculation. 
 
Intraocular pressure measurements will be provided in subject data listings. 


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Quality of Life 
 
 
Modified Amblyopia Treatment Index (mATI) 
The Amblyopia Treatment Index (ATI) was developed by the Pediatric Eye Disease Investigator Group to 
measure the impact or burden of amblyopia treatment on the child and the family. The Modified 
Amblyopia Treatment Index (mATI) consists of 2 questionnaires. One is completed by a Parent/ Guardian 
while the second is completed by the subject at the Month 42 and Month 48 visits. The questionnaires 
consist of 16 or 15 questions respectively using a five-point Likert scale for each question. 
 
The questionnaires will be scored to an Overall Score and 3 subscales (Adverse Event, Treatment 
Compliance, and Social Stigma). Questionnaires with 3 or more missing or not applicable responses will 
not be scored or analyzed. For questionnaires with 1 or 2 missing or not applicable responses, these 
responses will be imputed with the average score for all completed items. See Table 4: Modified 
Amblyopia Treatment Index Scoring for scoring methodology. 
Table 4: Modified Amblyopia Treatment Index Scoring 
Score 
Parent 
Child 
Overall 
Mean of (Items 1*, 2, 3, 4, 5, 6, 
7, 8, 9*, 10, 11, 12, 13, 14*, 15, 
16) 
Mean of (Items 1, 2, 3, 4, 5, 6, 7, 
8*, 9, 10, 11, 12, 13*, 14, 15) 
Adverse effect subscale 
Mean of (Items 2, 3, 4, 7, 8, 9*, 
13, 15) 
Mean of (Items 2, 3, 4, 86, 97, 
8*, 12, 14) 
Treatment compliance subscale 
Mean of (Items 1*, 5, 6, 10, 12) 
Mean of (Items 1, 5, 9, 11) 
Social stigma subscale 
Item 11 
Item 10 
*Reverse scoring applied. Value used in scoring = (6- reported score) 
 
Overall and subscale scores for mATI will be summarized by visit and Stage 2 treatment group using 
descriptive statistics as both a continuous and categorical variable. Individual item and all scores will be 
listed. 


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Interim Analyses 
 
In order to determine the efficacy of Atropine Sulfate Ophthalmic Solution in progression of childhood 
myopia, an analysis will be performed after all subjects complete or withdraw from Stage 1. At that time, 
on Stage 1 treatment assignments will be unblinded and no analyses or summaries will be provided for 
Stage 2 results. All study personnel, not including Investigators, site staff, and clinical research associates 
(CRAs), may be unblinded for Stage 1 at this time. 
 
All analyses will be performed as documented in the SAP. No decisions regarding the study or changes in 
the study are to be made at that time. 


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Changes from Analysis Planned in Protocol 
 
Not all sites used the same Vertex distance (VD) in mm when measuring refraction with autorefractor. All 
averaged SER from each participant used in tables and analyses will be normalized to a VD of 0 mm to 
the corneal plane. The normalization will be applied using 
 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 = 
100 
100 
𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 
 
 
where SER is the original SER from CRF. 
೦𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆೦ − ೦ 10 ೦ 


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Programming Considerations 
 
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS for Windows, 
Release 9.4 (SAS Institute Inc., Cary, NC, USA). Computer-generated table, listing and figure output will 
adhere to the following specifications. 
 
 
General Considerations. 
• 
One SAS program can create several outputs, or a separate SAS program will be created for each 
output. 
 
• 
Each output will be stored in a separate file. 
 
• 
Output files will be delivered in Word format or portable document format pdf. 
 
• 
Numbering of TFLs will follow ICH E3 guidance 
 
 
Table, Listing, and Figure Format 
 
General 
• 
All TFLs will be produced in landscape format on American letter size, unless otherwise specified. 
 
• All TFLs will be produced using the Courier New font, size 8 which is the smallest acceptable point 
size for the Regulatory Authorities. 
 
• The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides. 
 
• Headers and footers for figures will be in Courier New font, size 8 which is the smallest acceptable 
point size for the Regulatory Authorities. 
 
• Legends will be used for all figures with more than 1 variable, group, or item displayed. 
 
• TFLs will be in black and white (no color), unless otherwise specified 
 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
 
• Only standard keyboard characters will be used in the TFLs. Special characters, such as non- 
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
 
 
Headers 
• All output should have the following header at the top left of each page: 
 
• 
Vyluma, Inc. Protocol CP-NVK002-0001 (Syneos Health study number 1) 


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• Draft/Final Run <date> 
 
• All output should have Page n of N at the top or bottom right corner of each page. TFLs are 
internally paginated in relation to the total length (i.e., the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
 
• The date output was generated should appear along with the program name as a footer on each 
page. 
 
 
Display Titles 
• Each TFL are identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering is 
strongly recommended, but sponsor preferences are obtained before final determination. A decimal 
system (x.y and x.y.z) are used to identify TFLs with related contents. The title is centered. The 
analysis set are identified on the line immediately following the title. The title and table designation 
are single-spaced. A solid line spanning the margins will separate the display titles from the 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(ITT Analysis Set) 
 
 
 
Column Headers 
• Column headings are displayed immediately below the solid line described above in initial upper- 
case characters. 
 
• In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the treatment group columns and total column (if applicable). P-values may be presented under 
the total column or in separate p-value column (if applicable). Within-treatment comparisons may 
have p-values presented in a row beneath the summary statistics for that treatment. 
 
• For numeric variables, include “unit” in column or row heading when appropriate. 
 
• Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set. 
 
• 
The order of treatment groups in the tables and listings will be Placebo first then Atropine Sulfate 
Ophthalmic Solution, 0.01%, and Atropine Sulfate Ophthalmic Solution, 0.02% followed by a total 
column (if applicable). 
 
 
Body of the Data Display 
13.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
 
• Alphanumeric values are left-justified; 
 
• Whole numbers (e.g., counts) are right-justified; and 


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• Numbers containing fractional portions are decimal aligned. 
 
13.2.5.2. 
Table Conventions 
• Units will be included where available 
 
• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 for all treatment groups in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
 
• If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 subject represented in 1 or 
more groups are included. 
 
• An Unknown or Missing category are added to each parameter for which information is not 
available for 1 or more subjects. 
 
• Unless otherwise specified, the estimated mean and median for a set of values are printed out to 1 
more significant digit than the original values, and standard deviations are printed out to 2 more 
significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
 
N 
XX 
Mean 
XXX.X 
Std Dev 
X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
 
• P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
Every p-value less than 0.001 will be presented as <0.001. If the p-value are less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999 
 
• Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down 
to 0.0. A common convention is to display as '<0.1', or as appropriate with additional decimal 
places. Unless otherwise noted, for all percentages, the number of subjects in the analysis set for 
the treatment group who have an observation will be the denominator. Percentages after zero 


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counts should not be displayed and percentages equating to 100% are presented as 100%, without 
decimal places. 
 
• Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data are presented by the body system, treatment class, or SOC with the highest 
occurrence in the active treatment group in decreasing order, assuming all terms are coded. Within 
the body system, drug class and SOC, medical history (by preferred term), drugs (by ATC1 code), 
and adverse events (by preferred term) are displayed in decreasing order. If incidence for more 
than 1 term is identical, they should then be sorted alphabetically. Missing descriptive statistics or 
p-values which cannot be estimated are reported as “-”. 
• The percentage of subjects is normally calculated as a proportion of the number of subjects 
assessed in the relevant treatment group (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Describe details of this in 
footnotes or programming notes. 
 
• For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, describe in a footnote or programming note if the subject is included in 
the summary statistics for all relevant categories or just 1 category and the criteria for selecting the 
criteria. 
 
• Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont)” at the top of each subsequent page. The 
overall summary statistics for the subheading should only be output on the first relevant page. 
 
13.2.5.3. 
Listing Conventions 
• Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
 
• Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates are 
represented on subject listings as dashes (--JUL2000). Dates that are missing because they are 
not applicable for the subject are output as “N/A”, unless otherwise specified. 
 
• All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
 
• Units will be included where available 
 
13.2.5.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 


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Footnotes 
• A solid line spanning the margins will separate the body of the data display from the footnotes. 
 
• All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
 
• Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line, where possible. 
 
• Subject specific footnotes are avoided, where possible. 
 
• Footnotes will be used sparingly and add value to the table, figure, or listing. If more than six lines 
of footnotes are planned, then a cover page is strongly recommended to be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each page. 
 
• Analysis population definition will be provided in the footnote of each table. 
 
• The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (i.e., 
‘Program : myprogram.sas 
Listing source: 16.x.y.z’). 


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Quality Control 
 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures, or statistical analyses. An overview of the development of programs is detailed in Syneos Health 
SOP Developing Statistical Programs (3907). 
 
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS programs and 
output. Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS programs produce the output by checking for their logic, efficiency and commenting and by review 
of the produced output.” 


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References 
 
Fannin TE, Grosvenor T. Clinical Optics. 1st edition. Butterworth-Heinemann. 1987. 
Equation 3.16, page 71. 


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Index of Tables 
 
Header 
Table Number 
Name 
Analysis Set 
14. 
Tables, Figures, and Graphs Referred to 
but not Included in the Text 
14.1 
Demographic Data Summary Tables 
14.1.1 
Subject Disposition 
14.1.1.1.1 
Number of Subjects Enrolled and Study 
Termination – Stage 1 
Stage 1 Enrolled 
Set 
14.1.1.1.2 
Number of Subjects Enrolled and Study 
Termination – Stage 2 
Stage 2 Enrolled 
Set 
14.1.2 
Protocol Deviations 
14.1.2.1 
Major Protocol Deviations 
Intent-to-Treat Set 
14.1.3 
Demographic and Baseline Characteristics 
14.1.3.1 
Subject Demographic and Baseline 
Characteristics 
14.1.3.1.1.1 
Subject Demographic and Baseline 
Characteristics – Stage 1 Subjects 
Stage 1 Safety Set 
14.1.3.1.1.2 
Subject Demographic and Baseline 
Characteristics – Stage 2 Subjects 
Stage 2 Safety Set 
14.1.3.1.2.1 
Subject Demographic and Baseline 
Characteristics – Stage 1 Subjects 
Stage 1 Intent-to- 
Treat Set 
14.1.3.1.2.2 
Subject Demographic and Baseline 
Characteristics – Stage 2 Subjects 
Stage 2 Intent-to- 
Treat Set 
14.1.3.1.3.1 
Subject Demographic and Baseline 
Characteristics – Stage 1 Subjects 
Stage 1 Modified 
Intent-to-Treat Set 
14.1.3.1.3.2 
Subject Demographic and Baseline 
Characteristics – Stage 2 Subjects 
Stage 2 Modified 
Intent-to-Treat Set 
14.1.3.1.4.1 
Subject Demographic and Baseline 
Characteristics – Stage 1 Subjects 
Stage 1 Per 
Protocol Set 
14.1.3.1.4.2 
Subject Demographic and Baseline 
Characteristics – Stage 2 Subjects 
Stage 2 Per 
Protocol Set 
14.1.3.1.5.1 
Subject Demographic and Baseline 
Characteristics – Stage 1 Subjects 
Stage 1 Modified 
Per Protocol Set 
14.1.3.1.5.2 
Subject Demographic and Baseline 
Characteristics – Stage 2 Subjects 
Stage 2 Modified 
Per Protocol Set 
14.1.3.2 
Baseline Disease Characteristics 
14.1.3.2.1.1 
Baseline Disease Characteristics – Stage 1 
Subjects 
Stage 1 Safety Set 
14.1.3.2.1.2 
Baseline Disease Characteristics – Stage 2 
Subjects 
Stage 2 Safety Set 
14.1.3.2.2.1 
Baseline Disease Characteristics – Stage 1 
Subjects 
Stage 1 Intent-to- 
Treat Set 
14.1.3.2.2.2 
Baseline Disease Characteristics – Stage 2 
Subjects 
Stage 2 Intent-to- 
Treat Set 
14.1.3.2.3.1 
Baseline Disease Characteristics – Stage 1 
Subjects 
Stage 1 Modified 
Intent-to-Treat Set 
14.1.3.2.3.2 
Baseline Disease Characteristics – Stage 2 
Subjects 
Stage 2 Modified 
Intent-to-Treat Set 
14.1.3.2.4.1 
Baseline Disease Characteristics – Stage 1 
Subjects 
Stage 1 Per 
Protocol Set 


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Header 
Table Number 
Name 
Analysis Set 
14.1.3.2.4.2 
Baseline Disease Characteristics – Stage 2 
Subjects 
Stage 2 Per 
Protocol Set 
14.1.3.2.5.1 
Baseline Disease Characteristics – Stage 1 
Subjects 
Stage 1 Modified 
Per Protocol Set 
14.1.3.2.5.2 
Baseline Disease Characteristics – Stage 2 
Subjects 
Stage 2 Modified 
Per Protocol Set 
14.1.3.3 
Medical History 
14.1.3.3.1 
Ocular Medical History by System Organ 
Class and Preferred Term 
Safety Set 
14.1.3.3.2 
Medical History by System Organ Class 
and Preferred Term 
Safety Set 
14.1.4 
Medications 
14.1.4.1 
Prior Medications 
Safety Set 
14.1.4.2.1 
Concomitant Medications – Stage 1 
Stage 1 Safety Set 
14.1.4.2.2 
Concomitant Medications – Stage 2 
Stage 2 Safety Set 
14.1.5.1 
Treatment Compliance 
14.1.5.1.1.1 
Treatment Compliance – Stage 1 
Stage 1 Safety Set 
14.1.5.1.1.2 
Treatment Compliance – Stage 2 
Stage 2 Safety Set 
14.1.5.1.2.1 
Treatment Compliance – Stage 1 
Stage 1 Intent-to- 
Treat Set 
14.1.5.1.2.2 
Treatment Compliance – Stage 2 
Stage 2 Intent-to- 
Treat Set 
14.1.5.1.3.1 
Treatment Compliance – Stage 1 
Stage 1 Modified 
Intent-to-Treat Set 
14.1.5.1.3.2 
Treatment Compliance – Stage 2 
Stage 2 Modified 
Intent-to-Treat Set 
14.1.5.1.4.1 
Treatment Compliance – Stage 1 
Stage 1 Per 
Protocol Set 
14.1.5.1.4.2 
Treatment Compliance – Stage 2 
Stage 2 Per 
Protocol Set 
14.1.5.1.5.1 
Treatment Compliance – Stage 1 
Stage 1 Modified 
Per Protocol Set 
14.1.5.1.5.2 
Treatment Compliance – Stage 2 
Stage 2 Modified 
Per Protocol Set 
14.1.5.2 
Extent of Exposure 
14.1.5.2.1.1 
Extent of Exposure – Stage 1 
Stage 1 Safety Set 
14.1.5.2.1.2 
Extent of Exposure – Stage 2 
Stage 2 Safety Set 
14.1.5.2.2.1 
Extent of Exposure – Stage 1 
Stage 1 Intent-to- 
Treat Set 
14.1.5.2.2.2 
Extent of Exposure – Stage 2 
Stage 2 Intent-to- 
Treat Set 
14.1.5.2.3.1 
Extent of Exposure – Stage 1 
Stage 1 Modified 
Intent-to-Treat Set 
14.1.5.2.3.2 
Extent of Exposure – Stage 2 
Stage 2 Modified 
Intent-to-Treat Set 
14.1.5.2.4.1 
Extent of Exposure – Stage 1 
Stage 1 Per 
Protocol Set 
14.1.5.2.4.2 
Extent of Exposure - Stage 2 
Stage 2 Per 
Protocol Set 
14.1.5.2.5.1 
Extent of Exposure – Stage 1 
Stage 1 Modified 
Per Protocol Set 


Statistical Analysis Plan for Interventional Studies 
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Header 
Table Number 
Name 
Analysis Set 
14.1.5.2.5.2 
Extent of Exposure - Stage 2 
Stage 2 Modified 
Per Protocol Set 
14.2 
Efficacy Data Summary Figures and Tables 
14.2.1 
Proportion of Subjects’ Eyes who Show 
less than 0.5 D Myopia Progression 
(Normalized SER) from Baseline 
14.2.1.1.1 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
Mixed Effects Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.1.2.1 
Analysis of the Composite Proportion of 
Subjects who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
Supportive Analysis 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.1.2.2 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
Sensitivity Analysis 
Stage 1 Intent-to- 
Treat Set 
14.2.1.2.4 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
Sensitivity Analysis 
Stage 1 Modified 
Per Protocol Set 
14.2.1.2.6 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
Sensitivity Analysis 
Stage 1 Per 
Protocol Set 
14.2.1.3 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 
Tipping Point Analysis 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.1.4.1 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
On-Treatment Analysis 
Stage 1 Modified 
Intent-to-Treat Set 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
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Page 59 of 76 
 
 
 
Header 
Table Number 
Name 
Analysis Set 
14.2.1.4.2 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
On-Treatment Analysis 
Stage 1 Intent-to- 
Treat Set 
14.2.1.5.1 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(6-8 years old vs. 9-10 years old) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.1.5.2 
Summary of the Proportion of Subjects’ 
Eyes who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(6-8 years old vs. 9-10 years old) 
Stage 1 Intent-to- 
Treat Set 
14.2.1.6.1 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(Baseline SER -0.50 to -3.00 D 
versus -3.01 to -6.00 D) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.1.6.2 
Summary of the Proportion of Subjects’ 
Eyes who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(Baseline SER -0.50 to -3.00 D 
versus -3.01 to -6.00 D) 
Stage 1 Intent-to- 
Treat Set 
14.2.1.7.1 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(Asian vs. Non-Asian) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.1.7.2 
Summary of the Proportion of Subjects’ 
Eyes who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(Asian vs. Non-Asian) 
Stage 1 Intent-to- 
Treat Set 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
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Filing requirements: TMF 
Page 60 of 76 
 
 
 
Header 
Table Number 
Name 
Analysis Set 
14.2.1.8.1 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(Dark Irides vs. Light Irides) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.1.8.2 
Summary of the Proportion of Subjects’ 
Eyes who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(Dark Irides vs. Light Irides) 
Stage 1 Intent-to- 
Treat Set 
14.2.1.9.1 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(U.S. vs, E.U.) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.1.9.2 
Summary of the Proportion of Subjects’ 
Eyes who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(U.S. vs, E.U.) 
Stage 1 Intent-to- 
Treat Set 
14.2.1.10.1 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(Female vs. Male.) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.1.10.2 
Summary of the Proportion of Subjects’ 
Eyes who Show less than 0.5 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
(Female vs. Male) 
Stage 1 Intent-to- 
Treat Set 
14.2.2 
Secondary Efficacy Parameters 
14.2.2.1 
Change from Baseline in Normalized SER 
14.2.2.1.1 
Analysis of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.2.1.4 
Analysis of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
Mixed Effect Model 
Stage 1 Intent-to- 
Treat Set 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
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Header 
Table Number 
Name 
Analysis Set 
14.2.2.1.7 
Summary of the Change from Study 
Baseline in Normalized SER (D) by Stage, 
Treatment Group and Visit 
Modified Intent-to- 
Treat Set 
14.2.2.1.8 
Summary of the Change from Study 
Baseline in Normalized SER (D) by Stage, 
Treatment Group and Visit 
Intent-to-Treat Set 
14.2.2.2 
Change from Baseline in Axial Length at 
Month 36 
14.2.2.2.1 
Analysis of the Change from Baseline in 
Axial Length (mm) in Stage 1 by Treatment 
Group and Visit 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.2.2.4 
Analysis of the Change from Baseline in 
Axial Length (mm) in Stage 1 by Treatment 
Group and Visit 
Mixed Effect Model 
Stage 1 Intent-to- 
Treat Set 
14.2.3 
Tertiary Efficacy Parameters 
14.2.3.1 
Proportion of Subjects’ Eyes who Show 
less than 0.75 D Myopia Progression 
(Normalized SER) from Baseline 
14.2.3.1.1 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.75 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
Mixed Effects Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.1.3 
Analysis of the Proportion of Subjects’ Eyes 
who Show less than 0.75 D Myopia 
Progression (Normalized SER) from 
Baseline in Stage 1 by Treatment Group 
and Visit 
Mixed Effects Model 
Stage 1 Intent-to- 
Treat Set 
14.2.3.2 
Time to Change in Myopia of -0.75 D 
Normalized SER 
14.2.3.2.1 
Analysis of Time to Change from Baseline 
in Myopia Progression of -0.75 D 
Normalized SER in Stage 1 by Treatment 
Group 
Cox Proportional Hazards Regression 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.2.3 
Analysis of Time to Change from Baseline 
in Myopia Progression of -0.75 D 
Normalized SER in Stage 1 by Treatment 
Group 
Cox Proportional Hazards Regression 
Stage 1 Intent-to- 
Treat Set 
14.2.3.3 
New Prescriptions Given After the Start of 
Treatment due to Progression, at Month 36 
14.2.3.3.1 
Analysis of the New Prescriptions Given 
After the Start of Treatment due to 
Progression, at Month 36 
Cochran-Mantel-Haenszel Test 
Stage 1 Modified 
Intent-to-Treat Set 


Statistical Analysis Plan for Interventional Studies 
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Header 
Table Number 
Name 
Analysis Set 
14.2.3.3.2 
Analysis of the New Prescriptions Given 
After the Start of Treatment due to 
Progression, at Month 36 
Cochran-Mantel-Haenszel Test 
Stage 1 Intent-to- 
Treat Set 
14.2.3.4 
Subjects who Progressed to High Myopia 
(Normalized SER -6.00 D or more myopic) 
at Month 36 
14.2.3.4.1 
Analysis of the Proportion of Subjects who 
Progressed to High Myopia (Normalized 
SER -6.00 D or more myopic) at Month 36 
by Baseline Myopia 
Mixed Effects Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.4.2 
Analysis of the Proportion of Subjects who 
Progressed to High Myopia (Normalized 
SER -6.00 D or more myopic) at Month 36 
by Baseline Myopia 
Mixed Effects Model 
Stage 1 Intent-to- 
Treat Set 
14.2.3.5 
Interaction between Demographic Variables 
and Normalized SER 
14.2.3.5.1.1 
Analysis of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(6-8 years old vs. 9-10 years old) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.5.1.2 
Summary of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(6-8 years old vs. 9-10 years old) 
Stage 1 Intent-to- 
Treat Set 
14.2.3.5.2.1 
Analysis of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(Baseline SER -0.50 to -3.00 D 
versus -3.01 to -6.00 D D) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.5.2.2 
Summary of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(Baseline SER -0.50 to -3.00 D 
versus -3.01 to -6.00 D D) 
Stage 1 Intent-to- 
Treat Set 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
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Filing requirements: TMF 
Page 63 of 76 
 
 
 
Header 
Table Number 
Name 
Analysis Set 
14.2.3.5.3.1 
Analysis of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(Asian vs. Non-Asian) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.5.3.2 
Summary of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(Asian vs. Non-Asian) 
Stage 1 Intent-to- 
Treat Set 
14.2.3.5.4.1 
Analysis of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(Dark Irides vs. Light Irides) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.5.4.2 
Summary of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(Dark Irides vs. Light Irides) 
Stage 1 Intent-to- 
Treat Set 
14.2.3.5.5.1 
Analysis of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(U.S. vs, E.U.) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.5.5.2 
Summary of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(U.S. vs, E.U.) 
Stage 1 Intent-to- 
Treat Set 
14.2.3.5.6.1 
Analysis of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(Female vs. Male.) 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.5.6.2 
Summary of the Change from Baseline in 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
(Female vs. Male) 
Stage 1 Intent-to- 
Treat Set 
14.2.3.6 
Change from Baseline in Crystalline Lens 
Thickness at Month 36 
14.2.3.6.1 
Analysis of the Change from Baseline in 
Crystalline Lens Thickness (mm) in Stage 1 
by Treatment Group and Visit 
Mixed Effect Model 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.6.2 
Analysis of the Change from Baseline in 
Crystalline Lens Thickness (mm) in Stage 1 
by Treatment Group and Visit 
Mixed Effect Model 
Stage 1 Intent-to- 
Treat Set 
14.2.3.7 
Rebound Assessment 
14.2.3.7.1.1 
Rebound Assessment Based on the 
Change from Stage 2 Baseline (Month 36) 
in Normalized SER (D) at Months 42 and 
48 by Stage 1 and Stage 2 Treatment 
Combinations and Visit 
Stage 2 Modified 
Intent-to-Treat Set 


Statistical Analysis Plan for Interventional Studies 
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Header 
Table Number 
Name 
Analysis Set 
14.2.3.7.1.2 
Rebound Assessment Based on the 
Change from Stage 2 Baseline (Month 36) 
in Normalized SER (D) at Months 42 and 
48 by Stage 1 and Stage 2 Treatment 
Combinations and Visit 
Stage 2 Intent-to- 
Treat Set 
14.2.3.7.2.1 
Rebound Assessment Based on the 
Responders at Months 42 and 48 by Stage 
1 and Stage 2 Treatment Combinations and 
Visit 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.3.7.2.2 
Rebound Assessment Based on the 
Responders at Months 42 and 48 by Stage 
1 and Stage 2 Treatment Combinations and 
Visit 
Stage 2 Intent-to- 
Treat Set 
14.2.4 
Exploratory Analyses 
14.2.4.1.1 
Proportion of Subjects’ Eyes with Higher 
Myopia (SER at least 3.00 D) at Stage 1 
Baseline who Show less than 0.75 D 
Myopia Progression (Normalized SER) at 
Month 36 
14.2.4.1.1.1 
Summary of the Proportion of Subjects’ 
Eyes with Higher Myopia (SER at least 3.00 
D) at Stage 1 Baseline who Show less than 
0.75 D Myopia Progression (Normalized 
SER) at Month 36 by Treatment Group 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.4.1.1.2 
Summary of the Proportion of Subjects’ 
Eyes with Higher Myopia (SER at least 3.00 
D) at Stage 1 Baseline who Show less than 
0.75 D Myopia Progression (Normalized 
SER) at Month 36 by Treatment Group 
Stage 1 Intent-to- 
Treat Set 
14.2.4.1.2 
Change from Study Baseline in Normalized 
SER in Stage 2 
14.2.4.1.2.1 
Analysis of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
Mixed Effect Model 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.1.2.4 
Analysis of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
Stage 2 Intent-to- 
Treat Set 
14.2.4.1.2.5 
Analysis of the Change from Study 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
Mixed Effect Model 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.1.2.6 
Analysis of the Change from Study 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
Stage 2 Intent-to- 
Treat Set 


Statistical Analysis Plan for Interventional Studies 
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Header 
Table Number 
Name 
Analysis Set 
14.2.4.2 
Proportion of Subjects’ Eyes who Show 
less than 0.5 D Myopia Progression 
(Normalized SER) from Stage 2 Baseline in 
Stage 2 
14.2.4.2.1 
Summary of the Proportion of Subjects’ 
Eyes who Show less than 0.5 D Myopia 
Progression (Normalized SER) from Stage 
2 Baseline in Stage 2 by Stage 1 to Stage 2 
Treatment Description and Visit 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.2.2 
Summary of the Proportion of Subjects’ 
Eyes who Show less than 0.5 D Myopia 
Progression (Normalized SER) from Stage 
2 Baseline in Stage 2 by Stage 1 to Stage 2 
Treatment Description and Visit 
Stage 2 Intent-to- 
Treat Set 
14.2.4.3 
Proportion of Subjects’ Eyes who Show 
less than 0.75 D Myopia Progression 
(Normalized SER) from Stage 2 Baseline in 
Stage 2 
14.2.4.3.1 
Summary of the Proportion of Subjects’ 
Eyes who Show less than 0.75 D Myopia 
Progression (Normalized SER) from Stage 
2 Baseline in Stage 2 by Stage 1 to Stage 2 
Treatment Description and Visit 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.3.2 
Summary of the Proportion of Subjects’ 
Eyes who Show less than 0.75 D Myopia 
Progression (Normalized SER) from Stage 
2 Baseline in Stage 2 by Stage 1 to Stage 2 
Treatment Description and Visit 
Stage 2 Intent-to- 
Treat Set 
14.2.4.4 
Time to Change from Stage 2 Baseline in 
Myopia of -0.75 D Normalized SER in 
Stage 2 
14.2.4.4.1 
Summary of Time to Change from Stage 2 
Baseline in Myopia of -0.75 D Normalized 
SER in Stage 2 by Stage 1 to Stage 2 
Treatment Description 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.4.2 
Summary of Time to Change from Stage 2 
Baseline in Myopia of -0.75 D Normalized 
SER in Stage 2 by Stage 1 to Stage 2 
Treatment Description 
Stage 2 Intent-to- 
Treat Set 
14.2.4.5 
New Prescriptions Given during Stage 2 
14.2.4.5.1 
Summary of the New Prescriptions Given 
during Stage 2 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.5.2 
Summary of the New Prescriptions Given 
during Stage 2 
Stage 2 Intent-to- 
Treat Set 
14.2.4.6 
Proportion of Subjects who Progressed to 
High Myopia (Normalized SER -6.00 D or 
more myopic) at Month 48 by Baseline 
Myopia in Stage 2 
14.2.4.6.1 
Summary of the Proportion of Subjects who 
Progressed to High Myopia (Normalized 
SER -6.00 D or more myopic) at Month 48 
by Baseline Myopia in Stage 2 
Stage 2 Modified 
Intent-to-Treat Set 


Statistical Analysis Plan for Interventional Studies 
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Page 66 of 76 
 
 
 
Header 
Table Number 
Name 
Analysis Set 
14.2.4.6.2 
Summary of the Proportion of Subjects who 
Progressed to High Myopia (Normalized 
SER -6.00 D or more myopic) at Month 48 
by Baseline Myopia in Stage 2 
Stage 2 Intent-to- 
Treat Set 
14.2.4.7 
Interaction between Demographic Variables 
and Normalized SER in Stage 2 
14.2.4.7.1.1 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(6-8 years old vs. 9-10 years old) 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.7.1.2 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(6-8 years old vs. 9-10 years old) 
Stage 2 Intent-to- 
Treat Set 
14.2.4.7.2.1 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(Baseline SER -0.50 to -3.00 D vs. -3.01 to 
-6.00 D D) 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.7.2.2 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(Baseline SER -0.50 to -3.00 D vs. -3.01 to 
-6.00 D D) 
Stage 2 Intent-to- 
Treat Set 
14.2.4.7.3.1 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(Asian vs. Non-Asian) 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.7.3.2 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(Asian vs. Non-Asian) 
Stage 2 Intent-to- 
Treat Set 
14.2.4.7.4.1 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(Dark Irides vs. Light Irides) 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.7.4.2 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(Dark Irides vs. Light Irides) 
Stage 2 Intent-to- 
Treat Set 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Vyluma, Inc.; Protocol No.: CP-NVK002-0001Inc.  
This document is confidential. 
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Filing requirements: TMF 
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Header 
Table Number 
Name 
Analysis Set 
14.2.4.7.5.1 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(U.S. vs. E.U.) 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.7.5.2 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(U.S. vs. E.U.) 
Stage 2 Intent-to- 
Treat Set 
14.2.4.7.6.1 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(Female vs. Male) 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.7.6.2 
Summary of the Change from Stage 2 
Baseline in Normalized SER (D) in Stage 2 
by Stage 1 to Stage 2 Treatment 
Description and Visit 
(Female vs. Male) 
Stage 2 Intent-to- 
Treat Set 
14.2.4.8 
Change from Stage 2 Baseline in 
Crystalline Lens Thickness (mm) in Stage 2 
14.2.4.8.1 
Summary of the Change from Stage 2 
Baseline in Crystalline Lens Thickness 
(mm) in Stage 2 by Stage 1 to Stage 2 
Treatment Description and Visit 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.8.2 
Summary of the Change from Stage 2 
Baseline in Crystalline Lens Thickness 
(mm) in Stage 2 by Stage 1 to Stage 2 
Treatment Description and Visit 
Stage 2 Intent-to- 
Treat Set 
14.3 
Safety Data Summary Tables 
14.3.1 
Adverse Events 
14.3.1.1.1 
Overall Summary of Treatment-Emergent 
Adverse Events - Stage 1 
Stage 1 Safety Set 
14.3.1.1.2 
Overall Summary of Treatment-Emergent 
Adverse Events - Stage 2 
Stage 2 Safety Set 
14.3.1.2.1.1 
Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term - 
Stage 1 
Stage 1 Safety Set 
14.3.1.2.1.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class and 
Preferred Term - Stage 1 
Stage 1 Safety Set 
14.3.1.2.1.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class and 
Preferred Term - Stage 1 
Stage 1 Safety Set 
14.3.1.2.2.1 
Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term - 
Stage 2 
Stage 2 Safety Set 
14.3.1.2.2.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class and 
Preferred Term - Stage 2 
Stage 2 Safety Set 


Statistical Analysis Plan for Interventional Studies 
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Header 
Table Number 
Name 
Analysis Set 
14.3.1.2.2.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class and 
Preferred Term - Stage 2 
Stage 2 Safety Set 
14.3.1.3.1.1 
Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and 
Maximum Severity – Stage 1 
Stage 1 Safety Set 
14.3.1.3.1.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Maximum Severity – Stage 1 
Stage 1 Safety Set 
14.3.1.3.1.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Maximum Severity – Stage 1 
Stage 1 Safety Set 
14.3.1.3.2.1 
Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and 
Maximum Severity – Stage 2 
Stage 2 Safety Set 
14.3.1.3.2.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Maximum Severity – Stage 2 
Stage 2 Safety Set 
14.3.1.3.2.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Maximum Severity – Stage 2 
Stage 2 Safety Set 
14.3.1.4.1.1 
Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and 
Relationship to Study Drug – Stage 1 
Stage 1 Safety Set 
14.3.1.4.1.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Relationship to Study Drug – 
Stage 1 
Stage 1 Safety Set 
14.3.1.4.1.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Relationship to Study Drug – 
Stage 1 
Stage 1 Safety Set 
14.3.1.4.2.1 
Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and 
Relationship to Study Drug – Stage 2 
Stage 2 Safety Set 
14.3.1.4.2.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Relationship to Study Drug – 
Stage 2 
Stage 2 Safety Set 
14.3.1.4.2.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Relationship to Study Drug – 
Stage 2 
Stage 2 Safety Set 
14.3.1.5.1.1 
Treatment-Related Treatment-Emergent 
Adverse Events by System Organ Class 
and Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.5.1.2 
Ocular Treatment-Related Treatment- 
Emergent Adverse Events by System 
Organ Class and Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.5.1.3 
Non-Ocular Treatment-Related Treatment- 
Emergent Adverse Events by System 
Organ Class and Preferred Term – Stage 1 
Stage 1 Safety Set 


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Header 
Table Number 
Name 
Analysis Set 
14.3.1.5.2.1 
Treatment-Related Treatment-Emergent 
Adverse Events by System Organ Class 
and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.5.2.2 
Ocular Treatment-Related Treatment- 
Emergent Adverse Events by System 
Organ Class and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.5.2.3 
Non-Ocular Treatment-Related Treatment- 
Emergent Adverse Events by System 
Organ Class and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.6.1.1 
Serious Treatment-Emergent Adverse 
Events by System Organ Class and 
Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.6.1.2 
Serious Ocular Treatment-Emergent 
Adverse Events by System Organ Class 
and Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.6.1.3 
Serious Non-Ocular Treatment-Emergent 
Adverse Events by System Organ Class 
and Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.6.2.1 
Serious Treatment-Emergent Adverse 
Events by System Organ Class and 
Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.6.2.2 
Serious Ocular Treatment-Emergent 
Adverse Events by System Organ Class 
and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.6.2.3 
Serious Non-Ocular Treatment-Emergent 
Adverse Events by System Organ Class 
and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.7.1.1 
Serious Treatment-Related Treatment- 
Emergent Adverse Events by System 
Organ Class and Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.7.1.2 
Serious Ocular Treatment-Related 
Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term – 
Stage 1 
Stage 1 Safety Set 
14.3.1.7.1.3 
Serious Non-Ocular Treatment-Related 
Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term – 
Stage 1 
Stage 1 Safety Set 
14.3.1.7.2.1 
Serious Treatment-Related Treatment- 
Emergent Adverse Events by System 
Organ Class and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.7.2.2 
Serious Ocular Treatment-Related 
Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term – 
Stage 2 
Stage 2 Safety Set 
14.3.1.7.2.3 
Serious Non-Ocular Treatment-Related 
Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term – 
Stage 2 
Stage 2 Safety Set 
14.3.1.8.1.1 
Treatment-Emergent Adverse Events 
Leading to Study Withdrawal by System 
Organ Class and Preferred Term – Stage 1 
Stage 1 Safety Set 


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Header 
Table Number 
Name 
Analysis Set 
14.3.1.8.1.2 
Ocular Treatment-Emergent Adverse 
Events Leading to Study Withdrawal by 
System Organ Class and Preferred Term – 
Stage 1 
Stage 1 Safety Set 
14.3.1.8.1.3 
Non-Ocular Treatment-Emergent Adverse 
Events Leading to Study Withdrawal by 
System Organ Class and Preferred Term – 
Stage 1 
Stage 1 Safety Set 
14.3.1.8.2.1 
Treatment-Emergent Adverse Events 
Leading to Study Withdrawal by System 
Organ Class and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.8.2.2 
Ocular Treatment-Emergent Adverse 
Events Leading to Study Withdrawal by 
System Organ Class and Preferred Term – 
Stage 2 
Stage 2 Safety Set 
14.3.1.8.2.3 
Non-Ocular Treatment-Emergent Adverse 
Events Leading to Study Withdrawal by 
System Organ Class and Preferred Term – 
Stage 2 
Stage 2 Safety Set 
14.3.1.9.1.1 
Treatment-Emergent Adverse Events 
Leading to Permanent Discontinuation of 
Study Drug by System Organ Class and 
Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.9.1.2 
Ocular Treatment-Emergent Adverse 
Events Leading to Permanent 
Discontinuation of Study Drug by System 
Organ Class and Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.9.1.3 
Non-Ocular Treatment-Emergent Adverse 
Events Leading to Permanent 
Discontinuation of Study Drug by System 
Organ Class and Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.9.2.1 
Treatment-Emergent Adverse Events 
Leading to Permanent Discontinuation of 
Study Drug by System Organ Class and 
Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.9.2.2 
Ocular Treatment-Emergent Adverse 
Events Leading to Permanent 
Discontinuation of Study Drug by System 
Organ Class and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.9.2.3 
Non-Ocular Treatment-Emergent Adverse 
Events Leading to Permanent 
Discontinuation of Study Drug by System 
Organ Class and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.10.1.1 
Treatment-Emergent Adverse Events 
Leading to Death by System Organ Class 
and Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.10.1.2 
Ocular Treatment-Emergent Adverse 
Events Leading to Death by System Organ 
Class and Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.10.1.3 
Non-Ocular Treatment-Emergent Adverse 
Events Leading to Death by System Organ 
Class and Preferred Term – Stage 1 
Stage 1 Safety Set 


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Header 
Table Number 
Name 
Analysis Set 
14.3.1.10.2.1 
Treatment-Emergent Adverse Events 
Leading to Death by System Organ Class 
and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.10.2.2 
Ocular Treatment-Emergent Adverse 
Events Leading to Death by System Organ 
Class and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.10.2.3 
Non-Ocular Treatment-Emergent Adverse 
Events Leading to Death by System Organ 
Class and Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.11.1.1 
Treatment-Emergent Adverse Events 
Associated with Antimuscarinic Function by 
System Organ Class and Preferred Term – 
Stage 1 
Stage 1 Safety Set 
14.3.1.11.1.2 
Ocular Treatment-Emergent Adverse 
Events Associated with Antimuscarinic 
Function by System Organ Class and 
Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.11.1.3 
Non-Ocular Treatment-Emergent Adverse 
Events Associated with Antimuscarinic 
Function by System Organ Class and 
Preferred Term – Stage 1 
Stage 1 Safety Set 
14.3.1.11.2.1 
Treatment-Emergent Adverse Events 
Associated with Antimuscarinic Function by 
System Organ Class and Preferred Term – 
Stage 2 
Stage 2 Safety Set 
14.3.1.11.2.2 
Ocular Treatment-Emergent Adverse 
Events Associated with Antimuscarinic 
Function by System Organ Class and 
Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.11.2.3 
Non-Ocular Treatment-Emergent Adverse 
Events Associated with Antimuscarinic 
Function by System Organ Class and 
Preferred Term – Stage 2 
Stage 2 Safety Set 
14.3.1.12.1.1 
Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and 
Sex – Stage 1 
Stage 1 Safety Set 
14.3.1.12.1.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Sex – Stage 1 
Stage 1 Safety Set 
14.3.1.12.1.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Sex – Stage 1 
Stage 1 Safety Set 
14.3.1.12.2.1 
Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and 
Sex – Stage 2 
Stage 2 Safety Set 
14.3.1.12.2.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Sex – Stage 2 
Stage 2 Safety Set 
14.3.1.12.2.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Sex – Stage 2 
Stage 2 Safety Set 


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Header 
Table Number 
Name 
Analysis Set 
14.3.1.13.1.1 
Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and 
Race – Stage 1 
Stage 1 Safety Set 
14.3.1.13.1.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Race – Stage 1 
Stage 1 Safety Set 
14.3.1.13.1.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Race – Stage 1 
Stage 1 Safety Set 
14.3.1.13.2.1 
Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and 
Race – Stage 2 
Stage 2 Safety Set 
14.3.1.13.2.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Race – Stage 2 
Stage 2 Safety Set 
14.3.1.13.2.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Race – Stage 2 
Stage 2 Safety Set 
14.3.1.14.1.1 
Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and 
Age – Stage 1 
Stage 1 Safety Set 
14.3.1.14.1.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Age – Stage 1 
Stage 1 Safety Set 
14.3.1.14.1.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Age – Stage 1 
Stage 1 Safety Set 
14.3.1.14.2.1 
Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and 
Age – Stage 2 
Stage 2 Safety Set 
14.3.1.14.2.2 
Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Age – Stage 2 
Stage 2 Safety Set 
14.3.1.14.2.3 
Non-Ocular Treatment-Emergent Adverse 
Events by System Organ Class, Preferred 
Term, and Age – Stage 2 
Stage 2 Safety Set 
14.3.2 
Listings of Deaths, Other Serious, and 
Significant Adverse Events 
14.3.2.1 
Listing of Deaths 
Safety Set 
14.3.2.2.1 
Listing of Serious Ocular Treatment- 
Emergent Adverse Events 
Safety Set 
14.3.2.2.2 
Listing of Serious Non-Ocular Treatment- 
Emergent Adverse Events 
Safety Set 
14.3.2.3.1 
Listing of Treatment-Emergent Adverse 
Events Leading to Permanent 
Discontinuation of Study Drug 
Safety Set 
14.3.2.3.2 
Listing of Ocular Treatment-Emergent 
Adverse Events Leading to Permanent 
Discontinuation of Study Drug 
Safety Set 
14.3.2.3.3 
Listing of Non-Ocular Treatment-Emergent 
Adverse Events Leading to Permanent 
Discontinuation of Study Drug 
Safety Set 


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Header 
Table Number 
Name 
Analysis Set 
14.3.2.4.1 
Listing of Treatment-Emergent Adverse 
Events Leading to Withdrawal from Study 
Safety Set 
14.3.2.4.2 
Listing of Ocular Treatment-Emergent 
Adverse Events Leading to Withdrawal from 
Study 
Safety Set 
14.3.2.4.3 
Listing of Non-Ocular Treatment-Emergent 
Adverse Events Leading to Withdrawal from 
Study 
Safety Set 
14.3.3 
Not to be used 
for any Tables 
Narratives of Deaths, Other Serious, and 
Certain Other Significant Adverse Events 
(NOTE: this section is for Medical Writing 
narratives only, normally not completed by 
Syneos Health Biostatistics. No tables 
should go here.). 
14.3.4 
Abnormal Laboratory Value (each subject) 
14.3.4.1 
Ophthalmic Safety Assessment Data 
14.3.4.1.1.1 
Monocular Best-Corrected Visual Acuity 
Results – Stage 1 
Stage 1 Safety Set 
14.3.4.1.1.2 
Monocular Best-Corrected Visual Acuity 
Results – Stage 2 
Stage 2 Safety Set 
14.3.4.1.2.1 
Pupil Size (mm) – Stage 1 
Stage 1 Safety Set 
14.3.4.1.2.2 
Pupil Size (mm) – Stage 2 
Stage 2 Safety Set 
14.3.4.1.3.1 
Slit Lamp Examination Results – Stage 1 
Stage 1 Safety Set 
14.3.4.1.3.2 
Slit Lamp Examination Results – Stage 2 
Stage 2 Safety Set 
14.3.4.1.4.1 
Dilated Fundus Examination Results – 
Stage 1 
Stage 1 Safety Set 
14.3.4.1.4.2 
Dilated Fundus Examination Results – 
Stage 2 
Stage 2 Safety Set 
14.3.4.1.5.1 
Tonometry - Intraocular Pressure (mmHg) – 
Stage 1 
Stage 1 Safety Set 
14.3.4.1.5.2 
Tonometry - Intraocular Pressure (mmHg) – 
Stage 2 
Stage 2 Safety Set 
14.3.4.2 
Vital Signs and Physical Findings 
14.3.4.2.1 
Vital Signs and Physical Findings – Stage 1 
Stage 1 Safety Set 
14.3.4.2.2 
Vital Signs and Physical Findings – Stage 2 
Stage 2 Safety Set 
14.3.4.3 
Quality of Life 
14.3.4.3.1 
Modified Amblyopia Treatment Index 
(mATI) 
Stage 2 Safety Set 


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Index of Figures 
 
Header 
Figure 
Number 
Name 
Analysis Set 
14. 
Tables, Figures, and Graphs Referred to 
but not Included in the Text 
14.2 
Efficacy Data Summary Figures and 
Tables 
14.2.1 
Proportion of Subjects’ Eyes who Show 
less than 0.5 D Myopia Progression 
(Normalized SER) from Baseline 
14.2.1.1.2 
Proportion of Subjects’ Eyes who Show 
less than 0.5 D Myopia Progression 
(Normalized SER) from Baseline in 
Stage 1 by Treatment Group and Visit 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.1.2.3 
Proportion of Subjects’ Eyes who Show 
less than 0.5 D Myopia Progression 
(Normalized SER) from Baseline in 
Stage 1 by Treatment Group and Visit 
Stage 1 Intent-to- 
Treat Set 
14.2.1.2.5 
Proportion of Subjects’ Eyes who Show 
less than 0.5 D Myopia Progression 
(Normalized SER) from Baseline in 
Stage 1 by Treatment Group and Visit 
Stage 1 Modified Per 
Protocol Set 
14.2.1.2.7 
Proportion of Subjects’ Eyes who Show 
less than 0.5 D Myopia Progression 
(Normalized SER) from Baseline in 
Stage 1 by Treatment Group and Visit 
Stage 1 Per Protocol 
Set 
14.2.2.1 
Change from Baseline in Normalized 
SER 
14.2.2.1.2 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.2.1.3 
Change from Baseline in Normalized 
SER (D) in Stage 1 by Treatment Group 
and Visit 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.2.1.5 
Normalized SER (D) in Stage 1 by 
Treatment Group and Visit 
Stage 1 Intent-to- 
Treat Set 
14.2.2.1.6 
Change from Baseline in Normalized 
SER (D) in Stage 1 by Treatment Group 
and Visit 
Stage 1 Intent-to- 
Treat Set 
14.2.2.2 
Change from Baseline in Axial Length 
14.2.2.2.2 
Axial Length (mm) in Stage 1 by 
Treatment Group and Visit 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.2.2.3 
Change from Baseline in Axial Length 
(mm) in Stage 1 by Treatment Group 
and Visit 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.2.2.5 
Axial Length (mm) in Stage 1 by 
Treatment Group and Visit 
Stage 1 Intent-to- 
Treat Set 
14.2.2.2.6 
Change from Baseline in Axial Length 
(mm) in Stage 1 by Treatment Group 
and Visit 
Stage 1 Intent-to- 
Treat Set 
14.2.3.1 
Proportion of Subjects’ Eyes who Show 
less than 0.75 D Myopia Progression 
(Normalized SER) from Baseline 


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Header 
Figure 
Number 
Name 
Analysis Set 
14.2.3.1.2 
Proportion of Subjects’ Eyes who Show 
less than 0.75 D Myopia Progression 
(Normalized SER) from Baseline in 
Stage 1 by Treatment Group and Visit 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.1.4 
Proportion of Subjects’ Eyes who Show 
less than 0.75 D Myopia Progression 
(Normalized SER) from Baseline in 
Stage 1 by Treatment Group and Visit 
Stage 1 Intent-to- 
Treat Set 
14.2.3.2 
Change from Baseline in Normalized 
SER 
14.2.3.2.2 
Kaplan-Meier Curve for Time to Change 
from Baseline in Myopia Progression of 
-0.75 D Normalized SER in Stage 1 by 
Treatment Group 
Stage 1 Modified 
Intent-to-Treat Set 
14.2.3.2.4 
Kaplan-Meier Curve for Time to Change 
from Baseline in Myopia Progression of 
-0.75 D Normalized SER in Stage 1 by 
Treatment Group 
Stage 1 Intent-to- 
Treat Set 
14.2.4.1 
Change from Baseline in Normalized 
SER in Stage 2 
14.2.4.1.2.2 
Normalized SER (D) in Stage 2 by 
Stage 1 to Stage 2 Treatment 
Description and Visit 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.1.2.3 
Change from Stage 2 Baseline in 
Normalized SER (D) in Stage 2 by 
Stage 1 to Stage 2 Treatment 
Description and Visit 
Stage 2 Modified 
Intent-to-Treat Set 
14.2.4.1.2.4.1 
Normalized SER (D) in Stage 2 by 
Stage 1 to Stage 2 Treatment 
Description and Visit 
Stage 2 Intent-to- 
Treat Set 
14.2.4.1.2.4.2 
Change from Stage 2 Baseline in 
Normalized SER (D) in Stage 2 by 
Stage 1 to Stage 2 Treatment 
Description and Visit 
Stage 2 Intent-to- 
Treat Set 


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Index of Listings 
 
Header 
Table Number 
Name 
Analysis Set 
(Example) 
16.2 
Subject Data Listings 
16.2.1 
Discontinued Subjects 
16.2.1.1 
Subject Disposition 
Enrolled Set 
16.2.2 
Protocol Deviations 
16.2.2.1 
Protocol Deviations 
Enrolled Set 
16.2.3 
Subjects Excluded from the Efficacy 
Analysis 
16.2.3.1 
Inclusion/Exclusion Criteria 
Enrolled Set 
16.2.3.2 
Exclusions from Analysis Sets 
Enrolled Set 
16.2.4 
Demographic Data 
16.2.4.1 
Demographics 
Intent-to-Treat Set 
16.2.4.2 
Medical History 
Intent-to-Treat Set 
16.2.4.3 
Ocular History 
Intent-to-Treat Set 
16.2.4.4 
Baseline Disease Characteristics 
Intent-to-Treat Set 
16.2.4.5 
Prior and Concomitant Medications 
Intent-to-Treat Set 
16.2.5 
Compliance 
16.2.5.1 
Study Drug Adherence 
Safety Set 
16.2.5.2 
Study Drug Exposure and Treatment 
Compliance 
Safety Set 
16.2.6 
Individual Efficacy Response Data 
16.2.6.1 
Cycloplegic Autorefraction 
Intent-to-Treat Set 
16.2.6.2 
Axial Length and Crystalline Lens 
Thickness 
Intent-to-Treat Set 
Adverse Event Listings 
16.2.7.1 
Adverse Events 
Safety Set 
16.2.7.2 
Severe Adverse Events 
Safety Set 
16.2.7.3 
Study Drug Related Adverse Events 
Safety Set 
16.2.7.4 
Study Drug Related Serious Adverse 
Events 
Safety Set 
16.2.8 
Listing of physical examination by subject 
16.2.8.1.1 
Urine Pregnancy Test 
Intent-to-Treat Set 
Other Safety Data 
16.2.8.2.1 
Best Corrected Visual Acuity 
Intent-to-Treat Set 
16.2.8.2.2 
Photonic Pupil Size Measurement 
Intent-to-Treat Set 
16.2.8.2.3 
Slit lamp Examination 
Intent-to-Treat Set 
16.2.8.2.4 
Dilated Fundus Examination 
Intent-to-Treat Set 
16.2.8.2.5 
Tonometry 
Intent-to-Treat Set 
16.2.8.2.6 
Modified ATI Questionnaires 
Intent-to-Treat Set 
16.2.8.2.7 
Telephone Contact 
Intent-to-Treat Set 
16.2.8.2.8 
Vital Signs and Physical Findings 
Intent-to-Treat Set